Bookmark this site!
MS TREATMENTS: TYSABRI/NATALIZUMAB
Goto page Previous  1, 2, 3, 4  Next
 
Post new topic   Reply to topic    msspeaks Forum Index -> MS - RESEARCH, ARTICLES, ABSTRACTS, DISCUSSION
View previous topic :: View next topic  
Author Message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Oct 03, 2007 8:58 am    Post subject: (Article) Delayed Tysabri allergy in patient w/MS Reply with quote

From Medscape Medical News, October 3, 2007:

Quote:
Delayed Natalizumab Allergy Seen in Patient With Multiple Sclerosis





NEW YORK (Reuters Health) Sept 26 - Although most hypersensitive reactions to natalizumab occur within hours of the first dose, such responses may be delayed, according to a case report by German researchers.

In the September issue of the Archives of Neurology, Dr. Markus Krumbholz of Ludwig Maximilian University, Munich, and colleagues report on a 23-year-old man with relapsing-remitting multiple sclerosis (MS).

Eight hours after his second infusion of natalizumab he collapsed, developed a fever, arthralgias, urticarial exanthema, and a swollen lower lip.

The patient had had no history of allergic reactions and his concomitant medication had not changed over the previous weeks. After excluding an underlying infection, the researchers treated the man with oral prednisone for 2 days. All symptoms subsequently resolved.

He tested positively for anti-natalizumab antibodies 5 weeks after his initial treatment with the agent and exhibited persistent antibody titers 8 and 12 weeks later. The researchers diagnosed a delayed allergic reaction and switched his therapy to mitoxantrone.

Thus, Dr. Krumbholz and his associates advise, "patients and treating physicians should be aware that delayed hypersensitivity reactions, such as serum sickness, can develop during treatment with natalizumab."

"If unusual symptoms consistent with an allergic reaction occur during the first days after infusion, patients should contact their neurologists to initiate appropriate medical treatment," they conclude.

Arch Neurol 2007;64:1331-1333.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sun Oct 14, 2007 1:17 pm    Post subject: (Abstract) Impact of Tysabri on MS severity... Reply with quote

From the ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) conference in Prague, October 11-14, 2007:

Quote:
Immunomodulation 2

Saturday, October 13, 2007, 15:30 - 17:00

Impact of natalizumab on multiple sclerosis severity: analysis of patients and subgroups from the AFFIRM study using the Multiple Sclerosis Severity Scale

J. Herbert, L. Kappos, G. Giovannoni, E. Havrdova, M. Hutchinson, F. Lublin, D. Miller, P. O'Connor, J.T. Phillips, C.H. Polman, A. Wajgt, J. Bacon, I. Kister, A. Pace, M. Panzara (New York, USA; Basel, CH; London, UK; Prague, CZ; Dublin, IRL; Toronto, CAN; Dallas, USA; Amsterdam, NL; Katowice, PL; Cambridge, USA)

Background:

The Multiple Sclerosis Severity Scale (MSSS) is an algorithm originally developed to give a better assessment of MS severity, and may be a more sensitive measure of disease severity than outcomes currently used in clinical studies. We examined the effects of natalizumab monotherapy on disease severity as measured by the MSSS in the overall study population and in 2 subgroups of patients from the AFFIRM study.

Methods:

Expanded Disability Status Scale (EDSS) scores and disease duration were used to assign MSSS scores to patients in the overall study population, highly active patients (patients with >=2 relapses in the year prior to study entry and >=1 gadolinium-enhancing lesions at study entry), and non–highly active patients.

Patients were assigned to 1 of 6 MSSS severity groups at baseline and study completion, and analyses were conducted at these 2 time points. Shifts between MSSS severity groups from baseline to study completion were determined.

Results:

Natalizumab (n=613) and placebo (n=311) patients were well matched for median baseline MSSS score (3.55 vs. 3.69; P=0.708) and for MSSS group assignment at baseline (P=0.887). At study termination, the median MSSS score was 2.60 in natalizumab patients compared with 2.87 in placebo patients (P<0.001). In both highly active (n=206) and non–highly active patients (n=718), median MSSS scores at study completion were significantly lower in natalizumab patients compared with placebo patients. More natalizumab patients than placebo patients shifted to a lower severity group (46% vs. 37%) and fewer patients shifted to a higher severity group (10% vs. 20%) during the study (P<0.001). Similar results were seen between treatment groups in both subgroups.

In the overall study population, the median MSSS change from baseline was significantly greater in natalizumab patients compared with placebo patients (-0.68 vs. -0.38; P<0.001).

Conclusions:

Compared with placebo, natalizumab treatment produced a significant shift in MSSS scores from baseline to study completion in the overall AFFIRM study population, as well as in the highly active and non–highly active patient subgroups. These results demonstrate that natalizumab treatment effectively reduces disease severity, regardless of baseline disease activity.

Re-analysis of other MS studies using this scale may help better assess the sensitivity of the MSSS as a measure of therapeutic efficacy.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sun Oct 14, 2007 1:25 pm    Post subject: (Abstract) Tysabri & "disease-free" patients Reply with quote

From the ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) Conference in Prague, October 11-14, 2007:

Quote:
Immunomodulation 2

Saturday, October 13, 2007, 15:30 - 17:00

Natalizumab increases the proportion of patients with multiple sclerosis who are disease-free

E. Havrdova, G. Giovannoni, M. Hutchinson, L. Kappos, F. Lublin, D.H. Miller, P. O'Connor, J.T. Phillips, C.H. Polman, A. Wajgt, A. Pace, R. Kim, M. Panzara (Prague, CZ; London, UK; Dublin, IRL; Basel, CH; New York, USA; Toronto, CAN; Dallas, USA; Amsterdam, NL; Katowice, PL; Cambridge, USA)

Background:

Disease remission, defined as the absence of disease activity without concomitant medication use, has been considered the ultimate goal of treatment in immune-mediated diseases such as rheumatoid arthritis, psoriasis, and Crohn’s disease. The availability of more aggressive treatment strategies (eg, biologics) has increased the ability to achieve remission in these diseases. In the pivotal phase 3 clinical trial (the AFFIRM study), natalizumab (TYSABRI®) monotherapy was shown to reduce significantly the annualised relapse rate by 68% and the sustained disability progression by 42%-54% in patients with relapsing MS.

Analyses of data from AFFIRM were conducted to determine the effect of natalizumab on the proportion of disease-free patients compared with placebo. The analyses explored various definitions of disease-free to determine their utility as potential endpoints in MS trials.

Methods:

Patients were randomly assigned in a 2:1 ratio to receive either natalizumab 300 mg (n=627) or placebo (n=315) intravenously once every 4 weeks for up to 116 weeks. Analyses were conducted to determine the proportion of disease-free patients as defined by clinical and MRI measures over the 2-year treatment period.

Clinically, disease-free was defined as no relapses and no progression of disability (>=1.0-point increase in Expanded Disability Status Scale score from a baseline EDSS of >=1.0, or a >=1.5-point increase in EDSS from a baseline EDSS of 0, sustained for 12 weeks). MRI disease-free was defined as no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions.

Results:

The proportion of disease-free patients over 2 years was significantly higher in the natalizumab group compared with the placebo group regardless of how disease-free was defined: clinical measures (64.3% natalizumab vs. 38.9% placebo; P<0.0001), MRI measures (57.7% natalizumab vs. 14.2% placebo; P<0.0001).

When both clinical and MRI measures were used (the most stringent definition), 36.7% of natalizumab patients were disease-free compared with 7.2% of placebo patients (P<0.0001).

Conclusion:

Natalizumab significantly increased the proportion of disease-free patients compared with placebo. Further studies are warranted to determine if natalizumab can induce a state of disease remission (allowing discontinuation of treatment) in patients with MS. It would also be interesting to determine how long such disease-free patients can go without treatment and stay in remission.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Oct 18, 2007 7:14 pm    Post subject: (Abstract) 3 cases of herpes reactivation in MS patients... Reply with quote

Another abstract from the recent ECTRIMS conference:

Quote:
Three cases of herpes reactivation in MS patients on natalizumab monotherapy

I. Kister, J. Herbert (New York, USA)

Background:

Suppression of immune surveillance by Natalizumab can lead to reactivation of latent viruses, as dramatically illustrated in the case of JC Virus. It is unclear whether Natalizumab may also predispose to reemergence of other neurotropic viruses. Reports of lethal herpes encephalitis in one patient and herpes meningitis in another suggest a possible role for Natalizumab in herpesvirus reactivation.

Objectives:

To report two patients with VZV and one with HSV skin eruption temporally related to initiation of Natalizumab monotherapy. To review the data on adverse events (AE) related to herpetic infections during trial and post-marketing periods.

Case reports:


Patient #1: 33-year-old Caucasian woman with unstable relapsing-remitting MS (RRMS) and recurrent annual herpes simplex lip sores since adolescence. After initiating Natalizumab, she experienced re-emergence of herpetic lesions several hours after each of four consecutive infusions. Lesions resolved spontaneously within a few days. With Valacyclovir prophylaxis she has not had further recurrences.

Patient #2: 37-year-old African-American woman with RRMS and history of childhood chickenpox developed herpes zoster ophthalmicus three weeks after her second infusion of Natalizumab. She has recovered without sequelae with high-dose oral Valacyclovir, and continues uneventful treatment on prophlaxis.

Patient #3: 31 year old Hispanic woman with malignant MS recalcitrant to multiple therapies and history of thoracic herpes zoster one year previously suffered a recurrence of zoster rash in same location 10 days following the first dose of Natalizumab.

Discussion:
In Natalizumab MS pivotal trials, the percentage of patients with ‘herpes zoster’ was 2% in both treated and placebo groups. However, incidence of zoster in the placebo arm of 1%/year is several times higher than that reported for the general population (~0.2%/year). This discrepancy may be because documentation of rash was not required for report of zoster-related AE. The apparent increase in incidence among placebo patients may have obscured the effect of the drug on true herpes reactivation.

Conclusion:

Natalizumab therapy may be associated with reactivation of herpesviruses. We suggest close monitoring for signs and symptoms of herpetic infections involving the skin and CNS in all patients on Natalizumab. More rigorous definitions of herpes-related adverse events are required to enable accurate estimates of excess risk, if any.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sat Oct 27, 2007 2:40 pm    Post subject: (Abstract) Kinetics of brain atrophy in 1st year of Tysabri Reply with quote

From the ECTRIMS conference in Prague, October 11-14, 2007:

Quote:
The kinetics of brain atrophy during the first year of treatment with natalizumab

E. Fisher, R. Rudick, C.M. Dalton, D. MacManus, D.H. Miller, N. Lucas, A. Hulme, M. Panzara (Cleveland, USA; London, UK; Cambridge, San Diego, USA)

Objectives:

(1) To determine the kinetics of brain atrophy during the first year of natalizumab therapy in multiple sclerosis (MS) patients; (2) to determine the relationship between inflammatory lesions and brain atrophy during natalizumab treatment.

Background:

Treatment with anti-inflammatory drugs is associated with increased brain atrophy during the first year of treatment followed by decreased atrophy during the second year. This may be from a combination of (1) lag time between inflammation and tissue loss, (2) resolution of edema because of anti-inflammatory effects (“pseudoatrophy”), and (3) treatment effects, including toxicity. These factors have not been systematically explored.

Methods:

Brain parenchymal fraction (BPF) was measured from frequent MRIs acquired from 213 relapsing MS patients who participated in a phase 2 study of natalizumab. Scans were acquired 1 month pre-study, at baseline, monthly from Months 1 to 6 (during treatment with natalizumab or placebo), and at Months 9 and 12. Atrophy rates were calculated and compared between groups for the following time periods: early treatment (Months 0-4), late treatment (Months 4-6), and post-treatment (Months 6-12). Correlations between BPF changes and the volume of gadolinium-enhancing (Gd) lesions were determined.

Results:

148 subjects (100 natalizumab, 48 placebo) had analysable MRIs for all 10 time points. In the natalizumab group, there was an initial decrease in BPF in the early treatment period coinciding with the decrease in Gd lesions, followed by a leveling off in the late treatment period, which persisted in the post-treatment period. There was a trend towards greater BPF decline in the early treatment period (-0.0016 vs. -0.0006, P=0.25) and less BPF decline in late treatment period (-0.0000 vs. -0.0013, P=0.18) in the natalizumab group compared with the placebo group. BPF change was significantly correlated with Gd lesion volume change in the early treatment period (r=0.20, P=0.05) and the post-treatment period (r=0.26, P=0.01), but not in the late treatment period or in the placebo group during any of the intervals.

Conclusions:

The pattern of atrophy progression during this 1-year study suggests that natalizumab has a beneficial effect on brain atrophy beginning about 4 months after treatment initiation, following a period of pseudoatrophy from edema resolution. Overall, these results clarify the kinetics of the natalizumab effect on brain atrophy.


http://tinyurl.com/yo3ulq
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Feb 06, 2008 5:37 pm    Post subject: (Article excerpt) Melanoma complicating Tysabri MS treatment Reply with quote

This is in the "Correspondence" section of the New England Journal of Medicine, February 7, 2008. I don't have access to the entire text but here are the first 100 words of it:

Quote:




Volume 358:647-648 February 7, 2008 Number 6




Melanoma Complicating Treatment with Natalizumab for Multiple Sclerosis

Since this article has no abstract, we have provided an extract of the first 100 words of the full text and any section headings.

To the Editor:
We report on two cases of melanoma in women with multiple sclerosis who were treated with natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals), a humanized monoclonal antibody against 4 integrins.

Patient 1 was a 46-year-old woman who, shortly after receiving her first dose of natalizumab, noticed a rapidly changing mole on her shoulder; on evaluation, it proved to be a thick, nonulcerated melanoma with metastatic disease in the regional lymph nodes.

Patient 2 was a 45-year-old woman who had a long-standing ocular nevus that developed into an ocular melanoma after the administration of several doses of natalizumab ....







Anyone wanting the full text needs to be a paid subscriber, but you could probably find it in a good medical library.
Back to top
View user's profile Send private message
ewizabeth



Joined: 29 May 2006
Posts: 549
Location: Near Chicago

PostPosted: Wed Feb 06, 2008 8:15 pm    Post subject: Reply with quote

Wow, I've been thinking of having my moles checked out, and need to make an appointment. I don't have a lot, but it won't hurt to have them checked anyway. Thanks for posting this Agate.
_________________
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!
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Feb 06, 2008 8:22 pm    Post subject: Another article on this topic Reply with quote

From WebMD,"Tysabri May Be Linked to Melanoma," February 6, 2008:

http://www.webmd.com/multiple-sclerosis/news/20080206/tysabri-linked-to-melanoma
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Feb 27, 2008 6:46 pm    Post subject: (Article) Tysabri may cause liver injury, US says Reply with quote

From Bloomberg.com, February 27, 2008:

Quote:
Updated: New York, Feb 27 20:41London, Feb 28 01:41Tokyo, Feb 28 10:41

Biogen's Tysabri May Cause Liver Injury, U.S. Says (Update4)
By Luke Timmerman and Catherine Larkin

Feb. 27 (Bloomberg) -- Biogen Idec Inc. and Elan Corp.'s multiple sclerosis medicine Tysabri may harm the liver within six days of the first dose, U.S. regulators said, urging doctors to warn patients about the risk.

Patients should stop taking Tysabri if they develop jaundice or other symptoms, according to a letter this month to doctors from the drugmakers and posted today on the Food and Drug Administration's Web site. The companies said not all doctors were aware of the risk, added to prescribing information in January when the drug was approved for an expanded use.

Biogen and Elan had pulled Tysabri from the market in February 2005 because two patients developed fatal brain infections. The drug was reintroduced in July 2006 after the FDA decided the benefits of slowing MS relapses outweighed the risks. About 21,000 patients used Tysabri, Biogen's fastest-growing product, at the end of 2007, according to the company. Worldwide sales reached $129 million in the fourth quarter.

``This is a drug with a cloud of risk hanging over it, and each additional risk is unwelcome,'' said Jason Kantor, an analyst with RBC Capital Markets in San Francisco, in a telephone interview. ``I don't think this will have a material impact on use of Tysabri, but if more of these things pile up it will become less compelling.''

Biogen fell $1.40, or 2.3 percent, to $60.13 at 4 p.m. New York time in Nasdaq Stock Market composite trading. Elan's American depositary receipts fell $1.54, or 6.3 percent, to $22.77 in New York Stock Exchange composite trading. Each receipt equals one ordinary share of Elan, based in Dublin. Biogen is based in Cambridge, Massachusetts.

Evidence

The warning letter, issued this month, noted that some patients developed unusually high levels of liver enzymes in the blood, a sign of damage. It recurred in some patients after they received another dose, ``providing evidence that Tysabri caused the injury,'' according to the letter.

Liver injuries were disclosed in updated prescribing information in January, when Tysabri won an additional U.S. approval for Crohn's disease, a bowel disorder.

Gastroenterologists, who treat Crohn's patients, were notified at the time, and now the warning has been sent to physicians who prescribe the medicine for MS, said Shannon Altimari, a Biogen spokeswoman, in a telephone interview.

Reversible Damage

In July, the FDA cited 28 cases of liver injury associated with Tysabri since November 2004, four of them potentially serious. Elan spokesman Andrew Lewis said at the time the cases were from ``post-marketing experience.''

Clinical trials that compared Tysabri to a placebo found a ``comparable'' rate of liver injury, Altimari said. The cases of liver injury have been reversible after patients stopped taking the medicine, she said. None of the patients with liver damage needed a transplant or died from the side effect, she said.

Biogen is counting on sales of Tysabri to fuel its growth. The company said this month that it expects 100,000 patients to be taking Tysabri by the end of 2010, which translates to about $2.8 billion in annual sales at current prices. The stock has gained 30 percent in the 12 months before today.

Many other drugs are linked to liver injury, and it's possible rare cases that wouldn't be spotted are being found with Tysabri because it is closely monitored for infection risk, Kantor at RBC said.

To contact the reporters on this story: Luke Timmerman in San Francisco at +1- ltimmerman@bloomberg.net ; Catherine Larkin in Washington at clarkin4@bloomberg.net .








|
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Feb 28, 2008 9:29 am    Post subject: FDA alert Reply with quote

From Physician's First Watch, February 28, 2008, here is the US FDA alert about this:



Quote:
Tysabri (natalizumab)

Audience: Neurologists, other healthcare professionals, patients

[Posted 02/27/2008] Biogen Idec, Elan and FDA notified healthcare professionals of reports of clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose of Tysabri. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. Tysabri should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians should inform patients that Tysabri may cause liver injury.



http://www.fda.gov/medwatch/safety/2008/safety08.htm#Tysabri
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Mar 03, 2008 3:33 pm    Post subject: (AAN abstract) Tysabri reduces MS severity... Reply with quote

To be presented at the AAN conference in April:

Quote:
[P04.169] Natalizumab Reduces Multiple Sclerosis Severity: Analysis of Patients from the AFFIRM and SENTINEL Studies Using the Multiple Sclerosis Severity Scale

Joseph Herbert, Fair Lawn, NJ, Ludwig Kappos, Peter Calabresi, Baltimore, MD, Christian Confavreux, Lyon, France, Steven Galetta, Philadelphia, PA, Gavin Giovannoni, Eva Havrdova, Praha, Czech Republic, Michael Hutchinson, Dublin, Ireland, Fred Lublin, David Miller, London, United Kingdom, Paul W. O'Connor, Toronto, ON, Canada, J. Phillips, Dallas, TX, Chris Polman, Amsterdam, Netherlands, Ernst-Wilhelm Radue, Basel, Switzerland, Richard Rudick, Solon, OH, William Stuart, Atlanta, GA, Andrzej Wajgt, Katowice-Ligota, Poland, Bianca Weinstock-Guttman, Buffalo, NY, Daniel Wynn, Northbrook, IL, Joshua Bacon, New York, NY, Ilya Kister, Brooklyn, NY, Amy Pace, Michael Panzara, Cambridge, MA

OBJECTIVE:

To assess the effects of natalizumab (TYSABRI) on disease severity in relapsing multiple sclerosis (MS) patients using the MS Severity Scale (MSSS).

BACKGROUND:

Natalizumab's effect on traditional MS outcomes is well established; natalizumab significantly reduced annualized relapse rates by up to 68% and the risk of sustained disability progression by up to 54% compared with placebo in pivotal studies. The MSSS relates disability to disease duration and may be a more sensitive measure of disease progression than traditional outcomes.

DESIGN/METHODS:

Patients received intravenous natalizumab 300 mg monotherapy or placebo (AFFIRM), or natalizumab+interferon beta-1a or placebo+interferon beta-1a (SENTINEL) every 4 weeks for up to 116 weeks. Patients were assigned to 1 of 6 disease severity groups based on MSSS score at baseline and study completion. Analyses were conducted using baseline Expanded Disability Status Scale (EDSS) scores and those confirmed at study completion.

RESULTS:

At baseline, median MSSS scores for natalizumab-treated and placebo patients were similar (AFFIRM: 3.55 vs. 3.69, P=0.708; SENTINEL: 3.34 vs. 3.25, P=0.660); patients in both treatment groups were similarly distributed among the 6 MSSS severity groups (AFFIRM: P=0.887; SENTINEL: P=0.440). At study completion, median MSSS change from baseline was greater in natalizumab-treated patients compared with placebo (AFFIRM: -0.68 vs. -0.38, P<0.001; SENTINEL: -0.56 vs. -0.34, P<0.001). More natalizumab-treated patients shifted to a lower severity group (AFFIRM: 46% vs. 37%; SENTINEL: 41% vs. 34%) and fewer to a higher severity group (AFFIRM: 10% vs. 20%; SENTINEL: 15% vs. 19%) during treatment (P0.022).

