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MS TREATMENTS: TYSABRI/NATALIZUMAB
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agate
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PostPosted: Tue Aug 08, 2006 1:19 pm    Post subject: MS TREATMENTS: TYSABRI/NATALIZUMAB Reply with quote

Here's an updated Tysabri thread.

Last edited by agate on Sat Mar 02, 2013 2:37 pm; edited 2 times in total
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mmcc



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PostPosted: Thu Aug 10, 2006 6:09 pm    Post subject: Reply with quote

Got the call from Biogen today - my doc and I are both officially in the Touch progam. He told me:

Medicare pays 80%.

Carefirst Blue Cross/Blue Shield has established what they will pay, although he didn't know what it was offhand.

Apparently anyone with these insurances will at least have some type of coverage.

I think other than a few days for the insurance company to send the details of what they will pay, at this point I am just waiting for the infusion center to be ready - should be in the next 2 weeks.

YEAH!!!!!! cheers
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agate
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PostPosted: Thu Aug 10, 2006 6:41 pm    Post subject: Reply with quote

Wonderful news! I'm so glad that this isn't being delayed any longer.
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PostPosted: Thu Aug 10, 2006 8:35 pm    Post subject: Reply with quote Edit/Delete this post

I'm glad to hear about your news, mmcc. The best of luck to you,
Joy
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Matt



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PostPosted: Thu Aug 10, 2006 10:33 pm    Post subject: Reply with quote

I just can't wait to hear back if it helps you. I'm really hoping. In terms of efficacy, it sounds like one of the most pomising drugs so far.
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PostPosted: Fri Aug 11, 2006 6:52 am    Post subject: Reply with quote

Have you heard yet how much the drug infusions themselves will be, mmcc?

So you will have to pay 20% of that?

What about the hospital/infusion center costs . . . are they covered at 80% too.

Any idea how much the total cost is, for someone without insurance?

Cherie
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mmcc



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PostPosted: Fri Aug 11, 2006 7:17 am    Post subject: Reply with quote

The price is $2,800 per infusion - in short, unless there is an assistance program, no one could ever afford this without insurance or medicare, but I think that now most people getting Novantrone will have failed at other MS drugs first, so they are likely to be on SS and therefore get Medicare.

Personally, I would shocked if anyone took Tysabri as a first line drug unless they were hit incredibly hard with the first attack - I am sure it will happen, but rarely.

20% is still a helluva lot to pay.

I have heard that there is a problem with Medicare patients who are on HMO's but I don't know that for a fact and I am not sure it has been resolved.

The drug companies, including Biogen, have had assistance programs before, so I assume they will be setting one up.

I have insurance and medicare so I don't expect to pay anything.

Infusions in the hospital cost me nothing or $10 - can't remember which - I had 12 Novantrone infusions with the same insurance.

I know that when my daughter had an infusion a year ago (right before she lost her insurance) she wound up $300 out of pocket.

I know of someone else who had to pay $150, so I think it totally varies with insurance.
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PostPosted: Fri Aug 11, 2006 7:19 am    Post subject: Reply with quote

Thanks.

I recall someone on BT saying that it was close to $5,000 all up, for the one infusion they got before it was pulled.

Glad to hear it will not be out of reach for many people.
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mmcc



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PostPosted: Fri Aug 11, 2006 7:30 am    Post subject: Reply with quote

Is Tysabri permitted in Canada? I seem to recall that it was approved there, but with BT gone, I can't check.
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PostPosted: Fri Aug 11, 2006 8:46 am    Post subject: Reply with quote

Someone on another board (who is from Canada) has mentioned waiting, but it doesn't seem the decision has been made yet.

Since discussions about this drug have been very thorough, and going on a L-O-N-G time, that might speed up the approval process.

On the other hand, they've been known to hold back for a few years when there is potential concern about safety too.

Cherie
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agate
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PostPosted: Sat Aug 12, 2006 11:30 am    Post subject: Reply with quote

I found this on the Canadian MS Society Website:

Quote:
www.mssociety.ca
Medical Update Memo
June 9, 2006

SUMMARY

The Food and Drug Administration (FDA) has approved the return to market in the United
States of Tysabri® (natalizumab) as a therapy for people with relapsing multiple sclerosis.
The approval is based on positive results from two clinical trials showing that Tysabri significantly
reduced the risk of sustained progression of disability and the rate of clinical relapse
in people with relapsing MS. It follows an extensive FDA review of the product after the
withdrawal of Tysabri from the market in 2005 because of safety concerns. In Canada,
Tysabri is currently under priority review by Health Canada.


The date for this is June 9, but I couldn't find any more recent updates.
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mmcc



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PostPosted: Sat Aug 12, 2006 11:39 am    Post subject: Reply with quote

Thanks, agate
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lady_express_44



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PostPosted: Sat Aug 12, 2006 11:44 am    Post subject: Reply with quote

Has anyone else heard the wash-out for the CRABs has changed to four weeks (not two), before starting on T?

Someone on MSW (New Treatments board) said that he just got confirmation of that from Biogen, and now has to wait another week before starting . . .

(Personally, I'd wait much longer, but . . . )
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mmcc



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PostPosted: Sat Aug 12, 2006 11:48 am    Post subject: Reply with quote

lady_express_44 wrote:
Has anyone else heard the wash-out for the CRABs has changed to four weeks (not two), before starting on T?


My doctor's MS clinic and hospital is requiring 4 weeks, not Biogen or the FDA.
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lady_express_44



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PostPosted: Sat Aug 12, 2006 11:52 am    Post subject: Reply with quote

Ok.

He said that someone from Biogen had advised him of that.

Either way, it sounds like that's the plan now . . . or is it still 2 weeks, but the clinics/hospitals might "suggest" or "require" more time?
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mmcc



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PostPosted: Sat Aug 12, 2006 2:10 pm    Post subject: Reply with quote

I was told by a Biogen rep that it was 2 weeks, and I would assume that hasn't changed since the FDA and Biogen agreed on the wording after taking months to do it.
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PostPosted: Wed Aug 23, 2006 10:20 am    Post subject: Reply with quote

From Sarah Beaubien,
Your Guide to Multiple Sclerosis.

I don't think (?) I've seen a relatively simple description of how Tysabri apparently works on this board yet, so I thought I'd add this:

How It Works
Tysabri and Integrins
The immune cells that cause inflammation and damage nerve fibers and myelin in multiple sclerosis are called lymphocytes. These immune cells—like many cells—make use of integrins to get signals to or from other molecules. Like a puzzle piece, the integrin and another molecule fit together. While connected, the integrin receives a signal from the other molecule outside the lymphocyte, which results in a signal to the inside of the lymphocyte, which causes another signal, and another, and so on. This domino effect is called a signaling cascade.

Tysabri and the Signaling Cascade
Understanding the signaling cascade in lymphocyte integrins is critical to the success of the drug Tysabri.

A certain lymphocyte integrin (called VLA-4) recognizes a molecule on a cell (called VCAM-1) that is responsible for transporting blood and other fluids to the central nervous system. VLA-4 signals VCAM-1, docks to it, and rides with it to the inside of the central nervous system. Simply put, multiple sclerosis is caused by one molecule thumbing a ride across the blood brain barrier and hitchhiking into the central nervous system. This sort of cellular hitchhiking allows potentially harmful molecules inside the central nervous system. Once in, they can wreak havoc on nerve fibers.

Tysabri works by creating a “look-alike” molecule, which bonds to the VLA-4. By occupying the receptor VLA-4, it prevents it from signaling molecules such as VCAM-1. If VLA-4 cannot get a ride into the central nervous system then it cannot do damage to nerve fibers and myelin.

Drawbacks of Tysabri
The issue with Tysabri is that by preventing lymphocytes from traveling into the central nervous system, it may prevent them from doing good work as well. The reduction of lymphocyte migration puts the patient at risk of other infections.

http://ms.about.com/od/immunomodulators/a/TysabriWorks.htm
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PostPosted: Sat Aug 26, 2006 1:08 pm    Post subject: Reply with quote

Immune surveillance in multiple sclerosis patients treated with natalizumab

Ann Neurol. 2006; 59(5):743-7 (ISSN: 0364-5134)

Quote:

Original Article
Immune surveillance in multiple sclerosis patients treated with natalizumab
Olaf Stüve, MD 1 2 3 *, Christina M. Marra, MD 4, Keith R. Jerome, MD, PhD 5 6 9, Linda Cook, PhD 5 6 9, Petra D. Cravens, PhD 2, Sabine Cepok, PhD 3, Elliot M. Frohman, MD, PhD 2, J. Theodore Phillips, MD, PhD 7, Gabriele Arendt, MD 3, Bernhard Hemmer, MD 3, Nancy L. Monson, PhD 2 8, Michael K. Racke, MD 2 8
1Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, TX
2Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX
3Department of Neurology, the Heinrich Heine University, Düsseldorf, Germany
4Department of Neurology, University of Washington, Seattle, WA
5Department of Laboratory Medicine, University of Washington, Seattle, WA
6Fred Hutchinson Cancer Research Center, Seattle, WA
7Multiple Sclerosis Center at Texas Neurology, Dallas, TX
8Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX
9Department of Neurology, Heinrich Heine University, Düsseldorf, Germany

email: Olaf Stüve (olaf.stuve@utsouthwestern.edu)

*Correspondence to Olaf Stüve, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9036

Funded by:
NIH (National Institute of Neurological Disorders and Stroke); Grant Number: NS 37513, NS 44250, NS 40993
National Multiple Sclerosis Society; Grant Number: RG 2969-B-7
Deutsche Forschungsgemeinschaft; Grant Number: He2386/4-1, He2386/4-2
Adult AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases; Grant Number: AI 38858, AI 27664

Abstract


Objective
Our objective was to test whether natalizumab, an antibody against very late activating antigen (VLA)-4, interferes with central nervous system immune surveillance as assessed by leukocyte cell numbers and cellular phenotypes in cerebrospinal fluid (CSF) and peripheral blood.

Methods
Cell numbers and cellular phenotypes in CSF and peripheral blood were analyzed in multiple sclerosis (MS) patients treated with natalizumab, untreated MS patients, and patients with other neurological disease (OND). JC virus DNA in the CSF and peripheral blood was quantified by kinetic polymerase chain reaction.

Results
CSF leukocyte counts, CD4+ and CD8+ T cells, CD19+ B cells, and CD138+ plasma cells were significantly lower in natalizumab-treated MS patients compared with OND patients and untreated MS patients. JC virus DNA was not detected in CSF or peripheral blood from natalizumab-treated patients. Six months after cessation of natalizumab therapy, low lymphocyte counts in the CSF persisted. The patient with the highest total leukocyte and CD4+ and CD8+T-cell counts in the CSF experienced a clinical relapse.

Interpretation
These data suggest that natalizumab treatment results in a prolonged decrease of lymphocytes in the CSF and are consistent with the hypothesis that natalizumab impairs immune surveillance of the central nervous system. Ann Neurol 2006;59:743-747



--------------------------------------------------------------------------------
Received: 30 October 2005; Revised: 10 March 2006; Accepted: 11 March 2006
Digital Object Identifier (DOI)

10.1002/ana.20858 About DOI


Article Text



Natalizumab (Tysabri, Biogen-Idec, Cambridge, MA and Elan Pharmaceuticals, Dublin, Ireland) is a humanized monoclonal antibody that binds to the adhesion molecule very late activation antigen 4 (VLA-4) expressed by all white blood cells except neutrophils. By preventing the interaction of VLA-4 with its ligand, vascular cell adhesion molecule 1 (VCAM-1), natalizumab was designed to prevent extravasation of leukocytes.[1] Approximately 3,000 patients were enrolled in clinical trials to evaluate the effectiveness of natalizumab in MS,[2-4] Crohn's disease, and rheumatoid arthritis. Two MS patients and one patient with Crohn's disease in these trials developed progressive multifocal leukoencephalopathy (PML),[5-7] a brain infection caused by JC virus (JCV), usually seen in immunocompromised patients.

The purpose of this study was to examine the cerebrospinal fluid (CSF) and peripheral blood lymphocyte profiles of MS patients treated with natalizumab in the context of an increased risk of PML or of potentially other opportunistic infections.


Subjects and Methods



Patients
The patient characteristics and source of samples are shown in the Table. Lymphocyte phenotypes were assessed in CSF and peripheral blood (PB) from 22 multiple sclerosis (MS) patients who received natalizumab in clinical trials and 1 patient who received natalizumab after its approval. Samples from 14 of the 23 natalizumab-treated patients were reanalyzed 6 months after study entry. Controls included 16 patients with other neurological diseases (OND; headache, polyneuropathy, normal pressure hydrocephalus) and 35 patients with clinically definite MS not treated with natalizumab. All MS patients in this study had the relapsing-remitting clinical phenotype.


Table . Patient Characteristics

--------------------------------------------------------------------------------

Cohort No. of Patients, Median (range) Age (yr) Sex Ethnicity,a Median (range) Age MS Diagnosis,b Median (range) EDSS

--------------------------------------------------------------------------------

UTSW MS Natalizumab cohort 13 43 (31-54) 6.5:1 13 W 36 (22-50) 2.0 (1.5-4.0)
MSCTN MS Natalizumab cohort 10 49 (37-53) 10:0 10 W 38 (24-47) 3.5 (0-6.0)
UTSW MS control cohort 8 49 (31-67) 1:1.7 8 W 44 (23-57) 4.0 (1.0-6.0)
UTSW OND patient cohort 3 30 (24-45) 3:0 3 W N/A N/A
HHUD OND controls 17 33 (16-79) 1:0.9 17 W N/A N/A
HHUD MS patient cohort 35 37 (18-59) 2.6:1 35 W 29 (16-51) 2.0 (0-5.0)
ACTG PML cohort 8 36 (31-45) 1:1.6 1 B, 4 W, 2 H, 1 NA N/A N/A


--------------------------------------------------------------------------------


Cellular phenotypes were assessed in blood and cerebrospinal fluid (CSF) from MS patients enrolled in the SENTINEL and AFFIRM trials at UTSW and at MSCTN, Dallas. One MS patient who received natalizumab at UTSW after its approval was also included. MS patients, and OND patients whose CSF had been examined at HHUD within 1 year were enrolled as control subjects. Additional controls from UTSW included MS patients not treated with natalizumab and OND patients with headache, polyneuropathy, and normal pressure hydrocephalus.
UTSW = University of Texas Southwestern Multiple Sclerosis Center; MS = multiple sclerosis; MSCTN = Multiple Sclerosis Center at Texas Neurology, Dallas; OND = other neurological diseases; HHUD = Heinrich Heine University in Düsseldorf; ACTG = AIDS Clinical Trials Group; PML: progressive multifocal leukoencephalopathy; EDSS = Expanded Disability Status Scale; B = black; W = white; H = Hispanic; NA = Native American N/A = not applicable.



JCV DNA was quantitated in CSF and serum collected at study entry in the natalizumab-treated MS patients, 3 OND patients, 8 patients with clinically definite MS not treated with natalizumab,[8] and 8 patients with progressive multifocal leukoencephalopathy (two CSF, eight plasma).[9]

Informed consent was obtained from all patients; all study procedures were approved by the respective institutional review boards.


Lymphocyte Counts
Peripheral blood mononuclear cells (PBMCs) were purified by density gradient centrifugation using Ficoll-Paque (Amersham Pharmacia, Uppsala, Sweden). CSF cells were collected by centrifugation. Leukocytes were counted by light microscopy. The lower limit of detection was 250 cells/ml. Absolute cell counts in the PB were determined by a commercial clinical laboratory.


Flow Cytometry
PBMCs were stained for flow cytometry using standard methods. Data were acquired on a FACS Calibur instrument (BD Biosciences, San Jose, CA) and analyzed using the CellquestPro (BD Biosciences) or Flowjo (Treestar, Ashland, OR) software packages. All flow cytometry plots were reviewed by three of the investigators (O.S., S.C., and B.H.).


Neutralizing Antibody Assay
Sera from all patients were tested for natalizumab-binding antibodies every 12 weeks by a commercial laboratory.


Kinetic Polymerase Chain Reaction
Quantitation of JCV DNA was performed using Taqman PCR according to published methods,[9] except that DNA was extracted from 220l of serum, plasma, or CSF. A subset of the serum samples that had weak amplification signals were reextracted with 1.0ml of serum using the Roche Magnapure and the Roche Large Volume TNA kit (Roche Molecular Systems, Alameda, CA).


Data Analysis
Correlations between continuous and categorical variables were assessed using the Mann-Whitney U test. p values less than 0.05 were considered significant.


Results



Patients
Patients in the natalizumab treatment group received a median of 30 doses (range, 1-41). The median interval between the last natalizumab dose and the day CSF and peripheral blood were obtained was 34 days (range, 5-45 days) at entry and 175 days (range, 139-188 days) at follow-up.


Cerebrospinal Fluid Lymphocyte Counts and Phenotypes
All CSF samples that contained one red blood cells were excluded from the analysis. Fifteen CSF samples from natalizumab-treated MS patients were analyzed at baseline, and 13 samples were analyzed at 6 months follow-up. There were no demographic differences between patients who were excluded from CSF analysis versus those who were included (data not shown). There was mild CSF pleocytosis in the MS cohort compared with the OND cohort (Fig 1 A). Compared with MS patients not treated with natalizumab, CSF from natalizumab-treated MS patients had significantly fewer white blood cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD138+ plasma cells (see Fig 1 A-E).


Figure 1. Natalizumab decreases the number of lymphocytes in cerebrospinal fluid. At study entry, the number of (A) white blood cells (WBCs), (B) CD4+ T cells, (C) CD8+ T cells, (D) CD19+ B cells, and (E) CD138+ plasma cells in cerebrospinal fluid (CSF) was compared between patients with other neurological diseases (OND), multiple sclerosis (MS) patients who were not treated with natalizumab (MS), and MS patients treated with natalizumab [(MS (Nat)]. A mild CSF pleocytosis was observed in MS patients who had not received natalizumab therapy (A), compared with the OND patient cohort (A). Compared with MS patients not treated with natalizumab, treatment with natalizumab significantly reduced the numbers of T lymphocytes, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD138+ plasma cells in the CSF (A-E). Six months after cessation of therapy, the CSF cellular phenotype of 14 natalizumab-treated MS patients was reanalyzed [MS (Nat) 6 Mo]. The number of CSF white blood cells (A), CD4+ T cells (B), CD8+ T cells (C), CD19+ B cells (D), and CD138+ plasma cells (E) remained significantly lower than those in MS patients not treated with natalizumab. During the 6-month interval, one patient had a clinical relapse. This patient (indicated by a red triangle and an arrow) had the highest white blood cell, CD4+ and CD8+ T cell counts of the cohort (A-C).
[Normal View 60K | Magnified View 150K]



Peripheral Blood Leukocyte and Lymphocyte Counts
Total leukocytes and lymphocytes in PB of natalizumab-treated MS patients at study entry were within normal limits (Fig 2).


Figure 2. White blood cell (WBC) and lymphocyte (LC) numbers in peripheral blood (PB) of natalizumab-treated MS patients are normal at 1 and 6 months.
[Normal View 26K | Magnified View 45K]



Neutralizing Antibody Assay and JCV Polmerase Chain Reaction
Serum natalizumab-binding antibodies were not detected in treated patients (data not shown). JCV was not detected in CSF or plasma from OND, MS, or natalizumab-treated MS patients (data not shown). JCV was detected in both CSF samples from PML patients and in two of eight plasma samples (data not shown).


Six-Month Follow-up
Six months after cessation of nataluzimab, CSF white blood cells (see Fig 1A), CD4+ T cells (see Fig 1B), CD8+ T cells (see Fig 1C), CD19+ B cells (see Fig 1D), and CD138+ plasma cells (see Fig 1E) remained significantly lower than in the MS patients. During follow-up, one natalizumab-treated MS patient had a clinical relapse. This patient had the highest total CSF white blood cell, CD4+, and CD8+ T-cell counts of the follow-up group (Figs 1A-C). CD19+ and CD138+ cells were undetectable in the CSF of this patient.

PB lymphocytes decreased significantly but remained within normal limits (see Fig 2). The total white blood cell numbers did not change (see Fig 2).


Discussion


We show that natalizumab treatment results in a decrease in all major lymphocyte subsets in CSF. These effects last far longer than would be expected, given that the mean half-life of free natalizumab after repeated administration of 300mg per month is 11 days.[10] Our data strongly suggest that the binding half-life of natalizumab to VLA-4 is significantly longer than predicted. Based on our pharmacokinetic data, continuous monthly administration of natalizumab results in prolonged reduction of CSF lymphocytes. Thus, even if laboratory markers of increased risk of subsequent opportunistic infections, such as PML, could be identified, stopping therapy at that time may not prevent the risk of a subsequent clinically evident infection.

With regard to risk of PML in natalizumab-treated MS patients, reduction of both CSF CD4+ T cells and CD8+ T cells seems counterintuitive. It has been challenging to detect JCV-responsive CD4+ T cells in PML patients.[11] In contrast, JCV-specific CD8+ T cells are detectable in the peripheral blood of PML patients, and their presence is associated with a more favorable clinical outcome.[12][13] Specifically, most of the CD8+ T cell responses are directed toward an HLA-A*0201-restricted JCV epitope, VP1p36.[14] One explanation for the importance of CD4+ T cells in the cellular immune response to JCV infection is that initiation and perpetuation of antigen-specific CD8+ T-cell responses may require the help of CD4+ T cells, supplied in the form of cytokines and other inflammatory mediators.[15]

Although we did not identify JCV in CSF from any of the 23 natalizumab-treated patients, the 95% confidence interval around our estimate (0-14.8%) does not exclude the possibility that some samples could have been positive. Studies in HIV patients show that detection of JCV DNA in CSF in the appropriate clinical setting is diagnostic of PML, but lack of detection does not exclude the diagnosis.[16] Identification of JCV DNA in CSF or blood in a neurologically asymptomatic individual is of unknown significance; detection may or may not confer increased risk of subsequent PML.

Limitations of our study should be acknowledged. Our sample size was relatively small and our subjects were taken from different cohorts. Nonetheless, we were able to identify statistically significant relationships between natalizumab treatment and CSF cellular composition.

Our data provide one potential mechanism to explain the increased risk of PML in MS patients treated with natalizumab. They also suggest that caution should be exercised in anticipating the benefits of surveillance for PML or other opportunistic infections in patients receiving natalizumab. Should natalizumab become available for clinical use, further studies will need to be performed to confirm and further investigate the significance of our observations.


Acknowledgements


This work was supported by grants from the NIH (National Institute of Neurological Disorders and Stroke, NS 37513, NS 44250, M.K.R.; NS 40993, N.L.M., National Multiple Sclerosis Society RG 2969-B-7, M.K.R.), Deutsche Forschungsgemeinschaft (He2386/4-1 and He2386/4-2, B.H., S.C.); and the Adult AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (AI 38858 and AI 27664).

We thank the patients for participation in this study. In addition, we thank Dr F. Vogel, G. Remington, J. Lee, J. Phillips, J. Fowler, N. Perna, and S. Sinha for assistance in data acquisition; L. Tantalo and A. Colina for technical assistance; Drs A. Lovett-Racke, C. Whitacker, H. McFarland, L. Steinman, M. Panzara, R. Martin, S. Zamvil, and T. Menge for critical review of the manuscript.

None of the authors reports a conflict of interest. Although the AFFIRM monotherapy trial and the SENTINEL add-on trial with interferon beta-1a (Avonex) were sponsored by Biogen Idec Inc. and Elan Corp., the manufacturers of natalizumab, the work presented in this study was not.

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14 Du Pasquier RA, Kuroda MJ, Schmitz JE, et al. Low frequency of cytotoxic T lymphocytes against the novel HLA-A*0201-restricted JC virus epitope VP1(p36) in patients with proven or possible progressive multifocal leukoencephalopathy. J Virol 2003; 77: 11918-11926. Links
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PostPosted: Sat Aug 26, 2006 1:09 pm    Post subject: Reply with quote

The thing about figure one, which I couldn't give you, is that it shows that all of the Tysabri patients were affected in nearly the same way in terms of CSF leukocyte counts.
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Matt



Joined: 21 May 2006
Posts: 961

PostPosted: Sun Aug 27, 2006 11:33 am    Post subject: Reply with quote

I will post a number of articles all from:

NEJM Volume 354:899-910 March 2, 2006 Number 9


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A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

Chris H. Polman, M.D., Paul W. O'Connor, M.D., Eva Havrdova, M.D., Michael Hutchinson, M.D., Ludwig Kappos, M.D., David H. Miller, M.D., J. Theodore Phillips, M.D., Ph.D., Fred D. Lublin, M.D., Gavin Giovannoni, M.D., Andrzej Wajgt, M.D., Martin Toal, M.B., M.F.P.M., Frances Lynn, M.Sc., Michael A. Panzara, M.D., M.P.H., Alfred W. Sandrock, M.D., Ph.D., for the AFFIRM Investigators




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ABSTRACT

Background Natalizumab is the first 4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis.

Methods Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years.

Results Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan–Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent).

Conclusions Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300 [ClinicalTrials.gov] .)




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Relapsing multiple sclerosis is characterized by the intermittent development of inflammatory lesions in the brain and spinal cord, resulting in plaques of demyelination and axonal loss. Lymphocyte migration across the blood–brain barrier is thought to be an important early step in the formation of lesions.1 The interaction of 41 integrin, a protein on the surface of lymphocytes, with vascular-cell adhesion molecule 1 (VCAM-1), which is expressed on the surface of vascular endothelial cells in brain and spinal cord blood vessels, mediates the adhesion and migration of lymphocytes in areas of inflammation.2,3,4,5,6 Furthermore, the interaction of 41 integrin with ligands such as fibronectin3 and osteopontin7 may modulate the survival, priming, and activation of leukocytes that have gained access to the parenchyma of the central nervous system.8,9,10,11 Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals), which belongs to a new class of selective adhesion-molecule inhibitors, binds to the 4 subunit of 41 and 47 integrins and blocks binding to their endothelial receptors (VCAM-1 and mucosal addressin-cell adhesion molecule 1, respectively), thereby attenuating inflammation.12 Natalizumab may also modulate ongoing inflammatory reactions by inhibiting the binding of 4-positive leukocytes with fibronectin and osteopontin.
Current therapies for multiple sclerosis, including interferon beta and glatiramer acetate, are only moderately effective, reducing the annualized rate of relapse by about one third.13,14,15,16 On the basis of the favorable results of a phase 2 trial of natalizumab in patients with relapsing multiple sclerosis,17 a two-year phase 3 clinical trial, the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, was initiated to confirm the efficacy of natalizumab in relapsing multiple sclerosis and to evaluate the safety of long-term treatment.

Methods

Patients

Ninety-nine clinical centers in Europe, North America, Australia, and New Zealand enrolled 942 patients beginning on November 6, 2001. All patients gave written informed consent. The study protocol was developed by the investigator advisory committee and sponsors, was approved by central and local ethics committees, and was overseen by an independent safety-monitoring committee. Study data were collected by the investigators and an independent organization (PPD International) and were held and analyzed by Biogen Idec and Elan Pharmaceuticals. All members of the publication committee had full access to the data. During the study, the investigator advisory committee and sponsor representatives met at least monthly to discuss study progress. The manuscript was written by Drs. Polman and Panzara, with input from all coauthors. All authors vouch for the veracity and completeness of the data and data analysis.

Enrollment was limited to men and women who were between the ages of 18 and 50 years and had a diagnosis of relapsing multiple sclerosis18; who had a score of 0 to 5.0 on the Expanded Disability Status Scale (EDSS), a rating that ranges from 0 to 10, with higher scores indicating more severe disease19; who had undergone magnetic resonance imaging (MRI) showing lesions consistent with multiple sclerosis; and who had had at least one medically documented relapse within the 12 months before the study began. Patients with disease that was categorized as primary progressive, secondary progressive, or progressive relapsing were excluded.20 Additional exclusion criteria included the following: a relapse within 50 days before the administration of the first dose of the study drug, treatment with cyclophosphamide or mitoxantrone within the previous year, or treatment with interferon beta, glatiramer acetate, cyclosporine, azathioprine, methotrexate, or intravenous immune globulin within the previous 6 months. Patients who had received treatment with interferon beta, glatiramer acetate, or both for more than six months were also excluded.

Study Design and Randomization

Patients were randomly assigned in a 2:1 ratio to receive either natalizumab (at a dose of 300 mg) or placebo by intravenous infusion every 4 weeks for up to 116 weeks. Patients were randomly assigned to treatment that was stratified according to study site in blocks of three (two active, one placebo) with the use of a computer-generated block randomization schedule and a multidigit identification number, implemented by an interactive voice-response system. All study personnel, patients, sponsor personnel involved in the conduct of the study, and the investigator advisory committee were unaware of treatment assignments throughout the study.

Study Procedures and End Points

At each study site, primary and backup examining neurologists and primary and backup treating neurologists were designated. Treating neurologists were responsible for all aspects of patient care, including the management of adverse events and the treatment of relapsing disease. Examining neurologists performed objective evaluation with use of the EDSS and neurologic examination during all study visits; they were not in contact with patients in any other capacity, so as to reduce the possibility of being unblinded by side effects or laboratory assessments.

Patients visited the clinic every 12 weeks for scoring on the EDSS, blood chemical and hematologic analyses, evaluation of adverse events, and testing for anti-natalizumab antibodies. Patients were also seen by the treating neurologist at unscheduled visits within 72 hours after the onset of new neurologic symptoms. If a relapse was suspected, the patient was referred to the examining neurologist, who evaluated the patient within five days after the event. Relapses were defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted for at least 24 hours and were accompanied by new neurologic signs found by the examining neurologist. At the discretion of the treating neurologist, relapses were treated with intravenous methylprednisolone at a dose of 1000 mg per day for three or five days. Patients whose disability progression was sustained for 12 weeks were allowed to continue participation in the study and were given the option of adding an available treatment for multiple sclerosis as rescue medication per protocol while continuing to receive the study drug. Patients were strongly encouraged to remain in the study for follow-up assessments even if they had discontinued the study drug.

Proton-density–weighted or T2-weighted and gadolinium-enhanced T1-weighted MRI scans of the brain were obtained at baseline, at week 52, and at week 104. Contiguous, 3-mm-thick axial slices through the whole brain were acquired. MRI analysis was performed at the Central Reading Center at the Institute of Neurology, University College London, by experienced raters who were unaware of treatment assignment.

The study had primary and secondary end points at two prespecified times. An assessment of the inflammatory characteristics of the disease was performed at one year and of the progression of the irreversible destructive process at two years. At one year, the primary end point was the rate of clinical relapse, and secondary efficacy end points were the number of new or enlarging hyperintense lesions as detected by T2-weighted MRI, the number of lesions as detected by gadolinium-enhanced MRI, and the proportion of relapse-free patients. At 2 years, the primary end point was the cumulative probability of sustained progression of disability, which was defined as an increase of 1.0 or more on the EDSS from a baseline score of 1.0 or more or an increase of 1.5 or more from a baseline score of 0 that was sustained for 12 weeks (progression could not be confirmed during a relapse). Secondary efficacy end points at two years were the rate of clinical relapse, the volume of lesions as detected by T2-weighted MRI, the number of new hypointense lesions as detected by unenhanced T1-weighted MRI, and the progression of disability as measured by the Multiple Sclerosis Functional Composite. This report presents data on the one-year and two-year primary end points and the one-year secondary end points for which data were also available at two years.

Binding antibodies against natalizumab were assessed with the use of an enzyme-linked immunosorbent assay. Samples that were positive for binding antibodies (0.5 µg per milliliter) were further tested by flow cytometry to assess the ability of the antibodies to interfere with the binding of natalizumab to 4 integrin.

Statistical Analysis

The estimate of sample size was based on data from previous trials of natalizumab17 and of interferon beta-1a13 with the use of two-sided tests, with an alpha level of 0.05. The annualized rate of relapse at one year was predicted to be 0.6 with natalizumab and 0.9 with placebo. For an annualized relapse rate, a likelihood-ratio test was used to determine the sample size required for 90 percent power (n=765), with a 2:1 ratio of natalizumab to placebo. With an assumed dropout rate of 15 percent and rounding, the number of patients needed was estimated to be 900. In order to power the study for the two-year end point of disability progression, progression rates at the end of two years were assumed to be 34.9 percent for the placebo group and 22.7 percent for the natalizumab group. Simulations of the log-rank test for survival were run with 60 percent of the accrual in the first 24 weeks and the remainder in the next 24 weeks, assuming a 20 percent dropout rate over the 2-year study. The sample size of 900 provided 90 percent power with the use of a Bonferroni adjustment for multiple end points, maintaining the type 1 error rate of 0.05.

P values that are reported for most baseline demographic and disease characteristics were calculated with the use of a t-test to compare differences in means. The exceptions were sex, race, and diagnosis of multiple sclerosis by the McDonald criteria,18 for which a chi-square statistic was used to compare treatment groups.

The primary end point at two years was the cumulative probability of sustained progression of disability. This was assessed by an analysis of the time until the onset of the progression of disability that was sustained over 12 weeks with the use of the Cox proportional-hazards model. The annualized rate of relapse (the primary end point at one year) was calculated by Poisson regression; relapses that occurred after rescue treatment was initiated for patients who had had a sustained progression of disability (per protocol) were censored. The predefined statistical models included baseline scores on the EDSS for sustained progression of disability and the number of relapses in the previous year for the relapse rate. Additional baseline factors were tested for inclusion in each of the models, including the EDSS score (3.5 or >3.5), the presence or absence of lesions as detected by gadolinium-enhanced MRI, the number of hyperintense lesions as detected by T2-weighted MRI (<9 or 9), and age (<40 or 40 years).21,22,23 Each covariate was tested in the model for statistical significance with the use of a backward-selection procedure, and only statistically significant covariates (P0.10) were included in the model. Only age was included in the final model for disability progression; the EDSS score, the presence or absence of lesions as detected by gadolinium-enhanced MRI, and age were included for the rate of relapse.

For the progression of disability, a sensitivity analysis was conducted on the change in EDSS scores that was sustained for 24 weeks. For the annualized relapse rate, sensitivity analyses were performed with and without censoring, as well as with and without adjustment for significant covariates. The unadjusted relapse rate was calculated as the total number of relapses divided by the total number of patient-years followed for each treatment group. The Hochberg procedure24 for multiple comparisons was used for the analysis of the two primary end points (the annualized relapse rate and the time to sustained progression of disability). Hence, the significance level was set so that if the higher of the P values for the analyses of these end points was 0.05, then both end points were considered to be statistically significant; otherwise, the lower of the P values was tested at a significance level of 0.025.

Secondary efficacy end points were rank-ordered, and a closed testing procedure was used, so that if statistical significance was not achieved for an end point, end points of a lower rank were not considered to be statistically significant. Secondary efficacy end points were analyzed by logistic regression that included a term for the treatment group and the respective baseline measure as a covariate. In the analyses of secondary end points, missing values were imputed using the mean for the respective measures in the study population.

Differences between treatment groups with regard to adverse events were analyzed by the chi-square test, and serious adverse events were analyzed by Fisher's exact test. Poisson regression was used to calculate the difference between the rates of infection in each treatment group.

All analyses followed the intention-to-treat principle. All reported P values are two-tailed. The one-year analyses occurred when 900 patient-years of data had been collected. The date on which the database was locked for the two-year analyses was January 31, 2005, which resulted in 2076 patient-years of observation and 1338 patient-years of exposure to natalizumab.

Results

Study Population

Among the 942 patients, 627 were assigned to receive natalizumab and 315 to receive placebo. There were no significant differences in baseline characteristics between the treatment groups (Table 1). A total of 856 patients (91 percent) completed the 120-week study (Figure 1), and 83 patients (a total of 9 percent, including 8 percent of patients in the natalizumab group and 10 percent of those in the placebo group) withdrew from the study. Thirty-nine patients discontinued the study drug but completed follow-up (a total of 4 percent, including 4 percent of patients in the natalizumab group and 5 percent of those in the placebo group). Three patients who were assigned to receive placebo were never treated; these patients were included in the intention-to-treat efficacy analyses but were excluded from the safety analyses.

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Table 1. Baseline Characteristics of the Patients.




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Figure 1. Patient Enrollment.



Efficacy

A sustained progression of disability over two years (the two-year primary end point) was significantly less likely in the natalizumab group than in the placebo group (Figure 2). At two years, the cumulative probability of progression (on the basis of Kaplan–Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001), which represents a decrease of 12 percentage points or a relative 42 percent decrease in the risk of a sustained progression of disability with natalizumab (Table 2). The sensitivity analysis of progression of disability that was sustained for 24 weeks yielded a 54 percent risk reduction in the natalizumab group (hazard ratio, 0.46; 95 percent confidence interval, 0.33 to 0.64; P<0.001).


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Figure 2. Kaplan–Meier Plots of the Time to Sustained Progression of Disability among Patients Receiving Natalizumab, as Compared with Placebo.
Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77). The cumulative probability of progression was 17 percent in the natalizumab group and 29 percent in the placebo group.




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Table 2. End Points as Determined by Clinical Results and MRI Evaluation.



After one year of treatment, natalizumab reduced the annualized rate of relapse to 0.26 relapse per year, as compared with 0.81 relapse per year in the placebo group (P<0.001) (Table 2). The 68 percent relative reduction in the annualized rate of relapse produced by natalizumab was maintained at two years (P<0.001). Subgroup and sensitivity analyses showed results consistent with the primary analysis. The proportion of relapse-free patients was significantly higher in the natalizumab group than in the placebo group at one year (77 percent vs. 56 percent, P<0.001) and at two years (67 percent vs. 41 percent, P<0.001). Natalizumab reduced the risk of relapse over two years by 59 percent (hazard ratio, 0.41; 95 percent confidence interval, 0.34 to 0.51; P<0.001). An analysis of relapse in 51 patients in the natalizumab group and 27 patients in the placebo group who discontinued the study drug showed a return to baseline disease activity when natalizumab therapy was stopped but no evidence of rebound; 25 relapses were reported by 15 patients in the natalizumab group (29 percent) after discontinuation of the study medication, as compared with 13 relapses reported by 8 patients in the placebo group (30 percent), giving an annualized relapse rate of 0.495 for patients receiving natalizumab, as compared with a rate of 0.608 for those receiving placebo (data not shown).

Natalizumab reduced the mean number of new or enlarging hyperintense lesions detected by T2-weighted MRI over two years by 83 percent, as compared with placebo (P<0.001) (Table 2). Over two years, no new or enlarging hyperintense lesions developed in 57 percent of patients in the natalizumab group, as compared with 15 percent of patients in the placebo group. In contrast, 68 percent of patients in the placebo group had at least three new or enlarging hyperintense lesions, as compared with only 18 percent of patients in the natalizumab group. Natalizumab reduced the mean number of lesions as detected by gadolinium-enhanced MRI by 92 percent as compared with placebo at both one year and two years (P<0.001) (Table 2). In addition, lesions detected by gadolinium-enhanced MRI were absent in 97 percent of patients in the natalizumab group as compared with 72 percent of patients in the placebo group on MRI scanning at two years.

Safety

Over the course of the two-year study, 596 patients receiving natalizumab (95 percent) and 300 of the 312 patients receiving placebo (96 percent) reported at least one adverse event. As shown in Table 3, adverse events that were significantly more common in the natalizumab group were fatigue and allergic reaction. The most severe adverse events reported by patients were mild in 17 percent, moderate in 55 percent, and severe in 23 percent of patients in the natalizumab group and mild in 13 percent, moderate in 56 percent, and severe in 27 percent in the placebo group. Serious adverse events were observed in 19 percent of patients receiving natalizumab and in 24 percent of patients receiving placebo (P=0.06); the most common serious adverse events were relapsing multiple sclerosis (6 percent with natalizumab and 13 percent with placebo; P<0.001), cholelithiasis (<1 percent with natalizumab and <1 percent with placebo), and the need for rehabilitation therapy (<1 percent with natalizumab and <1 percent with placebo). Two deaths occurred during the study, both in the natalizumab group. One patient, who died of malignant melanoma, had a history of malignant melanoma and had noted a new lesion at the time of receiving the first dose of natalizumab; he had received a total of five doses of natalizumab before receiving a confirmed diagnosis. A second patient died of alcohol intoxication after having received 25 doses of natalizumab.

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Table 3. Adverse Events.



Infections were generally mild to moderate in severity and did not lead to drug discontinuation. The overall incidence of infection was 79 percent in each treatment group and occurred at a rate of 1 per patient-year in each group. When the rate was reanalyzed to include multiple occurrences of infection, it went up in each group, as expected. However, there remained no significant differences between the groups, with infections occurring at a rate of 1.52 per patient-year in the natalizumab group and 1.42 per patient-year in the placebo group (P=0.32). Common infections were nasopharyngitis (32 percent of patients receiving natalizumab and 33 percent of patients receiving placebo), influenza (17 percent and 16 percent, respectively), upper respiratory tract viral infection (13 percent and 15 percent), urinary tract infection not otherwise specified (13 percent and 12 percent), upper respiratory tract infection not otherwise specified (13 percent and 11 percent), and pharyngitis (12 percent and 10 percent). Serious infections occurred in 3.2 percent of patients receiving natalizumab and in 2.6 percent of patients receiving placebo. In the natalizumab group, the serious infections included four cases of pneumonia and five cases of urinary tract infection or urosepsis; the remaining infections that were reported as serious were of various causes and included pilonidal cyst infection, cellulitis, febrile infection, gastroenteritis, cryptosporidial diarrhea, mononucleosis, osteomyelitis, sinusitis, tonsillitis, viral infection, appendicitis, and an infection of unclear cause. In the placebo group, serious infections included two cases of appendicitis, two cases of gastroenteritis, and one case each of infection not otherwise specified, bladder infection, cystitis, and influenza.

A total of six cases of cancer were reported — one case (<1 percent) in the placebo group and five cases (<1 percent) in the natalizumab group. The five cases of cancer that occurred in natalizumab-treated patients included three cases of breast cancer, one case of stage 0 cervical cancer, and one case of newly diagnosed metastatic melanoma. There was one case of basal-cell carcinoma in the placebo group.

Infusion reactions were defined as any event that occurred within two hours after the start of the one-hour infusion; they were reported in 148 patients receiving natalizumab (24 percent) and in 55 patients receiving placebo (18 percent) (P=0.04). The most common infusion reaction was headache (5 percent with natalizumab and 3 percent with placebo). Most reactions were treated symptomatically and did not result in discontinuation of the study drug. Hypersensitivity reactions were defined as reports of hypersensitivity, allergic reaction, or anaphylactic or anaphylactoid reaction by the investigator, as well as any report of urticaria, allergic dermatitis, or hives. The category was determined by the investigator on the basis of clinical judgment and severity. Twenty-five patients receiving natalizumab (4 percent) had 27 hypersensitivity reactions: 12 cases of urticaria or generalized urticaria, 1 of allergic dermatitis, 8 of a reaction called hypersensitivity, and 5 of anaphylactic or anaphylactoid reactions (urticaria plus other signs). One patient with a hypersensitivity reaction during the 7th infusion received other doses according to schedule and had an anaphylactic or anaphylactoid reaction during the 13th infusion. Fifteen reactions occurred on the second infusion. Eight hypersensitivity reactions (1.3 percent) were reported as serious adverse events among all patients receiving natalizumab, of which 5 reactions (0.8 percent) were considered serious systemic reactions (i.e., anaphylactic or anaphylactoid reactions). Per protocol, the study drug was to be discontinued in all patients who had hypersensitivity reactions. Five of the eight patients with serious adverse events had respiratory or chest symptoms, but only one patient required supplemental oxygen. No cardiovascular compromise was associated with any of these events, although one patient did receive epinephrine. All patients recovered without sequelae.

Because of adverse effects, 6 percent of the patients receiving natalizumab and 4 percent of those receiving placebo discontinued the study drug, and 3 percent of patients receiving natalizumab and 2 percent receiving placebo withdrew from the study. There were no significant differences between treatment groups in the proportions of patients with clinically notable changes in laboratory values. Increases in the number of lymphocytes, monocytes, eosinophils, and basophils were seen in natalizumab-treated patients without elevations in the number of neutrophils. These increases are consistent with expression of 41 on these white-cell subgroups and are a known pharmacodynamic effect of natalizumab. Increases in nucleated red cells were also seen transiently in a small number of patients. All changes were reversible, were without clinical effects, and returned to baseline levels, usually within 16 weeks after the last dose was administered.

Immunogenicity

Fifty-seven patients receiving natalizumab (9 percent) had detectable antibodies at some time during the study. Of these 57 patients, persistent antibodies to natalizumab (antibodies detected at 2 times that were 42 days apart) developed in 37 patients (6 percent), who also had an increase in infusion-related adverse events and a loss of efficacy of natalizumab.

Discussion

The results of AFFIRM support the hypothesis that the interaction between 41 integrin and its targets is an important component of inflammation of the central nervous system in multiple sclerosis and that the disruption of these interactions and the resultant attenuation of inflammation are beneficial to patients. In patients with relapsing multiple sclerosis, natalizumab significantly reduced the risk of progression of disability and the annualized rate of relapse over two years of treatment. The effect of natalizumab was rapid in onset and was sustained. In addition, efficacy was observed in terms of all secondary end points (an 83 percent reduction in the number of lesions as detected by T2-weighted MRI and a 92 percent reduction in the number of lesions as detected by gadolinium-enhanced MRI) and all sensitivity analyses of the primary end points, indicating the robustness of the result.

Disease-modifying therapies have become the cornerstone of treatment for patients with relapsing multiple sclerosis. The two-year registration trials of the therapies that are currently available (interferon beta products and glatiramer acetate) have shown that these agents reduce the annualized rate of relapse by about one third.13,14,15,16 In addition, neither interferon beta-1b nor glatiramer acetate had statistically significant effects on the progression of disability in patients with relapsing disease.14,15 Hence, there remains a need for more effective treatments for relapsing multiple sclerosis. The results of this study suggest that natalizumab may offer greater benefit to patients with relapsing multiple sclerosis than the other therapies.

The data presented here represent 30 percent of the placebo-controlled experience (patient-years of exposure) with natalizumab in patients with multiple sclerosis or Crohn's disease and 48 percent of the experience with natalizumab in patients with multiple sclerosis. In our study, natalizumab was safe as monotherapy over two years. In February 2005, all administration of natalizumab was voluntarily suspended by the manufacturers when they were notified of two cases of progressive multifocal leukoencephalopathy (PML). Both patients had received more than two years of natalizumab in combination with interferon beta-1a in a separate trial. Later, an additional case of PML was identified in a patient with Crohn's disease who had previously received a mistaken diagnosis of astrocytoma. The patient had received eight infusions of natalizumab. Detailed case histories of these three patients have been published elsewhere.25,26,27 An extensive safety evaluation of patients who received natalizumab in a clinical trial, also reported in this issue of the Journal, found no new confirmed cases of PML in patients treated with natalizumab.28 (The results of another clinical trial of natalizumab — in this case, administered with interferon beta-1a — also appear in this issue.29)

In conclusion, our study provides evidence that natalizumab significantly reduces the progression of disability and the occurrence of clinical relapse and suppresses the formation of lesions as visualized by MRI in patients with relapsing multiple sclerosis. Moreover, our data indicate that efficacy is realized early and persists throughout the treatment period. Within the 30-month evaluation period of this trial, natalizumab monotherapy had an excellent safety and tolerability profile. Continued assessments of long-term treatment with natalizumab will better define the safety profile of this effective therapy and establish its place in the arsenal of treatments for relapsing multiple sclerosis.




Supported by Biogen Idec and Elan Pharmaceuticals. Data were analyzed by Biogen Idec and Elan Pharmaceuticals.

Dr. Polman reports having received consulting fees from Biogen Idec, Schering, Teva, Serono, Novartis, GlaxoSmithKline, and Antisense Therapeutics; lecture fees from Biogen Idec, Schering, and Teva; and grant support from Biogen Idec and Schering, Wyeth, and GlaxoSmithKline. Dr. O'Connor reports having received consulting fees from Biogen Idec, Bristol-Myers Squibb, Sanofi-Aventis, Novartis, Serono, Schering, and Wyeth; lecture fees from Biogen Idec; and grant support from Biogen Idec, Novartis, Sanofi-Aventis, Schering, BioMS, Bristol-Myers Squibb, and Genentech. Dr. Havrdova reports having received consulting fees from Biogen Idec and Serono and lecture fees from Schering, Biogen Idec, Serono, and Teva. Dr. Hutchinson reports having received consulting fees from Biogen Idec; lecture fees from Serono, Schering, and Biogen Idec; and grant support from Serono, Schering, and Biogen Idec. Dr. Kappos reports having received grant support from Biogen Idec, Schering, Wyeth, Novartis, Serono, Teva, Sanofi-Aventis, and GlaxoSmithKline. Dr. Miller reports having received consulting fees from Biogen Idec, Wyeth, Novartis, UCB Pharma, and Bristol-Myers Squibb; lecture fees from Biogen Idec and Serono; and grant support from Biogen Idec, GlaxoSmithKline, and Schering. Dr. Phillips reports having received consulting fees from Biogen Idec, Teva, and Genzyme and lecture fees from Biogen Idec. Dr. Lublin reports having received grant support from Biogen Idec, Teva, Acorda, and Merck and consulting and lecture fees from Biogen Idec, Berlex, Teva, Novartis, Schering-Plough, Serono, Pfizer, Amgen, and Antisense Therapeutics. Dr. Giovannoni reports having received consulting fees from Biogen Idec, Serono, Teva, and Schering; lecture fees from Biogen Idec, Serono, Teva, and Schering; and grant support from Biogen Idec, GlaxoSmithKline, and Teva. Dr. Toal reports having formerly been employed by Biogen Idec. Ms. Lynn, Dr. Panzara, and Dr. Sandrock report having equity interests in and being employed by Biogen Idec. No other potential conflict of interest relevant to this article was reported.

We are indebted to Nancy Bormann for her editorial assistance.

* Additional members of the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study group are listed in the Supplementary Appendix, available with the full text of this article at www.nejm.org.


Source Information

From the Vrije Universiteit Medical Center, Amsterdam (C.H.P.); St. Michael's Hospital, Toronto (P.W.O.); General Teaching Hospital, Prague, Czech Republic(E.H.); St. Vincent's University Hospital, Dublin, Ireland (M.H.); University Hospital Basel, Basel, Switzerland (L.K.); Institute of Neurology, London (D.H.M., G.G.); Texas Neurology, Dallas (J.T.P.); Mt. Sinai School of Medicine, New York (F.D.L.); Silesian Medical University, Katowice, Poland (A.W.); and Biogen Idec, Cambridge, Mass. (M.T., F.L., M.A.P., A.W.S.).

Address reprint requests to Dr. Polman at the VU Medical Center, P.O. Box 7057, Amsterdam 1007 MB, the Netherlands, or at ch.polman@vumc.nl.

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Carlos TM, Schwartz BR, Kovach NL, et al. Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood 1990;76:965-970. [Erratum, Blood 1990;76:2420.] [Abstract/Full Text]
Bayless KJ, Meininger GA, Scholtz JM, Davis GE. Osteopontin is a ligand for the 41 integrin. J Cell Sci 1998;111:1165-1174. [Abstract]
Davis LS, Oppenheimer-Marks N, Bednarczyk JL, McIntyre BW, Lipsky PE. Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules. J Immunol 1990;145:785-793. [Abstract]
Chan PY, Aruffo A. VLA-4 integrin mediates lymphocyte migration on the inducible endothelial cell ligand VCAM-1 and the extracellular matrix ligand fibronectin. J Biol Chem 1993;268:24655-24664. [Abstract/Full Text]
O'Regan AW, Chupp GL, Lowry JA, Goetschkes M, Mulligan N, Berman JS. Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro. J Immunol 1999;162:1024-1031. [Abstract/Full Text]
Chabas D, Baranzini SE, Mitchell D, et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001;294:1731-1735. [Abstract/Full Text]
Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against 41 integrin. Nature 1992;356:63-66. [CrossRef][ISI][Medline]
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285-294. [Erratum, Ann Neurol 1996;40:480.] [CrossRef][ISI][Medline]
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-661. [Abstract]
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 1995;45:1268-1276. [Abstract]
PRISMS (Prevention of Relapses and Disability by Interferon -1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon -1a in relapsing/remitting multiple sclerosis. Lancet 1998;352:1498-1504. [Erratum, Lancet 1999;353:678.] [CrossRef][ISI][Medline]
Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15-23. [Abstract/Full Text]
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001;50:121-127. [CrossRef][ISI][Medline]
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444-1452. [Abstract]
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996;46:907-911. [Abstract]
Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898-904. [Abstract/Full Text]
Beck RW, Chandler DL, Cole SR, et al. Interferon beta-1a for early multiple sclerosis: CHAMPS trial subgroup analyses. Ann Neurol 2002;51:481-490. [CrossRef][ISI][Medline]
Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112:133-146. [Abstract/Full Text]
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988;75:800-802. [Abstract/Full Text]
Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369-74. [Abstract/Full Text]
Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-381. [Abstract/Full Text]
Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-368. [Abstract/Full Text]
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924-933. [Abstract/Full Text]
Rudick RA, Stuart WH, Calabresi PA, et al. A randomized, placebo-controlled trial of natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911-923. [Abstract/Full Text]





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Natalizumab for Relapsing Multiple Sclerosis
Tenser R. B., Jeffery D. R., Meyer M. A., Polman C. H., Rudick R. A., Major E. O., Yousry T. A., Clifford D. B., Ropper A. H.
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N Engl J Med 2006; 354:2387-2389, Jun 1, 2006. Correspondence


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NEJM Volume 354:911-923 March 2, 2006 Number 9
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Natalizumab plus Interferon Beta-1a for Relapsing Multiple Sclerosis

Richard A. Rudick, M.D., William H. Stuart, M.D., Peter A. Calabresi, M.D., Christian Confavreux, M.D., Steven L. Galetta, M.D., Ernst-Wilhelm Radue, M.D., Fred D. Lublin, M.D., Bianca Weinstock-Guttman, M.D., Daniel R. Wynn, M.D., Frances Lynn, M.Sc., Michael A. Panzara, M.D., M.P.H., Alfred W. Sandrock, M.D., Ph.D., for the SENTINEL Investigators




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ABSTRACT

Background Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an 4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies.

Methods We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years.

Results Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan–Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T2-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients.

Conclusions Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966 [ClinicalTrials.gov] .)




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The adhesion molecule 41 integrin is a key initiator of the inflammatory cascade involved in the pathogenesis of multiple sclerosis.1,2,3,4 Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is the first 4 integrin antagonist in a new class of selective adhesion-molecule inhibitors for the treatment of multiple sclerosis. Natalizumab binds to 4 integrin on the surface of leukocytes, inhibiting their migration into the brain and thereby reducing inflammation.
Current disease-modifying therapies for relapsing–remitting multiple sclerosis (interferon beta and glatiramer acetate) are only partially effective,5,6,7,8 and most patients with multiple sclerosis have breakthrough disease activity despite therapy with these agents. Hence, there is a need for additional treatment options in multiple sclerosis. Natalizumab is an attractive therapy to add to current disease-modifying therapies in patients with breakthrough disease because preliminary efficacy9 and safety10 data have been favorable and because the mechanism of action of natalizumab may complement those of other disease-modifying therapies.11,12,13,14,15,16,17

The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study was a two-year, phase 3 clinical trial designed to determine whether natalizumab, when added to interferon beta-1a, has efficacy in addition to that associated with interferon beta-1a alone. The trial was also designed to confirm the safety of natalizumab when added to interferon beta-1a.