CONCLUSIONS/RELEVANCE:

The distribution of AFFIRM and SENTINEL patients among the MSSS disease severity groups at baseline was as expected for a population of relapsing MS patients with EDSS scores from 0-5.5. Natalizumab effectively reduced disease severity on the MSSS in relapsing MS patients. MSSS may be a useful measure of disease progression in MS clinical studies.

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

Wednesday, April 16, 2008 7:00 AM

Poster Sessions IV: Multiple Sclerosis and Related Diseases: Outcomes and Scales I (7:00 AM-10:00 AM)



Biogen Idec supported this one, but there are a lot of big names in MS research listed as the authors...
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sat Mar 22, 2008 11:03 pm    Post subject: (Abstract) Tysabri/MS: risky market approval Reply with quote

From PubMed, March 22, 2008:

Quote:
Prescrire Int. 2008 Feb;17(93):7-10.

Natalizumab: new drug. Multiple sclerosis: risky market approval

[No authors listed]

(1) In relapsing-remitting multiple sclerosis, the standard therapy (other than symptomatic treatment) is interferon beta. It prevents about one exacerbation every 2.5 years but has no demonstrated effect on the progression of disability. However, interferon beta can cause serious adverse effects.

(2) Natalizumab, an immunosuppressant, has been approved for first-line treatment of patients with "aggressive" multiple sclerosis (with frequent exacerbations) and for second-line treatment after failure of interferon beta.

(3) In first-line treatment, natalizumab has not been compared with interferon beta. In a double-blind placebo-controlled trial involving 942 patients who were treated for 2 years, natalizumab prevented about 1 exacerbation every 2 years (0.24 versus 0.73 exacerbations per year). A retrospective subgroup analysis suggested that efficacy was better in patients with aggressive disease. As this was a post-hoc subgroup analysis, this exploratory hypothesis requires further testing. Natalizumab appeared to slow the progression of disability, but this result is undermined by the small percentage of patients who had an exacerbation (18% versus 27%).

(4) In second-line treatment, a combination of natalizumab and interferon beta (rather than natalizumab monotherapy) was compared with interferon beta in 1171 patients in whom interferon beta had failed. The combination prevented about one exacerbation every 2.5 years. It is not known whether a combination of natalizumab and interferon is more effective than natalizumab alone.

(5) Three cases of progressive multifocal leukoencephalopathy occurred during clinical trials, two of which were fatal. The risk of this viral infection, which is usually symptomatic only in severely immunosuppressed patients, was estimated at about 1 case per 1000 patients on natalizumab.

(6) Little is known of the risks of long-term treatment with natalizumab, especially the risks of infections and cancer.

(7) During two years of treatment, 6% of patients developed persistent anti-natalizumab antibodies, leading to reduced efficacy and a higher incidence of reactions during the infusion, as well as hypersensitivity reactions.

(8) In practice, given the poorly assessed and potentially fatal risks of long-term treatment with natalizumab, the limited improvement in efficacy does not justify the use of natalizumab other than in comparative trials.

PMID: 18354844

_________________
MS diagnosed 1980.

Avonex 2002-2005. Copaxone 2007-2010.


Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Tue Mar 25, 2008 2:08 pm    Post subject: (Abstract) Natalizumab: A new treatment for RRMS Reply with quote

From PubMed, March 25, 2008:

Quote:
Ther Clin Risk Manag. 2007 Jun;3(2):259-268

Natalizumab: A new treatment for relapsing remitting multiple sclerosis

Hutchinson M.
Department of Neurology, St. Vincent’s University Hospital, Dublin Ireland.

Natalizumab, a new disease-modifying therapy for relapsing remitting multiple sclerosis (RRMS), is a humanized monoclonal antibody which binds to alpha(4)beta(1)-integrin.

In a Phase 3 trial, 2 years of natalizumab monotherapy reduced the mean annualized relapse rate (ARR) by 68% compared with placebo (p < 0.001), and the risk of sustained disability progression was reduced by 42% in the natalizumab group (hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.43-0.77; p < 0.001).

Natalizumab decreased the mean number of new or enlarging T2-hyperintense lesions by 83% over 2 years and the mean number of Gd+ lesions by 92% at 2 years (both p < 0.001).

In another Phase 3 trial, natalizumab with interferon (IFN) beta-1a reduced the mean ARR by 55% at 2 years compared with IFNbeta-1a alone (p < 0.001) and risk of sustained disability progression was reduced by 24% (HR 0.76; 95% CI 0.61-0.96; p = 0.02).

Six percent of patients developed persistent antinatalizumab antibodies with loss of efficacy.

The risk of developing progressive multifocal leukoencephalopathy (PML) is been estimated at 1:1000 over 18 months; the longer term risk for PML is uncertain.

The benefits and risks of natalizumab support its use as monotherapy for RRMS with high disease activity despite treatment with IFNbeta, and for patients with rapidly evolving severe RRMS.

PMID: 18360634
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Mar 28, 2008 10:58 pm    Post subject: (Article) European agency warns of potential liver injury... Reply with quote

From Doctor's Guide, March 27, 2008:

Quote:
European Agency Warns of Potential Liver Injury With Natalizumab Treatment

LONDON -- March 20, 2008 -- The European Medicines Agency (EMEA) has concluded that warnings about liver injury should be added to the product information for natalizumab (Tysabri). Natalizumab is used to treat relapsing-remitting multiple sclerosis (MS) in patients with high disease activity despite treatment with a beta-interferon or whose disease is severe and evolving rapidly.

Following a review of reports of liver injury in patients treated with natalizumab, the EMEA's Committee for Medicinal Products for Human Use (CHMP) concluded that there is a need to update the product information for natalizumab to warn patients and prescribers that liver injury may occur.

Doctors should monitor the liver function of patients receiving natalizumab. Patients who observe any signs of liver injury, such as yellowing of the skin or the whites of the eyes, or unusual darkening of the urine should see their doctor.

The CHMP has requested that Elan, the marketing authorisation holder for natalizumab, submit a variation to the marketing authorisation to implement these changes.

As with all medicinal products, the EMEA will continue to monitor natalizumab closely to ensure that the benefits of the medicine continue to outweigh its risks.


SOURCE: European Medicines Agency



Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Apr 09, 2008 6:37 pm    Post subject: (Abstract) New drugs: natalizumab Reply with quote

From PubMed, April 9, 2008:

Quote:
Ned Tijdschr Geneeskd. 2008 Mar 1;152(9):499-500.

[New drugs: natalizumab]

[Article in Dutch]


van Bronswijk H, Dubois EA, van Gerven JM, Cohen AF.
Leids Universitair Medisch Centrum, Albinusdreef 2, 2333 ZA Leiden.

The drug natalizumab represents a new pharmacological approach in the treatment of very active relapsing-remitting multiple sclerosis (MS). It is a humanised murine monoclonal antibody and binds to an integrin on the surface of lymphocytes, thereby preventing them from transmigrating across the endothelium and causing inflammation in the nervous tissue.

The drug has been shown to decrease the occurrence of relapses and progression of MS. A few severe adverse effects (such as the viral progressive multifocal leuko-encephalopathy) have been reported, and its clinical and long-term effects are not fully known at present. Therefore, further research is required to determine the role of natalizumab in clinical practice.

PMID: 18389881
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu May 01, 2008 2:20 pm    Post subject: Reactivation of HHV6 in Tysabri-treated MS patients Reply with quote

From PubMed, May 1, 2008:

Quote:
PLoS ONE. 2008 Apr 30;3(4):e2028.

Reactivation of human herpesvirus-6 in natalizumab-treated multiple sclerosis patients

Yao K, Gagnon S, Akhyani N, Williams E, Fotheringham J, Frohman E, Stuve O, Monson N, Racke MK, Jacobson S.
Viral Immunology Section, National Institutes of Health, Bethesda, Maryland, United States of America.

The alpha(4) integrin antagonist natalizumab was shown to be effective in patients with immune-mediated disorders but was unexpectedly associated with JC polyomavirus associated progressive multifocal leukoencephalopathy (PML) in two multiple sclerosis (MS) and one Crohn's disease patients. Impaired immune surveillance due to natalizumab treatment may have contributed to the JCV reactivation. As HHV-6 has been suggested to play a role in MS, we asked whether this virus could also have been reactivated during natalizumab therapy.

Matched sera and CSF from a limited set of MS patients treated with and without natalizumab were examined for evidence of HHV-6. In addition, we also superinfected a persistent JC virus infected glial cell with HHV-6A to determine if JC virus can be increased. Elevated serum HHV6 IgG and HHV-6A DNA was detected in the CSF of a subset of patients but not controls.

We confirmed that superinfection with HHV-6 of a JC virus infected glial cells increased expression of JCV.

These results support the hypothesis that treatment with natalizumab may be associated with reduced immune surveillance resulting in reactivation of viruses associated with MS pathogenesis.

PMID: 18446218
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon May 12, 2008 1:53 pm    Post subject: (Abstract) Delayed infusion reactions after Tysabri Reply with quote

From Archives of Neurology,May 2008:

Quote:
Allergic and Nonallergic Delayed Infusion Reactions During Natalizumab Therapy

Kerstin Hellwig, MD; Sebastian Schimrigk, MD; Malte Fischer, MD; Aiden Haghikia, MD; Thomas Müller, MD; Andrew Chan, MD; Ralf Gold, MD


Arch Neurol. 2008;65(5):656-658.

Background

The monoclonal antibody natalizumab is a novel therapeutic option in the treatment of relapsing forms of multiple sclerosis. In general, therapy with natalizumab is well tolerated. Allergic reactions and acute infusion reactions typically occur during or shortly after infusion, with a peak at the second infusion. Delayed infusion reactions resembling serum sickness–type reactions (type III reaction) are commonly reported in other monoclonal antibody therapies (eg, infliximab and rituximab), but are not described yet for natalizumab.

Results

Delayed infusion reactions occurred in 4 of 40 relapsing-remitting multiple sclerosis patients treated with natalizumab.

Conclusions

Clinicians need to consider the occurrence of infusion reactions, with especially delayed reactions occurring more frequently than previously assumed. Our cases illustrate that some of these infusion reactions may be treated effectively with steroids and reduction of the infusion rate. In cases of antibody-mediated reactions, treatment should be stopped immediately.


Author Affiliations: Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.








Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Jun 19, 2008 8:36 am    Post subject: (Abstract) Paradoxically aggressive MS w/Tysabri Reply with quote

From Multiple Sclerosis, June 1, 2008:

Quote:
Multiple Sclerosis, Vol. 14, No. 5, 708-710 (2008)
DOI: 10.1177/1352458507087135


case-report

Paradoxically aggressive multiple sclerosis in the face of natalizumab therapy

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

In the pivotal trials of natalizumab in the treatment of relapsing-remitting multiple sclerosis (AFFIRM and SENTINEL), a dramatic reduction in relapse rate, new or enlarging T2-hyperintense lesions, and mean number of gadolinium-enhancing lesions was observed. While both relapses and new MRI lesions were observed in these trials, there has been no comment on the presence of aggressive disease in the face of natalizumab treatment. I report a 31-year-old woman with relapsing remitting MS of 12 years duration who developed aggressive demyelinating disease four months after the initiation of natalizumab. The clinical worsening was accompanied by a significant increase in new large T2-hyperintense signal abnormalities and in both solid and C-shaped contrast-enhancing lesions. Neither the clinical severity nor the striking MRI abnormalities had been noted earlier in her disease course. Neutralizing antibodies to natalizumab were not detected.

She subsequently responded to combination therapy of pulsed methylprednisolone and daily glatiramer acetate.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Jul 10, 2008 7:27 pm    Post subject: Update on melanoma/Tysabri connection Reply with quote

The National MS Society has supplied a news update on the presumed link between melanoma and Tysabri (July 2, 2008):

Quote:
Jul 02, 2008

Previous Report of Two Cases of Melanoma (Skin Cancer) Reported in People Taking Tysabri for MS Updated with Company Rebuttal

Originally Reported on February 7, 2008 - See Update Below, July 2, 2008

Physicians in Boston have reported two cases of melanoma (skin cancer) that developed in women in their practice who were administered Tysabri® (natalizumab, Biogen Idec and Elan Pharmaceuticals) to treat their multiple sclerosis. John T. Mullen, MD, and two colleagues (Beth Israel Deaconess Hospital, Boston) reported the cases in the New England Journal of Medicine (2008;358[6]:647-8). The melanomas developed early in the course of treatment, but it cannot be confirmed from these case reports that Tysabri caused them. However, the authors advise against treating individuals with Tysabri when there is a personal or family history of melanoma or in patients with atypical moles or ocular nevus (spot at the back of the eye).

Background:

Tysabri is a laboratory-produced monoclonal antibody that is approved for patients with relapsing forms of MS to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. It is designed to hamper movement of potentially damaging immune cells from the bloodstream, across the "blood-brain barrier" into the brain and spinal cord.

Details:

Dr. Mullen’s team reports that a 46-year-old woman developed a melanoma shortly after receiving her first dose of Tysabri, and an ocular nevus developed into a melanoma after several doses in a 45-year-old woman with a family history of melanoma . A case of melanoma also appeared in the AFFIRM study – which involved 942 individuals with relapsing MS, who received either Tysabri or inactive placebo by intravenous infusions every four weeks for more than two years – in a patient with a history of malignant melanoma.

It cannot be confirmed from these reports that there is a causal link between Tysabri administration and the occurrence of melanoma. However, given these occurrences, the authors recommend that Tysabri not be administered to people with a history or family history of melanoma.

“These reports raise concern and they underscore the importance of carefully tracking patients on powerful medications like Tysabri,” said Dr. John R. Richert, executive vice president of research and clinical programs at the National MS Society. “This drug is relatively new to the market, and as experience grows we are bound to learn more about its benefits as well as possible adverse events,” Dr. Richert added.

JULY 2, 2008 UPDATE:

In a letter to the editor published in the July 3, 2008 issue of the New England Journal of Medicine (2008; 359[1]:99-100), Dr. Michael A. Panzara and other representatives of Biogen Idec, Inc., pointed out that individual case reports, such as were reported by Dr. Mullen and colleagues, do not provide an adequate basis for proving cause and effect. The authors reviewed safety data from several clinical trials of Tysabri involving thousands of people and found that the incidence of melanoma was similar in those who received Tysabri (0.07%) compared to those who received inactive placebo (0.10%). In addition, a review by the authors of the company’s post-marketing safety surveillance data did not indicate in increased risk of melanoma in over 21,000 treated patients (as of December 2007).






http://tinyurl.com/5l7beo
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Jul 30, 2008 6:13 pm    Post subject: (Abstract) Quantitative risk-benefit analysis of Tysabri Reply with quote

From PubMed, July 30, 2008:

Quote:
Neurology. 2008 Jul 29;71(5):357-64.

Quantitative risk-benefit analysis of natalizumab

Thompson JP, Noyes K, Dorsey ER, Schwid SR, Holloway RG.
University of Rochester Medical Center, 601 Elmwood Ave., Box 673, Rochester, NY 14642 robert_holloway@urmc.rochester.edu.

OBJECTIVE:

To model the long-term risks and benefits of natalizumab in individuals with relapsing multiple sclerosis (MS).

METHODS:

We created a Markov model to evaluate treatment effects on reducing relapses and slowing disease progression using published natural history data and clinical trial results. Health changes, measured in quality-adjusted life-years (QALYs), were based on patient health preferences. Patient cohorts treated with no disease-modifying treatment, natalizumab, subcutaneous interferon beta-1a, and a theoretical "perfect" MS treatment were modeled. Sensitivity analysis was used to explore model uncertainty, including varying risks of developing progressive multifocal leukoencephalopathy (PML).

RESULTS:

Treatment with natalizumab resulted in 9.50 QALYs over a 20-year time horizon, a gain of 0.80 QALYs over the untreated cohort and 0.38 QALYs over interferon beta-1a. The health loss due to PML was small (-0.06 QALYs).

To offset natalizumab's incremental health gain over interferon beta-1a, the risk had to increase from 1 to 7.6 PML per 1,000 patients treated over 17.9 months. The "perfect" MS treatment accumulated 10.59 QALYs over the 20-year time horizon, 1.89 QALYs above the untreated cohort. Interferon beta-1a resulted in greater QALY gains compared with natalizumab if natalizumab's relative relapse reduction was reduced from 68% to 35% or if interferon beta-1a's relative reduction was increased from 32% to 65%.

CONCLUSIONS:

A more than sevenfold increase in actual risk of progressive multifocal leukoencephalopathy was required to decrease natalizumab's health gain below that of interferon beta-1a, and there remains considerable room for additional gains in health (>50%) beyond those already achieved with current therapies.

PMID: 18663181
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Jul 31, 2008 5:06 pm    Post subject: 2 new cases of PML in MS patients using Tysabri Reply with quote

From the Wall Street Journal, August 1, 2008:

Quote:
New Cases of Rare Brain Disease
Reported in Tysabri Users


By KEITH WINSTEIN
July 31, 2008 6:16 p.m.

Two multiple-sclerosis patients taking the drug Tysabri have developed a rare and often-deadly brain infection, Biogen Idec Inc. and Elan Corp. said.

Both patients are in Europe and still alive, the companies said in a filing with the U.S. Securities and Exchange Commission.

The two cases of the infection, known as progressive multifocal leukoencephelopathy or PML, are the first for Tysabri since it was reintroduced in 2006 under restrictive prescribing rules meant to monitor its risks. The drug was withdrawn in 2005 after three patients in clinical trials developed the infection, which is rarely seen in multiple sclerosis.

Uncertainties over Tysabri's risks are one of the major reasons large pharmaceutical companies declined to bid for Biogen in an auction last fall, the company has said. Investors reacted to the news by punishing the companies' stocks in after-hours trading.

About 31,800 patients are taking Tysabri, the companies said last week, and about 6,600 have taken the drug for more than 18 months. The duration is important -- in the past, it took more than two years for PML to be diagnosed in Tysabri patients. The companies have estimated Tysabri's PML risk as 1-in-1,000.

In an interview in July, Biogen's chief executive, James Mullen, had predicted Tysabri's sales would pass $1 billion a year on an annualized basis by the end of 2008 -- the conventional marker for blockbuster status.

Biogen last week reported that its overall second-quarter profit jumped 11% and raised its 2008 financial outlook on strong sales of Tysabri and its other MS drug, Avonex. For the second quarter, Biogen's portion of sales from Tysabri more than tripled to $147 million. The balance of the Tysabri sales goes to Biogen's partner on the drug, Elan Corp.

Write to Keith Winstein at keith.winstein@wsj.com

Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Aug 01, 2008 4:12 pm    Post subject: From the National MS Society Reply with quote

From the National MS Society Website, August 1, 2008:

Quote:
Two New Cases of PML Develop in People with MS Taking Tysabri

Biogen Idec and Elan Pharmaceuticals informed drug regulatory authorities about two new confirmed cases of PML in individuals who were taking Tysabri® (natalizumab) as a monotherapy (not in combination with other therapies). PML (progressive multifocal leukoencephalopathy) is a viral infection of the brain that usually leads to death or severe disability. Although FDA prescribing information includes a black box warning about the risk of PML, the three previous cases of PML that occurred in the context of clinical trials were in patients who had taken Tysabri in association with other immune-modulating or immune-suppressing medications.

Details: The companies held a conference call for prescribers and investors to provide details about the two cases, both of which occurred in European males. One had received Tysabri as a first line therapy because of the aggressive nature of his disease, and had been on Tysabri alone for 17 months before developing a slowly progressive focal twitching and weakness in one arm. Brain MRI showed a non-typical lesion but his spinal fluid was negative for JC virus until it was done a second time. He received five courses of plasma exchange and is currently stable and at home.

The second case has been reported to be a male who had received immune-suppressing and immune-modulating therapies in the past. He used Tysabri alone for 14 months before developing weakness on one side of the body. Despite treatment with steroids his symptoms progressed and included cognitive changes. His MRI was not typical for MS, and spinal fluid was positive for JC virus. He is reported to be hospitalized and is slated to receive plasma exchange therapy.

Background: Tysabri is a laboratory-produced monoclonal antibody. It is designed to hamper movement of potentially damaging immune cells from the bloodstream, across the “blood-brain barrier” into the brain and spinal cord. It has been shown to be effective in reducing the risk of disability progression and exacerbations (relapses).

In the United States, the drug is available only through a risk management program called TOUCH, and is only available through doctors and infusion sites enrolled in the program. The program is designed to monitor patients for possible signs of PML and other serious opportunistic infections. Separate risk management plans are also in place in individual countries in Europe.

The companies recently reported that nearly 32,000 patients have been dosed with Tysabri. Of those, nearly 14,000 have been on the drug for at least 12 months, and 6,600 have been on the drug for at least 18 months. Up to this time there have been no previous confirmed cases of PML in patients using the drug as monotherapy.