Methods

Patients

One hundred twenty-four clinical centers in Europe and the United States enrolled 1196 patients beginning on January 14, 2002. All patients gave written informed consent. The study protocol was developed by the investigator advisory committee and the sponsors and was approved by central and local ethics committees, and the study was overseen by an independent safety-monitoring committee. Data were collected by the investigators and an independent organization (PPD International) and were held and analyzed by Biogen Idec and Elan Pharmaceuticals. During the study, the investigator advisory committee and representatives of Biogen Idec met at least monthly to review and manage the study. The manuscript was written by Drs. Rudick and Panzara, with input from each of the other authors; all the authors vouch for the veracity and completeness of the data and analyses.

Eligible patients were 18 to 55 years of age; had a diagnosis of relapsing–remitting multiple sclerosis,18 a score on the Expanded Disability Status Scale (EDSS) (possible scores range from 0 to 10, with higher scores indicating more severe disease) between 0 and 5.0,19 and a magnetic resonance imaging (MRI) scan revealing lesions consistent with a diagnosis of multiple sclerosis; had received treatment with interferon beta-1a for at least 12 months before randomization; and had had at least one relapse during the 12-month period before randomization. Patients were ineligible if they had primary progressive, secondary progressive, or progressive relapsing multiple sclerosis20; if they had had a relapse within 50 days before randomization; or if they had been treated with an approved disease-modifying therapy other than interferon beta-1a intramuscularly once weekly within the 12-month period before randomization.

Study Design and Randomization

This study was a randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial. Data from 1171 of the 1196 patients enrolled were analyzed, because a single center with 25 patients was excluded before unblinding owing to irregularities in data. Patients were randomly assigned, in a 1:1 ratio, to receive 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks in addition to interferon beta-1a (Avonex, Biogen Idec) at a dose of 30 µg intramuscularly once weekly for up to 116 weeks. Randomization was stratified according to study site in blocks of four (two active and two placebo) with the use of a computer-generated schedule and a multidigit identification number, implemented by way of an interactive voice-response system. All study personnel, patients, sponsor personnel involved in the conduct of the study, and members of the investigator advisory committee were blinded to the treatment assignments throughout the study.

Study Procedure and End Points

Each site designated primary and backup examining neurologists and treating neurologists. The examining neurologists performed the EDSS and neurologic examinations but were otherwise not involved in the patients' medical care. The treating neurologists were responsible for all patient care, including the management of adverse events and relapses of multiple sclerosis.

Clinical visits every 12 weeks included assessment of relapses, EDSS evaluation, blood chemical and hematologic tests, assessment of any adverse events, and immunogenicity studies. Patients were also seen by a treating neurologist during unscheduled visits within 72 hours after the development of new symptoms so that they could be assessed for possible relapses or adverse events. If a relapse was suspected, the patient was evaluated by the examining neurologist. Relapses were defined as the development of new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new, objective neurologic findings. At the discretion of the treating neurologist, relapses were treated with intravenous methylprednisolone at a dose of 1000 mg per day for three or five days. Patients who had disability progression that was sustained for 12 weeks were asked to provide consent to continue study participation and were given the option of adding an available multiple sclerosis treatment as rescue medication, according to protocol, while continuing to receive the study drug. Patients who discontinued the study drug were strongly encouraged to remain in the study for follow-up assessments, and all patients who continued to participate in the study were evaluated (according to the intention-to-treat principle).

Proton-density, T2-weighted MRI scans and gadolinium-enhanced T1-weighted MRI scans of the brain were obtained at baseline and at weeks 52 and 104. Forty contiguous, 3-mm-thick axial slices were acquired. MRI analyses were performed centrally at the MS-MRI Evaluation Center (Basel, Switzerland) by blinded raters. The scans were checked for artifacts, compliance with scanning requirements, and repositioning.

The primary efficacy end point was the rate of clinical relapse at one year. Secondary end points at one year were the number of new or enlarging T2-hyperintense lesions, the number of gadolinium-enhancing lesions, and the proportion of patients free of relapse. The primary efficacy end point at two years was the cumulative probability of sustained disability progression, defined as an increase by at least 1.0 point in the EDSS score from a baseline score of at least 1.0 or an increase by at least 1.5 points in the EDSS score from a baseline score of 0, sustained for 12 weeks; progression could not be confirmed during a relapse. Secondary end points at two years were the rate of clinical relapse, the volume of T2-hyperintense lesions, the number of new T1-hypointense lesions, and disability as measured by the Multiple Sclerosis Functional Composite.21 This report presents data pertaining to primary end points and key secondary efficacy end points, as well as safety data. Results pertaining to additional secondary end points and tertiary end points are not included in this report.

Binding antibodies against natalizumab were assessed with use of an enzyme-linked immunosorbent assay. Positive samples (0.5 µg per milliliter) were further tested in a flow-cytometry assay to determine whether these antibodies interfered with the binding of natalizumab to 4 integrin.

Statistical Analysis

The sample size was estimated, on the basis of data from previous trials of natalizumab9 and interferon beta-1a,6 with the use of two-sided tests with an experiment-wise alpha of 0.05. The annualized rate of relapse among patients receiving combination therapy at one year was predicted to be 0.6, as compared with 0.9 among patients receiving interferon beta-1a alone. For the annualized relapse rate, the likelihood-ratio test was used to determine the sample size with half the patients receiving active drug and half receiving placebo. With an assumed dropout rate of 17 percent, rounding, a type I error rate of 2.5 percent, and a type II error rate of 90 percent, the number of patients needed was estimated to be 1200. To power the study for the two-year end point of disability progression, we assumed a progression rate of 34.9 percent at the end of two years in the group assigned to interferon beta-1a alone and a progression rate of 22.7 percent at the end of two years (a 35 percent improvement) in the combination-therapy group. Simulations of the log-rank test were run with 60 percent of the accrual in the first 24 weeks and the remainder in the next 24 weeks. With an assumed dropout rate of 20 percent, the sample size of 1200 provided at least 92 percent power with a Bonferroni adjustment for multiple end points and with the type I error rate maintained at 5 percent.

The baseline characteristics of the patients were analyzed with the use of a t-test, with the exceptions of sex, race, and diagnosis of multiple sclerosis (based on the McDonald criteria18), which were analyzed with the use of a chi-square test. The time to the onset of disability progression sustained for 12 weeks was used to determine the cumulative probability of disability progression estimated by the Kaplan–Meier method. The Cox proportional-hazards model, adjusted for the baseline EDSS score, was used to compare the Kaplan–Meier curves. The annualized relapse rate was calculated by Poisson regression and adjusted for the number of relapses in the year before randomization; data pertaining to relapses that occurred after rescue treatment was initiated (per protocol) were censored. Additional baseline factors were tested for inclusion in each of the models: EDSS score (3.5 or >3.5), gadolinium-enhancing lesions (present or absent), the number of T2-hyperintense lesions (<9 or 9), and age (<40 or 40 years).22,23,24 Each covariate was tested in the model for statistical significance by a backward-selection procedure, and only statistically significant covariates (P0.10) were included in the final models. No additional covariates were included in the analysis of disability progression. Three additional covariates (baseline EDSS score, the presence or absence of gadolinium-enhancing lesions at baseline, and age) were included in the analysis of relapse rate.

A sensitivity analysis of disability progression (based on the change in EDSS score) sustained for 24 weeks was also conducted. For the annualized rate of relapse, sensitivity analyses were performed with and without censoring, as well as with and without adjustment for significant covariates. The unadjusted rate of relapse was calculated as the total number of relapses divided by the total number of subject-years of follow-up in each treatment group. The Hochberg procedure25 for multiple comparisons was used in the analysis of the two primary end points; hence, the significance level was set such that if the higher of the P values for the analyses of these end points was less than or equal to 0.05, then both end points were considered to be statistically significant; otherwise, the lower of the P values was tested at a significance level of 0.025.

Secondary efficacy end points were rank-ordered, and a closed testing procedure was used such that if statistical significance was not achieved for a given end point, then end points of a lower rank were considered not statistically significant. Secondary efficacy end points were analyzed by logistic regression with a term for treatment group and with their respective baseline values as covariates; missing values were imputed by using the mean in the study population.

Adverse events were analyzed with use of the chi-square test, and serious adverse events were analyzed with use of Fisher's exact test. Poisson regression was used to calculate the difference between the rates of infection in each treatment group.

All analyses followed the intention-to-treat principle. All reported P values are two-tailed. The date on which the database was locked for the two-year analyses was May 31, 2005, and as a result there were 2528 patient-years of observation and 1222 patient-years of exposure to natalizumab.

Results

Patients

SENTINEL was stopped approximately one month early, on February 28, 2005, because of two reports of progressive multifocal leukoencephalopathy (PML). Of the 1171 patients, a total of 1003 (86 percent) completed the 120-week study; 168 patients (14 percent overall; 12 percent of the group assigned to interferon beta-1a plus natalizumab and 16 percent of the group assigned to interferon beta-1a alone) withdrew from the study (Figure 1). Sixty-four patients discontinued the study drug but completed follow-up (5 percent overall; 5 percent of the combination-therapy group and 6 percent of the group assigned to interferon beta-1a alone). There were no significant differences in demographic or disease-related characteristics at baseline between the two treatment groups, with the exception of the duration of disease (median, seven years in the combination-therapy group and eight years in the group assigned to interferon beta-1a alone; P=0.02) (Table 1).


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Figure 1. Disposition of Patients during the Two-Year SENTINEL Study.



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Table 1. Baseline Characteristics of the Patients.



The SENTINEL data represent 28 percent of the placebo-controlled experience with natalizumab (in terms of patient-years of exposure) in both multiple sclerosis and Crohn's disease and 44 percent of the overall experience in multiple sclerosis.

Efficacy

Kaplan–Meier estimates of the cumulative probability of sustained disability progression at 2 years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone (Figure 2 and Table 2). Combination therapy resulted in a 24 percent decrease in the risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). In the sensitivity analysis of the risk of disability progression sustained for 24 weeks, estimates of the cumulative probability of progression by 2 years were 15 percent for combination therapy and 18 percent for interferon beta-1a alone (representing an 18 percent reduction with combination therapy); however, this difference was not statistically significant (P=0.17).


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Figure 2. Kaplan–Meier Plots of the Time to Sustained Disability Progression.
The hazard ratio for sustained progression in the combination-therapy group as compared with the group given interferon beta-1a alone was 0.76 (95 percent confidence interval, 0.61 to 0.96).




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Table 2. Clinical and Magnetic Resonance Imaging End Points.



Combination therapy reduced the annualized rate of relapse at one year, which was 0.82 with interferon beta-1a alone, to 0.38 (P<0.001) — a 54 percent reduction (Table 2). This difference was maintained at two years, at which time the rate was 0.75 with interferon beta-1a alone and 0.34 with combination therapy (a 55 percent reduction with combination therapy, P<0.001). Subgroup analyses (according to relapse history, EDSS score, age, sex, the presence or absence of gadolinium-enhancing lesions, and the number of T2-hyperintense lesions) and a sensitivity analysis of relapse rate showed consistent results. The proportion of patients who were relapse-free at two years was 54 percent in the combination-therapy group, as compared with 32 percent in the group assigned to interferon beta-1a alone (P<0.001). The risk of relapse was 50 percent lower with combination therapy (hazard ratio, 0.50; 95 percent confidence interval, 0.43 to 0.59; P<0.001).

The number of new or enlarging T2-hyperintense lesions over the two-year period was reduced from 5.4 with interferon beta-1a alone to 0.9 with combination therapy (P<0.001), representing an 83 percent reduction with combination therapy (Table 2). The mean number of gadolinium-enhancing lesions at two years was 0.9 with interferon beta-1a alone and 0.1 with combination therapy, representing an 89 percent reduction (P<0.001).

Safety

At least one adverse event was reported by 584 patients assigned to receive interferon beta-1a plus natalizumab (>99 percent) and 578 assigned to receive interferon beta-1a alone (>99 percent). Adverse events significantly associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema (Table 3). The worst adverse events associated with combination therapy were mild in 10 percent of the patients, moderate in 54 percent, and severe in 35 percent; the respective percentages for interferon beta-1a alone were 5 percent, 57 percent, and 37 percent. Serious adverse events were observed in 18 percent of the patients assigned to combination therapy and 21 percent of those assigned to interferon beta-1a alone (P=0.23). The most common serious adverse event was a relapse of multiple sclerosis, which occurred in 5 percent of the patients in the combination-therapy group and 9 percent of those in the interferon beta-1a group (P=0.002). One of the serious adverse events reported was PML, which occurred in a patient who had received 29 doses of natalizumab. A second patient received a diagnosis of PML after her completion of the two-year study and after she had received 37 doses of natalizumab. The details of these cases of PML have been reported previously.26,27 Two of the patients assigned to interferon beta-1a alone died: one was a 47-year-old woman with a history of sinus arrhythmia and heart murmur, and the other was a 23-year-old woman with a history of headache, pain, and use of prescribed methadone who died during sleep.

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Table 3. Adverse Events.



Depression was assessed every six months with use of the Beck Depression Inventory II.28 There were no differences between the treatment groups in Beck Depression Inventory II scores during the study (data not shown).

The incidence of infection was 83 percent in the combination-therapy group and 81 percent in the group assigned to interferon beta-1a alone; infections occurred at a rate of 1 per patient-year in each group. When the data pertaining to infection were reanalyzed to include multiple occurrences, the rate increased in each group, as expected. However, there remained no significant difference between the groups, with infection rates of 1.54 per patient-year with combination therapy and 1.53 per patient-year with interferon beta-1a alone (P=0.95). Common infections were nasopharyngitis (39 percent vs. 35 percent); urinary tract infection, not otherwise specified (18 percent vs. 19 percent); sinusitis, not otherwise specified (18 percent vs. 15 percent); upper respiratory tract infection, not otherwise specified (17 percent vs. 18 percent); and influenza (17 percent vs. 15 percent). Serious infections occurred in 2.7 percent and 2.9 percent of the patients assigned to combination therapy and interferon beta-1a alone, respectively. There were no cases of tuberculosis. The incidence of cancer was 1 percent in the combination-therapy group and 2 percent in the group assigned to interferon beta-1a alone.

Infusion reactions, defined as any event occurring within two hours after the start of an infusion, occurred in 24 percent of the patients in the combination-therapy group and 20 percent of those in the group assigned to interferon beta-1a alone (P=0.11). The most common infusion reaction was headache. Most reactions were treated symptomatically and did not result in discontinuation of the study drug. Hypersensitivity reactions included all events reported on the basis of clinical judgment as hypersensitivity, an allergic reaction, an anaphylactic or anaphylactoid reaction, urticaria, or hives by the investigator and were categorized according to severity. Eleven patients assigned to combination therapy (1.9 percent) had a hypersensitivity reaction; 8 of the 11 hypersensitivity reactions were isolated cases of urticaria (2 of which were severe). In addition, two patients assigned to interferon beta-1a alone (0.3 percent) had hypersensitivity reactions associated with the infusion of placebo; both were cases of mild urticaria. There was no cardiopulmonary compromise associated with any event. Natalizumab was discontinued, and the episodes resolved without sequelae.

Eight percent of the patients in the combination-therapy group and 7 percent of those in the group assigned to interferon beta-1a alone discontinued the study drug because of an adverse event. Three percent and 2 percent, respectively, withdrew from the study because of an adverse event.

Natalizumab-treated patients had increases in lymphocytes, monocytes, eosinophils, and basophils — changes consistent with the drug's known pharmacodynamic effects and the presence of 4 integrins on these cell types. Increases in nucleated red cells also were seen transiently in a small number of patients. These laboratory changes were not associated with any clinical manifestations and were reversible, with values returning to baseline within 16 weeks after the last dose. Elevations in neutrophils were not observed. No increase in the incidence of chemical abnormalities, including the results of liver-function tests, was observed with combination therapy.

Immunogenicity

Seventy patients (12 percent of the combination-therapy group) had antibodies to natalizumab. Persistent antinatalizumab antibodies (detectable on at least two occasions 42 or more days apart) developed in 38 patients (6 percent), resulting in a loss of efficacy and an increase in infusion-related adverse events. The incidence of new neutralizing antibodies to interferon beta-1a was 1 percent among patients assigned to combination therapy and less than 1 percent among those assigned to interferon beta-1a alone.

Discussion

Phase 3 trials have shown that over a two-year period, 62 to 75 percent of patients have clinical relapses while receiving interferon beta therapy.5,6,8 For patients who have breakthrough disease while receiving disease-modifying therapies, clinical practice includes the addition of a second partially effective agent; however, there is no class I evidence to support this treatment strategy. The primary objective of SENTINEL was to address this common clinical scenario — specifically, to determine whether the addition of natalizumab to interferon beta-1a would reduce breakthrough disease activity in patients already receiving interferon beta-1a therapy. This approach has been used effectively in the development of combination therapy for rheumatoid arthritis.29,30,31,32

The addition of natalizumab to interferon beta-1a reduced the risk of disability progression by 24 percent over a two-year period as compared with interferon beta-1a alone (P=0.02). The sensitivity analysis of disability sustained for 24 weeks did not reach statistical significance (P=0.17); however, that analysis was exploratory, and the study was not adequately powered to assess the treatment effect on the basis of this definition. We also found that combination therapy reduced the annualized rate of relapse by 55 percent over a two-year period as compared with interferon beta-1a alone (P<0.001).

Accumulation of T2-hyperintense MRI lesions has been linked to future progression of brain atrophy33 and long-term disability34,35 in relapsing multiple sclerosis. The number of new or enlarging T2-hyperintense lesions in patients receiving interferon beta-1a alone was similar to the findings of another study of interferon beta-1a in relapsing multiple sclerosis that used the same imaging methods.36 The addition of natalizumab to interferon beta-1a further reduced the number of new or enlarging T2-hyperintense lesions by 83 percent, and approximately two thirds of the patients assigned to combination therapy remained free of new lesions for two years.

Natalizumab interferes with the activity of 4 integrin, altering cell migration into the central nervous system and possibly blocking interactions between 4 integrin and its ligands within the central nervous system itself.1,2,3,4 Interferon beta has pleiotropic effects on cellular functions that are relevant to efficacy in multiple sclerosis and distinct from those of natalizumab.11,12,13,14 In addition, studies have shown that, like natalizumab, interferon beta may prevent leukocyte migration across the blood–brain barrier by altering the expression of adhesion molecules.15,16,17 The additional efficacy of the combination over that conferred by interferon beta alone suggests that the interaction between 41 integrin and its targets is a key mediator of inflammation and subsequent demyelination in multiple sclerosis.

In February 2005, administration of natalizumab was suspended when two cases of PML were identified. In one of the cases, PML was diagnosed during SENTINEL, and in the other it was diagnosed after the patient had completed SENTINEL and had begun participating in an open-label safety study of natalizumab and interferon beta-1a. Later, an additional case of PML was identified post mortem in a patient with Crohn's disease who had previously received a diagnosis of astrocytoma. Details of these three cases have recently been published.26,27,37 An extensive safety evaluation of patients in clinical trials who were receiving natalizumab at the time of the drug suspension did not identify additional cases of PML (see the article by Yousry et al. in this issue of the Journal38). The mechanisms by which natalizumab may increase the risk of PML are unknown, but they may involve altered trafficking of lymphoid cells harboring latent JC virus, decreased immune surveillance, or a combination of these processes.39 The role of interferon beta in combination with natalizumab is also not clear, given that PML has never been associated with interferon beta alone.

SENTINEL was designed to determine whether natalizumab added to interferon beta-1a is better than interferon beta-1a alone. The results of all prespecified analyses of primary and secondary end points were positive and statistically significant. A natalizumab-monotherapy group was not included in the trial because this design would have required withdrawal of an approved therapy in order to switch to an experimental one at a time (in 2001) when the long-term safety and efficacy of natalizumab were unknown. This approach was believed to be unacceptable by the investigator advisory committee. Hence, additional studies would be required to determine whether combination therapy with natalizumab and interferon beta-1a is more efficacious than natalizumab alone and to define further the role of natalizumab combination therapy in clinical practice. The results of another trial of natalizumab, administered without interferon beta-1a, also appear in this issue of the Journal.40

SENTINEL systematically evaluated combination therapy as compared with standard interferon beta therapy in relapsing multiple sclerosis. The study showed that in patients with multiple sclerosis who have breakthrough disease during interferon beta treatment, combination therapy has significant benefits when compared with interferon beta-1a alone. Additional studies will be required for further assessment of the long-term safety of combination therapy with natalizumab and for assessment of its efficacy relative to that of natalizumab alone.




Supported by Biogen Idec and Elan Pharmaceuticals.

Drs. Rudick and Stuart report having received consulting fees, lecture fees, and grant support from Biogen Idec. Dr. Calabresi reports having received consulting fees from Biogen Idec, Teva, Schering, and Novartis; lecture fees from Biogen Idec and Teva; and grant support from Biogen Idec and Genentech. Dr. Confavreux reports having received consulting and lecture fees from Biogen Idec, Sanofi-Aventis, Schering, Serono, and Teva. Dr. Galetta reports having received consulting fees, lecture fees, and grant support from Biogen Idec. Dr. Radue reports having received lecture fees from Biogen Idec. Dr. Lublin reports having received grant support from Biogen Idec, Teva, Acorda, and Merck and consulting or lecture fees from Biogen Idec, Berlex, Teva, Novartis, Schering-Plough, Serono, Pfizer, Amgen, and Antisense Therapeutics. Dr. Weinstock-Guttman reports having received lecture fees from Biogen Idec and Teva and grant support from Biogen Idec. Dr. Wynn reports having received consulting fees from Biogen Idec, Teva, Serono, and Avanir Pharmaceuticals and lecture fees from Biogen Idec, Teva, Pfizer, and Serono. Ms. Lynn, Dr. Panzara, and Dr. Sandrock report having equity interest in and being employees of Biogen Idec. No other potential conflict of interest relevant to this article was reported.

* The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) Investigators are listed in the Supplementary Appendix, available with the full text of this article at www.nejm.org.


Source Information

From the Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland (R.A.R.); the MS Center of Atlanta, Atlanta (W.H.S.); the Johns Hopkins Multiple Sclerosis Center, Baltimore (P.A.C.); Hôpital Neurologique, Lyon, France (C.C.); University of Pennsylvania School of Medicine, Philadelphia (S.L.G.); University Hospital Basel, Basel, Switzerland (E.-W.R.); Mt. Sinai School of Medicine, New York (F.D.L.); Baird Multiple Sclerosis Center, State University of New York at Buffalo, Buffalo (B.W.-G.); Consultants in Neurology Multiple Sclerosis Center, Northbrook, Ill. (D.R.W.); and Biogen Idec, Cambridge, Mass. (F.L., M.A.P., A.W.S.).

Address reprint requests to Dr. Rudick at the Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, or at rudickr@ccf.org.

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Natalizumab for Relapsing Multiple Sclerosis
Tenser R. B., Jeffery D. R., Meyer M. A., Polman C. H., Rudick R. A., Major E. O., Yousry T. A., Clifford D. B., Ropper A. H.
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N Engl J Med 2006; 354:2387-2389, Jun 1, 2006. Correspondence


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NEJM Volume 354:924-933 March 2, 2006 Number 9

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Evaluation of Patients Treated with Natalizumab for Progressive Multifocal Leukoencephalopathy

Tarek A. Yousry, Dr.Med.Habil., Eugene O. Major, Ph.D., Caroline Ryschkewitsch, B.S., Gary Fahle, B.S., Steven Fischer, M.D., Ph.D., Jean Hou, B.S., Blanche Curfman, B.S., Katherine Miszkiel, M.D., Nicole Mueller-Lenke, M.D., Esther Sanchez, M.D., Frederik Barkhof, M.D., Ph.D., Ernst-Wilhelm Radue, M.D., Hans R. Jäger, M.D., and David B. Clifford, M.D.




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ABSTRACT

Background Progressive multifocal leukoencephalopathy (PML) was reported to have developed in three patients treated with natalizumab. We conducted an evaluation to determine whether PML had developed in any other treated patients.

Methods We invited patients who had participated in clinical trials in which they received recent or long-term treatment with natalizumab for multiple sclerosis, Crohn's disease, or rheumatoid arthritis to participate. The clinical history, physical examination, brain magnetic resonance imaging (MRI), and testing of cerebrospinal fluid for JC virus DNA were used by an expert panel to evaluate patients for PML. We estimated the risk of PML in patients who completed at least a clinical examination for PML or had an MRI.

Results Of 3417 patients who had recently received natalizumab while participating in clinical trials, 3116 (91 percent) who were exposed to a mean of 17.9 monthly doses underwent evaluation for PML. Of these, 44 patients were referred to the expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus. No patient had detectable JC virus DNA in the cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but it could not be ruled out in one patient who had multiple sclerosis and progression of neurologic disease because data on cerebrospinal fluid testing and follow-up MRI were not available. Only the three previously reported cases of PML were confirmed (1.0 per 1000 treated patients; 95 percent confidence interval, 0.2 to 2.8 per 1000).

Conclusions A detailed review of possible cases of PML in patients exposed to natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months. The risk associated with longer treatment is not known.




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Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is encountered most frequently in the setting of immunodeficiency.1 The disease is caused by the human polyomavirus JC virus, a common and widespread infection in humans. PML was reported in three patients who received natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals).2,3,4 Natalizumab is a recombinant humanized antibody directed to the 4 integrins, both 41 and 47.5 The drug was approved by the Food and Drug Administration (FDA) for the treatment of relapsing forms of multiple sclerosis in November 2004 and is being investigated for the treatment of Crohn's disease and rheumatoid arthritis. Because of the occurrence of PML, the use of natalizumab was suspended on February 28, 2005.6 We report the evaluation of patients exposed to natalizumab for the occurrence of PML.
Methods

Independent Adjudication Committee

An independent adjudication committee (IAC) was established with a formal charter approved by the members of the committee. The committee included a neurovirologist with experience with JC virus and PML (who served as the chair of the committee), a neuroradiologist, and a clinical neurologist (see Appendix). The committee agreed to evaluate all suspected cases of PML in patients who had been exposed to natalizumab to determine whether a diagnosis of PML was confirmed, indeterminate, or ruled out. The committee established criteria for the neuroradiologic evidence and laboratory assays used in the diagnosis of PML. Biogen Idec and Elan Pharmaceuticals assisted in the collection of the data. Physicians who were representatives of each of these companies were nonvoting participants in the discussion of the materials reviewed but were excluded from closed sessions of the IAC.

Patients

A total of 3826 patients who had participated in recent clinical trials of natalizumab were recruited for the evaluation (Figure 1). Eligible patients included those with multiple sclerosis who were participating in the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis7 (AFFIRM) study (NCT00027300 [ClinicalTrials.gov] ), the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) trial (NCT00030966 [ClinicalTrials.gov] ),8 and the Natalizumab in Combination with Glatiramer Acetate in Patients with Relapsing-Remitting Multiple Sclerosis study (NCT00097760 [ClinicalTrials.gov] ); patients with Crohn's disease who were participating in the international Efficacy of Natalizumab as Crohn's Therapy trial (ENACT-1, NCT00032799 [ClinicalTrials.gov] ), the Evaluation of Natalizumab as Continuous Therapy (ENACT-2, NCT00032786 [ClinicalTrials.gov] ), and the Clinical Trial of Natalizumab in Individuals with Moderately to Severely Active Crohn's Disease (ENCORE) (NCT00078611 [ClinicalTrials.gov] ); patients with rheumatoid arthritis participating in a phase 2 Natalizumab in the Treatment of Rheumatoid Arthritis in Subjects Receiving Methotrexate trial (NCT00083759 [ClinicalTrials.gov] ); and all patients participating in open-label safety-extension trials (NCT00276172 [ClinicalTrials.gov] ). Of the 3826 patients recruited, 409 had received placebo but were recruited because blinding had not yet been broken; therefore, 3417 patients who had received natalizumab in these trials were included in our study. Because PML is known to be a progressive and often fatal neurologic disease, it was believed that recruiting patients with remote exposure to natalizumab was not required. All previous studies included three to six months of observation after exposure to the drug, and adverse events were reported. The 1708 subjects who had been enrolled in nine trials involving patients with multiple sclerosis that ended before 2001 and in seven trials involving patients with Crohn's disease that ended before 2003 were not actively recruited for this safety evaluation, but we performed a review of the integrated natalizumab safety database, including serious adverse events reported in these studies.


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Figure 1. Evaluation of Patients for Progressive Multifocal Leukoencephalopathy (PML) by the Independent Adjudication Committee (IAC).
The asterisk indicates official counts of patients as of the locking of the interim database (on August 4, 2005, for patients with multiple sclerosis [MS], and on August 24, 2005, for patients with Crohn's disease [CDJ] or rheumatoid arthritis [RA]). CSF denotes cerebrospinal fluid, NIH National Institutes of Health, MRI magnetic resonance imaging, and JCV JC virus.




Approximately 7000 patients received one to three doses of natalizumab between November 2004 and February 2005, after the drug became commercially available. Prescribing physicians of commercially treated patients were notified by a "Dear Healthcare Professional" letter (the letter is in the Supplementary Appendix, available with the full text of this article at www.nejm.org) that recommended evaluating and reporting adverse events, and referred cases were eligible for evaluation by the IAC. Two patients treated commercially after FDA approval of natalizumab and one pediatric patient receiving the drug for compassionate use were referred for evaluation.

Evaluation for PML

Treating physicians were asked to submit a structured evaluation, including a detailed history, a physical evaluation, and a neurologic evaluation performed by a neurologist for all patients who had participated in the named studies, to arrange for brain magnetic resonance imaging (MRI), and to obtain samples of cerebrospinal fluid, when possible, for all patients. This information was reviewed locally, and patients for whom there were any findings potentially consistent with PML on clinical examination or MRI were referred to the IAC for evaluation. All MRIs were forwarded to one of three reading centers (in London and Basel, Switzerland, for scans of patients with multiple sclerosis and in Amsterdam for patients with Crohn's disease or rheumatoid arthritis) for secondary review. If a reading center found suspicious lesions, cases were forwarded for evaluation to the IAC. Samples of cerebrospinal fluid were sent to laboratories of the National Institutes of Health (NIH) for evaluation.

Diagnostic Criteria

The IAC determined that patients whose evaluation fulfilled all three of the following criteria would receive a diagnosis of confirmed PML: progressive clinical disease, MRI findings typical of PML, and detectable JC virus DNA in the cerebrospinal fluid. Cerebrospinal fluid testing (if not already available) and repeated MRI studies were requested for all patients for whom findings on the neurologic examination were consistent with PML. If follow-up examinations could not be obtained, the IAC considered the diagnosis as indeterminate for PML. The absence of progressive neurologic disease coupled with either lesions on MRI that were not typical of PML or undetectable JC virus DNA in the cerebrospinal fluid was considered sufficient evidence to rule out PML.

Clinical and Imaging Investigation and Criteria

Patients were assessed clinically, including for cognitive, motor, and visual symptoms or signs, and neurologic deterioration was considered potentially consistent with a diagnosis of PML. The MRI protocol consisted of axial T2-weighted sequences and plain and enhanced T1-weighted sequences. Previous MRI studies, for comparison, were generally available for patients with multiple sclerosis but were rarely available for those with Crohn's disease or rheumatoid arthritis. For follow-up examinations, an additional fluid-attenuated inversion recovery sequence was requested.

An ad hoc committee (see Appendix) consisting of five neuroradiologists with experience in the imaging of white-matter diseases, supported by a neurologist with expertise in demyelinating diseases, developed guidelines for the detection by MRI of PML in the presence of multiple sclerosis lesions (Table 1). The guidelines were designed to assist in the diagnosis of PML, although no feature is pathognomonic.

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Table 1. Features Visualized on Magnetic Resonance Imaging to Be Considered in the Differential Diagnosis of Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy.



Laboratory Investigation

Samples of cerebrospinal fluid were independently and concurrently tested for JC virus DNA at two NIH laboratories with use of assays validated by certification by the Clinical Laboratory Improvement Amendment program, in the Laboratory of Molecular Medicine and Neuroscience (LMMN) at the National Institute of Neurological Disorders and Stroke and in the Division of Laboratory Medicine (DLM). The assay performed at the DLM was approximately one order of magnitude less sensitive than that performed at the LMMN because of different methods of DNA template extraction.9,10 The LMMN performed nucleic-acid extraction with the use the QIAamp viral RNA mini-kit (Qiagen), according to the manufacturer's instructions. A starting volume of 200 µl of the sample was extracted and eluted to 50 µl. All samples were assayed in duplicate with the use of 10 µl of DNA template by polymerase chain reaction (PCR) (TaqMan PCR chemistry, Applied Biosystems) and the ABI 7500 sequence-detection system (Applied Biosystems). The locations of the primer and probe, the cycling conditions, and the standard curve design have been described previously.9 The DLM used the MagNa Pure Instrument (Roche) for sample extraction, with a starting volume of 1 ml eluted to 50 µl. A volume of 10 µl of template was used for each reaction, and each sample was run once. The DLM performed quantitative PCR (Rotor-Gene, Corbett Research).

Statistical Analysis

We based our estimate of the risk of PML on the three confirmed cases originally identified and on the 3116 patients in the clinical trials who had been exposed to natalizumab and were clinically evaluated for PML with the use of, at least, a history and a physical examination or MRI designed to rule out PML. The three patients with PML previously reported had received 8, 29, and 37 monthly infusions of natalizumab and had participated in the clinical trials included in our evaluation. The 95 percent confidence interval was calculated with the use of the method for a binomial proportion.

Results

Of the 3826 patients who had participated in the named clinical trials and were recruited for enrollment in this study, 3389 (89 percent) agreed to participate. Of these 3826 patients, 3417 had received natalizumab, and of these patients, the history and either physical examination or MRI were available for 3116 (91 percent). Some patients who had received placebo were recruited, because at the time when this safety evaluation was initiated, the blinding was still maintained in some ongoing trials and because controls were needed for cerebrospinal fluid testing. Of the 3389 patients assessed for PML, MRI scans were available for 2917, and results of cerebrospinal fluid testing were available for 396; 437 patients were excluded (Figure 1).

The majority (2700) of the patients included in the evaluation had received the last dose of natalizumab on or after December 1, 2004. Of the patients with multiple sclerosis, 97 percent had undergone MRI or a neurologic examination within three months after the last dose. Patients who had participated in the clinical trials involving people with Crohn's disease or rheumatoid arthritis were evaluated later, with 27 percent evaluated within three months after the last dose and 91 percent evaluated within six months after the last dose. Patients with multiple sclerosis treated with natalizumab had received a mean of 21.4 infusions and a median of 30 (range, 1 to 41), whereas those with Crohn's disease or rheumatoid arthritis had received a mean of 12.6 monthly infusions and a median of 7 (range, 1 to 39). The mean exposure to natalizumab among all patients included in the evaluation was 17.9 monthly infusions, with a median of 17 (range, 1 to 41). Forty-four patients were referred to the IAC for evaluation (Table 2), and the three cases of PML previously reported were also evaluated by the IAC.

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Table 2. Cases Referred to the Independent Adjudication Committee (IAC) for Evaluation for Progressive Multifocal Leukoencephalopathy (PML).



Table 2 lists the cases and evidence available for evaluation by the IAC. For each case, the IAC reviewed the patient's clinical history, the local neurologist's examination report, the findings on MRI, the results of cerebrospinal fluid testing, and the PCR assay for JC virus DNA. If the IAC did not unanimously find that the evidence was sufficient to rule out PML, then it recommended repeating the MRI and collecting a sample of cerebrospinal fluid, if none was available. Four patients (Cases 1, 2, 3, and 4) had normal clinical examinations, and three (Cases 5, 6, and 7) had examinations that showed stable, known abnormalities; for these seven patients, MRI scans inconsistent with a diagnosis of PML and negative results of cerebrospinal fluid testing for JC virus DNA were reported. For 16 patients (Cases 8 through 23) whose baseline evaluations suggested active neurologic disease, MRI was repeated at a minimum recommended interval between scanning procedures to detect changes consistent with PML on MRI. Eight of these 16 patients also had no detectable JC virus DNA in the cerebrospinal fluid. For 19 other patients (Cases 24 through 42), the history and MRI were not consistent with PML, and a diagnosis of PML was ruled out without cerebrospinal fluid testing for JC virus DNA. One case (Case 43) was referred to the IAC for evaluation because MRI was precluded because of the patient's size. However, the neurologic examination and cerebrospinal fluid testing for this patient with Crohn's disease did not indicate a neurologic disease, and PML was ruled out in the absence of MRI. One patient (Case 44) with a history of progressive multiple sclerosis preceding the use of natalizumab was evaluated on the basis of only a single MRI scan. Recommended repeated MRI and cerebrospinal fluid testing were not performed; the IAC therefore classified this case as indeterminate.

Samples of plasma or serum were collected for exploratory analysis only and not as part of the risk analysis or for use in the diagnosis of PML. However, in one patient (Case 28 in Table 2) in whom the plasma viral load was high (8733 copies per milliliter), a finding of JC virus DNA was reported by the LMMN and the case was reviewed by the IAC at the sponsor's request. Neurologic examination revealed chronic cognitive changes, and the MRI was consistent with old ischemic disease in this 49-year-old man with Crohn's disease and ankylosing spondylitis, who had undergone several bowel-resection procedures. The committee ruled out PML in this case.

The IAC reviewed the records of serious adverse events and deaths that had occurred during the period of the natalizumab trials and within the three to six months after participating patients had received the last dose of natalizumab. Details with respect to adverse events have been published previously11 or are reported elsewhere in this issue of the Journal.7,8 Other than the two previously reported deaths,4,12 no deaths were suspicious for association with PML.

The IAC ruled out PML in 43 of the 44 cases referred to the committee, and 1 case was classified as indeterminate because follow-up examinations could not be obtained. The three previously reported cases of PML (two in patients with multiple sclerosis who had participated in the SENTINEL study [NCT00030966 [ClinicalTrials.gov] ] and one in a patient with Crohn's disease who had participated in both the ENACT-1 and ENACT-2 trials [NCT00032799 [ClinicalTrials.gov] and NCT00032786 [ClinicalTrials.gov] , respectively]) were initially reviewed by the committee. All three cases fulfilled the diagnostic criteria for PML established by the committee and have been described by investigators at their local sites.2,3,4

Estimate of Risk of PML

Of 3116 patients who had participated in the named clinical trials for whom histories and neurologic examinations or MRIs were available for evaluation and who were included in the safety analysis, no new cases were identified. Only the three previously identified cases of PML were confirmed and were included in the estimate of the risk of PML. We estimated that the incidence of PML associated with exposure to natalizumab is 1.0 case per 1000 patients (95 percent confidence interval, 0.2 to 2.8 per 1000) in this population who received a mean of 17.9 monthly doses of natalizumab.

Discussion

After the evaluation of more than 3000 patients who were treated with natalizumab, no new cases of PML were identified. The evaluation was rigorous and careful, but several limitations of this study need to be acknowledged. The assessment of these patients was complicated by the presence of underlying neurologic dysfunction in those who had multiple sclerosis, including lesions on MRI, and by the occurrence of incidental lesions on MRI in those who had rheumatoid arthritis or Crohn's disease.13

The criteria of the IAC for a diagnosis of PML required evidence of active neurologic disability. The possibility that PML might have different clinical behavior in the setting of natalizumab was recognized. The possibility of nonprogressive disease cannot be totally ruled out. However, because the known cases in which treatment with natalizumab was associated with PML were of aggressive disease, the hypothesis that PML in this setting might be clinically and neuroradiologically silent is not suggested by current evidence. It was also recognized that PML might develop in a clinically silent area of the brain.

We used MRI as the most sensitive tool for screening for PML,14 because it has the potential of detecting lesions at an early stage, possibly before they are clinically detectable. Prospective criteria, along with scans obtained before the initiation of treatment which could be used for comparison, resulted in only one referral to the IAC based on MRI from among the population with multiple sclerosis. Incidentally discovered underlying abnormalities in patients with Crohn's disease or rheumatoid arthritis resulted in more MRI-based referrals to the committee, but the application of MRI criteria combined with clinical evidence and the results of cerebrospinal fluid testing made for a small number of referrals of patients from this population. On repeated scanning in suspected cases, no patients with worsening lesions on MRI were found.

Cerebrospinal fluid evidence alone is not sufficient to rule out PML, since it is recognized that JC virus DNA testing, although almost 100 percent specific, is not perfectly sensitive for the pathological diagnosis of PML.15 The absence of detectable JC virus in the cerebrospinal fluid of 396 patients is reassuring with respect to the possibility that smoldering or subclinical PML might be present, since the sensitivity of cerebrospinal fluid detection for PML usually exceeds 90 percent.

One of the limitations of this study results from the collection of data only after the discontinuation of natalizumab. Therapy with the drug was immediately stopped pending safety evaluation. In the setting of the human immunodeficiency virus, the reversal of immunodeficiency effected by potent antiretroviral therapy has been shown in some cases to stop the clinical progression of PML13 and progression on MRI.16 Improved immunodeficiency may result in a decline in JC virus DNA in the cerebrospinal fluid.15 Although the organization of the safety evaluation took several weeks, 97 percent of the patients who had multiple sclerosis and were involved in our study were evaluated within three months after the drug was discontinued. Because natalizumab was thought to be active during this interval, the delay of the evaluation appears unlikely to have greatly diminished the validity of the evaluation. The evaluation was slightly more delayed for patients with Crohn's disease or rheumatoid arthritis, but 91 percent of the evaluations for these patients were accomplished within six months after receipt of the final dose of natalizumab.

The safety analysis performed by the IAC was not designed as a prospective epidemiologic study. We chose to estimate the risk of PML in this setting on the basis of a calculation with the use of the number of cases of PML according to the number of patients exposed to natalizumab who were prospectively examined. We do not know the duration of exposure to natalizumab required to put patients at risk for PML. Patients reported as having a diagnosis of PML had received 8 to 37 monthly infusions, whereas the median exposure in the examined population was 30 infusions among patients with multiple sclerosis and 7 among those with Crohn's disease or rheumatoid arthritis. It is estimated that there have been approximately 5200 patient-years of exposure to natalizumab to date. Our evaluation recruited patients directly from the clinical trials but encouraged referrals from physicians who treated the estimated 7000 commercially treated patients. In our risk analysis, the commercially treated patients and those treated in trials that were not included in our evaluation were not included in the denominator. PML is generally a serious, disabling neurologic disease, and we believe that if cases of PML occurred in these other populations, these cases would probably have been detected. However, we think it is appropriate that our risk estimate was based only on patients who had participated in the clinical trials examined in this study, for three reasons: patients who were not included in this evaluation were not formally assessed for PML; we were not able to ascertain the duration of exposure of commercially treated patients; and most of the patients who had participated in the clinical trials and the commercially treated patients had only brief exposures to natalizumab. Our assessment of the neurologic examinations, MRI studies, and laboratory data for more than 3000 patients exposed to natalizumab confirmed the diagnosis of PML in three patients but did not identify any additional cases.



Supported by the National Institutes of Health (NIH), through the Division of Intramural Programs, for analyses performed at the Laboratory of Molecular Medicine and Neuroscience, the Institute for Neurological Disorders and Stroke, and the Division of Laboratory Medicine Clinical Center. Biogen Idec and Elan Pharmaceuticals provided support for the clinical procedures and magnetic resonance imaging performed and provided some reagents and supplies for laboratory testing.

Drs. Yousry and Clifford report having received reimbursement for time required to perform duties as members of the independent adjudication committee; Drs. Yousry, Miszkiel, and Jäger, reimbursement for activities related to the reading center; Drs. Sanchez and Barkhof, reimbursement for time related to this project; Dr. Radue, grant support from Biogen Idec, Novartis, and Sanofi; and Dr. Clifford, consulting fees from Biogen Idec, Boehringer Ingelheim, Pfizer, and Genzyme, speaker's fees from Bristol-Myers Squibb and Boehringer Ingelheim, and research support from Savient Pharmaceuticals, NeurogesX, Schering-Plough, Roche, Bavarian Nordic, and Pfizer. None of the authors hold a financial interest in Biogen Idec or Elan Pharmaceuticals. None of the authors at the NIH received reimbursement or compensation for this study. No other potential conflict of interest relevant to this article was reported.

We are indebted to the many local investigators and radiologists who provided the data required for this analysis; to the patients involved in the studies who underwent the procedures; and to the many staff members who coordinated the clinical activities and made the data available for review by the independent adjudication committee (IAC).


Source Information

From the Institute of Neurology, Queen Square, London (T.A.Y., K.M., H.R.J.); the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, Md. (E.O.M., C.R., J.H., B.C.); the Department of Laboratory Medicine, NIH Clinical Center, Bethesda, Md. (G.F., S.F.); the Department of Neuroradiology, University of Basel, Basel, Switzerland (N.M.-L., E.-W.R.); the Department of Radiology, Vrije Universiteit Medical Centre, Amsterdam (E.S., F.B.); and the Departments of Neurology and Medicine, School of Medicine, Washington University, St. Louis (D.B.C.).

Drs. Yousry, Major, and Clifford contributed equally to this article.

Address reprint requests to Dr. Major at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Dr., Bldg. 10, Rm. 3B14, Bethesda, MD 20892-1296, or at majorg@ninds.nih.gov.

References


Koralnik IJ. New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 2004;17:365-370. [CrossRef][ISI][Medline]
Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-381. [Abstract/Full Text]
Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369-374. [Abstract/Full Text]
Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-368. [Abstract/Full Text]
Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 2005;64:1336-1342. [Abstract/Full Text]
Adelman B, Sandrock A, Panzara MA. Natalizumab and progressive multifocal leukoencephalopathy. N Engl J Med 2005;353:432-433. [Full Text]
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910. [Abstract/Full Text]
Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911-923. [Abstract/Full Text]
Ryschkewitsch CF, Jensen P, Hou J, Fahle G, Fischer S, Major EO. Comparison of PCR-southern hybridization and quantitative real-time PCR for the detection of JC and BK viral nucleotide sequences in urine and cerebrospinal fluid. J Virol Methods 2004;121:217-221. [CrossRef][ISI][Medline]
Major EO, Ryschkewitsch C, Fahle G, et al. The laboratory evaluation for JC virus DNA in cerebrospinal fluid and plasma from multiple sclerosis patients participating in the phase III clinical trials of natalizumab. Mult Scler 2005;11:Suppl 1:s181-s181.
Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 2005;353:1912-1925. [Abstract/Full Text]
Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy, natalizumab, and multiple sclerosis. N Engl J Med 2005;353:1745-1745.
Geissler A, Andus T, Roth M, et al. Focal white-matter lesions in brain of patients with inflammatory bowel disease. Lancet 1995;345:897-898. [CrossRef][ISI][Medline]
Whiteman ML, Post MJ, Berger JR, Tate LG, Bell MD, Limonte LP. Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical and pathologic correlation. Radiology 1993;187:233-240. [Abstract]
Yiannoutsos CT, Major EO, Curfman B, et al. Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy. Ann Neurol 1999;45:816-821. [CrossRef][ISI][Medline]
Thurnher MM, Post MJ, Rieger A, Kleibl-Popov C, Loewe C, Schindler E. Initial and follow-up MR imaging findings in AIDS-related progressive multifocal leukoencephalopathy treated with highly active antiretroviral therapy. AJNR Am J Neuroradiol 2001;22:977-984. [Abstract/Full Text]
Appendix
The independent adjudication committee included the following members: E.O. Major, neurovirologist and committee chair (National Institutes of Health, Bethesda, Md.); T.A. Yousry, neuroradiologist (Institute of Neurology, Queen Square, London); and D.B. Clifford, clinical neurologist (School of Medicine, Washington University, St. Louis). The members of the ad hoc committee that developed guidelines for the detection on magnetic resonance imaging of progressive multifocal leukoencephalopathy in the presence of multiple sclerosis lesions were the following neuroradiologists — T.A. Yousry, H.R. Jäger (Institute of Neurology, Queen Square, London); E.-W. Radue, N. Mueller-Lenke (University of Basel, Basel, Switzerland), and M.A. van Buchem (Leiden University Medical Center, Leiden, the Netherlands). They were supported by neurologist D.H. Miller (Institute of Neurology, London).






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N Engl J Med 2006; 354:2387-2389, Jun 1, 2006. Correspondence


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agate
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PostPosted: Wed Aug 30, 2006 8:43 am    Post subject: Financial aid for Tysabri Reply with quote

Quote:
Financial Assistance for MS Patients

Here is some information for MS patients on getting financial assistance with the expense of Tysabri and other MS drugs, and for those who want to make a tax deductible donation to assist MS patients.

For MS patients who may want to be evaluated for the new MS drug Tysabri, you must first qualify for Tysabri under its labeling and get enrolled in the TOUCH program through a TOUCH-enrolled neurologist. If you do not have a TOUCH-enrolled neurologist, within the next few weeks Biogen's MS ActiveSource program (1-800-456-2255) will be set up to give you several nearby TOUCH-enrolled neurologists organized by ZIP Code. Once you have been examined by a TOUCH-enrolled neurologist, obtained your required baseline MRI and have been enrolled in the TOUCH program, you will be assigned a Case Manager by Biogen through their MS ActiveSource program. The Case Manager will assist you and your neurologist with insurance reimbursement issues, including insurance co-payment assistance or with getting free Tysabri if you do not have insurance.


This information below is also applicable to those seeking assistance with the cost of other MS drugs.

Co-payment Assistance:


While MS Patients For Choice is getting itself organized as a 501(c)(3), there is an existing organization that can assist MS patients who need assistance with Tysabri co-payments, the National Organization for Rare Diseases.


Here is their contact information:


NORD MS Premium /Co-Payment Assistance Program
Conditions:
Multiple Sclerosis
Contact:
1-800-634-7207
NORD MS Medicare Co-Payment Assistance Program
Conditions:
Multiple Sclerosis (MS)
Contact:
1-866-924-0100

Free Tysabri for the Uninsured and Under Insured:

Biogen may be agreeable to making free Tysabri available to those patients who are uninsured and under insured. Work with your Case Manager at MS ActiveSource to pursue this route.

How Others Can Help:

NORD is in discussions with Biogen about setting up a fund specifically for Tysabri co-payments for privately insured patients. However, it is against the law for such a fund to be set up specifically earmarked for Tysabri for Medicare and Medicaid patients, and most drug companies are reluctant to contribute to a general fund for MS patients as those funds can be used for the competitors' drugs (who may not be making similar contributions). However, individuals can make contributions that are earmarked for co-payment assistance for a specific drug, so here is a link to the NORD website to make such a tax deductible contribution: http://www.rarediseases.org/helping/donate

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lady_express_44



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PostPosted: Wed Aug 30, 2006 8:45 am    Post subject: Reply with quote

Thanks for posting that Agate!
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PostPosted: Sun Sep 03, 2006 2:40 pm    Post subject: Infusion site locations available Reply with quote

The website www.MSPatientsForChoice.org now has updated information, including Google maps for all of the US ZIP Code ranges so you can look for the closest TOUCH-enrolled Tysabri infusion sites.

There are about 500 TOUCH-enrolled Tysabri infusion sites, with about 100 being added each week.

If you know how to navigate Google maps, you won't have a problem with these. You can drag the map with your mouse, or use the scale in the upper left (or the wheel if your mouse has a wheel) to zoom in or out. You can zoom in all the way to see the precise location of a particular clinic. Use the "Hybrid" button in the upper right to see an aerial photo with a street map.

You can click on any of the infusion sites listed on the left side see the precise location. Here is a link to the page with the infusion site maps:

http://www.mspatientsforchoice.org/in.htm
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PostPosted: Thu Sep 28, 2006 7:20 pm    Post subject: (Abstract) Tysabri effect on brain atrophy & cognition Reply with quote

From the 22nd Congress of ECTRIMS, September 27-30, 2006, in Madrid:

Quote:
Immunomodulation - Part I

Thursday, September 28, 2006

The effects of natalizumab on brain atrophy and cognitive function: results from the AFFIRM study

E. Fisher, P.W. O'Connor, E. Havrdova, M. Hutchinson, L. Kappos, D.H. Miller, J.T. Phillips, C.H. Polman, F.D. Lublin, G. Giovannoni, A. Wajgt, R.A. Rudick, F. Lynn, M.A. Panzara, A.W. Sandrock for the AFFIRM and SENTINEL Investigators

Studies have shown that brain atrophy correlates with cognitive change in multiple sclerosis (MS) patients. The efficacy and safety of natalizumab (TYSABRI), an alpha4-integren antagonist, were evaluated in a randomized, double-blind, placebo-controlled phase 3 trial (the AFFIRM study).

Results from AFFIRM showed that natalizumab significantly reduced the cumulative probability of sustained disability progression and annualized relapse rate over 2 years compared with placebo. On MRI, there were 92% fewer gadolinium-enhancing lesions and 83% fewer new or enlarging T2-hyperintensities in the natalizumab group compared with placebo. Changes in brain parenchymal fraction (BPF) (a normalized measure of whole brain atrophy) and scores on the 3-second Paced Auditory Serial Addition Test (PASAT 3) (a measure of cognitive function) were additional pre-specified end points in AFFIRM.

There were 942 patients randomized to natalizumab (n=627) or placebo (n=315). During Year 1, the mean percent change in BPF was significantly greater with natalizumab compared with placebo (-0.558 vs -0.395, p=0.002). In contrast, during Year 2, mean percent change in BPF was significantly less in the natalizumab group compared with placebo (-0.242 vs -0.427, p=0.004).

Natalizumab significantly reduced the proportion of patients with worsening (0.5 standard deviation decrease) in PASAT 3 score sustained for 12 weeks by 43% compared with placebo (hazard ratio [95% confidence interval] = 0.57 [0.37, 0.89]; p=0.013). A positive correlation was observed between change in BPF and time to sustained worsening of cognitive function over 2 years in placebo patients (SRCC=0.213, p=0.0004).

In natalizumab patients, there was no correlation between BPF change and time to sustained worsening of cognitive function (SRCC=0.014, p=0.734). Natalizumab significantly reduced brain atrophy during the second year of treatment and significantly improved cognitive function.

Consistent with previous studies, brain atrophy was correlated with worsening cognitive function in the placebo group. The dissociation between atrophy and cognitive function in the natalizumab group indicates that the increased atrophy rate in the first year may be due to resolution of edema rather than actual tissue loss, which would be consistent with the dramatic reduction in active lesions. Correlations broken down by year and the kinetics of BPF change in Year 1 are currently under investigation.
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PostPosted: Fri Sep 29, 2006 11:53 am    Post subject: Reply with quote

Hi Agate,

Thanks for this informative thread and all who've contributed!

I am thinking about asking my doctor about it when I see him a month from now, because in many ways, I am getting worse I think, but very gradually.

Maybe he'll have a change of heart about it since it has been reapproved. I know they are doing infusions there, so we'll see what he says.

I am having so much pain now, and I think it's maybe in part from the Copaxone.

I'll be sure to report back with what he says, and I'll try to write down any details so it doesn't go in one ear and out the other. scratch

BTW, I did not handle the interferons well at all either, so I assume I would be eligible.
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Ewizabeth
DX 01/28/03 RRMS
Formerly Avonex, Rebif & Copaxone
Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Fri Sep 29, 2006 12:30 pm    Post subject: Reply with quote

Does anyone know the stat for Tysabri on the "slowing of progression"?