Recent, small-scale studies supported by Biogen Idec have investigated the use of plasma exchange, a blood-cleansing treatment, to clear the bloodstream of Tysabri in the event of PML, for which there is no established therapy. The studies suggested that plasma exchange could indeed clear much of the drug from a person’s bloodstream, but it was not possible to determine experimentally whether that would lead to a reduction of PML symptoms.

Comment: These incidents of PML are unfortunate and disappointing, and we hope for the best possible outcomes for these individuals and their families. However, their occurrence is within range of the predicted frequency of PML cases, estimated by a published report and by the FDA, of approximately 1 in 1,000 people taking the drug. “We are encouraged that the risk management plans in place for early surveillance, such as the TOUCH program in the U.S., are doing the intended job of identifying possible cases of PML early so that patients can be treated quickly,” said John R. Richert, MD, executive vice president of research and clinical programs at the National MS Society . “It will be important to observe whether plasma exchange therapy in these new cases will have an ameliorating effect on their PML.”

These incidents highlight the need for individuals taking Tysabri to be sensitive to any occurrence of new, unusual symptoms and to contact their prescribing physician or infusion nurse immediately if they occur. Signs of PML may include any new or worsening neurological symptoms such as any changes in thinking, eyesight, balance, strength and other symptoms.

Tysabri is a registered trademark of Biogen Idec and Elan.

The National MS Society is proud to be a source of information about MS. Our comments are based on professional advice, published experience and expert opinion, but do not represent individual therapeutic recommendation or prescription. For specific information and advice, consult your personal physician.




Interesting that the immunomodulating therapies the one patient had been on in the past haven't been named....
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sun Aug 03, 2008 7:48 am    Post subject: The 2 new PML cases are in Germany and Sweden Reply with quote

According to a Wall Street Journal article August 2, the two new PML cases in MS patients taking Tysabri are in Germany and Sweden:

http://tinyurl.com/6e5r8u
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sun Aug 03, 2008 8:37 pm    Post subject: Reply with quote

It looks as if the European MS patients on Tysabri are on a program similar to the TOUCH program for monitoring responses to Tysabri. This is a poster presented by Biogen Idec at the AAN conference in April 2007:

http://tinyurl.com/5bbv7p
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Aug 04, 2008 7:15 am    Post subject: Reply with quote

From BioWorld Today, August 4, 2008:

Quote:

'Déjà Vu All Over Again'


New PML Cases Mar Tysabri's Two-Year Anniversary in MS


By Jennifer Boggs
Assistant Managing Editor


Biogen Idec Inc. and Elan Corp. plc reported two new cases of PML - though not much else, to the chagrin of investors and analysts - linked to multiple sclerosis therapy Tysabri (natalizumab), spoiling the controversial drug's two-year anniversary of its re-launch onto the market.

The news, which came a week after Biogen executives triumphantly hailed in the firm's second-quarter earnings call that no new cases of the potentially fatal brain disease had been confirmed in the past two years, sent shares of both companies reeling. Cambridge, Mass.-based Biogen's stock (NASDAQ:BIIB) sank 28 percent, losing $19.75 to close Friday at $50.01, while shares of smaller Elan (NYSE:ELN) plunged 50 percent, or $10.12, to close at $9.93.

It was the second big drop for Elan in less than a week. The Dublin, Ireland-based firm fell 42 percent after data from a Phase II trial of Alzheimer's disease drug bapineuzumab indicated a dangerous brain-swelling condition in some patients. (See BioWorld Today, July 31, 2008.)

During an investor call Friday morning, Biogen management reported that two Tysabri patients in Europe had confirmed cases of PML (progressive multifocal leukoencephalopathy), an infection of the white matter caused by the JC virus and occurring in patients who are immune-suppressed, based on the detection of JC viral DNA in the cerebrospinal fluid (CSF). The first patient, who was diagnosed with aggressive MS in 2006 and was treatment-naïve prior to receiving 17 months of Tysabri monotherapy, was treated by plasmapheresis and is "stable and at home," said Cecil Pickett, president of research and development at Biogen.

The second patient, who has relapsing MS and had received 10 years of prior therapy before being switched to Tysabri, received 14 months of the drug. That patient currently is hospitalized and "clinically stable," Pickett said, and is set to undergo plasmapheresis, a process that entails an exchange of plasma so that Tysabri is removed from the patient's serum.

Biogen was notified of the first case July 30 and the second case July 31, said Al Sandrock, the company's senior vice president of neurology.

Tysabri, which initially was approved in late 2004, was pulled from shelves a few months later after reports of two PML cases, one of them fatal. The news walloped shares of both firms, especially Elan, which saw its stock fall 70 percent on Tysabri's withdrawal. (See BioWorld Today, March 1, 2005.)

The latest information seems like "déjà vu all over again," said analyst Eric Schmidt, of Cowen and Co., who wrote in a research note that, although the news is "not shocking," it does appear to dispel earlier theories that the PML link might be limited to a Tysabri-plus-Avonex combination regimen, since both patients were receiving Tysabri as a monotherapy. That makes PML "clearly a Tysabri side effect."

Lazard Capital Markets LLC analyst Joel Sendek also viewed the news as no surprise "given Tysabri's history." But, he raised concerns in a research note that, in the latest cases, "PML emerged earlier in patient treatment than we would expect, at 14 and 17 months of treatment."

The risk of PML was included in Tysabri's label when the drug was granted a rare second approval in 2006, and patients receiving the drug are required to be monitored and tested at the earliest sign of unusual worsening or symptoms using brain MRI and CSF testing.

But analysts on the call pointed out that CSF testing might not be a reliable method. In the case of the first patient, for instance, initial CSF tests were negative though subsequent testing revealed the presence of the JC virus.

Company executives declined to disclose how many suspected PML cases there have been, though Carmen Bozic, vice president of drug safety and risk management, said the firm has gotten reports from physicians conducting plasma exchange "simply on the basis of clinical suspicion."

The company's evasiveness on that issue, however, did not sit well with analysts. In a research note following the call, Christopher Raymond, of Robert W. Baird & Co., said that investors "came away wholly unsatisfied by the limited information" regarding the "potential backlog of 'suspected' PML cases."

Management also declined to speculate on the risk of PML in MS patients, stating that there had been too few cases to determine a pattern.

At the advisory meeting prior to Tysabri's second approval, experts estimated that PML could occur in one of every 1,000 patients. (See BioWorld Today, March 9, 2006.)

As of June 30, there were 31,800 patients worldwide being treated with Tysabri. Of those, 13,900 have been on the drug for more than 12 months, and 6,600 patients have taken Tysabri for more than 18 months.

Biogen has said its goal is to have 100,000 patients on the drug by the end of 2010. Bozic said on the call that the company's goal does contemplate "a certain amount of PML [cases], consistent with the label," though she would comment further.

Also unclear is what the latest PML news could mean for Tysabri from both regulatory and sales standpoints. Biogen executives repeatedly declined to offer any guidance on those issues, stating that the investor call was intended to discuss the medical reports only. "Speculating on future action is not the purpose of this call," Bozic said at one point.

It's doubtful that patients will be deterred - after all, patients and patient advocate groups were strong supporters of the drug's re-launch. But analyst Jonathan Aschoff, of Brean Murray Carret & Co., said there's a good chance the FDA will increase restrictions on Tysabri's label. But, even absent a labeling change, he wrote in a research note, "physicians will from now on consciously prescribe Tysabri as a third-line treatment after patients fail other options."

Sales of Tysabri totaled $200 million for the second quarter.

Analyst Michael Aberman, of Credit Suisse Securities, said in a note that Tysabri sales likely will be affected by the PML news due to "patients stopping therapy because they were initially reassured that monotherapy carries a smaller risk," and to "a significant drop in new patient starts."

Tysabri gained FDA approval in January in Crohn's disease, and Biogen launched the drug in that indication at the end of the first quarter. Tysabri also is expected to start clinical testing in multiple myeloma.



Published August 4, 2008


Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Aug 06, 2008 2:02 pm    Post subject: Blog about Tysabri and PML Reply with quote

This blog (Wall Street Journal, August 1) and the comments on it might be of some interest:

http://tinyurl.com/5z24x9
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Aug 06, 2008 6:08 pm    Post subject: (Irish Times) Irish Tysabri users not properly monitored? Reply with quote

From the Irish Times, August 2, 2008:

Quote:
Tysabri users not properly monitored, says expert

DR MUIRIS HOUSTON, Medical Correspondent


Patients with multiple sclerosis (MS) who are taking the drug Tysabri are not being properly monitored for serious side effects because of health service budgetary cutbacks, a leading neurologist has warned.

Following the announcement yesterday of two new cases of progressive multifocal leukoencephalopathy (PML), a known Tysabri side-effect, by the manufacturer, Biogen, Dr Orla Hardiman, consultant neurologist at Beaumont Hospital, Dublin, said she was not surprised at the finding. "This shows the surveillance [for side-effects] has worked."

However, Dr Hardiman said she is concerned that not all MS patients in the Republic who are taking Tysabri are being adequately monitored for serious side-effects such as PML.

"Tysabri is a good drug as long as you monitor people adequately. The difficulty is that this is not happening in Ireland. In the absence of a comprehensive approach by the HSE [Health Service Executive] to the issue of additional costs involved in monitoring patients taking Tysabri, patients are at risk."

The MS expert said that patients taking Tysabri, which is given intravenously, must have an MRI (brain) scan performed every six months as well as a comprehensive clinical examination by a consultant neurologist or a clinical nurse specialist. "The recent recruitment restrictions [in the health service] have affected our ability to carry out these checks. The risk of Tysabri rises when the surveillance is not done, so this is a wake-up call for MS patients in the Republic," Dr Hardiman told The Irish Times.

PML is a potentially fatal disease of the central nervous system. The rare condition was first noticed in a small number of patients taking Tysabri in 2005, leading to its withdrawal from the market.

The drug was reintroduced by both the Food and Drug Administration in the US and the European Medicines Agency on condition that a series of safety checks, aimed at picking up PML at an early stage, were offered to patients.

MS Ireland, the patient advocacy group, said in a statement: "We advise all members to continue with their treatment, but to always be vigilant for any changes in their health."

In a statement to the Irish Stock Exchange, the pharmaceutical company Elan confirmed that two new cases of Tysabri-related PML had been identified in the EU.

One patient had been taking the drug for 17 months, while the second was prescribed Tysabri for 14 months. Sources have confirmed that neither patient was being treated in the Republic, where between 100 and 150 people are receiving the MS drug.

Tysabri has been shown to reduce the progression of disability in MS by 42 per cent over a two-year period. In certain patients with a relapsing form of MS, treatment with the drug has succeeded in stopping further relapse.

Elan shares lost half their value in Dublin yesterday on the news of the new PML cases.

Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Aug 15, 2008 2:21 pm    Post subject: (Abstract) Early relapses after first dose of Tysabri in MS Reply with quote

From PubMed, August 15, 2008:

Quote:
Mult Scler. 2008 Aug 13

Early relapses after the first dose of natalizumab in active multiple sclerosis patients

Centonze D, Furlan R, Gasperini C, Salvetti M, Battistini L.
Department of Neuroscience, Neurologic Clinics, Tor Vergata University, Rome, Italy; European Center for Brain Research (CERC)/Fondazione Santa Lucia, Rome, Italy.

Background

Natalizumab is prescribed in Italy in patients who experienced at least two clinical relapses during a 12-month therapy with other approved immunomodulatory agents.

Results

In 7 of 35 patients selected on the basis of these recommendations, we have observed clinical relapses occurring within 24 h after the first dose of natalizumab.

Conclusion

The mechanism by which a first injection of natalizumab may precipitate a clinical relapse in patients with MS is unknown. We speculate that natalizumab can promote the release of inflammatory mediators from lymphocytes present in the central nervous system at the time of the first infusion, thus favoring the clinical manifestation of a pre-existing active lesion.

PMID: 18701574


Are they saying that in some people Tysabri can actually make the MS worse?
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Fri Aug 15, 2008 10:00 pm    Post subject: Re: (Abstract) Early relapses after first dose of Tysabri in Reply with quote

agate wrote:
Are they saying that in some people Tysabri can actually make the MS worse?


Yes, but perhaps only initially. scratch

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Aug 15, 2008 11:30 pm    Post subject: Reply with quote

I don't know if NewsInferno.com is a reliable source, but this just reached me:

Quote:
Tysabri PML Cases Get Attention of European Drug Agency

Date Published: Thursday, August 14th, 2008



European health regulators are taking a hard look at two cases of a potentially lethal brain infection linked to the drug Tysabri. About 31,800 people take Tysabri, which is also used to treat multiple sclerosis and Crohn’s disease, a digestive condition. Earlier this month, Elan and Biogen Idec, the makers of the drug, revealed that three* European Tysabri patients had been diagnosed with progressive multifocal leukoencephalopathy, or PML.

PML attacks the brain and central nervous system and is usually fatal. Symptoms include vision problems, loss of coordination, and memory loss. Patients who survive the disease are often permanently disabled. In 2006, Tysabri was temporarily removed from the US market after it was learned that some patients died of PML during its clinical trials. But it was returned to the market a year later.

According to Biogen Idec and Elan, one of the European PML patients is ambulatory and the other is hospitalized. One patient had been taking Tysabri for 14 months and the other for 17. The most disturbing aspect of these latest PML cases, however, is that both patients had been taking Tysabri as monotherapy - with no other drugs. It had been theorized that patients contracting PML had done so because of exposure to multiple medications and that monotherapy with Tysabri was less risky.

On Wednesday, the European Medicines Agency said it was assessing the two cases of PML. The agency said it would then decide whether any changes were necessary to the currently approved label for product.

In 2005, the law firm Parker Waichman Alonso LLP was retained by the estate of Anita Smith, a patient who died from a confirmed case of PML after taking Tysabri during a clinical trial. In its 2005 Annual Report, Elan Inc. informed shareholders that it had entered into settlement talks with the lawyers representing Anita Smith’s estate. When contacted, Jerry Parker, the managing partner of Parker Waichman Alonso LLP said the Anita Smith Tysabri case had been resolved, but that the case was confidential.



*I'm fairly sure they mean 2 patients, not 3.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Aug 27, 2008 6:04 pm    Post subject: FDA approves changes in Tysabri label Reply with quote

From the MS Foundation's MSFYi Newsletter, August 27, 2008:

Quote:
Tysabri Label Update

The FDA has approved changes to Tysabri package inserts following two new cases of the potentially deadly brain infection progressive multifocal leukoencephalopathy (PML) in people taking the drug in the European Union.

The changes update Tysabri’s label to include information about the two new cases, as well as to indicate that the cases occurred in people who were taking the drug as a monotherapy. Previous cases of PML occurred in people who were taking Tysabri in combination with another immunomodulatory drug.

Tysabri’s packaging now states that the connection between the duration of treatment and PML is unknown, but that most cases of the infection have been seen in people taking the drug for more than one year.

Both people who were diagnosed with PML in the EU have now undergone plasma washing to remove Tysabri from their systems. No further update on their condition is available at this time.

The FDA-approved changes also make clearer who is a candidate for Tysabri, saying that the drug generally is recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy. Previously, the packaging indicated Tysabri was for use in people who had tried several other failed therapies. The change may assist people taking Tysabri in getting coverage of the drug from their insurance company.

Despite the recent cases, the FDA has said it still believes there is a lower risk of PML when Tysabri is taken as a monotherapy.

The updated prescribing information and patient medication guide for Tysabri can be viewed at http://www.tysabri.com.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sun Aug 31, 2008 10:39 am    Post subject: A little more on the 2 PML patients Reply with quote

From http://tinyurl.com/6lnguu. The headline is a bit misleading, IMO. One patient isn't out of the woods yet.

Quote:


Two MS patients treated with Tysabri recovering from PML

Last Updated: 2008-08-26 16:04:45 -0400 (Reuters Health)

LONDON (Reuters) - Two European patients who developed progressive multifocal leukoencephalopathy (PML) after being given Biogen Idec and Elan Corp's multiple sclerosis drug Tysabri are now recovering, a researcher involved in their care said on Tuesday.

One patient in Scandinavia is out of risk while a second man in Germany is in the early recovery phase, Ralf Gold of the Ruhr University Bochum, Germany, told Reuters.

Gold, who presented an update on the cases at the annual meeting of the European Federation of Neurological Societies in Madrid, said he was optimistic both men would survive.

"For the Swedish patient now, there's no question he is out of risk. For the other, I have moderate optimism," he said in a telephone interview.

Tysabri was withdrawn in 2005 when three cases of PML were reported, but returned to the market in 2006 with warnings and tougher prescription guidelines.

Gold said the new cases underlined the need for vigilance, but Tysabri remained a "very effective therapy" and the two cases need not change current prescribing practice.

However, if further cases of PML were seen in the coming months, the risk/benefit balance might have to be reassessed.

The latest cases involved patients who were using Tysabri as monotherapy for more than a year. Previously, PML had been seen in patients taking Tysabri with other medicines.

"These cases came earlier than expected under monotherapy. I always expected to see some in 2009; I never expected to see them in 2008," Gold said.



[Emphasis added.] "Moderate optimism" sounds a bit weaselly to me but at least it's better than no optimism...
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Sep 04, 2008 4:51 pm    Post subject: (Abstract) AAN assessment: Use of Tysabri for treating MS Reply with quote

From PubMed, September 4, 2008:

Quote:
Neurology. 2008 Sep 2;71(10):766-73.

Assessment: The use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Goodin DS, Cohen BA, O'Connor P, Kappos L, Stevens JC.
1080 Montreal Ave., St. Paul, MN 55116. guidelines@aan.com.

The clinical and radiologic impact of natalizumab (Tysabri) as therapy for multiple sclerosis (MS) is assessed.

On the basis of Class I evidence, natalizumab has been demonstrated to reduce measures of disease activity and to improve measures of disease severity in patients with relapsing-remitting (RR) MS (Level A).

The relative efficacy of natalizumab compared to current disease-modifying therapies cannot be defined accurately (Level U).

Similarly, the value of natalizumab in the treatment of secondary progressive (SP) MS is unknown (Level U). The value of combination therapy using natalizumab and interferon in the treatment of RRMS is also unknown (Level U).

There is an increased risk of developing progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients (Level A for combination therapy, Level C for monotherapy) and possibly an increased risk of other opportunistic infections (Level C).

The PML risk in a pooled clinical trial cohort has been estimated to be 1 person for every 1,000 patients treated for an average of 17.9 months, although this figure could change in either direction with more experience with the drug.

PMID: 18765653
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Sep 11, 2008 9:01 am    Post subject: Tysabri being tested for multiple myeloma Reply with quote

There is an open-label study to see if Tysabri works against multiple myeloma. You can read more here:

http://tinyurl.com/6z5tng
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Sep 19, 2008 2:00 pm    Post subject: One PML patient deteriorating, one improving Reply with quote

From Reuters.com, September 19, 2008:

Quote:
One Tysabri PML patient deteriorates, one improves

BOSTON (Reuters) - One of two patients who developed a potentially deadly brain infection after taking the multiple sclerosis drug Tysabri is deteriorating, while one is recovering, according to a researcher involved in their care.

Dr. Ralf Gold of the Ruhr University Bochum, Germany, said in an interview Friday that a 52-year-old German patient who is hospitalized near the town of Freiburg is close to a coma and being fed through tubes.

The other patient, a 37-year-old Swede, is in a rehabilitation center near Stockholm and suffering only from mild weakness on one side of his body.

The drug, made by Biogen Idec Inc and Elan Corp, was temporarily withdrawn from the market in 2005 after being linked with three cases of an often lethal infection known as multifocal leukoencephalopathy, or PML.

It was reintroduced with stricter warnings in 2006 and no new cases were reported until the end of July, when Biogen announced that the two patients had developed the infection.

(Reporting by Toni Clarke, editing by Gerald E. McCormick)

Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Sep 19, 2008 3:24 pm    Post subject: More info here Reply with quote

For a bit more information, see:

http://tinyurl.com/4nw2f5
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Sep 19, 2008 7:47 pm    Post subject: (Abstract) Open use of Tysabri: NABs & clinical data Reply with quote

From PubMed, September 19, 2008:

Quote:
Nervenarzt. 2008 Jun;79(6):716-9

[Open use of natalizumab. Neutralising antibodies and clinical data]

[Article in German]


Haghikia A, Fischer M, Hellwig K, Linker R, Chan A, Hohlfeld R, Gold R.
St.-Josef-Hospital, Neurologische Klinik der Ruhr-Universität, Gudrunstrasse 56, Bochum, Germany. Aiden.Haghikia@rub.de

BACKGROUND:

Since June 2006 natalizumab has been available for use as monotherapy in relapsing-remitting MS with high disease activity. The AFFIRM study showed the occurrence of persisting and neutralising antinatalizumab antibodies (nAb) in 6% of the patients. We present data revealing the number of nAb-positive patients assessed in our independent laboratory. Additionally we provide retrospective clinical data on the efficacy of natalizumab as escalating immunotherapy.

PATIENTS AND METHODS:

Blood samples of patients treated with natalizumab in Germany were tested for nAb using an enzyme-linked immunosorbent assay. If nAb were detectable at a single time point, the according patients were categorised as transiently positive. They were diagnosed as persistently positive if they had nAb at two or more time points which were at least 6 weeks apart. The treating neurologists sending the serum samples were asked to provide clinical data of their patients.