I know the secondary outcome for the trials (reduced number of relapses) looked very encouraging, but I don't recall the stats for "reducing disease progression" to be significantly favourable.

Cherie
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PostPosted: Fri Sep 29, 2006 1:50 pm    Post subject: Reply with quote

Maybe this will help a little:

From ECTRIMS, Madrid, September 29, 2006:

Quote:
Friday, September 29, 2006

Results of clinical and magnetic resonance imaging analyses following cessation of natalizumab dosing in patients with multiple sclerosis

P.W. O'Connor, A. Goodman, L. Kappos, F.D. Lublin, D.H. Miller, C.H. Polman, R.A. Rudick, F. Lynn, M.A. Panzara, A.W. Sandrock for the AFFIRM and SENTINEL Investigators


Natalizumab is a selective alpha4-integrin antagonist that significantly reduced annualized relapse rate and magnetic resonance imaging (MRI)-detectable brain lesion development in patients with relapsing multiple sclerosis (MS) during phase 3 studies. Dosing of natalizumab was voluntarily suspended when 3 cases (2 in MS and 1 in Crohn’s disease) of progressive multifocal leukoencephalopathy (PML) were reported during natalizumab therapy.

This paper reports annualized relapse rate and the number of gadolinium-enhancing (Gd+) lesions over time following suspension of natalizumab dosing. Patients who completed AFFIRM, SENTINEL, or GLANCE studies were eligible to participate in an open-label extension study that evaluated the long-term safety and tolerability of natalizumab. SENTINEL and the open-label extension study were terminated early due the voluntary suspension of natalizumab.

All patients who received natalizumab were examined by physicians at a dose-suspension safety evaluation; at this evaluation, patients were also assessed for adverse events and had a cranial MRI scan.

In addition, patients who participated in the safety-extension study continued with follow-up visits every 3 months for up to 12 months. At these visits, and at unscheduled visits during this time, relapses were assessed. The annualized relapse rate was 0.175 (n=1866; 95% CI: 0.114, 0.259) during the 1st month post dosing, 0.262 (n=1853; 95% CI: 0.184, 0.361) during the 2nd month post dosing, and 0.270 (n=1839; 95% CI: 0.191, 0.371) during the 3rd month post dosing, peaking at 0.64 (n=1756; 95% CI: 0.51, 0.79) during the 7th month post dosing; at no time did it exceed the placebo/Avonex control relapse rate during the 2nd year of the AFFIRM and SENTINEL studies (0.67). The mean number (± SD) of Gd+ lesions was 0.1 (± 0.4) at 2–3 months post dosing (n=147), 0.4 (±1.1) at >3–4 months post dosing (n=65), and 1.0 (± 3.2) at >4–6 months post dosing (n=70); the number of Gd+ lesions was lower than the baseline (pre-dose) number of Gd+ lesions (1.5 [± 4.2]; n=339) for 6 months post dosing.

These findings are consistent with pharmacodynamic data showing that both alpha4-integrin saturation levels and lymphocyte counts return to baseline within 12 to 16 weeks. Consistent with the results of a phase 2 study of natalizumab in MS, which was designed to specifically test for rebound, clinical and MRI data indicate the absence of a rebound effect after cessation of natalizumab dosing.
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PostPosted: Fri Sep 29, 2006 7:02 pm    Post subject: Reply with quote

This might help with your question, Cherie. It sounds as if they don't exactly know how Tysabri affects disease progression. I highlighted the part of this article that seems to say that. It's a different summary of the study cited in my previous post, apparently:

Quote:
New Data on TYSABRI(R) Presented at ECTRIMS Congress Demonstrate Significant Improvement in Cognitive Function in Patients with Multiple Sclerosis

28.09.2006 13:30:00



Biogen Idec (NASDAQ: BIIB) and Elan Corporation, plc (NYSE: ELN) announced today that data from the Phase III AFFIRM monotherapy study demonstrated that treatment with TYSABRI® (natalizumab) significantly reduced the proportion of multiple sclerosis (MS) patients with worsening cognitive function as measured by the 3-second Paced Auditory Serial Addition Test (PASAT 3).

These data, presented at the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Madrid, Spain, contribute to existing data which demonstrate the overall therapeutic benefits of TYSABRI, including its significant impact on relapse reduction, disability progression and MRI measures.

TYSABRI has demonstrated a 68% relative reduction in the annualized relapse rate compared to placebo and a 42% reduction in the relative risk of disability progression, as published in the New England Journal of Medicine. Cognitive deficits are under-recognized and often misdiagnosed as depression, stress or other personality disorders. Studies have shown that approximately 43% to 65% of MS patients show measurable cognitive impairment in formal testing.1 Cognitive dysfunction can occur early in MS and in patients with relatively mild physical disability. These deficits have a substantial effect on the daily functioning of patients. Areas impacted by cognitive dysfunction include memory, ability to process information and learning. 1,2

The AFFIRM study was a two-year, randomized, multi-center, placebo-controlled, double-blind study of 942 patients conducted in 99 sites worldwide, evaluating the effect of TYSABRI on the progression of disability and the rate of clinical relapses. Evaluating the effect of TYSABRI on cognitive function was a pre-specified endpoint of the AFFIRM study. Cognitive function was assessed using the 3-second Paced Auditory Serial Addition Test (PASAT 3), a test of auditory information processing.

The study showed that treatment with TYSABRI reduced the risk of sustained cognitive worsening by 43% (p=0.013) when compared to placebo. These cognitive function data complement the previously presented results of the AFFIRM study, which demonstrated a significant effect of TYSABRI on two-widely accepted health-related quality of life measures, the Short Form-36 Health Survey and the Visual Analogue Scale. "Neuropsychological dysfunction significantly diminishes quality of life in many patients with multiple sclerosis, impacting everything from employment to social interaction. It is responsible for much hardship experienced by MS patients. The important positive effects of TYSABRI on cognitive functioning and quality of life add to the important benefits already reported on progression of disability and relapses. This provides strong evidence that observed neurologic benefits translate into important improvements as perceived by the patients,” said Richard Rudick, MD, Director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

About TYSABRI In the US, TYSABRI is approved as a monotherapy treatment for relapsing forms of MS. TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Patients should be monitored at regular intervals for any new or worsening signs or symptoms suggestive of PML. Because of the increased risk of PML, TYSABRI is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, alternate MS therapies. It is available in the US only through a restricted distribution program called the TOUCH Prescribing Program.

According to product labeling, after two years, TYSABRI treatment led to a 67% relative reduction (p<0.001) in the annualized relapse rate compared to placebo and reduced the relative risk of disability progression by 42% (p<0.001).

TYSABRI treatment also resulted in sustained and statistically significant reductions in brain lesion activity as measured by MRI. Changes in MRI findings often do not correlate with changes in the clinical status of patients (e.g., disability progression). The prognostic significance of the MRI findings in these studies has not been evaluated.

In the European Union, TYSABRI is indicated as a single disease-modifying therapy in highly active relapsing-remitting MS patients. Because of the increased risk of PML, it is for patients with high disease activity despite treatment with a beta-interferon or in patients with rapidly evolving severe relapsing-remitting MS.

According to product labeling in the EU, after two years, TYSABRI treatment led to a 68% relative reduction (p<0.001) in the annualized relapse rate compared to placebo and reduced the relative risk of disability progression by 42-54% (p<0.001). Serious adverse events that occurred in TYSABRI-treated patients included hypersensitivity reactions (e.g., anaphylaxis), infections, depression and gallstones.

In MS trials, the incidence and rate of other serious and common adverse events, including the overall incidence and rate of infections, were balanced between treatment groups. Herpes infections were slightly more common in patients treated with TYSABRI.

Serious opportunistic and other atypical infections have been observed in TYSABRI-treated patients, some of whom were receiving concurrent immunosuppressants. Common adverse events reported in TYSABRI-treated patients include headache, fatigue, infusion reactions, urinary tract infections, joint and limb pain, lower respiratory infections, rash, gastroenteritis, abdominal discomfort, vaginitis, and diarrhea.

For more information about TYSABRI please visit http://www.tysabri.com, http://www.biogenidec.com or http://www.elan.com, or call 1-800-456-2255.

1 Rao SM, et al. Neurology. 1991;41:685-691 2 Amato MP, et al. Arch Neurol. 1995;52:168-172
-bw-






(From http://boerse.finanzen.net/news/news_detail.asp?NewsNr=433360)
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PostPosted: Mon Oct 09, 2006 2:08 pm    Post subject: Extract of an article Reply with quote

This is an extract from an article appearing in Archives of Neurology.


Quote:
Vol. 63 No. 10, October 2006







Natalizumab and Immune Cells

Arch Neurol. 2006;63:1366-1367.


Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.



Understanding the mechanisms underlying the unfortunate occurrence of progressive multifocal leukoencephalopathy (PML), a disease caused by reactivation of the JC polyomavirus, in a small subset of patients during treatment of autoimmune disease with natalizumab is important at several levels. The most important and immediate outcome would be a more complete appreciation of the risk of PML, not only with natalizumab therapy but also with other immunomodulatory therapeutic strategies currently in development.

The second most important outcome would be the potential for the development of approaches for monitoring patients treated with natalizumab and other therapies that may have similar risks, in turn allowing for the safer use of these treatments.

Finally, an understanding of the mechanism(s) contributing to the association of PML with natalizumab therapy may provide new insights into the disease processes in multiple sclerosis and PML.

Two general mechanisms have been suggested to explain the association between natalizumab treatment . . .






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PostPosted: Mon Oct 09, 2006 2:16 pm    Post subject: Reply with quote

Here is an abstract from Archives of Neurology, October 2006:

Quote:
Vol. 63 No. 10, October 2006



Altered CD4+/CD8+ T-Cell Ratios in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis

Olaf Stüve, MD, PhD; Christina M. Marra, MD; Amit Bar-Or, MD; Masaaki Niino, MD; Petra D. Cravens, PhD; Sabine Cepok, PhD; Elliot M. Frohman, MD, PhD; J. Theodore Phillips, MD, PhD; Gabriele Arendt, MD; Keith R. Jerome, MD, PhD; Linda Cook, PhD; Francois Grand'Maison, MD; Bernhard Hemmer, MD; Nancy L. Monson, PhD; Michael K. Racke, MD


Arch Neurol.
2006;63:1383-1387.

Background Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an 41 integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection.

Objective To test the effect of natalizumab treatment on the CD4+/CD8+ T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.

Design
Prospective longitudinal study.

Setting Academic and private multiple sclerosis centers.

Patients Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus–infected patients.

Main Outcome Measures CD4+ and CD8+ T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound 4 integrin on peripheral blood CD4+ and CD8+ T cells was analyzed before and after natalizumab therapy.

Results Natalizumab therapy decreased the CSF CD4+/CD8+ ratio of patients with MS to levels similar to those of human immunodeficiency virus–infected patients. CD4+/CD8+ ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4+/CD8+ ratios normalized. The expression of unbound 4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4+ vs CD8+ T cells.

Conclusions
Natalizumab treatment alters the CSF CD4+/CD8+ ratio. Lower expression of unbound 4 integrin on CD4+ T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.


Author Affiliations: Department of Neurology (Drs Stüve, Cravens, Frohman, Monson, and Racke) and Center for Immunology (Drs Monson and Racke), University of Texas Southwestern Medical Center at Dallas; Neurology Section, VA North Texas Health Care System, Medical Service, Dallas (Dr Stüve); Departments of Neurology (Dr Marra) and Laboratory Medicine (Drs Jerome and Cook), University of Washington, Seattle; Department of Neurology and Neurosurgery, Montreal Neurological Institute (Drs Bar-Or and Niino), and Department of Microbiology and Immunology (Dr Bar-Or), McGill University, Montreal, Quebec; Fred Hutchinson Cancer Research Center, Seattle (Drs Jerome and Cook); Department of Neurology, Heinrich Heine University, Düsseldorf, Germany (Drs Stüve, Cepok, Arendt, and Hemmer); Multiple Sclerosis Center at Texas Neurology, Dallas (Dr Phillips); and MS Clinic l'Hôpital Charles LeMoyne, Montreal (Dr Grand'Maison).






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PostPosted: Tue Oct 24, 2006 2:59 pm    Post subject: Reply with quote

This was in the Boston Globe, online edition, 10/24/06:

Quote:
Doctors appear wary of Tysabri
By Reuters | October 24, 2006

Doctors are proving more leery than many had expected about prescribing the multiple sclerosis drug Tysabri, which was relaunched in July after being suspended because of safety concerns.

Over the past month or so, analysts have reduced their 2006 sales forecasts as it becomes clear that doctors wary of the risk of the rare but potentially fatal brain disease PML are reserving the drug as a last resort.

The drug, which is made by Biogen Idec Inc. and Irish partner Elan Corp. PLC, had been expected by some analysts to generate sales this year of more than $100 million, but that figure has dropped dramatically.

Ian Hunter, an analyst at Goodbody stockbrokers in Dublin, said yesterday he has cut his full-year Tysabri forecast to $25.7 million from $78 million, in part because of continuing safety concerns and the complexity of reimbursement systems in Europe.

A survey of 63 neurologists conducted by Reuters Primary Research indicates that in 2006 Tysabri will be used in less than 1 percent of MS patients -- translating into revenue of under $30 million.

Since July, only 47 of more than 8,500 patients treated by the physicians surveyed by Reuters had used Tysabri, even though more than 700 patients had discussed using it, according to the report.

And more than 75 percent of the patients who had used Tysabri prior to its 2005 suspension have decided not to use it since its reintroduction, the survey showed.

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PostPosted: Wed Oct 25, 2006 3:13 am    Post subject: Reply with quote

Quote:
And more than 75 percent of the patients who had used Tysabri prior to its 2005 suspension have decided not to use it since its reintroduction, the survey showed.


Maybe that article should read "Patients wary of Tysabri".
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PostPosted: Thu Nov 02, 2006 12:39 pm    Post subject: More on the NMSS Webcasts Reply with quote

Quote:


November 2006



Please join us for the second video webcast in a two- part series discussing the recently reapproved therapy for MS - Tysabri.

Tysabri: What You Need to Know
A Look at the Infusion Process


Our presenter is John Richert, MD, Vice President of the National MS Society's Research and Clinical Programs Department. Dr. Richert earned his B.A. from Cornell University, then an M.D. from the University of Rochester Medical School. He did his residency in medicine at the University of Rochester, served in the U.S. Air Force for two years, and did another residency in neurology at the Mayo Clinic. Dr. Richert then pursued his interest in myelin and immunology by accepting a postdoctoral fellowship from the National MS Society, conducting studies at the National Institutes of Health for several years before joining the faculty at Georgetown University in 1980.

This webcast will focus on:

Preparing for a Tysabri infusion

What to expect during the infusion

Is Tysabri right for me?


Click here to go to this webcast:

http://skins.broadbandvideo.com/nmss/event.asp?showid=36703&clipid=36703


This webcast is pre-recorded and may be played at any time.

Please note if you have a pop-up blocker on your computer, you will need to disable it prior to participating in an MS Learn Online webcast.


Upcoming Webcasts

November 9 - Positive Relationships: At Home and at Work with MS

November 16 - Positive Relationships: Care Partners







Funding for this program was provided as an unrestricted educational grant from several National MS Society chapters.




Email: mslearnonline@nmss.org
Web: http://www.nationalmssociety.org





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PostPosted: Thu Nov 23, 2006 6:25 pm    Post subject: (Abstract) Medical student with MS can't get Tysabri Reply with quote

From PubMed, 11/23/06:

Quote:
Ann Neurol. 2006 Nov 21;60(5):A10-A11

Recombinant therapeutics: From bench to bedside (if your health plan concurs)

Hauser SL, Johnston SC.

A talented medical student at our institution was recently diagnosed with multiple sclerosis (MS). Beta interferon was prescribed; however, her annual cap from student health insurance coverage for outpatient drug expenses is only $3,000, a sum that would be exceeded within 3 months and leave her without coverage for symptomatic medications also required for her care.

Unable to pay for the treatment from personal resources, she qualified to receive beta interferon without cost from a universal access program established by the manufacturer. Unfortunately, it was evident within a few months that she had a poor therapeutic response, so her physician prescribed natalizumab.

Her health care plan requires that infusion therapy be given at the hospital's infusion center, yet for various reasons, the drug was not yet approved by the formulary. She remains unable to receive the drug.

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PostPosted: Fri Nov 24, 2006 2:46 pm    Post subject: (Abstract) Review of PML and Tysabri Reply with quote

From PubMed, November 24, 2006:

Quote:
Neurologist. 2006 Nov;12(6):293-298.

Review of Progressive Multifocal Leukoencephalopathy and Natalizumab

Aksamit AJ.
From the Mayo Clinic College of Medicine, Department of Neurology, Rochester, Minnesota.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML), a destructive demyelinating infection which lytically infects oligodendrocytes, has occurred in patients treated with natalizumab [Tysabri]. Magnetic resonance imaging (MRI) scan imaging of the brain gives clues to diagnosis but is nonspecific in distinguishing multiple sclerosis from PML. Spinal fluid detection of JC virus is specific but incompletely sensitive. Associated immunosuppression is typically of the cell-mediated type but can be poorly defined on clinical grounds.

REVIEW SUMMARY: It is apparent that natalizumab is a predisposing factor for developing PML from the 3 cases of natalizumab-treated patients. There is no reliable presymptomatic way to detect PML or JC virus infection of the brain by virologic or imaging surveillance techniques.

One patient with multiple sclerosis and natalizumab treatment has survived, indicating that withdrawal of antibody, possibly in combination with antiviral therapy, may permit survival. However, immune reconstitution disease is a risk after immune restoration and withdrawal of natalizumab. PML deficits would be expected to be permanent. The estimate of incidence of PML in natalizumab-treated patients is 1 per 1000. The duration of natalizumab treatment may be an independent risk factor for development of PML.

CONCLUSION: PML, a usually fatal neurologic infection, should be considered as a risk factor when using natalizumab. The treatment of multiple sclerosis patients with natalizumab is a matter of informed risk, individualized for each multiple sclerosis patient.

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PostPosted: Tue Nov 28, 2006 4:39 pm    Post subject: (Article) Doctors use caution with Tysabri Reply with quote

From the Multiple Sclerosis Foundation Internet Newsletter, November 2006:

Quote:
DOCTORS USE CAUTION WITH TYSABRI®

Doctors are proving more cautious than expected about prescribing Tysabri, which was re-launched in July after being suspended due to safety concerns.

A Reuters Primary Research survey of 63 neurologists indicates that Tysabri will be used in less than 1 percent of MS patients during 2006.

Since July, only 47 of more than 8,500 patients treated by physicians surveyed had used Tysabri, despite the fact that more than 700 patients had discussed using it.

The survey also showed that more than 75 percent of the patients who had used Tysabri prior to its suspension have decided not to use it since its reintroduction.

"At our center, we recommend Tysabri cautiously," confirms Dr. Roger Williams, Medical Director of the Northern Rockies MS Center in Billings, Montana. "Initially, we may have considered Tysabri as first-line therapy for relapsing-remitting MS. Now, we use it for patients with breakthrough disease after one or two of the C-R-A-B drugs. Hence, it now competes with Novantrone and Cytoxan as a potentially more aggressive and effective therapy, but one that is risky, riskier than the C-R-A-B drugs but comparable to chemotherapy. We have enrolled eight patients for Tysabri. All patients have been pre-approved by third party payers. However it may take three to four months to work out the glitches of reimbursement."

"I am also being cautious with Tysabri," adds Dr. Ben Thrower, Medical Director of the MS Center at Shepherd Center in Atlanta, Georgia. "I use it in individuals who have failed the A-B-C-R drugs and who have aggressive enough disease to warrant the risk. The problem is that we really don't know what the true, long-term risk of PML will be. We work with a little over 2,000 people with MS, but only consider about 17 of them to be Tysabri candidates."

Another issue may be the 'Touch' Program, a special training required for physicians prescribing and personnel administering Tysabri. "I have yet to be 'touched' by Biogen-Idec so I cannot prescribe Tysabri yet," says Dr. Greg Zarelli, Staff Physician in the Department of Neurology at Kaiser-Permanente NW in Clackamas, Oregon.


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PostPosted: Tue Nov 28, 2006 7:52 pm    Post subject: Reply with quote

Agate,

This sounds sort of typical I guess from what I've been reading lately. My doctor works in an MS clinic and has about a thousand patients. Only about 15 of them are on Tysabri. He's being very cautious, and is careful to warn about the risks.
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PostPosted: Fri Dec 01, 2006 3:08 pm    Post subject: (Abstract) Natalizumab [Tysabri] Reply with quote

From PubMed, 12/1/06:

Quote:
Drugs Today (Barc). 2006 Oct;42(10):639-55

Natalizumab


Berger JR.
Department of Neurology, University of Kentucky College of Medicine, Kentucky Clinic, Lexington, Kentucky, USA. jrbneuro@uky.edu.

Medical therapeutics has entered a new and exciting era with the development of biological agents that target specific sites. In the studies performed to date, natalizumab, a humanized monoclonal antibody to alpha4 integrin, when administered intravenously at monthly intervals, appeared to be highly beneficial with respect to decreasing both relapse rate and contrast-enhancing lesions in multiple sclerosis. Salutary actions on other disease parameters were also observed.

However, treatment with natalizumab was complicated by the development of a rare demyelinating disease of the brain - progressive multifocal leukoencephalopathy (PML) - that developed in three patients in clinical trials of the drug. Currently, the estimated incidence for the development of PML with natalizumab treatment is 1:1,000 after approximately 18 months of therapy; however, as the development of PML is a stochastic event, it is quite possible that higher rates will be observed after longer treatment courses.

Curiously, other opportunistic infections were not observed at higher rates in the treated groups when compared to controls, suggesting a specific association between natalizumab, and perhaps other alpha4 integrin blockers, and PML. Postmarketing surveillance studies should answer this and other questions related to the use of natalizumab
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PostPosted: Wed Dec 13, 2006 10:05 am    Post subject: (Article) NHS Scotland rejects Tysabri Reply with quote

Quote:

Wednesday, 13th December 2006
Health

Tue 12 Dec 2006

NHS Scotland rejects use of new drug for MS

Multiple sclerosis campaigners expressed dismay yesterday as a breakthrough treatment for the disease was rejected for use on the NHS in Scotland.

On Saturday, The Scotsman reported that the Scottish Medicines Consortium (SMC) had decided not to recommend the drug Tysabri.

The drugs rationing body confirmed its stance yesterday, meaning about 1,000 Scottish MS patients are unlikely to receive the treatment on the NHS.

Many will instead opt to pay the £15,000-a-year cost themselves in efforts to improve their quality of life.

Chris Jones, chief executive of the MS Trust, said: "We share the sadness of Scots with MS at this decision, particularly those for whom Tysabri offered their only chance of holding back this cruel disease.

"Clinicians will be prevented from prescribing an effective licensed treatment to people in need.

"We urge people with MS to continue fighting for Tysabri on an individual basis."

In delivering its verdict, the SMC said that the economic case for Tysabri had not been demonstrated.

Mark Hazelwood, director of the MS Society Scotland, said: "No other drug has shown this potential to reduce disability, and any short-term savings are likely to be outpaced by the devastating financial costs of living with severe, progressive disability - not to mention the emotional costs to people with MS and their friends and families."

SNP MSP Tricia Marwick, an MS campaigner, said she was "deeply disappointed" by the decision on Tysabri.

This article: http://news.scotsman.com/health.cfm?id=1842272006
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PostPosted: Wed Dec 13, 2006 3:59 pm    Post subject: An editorial opposing Scotland's NHS decision Reply with quote

From The Herald (UK), December 12, 2006:

Quote:
Cost v quality of life

Editorial Comment December 12 2006

The first known case of multiple sclerosis (MS) was described in 1396. The patient was an ice skater in the Low Countries, now the Netherlands. This guaranteed the country a place in medical history. Scotland has, unfortunately, written itself into the MS textbooks because it has the highest proportion of people suffering from the degenerative condition in the world. Why this should be so is not clear. MS has ill-defined genetic links that do not point to a recognisable hereditary pattern. But it seems there might be links between climate, the effects of smoking and MS.

Since science has yet to uncover what causes MS, a process which, when successfully completed, should open the door on a cure, it is imperative that treatments are developed and made available to improve the outlook for patients (in Scotland there are more than 10,400 with the condition). Drugs are available on prescription that reduce the frequency and severity of attacks. One drug, Tysabri, has been licensed for use in Britain, the United States and Europe which has been proved to be effective in alleviating the impact of some of the most severe forms of MS. It is estimated that some 10% of MS sufferers in Scotland could benefit from receiving Tysabri on prescription.

However, the Scottish Medicines Consortium (SMC) decided yesterday that the drug should not be prescribed on the NHS. Its reasons were economic. Tysabri costs some £15,000 a year for each patient. Prescribing the drug would present the NHS with an annual bill in the region of £15m. It is a significant amount of money, even for a health service that, in a year or two, will benefit from an annual investment of £10bn. But it must demonstrate it can make each penny count for patients. It does not do so by throwing money around irresponsibly.

Economics, the dismal science, led the SMC to conclude that there is more to be lost than gained from an account that prescribed Tysabri. The decision can be questioned, on several counts. Standard MS treatments cost about £8000 for each patient. The climb to £14,690 for each of the limited number of patients who would benefit from Tysabri would not be so steep or onerous as might initially appear to be the case. Any book-keeping exercise should also take account of the cost, financial and emotional, of caring for patients with the form of MS that threatened to run out of control. The burden of care falls on relatives of the patients as well as the state.

Were these factors taken into full account? Tysabri has been shown to work in treating people who have failed to improve with interferon (prescribed) and who have rapidly-developing MS. In most cases it has a positive physical and psychological impact that rubs off on the families of sufferers. It has been approved for treatment in some countries. Given the high incidence of MS in Scotland, there is a strong case for that happening in this country for those with the severe forms of the condition.

Graeme Brown, of Linlithgow, is a sufferer, but a chemotherapy drug has given him the independence, confidence and reassurance to lead as normal a life as possible; certainly a much better life than without the treatment. However, its toxicity means he can receive it for only another year. Tysabri would be the obvious alternative. But the SMC's advice means a door that should have been open has been closed in his face. He cannot understand this. Nor can we. Is it possible, in such circumstances, to put a price on quality of life? The decision is short-sighted.



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PostPosted: Sat Dec 16, 2006 7:34 pm    Post subject: Reply with quote

This came to me in an MS newsletter I receive. The source is identified only as "a Tysabri advocate." Its content seemed important enough to post it even though the source isn't clearly identified.

Quote:
... I just want to forewarn you so we can all react in an appropriate way if/when the following eventuality occurs.

I do want to alert you to something I heard, though, that there is concern that false or unconfirmed reports of PML may be introduced, sponsored by hedge funds or even the MS competitors, in an attempt to scare patients. Under the TOUCH program, Biogen and Elan know every patient that is taking Tysabri, as they all need to be enrolled in TOUCH, together with all prescribing neurologists and infusion clinics. Everyone involved with each patient is obligated to follow the protocol in the TOUCH program, including reporting all cases of suspected PML to Biogen and then the FDA. Therefore, unlike the suspected (and subsequently proven false) cases of PML reported in the media during the summer of 2005, any suspected cases will be fully investigated and appropriate action taken before they should be reported publicly.


Also, we should all remember that even though we hope there will be no cases of PML, FDA and its independent expert Tysabri Advisory Committee estimated an acceptable level of risk of 1 in 1,000 patients, and fully anticipate that there will be PML cases. Their approval process is predicated on that level of risk, and FDA has stated that it will not review the approval of Tysabri unless PML is encountered in larger numbers than 1 in 1,000 patients (or other adverse effects are encountered that rise above known levels of risk, and change the overall risk/benefit assessment).

Thus, if there is an average number of MS patients on Tysabri in 2007 of 25,000, a year or two after they begin dosing, FDA is aware that there may be 10, 15 or even 25 cases of PML, even though all of us hope and many of us suspect that the actual number will be quite low. Indeed, if there are any cases of PML, it is hoped that the additional data they present will permit the level of risk to certain subgroups to be more accurately assessed. For example, some neurologists believe that while the general risk to Tysabri monotherapy patients will be well below the 1 in 1,000 level, it may be higher in the subgroup of patients who were previously on Novantrone or Cytoxan. There are no data to support that theory, just scientifically-based concerns, so those patients are being monitored even more closely.

All of us who communicate with MS patients should think ahead of time how we will respond to any PML reports, confirmed or otherwise.

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PostPosted: Fri Dec 29, 2006 9:43 am    Post subject: Reply with quote

This item was in PubMed recently, but since it has no abstract, all I can post is the title and journal information. However, since the subject looks important to patients on (or considering) Tysabri, here is the information, in case anyone wants to look the article up:

Quote:
Phillips JT, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Polman CH, Lublin FD, Giovannoni G, Wajgt A, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators

Infusion-related hypersensitivity reactions during natalizumab treatment

Neurology. 2006 Nov 14;67(9):1717-8. No abstract available.

PMID: 17101921 [PubMed - indexed for MEDLINE]
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PostPosted: Tue Feb 06, 2007 2:51 pm    Post subject: (Abstract) Subtle BBB disruption in Tysabri trial in RRMS Reply with quote

From PubMed, 2/6/07:

Quote:
J Neurol. 2007 Feb 3

A study of subtle blood brain barrier disruption in a placebo-controlled trial of natalizumab in relapsing remitting multiple sclerosis

Soon D, Altmann DR, Fernando KT, Giovannoni G, Barkhof F, Polman CH, O'connor P, Gray B, Panzara M, Miller DH.
Dept. of Neuroinflammation, Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom, d.miller@ion.ucl.ac.uk.

Natalizumab [Tysabri], an anti-alpha4 integrin antibody, significantly reduces the number of visibly enhancing multiple sclerosis (MS) lesions. In this substudy of a 2-year trial of natalizumab monotherapy versus placebo, contrast-enhanced imaging investigated for subtle blood brain barrier (BBB) leakage in relapsing-remitting (RRMS) patients, and whether such leakage is modified by natalizumab.

After 24 weeks on treatment, 40 patients from 3 centres (27 on natalizumab and 13 on placebo) were studied. T(1) weighted images were obtained before and at set timepoints up to 46 minutes after gadolinium (Gd)-DTPA (0.3mmol/kg to 18 patients, 0.15mmol/kg to 22). Paired regions of interest were placed around non-enhancing lesions and contralateral normal appearing white matter (NAWM). BBB leakage was inferred through post-Gd T(1) weighted signal intensity (SI) change. SI change was greater in T(2) non-enhancing lesions than paired NAWM at all timepoints (P < 0.005), indicating BBB leakage in lesions. No significant difference in inferred BBB leakage was observed between treatment arms as measured by SI change of lesions (P > 0.05 for all timepoints, joint test P = 0.24), or in SI change of NAWM (joint test P = 0.37). T(1) hypointense and isointense lesions exhibited similar SI changes (joint test P = 0.12).

There is evidence of a subtle BBB leakage within visibly non-enhancing lesions in RRMS that was not modified by alpha4 integrin blockade in this substudy cohort.

PMID: 17277910
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PostPosted: Mon Feb 12, 2007 3:32 pm    Post subject: (Abstract) Potential risk of PML w/Tysabri... Reply with quote

From Archives of Neurology, February 2007:

Quote:
Vol. 64 No. 2, February 2007




Potential Risk of Progressive Multifocal Leukoencephalopathy With Natalizumab Therapy--
Possible Interventions


Olaf Stüve, MD, PhD; Christina M. Marra, MD; Petra D. Cravens, PhD; Mahendra P. Singh, PhD; Wei Hu, MD, PhD; Amy Lovett-Racke, PhD; Nancy L. Monson, PhD; J. Theodore Phillips, MD, PhD; Jan W. Cohen Tervaert, MD, PhD; Richard A. Nash, MD; Hans-Peter Hartung, MD; Bernd C. Kieseier, MD; Michael M. Racke, MD; Elliot M. Frohman, MD, PhD; Bernhard Hemmer, MD


Arch Neurol. 2007;64:169-176.

Natalizumab (Tysabri) is an effective therapy for multiple sclerosis. Recently, 3 patients who were treated with natalizumab developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyomavirus JC.

The pathogenesis of natalizumab-associated PML may be different from that of PML not associated with the drug. We reviewed biologically feasible interventions for patients diagnosed as having PML or other infections while receiving natalizumab therapy.

Existing interventions include antiviral treatment, immunomodulatory therapies, hematopoietic growth factors, plasma exchange, intravenous immunoglobulins, and leukapheresis and autotransfusion of leukocytes. In addition, we examined the feasibility of experimental therapies, including small interfering RNA, the in vivo use of antiserum, and recombinant natalizumab-blocking molecules. There is only circumstantial evidence that any of the proposed treatments will benefit patients with multiple sclerosis treated with natalizumab who may develop PML. In addition, the expected incidence of PML in this patient population will likely be too low to test any of the proposed interventions in a controlled manner.

Because it is currently impossible to identify patients at risk, and thus to prevent PML as a consequence of natalizumab therapy, it is important that neurologists be aware of possible therapeutic interventions.


Author Affiliations: Neurology Section, Medical Service, Veterans Affairs North Texas Health Care System, Dallas (Dr Stüve); Departments of Neurology (Drs Stüve, Cravens, Singh, Hu, Monson, and Frohman) and Ophthalmology (Dr Frohman) and Center for Immunology (Drs Stüve and Monson), The University of Texas Southwestern Medical Center at Dallas; Department of Neurology, Heinrich Heine University, Düsseldorf, Germany (Drs Stüve, Hartung, Kieseier, and Hemmer); Department of Neurology, University of Washington, Seattle (Dr Marra); Multiple Sclerosis Center at Texas Neurology, Dallas (Dr Phillips); Department of Clinical and Experimental Immunology, University Hospital Maastricht, Maastricht, the Netherlands (Dr Cohen Tervaert); Fred Hutchinson Cancer Research Center, Seattle (Dr Nash); and Department of Neurology, The Ohio State University Medical Center, Columbus (Drs Lovett-Racke and Racke).






One of the authors listed, Theodore J. Phillips, is also the author of the editorial for which an extract has been posted in this forum ("What causes MS to worsen?").
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PostPosted: Fri Mar 02, 2007 3:40 pm    Post subject: (Abstract) PML compared w/RRMS Reply with quote

Scheduled for the upcoming AAN conference in May 2007:

Quote:
Clinical and MRI Characteristics of Progressive Multifocal Leukoencephalopathy (PML): Comparison with Relapsing-Remitting Multiple Sclerosis (RRMS)

Aaron Boster, Detroit, MI, Christina Endress, Stephanie Hreha, Fen Bao, Imad Zak, Basil Shah, Christina Caon, Alexandros Tselis, Kenneth Tyler, Denver, Michael Racke, Columbus, Omar Khan, Detroit

OBJECTIVE: To describe the clinical and MRI presentations of PML, and identify characteristics that may help in differentiating PML from RRMS.

BACKGROUND:
There is renewed interest in PML after the development of PML in three natalizumab-treated patients. PML is known to occur in immunocompromised hosts. The potential risk of developing PML associated with natalizumab has created the need for identifying patients at the earliest stages of PML.

Furthermore, it also requires the neurologist to distinguish PML from RRMS, for which natalizumab is approved . Clinical and MRI characteristics of PML compared to RRMS are timely information for the neurologists.

DESIGN/METHODS: We conducted a retrospective chart review of all PML cases at three urban teaching hospitals in Detroit from 1980 to date. Analysis from one hospital was completed at the time of this submission and ongoing at other hospitals.

RESULTS: At the time of this submission, 39 PML (90% HIV+) cases were identified, confirmed by JCV CSF PCR (31%), brain biopsy (67%), and rarely autopsy. Polysymptomatic presentations were common although monosymptomatic onset with hemiplegia (28%) and mental status changes (18%) was also seen.

Brain MRI showed most HIV+ PML lesions to be confluent, granular, and hyperintense on T2W images without gadolinium enhancement. However, crescent shaped cerebellar lesions, transcallosal banding pattern, and gadolinium enhancement were identified in non-HIV PML patients. PML case identification including MRI analysis is under way at two additional urban teaching hospitals at the time of this submission. Furthermore, brain MRI with PML will be compared with RRMS.

CONCLUSIONS/RELEVANCE: Confluent granular lesions on dual-echo MRI images may be a distinct feature of PML in HIV while gadolinium enhancement and unusual T2 lesions may be more common in non-HIV PML. Non-HIV PML brain MRI may be more similar to RRMS. Further clinical and image analysis including regional and global atrophy is under way.

Supported by: Partners Multiple Sclerosis Fellowship Program.


Tuesday, May 1, 2007 11:30 AM
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PostPosted: Wed Mar 07, 2007 8:18 pm    Post subject: (Abstract) Tysabri safety in patients w/RRMS... Reply with quote

Scheduled for the upcoming AAN conference in May:

Quote:
The Safety of Natalizumab in Patients with Relapsing Multiple Sclerosis: An Update from TOUCH and TYGRIS

Carmen Bozic, Glyn Belcher, Mariska Koojimans, Richard Kim, Frances Lynn, Michael Panzara, Cambridge, MA

OBJECTIVE: To report an update on the safety of natalizumab in relapsing multiple sclerosis (MS) patients.

BACKGROUND: Natalizumab (TYSABRI), an alpha-4-integrin antagonist, provides significant efficacy in the treatment of relapsing MS. Although natalizumab was well tolerated in clinical studies, three cases of progressive multifocal leukoencephalopathy (PML) occurred; two in MS patients receiving natalizumab plus interferon beta-1a and one in a Crohn's disease patient. A prescribing program and global observational study are being conducted to further assess the safety of natalizumab.

DESIGN/METHODS: Before initiating natalizumab treatment, all US patients, physicians and infusion centers must enroll into the TOUCH Prescribing Program (TYSABRI Outreach: Unified Commitment to Health).

The TOUCH Prescribing Program is a safety registry designed to determine the incidence of and risk factors for serious opportunistic infections (OIs), including PML, and to monitor patients for signs and symptoms of PML while assuring informed benefit/risk discussions prior to initiating natalizumab treatment. Physicians report on PML, serious OIs, deaths and natalizumab discontinuation, on an ongoing basis.

In addition, approximately 5,000 natalizumab-treated patients worldwide, including 3,000 patients from TOUCH, will be enrolled in a global observational study called TYGRIS (TYSABRI Global ObseRvation Program In Safety). Patients in TYGRIS are evaluated at baseline and every 6 months thereafter for 5 years. The following information is being collected: medical/MS history; prior natalizumab use; prior use of immunomodulatory, antineoplastic, or immunosuppressive agents; and all serious adverse events, including PML and other serious OIs, and malignancies.

RESULTS: Available safety data from patients receiving natalizumab worldwide will be presented.

CONCLUSIONS/RELEVANCE: Information from these studies will expand our knowledge of long-term natalizumab safety and further better quantify the risk of PML, serious OIs, and malignancy.

Supported by: Biogen Idec and Elan Pharmaceuticals, Inc.


Thursday, May 3, 2007 7:00 AM

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PostPosted: Wed Mar 07, 2007 8:24 pm    Post subject: (Abstract) PML characteristics compared w/RRMS Reply with quote

Scheduled for the upcoming AAN conference in May:

Quote:
Clinical and MRI Characteristics of Progressive Multifocal Leukoencephalopathy (PML): Comparison with Relapsing-Remitting Multiple Sclerosis (RRMS)

Aaron Boster, Detroit, MI, Christina Endress, Stephanie Hreha, Fen Bao, Imad Zak, Basil Shah, Christina Caon, Alexandros Tselis, Kenneth Tyler, Denver, Michael Racke, Columbus, Omar Khan, Detroit

OBJECTIVE: To describe the clinical and MRI presentations of PML, and identify characteristics that may help in differentiating PML from RRMS.

BACKGROUND: There is renewed interest in PML after the development of PML in three natalizumab-treated patients. PML is known to occur in immunocompromised hosts. The potential risk of developing PML associated with natalizumab has created the need for identifying patients at the earliest stages of PML. Furthermore, it also requires the neurologist to distinguish PML from RRMS, for which natalizumab is approved . Clinical and MRI characteristics of PML compared to RRMS is timely information for the neurologists.

DESIGN/METHODS:
We conducted a retrospective chart review of all PML cases at three urban teaching hospitals in Detroit from 1980 to date. Analysis from one hospital was completed at the time of this submission and ongoing at other hospitals.

RESULTS: At the time of this submission, 39 cases PML (90% HIV+) cases were identified, confirmed by JCV CSF PCR (31%), brain biopsy (67%), and rarely autopsy. Polysymptomatic presentations were common although monosymptomatic onset with hemiplegia (28%) and mental status changes (18%) were also seen. Brain MRI showed most HIV+ PML lesions to be confluent, granular, and hyperintense on T2W images without gadolinium enhancement. However, crescent-shaped cerebellar lesions, transcallosal banding pattern, and gadolinium enhancement were identified in non-HIV PML patients. PML case identification including MRI analysis is under way at two additional urban teaching hospitals at the time of this submission. Furthermore, brain MRI with PML will be compared with RRMS.

CONCLUSIONS/RELEVANCE: Confluent granular lesions on dual-echo MRI images may be a distinct feature of PML in HIV while gadolinium enhancement and unusual T2 lesions may be more common in non-HIV PML. Non-HIV PML brain MRI may be more similar to RRMS. Further clinical and image analysis including regional and global atrophy is under way.

Supported by: Partners Multiple Sclerosis Fellowship Program.

Tuesday, May 1, 2007 11:30 AM
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PostPosted: Fri Mar 09, 2007 3:16 pm    Post subject: (Abstract) Health-related quality of life in MS re Tysabri Reply with quote

Scheduled for the upcoming AAN conference in May:

Quote:
Health-Related Quality of Life in Multiple Sclerosis: Effects of Natalizumab

Richard Rudick, Deborah Miller, Cleveland, OH, Michael Hutchinson, Dublin, Ireland, Peter Calabresi, Baltimore, MD, Christian Confavreux, Lyon, France, Steven Galetta, Philadelphia, PA, Gavin Giovannoni, Eva Havrdova, Praha 2, Czech Republic, Ludwig Kappos, Fred Lublin, New York, NY, David Miller, London, United Kingdom, Paul W. O'Connor, Toronto, ON, Canada, J. Theodore Phillips, Dallas, TX, Chris Polman, Amsterdam, Netherlands, Ernst-Wilhelm Radue, Basel, Switzerland, William Stuart, Atlanta, GA, Andrzej Wajgt, Katowice-Ligota, Poland, Bianca Weinstock-Guttman, Buffalo, NY, Daniel Wynn, Northbrook, IL, Frances Lynn, Michael Panzara, Cambridge, MA, for the AFFIRM and SENTINEL Investigators

OBJECTIVE: To report the relationship between disease activity and health-related quality of life (HRQoL) in patients with relapsing multiple sclerosis (MS), and the impact of natalizumab.

BACKGROUND: MS is associated with reduced HRQoL. In a phase 3 clinical study (AFFIRM study), natalizumab monotherapy reduced the risk of sustained disability progression by 42% and annualized relapse rate by 68% in relapsing MS. To determine if clinical benefits extend to improved quality of life, HRQoL measures were included in natalizumab clinical studies (AFFIRM and SENTINEL).

DESIGN/METHODS: Patients in AFFIRM received natalizumab 300mg (n=627) or placebo (n=315); patients in SENTINEL were randomized to receive interferonb-1a plus natalizumab 300mg (n=589), or interferonb-1a plus placebo (n=582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale (VAS) were administered at baseline, Weeks 24, 52, and 104. The odds ratio of a clinically meaningful improvement or worsening, defined as a 0.5-SD change, on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the SF-36 were analyzed using logistic regression controlling for treatment and baseline score.

RESULTS: Baseline SF-36 scores were significantly lower than the general US population. Lower SF-36 scores were correlated with higher EDSS scores, sustained progression of disability, relapses, and increased volume of MRI lesions, indicating that SF-36 scores reflected severity and progression of MS. In both studies, natalizumab-treated patients were significantly more likely to experience clinically important improvement on the PCS at Week 104 (AFFIRM: odds ratio [OR]=1.54, 95% confidence interval [CI], 1.06-2.23; SENTINEL: OR=1.47, 95% CI, 1.08-2.03), and less likely to experience clinically important worsening than placebo or interferonb-1a patients, respectively (AFFIRM: OR=0.63, 95% CI, 0.45-0.88; SENTINEL: OR=0.64, 95% CI, 0.47-0.87). Similar trends were observed on the MCS.

CONCLUSIONS/RELEVANCE: HRQoL scores correlated with neurologic and MRI measures of disease severity and activity, and improved significantly with natalizumab therapy.

Supported by: Biogen Idec and Elan Pharmaceuticals, Inc.

Wednesday, May 2, 2007 4:00 PM
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PostPosted: Fri Mar 09, 2007 8:00 pm    Post subject: Reply with quote

This is impressive Agate, I have to admit. And since I'm not on treatment now, I'm starting to think about whether Tysabri might be the next thing for me. I haven't had a lot of luck with the other treatments, they've all given me some pretty significant side effects...

Quote:
RESULTS: Baseline SF-36 scores were significantly lower than the general US population. Lower SF-36 scores were correlated with higher EDSS scores, sustained progression of disability, relapses, and increased volume of MRI lesions, indicating that SF-36 scores reflected severity and progression of MS. In both studies, natalizumab-treated patients were significantly more likely to experience clinically important improvement on the PCS at Week 104 (AFFIRM: odds ratio [OR]=1.54, 95% confidence interval [CI], 1.06-2.23; SENTINEL: OR=1.47, 95% CI, 1.08-2.03), and less likely to experience clinically important worsening than placebo or interferonb-1a patients, respectively (AFFIRM: OR=0.63, 95% CI, 0.45-0.88; SENTINEL: OR=0.64, 95% CI, 0.47-0.87). Similar trends were observed on the MCS.

CONCLUSIONS/RELEVANCE: HRQoL scores correlated with neurologic and MRI measures of disease severity and activity, and improved significantly with natalizumab therapy.

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DX 01/28/03 RRMS
Formerly Avonex, Rebif & Copaxone
Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Fri Mar 09, 2007 8:11 pm    Post subject: Reply with quote

I didn't realize (or had forgotten) that Tysabri is an option for you.

You could always go off it if it wasn't working out well.

Of course, the research you're referring to was supported by Biogen Idec and Elan--I don't know how much of a difference that makes since they can't publish outright lies without getting caught. Still, they MIGHT be skewing some of the results a tiny bit in favor of Tysabri...
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PostPosted: Fri Mar 09, 2007 9:32 pm    Post subject: Reply with quote

My doctor was listed as one of the principle investigators... I'll ask his opinion on this. He has not suggested it for me... so that's part of my hesitation. But then again, he knows I'm a good trial patient, and maybe there's an upcoming trial that would be a good one for me... scratch I sometimes wonder about that (like he's hoping I'll wait and be in another trial... ) And if so, I don't fault him for that. He's helping a lot of people with his work and it can be hard to find people who can adhere to the demands of being in a trial.
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Formerly Avonex, Rebif & Copaxone
Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Wed Mar 14, 2007 5:28 pm    Post subject: (Abstract) Tysabri effect on human lymphocyte interaction... Reply with quote

Scheduled for the upcoming AAN conference in May:

Quote:
[P01.045] Live Imaging of Natalizumab Mediated Effect on Human Lymphocyte Interaction with the Blood-Brain Barrier In Vivo

Caroline Coisne, Tardent Heidi, Britta Engelhardt, Bern, Switzerland

OBJECTIVE: Investigate the effect of natalizumab on human leukocyte recruitment across the blood-brain barrier (BBB) in vivo.

BACKGROUND: In multiple sclerosis (MS), and in its animal model, experimental autoimmune encephalomyelitis (EAE), circulating leukocytes gain access to the central nervous system (CNS) and cause inflammation, BBB breakdown and demyelination, which all set the stage for the development of the clinical manifestations of MS.

Thus, inflammatory cell recruitment across the BBB has been recognized as a major pathophysiological hallmark of MS and blocking leukocyte/endothelial interactions especially alpha 4-integrins by the anti-alpha 4-integrin antibody natalizumab (marketed as Tysabri by BiogenIdec/Elan) have proven beneficial for the treatment of MS. Nevertheless, direct in vivo evidence for the inhibition of T-cell interaction with the BBB endothelium by natalizumab in vivo is still lacking.

DESIGN/METHODS: In order to investigate the effect of natalizumab on human leukocyte interaction with the BBB in vivo, we have performed intravital fluorescence videomicroscopy using a spinal cord window preparation in mouse, which enables us to directly visualize CNS white matter microcirculation. Fluorescently labeled human T-cells were incubated with natalizumab (170g/400L) or vehicle control in vitro before injection into TNF-alpha stimulated mice. To assess permanent T-cell adhesion, several areas of the spinal cord microvasculature were scanned at different period of time after cell injection.

RESULTS: Adherence of T-cells to the inflamed BBB was reduced by approximately 50% in the natalizumab treated sample compared with controls.

CONCLUSIONS/RELEVANCE: This study provides the first in vivo evidence that natalizumab interferes with the adhesion of human mononuclear cells with the BBB in vivo. Although these findings do not preclude the possibility that natalizumab can have additional immunomodulatory effects, our data support the notion that a major aspect of the therapeutic efficacy of natalizumab is due to the inhibition of leukocyte recruitment across the BBB.

Supported by: The Swiss and the American National Multiple Sclerosis Society and BiogenIdec.

Tuesday, May 1, 2007 7:00 AM
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PostPosted: Tue Mar 27, 2007 6:13 pm    Post subject: (Abstract) Tysabri update Reply with quote

From PubMed, 3/27/07:

Quote:
Am J Health Syst Pharm. 2007 Apr 1;64(7):705-16

Natalizumab update

Sweet BV.
College of Pharmacy, University of Michigan, Ann Arbor.

PURPOSE: The pharmacology, pharmacokinetics, indications, clinical efficacy, adverse effects, drug interactions, and dosage and administration of natalizumab are reviewed.

SUMMARY: Natalizumab, the first commercially available selective adhesion-molecule inhibitor, is approved as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis (MS). Natalizumab exerts its immunologic effects by targeting the alpha4 integrin receptor, the site responsible for the migration of leukocytes from the blood into inflamed tissues. Because of the increased risk of progressive multifocal leukoencephalopathy (PML), natalizumab is generally recommended for patients who have had an inadequate response to or are intolerant of alternative MS therapies. Data evaluating the efficacy and safety of natalizumab for the treatment of MS are available from published Phase II and III trials. The most common adverse effects reported include headache, fatigue, urinary-tract infection, depression, arthralgia, and lower respiratory-tract infection.

The recommended dosage of natalizumab for the treatment of relapsing forms of MS is 300 mg administered by i.v. infusion over one hour once every four weeks. Natalizumab is available only through a risk-minimization program run by the manufacturer.

CONCLUSION: Natalizumab offers an effective treatment option for patients with MS who have had an inadequate response to or are intolerant of alternative MS therapies. Because of its potential to increase the risk of PML, the risks and benefits should be carefully weighed before initiating natalizumab therapy in patients with MS. Natalizumab should not be used to treat Crohn's disease or any other unapproved indication until more postmarketing safety data are available.

PMID: 17384355
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PostPosted: Thu Mar 29, 2007 2:08 pm    Post subject: (Abstract) Reactivation of JC virus & development of PML Reply with quote

From PubMed, 3/29/07:

Quote:
Neurology. 2007 Mar 27;68(13):985-90

Reactivation of JC virus and development of PML in patients with multiple sclerosis

Khalili K, White MK, Lublin F, Ferrante P, Berger JR.
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA 19122, USA. kamel.khalili@temple.edu

The attention of researchers and clinicians specializing in both multiple sclerosis (MS) and JC virus (JCV), the etiologic agent of progressive multifocal leukoencephalopathy (PML), was rekindled by the development of PML in two patients with MS enrolled in a clinical trial of combination therapy with natalizumab (Tysabri) and interferon beta-1A (Avonex) in recent years.

PML had not been previously reported with either MS or treatment with interferon beta alone. This occurrence of PML with alpha4beta1-integrin inhibition in MS raised a number of issues in terms both of the scientific understanding of these diseases and for the future of immunomodulatory treatment for MS.

In this review, we examine the current status of knowledge of the virus, its molecular biology, life cycle, and pathogenetic mechanisms, and how this relates to the basic science and clinical perspectives of MS. A better understanding of the specific steps from JCV infection to the development of PML is key to this issue.

Other critical issues for further investigation include the role of alpha4beta1-integrin inhibition by natalizumab in the re-expression of JCV from latent sites and in the inhibition of entry into the brain and peripheral sites.

PMID: 17389301
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PostPosted: Tue Apr 17, 2007 1:18 pm    Post subject: (Article) Tysabri combats vision loss Reply with quote

From HealthDay, April 17, 2007:

Quote:
Multiple Sclerosis Drug Combats Vision Loss

But doctors must weigh the potential risks of Tysabri, experts say
By Steven Reinberg
HealthDay Reporter

TUESDAY, April 17 (HealthDay News) -- A controversial multiple sclerosis drug called Tysabri also reduces vision loss associated with the disease by 47 percent, a new study found.

"Vision loss is probably one of the most disabling things that happens to people with MS," said lead researcher Dr. Laura J. Balcer, an associate professor of neurology at the University of Pennsylvania School of Medicine. "The exciting thing is, first, that we now have an eye-chart test that can pick that up and can show if treatments help vision. Second, this particular drug appears to help prevent vision loss."

In the study, Balcer's group looked at the results of two trials -- called AFFIRM and SENTINEL -- that included 2,138 people with relapsing MS. More than half the patients received Tysabri (generic name natalizumab) every four weeks for two years.

To evaluate eyesight, the researchers used a specially developed eye chart of low contrast letters. They found vision loss was reduced by as much as 47 percent among the people taking Tysabri, compared with those taking a placebo.

"Vision is one more dimension of MS that the drug helps," Balcer said. "It has already been shown that the drug reduces the rates of relapses and disability."

Balcer thinks that other MS drugs may have similar effects on vision, and there is now a test that can be included in trials to evaluate this. "Now, we can get to see how these other medications may help vision," she said.

The findings are published in the April 17 issue of the journal Neurology.

Tysabri's history has been marked by some controversy.

It received U.S. Food and Drug Administration approval in November 2004, only to be pulled from the market three months later after several patients in clinical trials developed a rare but deadly viral infection of the brain called progressive multifocal leukoencephalopathy. In June 2006, the FDA allowed the drug to return to the mart, but with strict conditions. According to the new guidelines, Tysabri can only be administered by approved doctors, infusion sites and pharmacies that register and comply with a patient-safety program designed by Biogen-IDEC, the maker of Tysabri, and approved by the FDA.

One expert thinks that despite the vision benefit, Tysabri should be reserved for patients with aggressive MS or those who failed other medications.

"This study confirms the benefits of this particular MS drug in relapsing MS patients," said Dr. Anne H. Cross, a professor of neurology at Washington University School of Medicine, in St. Louis. "In addition, it validates the use of a new vision test which is relevant to MS."

But the benefit to vision doesn't negate the risks associated with the drug, Cross said. "I don't think I will change my prescribing habits based upon this paper," she said. "I will probably continue to use it in the same type of patients I have been using it in in the past."