RESULTS:

Forty-seven of 593 samples (9.1%) were nAb-positive, 19 of them (3.7%) persistently positive and two (0.3%) transiently. Twenty-six patients (5%) were not retested for nAb, as we did not receive material for confirmatory analysis. Infusion-related adverse events were reported for 53 patients (10.3%). Averages of 2.6 relapses per year were reported previous to natalizumab therapy and 0.3 per year during natalizumab therapy.

CONCLUSION:

During natalizumab therapy, testing for nAb should be strongly considered for further therapy decisions and in cases of suspected allergic reaction. Basically the obtained data compare with those of the AFFIRM study. Natalizumab is applied as escalating therapy in MS according to the recommendations of the MSTKG, and it seems to match the expectations in open-label use.

PMID: 18437340
Back to top
View user's profile Send private message
ewizabeth



Joined: 29 May 2006
Posts: 549
Location: Near Chicago

PostPosted: Fri Sep 19, 2008 8:00 pm    Post subject: Reply with quote

It's very sad that one patient won't recover well. I wonder if it was the age difference? or the level of disability? or the time that they caught it? I thought about that, I'm 50 and taking Tysabri after having MS for probably decades (mildly, but still there, in retrospect).
_________________
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!
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Sep 19, 2008 8:11 pm    Post subject: Reply with quote

Wonder if this is the reason?

Quote:
Gold said the 52-year-old German patient was not diagnosed until at least three months after developing the disease, whereas the Swedish patient's condition was identified in less than a month. As a result, the German patient had a higher level of the virus in his brain.



(from the article linked to above)

It sounds as if the symptoms and signs of PML weren't identified soon enough in the German patient.

But wouldn't it be exceptionally difficult to identify them in MS patients anyway, since PML is another neurological disorder? Would the patient ((or the doctor) be able to differentiate an MS symptom/sign from a PML symptom/sign?
Back to top
View user's profile Send private message
ewizabeth



Joined: 29 May 2006
Posts: 549
Location: Near Chicago

PostPosted: Fri Sep 19, 2008 9:18 pm    Post subject: Reply with quote

I think it would be difficult. Each month now, my neuro asks me if I've experienced any new tingling symptoms, or personality changes. Luckily I've done really well with it so far, and I hope that continues.
_________________
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!
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Sat Sep 20, 2008 7:36 am    Post subject: Reply with quote

As I recall, one patient was a drug virgin and very young, and the other had used AZT (is that the acronym?) previously, which may have lowered his immune system. It was the same drug that the guy who died from the Crohns/Tysabri trial was on, 8 months before he tried Tysabri too. Maybe it just lowers the immune system too much to risk using Tysabri after it.

I'm not sure "which" patient is still "recovering", and which is very unwell now (virgin or prior AZT user), but they both ended up with PML so obviously it can happen from Tysabri alone. But, maybe a person has a better chance of not dying from PML if they weren't on other heavy-duty immunesuppressants previously.

It was only 2 - 3 weeks ago that they announced that BOTH were "recovering", and now one isn't. It may be that the one that is still ok now might take a turn for the worst yet, and it is just taking longer cause they found it earlier. Or, maybe he will be ok in the long run . . . time will tell.

The problem is too that spinal tap results for the JC virus can be incorrect because they did test both of these patients fairly early on, and at least one test came back negative. That can complicate the PML dx process too, and delay the doctors from making a decision to cease the use of Tysabri and start the person on plasma.

It may also be that plasma isn't going to work to neutralize Tysabri quickly enough in all patients.

It's too early to know the answers, but I'm glad there aren't more people affected at this point.
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sat Sep 20, 2008 8:36 am    Post subject: Reply with quote

I'm not sure if AZT is an acronym for azathriopine, which I understood was the drug in question (also known as Imuran).

AZT is an acronym for azidothymidine (Zidovudine--brand name Retrovir), which has been given to treat HIV.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Sep 22, 2008 8:48 am    Post subject: (Article) Possible "sustained improvement" shown w Reply with quote

From IrishTimes.com, September 22, 2008:

Quote:
Tysabri trials show possibility of 'sustained improvement'

Elan's Tysabri drug has shown in tests that it may lead to sustained improvement of physical disability caused by multiple sclerosis, the company said today.

The phase three trial of the drug found it increased the probability of achieving sustained improvement in physical disability over two years when compared to placebo, and is the first evidence that the drug is associated with a significant improvement, rather than simply slowing or preventing the progression of disability in those living with relapsing multiple sclerosis.

"These results show that Tysabri treated patients are significantly more likely to experience a sustained improvement in disability compared to placebo patients. This finding from a post-hoc analysis of the pivotal Affirm trial supports both the earlier findings from the Affirm trial that Tysabri is associated with an improvement in quality of life as well as anecdotal evidence of recovery of function in some patients," said Frederick E. Munschauer, Department of Neurology, State University of New York at Buffalo.

"While, like Tysabri, other therapies have shown a slowing of progression in disability, this analysis represents the first evidence supporting a sustained improvement in function associated with an approved disease modifying therapy."

In a research note this morning, NCB Stockbrokers said the announcement was "significant".

"The news should at least offset any negative sentiment towards the drug amongst physicians following the recent PML cases," it said.

Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Tue Sep 23, 2008 2:16 pm    Post subject: (Abstract) Treating PML unfolding during Tysabri monotherapy Reply with quote

From the WCTRIMS in Montreal, September 19, 2008:

Quote:
Treatment of PML unfolding during monotherapy with natalizumab

R. Gold1; W. Wenning2; A. Haghikia1; J. Laubenberger2; D. Clfford3; P. Behrens2; A. Chan1
1. University Clinic Bochum at St. Josef Hospital, Bochum, Germany.
2. Regional Hospital, Offenburg, Germany.
3. Washington University, St. Louis, MO, USA.



Natalizumab is a novel highly effective treatment for relapsing remitting multiple sclerosis (MS). In clinical trials two MS patients developed progressive multifocal leucencephalopathy (PML) under combination therapy with natalizumab and interferon beta. Therefore monotherapy with natalizumab in highly active MS was approved by FDA and EMEA in July 2006.

Here we report on a 52-year-old MS patient who developed PML after 12 months of natalizumab monotherapy and describe the therapeutic algorithm.

Standard clinical follow-up including repetitive MRI and CSF analyses.

This patient suffered from MS for 21 years, and during that time had various treatments including azathioprine for five years. In May 2007 natalizumab was started because of ongoing disease activity with relapses. In the following year, the patient remained stable until May 2008 when symptoms of depression and a mild left-sided hemiparesis appeared. When these symptoms progressed despite treatment with repetitive high-dose glucocorticosteroid therapy and atypical lesions in cranial MRI were noted, the patient was referred to our neurological department in July 2008.

At this time, another cranial MRI showed two enlarging lesions in the periinsular region of the right temporal lobe and perithalamic white matter. CSF was examined twice, and up to 2100 copies/ml of JC-virus was detected.

In addition, the cellular immunocompetence of the patient, as measured by an FDA-approved bioenergetic assay, was in the range of severely immunosuppressed patients. After plasma exchange therapy with plasmapheresis and immunoabsorption, in combination with virustatic treatment with mefloquine the patient immediately stabilized with respect to mood and cognition, concomitant with normalisation of peripheral immunocompetence. Further follow-up data will be presented.

Details of the patient’s clinical course and subsequent interventions that possibly led to improved outcome will be discussed.









Am I right in assuming that this patient is the 52-year-old German man who at last report was "deteriorating"?
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Oct 13, 2008 6:26 pm    Post subject: Decreased dendritic cells & CD4+ T cells...due toTysabri Reply with quote

Archives of Neurology, early release article, October 13, 2008:

Quote:

Decrease in the Numbers of Dendritic Cells and CD4+ T Cells in Cerebral Perivascular Spaces Due to Natalizumab

Maria del Pilar Martin, PhD; Petra D. Cravens, PhD; Ryan Winger; Elliot M. Frohman, MD, PhD; Michael K. Racke, MD; Todd N. Eagar, PhD; Scott S. Zamvil, MD, PhD; Martin S. Weber, MD; Bernhard Hemmer, MD; Nitin J. Karandikar, MD, PhD; B.K. Kleinschmidt-DeMasters, MD; Olaf Stüve, MD, PhD


Arch Neurol. 2008;65(12):(doi:10.1001/archneur.65.12.noc80051).

Objective

To extend our studies on the prolonged and differential effect of natalizumab on T lymphocyte numbers in the cerebrospinal fluid, we investigated the number and phenotypes of leukocytes and the expression of major histocompatibility complex (MHC) classes I and II in cerebral perivascular spaces (CPVS). We hypothesized that natalizumab reduces the number of antigen presenting cells in CPVS.

Design

A case-control study in which inflammatory cell numbers in the CPVS of cerebral tissue were assessed by immunohistochemical staining.

Subjects

A patient with multiple sclerosis (MS) who developed progressive multifocal leukoencephalopathy (PML) during natalizumab therapy. Controls included location-matched cerebral autopsy material of patients without disease of the central nervous system, patients with MS not treated with natalizumab, and patients with PML not associated with natalizumab therapy.

Results

The absolute number of CPVS in the patient with MS treated with natalizumab was significantly lower than in the control groups owing to extensive destruction of the tissue architecture. The expression of MHC class II molecules and the number of CD209+ dendritic cells were significantly decreased in the CPVS of the patient with MS treated with natalizumab. No CD4+ T cells were detectable.

Conclusions

Our observations may explain the differential and prolonged effects of natalizumab therapy on leukocyte numbers in the cerebrospinal fluid.



Author Affiliations:

Departments of Neurology (Drs Martin, Cravens, Frohman, Eagar, and Stüve and Mr Winger), Ophthalmology (Dr Frohman), Immunology (Drs Eagar, Karandikar, and Stüve), and Pathology (Dr Karandikar), University of Texas Southwestern Medical Center at Dallas; Departments of Neurology, The Ohio State University Medical Center, Columbus (Dr Racke), University of California, San Francisco (Drs Zamvil and Weber), and Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany (Drs Weber and Hemmer); Departments of Pathology, Neurology, and Neurosurgery, University of Colorado, Denver (Dr Kleinschmidt-DeMasters); and the Neurology Section, Veterans Affairs North Texas Health Care System, Medical Service, Dallas (Dr Stüve).




Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Fri Oct 24, 2008 6:10 pm    Post subject: Re: Decreased dendritic cells & CD4+ T cells...due toTys Reply with quote

agate wrote:
Archives of Neurology, early release article, October 13, 2008:

Quote:

Decrease in the Numbers of Dendritic Cells and CD4+ T Cells in Cerebral Perivascular Spaces Due to Natalizumab

Maria del Pilar Martin, PhD; Petra D. Cravens, PhD; Ryan Winger; Elliot M. Frohman, MD, PhD; Michael K. Racke, MD; Todd N. Eagar, PhD; Scott S. Zamvil, MD, PhD; Martin S. Weber, MD; Bernhard Hemmer, MD; Nitin J. Karandikar, MD, PhD; B.K. Kleinschmidt-DeMasters, MD; Olaf Stüve, MD, PhD


Arch Neurol. 2008;65(12):(doi:10.1001/archneur.65.12.noc80051).

Objective

To extend our studies on the prolonged and differential effect of natalizumab on T lymphocyte numbers in the cerebrospinal fluid, we investigated the number and phenotypes of leukocytes and the expression of major histocompatibility complex (MHC) classes I and II in cerebral perivascular spaces (CPVS). We hypothesized that natalizumab reduces the number of antigen presenting cells in CPVS.

Design

A case-control study in which inflammatory cell numbers in the CPVS of cerebral tissue were assessed by immunohistochemical staining.

Subjects

A patient with multiple sclerosis (MS) who developed progressive multifocal leukoencephalopathy (PML) during natalizumab therapy. Controls included location-matched cerebral autopsy material of patients without disease of the central nervous system, patients with MS not treated with natalizumab, and patients with PML not associated with natalizumab therapy.

Results

The absolute number of CPVS in the patient with MS treated with natalizumab was significantly lower than in the control groups owing to extensive destruction of the tissue architecture. The expression of MHC class II molecules and the number of CD209+ dendritic cells were significantly decreased in the CPVS of the patient with MS treated with natalizumab. No CD4+ T cells were detectable.

Conclusions

Our observations may explain the differential and prolonged effects of natalizumab therapy on leukocyte numbers in the cerebrospinal fluid.



Author Affiliations:

Departments of Neurology (Drs Martin, Cravens, Frohman, Eagar, and Stüve and Mr Winger), Ophthalmology (Dr Frohman), Immunology (Drs Eagar, Karandikar, and Stüve), and Pathology (Dr Karandikar), University of Texas Southwestern Medical Center at Dallas; Departments of Neurology, The Ohio State University Medical Center, Columbus (Dr Racke), University of California, San Francisco (Drs Zamvil and Weber), and Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany (Drs Weber and Hemmer); Departments of Pathology, Neurology, and Neurosurgery, University of Colorado, Denver (Dr Kleinschmidt-DeMasters); and the Neurology Section, Veterans Affairs North Texas Health Care System, Medical Service, Dallas (Dr Stüve).



I hope perhap this may lead to them monitoring these results, kinda like antibodies for the CRABs.

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Oct 29, 2008 4:50 pm    Post subject: Third PML case found in a Tysabri patient w/MS Reply with quote

This is from Bloomberg.com, October 29, 2008:

Quote:
Biogen Says Brain Illness Found in Tysabri Patient

By Elizabeth Lopatto

Oct. 29 (Bloomberg) -- Biogen Idec Inc. said a patient taking its multiple sclerosis drug Tysabri was diagnosed with a life-threatening brain illness, the third case reported since July.

The report sent shares down as much as $6.94, or 17 percent, to $35 in extending trading on the Nasdaq Stock Market. The patient was diagnosed with progressive multifocal leukoencephalopathy, or PML, after 14 Tysabri infusions, Biogen of Cambridge, Massachusetts said today in a regulatory filing.

Biogen and its marketing partner, Irish drugmaker Elan Corp., said in August they were revising Tysabri's prescribing information to show the rare brain infection may occur in patients taking the drug as a sole treatment. Two cases of Tysabri patients with PML, which has no cure, were reported on July 31, the first since the drug was reintroduced in the U.S. in 2006. The companies pulled Tysabri from the market in February 2005 after three patients, two of whom died, contracted the illness.

``If people hadn't been expecting another case, they were naive,'' said Bret Holley, an analyst for Oppenheimer & Co., in a telephone interview today. ``I don't think this will negatively affect prescriptions any further.''

More than 48,000 patients have taken Tysabri, Biogen told investors on Oct. 21, when the company released its earnings. Chief Executive Officer James Mullen said 100,000 patients will be taking the drug by 2010. Tysabri generated worldwide sales of $236 million in the third quarter.

``We got confirmation of PML in a Tysabri patient today,'' said Naomi Aoki, a Biogen spokeswoman, in a telephone interview. ``She is currently under the care of her treating physician.''

Previous Cases


Aoki declined to comment on the patient's condition. One of the previous patients was continuing to receive outpatient treatment and was improving. The other remained hospitalized, Aoki said.

``The rate is consistent with our expectations, given the information that's in the label,'' Aoki said.

PML is included in Tysabri's prescribing information as a possible side effect in 1 of every 1,000 patients taking the drug. The condition occurs when the JC virus, named with initials for the first patient diagnosed with it, evades the body's immune defenses and penetrates the brain, causing irreversible damage.

``While a new Tysabri PML case clearly isn't good news, it should come as little surprise, given the established pattern,'' Christopher Raymond, an analyst with Robert W. Baird said today in an investment note.

...

``The diagnosis was made based upon the detection of JC Virus DNA in the cerebrospinal fluid in the setting of clinical signs, symptoms and magnetic resonance imagining findings consistent with the diagnosis of PML,'' Biogen said in the filing.

To contact the reporter on this story: Elizabeth Lopatto in New York at elopatto@bloomberg.net



This was the first US case of PML since Tysabri was reintroduced. More info at Xconomy.com, October 29:

Quote:
Biogen Idec, Elan’s Tysabri Linked to First U.S. Case of Brain Infection

Luke Timmerman 10/29/08

Tysabri has been linked to its first U.S. case of an often-deadly brain infection since it was re-introduced to the domestic market two years ago. Cambridge, MA-based Biogen Idec (NASDAQ: BIIB) and its partner Elan said today they have notified regulators that a rare brain infection called PML has been diagnosed in a patient with multiple sclerosis, according to a regulatory filing.

The patient, a woman, has a history of taking other immune-suppressing drugs for MS, including beta-interferons, and methotrexate for a rheumatology condition, Biogen said. The infection was diagnosed early based on a doctor’s observation of possible symptoms, an MRI scan, and an examination of spinal fluid. The patient, who had taken 14 infusions of Tysabri over a little more than a year, is being treated by her physician, said company spokeswoman Naomi Aoki.

Tysabri is under intense scrutiny for its link to PML, since it was pulled off the market in February 2005 after doctors discovered two cases of the rare infection, which can be deadly. The FDA allowed Tysabri back to the U.S. market in July 2006 after deciding that the benefit of the drug-the most effective yet against MS-was worth the risk. The drug was brought back under a strict patient monitoring program called TOUCH. No new cases of the infection had been reported until this past July, when Biogen and Elan disclosed that two patients in Europe had been diagnosed. Since then, the first patient, who was described as remaining able to walk and live at home, has “continued to improve,” Aoki says. The second patient who was hospitalized remains in the hospital, but has also made improvement, Aoki says.

More than 35,000 patients worldwide were taking Tysabri as of the end of September, so three cases is well within the warning in the drug’s label that the chances of getting PML are about 1 case in 1,000. Two analysts who sent me their notes, Christopher Raymond of Robert W. Baird and Christopher James of Rodman & Renshaw, didn’t seem alarmed by the new case. Raymond said he still expects Tysabri to generate $1.6 billion in annual sales in 2011.

“Although the headline of a new PML case is never good for the stock, given the slowdown in patient additions highlighted by management on its third quarter conference call, we believe physicians may already be reacting to this reality” of new PML cases, Raymond said.

Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Nov 05, 2008 8:12 pm    Post subject: (Article) Tysabri--increased vigilance required in MS Reply with quote

From Therapeutic Advances in Neurological Disorders, vol. 1, no. 3, November 1, 2008

Quote:
http://tan.sagepub.com

Michael K. Racke and Olaf Stüve

Natalizumab: increased vigilance is required in treating patients with multiple sclerosis

The recent reporting of two new cases of progressive
multifocal leukoencephalopathy (PML) in
patients with multiple sclerosis (MS) receiving
natalizumab highlights the risks associated
with this agent in patients who do not respond
to conventional immunomodulatory therapy.
Since the introduction of natalizumab back into
the US and European markets, there had been
some optimism that perhaps the use of natalizumab
as a monotherapy would result in no new
cases of PML. The thought that occurrence of
PML would occur only when natalizumab was
used in combination with interferon or following
other immunosuppressive agents was proven to
be false when one of the patients who developed
a recent case of PML had not been on any other
MS medication. Thus, while the use of natalizumab
has proven to be a valuable addition in the
management of some patients with MS, it
appears that PML and immune reconstitution
inflammatory syndrome (IRIS) are rare but
significant complications that may afflict patients
receiving this therapy. In addition, the recent
reports of melanoma possibly being linked to
natalizumab-treated MS patients suggests that
infectious complications are not the only
obstacles faced by patients being treated with
this VLA-4 antagonist [Mullen et al. 2008].

It has to be emphasized that potentially fatal
infectious and noninfectious complications of
pharmacotherapies are not exclusive to natalizumab,
but have also occurred with other experimental
and approved agents [Hemmer et al.
2006]. For instance, the risk of acute myelogenous
leukemias after exposure to mitoxantrone appears
to be a rare but significant complication in
patients being treated with this chemotherapeutic
agent [Hasan et al. 2008]. The risk of cardiac toxicity is also a significant complication that may be faced by patients receiving this therap[Saccardi
et al. 2004].

However, these FDA-approved agents may be
joined by several new agents that also have significant risks associated with them. In the recent clinical trial examining alemtuzumab, six of
216 patients developed idiopathic thrombocytopenic
purpura (ITP), with one of these
patients suffering a fatal intracerebral hemorrhage.
The B-cell-depleting chimeric monoclonal
antibody rituximab has also been associated with
the development of PML in 27 patients with different
diseases. Furthermore, several of the newer
agents in therapeutic development and clinical
trials may also have rare but significant adverse
effects.

While all of these agents have significant
risks, they also offer hope to patients with MS
who do not respond optimally to interferon beta
or glatiramer acetate. A critical next step in
defining an optimal therapy for patients with
MS will be to identify (1) patients who will
benefit from a particular agent, and (2) patients
who will be at an increased risk of an adverse
outcome. The identification of biomarkers that
may include pharmacogenomics, proteomics,
and more traditional laboratory assays that measure
immunological responses will likely play an
important role. Such tools would significantly
reduce the anxiety of patients and physicians
alike in terms of the use of medications such as
natalizumab.