However, Nicholas LaRocca, the director of health care delivery and policy research at the National Multiple Sclerosis Society, said the new study provides additional insight into the benefits of the drug and may influence the decision whether to start using it or not.

"For patients who are on natalizumab or considering natalizumab, this gives them another piece of information to consider as they are trying to make their decision," he said.

According to the U.S. National Institutes of Health, multiple sclerosis is an unpredictable disease of the central nervous system that can range from relatively benign to somewhat disabling to devastating, as communication between the brain and other parts of the body is disrupted. Many researchers believe MS to be an autoimmune disease -- one in which the body, through its immune system, launches a defensive attack against its own tissues. In the case of MS, it is the nerve-insulating myelin that comes under assault.


SOURCES: Laura J. Balcer, M.D., associate professor of neurology, University of Pennsylvania School of Medicine, Philadelphia; Nicholas LaRocca, Ph.D., director of health care delivery and policy research, National Multiple Sclerosis Society, New York City; Anne H. Cross, M.D., professor, neurology, Washington University School of Medicine, St. Louis; April 17, 2007, Neurology



Here is the abstract from PubMed, 4/18/07:

Quote:
Neurology. 2007 Apr 17;68(16):1299-304

Natalizumab reduces visual loss in patients with relapsing multiple sclerosis

Balcer LJ, Galetta SL, Calabresi PA, Confavreux C, Giovannoni G, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Miller DH, O'Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA.
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. lbalcer@mail.med.upenn.edu

OBJECTIVE: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS). METHODS: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%).

RESULTS: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups.

CONCLUSIONS: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

PMID: 17438220
_____________________________________________________


--And now from WebMD Medscape Today, April 25, 2007:

Quote:



Natalizumab Reduces Vision Loss in Relapsing MS


Susan Jeffrey
Medscape Medical News 2007


April 19, 2007 — Results from 2 randomized studies show that treatment with natalizumab (Tysabri, Biogen Idec and Elan Corporation) reduces vision loss in patients with multiple sclerosis (MS). These results also confirm the utility of a tool called low-contrast acuity testing to measure vision loss as an outcome in MS clinical trials.

Despite the importance of vision to quality of life, previous studies in MS have not used standardized measures to assess vision loss in these patients, first author Laura J. Balcer, MD, from the University of Pennsylvania School of Medicine, in Philadelphia, told Medscape.

"We now have a new visual-outcome measure, used for the first time in MS trials, that is sensitive, and we also have good evidence from these trials that natalizumab not only reduces relapse rates and other aspects of disability but can prevent sustained visual loss as well," Dr. Balcer said.

Their report is published in the April 17 issue of Neurology.

A New Tool

These analyses used data from the previously published AFFIRM and SENTINEL trials, both randomized, double-blind, placebo-controlled phase 3 clinical trials of natalizumab in patients with relapsing MS. Natalizumab was used as monotherapy in 942 patients in the AFFIRM trial (Polman CH et al. N Engl J Med. 2006;354:899-910) and as add-on therapy to interferon beta-1a (Avonex, Biogen Idec) in 1196 patients in the SENTINEL trial (Rudick RA et al. N Engl J Med. 2006;354:911-923).

In AFFIRM, patients were randomized in a 2:1 ratio to receive 300 mg of natalizumab or placebo, given by intravenous infusion every 4 weeks for up to 116 weeks; in SENTINEL, the randomization was 1:1 to either 300-mg natalizumab or placebo by IV infusion every 4 weeks as add-on therapy for up to 116 weeks.

From study outset, both of these trials used a new vision test called low-contrast letter acuity (low-contrast Sloan letter charts, Precision Vision, LaSalle, Illinois). These charts are similar to those already used in ophthalmology clinical trials to measure visual acuity but use gray letters rather than black on a white background.

"As neuro-ophthalmologists, we have seen for many years patients with multiple sclerosis who are 20/20 on the traditional black-and-white eye chart, and yet they have symptoms of blurred vision and describe their vision as 'not quite right.' Many patients state that they don't function visually as well as they used to, even in the absence of any history of acute optic neuritis," Dr. Balcer said.

Evidence in the literature does suggest that patients with MS have trouble seeing gray objects on white, raising the possibility that low-contrast targets may be more sensitive to these subtle changes, she noted.

Although not primary outcomes, visual testing at 100% contrast and low-contrast, 2.5% and 1.25%, was done as prespecified tertiary end points in both of these trials.

The authors report that the risk for clinically significant vision loss, defined as 2-line worsening of acuity sustained over 12 weeks, at the lowest-contrast level of 1.25%, was reduced in the natalizumab treatment groups by 35% in AFFIRM and by 28% in SENTINEL.

[ONE CHART OMITTED]


Mean changes from baseline were significant for the placebo groups, reflecting worsening over the study period, they write.

"Despite an identical chart format and testing protocols, high-contrast visual acuity (about 100% contrast, or black-and-white chart) did not show significant differences between treatment groups in either study," the authors add.

"Further data analyses are under way to characterize the relationship of Sloan chart scores to measures of self-reported health and visual function (quality-of-life measures) on a longitudinal basis in AFFIRM and SENTINEL, to further characterize the relationship of low-contrast letter acuity to MRI measures of disease burden and to examine how this test may increase the capacity of the MSFC [MS Functional Composite] to detect treatment effects and to identify neurologic impairment in future MS trials," they conclude.

Dr. Balcer explained that the MSFC, which includes measures of ambulation, arm function, and cognition, has not yet included a vision component, because traditional high-contrast eye charts did not show sufficient sensitivity to be included.

She added that upcoming clinical trials including low-contrast acuity testing are planned to start probably within the year. "So we'll begin to see whether other medications for MS can prevent visual loss as well."

The AFFIRM and SENTINEL studies were supported by Biogen Idec and Elan. Dr. Balcer disclosed that she has received support for consulting on the development of visual-outcome measures for multiple sclerosis clinical trials from Biogen Idec, Centocor, Serono, Incyte, and Novartis. Disclosures for other coauthors appear in the paper.

Neurology. 2007;68:1299-1304.






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PostPosted: Tue Apr 17, 2007 2:44 pm    Post subject: (Abstract) Patient selection & monitoring recommendation Reply with quote

From PubMed, April 17, 2007:

Quote:
Lancet Neurol. 2007 May;6(5):431-41

Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring

Kappos L, Bates D, Hartung HP, Havrdova E, Miller D, Polman CH, Ravnborg M, Hauser SL, Rudick RA, Weiner HL, O'connor PW, King J, Radue EW, Yousry T, Major EO, Clifford DB.
University Hospital, Basel, Switzerland.

Natalizumab is a new treatment option for patients with active relapsing-remitting multiple sclerosis. In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months).

In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with natalizumab. On the basis of these reviews, we make recommendations for appropriate selection of candidates for natalizumab and pretreatment assessments.

In addition, a three-step diagnostic and management algorithm was developed to monitor natalizumab-treated patients with multiple sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments. Maintaining clinical vigilance allows for early suspension of natalizumab in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis if PML is confirmed.

PMID: 17434098
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PostPosted: Wed Apr 25, 2007 2:14 pm    Post subject: (Abstract) MRI outcomes in trial of Tysabri in RRMS Reply with quote

From PubMed, April 25, 2007:

Quote:
: Neurology. 2007 Apr 24;68(17):1390-401

MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS

Miller DH, Soon D, Fernando KT, MacManus DG, Barker GJ, Yousry TA, Fisher E, O'Connor PW, Phillips JT, Polman CH, Kappos L, Hutchinson M, Havrdova E, Lublin FD, Giovannoni G, Wajgt A, Rudick R, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators.
Institute of Neurology, University College London, London, UK. d.miller@ion.ucl.ac.uk

BACKGROUND: In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] study), involving 942 patients with relapsing multiple sclerosis (MS), natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study.

METHODS: The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years.

RESULTS: Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001).

Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients.

CONCLUSION: Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.

PMID: 17452584
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PostPosted: Wed May 02, 2007 2:20 pm    Post subject: (Abstract) Quantifying risks & benefits of Tysabri... Reply with quote

From PubMed, May 2, 2007:

Quote:
Neurology. 2007 May 1;68(18):1524-8

Quantifying the risks and benefits of natalizumab in relapsing multiple sclerosis

Dorsey ER, Thompson JP, Noyes K, Dick AW, Holloway RG, Schwid SR.
Department of Neurology, University of Rochester Medical Center, Rochester, NY 14620, USA. ray.dorsey@ctcc.rochester.edu

Using published data, we quantified the risk and benefits of natalizumab in relapsing multiple sclerosis using quality-adjusted life years (QALYs) as a metric.

Over the first 2 years of therapy, the negative health effects from progressive multifocal leukoencephalopathy were small (loss of 0.001 QALYs) relative to the positive effects on relapses and disability resulting in 0.033 QALYs (12 quality-adjusted days) gained.

For context, we performed an analogous calculation for interferon beta-1a, which also had a net health benefit of 0.033 QALYs (12 quality-adjusted days).

PMID: 17470756
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PostPosted: Thu May 03, 2007 1:38 pm    Post subject: (Abstract) Tysabri in MS: unclear patient benefits Reply with quote

From PubMed, May 3, 2007:

Quote:
Ned Tijdschr Geneeskd. 2007 Apr 14;151(15):852-5

[Natalizumab in multiple sclerosis: unclear patient benefits]

[Article in Dutch]

Schipper JP.
Ziekenhuis Bethesda, afd. Neurologie, Dr.G.H.Amshoffweg i, 7909 AA Hoogeveen. schipper.j@bethesda.nl

Two large randomised clinical trials were published in March 2006 that evaluated the effect of natalizumab on the incidence of disease exacerbation in patients with multiple sclerosis (MS). Both trials showed that natalizumab reduces the incidence of MS exacerbations, but it is unclear whether patients ultimately benefited from treatment.

It is clear that natalizumab is associated with serious adverse events, such as progressive multifocal leukoencephalopathy. Therefore, the use of natalizumab in patients with MS cannot be considered advisable at this time.

PMID: 17472115
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PostPosted: Fri May 04, 2007 2:26 pm    Post subject: (Abstract) Tysabri's efficacy over 3 years in RRMS patients Reply with quote

From the AAN Conference, May 2007:

Quote:
[P06.082] The Efficacy of Natalizumab Monotherapy over 3 Years of Treatment in Patients with Relapsing Multiple Sclerosis

Paul W. O'Connor, Toronto, ON, Canada, Andrew Goodman, Rochester, NY, Ludwig Kappos, Basel, Switzerland, Fred Lublin, New York, NY, David Miller, London, United Kingdom, Chris Polman, Amsterdam, Netherlands, Richard Rudick, Elizabeth Fisher, Cleveland, OH, Frances Lynn, Michael Panzara, Cambridge, MA

OBJECTIVE: To report the 3-year efficacy of natalizumab monotherapy in patients with relapsing multiple sclerosis (MS).

BACKGROUND: The efficacy of natalizumab was demonstrated in a randomized, placebo-controlled, 2-year study (AFFIRM). Patients who completed AFFIRM were eligible to receive natalizumab in an open-label safety-extension study. The primary objective of the safety-extension study was to assess safety of extended natalizumab treatment. Relapses and sustained progression were also measured.

DESIGN/METHODS: In the safety-extension study, all patients received natalizumab 300 mg intravenously every 4 weeks. Relapse data included relapses reported at unscheduled visits and as adverse events. Expanded Disability Status Scale (EDSS) score was assessed every 6 months. The study was stopped early due to natalizumab dosing suspension in February 2005, and patients received an MRI as part of the ensuing safety evaluation; brain parenchymal fraction (BPF) was assessed from these MRI scans.

RESULTS: Data from all patients randomized in AFFIRM (natalizumab, n=627 [531 dosed in safety-extension]; placebo, n=315 [259 dosed in safety-extension]) were included in this ITT analysis. Median total duration of natalizumab exposure was 2.72 years (min, max: 0.10, 3.15) in AFFIRM natalizumab patients and 0.60 years in AFFIRM placebo patients (min, max: 0.23, 0.93). In natalizumab patients, annualized relapse rate (ARR) was 0.23 and the proportion relapse free was 67% (Kaplan-Meier analysis) over the 3-year period; yearly ARRs were 0.26 in Year 0-1, 0.20 in Year 1-2, and 0.15 in Year 2-3. In placebo patients, the ARR in Year 2-3 after switching to natalizumab was 0.27 (the 2-year ARR in AFFIRM was 0.73). Kaplan-Meier estimates of the proportions of patients with 6-month sustained disability progression were 13% at 3 years in natalizumab patients and 23% at 2 years in placebo patients. BPF data will be reported.

CONCLUSIONS/RELEVANCE: Natalizumabs effects on relapses and disability progression may be sustained beyond 2 years.

Supported by: Biogen Idec and Elan Pharmaceuticals, Inc.
Category - MS and Related Diseases
SubCategory - Clinical Science

Thursday, May 3, 2007 7:00 AM


And a related article from the Boston Globe, 5/3/07:

Quote:

Biogen: no more findings of brain infection with new MS drug

May 3, 2007

BOSTON --No new cases of a serious brain infection have been reported among patients taking Biogen Idec's new multiple sclerosis drug since the FDA allowed it back into the market, the biotechnology company announced Thursday.

The potentially deadly side effect of the MS drug Tysabri is a brain infection known as progressive multifocal leukoencephalopathy, or PML.

Biogen withdrew Tysabri in February 2005 after two patients in clinical trials died. Last June, the FDA approved Tysabri under the condition that any patients taking the drug register with a program designed to ensure its safe use.

Thursday's announcement by Cambridge-based Biogen at the American Academy of Neurology's annual meeting was the first safety update since June.

Tysabri is being used by about 10,000 people worldwide in commercial or clinical trial settings, the company said.

On Wednesday, Biogen released first quarter earnings that showed a 7 percent increase in profits, though the company was short of Wall Street expectations. The company said earnings would be pulled down initially this year by the costs of ongoing clinical trial and the launch of Tysabri.

Biogen reported Tysabri revenues of $48 million, including about $36 million in the U.S., a 55 percent gain from last quarter, and about $12 million internationally, a 76 percent gain.

On Thursday, Biogen and its partner on Tysabri, Elan Corp. of Ireland, also released results of an extension of the original two-year study of Tysabri, which showed a 67 [percent?] reduction in the relapse rate of MS patients who took the drug for a third year.





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PostPosted: Fri May 04, 2007 3:07 pm    Post subject: Reply with quote

Hi Agate,

It looks like there was a very good report about Tysabri at the AAN meeting. My neuro and his research nurse attended this week.

I have an appt. to go in on May 16 to talk to him about Tysabri. I haven't been feeling well, and I know I need to be on treatment. The good report about Tysabri is a good thing.

Thanks for posting here! sunny
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Formerly Avonex, Rebif & Copaxone
Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Sun May 06, 2007 10:14 am    Post subject: Reply with quote

The MS Society of the UK has issued a plea for NHS coverage of Tysabri. I don't know if anyone here is in the UK, but here it is anyway:

Quote:
MS Society calls on NICE to revise Tysabri assessment

24 Apr 2007

The MS Society has expressed its grave concern over the National Institute for Clinical Excellence (NICE) evaluation report recommending that natalizumab (Tysabri) – a new therapy for people with rapidly evolving severe multiple sclerosis (MS) – should not be funded on the NHS.


The Society has submitted a response to a NICE consultation on the preliminary evaluation report and calls on the government watchdog to revise its current assessment on both clinical and ethical grounds.

People with this aggressive type of MS suffer repeated, disabling relapses, leading to disability progression that is approximately twice as fast as in people with less active multiple sclerosis. They rapidly lose their independence, work often becomes impossible and family members have to step in as carers.

NICE accepts the clinical efficacy of natalizumab in this severely affected group, yet it rejects it on cost grounds, based on the flawed comparison of ‘best supportive care’. The fair comparators are the current licensed drug therapies which these people would inevitably be on and the MS Society believes this would lead to a different conclusion regarding cost effectiveness.

Simon Gillespie, Chief Executive of the MS Society, said: "If this drug is not made available on the NHS once again people with MS will be disadvantaged when compared to people with MS in many other parts of the world."

The consultation deadline was 23 April and NICE will meet to consider submissions, including ours, on 8 May. Final recommendations are expected in July.

Further reading

NICE evaluation report of Tysabri (natalizumab):

http://guidance.nice.org.uk/page.aspx?o=419024



ewizabeth, I'm sorry you haven't been feeling well. But it sounds as if you're about to decide on Tysabri. Good luck at your appointment!
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PostPosted: Tue May 08, 2007 1:51 pm    Post subject: Reply with quote

Thanks Agate,

The appointment is next Wednesday. :-)
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Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Tue May 08, 2007 9:03 pm    Post subject: Reply with quote

ewizabeth wrote:
Hi Agate,

It looks like there was a very good report about Tysabri at the AAN meeting. My neuro and his research nurse attended this week.

I have an appt. to go in on May 16 to talk to him about Tysabri. I haven't been feeling well, and I know I need to be on treatment. The good report about Tysabri is a good thing.

Thanks for posting here! sunny


I hope you start feeling better soon.
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PostPosted: Wed May 09, 2007 3:21 pm    Post subject: Reply with quote

Matt wrote:

I hope you start feeling better soon.


Thanks Matt,

I had an "episode" out in the heat today, so I think I'm making the best decision...
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On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Tue May 15, 2007 1:53 pm    Post subject: (Abstract) Guidelines for using Tysabri in MS patients.... Reply with quote

From PubMed, May 15, 2007:

Quote:
J Neuroimmunol. 2007 May 10

Expert opinion: Guidelines for the use of natalizumab in multiple sclerosis patients previously treated with immunomodulating therapies

Gold R, Jawad A, Miller DH, Henderson DC, Fassas A, Fierz W, Hartung HP.
Department of Neurology at St. Josef-Hospital, University of Bochum, Gudrunstrasse 56, D-47901 Bochum, Germany.

Natalizumab (Tysabri(R)) (anti-VLA4) is a novel agent for treatment of relapsing multiple sclerosis (MS) [Polman C.H., O'Connor P.W., Havrdova E. et al., 2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899-910.]. Controlled trials have shown considerable efficacy in preventing relapses, in excess of that seen for other EMEA-approved disease modulating drugs. While well-tolerated and generally safe, three cases of progressive multifocal leukoencephalopathy (PML) occurred in the context of 3 clinical trials encompassing some 3300 patients using this drug in multiple sclerosis and Crohn's disease.

Immune-compromised patients, such as those receiving immunosuppressive medications, are at a higher risk of developing PML. Natalizumab was recently approved for the treatment of relapsing forms of MS. This includes patients who had an inadequate response to other therapies, and some of these patients will have already received immunosuppressants. These agents have the potential to cause prolonged effects on the immune system, even after dosing has been discontinued.

Determining that these patients are not immunocompromised will be an important safety issue to consider prior to the initiation of natalizumab therapy. This short report summarizes interdisciplinary practical recommendations from specialists in neuroimmunology, rheumatology, transplantation medicine and clinical immunology.

PMID: 17499366
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PostPosted: Wed May 23, 2007 2:05 pm    Post subject: (Article) Tysabri comparable to interferon for RMS Reply with quote

From WebMD's Medscape, May 22, 2007:

Quote:
Natalizumab Comparable to Interferon for Relapsing Multiple Sclerosis

NEW YORK (Reuters Health) May 11 - Natalizumab is comparable to interferon beta-1a in the net health benefits it provides for relapsing multiple sclerosis, an analysis of published data suggests.

Previous reports have shown natalizumab to be effective in preventing relapsing and slowing disease progression, but the drug has also been linked to an increased risk of progressive multifocal leukoencephalopathy (PML), which often proves fatal. Whether the benefits of natalizumab provides offsets this risk is unclear.

In the current study, Dr. Ray Dorsey, from the University of Rochester Medical Center in New York, and colleagues analyzed published data to assess the quality-adjusted life years (QALYs) gained with natalizumab. A comparison was then made with interferon beta-1a.

Data for the natalizumab analysis was drawn from the Natalizumab Safety and Efficacy in Relapsing Multiple Sclerosis (AFFIRM) trial, while the interferon data came from the Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study. Each study lasted roughly 2 years.

The investigators report their findings in the May 1st issue of Neurology.

The authors found that in terms of the effect on QALYs, natalizumab was minimally more effective than interferon at reducing disease relapses. The agents were comparable in their ability to slow disease progression. Because natalizumab did carry a slight risk of PML, the final net health effect of the drugs was nearly identical - 0.033 QALYs gained.

"Over the first 2 years of therapy, the health effect of natalizumab for the treatment of relapsing multiple sclerosis is much greater than the expected harm from PML," the authors conclude. Still, they write, long-term observational studies are needed to fully characterize the risk of PML with this drug.

Neurology 2007;68:1524-1528.
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PostPosted: Fri May 25, 2007 1:57 pm    Post subject: (Abstr.) "Thinking without thinking" about Tysabre Reply with quote

From PubMed, May 25, 2007:

Quote:
J Neurol Sci. 2007 May 21

"Thinking without thinking" about natalizumab and PML

Ransohoff RM.
Neuroinflammation Research Center, Department of Neurosciences, The Lerner Research Institute, The Cleveland Clinic Foundation, United States.

The novel multiple sclerosis (MS) therapeutic natalizumab has taken neurologists and their MS patients on a roller-coaster ride: initial encouraging efficacy data led to expedited release in the United States, followed by suspension of dosing with the unexpected occurrence of progressive multifocal leukoencephalopathy (PML) in three clinical trial participants. The drug was re-released in 2006, in a restricted distribution format.

Aside from PML, natalizumab treatment was not associated with opportunistic infections, suggesting the possibility that PML in these individuals was mechanism-based, and was not a consequence of generalized immunosuppression. This commentary proposes a hypothesis to account for PML in natalizumab-treated patients.

PMID: 17521672


Does anyone know what "mechanism-based" means? Maybe it's obvious and I'm just dense.


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PostPosted: Fri Jun 08, 2007 2:52 pm    Post subject: Checking--ewizabeth and Tysabri? Reply with quote

ewizabeth, isn't your first Tysabri infusion today?

Please let us know how it went - if you feel up to posting.
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PostPosted: Fri Jun 08, 2007 6:56 pm    Post subject: Reply with quote

Hi Agate,

It was Monday, and it went fine, no problems. It was a long day so my son and I didn't get home until 9pm, and I was exhausted and slightly headachy the next day, but otherwise fine.

Wednesday was a fabulous day, I got lots of stuff done, same with Thursday morning. Then I started to feel like my old tired self again. ;-) Today I was still tired, and same old symptoms, but otherwise fine.

Also, I've been dealing with a kitten with diarrhea, taking him to the vet, giving him liquid meds twice a day (!), cleaning the litterbox (a lot!) So, I figure I did pretty good this week, considering.

Also, I had physical therapy for my back and shoulder on Wednesday, and now they really hurt! No more of that, I'm cancelling the next 11 appts.

So, I guess you could say my Tysabri experience was good. The nurse did a good job and she'll be my nurse each time too.

Thanks for asking! I bet you didn't think you'd get such a long answer! Eye Rolling
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On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Fri Jun 08, 2007 7:09 pm    Post subject: Reply with quote

Congratulations on surviving the Tysabri initiation so well! I'm glad it didn't cause any problems for you.

A kitten with diarrhea can be quite a strain on the caregiver--Does anyone know what's ailing the kitten?

Maybe the PT person will be able to deal with the pain you're having, particularly since the PT caused it. Give them a chance to try, maybe? Or did the physical therapist strike you as not especially competent?
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PostPosted: Fri Jun 08, 2007 7:14 pm    Post subject: Reply with quote

We're trying to cure the diarrhea. He's getting an antibiotic that treats giardia and inflammation, and also a small dose of Kaopectate. He's on special food, and probiotics to replenish the good bacteria too. I hope we're doing the right thing, the poor little guy is being a trooper. Little Rocky is such a joy. sunny

I think the PT was very new and seemed very nervous. I think I'm better off to try to heal gradually on my own.
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PostPosted: Fri Jun 08, 2007 7:18 pm    Post subject: Reply with quote

I meant to add that diarrhea is a strain on the kitten, too--of course. But it sounds as if Rocky is in good hands. (My former cat who had quite a few ailments used to get diarrhea often from taking antibiotics. The problem was always to make sure she wasn't getting too dehydrated but was still on the road to recovery. The antibiotics were usually for ear infections.)

I agree that you're probably better off without the physical therapist. Maybe you can find a better one later on.
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PostPosted: Wed Jun 20, 2007 4:56 pm    Post subject: (Extract) Tysabri for MS Reply with quote

From New England Journal of Medicine, June 21, 2007:

Quote:
Volume 356:2622-2629 June 21, 2007 Number 25




Natalizumab for Multiple Sclerosis

Richard M. Ransohoff, M.D.

[An extract of the first 100 words only]

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author's clinical recommendations.

A 30-year-old woman was evaluated for consideration of treatment options for multiple sclerosis. Two years earlier she had reported having vertigo. The diagnosis of multiple sclerosis was confirmed by clinical evaluation, examination of cerebrospinal fluid, and magnetic resonance imaging . . .

The Clinical Problem

Pathophysiology and Effect of Therapy

Clinical Evidence

Clinical Use

Adverse Effects

Areas of Uncertainty

Guidelines

Recommendations


Source Information

From the Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland.

Address reprint requests to Dr. Ransohoff at the Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, NC30, 9500 Euclid Ave., Cleveland, OH 44195, or at ransohr@ccf.org.






I don't have access to the complete article. Anyone interested could try requesting a reprint from the address given above, though. I'm going to try that route too.
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PostPosted: Wed Jun 20, 2007 6:27 pm    Post subject: Reply with quote

agate wrote:
I meant to add that diarrhea is a strain on the kitten, too--of course. But it sounds as if Rocky is in good hands. (My former cat who had quite a few ailments used to get diarrhea often from taking antibiotics. The problem was always to make sure she wasn't getting too dehydrated but was still on the road to recovery. The antibiotics were usually for ear infections.)


Agate,

He finished his antibiotics and is doing much better. He's treated like a prince here, and he knows it. icon_smile He was so good taking his liquid medicine. He'll be going camping with us soon, we rent a deluxe camper for a week up in N. Wisconsin. He'll be able to look out the windows at chimpmunks, dogs, deer, birds and little kids playing. I hope he has a good time. :-)
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PostPosted: Wed Jun 20, 2007 7:34 pm    Post subject: Reply with quote

Glad he's feeling better!
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PostPosted: Wed Jun 20, 2007 7:42 pm    Post subject: Reply with quote

Thanks Matt, sunny

He's sleeping soundly on my lap right now. We had a vigorous game of fetch this morning. He fetches like a puppy. toothy7
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PostPosted: Wed Jun 20, 2007 10:25 pm    Post subject: Reply with quote

That's great that he's better!

Northern Wisconsin sounds just perfect. I've been there--years ago-- and I hope it hasn't changed since then.
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PostPosted: Fri Jun 22, 2007 2:49 pm    Post subject: (Abstract) Safety of Tysabri in patients w/RRMS... Reply with quote

From the 17th congress of the European Neurological Society, June 2007:

Quote:
The safety of natalizumab in patients with relapsing multiple sclerosis: an update from TOUCH and TYGRIS

C. Bozic, G. Belcher, M. Kooijmans, R. Kim, F. Lynn, M.A. Panzara (Cambridge, US)

Objective: To report an update on the safety of natalizumab in relapsing multiple sclerosis (MS) patients.

Background: Natalizumab (TYSABRI®), an alpha4-integrin antagonist, provides significant efficacy in the treatment of relapsing MS. Although natalizumab was well tolerated in clinical studies, three cases of progressive multifocal leukoencephalopathy (PML) occurred; two in MS patients receiving natalizumab plus interferon beta-1a and one in a Crohn’s disease patient. A prescribing program and global observational study are being conducted to further assess the safety of natalizumab.