A series of studies performed on patients enrolled
in the SENTINEL and AFFIRM trials in Dallas
suggest that these patients may have unexpected
biological consequences that result from treatment
with this agent [Stuve et al. 2006a; Stuve
et al. 2006b]. While our early observations
suggested a significant effect on lymphocyte
entry into the cerebrospinal fluid, it was somewhat
reassuring that no patients enrolled in
Dallas developed any opportunistic infection.
However, if natalizumab did have an adverse
effect on CNS immune surveillance, shouldn’t
there have been evidence to suggest that viruses
other than the John Cunningham (JC) virus also
reactivated following natalizumab therapy?

To address this issue, we examined the CSF and
serum of the Dallas natalizumab-treated cohort
for evidence of human herpes virus 6 (HHV-6)
reactivation, another virus thought to remain
latent in the adult central nervous system [Yao
et al. 2008]. Interestingly, natalizumab-treated
patients appear to have lower serum IgG levels
than MS patients that did not receive natalizumab.
Among transplant immunologists, HHV-6
reactivation is considered an indicator of
CNS immune suppression and increased risk
for subsequent viral reactivation. Despite this
low serum IgG level, we were able to detect
elevated titers of antibodies in the serum of
natalizumab-treated MS patients directed against
HHV-6. This would suggest that conditions in
natalizumab-treated patients are conducive for
these patients to mount an immune response
against HHV-6. It is also of interest that some
investigators suggest that HHV-6 may participate
in the transformation of the JC virus into a
pathogenic strain capable of initiating the
demyelinating pathology seen in patients with
PML [Mock et al. 1999].

One positive aspect of the unfortunate recent
events surrounding natalizumab is the heightened
vigilance with regard to potential side
effects of this drug. It is only through continued
study of patients receiving natalizumab and
attempting to understand the relationship of use
of the drug to the development of risk factors for
viral reactivation that we will be able to reduce
the concerns within the neurologic community
about the use of these novel therapies.

Conflict of interest statement
None declared.

References

Downloaded from http://tan.sagepub.com on November 5, 2008


[References omitted.]
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Thu Nov 06, 2008 1:09 pm    Post subject: Re: Third PML case found in a Tysabri patient w/MS Reply with quote

agate wrote:
More than 35,000 patients worldwide were taking Tysabri as of the end of September, so three cases is well within the warning in the drug’s label that the chances of getting PML are about 1 case in 1,000.


As of late July, there were 6600 people who had been on Tysabri for 18 months or longer, and their original estimate was 1:1000 AFTER 18 months of use.

Assuming that 6600 number includes the people who were in the trials, there have been 6 cases of PML now; 3 in the trials, 2 in Europe, 1 in the US. That is a ratio of 6:6600 which isn't THAT far off target.

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Nov 06, 2008 1:56 pm    Post subject: (Article) Biogen shares fall on illness report for MS drug Reply with quote

From Forbes.com, November 6, 2008:

Quote:
Biogen shares fall on illness report for MS drug

NEW YORK -
Biogen Idec Inc. shares tumbled Thursday after the biotechnology company reported a third multiple sclerosis patient taking Tysabri has a potentially fatal brain infection.

Shares fell $1.64, or 3.9 percent, to close at $40.30. The stock has traded between $38.04 and $78.57 over the last 52 weeks and has been weighed down since reports of two new cases of progressive multifocal leukoencephalopathy in August.

The rare viral infection, also called PML, is already listed as a risk for Tysabri patients. The drug was pulled from the market in 2005 after being linked to PML but was reintroduced under restricted sales conditions in mid-2006.

Biogen reported the latest case late Wednesday in a Securities and Exchange Commission filing.

The Cambridge, Mass., company has stood by the drug, saying the risks are clearly labeled and patients have to sign a waiver acknowledging those risks. Also, PML almost always occurs in people with a severe immune deficiency and multiple sclerosis is an autoimmune disorder.

Investors were a bit shaken by the company's third-quarter financial report, when the company said the number of new patients per week taking Tysabri fell between the second and third quarters. Analysts have given a mix of cautious and dismissive outlooks on the potential sales impact of the new reports.

"We do not find yesterday's disclosure surprising, nor do we think it will have much impact on Tysabri sales trends," said Cowen and Co. analyst Eric Schmidt, in a note to investors.

He reaffirmed a "Outperform" rating, saying the incidence of PML in Tysabri patients still remains less than 1 in 1,000, a rate the Food and Drug Administration deems acceptable.

As of September, 9,500 patients had been treated with the drug for over 18 months and about 35,000 people [in] all are using the drug worldwide.

Meanwhile, the company's lead revenue driver by far is the multiple sclerosis drug Avonex.

But Jefferies & Co. analyst Adam Walsh reaffirmed a "Hold" rating on the stock and lowered his price target to $40 from $50, citing the new PML case. He expects more cases to be reported, pressuring the stock and prompting physicians to decrease use of the drug.

"Despite the fact that PML is a known risk-factor with Tysabri, our (physician) survey suggested three new cases of PML would lead to an abrupt and sustained decrease in Tysabri utilization amongst multiple sclerosis doctors," he said in a note to investors.

Still, Lazard Capital Markets analyst Joel Sendek, citing another survey of physicians, said neurologists plan to continue using the drug despite the risks because of the Tysabri's benefit. He reaffirmed "Buy" rating.



[link to article no longer available]

Cherie, this article states that 9,500 patients have been on Tysabri for 18 months. I don't know if they're figuring in the number on Tysabri in the previous go-round, or whether the 9,500 includes people with Crohn's who've been on Tysabri.


Last edited by agate on Thu Dec 18, 2008 9:45 am; edited 1 time in total
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Thu Nov 06, 2008 11:53 pm    Post subject: Reply with quote

Hmmm... big jump since the end of July/08. I guess that makes sense though, since July was the two year anniversary and quite a few got on it in the six months to year.

It would be interesting to know how many are still on it, of that 9500. scratch But still the ratio would be correct.

There is "rumor" of 12 more "suspected" cases . . . but I sincerely hope that is bogus.

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Nov 06, 2008 11:58 pm    Post subject: Reply with quote

Yes, I've heard about the "12 suspected cases" too--and in one instance I believe it was "20 suspected cases." These are undoubtedly from the AERS {Adverse Events Reporting System), which is a list of every "adverse event" anyone ever suspects he/she might have had--anyone can list an "adverse event" on it, and patients often do. The vast majority of the adverse events turn out to be unrelated to the drug that is suspected of being responsible, as I understand it.
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Fri Nov 07, 2008 12:03 am    Post subject: Reply with quote

Yeah, that's probably true (about "reported" cases ...).

However, if they do prove to have PML, I doubt there's little doubt what caused it.

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sun Nov 09, 2008 9:12 am    Post subject: Tysabri sometimes a first-line therapy Reply with quote

I've been under the impression that Tysabri wasn't prescribed as a first-line therapy any longer, but the Fall 2008 issue of MS Focus, put out by the MS Foundation, has an article called "Your Questions about Tysabri Answered" (page 58), where a couple of doctors from the MS Institute at the Shepherd Center in Atlanta--Sherrill Loring, MD, and Ben Thrower, MD--answer some questions, like this one:

Quote:
Q.: Who is a good candidate for Tysabri?

A.: Different doctors have varying opinions on when to use Tysabri. Some pescribe it as a first-line therapy, before they try any other MS drug, in newly diagnosed patients with very aggressive MS. At Shepherd, we use Tysabri when a person has had at least one relapse in the past year, or has new lesions on MRI, as well as ongoing MS activity in spite of being treated with both a beta interferon (such as Avonex, Betaseron or Rebif) and Copaxone.
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Sun Nov 09, 2008 11:18 am    Post subject: Reply with quote

It is not supposed to be, Agate. It was intended for people who were unsuccessful on the other options, or had very aggressive MS. How they can determine "aggression" in the first few months (when they first put someone on a med), is obviously a questionable assessment. In fact, how do they know those people aren't PPMS, which Tysabri isn't recommended for either.

But I guess it is like all the meds . . . some doctors will allow someone with SPMS on Copaxone and it's not recommended for that category either.

The DIFFERENCE is that I don't think people with MS for 15 min should be told "this is the best choice out there" and that is what is happening. That first year is FULL of confusion and grief, and that is not the time to be making a decision on a risky med.

If there are already about 50,000 people in the US who are on Tysabri now, it shouldn't take long before the number of people using it surpasses the number of people estimated to even have the disease in the US (400,000). HA . . . this could get iinteresting!

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sun Nov 09, 2008 12:44 pm    Post subject: Reply with quote

Yes, there are neuros who will prescribe Copaxone for SPMS--and my neuro is a case in point. I have SPMS and am on Copaxone.

It interests me that so many neuros will prescribe these drugs, including Tysabri, for patients who weren't "supposed" to be on them (at least, in the judgment of the drug companies producing the drugs).

I suspect that neuros feel free to prescribe them based on their intuition about patients because they know perfectly well that everything "known" about MS might turn out to be guesswork and wrong at any time.
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Sat Nov 22, 2008 6:56 pm    Post subject: Reply with quote

I totally understand why people try & neuro's recommend the meds, because what have you got to lose, really?

What annoys me is that that is nothing short of "off label" use, just the same as some of the other "off-label" drugs we use (i.e. like LDN) ... but for some reason, people don't see it the same way.

With Tysabri, I just don't feel it is safe enough to take risks on "newbies" to this disease . . . or at least I don't trust doctors/neuros to make trustworthy decisions about using this med when rxing "off-label" (or off black-box warnings). How many people are pre-medicating with antihistimines when one of the two warnings is "DO NOT USE IF YOU ARE ALLERGIC". What part of allergic don't they get? angryfire

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sat Nov 22, 2008 7:29 pm    Post subject: Reply with quote

I agree completely about the extreme riskiness of prescribing Tysabri for someone newly diagnosed with MS.

As for whether prescribing a drug like Copaxone for somebody with SPMS is an "off label" way of prescribing, it probably isn't just because of the way the neuros seem to get around the rules. I've heard of a number of instances of this: A neuro fudges on the record-keeping by saying the patient has RRMS even though both doctor and patient are fully aware that the patient has SPMS or some other progressive type that isn't "officially" suitable for treatment with Copaxone.

I have a pretty good idea that many neuros feel that too little is known yet about the ABCRs, and that taking one of them is better than doing nothing for any person with MS.

I tend to agree with that when it comes to ABCRs.
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Sun Nov 23, 2008 10:37 am    Post subject: Reply with quote

Yes, I realize they can get around it by reclassifying, but that doesn't make that decision "right". They could "call" us alcoholics too, then put us all on Naltrexone . . . but if it's not true ... scratch Same difference.

The DMDs have been "scientifically proven" ONLY on a set demographic; people with Relapsing Multiple Sclerosis. They (most) haven't proven effective for Secondary Progressive because there is a different process going on with the disease during that stage; neurodegeneration vs. inflammatory process.

Having said that, I have no problem what-so-ever with them "working" the system to get people on a med, purely on the hopes that the med might help. I think that's smart, to be honest. It's still off-label though, just like LDN.

In both scenarios, there is no proof it will help, and little evidence it will hurt, so it makes equal sense to rx if that is what the patient wants. There is nothing more "illegal" or less "scientifically proven" about rxing LDN for MS then it is to rx Tysabri or Copaxone.

See what I am getting at?

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sun Nov 23, 2008 11:22 am    Post subject: Reply with quote

I do see, and I agree that the medical profession has been unnecessarily suspicious of patients wanting to try LDN for MS.

LDN, being "low-dose" in the first place, doesn't appear to do any harm, and so why can't the docs just write out an rx for it?

There are doctors who say MS is MS, and that classifying it as RRMS, SPMS, PPMS, etc., isn't a scientifically established method of dealing with it. There are some who say that MS is really several different diseases that happen to have much in common.

Since there's all this ambiguity, the ones who prescribe DMDs across the board to anyone diagnosed with MS are probably just playing the game on the theory that doing something is better than doing nothing.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Nov 26, 2008 8:29 pm    Post subject: (Summary) Evidence-based review of Tysabri Reply with quote

From Journal Watch Neurology, November 25, 2008:

Quote:
Summary and Comment

Evidence-Based Review of Natalizumab in MS
A review of the benefits and risks from this treatment


Natalizumab, a selective adhesion-molecule inhibitor, was introduced to the U.S. market for the treatment of relapsing-remitting multiple sclerosis (RRMS) in November 2004, then withdrawn in February 2005 after progressive multifocal leukoencephalopathy (PML) occurred in three trial participants, two with MS (see JW Neurol Jul 7 2005). It was reintroduced in July 2006 with a risk-management program (see JW Neurol Jun 26 2007). Now, members of the Therapeutics and Technology Assessment Subcommittee (TTAS) of the American Academy of Neurology have provided an evidence-based report on the use of natalizumab for treating MS.

The authors categorized as level A the evidence that, in RRMS, natalizumab reduces measures of disease activity (including clinical relapse rate and MRI parameters) and of disease severity (measured by progression rate on the expanded disability status scale and by cumulative MRI lesion burden). They noted that the value of natalizumab in secondary progressive MS is unknown. Although clinical trials indicated a substantial advantage of natalizumab over placebo, the authors emphasized that "the relative efficacy of natalizumab compared to other available disease-modifying therapies is unknown." They also categorized as level A the evidence of an increased risk for PML in patients using natalizumab in combination with other agents and emphasized that combination therapy should not be used. Finally, they designated as level C the evidence regarding risk for PML with natalizumab monotherapy.

Comment: Since the deliberations of the TTAS, two additional cases of PML have been reported from Europe in patients taking natalizumab as monotherapy, a fact that these authors briefly note. These cases, which occurred 14 and 17 months after treatment began, should now convert the level C classification for PML risk with natalizumab monotherapy to level A. More recently, an additional case of PML in the U.S. has been reported.

The authors recommend that "natalizumab be reserved for use in selected patients with relapsing-remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course," and contend, "This recommendation is very similar to that of the FDA." The prescribing information for natalizumab, however, contains no suggestion that the drug be used in the latter situation. Moreover, one of the patients recently reported to have developed PML was naive to any other disease-modifying therapy, suggesting that using natalizumab as first-line therapy might be hazardous. Further, this recommendation by the TTAS appears inconsistent with its conclusion that the drug’s efficacy relative to other therapies is undetermined.

Natalizumab appears effective in treating relapsing forms of MS, but physicians should be cautious in prescribing the drug because of the recent reports of PML in patients on monotherapy and because of continuing uncertainty about the incidence of this viral infection and of other possible opportunistic infections.

— Aaron E. Miller, MD

Dr. Miller is Professor of Neurology and Medical Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, New York City. He was an investigator in the SENTINEL trial.

Published in Journal Watch Neurology November 25, 2008

Citation(s):

Goodin DS et al. Assessment: The use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008 Sep 2; 71:766.







This should link to the entire article in Neurology:
http://www.neurology.org/cgi/content/full/71/10/766
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sat Nov 29, 2008 12:11 pm    Post subject: --About Levels A, B, C, and U (see article above) Reply with quote

Supplemental information that will help in understanding the article above. From the TTAS (Therapeutics and Technology Assessment Subcommittee of the AAN -- American Academy of Neurology) Mission Statement:

Quote:
AAN Classification of Evidence for Therapeutic Intervention

Class I: Randomized, controlled clinical trial with masked or objective outcome assessment in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are required: a) concealed allocation, b) primary outcome(s) clearly defined, c) exclusion/inclusion criteria clearly defined, and d) adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets b-d above OR a RCT in a representative population that lacks one criteria a-d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement*

Class IV:
Studies not meeting Class I, II or III criteria including consensus, expert opinion or a case report.
*Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

A= Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

B= Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)

C= Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

U= Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. (Studies not meeting criteria for Class I – Class III).

*In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome > 5 and the lower limit of the confidence interval is > 2).




Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Tue Dec 02, 2008 11:05 am    Post subject: (Article) Natalizumab: Increased vigilance required... Reply with quote

From Therapeutic Advances in Neurological Disorders,1: 155, November 1, 2008:

Quote:
Michael K. Racke and Olaf Stüve

Editorial

Natalizumab: increased vigilance is required in treating patients with multiple sclerosis


Published by:
http://www.sagepublications.com

The recent reporting of two new cases of progressive
multifocal leukoencephalopathy (PML) in
patients with multiple sclerosis (MS) receiving
natalizumab highlights the risks associated
with this agent in patients who do not respond
to conventional immunomodulatory therapy.
Since the introduction of natalizumab back into
the US and European markets, there had been
some optimism that perhaps the use of natalizumab
as a monotherapy would result in no new
cases of PML. The thought that occurrence of
PML would occur only when natalizumab was
used in combination with interferon or following
other immunosuppressive agents was proven to
be false when one of the patients who developed
a recent case of PML had not been on any other
MS medication. Thus, while the use of natalizumab
has proven to be a valuable addition in the
management of some patients with MS, it
appears that PML and immune reconstitution
inflammatory syndrome (IRIS) are rare but
significant complications that may afflict patients
receiving this therapy. In addition, the recent
reports of melanoma possibly being linked to
natalizumab-treated MS patients suggests that
infectious complications are not the only
obstacles faced by patients being treated with
this VLA-4 antagonist [Mullen et al. 2008].

It has to be emphasized that potentially fatal
infectious and noninfectious complications of
pharmacotherapies are not exclusive to natalizumab,
but have also occurred with other experimental
and approved agents [Hemmer et al.
2006]. For instance, the risk of acute myelogenous
leukemias after exposure to mitoxantrone appears
to be a rare but significant complication in
patients being treated with this chemotherapeutic
agent [Hasan et al. 2008]. The risk of cardiac toxicity is also a significant complication that may be faced by patients receiving this therapy [Saccardi et al. 2004].

However, these FDA-approved agents may be
joined by several new agents that also have significant risks associated with them. In the recent clinical trial examining alemtuzumab, six of
216 patients developed idiopathic thrombocytopenic
purpura (ITP), with one of these
patients suffering a fatal intracerebral hemorrhage.

The B-cell-depleting chimeric monoclonal
antibody rituximab has also been associated with
the development of PML in 27 patients with different
diseases. Furthermore, several of the newer
agents in therapeutic development and clinical
trials may also have rare but significant adverse
effects.

While all of these agents have significant
risks, they also offer hope to patients with MS
who do not respond optimally to interferon beta
or glatiramer acetate. A critical next step in
defining an optimal therapy for patients with
MS will be to identify (1) patients who will
benefit from a particular agent, and (2) patients
who will be at an increased risk of an adverse
outcome. The identification of biomarkers that
may include pharmacogenomics, proteomics,
and more traditional laboratory assays that measure
immunological responses will likely play an
important role. Such tools would significantly
reduce the anxiety of patients and physicians
alike in terms of the use of medications such as
natalizumab.

A series of studies performed on patients enrolled
in the SENTINEL and AFFIRM trials in Dallas
suggest that these patients may have unexpected
biological consequences that result from treatment
with this agent [Stuve et al. 2006a; Stuve
et al. 2006b]. While our early observations
suggested a significant effect on lymphocyte
entry into the cerebrospinal fluid, it was somewhat
reassuring that no patients enrolled in
Dallas developed any opportunistic infection.
However, if natalizumab did have an adverse
effect on CNS immune surveillance, shouldn’t
there have been evidence to suggest that viruses
other than the John Cunningham (JC) virus also
reactivated following natalizumab therapy?

To address this issue, we examined the CSF and
serum of the Dallas natalizumab-treated cohort
for evidence of human herpes virus 6 (HHV-6)
reactivation, another virus thought to remain
latent in the adult central nervous system [Yao
et al. 2008]. Interestingly, natalizumab-treated
patients appear to have lower serum IgG levels
than MS patients that did not receive natalizumab.
Among transplant immunologists, HHV-6
reactivation is considered an indicator of
CNS immune suppression and increased risk
for subsequent viral reactivation. Despite this
low serum IgG level, we were able to detect
elevated titers of antibodies in the serum of
natalizumab-treated MS patients directed against
HHV-6. This would suggest that conditions in
natalizumab-treated patients are conducive for
these patients to mount an immune response
against HHV-6. It is also of interest that some
investigators suggest that HHV-6 may participate
in the transformation of the JC virus into a
pathogenic strain capable of initiating the
demyelinating pathology seen in patients with
PML [Mock et al. 1999].

One positive aspect of the unfortunate recent
events surrounding natalizumab is the heightened
vigilance with regard to potential side
effects of this drug. It is only through continued
study of patients receiving natalizumab and
attempting to understand the relationship of use
of the drug to the development of risk factors for
viral reactivation that we will be able to reduce
the concerns within the neurologic community
about the use of these novel therapies.

Conflict of interest statement
None declared.



[References omitted.]

http://tan.sagepub.com/cgi/reprint/1/3/155?etoc


Last edited by agate on Wed Dec 17, 2008 6:16 pm; edited 1 time in total
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Dec 15, 2008 9:51 am    Post subject: Another PML case in a Tysabri patient? Reply with quote

The experts did say they were expecting more PML cases to turn up. It looks as if there's been another.

From www.24/7WallStreet.com:

Quote:
December 15, 2008

Day Trader Alert: Biogen Idec & Another PML Case (BIIB, ELN)

Biogen Idec Inc. (NASDAQ: BIIB) just came out with an SEC filing showing that on December 11, 2008, regulatory agencies were notified of a confirmed case of progressive multifocal leukoencephalopathy. In other words, it found another PML case in a multiple sclerosis patient treated with TYSABRI. This is also affecting shares of its partner Elan Corp. plc (NYSE: ELN).

This was in the commercial setting in the European Union as part of TYGRIS: TYSABRI Global Observational Program in Safety — ROW. Additional notes issued are as follows:

The diagnosis was made based upon the detection of JC Virus (JCV) DNA in the cerebrospinal fluid (CSF) in the setting of clinical signs, symptoms and magnetic resonance imaging (MRI) findings consistent with the diagnosis of PML.

Patient Background:

Patient has a history of MS and prior disease modifying therapies, including beta-interferons; patient received approximately 26 months of TYSABRI monotherapy; clinical vigilance led to early identification of signs and symptoms of possible PML and clinical evaluation which included MRI scanning and CSF testing; patient is under the care of patient’s treating physician.

Shares are now trading down 8% pre-market at $43.05, but this is on very thin trading volume and the spread appears to be very wide. As a reminder, these PML risks have been associated with TYSABRI and the company sees this from time to time now. To see how much this stock bounced off of lows after the dust settles, the 52-week trading range $37.21 to $73.59.

Elan Corp. plc (NYSE: ELN) is its partner, and its shares are down 6% pre-market at $6.74.

Jon C. Ogg
December 15, 2008



http://www.247wallst.com/2008/12/biogen-idec-ano.html

More on this:

Quote:
Elan confirms another case of PML

Monday, 15 December 2008 17:27

Elan has confirmed another case of progressive multifocal leukoencephalopathy (PML) in a multiple sclerosis patient being treated with its Tysabri drug. The case occurred in the European Union, the company added.

The patient had been treated with the drug for the past 26 months or so.

Elan and Biogen Idec, which is involved in the manufacture of the drug with the Athlone-based firm, withdrew Tysabri from the market in February 2005 after three patients, two of whom died, contracted PML.


The drug returned to the market in 2006 with warnings after the US Food and Drug Administration decided MS patients willing to accept the risks should be able to have access to the drug's potential benefits. The drug is given by injection once a month.

Elan said another patient had contracted PML in October, while another two were diagnosed in July.

At the end of September, about 35,500 patients were using Tysabri worldwide.

Elan shares closed four cent higher at €5.10 in Dublin this evening despite the news.



From http://www.rte.ie/business/2008/1215/elan.html


Last edited by agate on Mon Dec 15, 2008 6:52 pm; edited 2 times in total
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Dec 15, 2008 6:47 pm    Post subject: (Article) Biogen cites new setback for Tysabri Reply with quote

From the Wall Street Journal, December 16, 2008:

Quote:
Biogen Cites New Setback for MS Drug

By KEITH J. WINSTEIN

A German multiple-sclerosis patient taking the drug Tysabri contracted a serious brain infection, marking the seventh such case for the potent medicine, which was earlier withdrawn because of the same side effect.

The announcement, the fourth in recent months, may dim commercial prospects for Tysabri, which is seeing a reduction in some marketing efforts and may face competition from a more-convenient pill in coming years.

Biogen Idec Inc., which makes Tysabri, said it notified drug regulators on Thursday of the infection, called progressive multifocal leukoencephalopathy, or PML. The patient is hospitalized in Germany.

Biogen, of Cambridge, Mass., and its marketing partner, Ireland's Elan Corp., withdrew Tysabri in 2005 after three patients contracted PML, two of whom died. The drug was reintroduced in 2006 under a monitoring program that tries to reduce the risk.

Since then, four patients have contracted the infection -- two in Germany, one in Sweden, and one in Florida. None of the four have died, suggesting that monitoring and quick treatment may reduce the infection's severity.

The companies said the new case was in line with expectations. Tysabri's label now warns that PML is a known side effect. About 35,500 patients were taking Tysabri at the end of September, and about 9,500 have taken the drug, delivered as a monthly injection, for at least 18 months.

Many doctors believe Tysabri's benefits are worth the risks. In relapsing-remitting multiple sclerosis -- the kind Tysabri treats -- the body's immune system begins to attack nerves in the brain, causing bouts of numbness and tingling. Eventually, the disease progresses to a severe disability and patients are bedridden. In a two-year clinical trial, 17% of Tysabri patients became markedly more disabled -- compared with 29% given a dummy injection.

Last week, Elan, which markets Tysabri for the digestive condition Crohn's disease, said it would cut back on pitching the drug to doctors. The company is under pressure from a major shareholder to fire its chief executive and cut costs. "We just can't afford the cost structure for a full-fledged sales force," said Mary Stutts, a spokeswoman. Tysabri also may face competition from an experimental MS pill, called FTY720 or fingolimod, from Swiss drugmaker Novartis AG.

—Jeanne Whalen contributed to this article.
Write to Keith J. Winstein at keith.winstein@wsj.com



I wonder about this statement though:

Quote:
Eventually, the disease progresses to a severe disability and patients are bedridden.


It sounds as if someone with RRMS will always progress to a bedridden state. Not my understanding of it at all.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Tue Dec 16, 2008 10:05 am    Post subject: (News release) Tysabri may reduce immunity... Reply with quote

News release from the University of Texas Southwestern Medical Center, December 16, 2008:

Quote:
MS drug may reduce immunity, researchers find

DALLAS — Dec. 16, 2008 — A drug used to treat multiple sclerosis might make some patients vulnerable to brain infection by reducing the number of immune cells there, researchers at UT Southwestern Medical Center have found.

The findings also suggest that the drug, natalizumab, might be safer and more effective when given with treatment “holidays” instead of continuously over long periods, the researchers said.

“Natalizumab is very effective in keeping pro-inflammatory cells out of the brain to reduce damage from MS,” said Dr. Olaf Stüve, assistant professor of neurology at UT Southwestern and senior author of the study, which appears in the December issue of Archives of Neurology.

But the potential downside is interference with immune surveillance against infection, he said. Thus, infections of the brain or spinal cord may go undetected until they become a serious problem.

“However, our study has limitations because of the small number of autopsies that were involved,” Dr. Stüve said.

“Whether or not treatments other than prolonged, uninterrupted dosing may benefit patients with MS should be tested in controlled clinical trials,” he said.

Natalizumab was introduced in 2004 and almost immediately withdrawn after three people developed a brain infection called progressive multifocal leukoencephalopathy, or PML. Two of those patients died.

The drug, known as Tysabri, returned to the market in 2006 under stricter monitoring guidelines and label warnings about the risk of developing PML. Only five other drugs are approved for treating MS.

“It’s a very effective drug, and it’s clear that the vast majority of patients are greatly benefiting from its use,” said Dr. Stüve, who is also an assistant professor at the Dallas Veterans Affairs Medical Center.

MS is an autoimmune disease in which a person’s own body attacks the fatty coating surrounding nerve cells. Natalizumab is designed to prevent that autoimmune attack.

“Unlike other immunosuppressant drugs, natalizumab was specifically designed to interfere with the migration of immune cells into organs,” Dr. Stüve said. Most MS experts believe that these cells play a major role in the disease and that their ability to enter the central nervous system should be reduced.

“This type of infection has also been reported with several other types of immunosuppressant drugs that are being used to treat MS,” he said.

About 43,000 people have taken natalizumab since it was reintroduced in 2006, Dr. Stüve said, with three more people having developed PML. Because of the increased monitoring, these cases of PML were detected relatively early, he said.

The researchers previously have shown that natalizumab significantly reduces the number of immune cells in the cerebrospinal fluid, which bathes and protects the spine and brain. In particular, the number of CD4 T cells dropped 10 times more than the other types of immune cells. Activation and rapid division of CD4 T cells are vital for many immune responses.

In the current study, the researchers focused on the number of immune cells within the open spaces of the brain itself, known as cerebral perivascular spaces. Cells around these spaces are believed to be crucial in mounting autoimmune attacks on the body.

They examined postmortem brain tissue from one of the patients with MS who had died while taking natalizumab. Controls included tissue from patients with MS who were not treated with natalizumab, and from patients with PML who had not been treated with natalizumab.

Natalizumab caused a significant reduction in immune-related cells in the perivascular spaces of the person with MS, including a total depletion of CD4 T cells and the cells that activate them.

“The challenge will be to identify biomarkers that will help patients at risk for breakdown of immune surveillance,” Dr. Stüve said.

Other UT Southwestern researchers involved in the study were Dr. Maria del Pilar Martin, a former postdoctoral fellow; Dr. Petra Cravens, instructor of neurology; Ryan Winger, summer student; Dr. Elliot Frohman, professor of neurology; Dr. Todd Eagar, assistant professor of neurology; and Dr. Nitin Karandikar, associate professor of pathology.

Researchers from Ohio State University Medical Center; the University of California, San Francisco; Klinkim Rechts der Isar in Munich, Germany; and the University of Colorado, Denver, also participated.

The study was funded by the Dallas Veterans Affairs Research Corp., the Department of Veterans Affairs, the National Multiple Sclerosis Society, the Viragh Family Foundation, the Deutsch Forschungsemeinschaft and Teva Neuroscience


Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Dec 18, 2008 9:36 am    Post subject: A little more about this 7th PML case Reply with quote

This has a few more details about the new case:

Quote:
Tysabri Brain Disease Reported in Another Multiple Sclerosis Patient December 16th, 2008 •

Another multiple sclerosis patient has suffered a rare brain disease as a side effect of Tysabri. This is the seventh reported case of the potentially fatal brain infection, known as progressive multifocal leukoencephalopathy, linked to the drug, and at least the fourth known report to surface this year.

Tysabri (natalizumab), which is manufactured and distributed jointly by Biogen Idec and Elan Corporation, is used to treat multiple sclerosis (MS) and Crohn’s Disease. It is given by intravenous injection once every 28 days to help prevent cognitive decline, vision loss and relapse in MS patients.

On December 15, 2008, Biogen Idec disclosed in a filing with the SEC that regulatory agencies have been notified about a new confirmed case of progressive multifocal leukoencephalopathy in a multiple sclerosis patient treated with Tysabri in Europe.

Tysabri has previously been linked to the rare brain disease, which impacts the central nervous system and often results in death. PML causes progressive inflammation and damage to the white matter of the brain at multiple locations, and there is no cure for the infection. Symptoms could include paralysis, loss of vision, impaired speech, weakness, cognitive decline and death.

After Tysabri was initially launched in 2004, the drug was removed from the market the next year after three cases of progressive multifocal leukoencephalopathy were discovered among users, including two deaths.

The drug was re-introduced in 2006 with stronger warnings about the risk of PML and was only made available under strict guidelines for usage.

Since that time, this latest report is the fourth new case of PML to surface among users of Tysabri, with all four of the reports being disclosed this year.

The latest case involves an individual in Germany who received approximately 26 months of Tysabri monotherapy. The patient had a history of MS and prior disease modifying therapies, including beta-interferons. The signs and symptoms of PML were caught early, which may have reduced the severity of the brain infection.



http://tinyurl.com/4tdpz6
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Dec 19, 2008 1:54 pm    Post subject: New PML death for an MS patient on Tysabri Reply with quote

Bad news. This is not the most recently reported PML case.

Quote:
UPDATE:Patient On Biogen, Elan MS Drug Dies Of Brain Disease




By Thomas Gryta Of DOW JONES NEWSWIRES NEW YORK -(Dow Jones)- A multiple sclerosis patient being treated with Tysabri, from Biogen Idec Inc. (BIIB) and Elan Plc (ELN), has died of a previously disclosed occurrence of a rare brain infection.
Biogen originally reported the confirmed case of progressive multifocal leukoencephalopathy, or PML, in late October. Tysabri, key to the future growth of both companies, is very effective in fighting MS, but a suspected link to PML led to its withdrawal from the market for 18 months beginning in 2005.

Patients on the drug are now closely monitored and four cases of the often fatal infection have occurred since its July 2006 relaunch, but the death may quell hope that PML could be a treatable side effect of the drug.

Shares of Biogen were recently down $1.15, or 2.4%, to $46.86, while Elan dropped 32 cents, or 5%, to $5.96.

The patient who died was the third case and the only one in the U.S. The other three are in Europe and remain alive.

A Biogen spokeswoman said that the company was informed earlier this week of the death and wouldn't disclose more information out of respect for the patient and her family.

The patient received 14 monthly infusions of Tysabri as a monotherapy and was previously treated with Teva Pharmaceuticals Industries Inc.'s (TEVA) Copaxone, Bayer AG's (BAY.XE) Betaseron and Biogen's Avonex. She also took methotrexate for a rheumatological condition.

All of the patients that developed PML were given plasmapharesis, a process that removes large molecules from the blood, speeding up Tysabri's removal and allowing the immune system to fight the PML infection.

When the drug is removed from the system, patients often experience an inflammatory response as the immune system reconstitutes itself, which can lead to their condition getting worse before any improvement is seen.

The death of the patient may temper arguments that the intricate distribution and monitoring program used for Tysabri, and use of plasmapharesis may ease the risk of PML for patients. Biogen has hoped that PML could eventually could be a "survivable adverse event."

But given the severity of PML, some believe that the death of a patient shouldn't be a surprise.
"We think the odds of surviving PML are still better than initially thought," said analyst Geoffrey Meacham of JPMorgan.

Tysabri's label implies that one in every 1,000 patients could get PML, but the actual number remain well below that ratio. As of Sept. 30, more than 35,500 patients use Tysabri, with 9,500 patients on it for at least 18 months and 3,700 for more than two years.

Steven Harr, an analyst with Morgan Stanley, writes that the recent death may demonstrate that Tysabri's risk is consistent with the label, to the disappointment of some investors and physicians that thought it might actually be lower.

-By Thomas Gryta, Dow Jones Newswires; 201-938-2053; thomas.gryta@dowjones.com
C

Friday December 19th, 2008 / 19h40

Source : Dowjones Business News



http://tinyurl.com/4x2rux
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Mon Dec 22, 2008 11:29 pm    Post subject: Re: New PML death for an MS patient on Tysabri Reply with quote

[quote="agate"]Bad news. This is not the most recently reported PML case.

Quote:
UPDATE:Patient On Biogen, Elan MS Drug Dies Of Brain Disease

By Thomas Gryta Of DOW JONES NEWSWIRES NEW YORK -(Dow Jones)- A multiple sclerosis patient being treated with Tysabri, from Biogen Idec Inc. (BIIB) and Elan Plc (ELN), has died of a previously disclosed occurrence of a rare brain infection.
Biogen originally reported the confirmed case of progressive multifocal leukoencephalopathy, or PML, in late October.

A Biogen spokeswoman said that the company was informed earlier this week of the death and wouldn't disclose more information out of respect for the patient and her family.

All of the patients that developed PML were given plasmapharesis, a process that removes large molecules from the blood, speeding up Tysabri's removal and allowing the immune system to fight the PML infection.

When the drug is removed from the system, patients often experience an inflammatory response as the immune system reconstitutes itself, which can lead to their condition getting worse before any improvement is seen.

The death of the patient may temper arguments that the intricate distribution and monitoring program used for Tysabri, and use of plasmapharesis may ease the risk of PML for patients. Biogen has hoped that PML could eventually could be a "survivable adverse event."


Interesting . . .

In this article they are actually saying that she died from PML, but no where else is that stated so matter of factly (not that this article is necessarily accurate either . . .).

Apparently if it was PML, Biogen should be filing another 8-K form, even though they already filed one for the PML case itself. The fact that it is a death should provoke another 8-K though . . . well at least according to some ...

Also, it is supposedly not announced on the Biogen site ... which means perhaps that there has been no autopsy confirmation of a PML death yet.

Personally I think it's pretty obvious that she didn't die from apendicitis or a car accident ... but not according to some people.

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sat Jan 10, 2009 10:13 am    Post subject: Biogen to give weekly updates on Tysabri--no new PML cases Reply with quote

From EasyBourse.com, January 9, 2009:

Quote:
Biogen Says No New Brain Infections In First Tysabri Update



By Thomas Gryta Of DOW JONES NEWSWIRES

NEW YORK -(Dow Jones)- Biogen Idec Inc. (BIIB) reported that there were no new cases of a rare brain infection in users of its multiple sclerosis drug Tysabri in the first of its planned weekly Web-based updates on Friday.

The Cambridge, Mass., biotech, which sells Tysabri with Ireland's Elan Plc (ELN), will post the updates in an effort to more consistently disclose incidences of the often fatal condition.

A suspected link to progressive multifocal leukoencephalopathy, or PML, led to Tysabri's being pulled from the market for 18 months beginning in 2005. Since the relaunch, the company has reported that four people had confirmed cases of PML, with one dying.

This past summer marked the two-year anniversary of Tysabri's re-launch, raising Wall Street's anxiety over PML-related news. The timeline is important because two patients with PML in 2005 were using the drug for more than two years.

Biogen will post an update of PML cases on the investor relations section of its Web site every Friday at 4:30 p.m. EST and will continue to do so until July 24, which is the third anniversary of the drug's relaunch.

....

[Citigroup analyst Yaron] Werber has criticized Biogen's former policy of disclosing new cases through 8-K filings with the Securities and Exchange Commission as making investors nervous and pressuring the company's shares.

Biogen's stock, which closed up 30 cents, or 0.6%, at $48.25, is down 17% for the last 12 months.
Elan closed Friday down 31 cents, or 3.6%, at $8.39 and is down 67% in the last year. Tysabri is Elan's biggest seller, making it more sensitive to related news....

Werber expects the regular updates to help ease of the "fear of the unexpected" in Biogen shares. He agrees with stopping the disclosures in late July, when a clear picture of the PML risk in Tysabri should be firmly established.

"At some point they would be wise to cut this off," he said. "Because this sort of information is going to be very good for the competition. You can't go on marketing a product in this situation forever."

-By Thomas Gryta, Dow Jones Newswires; 201-938-2053; thomas.gryta@dowjones.com


Source : Dowjones Business News





http://www.easybourse.com/bourse-actualite/marches/biogen-says-no-new-brain-infections-in-first-tysabri-update-594041
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sat Jan 31, 2009 2:44 pm    Post subject: Biogen to post new PML cases online Reply with quote

From MSFYi Newsletter, January 31, 2009:

Quote:
Biogen to Post New PML Cases Online

People curious about PML cases linked to Tysabri can now find updated information on Biogen Idec Inc.’s website each Friday.

The reports began in January and are expected to continue until July 24, Tysabri’s third anniversary of being reintroduced to the US market after it was pulled in 2005 following several deadly cases of PML.

Since the drug’s reintroduction, four new PML cases have been reported, with one fatality.

See the reports at http://investor.biogenidec.com/phoenix.zhtml?c=148682&p=irol-TPME.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Feb 02, 2009 3:45 pm    Post subject: Plasmapheresis to improve outcome of PML Reply with quote

From the Cleveland Plain Dealer, February 2, 2009:

Quote:
Cleveland Clinic researchers find way to treat MS drug side effect

by Brie Zeltner / Plain Dealer reporter

Researchers at the Cleveland Clinic have found a way to help multiple sclerosis patients with a rare side effect from a common drug used to treat the disease.

Some MS patients taking the drug Tysabri develop a rare infection called progressive multifocal leukoencephalopathy, which is often fatal. Tysabri is used to keep white blood cells from entering the brain and attacking healthy nerves in MS patients. PML is caused by a virus that usually only infects immuno-compromised patients who do not have adequate white blood cells to fend it off.

The drug was temporarily withdrawn from the market in 2005 when the first two cases of PML emerged and was reintroduced a year later with stricter safety guidelines. There have been several more confirmed cases of PML since then.

In the Clinic study, researchers used plasmapheresis to clear Tysabri from the blood of 12 MS patients during a two-week period. Stopping treatment and quickly removing the drug from the patient's blood may improve the outcome for patients with PML, said Dr. Robert Fox, medical director of the Clinic's Mellen Center for multiple sclerosis in a news release.

Tysabri can take up to 12 weeks to clear from the bloodstream naturally and can cause reduced red and white blood cell counts for up to six months, the researchers said in the paper.

The study will be published in the Tuesday's issue of the journal Neurology.




You can see this article here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Feb 04, 2009 7:07 pm    Post subject: (Abstract) Tysabri effective 2nd-line therapy for RRMS Reply with quote

From PubMed, February 4, 2009:

Quote:
Eur J Neurol. 2009 Jan 27.

Natalizumab is effective as second-line therapy in the treatment of relapsing remitting multiple sclerosis

Putzki N, Kollia K, Woods S, Igwe E, Diener HC, Limmroth V.
Department of Neurology, University Hospital Essen, Essen, Germany.

Background:

Natalizumab has been recommended for the treatment of patients with relapsing-remitting multiple sclerosis with insufficient response to interferon-beta (IFN-beta) or glatiramer acetate (GA).

Method:

Prospective, observational study.

Results:

We found a reduction of the annualized relapse rate from 2.1 under IFN-beta or GA to 0.2 one year after switching to natalizumab. There were 94% fewer gadolinium-enhancing lesions with natalizumab.

Conclusion:

Natalizumab reduced short-term clinical and MRI activity in second-line therapy, and efficacy is comparable to first-line therapy as demonstrated in the pivotal trials.

PMID: 19187261


The abstract can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Feb 04, 2009 7:16 pm    Post subject: (Abstract) Plasma exchange to accelerate Tysabri clearance.. Reply with quote

From PubMed, February 4, 2009:

Quote:
Neurology. 2009 Feb 3;72(5):402-9.

Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function

Khatri BO, Man S, Giovannoni G, Koo AP, Lee JC, Tucky B, Lynn F, Jurgensen S, Woodworth J, Goelz S, Duda PW, Panzara MA, Ransohoff RM, Fox RJ.
Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, 9500 Euclid Ave., U-10, Cleveland, OH 44195 foxr@ccf.org.

BACKGROUND:

Accelerating the clearance of therapeutic monoclonal antibodies (mAbs) from the body may be useful to address uncommon but serious complications from treatment, such as progressive multifocal leukoencephalopathy (PML). Treatment of PML requires immune reconstitution. Plasma exchange (PLEX) may accelerate mAb clearance, restoring the function of inhibited proteins and increasing the number or function of leukocytes entering the CNS.

We evaluated the efficacy of PLEX in accelerating natalizumab (a therapy for multiple sclerosis [MS] and Crohn disease) clearance and alpha4-integrin desaturation. Restoration of leukocyte transmigratory capacity was evaluated using an in vitro blood-brain barrier (ivBBB).

METHODS:

Twelve patients with MS receiving natalizumab underwent three 1.5-volume PLEX sessions over 5 or 8 days. Natalizumab concentrations and alpha4-integrin saturation were assessed daily throughout PLEX and three times over the subsequent 2 weeks, comparing results with the same patients the previous month. Peripheral blood mononuclear cell (PBMC) migration (induced by the chemokine CCL2) across an ivBBB was assessed in a subset of six patients with and without PLEX.

RESULTS:

Serum natalizumab concentrations were reduced by a mean of 92% from baseline to 1 week after three PLEX sessions (p < 0.001). Although average alpha4-integrin saturation was not reduced after PLEX, it was reduced to less than 50% when natalizumab concentrations were below 1 mug/mL. PBMC transmigratory capacity increased 2.2-fold after PLEX (p < 0.006).

CONCLUSIONS:

Plasma exchange (PLEX) accelerated clearance of natalizumab, and at natalizumab concentrations below 1 mug/mL, desaturation of alpha4-integrin was observed. Also, CCL2-induced leukocyte transmigration across an in vitro blood-brain barrier was increased after PLEX. Therefore, PLEX may be effective in restoring immune effector function in natalizumab-treated patients.

PMID: 19188571


The abstract can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Feb 06, 2009 9:28 am    Post subject: Another case of PML? Reply with quote

It sounds as if there might be another case of PML in an MS patient on Tysabri. You can read about it here.

Also here.

Yes, there's a new case (February 5, 2009). It's listed here. The patient is not in the US and has been on Tysabri for 12 months.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed Feb 11, 2009 3:26 pm    Post subject: (Article) Third psoriatic PML case raises concerns.... Reply with quote

This contains some statements about Tysabri that seemed significant enough to post. From MedPage Today, February 11, 2009:

Quote:
SDEF: Third Psoriatic PML Case Raises More Concerns About Efalizumab

By Peggy Peck, Executive Editor, MedPage Today

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco


WAILEA, Hawaii, Feb. 11 -- Advocates of biologic therapies have been shaken by a third reported case of progressive multifocal leukoencephalopathy (PML) in a psoriasis patient on long-term efalizumab (Raptiva).

The PML issue emerged as a dominant theme during a panel discussion that wrapped up a morning devoted to psoriasis therapies at the Skin Disease Education Foundation's Hawaii Dermatology Seminar here.

Concern about the PML risk was heightened by the news that the most recent case involved a young patient -- a 47-year-old German. A 70-year-old man was the first case and the second was a 73-year-old woman.

But like the first two PML cases, the German patient was on efalizumab monotherapy for more than three years.

The timing of the PML onset was especially troubling because of what it suggests about the true risk, said Craig L. Leonardi, M.D., a dermatologist at Saint Louis University in St. Louis.


He noted that efalizumab exposure is often estimated at 46,000 worldwide, but he said that only about 400 patients have been treated with efalizumab for four years and the number treated for three years is about 1,100.


"If you are talking about three out of 1,100 that is a very different number than three out of 46,000," Dr. Leonardi said.


John Y.M. Koo, M.D., vice chairman of dermatology at the University of California San Francisco, sounded a similar note of alarm, pointing out that "one case, I say that might be a fluke," but "three cases, I worry that might be the tip of the iceberg."


Last fall the FDA ordered Genentech to add a boxed warning about PML to the efalizumab label, but that action was the result of a single case.

Both Dr. Leonardi and Dr. Koo said it was time to get proactive in advising patients to get off efalizumab rather than simply "giving them the choice."


But M. Shane Chapman, M.D., of Dartmouth Medical School and Dartmouth-Hitchcock Medical Center in Lebanon, N.H., said that taking patients off efalizumab is no easy task.


In addition to the risk of rebound, which Dr. Koo agreed was significant, Dr. Chapman said that although PML has not been reported with other biologics used to treat psoriasis, it has been reported in multiple sclerosis patients treated with natalizumab (Tysabri).


"My point is that putting the patient on another biologic may help us sleep better at night, but I'm not sure we're doing the patient any favors," Dr. Chapman said.


Natalizumab came to the market in late 2004 with much fanfare about its potential benefit for MS patients, but less than six months later reports of PML prompted Biogen Idec and distributor Elan, to withdraw the agent. It returned to the market in June 2006 under a strict management program.


A little over a year ago natalizumab was approved for Crohn's disease.


Earlier this month, Cleveland Clinic researchers reported that plasmapheresis rapidly cleared the drug, which, they said, reduced the risk of PML. But they did not address the risk of immune reconstitution inflammatory syndrome (IRIS), which can occur following plasmapheresis and is nearly as deadly as PML. (See: FDA Approves Natalizumab (Tysabri) for Crohn's Disease and Natalizumab Side Effect Potentially Treatable with Plasmapheresis)


For dermatologists worried about rebound, Dr. Koo said he recommended putting patients on cyclosporine, which, he said, virtually eliminated rebound in patients that he has taken off efalizumab.


Dr. Leonardi told MedPage Today that he does not use cyclosporine. Instead, he immediately starts patients on another biologic. "I haven't had any problem with rebound," he said.


Dr. Leonardi disclosed potential conflicts of interest with Abbott, Abgenix, Allergan, Amgen / Immunex, Biogen-IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Connetics, Corixa, Celgene, Centocor, Fujisawa, Genentech, Isis, and Medimmune.

Dr. Chapman disclosed potential conflicts of interest with Genentech, Centocor, and Abbott.


Dr. Koo disclosed potential conflicts of interest with Abbot. Amgen, Biogen, Bristol Meyers Squibb, Centacor, Connetics, Eisai, Fujisawa, Galderma, Genentech, Novartis, Serono, Teikoku, Valeant, and Warner-Chilcott.




Primary source: Skin Disease Education Foundation Hawaii Dermatology Seminar
Source reference:
Panel Discussion Psoriasis 2009 SDEF 2009.




You can see this article here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Feb 26, 2009 4:08 pm    Post subject: Biogen posts 2-year study of Tysabri Reply with quote

From MSFYi, the MS Foundation Internet newsletter for February 2009 (February 26, 2009):

Quote:
Biogen Posts Two-Year Study of Tysabri

Recent research has indicated the effectiveness of Tysabri (natalizumab) may increase over time in people with MS, showing that the proportion of people who were free of disease activity was greater in the second year of the study than the first.

According to data published in the March 2009 issue of The Lancet Neurology, after two years of Tysabri infusions, 37 percent of people showed no MS disease activity, compared to placebo, and 64 percent of those in the study had no outward signs of relapse or progression in their disability.

The study was a retrospective analysis of data from 596 people taking Tysabri, compared with those taking placebo.

Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sat Mar 07, 2009 2:32 pm    Post subject: Video of a Tysabri patient Reply with quote

Here is a video testimonial by a Tysabri patient who seems to be finding Tysabri very helpful:

http://news.bbc.co.uk/2/hi/uk_news/wales/7928456.stm
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Mar 09, 2009 2:15 pm    Post subject: (Abstract) [Herpes susceptibility in PwMS on Tysabri?] Reply with quote

To be presented at the annual AAN conference at the end of April:

Quote:
[S06.005] Toll-Like Receptor 7/8 Dysfunction in Patients with Multiple Sclerosis on Natalizumab

Nicoline Schiess, Tory Johnson, Peter Calabresi, Avindra Nath, Baltimore, MD

OBJECTIVE:

To determine whether patients with multiple sclerosis on Natalizumab therapy have abnormalities in toll-like receptors which may make them susceptible to herpes virus reactivation.

BACKGROUND:

Multiple sclerosis (MS) is a debilitating disease that results from central nervous system demyelination. Patients on Natalizumab therapy have been noted to develop herpes labialis and shingles eruptions temporally related to Natalizumab infusions. Toll-like receptors (TLRs) are human membrane receptor proteins that are part of the innate immune response. TLR 2,3,7 and 8 are known to be implicated in virus recognition. Thus far, the only TLR that has been examined in the MS patient population has been TLR 4, which is more specific for bacterial responses than viral responses. None of the other TLRs have been studied in MS patients.

DESIGN/METHODS:

IRB approval was obtained to collect blood samples from MS patients on Natalizumab therapy. To assess for TLR abnormalities we obtained blood from 7 MS patients and 6 healthy controls (HC). Peripheral blood mononuclear cells were isolated and stimulated with different TLR agonists including Pam3CSK4 (TLR 1/2), Poly I:C (TLR 3), ssPoly U/LyoVec (TLR 7/8), LPS (TLR 4) and ODN 2216 (TLR 9). IL-6 and granzyme B were measured by ELISA in culture supernatants three days later and compared to age and sex matched controls.

RESULTS:

There were no differences in TLR responses between the MS patients and HC for agonists to TLR 1 /2, 3 or 4. Both MS patients and HC showed similar responses to stimulation with phytohemagglutinin. However, a decrease in IL-6 and granzyme B production (P<0.006) was noted when stimulated with ssPoly U/ LyoVec, an agonist of TLR7/8.

CONCLUSIONS/RELEVANCE:

In our small cohort, we observed a decrease in inflammatory proteins induced by TLR7/8 ligands. This could be an effect of Natalizumab modulation of immune cells and render the host more susceptible [to] herpes reactivation.

Category - MS and Related Diseases - Basic Science

Tuesday, April 28, 2009 3:00 PM

Scientific Sessions: Multiple Sclerosis: Immunology I (2:00 PM-3:30 PM)




This abstract can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Mar 12, 2009 11:44 am    Post subject: (AAN) Tysabri in patients w/RRMS... Reply with quote

This study is funded by Biogen/Idec and Elan but it includes a description of the TOUCH and TYGRIS programs. The paper will be presented at the annual AAN conference at the end of April.

Quote:
[S11.005] Natalizumab in Patients with Relapsing Multiple Sclerosis: Updated Utilization and Safety Results Including TOUCH and TYGRIS

Carmen Bozic, Glyn Belcher, Richard Kim, Wellesley, MA, Robert Hyde, Zug, Switzerland, Frances Lynn, Mariska Kooijmans-Coutinho, Michael Panzara, Wellesley, MA

OBJECTIVE:

To report the most recent data on natalizumab utilization and safety in patients with relapsing multiple sclerosis (MS).

BACKGROUND:

Natalizumab (TYSABRI), an 4-integrin antagonist, provides significant efficacy for the treatment of relapsing MS; natalizumab monotherapy significantly reduced the annualized relapse rate by 68% and the risk of sustained disability progression by 42%54% compared with placebo in a pivotal phase 3 study. The TYSABRI Outreach: Unified Commitment to Health (TOUCH) Prescribing Program and the TYSABRI Global ObseRvation Program In Safety (TYGRIS) are part of a global risk management program that is further evaluating the safety of natalizumab.

DESIGN/METHODS:


TOUCH is a mandatory prescribing program for all patients, physicians, and infusion centers in the United States that ensures appropriate and informed use of natalizumab. The purpose of TOUCH is to monitor patients for signs and symptoms of progressive multifocal leukoencephalopathy (PML) and to assess the incidence of serious opportunistic infections associated with natalizumab.

TYGRIS is a voluntary global observational study that evaluates the long-term safety of natalizumab in the clinical practice setting. It is the largest long-term safety study of any MS therapy ever conducted. Information collected includes medical/MS history; prior natalizumab use; prior immunomodulatory, antineoplastic, or immunosuppressive agent use; and all serious adverse events.

Postmarketing safety data from countries that do not participate in TOUCH or TYGRIS are also collected.

RESULTS:

As of the end of September 2008, approximately 48,000 patients have been exposed to natalizumab in clinical study and postmarketing settings combined, and more than 35,500 patients were receiving natalizumab. The most current exposure and safety data will be presented.

CONCLUSIONS/RELEVANCE:

The benefit-risk profile of natalizumab remains favorable for patients with relapsing MS.

Supported by: Biogen Idec, Inc. and Elan Pharmaceuticals, Inc.


Category - MS and Related Diseases - Clinical Science

Tuesday, April 28, 2009 4:45 PM

Scientific Sessions: Multiple Sclerosis: Clinical Therapeutics and Interventions (3:45 PM-5:00 PM)



The abstract can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sun Mar 22, 2009 6:52 pm    Post subject: (AAN) Switch to Tysabri in suboptimal responders to DMDs Reply with quote

To be presented at the annual AAN conference at the end of April:

Quote:
[S11.004] Effect of Natalizumab Switch in Suboptimal-Responders to First-Line Disease Modifying Therapy

Tamara Castillo-Trivino, Elizabeth Crabtree-Hartman, Bruce Cree, Douglas Goodin, Ari Green, Stephen Hauser, Ellen Mowry, San Francisco, CA, Darin Okuda, El Granada, CA, Daniel Pelletier, Scott Zamvil, Emmanuelle Waubant, San Francisco, CA

OBJECTIVE:

To describe the clinical effect of switching patients with a sub-optimal response to first-line disease modifying therapies (DMT) (interferon beta [IFNB] and glatiramer acetate [GA]) to natalizumab compared to other second-line agents.

BACKGROUND:


Natalizumab monotherapy was shown in a pivotal trial to reduce relapse rate and disability progression in RRMS patients, most of whom were nave to DMT. However, while it is becoming common in clinical practice to switch patients with a poor response to IFNB or GA to natalizumab, the effectiveness of natalizumab monotherapy in this population is unknown.

DESIGN/METHODS:


We included all relapsing MS patients at UCSF receiving natalizumab who had previously failed first-line DMT with IFNB or GA. Controls included patients who failed first-line DMT and were offered to switch to natalizumab, but refused for a variety of reasons (insurance problems, fear of adverse effects) or switched to immunosuppressive agents. We compared annualized relapse rate (ARR) before and after switch or expected time of switch.

RESULTS:


We identified 54 patients who received treatment with natalizumab and 35 controls (mean time follow-up after switch 0.85 years 0.56 and 1.18 0.96, respectively). Race and sex were similar in both groups. Median EDSS (range) at switch was 3.25 (1-7) and 3.5 (0-7) in natalizumab and controls respectively. Mean treatment period before switch was considered was 5.8 2.8 and 3.6 2.6 years for natalizumab recipients and controls. Median ARR before switch was considered was 0.79 and 0.73 for cases and controls respectively (p=0.42, rank sum test). Both treatment with natalizumab or immunosuppressive agents decreased median ARR to 0 (range 0-8.02 vs 0-2.02; p=0.14, rank sum test).

CONCLUSIONS/RELEVANCE:

Switching to natalizumab monotherapy in patients with a suboptimal response to first-line DMT may be as effective as switching to immunosuppressive agents in reducing ARR in relapsing MS.

Category - MS and Related Diseases - Clinical Science

Tuesday, April 28, 2009 4:30 PM

Scientific Sessions: Multiple Sclerosis: Clinical Therapeutics and Interventions (3:45 PM-5:00 PM)


The abstract can be seen here.
Back to top
View user's profile Send private message
lady_express_44



Joined: 22 May 2006
Posts: 1314
Location: Vancouver, Canada

PostPosted: Mon Mar 23, 2009 10:46 pm    Post subject: Reply with quote

What does that mean? That Tysabri is as effective as Novantrone, azathioprine, steroids, or ....? scratch

Cherie
_________________
You can tell whether a man is clever by his answers.
You can tell whether a man is wise by his questions.
Naguib Mahfouz
Back to top
View user's profile Send private message Send e-mail
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Tue Mar 24, 2009 7:38 am    Post subject: Malaria drug being tried against PML Reply with quote

Biogen is working on using a malaria drug--Lariam (mefloquine)-- against PML, according to Bloomberg.com. Read more about it here.

Cherie, in the previous abstract they're saying that switching a patient who hasn't done well on the ABCRs to Tysabri is as effective as switching the same kind of patient to one of the immunosuppressants, which are methotrexate, azathioprine (Imuran), cyclophosphamide, or mitoxantrone (Novantrone). Steroids aren't immunosuppressants.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Mar 26, 2009 10:43 pm    Post subject: Reply with quote

The (Irish) Independent (March 27, 2009) has an article about Elan's stock that includes this at the end:

Quote:
Biogen announced this week that doctor confidence surrounding Tysabri was returning. Over 60pc of physicians of those sampled said the benefits of Tysabri outweighed the risks, compared with 45pc after the two PML cases in June 2008.

In addition, 74pc of neurologists said they intended to increase use of the multiple sclerosis treatment.



The article can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Sat Mar 28, 2009 1:42 pm    Post subject: (Abstract) Alpha4-Integrin antagonism w/Tysabri... Reply with quote

From PubMed, March 28, 2009:

Quote:
J Neurol. 2008 Dec;255 Suppl 6:58-65.

Alpha4-Integrin antagonism with natalizumab: effects and adverse effects

Stüve O, Gold R, Chan A, Mix E, Zettl U, Kieseier BC.
Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Rd., Dallas, TX 75216, USA. olaf.stuve@utsouthwestern.edu

Based on the results of two phase III clinical trials, the humanized recombinant monoclonal antibody natalizumab was approved for the treatment of relapsing forms of multiple sclerosis (MS). Since its initial approval in November 2004, it has been announced that six patients who received natalizumab in the context of clinical studies acquired an infection with the human polyoma virus JC and were diagnosed with progressive multifocal leukoencephalopathy (PML). Two of these individuals had a fatal outcome.

Our groups recently showed that natalizumab therapy results in a reduction of CD4(+) T cells within the cerebrospinal fluid (CSF) that is ten-fold more pronounced than the reduction in the number of CD8(+) T lymphocytes. Interestingly, it appears that the effect of natalizumab on cell numbers in the CSF persists for at least 6 months after cessation of treatment.

More recently, we studied the expression of major histocompatibility complex (MHC) I and II, and the number and phenotypes of leukocytes in cerebral perivascular spaces (CPVS). We observed that natalizumab therapy was associated with a significant decrease in the cell surface expression of MHC class II molecules, and the numbers of dendritic cells in CPVS.

In addition, no CD4(+) T cells were detectable in this compartment.

Our observations may explain the differential and prolonged effects of natalizumab therapy on different leukocyte subsets in the central nervous system. They also suggest that natalizumab treatment may result in prolonged immunosuppression in peripheral organs, and the delayed onset of adverse events.

PMID: 19300961


The abstract can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Mar 30, 2009 6:37 pm    Post subject: (Abstract) Tysabri in pts w/RRMS: AFFIRM & SENTINEL Reply with quote

From PubMed, March 25, 2009:

Quote:
J Neurol. 2009 Mar 18.

The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL

Hutchinson M, Kappos L, Calabresi PA, Confavreux C, Giovannoni G, Galetta SL, Havrdova E, 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; for the AFFIRM and SENTINEL Investigators.
Dept. of Neurology, St. Vincent's University Hospital, Dublin, Ireland, mhutchin@iol.ie.

The AFFIRM and SENTINEL studies showed that natalizumab was effective both as monotherapy and in combination with interferon beta (IFNbeta)-1a in patients with relapsing multiple sclerosis (MS).

Further analyses of AFFIRM and SENTINEL data were conducted to determine the efficacy of natalizumab in prespecified patient subgroups according to baseline characteristics: relapse history 1 year before randomization (1, 2, >/= 3), Expanded Disability Status Scale score (</= 3.5, > 3.5), number of T2 lesions (< 9, >/= 9), presence of gadolinium-enhancing (Gd+) lesions (0, >/= 1), age (< 40, >/= 40) and gender (male, female). A post hoc analysis was conducted to determine the efficacy of natalizumab in patients with highly active disease (i. e., >/= 2 relapses in the year before study entry and >/= 1 Gd+ lesion at study entry).

In both AFFIRM and SENTINEL studies natalizumab reduced the annualized relapse rates across all subgroups (except the small subgroups with < 9 baseline T2 lesions) over 2 years. In AFFIRM, natalizumab significantly reduced the risk of sustained disability progression in most subgroups. In SENTINEL, natalizumab significantly reduced the risk of sustained disability progression in the following subgroups: >/= 9 T2 lesions at baseline, >/= 1 Gd+ lesions at baseline, female patients and patients < 40 years of age. Natalizumab reduced the risk of disability progression by 64 % and relapse rate by 81 % in treatment-naive patients with highly active disease and by 58 % and 76 %, respectively, in patients with highly active disease despite IFNbeta-1a treatment.

These results indicate that natalizumab is effective in reducing disability progression and relapses in patients with relapsing MS, particularly in patients with highly active disease.