Design/Methods: Before initiating natalizumab treatment, all US patients, physicians and infusion centers must enroll into the TOUCH Prescribing Program (TYSABRI Outreach: Unified Commitment to Health). The TOUCH Prescribing Program is a safety registry designed to determine the incidence of and risk factors for serious opportunistic infections (OIs), including PML, and to monitor patients for signs and symptoms of PML while assuring informed benefit/risk discussions prior to initiating natalizumab treatment. Physicians report on PML, serious OIs, deaths and natalizumab discontinuation, on an ongoing basis. In addition, approximately 5,000 natalizumab-treated patients worldwide, including 3,000 patients from TOUCH, will be enrolled in a global observational study called TYGRIS (TYSABRI Global ObseRvation Program In Safety). Patients in TYGRIS are evaluated at baseline and every 6 months thereafter for 5 years. The following information is being collected: medical/MS history; prior natalizumab use; prior use of immunomodulatory, antineoplastic, or immunosuppressive agents; and all serious adverse events, including PML and other serious OI, and malignancies.

Results: Available safety data from patients receiving natalizumab worldwide will be presented.

Conclusions/Relevance: Information from these studies will expand our knowledge of long-term natalizumab safety and further better quantify the risk of PML, serious OIs, and malignancy.
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PostPosted: Tue Jun 26, 2007 7:55 am    Post subject: Reply with quote

Glad to hear everything went well with the Tysabri infusion, Ewizabeth.

Cherie
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PostPosted: Tue Jun 26, 2007 8:05 am    Post subject: Reply with quote

agate wrote:
From WebMD's Medscape, May 22, 2007:

Quote:
Natalizumab Comparable to Interferon for Relapsing Multiple Sclerosis

NEW YORK (Reuters Health) May 11 - Natalizumab is comparable to interferon beta-1a in the net health benefits it provides for relapsing multiple sclerosis, an analysis of published data suggests.

Previous reports have shown natalizumab to be effective in preventing relapsing and slowing disease progression, but the drug has also been linked to an increased risk of progressive multifocal leukoencephalopathy (PML), which often proves fatal. Whether the benefits of natalizumab provides offsets this risk is unclear.

In the current study, Dr. Ray Dorsey, from the University of Rochester Medical Center in New York, and colleagues analyzed published data to assess the quality-adjusted life years (QALYs) gained with natalizumab. A comparison was then made with interferon beta-1a.

Data for the natalizumab analysis was drawn from the Natalizumab Safety and Efficacy in Relapsing Multiple Sclerosis (AFFIRM) trial, while the interferon data came from the Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study. Each study lasted roughly 2 years.

The investigators report their findings in the May 1st issue of Neurology.

The authors found that in terms of the effect on QALYs, natalizumab was minimally more effective than interferon at reducing disease relapses. The agents were comparable in their ability to slow disease progression. Because natalizumab did carry a slight risk of PML, the final net health effect of the drugs was nearly identical - 0.033 QALYs gained.

"Over the first 2 years of therapy, the health effect of natalizumab for the treatment of relapsing multiple sclerosis is much greater than the expected harm from PML," the authors conclude. Still, they write, long-term observational studies are needed to fully characterize the risk of PML with this drug.

Neurology 2007;68:1524-1528.


I wonder how they determined that Tysabri was only "minimally more effective than interferon at reducing disease relapses." I realize that the stats are fairly comparable for reducing disease progression . . . but it is/was tauted as being 68% effective in reducing relapses, whereas CRABs are supposedly only 30% effective. scratch

I wonder if it has anything to do with this new way of comparing the drugs where they look at trial subject's prior history and disability status; ARR, NNT measurements.

agate wrote:
From the 17th congress of the European Neurological Society, June 2007:

Quote:
Assessing the net clinical benefit and absolute risk reduction of disease-modifying drugs in relapsing-remitting multiple sclerosis

A. Al-Sabbagh, R. Bennett, V. Divan, B. Singer (Rockland, St. Louis, US)

Objective: To compare the baseline disease severity levels and ARRs across the Class 1 studies with DMDs for RRMS. Clinicians and payers tend to compare the results of individual clinical trials utilizing relative risk reduction (RRR) for each therapy. However, the significance of inter-study variability, heterogeneity of the patient population, different baseline characteristics, and inconsistent placebo behaviors from different clinical trials makes comparison based on RRR inappropriate. Measurement of absolute risk reduction (ARR) may be a more appropriate assessment of benefit.

Methods: Class 1 studies published for the respective DMDs were reviewed and analyzed to compare the baseline EDSS and relapse rates across DMD study populations. The clinical benefit of DMDs versus placebo for two-year relapse rates and proportion of progression-free patients were compared across all studies using ARR and number needed to treat (NNT).

Results: For patients enrolled in the PRISMS study, the proportion of patients with 2, 3, or 4 relapses at baseline for Rebif-treated patients were 41%, 33%, and 26% respectively. For Tysabri-treated patients, the proportion of patients with 1, 2, or 3 relapses at baseline were 58%, 32% and 9%, respectively with no reported data for Avonex, Betaseron, and Copaxone.

The proportion of patients with baseline EDSS scores of 3 or more were higher in the Rebif treated patients compared with Avonex and Tysabri (41%, 33% [1], 33%, respectively) with no reported data for Betaseron and Copaxone. The ARR for annualized relapse rates were 0.15, 0.24, 0.40, 0.41, and 0.45 [2] for Avonex, Copaxone, Betaseron, Rebif, and Tysabri (NNTs: 6.7, 4.2, 2.5, 2.4, 2.2), respectively.

ARR for progression-free patients were 0.13 [3], 0.03, 0.08, 0.12, and 0.12 for Avonex, Copaxone, Betaseron, Rebif, and Tysabri (NNT: 7.7 [3], 33.3, 12.5, 8.7, 8.7) respectively.

Conclusion: Given the difference in baseline risk and severity levels across studies, ARR is the appropriate way to compare across DMDs in the absence of head-to-head clinical trials. Results based on ARR showed that Rebif has comparable therapeutic effect on efficacy measures when compared to Tysabri.


Cherie
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PostPosted: Tue Jun 26, 2007 10:01 am    Post subject: Reply with quote

I'm no statistician. I'm the sort of person who would pick a horse I liked the looks of (or its name) to bet on and pay little attention to who the favorite is, or what the odds are.

But maybe this will provide a clue or two to the terms being used (ARR, RRR, NNT):



http://tinyurl.com/3cnzrn
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PostPosted: Wed Jun 27, 2007 8:34 am    Post subject: Reply with quote

Stats were "my thing", once upon a time. I completed my 4th level university business/financial math, and statistics/economics . . . but that was when I had a brain. geek

I looked up that ARR and NTT too, when I saw your posting about it on the other thread. This is what I came across:

http://www.scottish.parliament.uk/business/research/pdf_res_notes/rn01-38.pdf

Basically what they are saying is that when you factor in the level of disability and history of attacks of the trial subjects, the drugs are about as effective as each other.

To be honest, I'm not sure that is a good way of evaluating efficacy either, but it does seem fairer than one trial taking those with a "1" EDSS (and/or low attack history), and comparing with those who are at a "4".

Cherie
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PostPosted: Wed Jun 27, 2007 11:02 pm    Post subject: Reply with quote

Hmm, then my neuro was probably right when (several years ago) he said I could choose Avonex, Betaseron, or Copaxone, and he didn't care which one I chose "because they're all pretty much alike in what they do." (Rebif wasn't around then.)
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PostPosted: Thu Jun 28, 2007 8:13 am    Post subject: Reply with quote

Yeah, except that I do think it's possible that Copaxone might work for people that the interferons don't, and Tysabri still help where all else has failed.

Cherie
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PostPosted: Thu Jun 28, 2007 8:47 am    Post subject: Reply with quote

I agree--and I'm sure the neuro I go to would agree too. In fact, he's said as much.

His statement about picking any of the three because they're all pretty much alike was made back when I hadn't tried any of the ABCRs yet.
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PostPosted: Mon Jul 09, 2007 2:03 pm    Post subject: (Extract) Post-LP headaches in MS patients on Tysabri Reply with quote

There's an article in Archives of Neurology, 64 (2007), 1055-1056, and this is an extract from it (the first 150 words):



Quote:



High Incidence of Post–Lumbar Puncture Headaches in Patients With Multiple Sclerosis Treated With Natalizumab: Role of Intrathecal Leukocytes

Olaf Stüve, MD, PhD; Petra D. Cravens, PhD; Mahendra P. Singh, PhD; Elliot M. Frohman, MD, PhD; J. Theodore Phillips, MD, PhD; Gina Remington, RN, BSN; Wei Hu, MD, PhD; Bernhard Hemmer, MD; Michael J. Olek, DO; Nancy L. Monson, PhD; Michael K. Racke, MD


Arch Neurol. 2007;64:1055-1056.


Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.



The reported frequency of post–lumbar puncture headache (PLPH) is as high as 70%.1 In contrast, the frequency of PLPH with an atraumatic 22-gauge Sprotte needles is 12.2%.2

Natalizumab (Tysabri; Biogen Idec, Cambridge, Massachusetts) is a recombinant humanized monoclonal antibody that binds to the 4 chain of the 41 and 47 integrins. Natalizumab reduces the extravasation of T lymphocytes, B lymphocytes, and plasma cells into the central nervous system.3-4 We tested the association between lymphocyte numbers in the peripheral blood and cerebrospinal fluid (CSF) and the frequency of PLPH in patients with relapsing-remitting multiple sclerosis who were receiving natalizumab therapy and 14 months after cessation of therapy.

Methods


Patients

Patients receiving . . .

Lumbar Puncture and Cell Analysis

Statistical Analyses


Results

Patients

Post–Lumbar Puncture Headache


Cell Numbers in Peripheral Blood and CSF



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PostPosted: Thu Jul 12, 2007 1:57 pm    Post subject: (Abstract) Tysabri for RRMS Reply with quote

From PubMed, July 12, 2007:

Quote:
Neurologist. 2007 Jul;13(4):182-7

Natalizumab (tysabri) treatment for relapsing multiple sclerosis

Johnson KP.
From the Department of Neurology, University of Maryland Baltimore School of Medicine, Maryland Center for Multiple Sclerosis, Baltimore, Maryland.

BACKGROUND: Natalizumab (Tysabri), a humanized monoclonal antibody which binds to the alpha4beta1 integrins of leukocytes, blocks attachment to cerebral endothelial cells, thus reducing inflammation at the blood-brain barrier.

Two pivotal randomized trials, one comparing active treatment to placebo and one comparing active treatment to placebo in relapsing multiple sclerosis (MS) patients receiving intramuscular interferon beta1alpha (Avonex), demonstrated significant efficacy for relapse control, decrease in sustained disability, and reduced numbers of new lesions on MRI.

REVIEW SUMMARY:Because of safety issues raised by the appearance of 2 cases of progressive multifocal leukoencephalopathy in MS patients exposed to natalizumab for relapsing MS, treatment has been restricted.

This review briefly outlines the inflammatory nature of MS plaques, the mechanism of action of natalizumab and the pathogenesis of progressive multifocal leukoencephalopathy. The mandatory guidelines for natalizumab use in the treatment of MS with natalizumab are explained. Special concerns facing the therapist electing to prescribe natalizumab are mentioned.

CONCLUSION: Natalizumab recently joined glatiramer acetate and beta interferon as an approved therapy for controlling relapsing MS. Unresolved safety issues currently restrict its use to monotherapy in patients who have had inadequate response to the other immunomodulating agents.

PMID: 17622909


This seems like just a summary of what is already well known, but since it's about Tysabri, and Tysabri is still controversial, here it is.
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PostPosted: Wed Aug 29, 2007 6:52 pm    Post subject: Sporadic help from Tysabri? (article) Reply with quote

From HealthTalk's "Ask the Doctor" section (questions answered by Patrick Parcells, MD), August 29, 2007:

Quote:
On-again, off-again with my new MS treatment

Question:

I have taken every treatment, and now I am on Tysabri. The first couple of infusions were like I had found the miracle drug. I felt great and needed no assistance in walking. Now after being on this for four months it seems as if it is not working like it did. I know it is new, but do you know if this is the way this stuff is going to work? (On and off when it comes to helping.) I just would like to know so I can learn how to control the depression it causes when it stops working.


Answer:

Tysabri (natalizumab) is the newest treatment we have for multiple sclerosis. It is given intravenously once a month. The clinical data from the Tysabri trials did not show that there was improvement in patients’ symptoms or multiple sclerosis disease itself, but that the drug prevented worsening of disability by 42 percent and prevented new relapses by 67 percent. There have been individual case reports of patients stating that they feel better and that their disease has improved but this was not shown in the clinical trials.

However, Tysabri was shown in the clinical trials to have noteworthy benefit on “quality of life” and it was the first MS treatment ever to show a statistically significant benefit with MS patients in this area. To have fluctuations, as you’ve described, is not unexpected. Many people go through periods of time where they feel better and other times when their symptoms get worse. Tysabri should be used with appropriate realization that its purpose is to prevent the disease from getting worse and not necessarily to make things better – although if they do get better we are certainly happy for that.

It would be difficult to know when the drug would “stop working.” The clinical trials went for two years and are being looked at even further, but we do not have any evidence long-term what will happen with Tysabri. Certainly, we’re hopeful that it will continue to be very effective in slowing down progression of disability and preventing relapses in the majority of patients.



Quote:


Dr. Patrick Parcells is a neurologist at Hampton Roads Neurology, Inc. in Newport News, Virginia. He is board certified by the American Board of Neurology and Psychiatry and the American Board of Electrodiagnostic Medicine and has served as president for the Virginia Neurological Society. He has studied epidemiological research on MS and has participated in research for Alzheimer's disease, migraine, epilepsy, stroke and neurologic (E&M) coding.

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PostPosted: Sat Sep 01, 2007 5:51 pm    Post subject: (Abstract) Anti-Tysabri antibodies (AFFIRM & SENTINEL) Reply with quote

From PubMed, September 1, 2007:

Quote:
Neurology. 2007 Aug 29



The incidence and significance of anti-natalizumab antibodies. Results from AFFIRM and SENTINEL

Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M, Kappos L, Miller DH, O'connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Lublin FD, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA; for the AFFIRM and SENTINEL Investigators.

From the Johns Hopkins Multiple Sclerosis Center (P.A.C.), Baltimore, MD; Institute of Neurology (G.G., D.H.M.), London, UK; Hôpital Neurologique (C.C.), Lyon, France; University of Pennsylvania School of Medicine (S.L.G.), Philadelphia; Neurological Department (E.H.), General Teaching Hospital, Prague, Czech Republic; St Vincent’s University Hospital (M.H.), Dublin, Ireland; University Hospitals Basel (L.K., E.-W.R.), Switzerland ; St. Michael’s Hospital (P.W.O’C.), Toronto, Ontario, Canada; Texas Neurology (J.T.P.), Dallas; VU Medical Centre (C.H.P.), Amsterdam, the Netherlands; Mellon Center for Multiple Sclerosis Treatment and Research (R.A.R.), Cleveland Clinic Foundation, OH; MS Center of Atlanta (W.H.S.), GA; Mt. Sinai School of Medicine (F.D.L.), New York; Silesian Medical University (A.W.), Katowice, Poland; Jacobs Neurological Institute (B.W.-G.), SUNY University at Buffalo, NY; Consultants in Neurology Multiple Sclerosis Center (D.R.W.), Northbrook, IL; and Biogen Idec, Inc. (F.L., M.A.P.), Cambridge, MA.

OBJECTIVE: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab.

METHODS: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon beta-1a [INFbeta1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab.

Antibodies to natalizumab were measured using an ELISA. Patients were categorized as "transiently positive" if they had detectable antibodies (>/=0.5 microg/mL) at a single time point or "persistently positive" if they had antibodies at two or more time points >/=6 weeks apart.

RESULTS: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression(p </= 0.05), relapse rate (p = 0.009), and MRI (p </= 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming antibody negative.

The incidence of infusion-related adverse events was significantly higher in persistently positive patients.

Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant.

CONCLUSIONS: The incidence of persistent antibody positivity associated with natalizumab is 6%. Reduced clinical efficacy is apparent in persistently positive patients. Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing.

PMID: 17761550
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PostPosted: Mon Sep 10, 2007 2:25 pm    Post subject: (Abstract) Delayed allergic reaction to Tysabri w/early NAbs Reply with quote

From Archives of Neurology, September 2007:

Quote:



Delayed Allergic Reaction to Natalizumab Associated With Early Formation of Neutralizing Antibodies

Markus Krumbholz, MD; Hannah Pellkofer, MD; Ralf Gold, MD; Lisa Ann Hoffmann, MD; Reinhard Hohlfeld, MD; Tania Kümpfel, MD


Arch Neurol. 2007;64:1331-1333.

Background

Natalizumab is a new therapeutic option for relapsing-remitting multiple sclerosis. As with other antibody therapies, hypersensitivity reactions have been observed. In the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) trial, infusion-related hypersensitivity reactions developed in 4% of patients, usually within 2 hours after starting the infusion.

Objective


To report a significant, delayed, serum sickness–like, type III systemic allergic reaction to natalizumab.

Design

Case report describing clinical follow-up and the serial measurement of antinatalizumab antibodies.

Patient

A 23-year-old man with relapsing-remitting multiple sclerosis developed a fever, arthralgias, urticarial exanthema, and a swollen lower lip during several days after his second infusion of natalizumab.

Results

The patient developed a delayed, serum sickness–like, type III systemic allergic reaction to natalizumab. Five weeks after initiation of this therapy, he tested positive for antinatalizumab antibodies and exhibited persistent antibody titers 8 and 12 weeks later. His symptoms completely resolved with a short course of oral glucocorticosteroids.

Conclusion

Clinicians and patients should be alert not only to immediate but also to significantly delayed substantial allergic reactions to natalizumab.


Author Affiliations: Institute for Clinical Neuroimmunology, Ludwig Maximilian University, Munich, Germany (Drs Krumbholz, Pellkofer, Hoffmann, Hohlfeld, and Kümpfel); and Department of Neurology, St Josef-Hospital, Ruhr University, Bochum, Germany (Dr Gold).








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PostPosted: Mon Sep 10, 2007 6:59 pm    Post subject: Reply with quote

Every time I go for the infusion, they question me at length about any new symptoms at any time, or any illness. This might be what they're looking for. I thought they were just looking for signs of PML, but I guess not.
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PostPosted: Thu Sep 13, 2007 11:31 am    Post subject: (Article) Disease activity increases after stopping Tysabri Reply with quote

From News-Medical.net, September 12, 2007:

Quote:
Disease activity increases after multiple sclerosis patients stop natalizumab

People with multiple sclerosis who stop taking the drug natalizumab may experience a rebound increase in disease activity, according to a study published September 12, 2007, in the online edition of Neurology, the medical journal of the American Academy of Neurology.

The study involved 21 people who had MRI scans of their brains taken before taking natalizumab and again an average of 15 months after receiving the last infusion of the drug. The drug is given by IV infusion once a month. The participants were divided into two groups: one group took the drug for an average of three years, and the other group took the drug for an average of two months.

The participants developed more than three times as many brain lesions, or areas of damage in the brain that are a marker of MS disease activity, in the 15-month period after discontinuing the drug than they had developed before they started taking the drug. The results were most pronounced for those who took the drug for only a short time; they developed five times as many brain lesions after stopping the drug than they did before they started taking it.

More research needs to be done with larger numbers of patients before any recommendations can be made about use of the drug, according to study author Machteld Vellinga, MD, of VU University Medical Center in Amsterdam, the Netherlands. "For now the recommendations remain the same-patients and their doctors should choose the most applicable treatment for them," she said.

Vellinga said it's not clear why discontinuing the drug would lead to increased disease activity, although an earlier animal study showed a similar result when rats with an animal model of multiple sclerosis were given a drug that suppresses the immune system.

The study came about because use of natalizumab was suspended in 2005 after three people participating in clinical trials for the drug developed a rare, often fatal brain disease called progressive multifocal leukoencephalopathy.

"All of our patients had an MRI shortly after the drug was suspended, and our neuroradiologist noticed that in some patients a considerable number of new lesions developed on their MRIs in the following year," said Vellinga. "We decided to do a formal analysis to see if this was actually the case." Vellinga noted that the results need to be confirmed in independent groups of patients.

The drug was reintroduced in 2006 with specific guidelines for its use and to monitor patients for signs of progressive multifocal leukoencephalopathy.

Source: News-Medical.Net


Last edited by agate on Thu Sep 13, 2007 1:32 pm; edited 1 time in total
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Matt



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PostPosted: Thu Sep 13, 2007 12:09 pm    Post subject: Reply with quote

This doesn't surprize me. Back when I had my spinal tap, they found a spirochete. Who knows how many spirochetes I would have had after a few months of no immune surveilance in my CNS. Of course, infections in the CNS probably cause an increase in disease activity.

With my now mild MS, Tysabri seems like quite a bad idea for ME at least.
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ewizabeth



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PostPosted: Thu Sep 13, 2007 12:38 pm    Post subject: Reply with quote

That study is interesting, but 21 patients is an extremely small sample size to draw any conclusions, considering there are an excess of 10,000 people taking Tysabri today.

I suppose if it did turn out to be true, a patient could have an IVSM treatment when going off Ty, or start high dose Rebif or maybe a one time dose of Novantrone to shock the system back to its "normal" MS state, whatever that would be. scratch
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Ewizabeth
DX 01/28/03 RRMS
Formerly Avonex, Rebif & Copaxone
Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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Matt



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PostPosted: Thu Sep 13, 2007 1:00 pm    Post subject: Reply with quote

ewizabeth wrote:
That study is interesting, but 21 patients is an extremely small sample size to draw any conclusions, considering there are an excess of 10,000 people taking Tysabri today.

I suppose if it did turn out to be true, a patient could have an IVSM treatment when going off Ty, or start high dose Rebif or maybe a one time dose of Novantrone to shock the system back to its "normal" MS state, whatever that would be. scratch


I hope they can do something like that if this does turn out to be true. I'm a bit worried though, because five times seems like a really huge number. I do hope that this is a result of the small size of the study, but I doubt it.

Quote:

The results were most pronounced for those who took the drug for only a short time; they developed five times as many brain lesions after stopping the drug than they did before they started taking it.
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agate
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PostPosted: Wed Sep 19, 2007 12:49 pm    Post subject: More about this Reply with quote

More on this research--from Medscape Medical News, September 19, 2007:

Quote:
Natalizumab Withdrawal Linked to Significant Lesion Increase In MS

Caroline Cassels
Medscape Medical News 2007




September 12, 2007 — New research suggests individuals with relapsing multiple sclerosis (MS) who are withdrawn from the monoclonal antibody natalizumab (Tysabri, Biogen-Idec) may experience a significant rebound increase in disease activity.

Researchers at the VU University Medical Center, in Amsterdam, the Netherlands, found patients with relapsing MS who stopped taking the drug developed 3 times as many brain lesions in the 15-month period after discontinuing natalizumab as they had before starting the medication.

Furthermore, with an observed 5-fold increase in brain lesions, this effect was most pronounced among individuals who took the drug for only a short time.

The study, which included 21 patients, came about because in 2005 natalizumab was withdrawn from the market and clinical trials put on hold after 3 patients in clinical studies developed progressive multifocal leukoencephalopathy (PML).

Following completion of a safety analysis of all patients treated with the drug, natalizumab was subsequently reintroduced in 2006, and clinical trials resumed under a Food and Drug Administration special restricted-distribution program with specific guidelines for use and monitoring of patients for signs of PML.

"All our patients had an MRI shortly after the drug was suspended, and our neuroradiologist noticed that in some patients a considerable number of new lesions developed during this 15-month interval. We decided to do a formal analysis to see whether this is actually the case," principal investigator Machteld Vellinga, MD, said in a statement from the American Academy of Neurology.

The study is published online September 12 in Neurology.

Rebound Effect

A total of 21 patients were included in the analysis — 9 women and 12 men, with a mean age of 39.8 years and mean disease duration of 5.8 years. All subjects were participants in the phase 3 program of 2 clinical trials — the Natalizumab Safety and Efficacy in Relapsing Remitting MS (AFFIRM) or the Safety and Efficacy of Natalizumab in Combination with Interferon beta-1a in Patients with Relapsing Remitting MS (SENTINEL).

Patients randomized to natalizumab had active treatment during the double-blind and extension phases of the study, with a median of 36 infusions. Those randomized to placebo received the drug only during the extension phase and received a median of 2 infusions.

To create the longest possible interval between pretreatment MRI scans, the earliest available brain MRI was chosen for each patient. A total of 42 pairs of scans were scored for new and enlarging T2 lesions.

According to the study, the median annualized number of active T2 lesions was increased in the postwithdrawal interval compared with the pretreatment interval. The researchers found no effect of age, sex, disease duration, MRI lesion load, or whether the subjects had been enrolled in either AFFIRM or SENTINEL trials.

Furthermore, the authors note, the increase in disease activity was much more pronounced in the placebo/natalizumab patients compared with the natalizumab/natalizumab subjects.

"Our data suggest a significant 'rebound' increase in the development of new and enlarging T2 lesions in patients with MS who discontinued natalizumab treatment, which appears to be driven by the patients with only short exposure to natalizumab," the investigators write.

Clinical Practice Remains The Same

It is not clear, said Dr. Vellinga, why discontinuation of the drug would lead to increased disease activity. However, she notes the finding of partial immunosuppression giving rise to extra disease activity has previously been observed in rats with an animal model of MS who were treated with low-dose cyclosporine A.

However, she added, further research needs to be done with larger numbers of patients before any recommendations can be made about the use of natalizumab.

"For now the recommendations remain the same — patients and their doctors should choose the most applicable treatment for them," she said.

Dr. Villenga declares no conflict of interest related to the study. Conflict-of-interest information for other authors is available in the paper.

Neurology. Published online September 12, 2007.
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agate
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PostPosted: Fri Sep 28, 2007 5:09 pm    Post subject: Still more about the rebound effect Reply with quote

From the MS Foundation newsletter, September 28, 2007:

Quote:
DOES TYSABRI HAVE A REBOUND EFFECT?

People with MS who stop taking Tysabri (natalizumab) may experience a rebound increase in disease activity, according to a study published September 12, 2007, in the online edition of Neurology, the medical journal of the American Academy of Neurology.

The study involved 21 people who had MRI scans of their brains taken before taking Tysabri and again an average of 15 months after receiving the last infusion of the drug, which is given by IV infusion once a month. The participants were divided into two groups. One group took the drug for an average of three years, and the other group took the drug for an average of two months.

The participants developed more than three times as many brain lesions in the 15-month period after discontinuing the drug than they had developed before they started taking the drug. The results were most pronounced for those who took the drug for only a short time. They developed five times as many brain lesions after stopping the drug than they did before they started taking it.

More research with larger numbers of patients is needed before any recommendations can be made about use of the drug. It's not clear why discontinuing the drug would lead to increased disease activity. However, in an earlier animal study of MS, a similar result was seen in rats when given a drug that suppresses the immune system.

The study came about because use of Tysabri was suspended in 2005 after three people developed a rare, often fatal brain disease called progressive multifocal leukoencephalopathy.

The drug was reintroduced in 2006 with specific guidelines for its use and to monitor patients for signs of progressive multifocal leukoencephalopathy.

"We have not seen a rebound effect with any of our other disease-modifying drugs," comments MSF Medical Advisor Ben Thrower, M.D. "It would be interesting to know how the patients were doing clinically when they had the increase in MRI activity because MRI activity in the form of new enhancing lesions and new T2 lesions is typically 5-10 times more frequent than actual relapses. However, some studies have correlated enhancing lesions with the risk for future disability. What I take from this study is that people stopping Tysabri need to be watched closely, especially if they have only been on the drug a few months. I don't know that it will change the way in which I use Tysabri as my Tysabri patients have usually failed other options."


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