PMID: 19308305


The abstract can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Thu Apr 09, 2009 6:04 pm    Post subject: (Abstract) Copaxone + Tysabri Phase 2 trial results Reply with quote

Quote:
Copaxone + Tysabri Phase 2 Trial Results = safe and tolerable
PMID: 19255407 [PubMed - indexed for MEDLINE]



Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA. andrew_goodman@urmc.rochester.edu

OBJECTIVE:

To evaluate the safety and tolerability of natalizumab when added to glatiramer acetate (GA) in patients with relapsing multiple sclerosis. The primary outcome assessed whether this combination would increase the rate of development of new active lesions on cranial MRI scans vs GA alone.

METHODS:

This phase 2, randomized, double-blind, placebo-controlled study included patients aged 19 to 55 years who were treated with GA for at least 1 year before randomization and experienced at least one relapse during the previous year. Patients received IV natalizumab 300 mg (n = 55) or placebo (n = 55) once every 4 weeks plus GA 20 mg subcutaneously once daily for < or = 20 weeks.

RESULTS:

The mean rate of development of new active lesions was 0.03 with combination therapy vs 0.11 with GA alone (p = 0.031). Combination therapy resulted in lower mean numbers of new gadolinium-enhancing lesions (0.6 vs 2.3 for GA alone, p = 0.020) and new/newly enlarging T2-hyperintense lesions (0.5 vs 1.3, p = 0.029). The incidence of infection and infusion reactions was similar in both groups; no hypersensitivity reactions were observed. One serious adverse event occurred with combination therapy (elective hip surgery). With the exception of an increase in anti-natalizumab antibodies with combination therapy, laboratory data were consistent with previous clinical studies of natalizumab alone.

CONCLUSION:

The combination of natalizumab and glatiramer acetate seemed safe and well tolerated during 6 months of therapy.

GLANCE: results of a phase 2, randomized, double-blind, placebo-controlled study.

Goodman AD, Rossman H, Bar-Or A, Miller A, Miller DH, Schmierer K, Lublin F, Khan O, Bormann NM, Yang M, Panzara MA, Sandrock AW; GLANCE Investigators.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Apr 10, 2009 1:59 pm    Post subject: (Abstract) PML: Undesirable side effect of immunotherapy Reply with quote

From PubMed, April 10, 2009:

Quote:
Nervenarzt. 2009 Apr 10.

[Progressive multifocal leukoencephalopathy : Undesirable side effect of immunotherapy.]

[Article in German]


Hartung HP, Warnke C, Hohlfeld R, Kieseier BC.
Neurologische Klinik, Heinrich-Heine-Universität, Moorenstrasse 5, 40225, Düsseldorf, Deutschland, hans-peter.hartung@uni-duesseldorf.de.

As new cases arise of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with the monoclonal antibody natalizumab, a critical discussion about risks and advantages of this specific kind of immunotherapy appears necessary.

Practical consequences and treatment options are addressed based on current concepts of PML's pathogenesis in patients treated with natalizumab. Critical patient selection based on risk:benefit considerations, limited therapy regimens, early diagnosis of PML by clinical and paraclinical criteria, and therapeutic perspectives for treating PML are discussed.

The risk of PML in patients with MS needs to be continually monitored and should be reduced with all means available to ensure optimal outcome.

PMID: 19357826


The abstract can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Apr 17, 2009 2:31 pm    Post subject: First quarter 2009 report on Tysabri Reply with quote

You can read BiogenIdec's report on Tysabri for the first quarter of 2009 at:

http://www.biogenidec.com/site/news-and-media.html?pr_id=../news/BiogenIDECPR_2008_52.htm

Here are the figures on Tysabri users:

Quote:
As of the end of March 2009, approximately 40,000 patients were on commercial and clinical TYSABRI therapy worldwide. To date, the safety data continues to support a favorable benefit-risk profile for TYSABRI. According to data available as of the end of March 2009:

In the U.S., approximately 20,800 patients were on TYSABRI therapy commercially;

In the rest of world, approximately 18,500 patients were on TYSABRI therapy commercially; and,

In global clinical trials, approximately 600 patients were on TYSABRI therapy.

Cumulatively, in the post-marketing setting:

Approximately 52,000 patients have been treated with TYSABRI; and,

Of those patients, approximately 24,900 have received at least one year of TYSABRI therapy, approximately 14,400 patients have received at least 18 months of TYSABRI therapy, and 6,800 patients have received at least 24 months of TYSABRI therapy.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Mon Apr 20, 2009 8:50 am    Post subject: 6th MS patient on Tysabri gets PML Reply with quote

A 6th MS patient to be on Tysabri since its reintroduction in 2006 has contracted progressive multifocal leukoencephalopathy (PML), according to this report, which isn't available in its entirety because I'm not a subscriber.

I'll try to find more details. I've heard that the patient is in Germany.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Tue Apr 28, 2009 4:48 pm    Post subject: Tysabri may promote healing around nerves... Reply with quote

From XConomy.com, April 28, 2009:



Quote:
Tysabri May Promote Healing Around Nerves, Study Says

Luke Timmerman 4/28/09

ambridge, MA-based Biogen Idec (NASDAQ: BIIB) and its partner, Elan, catch a lot of heat because their fastest-growing drug for multiple sclerosis is associated with a rare, potentially fatal brain infection called PML. But today they are pushing back a bit with a study that suggests the drug may provide an important benefit to balance against the risk—the potential ability to help promote healing around the frayed nerves of MS patients.

The finding is preliminary, from a small study of 62 patients who took natalizumab (Tysabri), and 26 patients in a control group followed for a year, according to research presented today at the American Academy of Neurology annual meeting in Seattle. Researchers at the Jacobs Neurological Institute in Buffalo, NY, led by Robert Zivadinov, found that natalizumab promoted re-myelination and stabilized de-myelination in lesions and brain tissue that appeared normal.

If this can be proven in larger studies, it’s the sort of finding that could change the risk/benefit equation for the drug. More than 400,000 people in the U.S. suffer from multiple sclerosis, a disease in which the immune system goes haywire and starts attacking the fatty coating around nerve fibers, called myelin. Existing MS drugs mostly work by tamping down the excess inflammation that that harms the myelin coating, but they don’t really stop the short-circuiting of nerve signals that gradually robs people of their balance, and ability to walk. Scientists have not observed that older drugs work well enough to allow myelin to naturally regenerate, but that’s one possibility for what was happening with patients in this study on natalizumab, says Al Sandrock, Biogen’s senior vice president for neurology R&D.

“It’s hard to be absolutely sure you have re-myelination going on,” Sandrock says. “Perhaps by decreasing inflammation you allow normal healing processes to take place.”

The study, sponsored by Biogen Idec, used an imaging technique known as magnetization transfer ratio (MTR). Generally, if researchers see an increase in MTR signal, that suggests the nerves may be re-myelinating, and a decreasing signal is associated with losing myelin, Sandrock says.

“What we have seen in these MRI data suggest that Tysabri may have the capacity to repair and possibly restore some of the damaged myelin sheath that protects nerve fibers. Results from this study support the continued investigation of the potential effects of Tysabri on this process,” Zivadinov said in a Biogen statement.

The finding is intriguing, but would need to be confirmed in subsequent studies, Sandrock says. Other imaging techniques may be more specific for spotting re-myelination, and even then, “the resolution is not where I’d like it,” Sandrock says.

Still, Biogen has to be hoping this could shift the focus away from PML fears, and perhaps revive the slowing growth rate of Tysabri sales. The drug generated $227 million in worldwide first quarter sales, a long shot from the $246 million that Wall Street analysts had been expecting.

Whether this can help revive Tysabri in the near-term or not, seeking ways to regenerate myelin for MS patients are clearly on Biogen’s research agenda. The company plans to move the first drug specifically designed to induce re-myelination into clinical trials later this year, a program I profiled back in August. Biogen hopes to bring that drug into human trials in late 2009 or early 2010, Sandrock says. He didn’t cite any new natalizumab trials that the company has planned to test the idea that it is able to spur re-myelination.

Luke Timmerman is the National Biotechnology Editor for Xconomy. You can e-mail him at ltimmerman@xconomy.com or call 206-624-2374
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Tue Apr 28, 2009 7:35 pm    Post subject: Another polyomavirus reactivated w/Tysabri? Reply with quote

From MedPage Today, April 28, 2009:

Quote:
AAN: Another Polyomavirus Appears Reactivated with Natalizumab

By John Gever, Senior Editor, MedPage Today

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

SEATTLE, April 28 -- The JC polyomavirus responsible for progressive multifocal leukoencephalopathy (PML) may not be the only such virus reactivated by natalizumab (Tysabri).

In a study of 57 patients receiving natalizumab for relapsing-remitting multiple sclerosis, twelve (22%) saw reactivation of the BK polyomavirus, which can cause nephropathy and hemorrhagic cystitis, reported Roisin Lonergan, M.S., a neurology fellow at St. Vincent's Hospital in Dublin, Ireland.


No cases of clinical disease or other overt adverse effects were seen in the study, which began in January 2007, Dr. Lonergan said in a poster presentation here at the American Academy of Neurology's annual meeting.

Nevertheless, monitoring patients taking natalizumab for BK polyomavirus reactivation and for renal dysfunction may be warranted, she suggested.

...

Natalizumab is a monoclonal antibody against the alpha4-integrin adhesion molecule. It is believed that this mechanism somehow allows latent infections with the JC polyomavirus, which are extremely common, to become active again.


But the JC virus responsible for PML is not the only common polyomavirus capable of causing significant illness, prompting the Irish study of possible BK virus reactivation.


Such reactivation has been seen in patients receiving kidney transplants and follow-up immunosuppressant treatment. Nephropathy caused by the virus is a frequent cause of graft failure in these patients.


Dr. Lonergan and colleagues prospectively evaluated 57 patients starting treatment with natalizumab.


They found BK virus in urine in three of 36 baseline samples prior to starting on the drug.


Subsequently, the virus was found in urine or blood samples in 12 patients, following a mean of 11.2 natalizumab doses (range 1 to 23).


The researchers also identified JC virus reactivation on one patient after a single dose. PML did not develop.


Nor did any cases of renal dysfunction occur, the researchers found. Renal profiles remained within normal limits in all patients.


Dr. Lonergan said the latter finding should be reassuring to patients on natalizumab therapy.


Absolute CD4- and CD8-positive cell counts did not decrease significantly overall with natalizumab.


However, four of the patients with BK virus reactivation showed transient reductions in CD4-positive cell counts shortly before the virus was detected in urine.


In three of these patients, moreover, a return of CD4-positive cell counts to baseline values paralleled suppression of BK virus replication.


Lily Jung, M.D., a neurologist at Swedish Neuroscience Institute in Seattle who was not involved with the study, said the findings could be significant.


She noted that urinary tract infections are not uncommon in multiple sclerosis patients. But the possibility that blood in the urine might reflect hemorrhagic cystitis related to BK reactivation, rather than an ordinary urinary tract infection, is a concern.


"They get blood in their urine, and it's very easy to . . . say it's a UTI rather than a reactivation of the polyomavirus," Dr. Jung said.


But she noted that no actual cases have been seen yet, a point echoed by Giancarlo Comi, M.D., a neurologist at Hospital San Raffaele in Milan, Italy, who also was not involved with the study.


He said BK virus reactivation was "theoretically" a concern, but the lack of dysfunction seen in the Irish study suggested that clinicians need not worry about it for now.


"To link this to a new risk, to me, there is no reason [now]," Dr. Comi said.


On the other hand, he suggested the findings could be helpful to virologists in shedding light on the dynamics of polyomaviruses.


No external funding for the study was reported.

No potential conflicts of interest were reported by Dr. Lonergan or Dr. Jung. One co-investigator on the study reported a relationship with Biogen Idec. Dr. Comi reported relationships with Teva, Merck Serono, Bayer-Schering, Novartis, sanofi-aventis, and Biogen-Dompe.




Primary source: Neurology
Source reference:
Lonergan R, et al "Reactivation of BK virus during natalizumab therapy in relapsing multiple sclerosis," Neurology 2009; 72:A34.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Wed May 06, 2009 6:55 pm    Post subject: (Abstract) Tysabri blocks adhesion of human T cells... Reply with quote

From PubMed, May 6, 2009:

Quote:
J Immunol. 2009 May 15;182(10):5909-13.

Cutting edge: Natalizumab blocks adhesion but not initial contact of human T cells to the blood-brain barrier in vivo in an animal model of multiple sclerosis

Coisne C, Mao W, Engelhardt B.
Theodor Kocher Institute, University of Bern, Bern, Switzerland.

The humanized anti-alpha(4) integrin Ab Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis. Natalizumab is thought to exert its therapeutic efficacy by blocking the alpha(4) integrin-mediated binding of circulating immune cells to the blood-brain barrier (BBB). As alpha(4) integrins control other immunological processes, natalizumab may, however, execute its beneficial effects elsewhere.

By means of intravital microscopy we demonstrate that natalizumab specifically inhibits the firm adhesion but not the rolling or capture of human T cells on the inflamed BBB in mice with acute experimental autoimmune encephalomyelitis (EAE).

The efficiency of natalizumab to block T cell adhesion to the inflamed BBB was found to be more effective in EAE than in acute systemic TNF-alpha-induced inflammation. Our data demonstrate that alpha(4) integrin-mediated adhesion of human T cells to the inflamed BBB during EAE is efficiently blocked by natalizumab and thus provide the first direct in vivo proof of concept of this therapy in multiple sclerosis.

PMID: 19414741
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri May 22, 2009 7:10 pm    Post subject: (Article) New PML case reported in MS patient on Tysabri Reply with quote

From Dow Jones Newswires, May 22, 2009:

Quote:


Biogen Reports Seventh PML Case In Tysabri MS Patient
By Thomas Gryta, Of DOW JONES NEWSWIRES

NEW YORK -(Dow Jones)- Biogen Idec Inc. (BIIB) reported that a seventh patient on its multiple sclerosis drug Tysabri, sold with Elan Plc (ELN), has the developed rare brain infection.

A suspected link to progressive multifocal leukoencephalopathy, or PML, led to Tysabri being pulled from the market for 18 months beginning in 2005. Prior to Friday, the company has reported that six people had confirmed cases of PML, with one dying, since the relaunch. The most recent case was reported on April 17.

Shares of Biogen closed Friday down 34 cents at $50.39, while Elan dropped 10 cents, or 1.4%, to $6.94.

The drug was allowed back on the market in 2006 because of its effectiveness in fighting the degenerative disease and the PML incidence remains well below the long-projected risk of one in 1,000 patients developing the infection.

The patient with the latest confirmed PML case took 24 doses of the monthly medication and was located in the U.S. - only the second case of the condition that has been located domestically since the relaunch.

Earlier this year, Biogen retreated from its long-held goal to reach 100,000 patients on Tysabri by the end of 2010. As of the end of March, about 40,000 patients were using Tysabri, up from 37,600 patients at the end of December.

Some believe that duration of therapy plays a role in Tysabri's risk. About 6, 800 patients have used the drug for more than two years, as of the end of March.

Biogen is posting a case update on the Internet every Friday at 4:30 p.m. EST until July 24 - the third anniversary of the drug's relaunch - by which time it expects the risk/benefit profile of Tysabri to be clearer.

Tysabri had 2008 sales of $813 million, but its longer-term sales trajectory, which is key to Biogen's future growth, will depend on the true incidence of PML, which is still coming into focus.

-By Thomas Gryta, Dow Jones Newswires; 201-938-2053; thomas.gryta@dowjones.com






This article can be seen here.

(Thanks, Cherie!)
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Jun 12, 2009 8:46 pm    Post subject: 8th PML case Reply with quote

From Bloomberg.com, June 12, 2009:

Quote:
Biogen Says Eighth Patient Has Infection From Tysabri (Update1)

By Tom Randall

June 12 (Bloomberg) -- Biogen Idec Inc. said a patient taking its multiple sclerosis drug Tysabri was diagnosed with a life-threatening brain illness, the eighth case reported in the last year.

The patient was confirmed to have progressive multifocal leukoencephalopathy, or PML, on June 10, according to a report on Cambridge, Massachusetts-based Biogen’s Web site. About 56,700 patients have been treated with Tysabri, the company said.

Biogen and marketing partner Elan Corp. pulled Tysabri from the market in 2005 after three patients developed the brain infection, including two who died. The U.S. Food and Drug Administration allowed sales to resume in July 2006 after deciding benefits for slowing MS relapses outweighed the risk. There were no reported infections for about two years after the drug’s reintroduction.

The likelihood of getting PML from Tysabri is about 1 in 1,000, according to the drug’s label. The infection occurs when a common germ, called JC virus, mutates, then evades the body’s immune defenses and penetrates the brain, causing irreversible damage. Researchers theorize that Tysabri may subdue defenses meant to keep the virus out of the brain. The virus breeds in brain cells, destroying them when it replicates.

...
[Paragraph about Raptiva omitted]
To contact the reporter on this story: Tom Randall in New York at trandall6@bloomberg.net.

Last Updated: June 12, 2009 18:05 EDT
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Jun 19, 2009 7:37 pm    Post subject: 9th PML case Reply with quote

From Interactive Investor, June 19, 2009:

Quote:
Biogen reports 9th case of PML in Tysabri patients

LOS ANGELES, June 19 (Reuters) - A ninth patient taking Biogen Idec Inc's multiple sclerosis drug Tysabri has developed a potentially deadly brain infection since the drug was reintroduced onto the market in July 2006.

The Cambridge, Massachusetts-based biotech company announced the news late on Friday on its website.
Biogen has said it does not plan to announce each new case of progressive multifocal leukoencephalopathy, or PML, except as a weekly update on its website.

Sales of Tysabri, Biogen's most important potential growth driver, have been curtailed by concerns over PML. The drug was temporarily withdrawn from the market in 2005 before being returned with stricter safety warnings.

Biogen has said physicians are becoming more comfortable with the risk of PML, but sales of Tysabri in the first quarter were $227 million, less than the $246 million analysts had expected.
Biogen sells Tysabri in partnership with Elan Corp Plc of Ireland.

Biogen's shares, which fell 32 cents to close at $51.67 on Nasdaq, were slightly higher at $51.74 after hours.


(Reporting by Deena Beasley; Editing by Gary Hill)
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Jun 26, 2009 10:32 pm    Post subject: New case of PML in a Tysabri patient Reply with quote

The 10th case of PML turned up in a Tysabri patient on June 23. The person is outside the US and has had 30 doses of Tysabri. You can see Biogen's updated list here.

Thanks to Cherie for calling attention to this on another board!
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Tue Jul 21, 2009 6:40 pm    Post subject: (Abstract) Tysabri efficacy in RRMS (German & Swiss stud Reply with quote

From PubMed, July 21, 2009:

Quote:
Eur J Neurol. 2009 Jul 9.

Efficacy of natalizumab in second-line therapy of relapsing-remitting multiple sclerosis: results from a multi-center study in German-speaking countries

Putzki N, Yaldizli O, Mäurer M, Cursiefen S, Kuckert S, Klawe C, Maschke M, Tettenborn B, Limmroth V.
Department of Neurology, University Clinic Essen, University of Duisburg-Essen, Germany.

Background:

Natalizumab has been recommended for the treatment of relapsing-remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta/glatiramer acetate (DMT) or aggressive MS. The pivotal trials were not conducted to investigate natalizumab monotherapy in this patient population.

Method:

Retrospective, multicenter study in Germany and Switzerland. Five major MS centers reported all RRMS patients who initiated natalizumab >/=12 months prior to study conduction.

Results:

Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with natalizumab was 19.3 +/- 6.1 months. We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >/= 1 EDSS point). Eighty-six per cent of patients with highly active disease (>/= 2 relapses in the year and >/= 1 Gadolinium (Gd)+ lesion at study entry, n = 20) remained relapse-free. The mean number of Gd-enhancing lesions was reduced to 0.1 (0.8 at baseline).

Discontinuation rate was 8.2% (4.1% for antibody-positivity).

Conclusion:

Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.

PMID: 19614963


The abstract can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Fri Jul 24, 2009 6:29 pm    Post subject: Another PML case Reply with quote

From cnbc.com, July 24, 2009:

Quote:
Biogen Idec Drug Linked to 11th Brain Disorder Case
An 11th patient taking Biogen Idec's multiple sclerosis drug Tysabri has developed a potentially deadly brain infection since July 2006, when it was reintroduced to the market.

The Cambridge, Mass.-based biotech company released the news on its Web site late on Friday.

Tysabri, which Biogen sells in conjunction with Irish drugmaker Elan ..., is considered critical to the future growth of both companies.

The drug was temporarily withdrawn from the market in 2005 after it was linked with a brain infection known as progressive multifocal leukoencephalopathy, or PML. It was brought back in 2006 with stricter safety warnings.

Biogen ... has recently adopted a more aggressively upbeat tone in marketing the drug, insisting physicians are becoming more comfortable with risk of PML.

That approach appears to be working. Sales of Tysabri accelerated in the second quarter, rising to $254 million from $200 million a year ago. The company said the drug is on track to generate some $1 billion in sales this year.

Even so, some analysts believe doctors may take patients off the drug for certain periods of time.

At the end of June, about 43,300 patients were on Tysabri, compared with 40,000 at the end of March. Biogen and Elan originally predicted 100,000 patients would be taking the drug by the end of 2010. The companies still believe they will reach that figure, but not within that time frame.

This is the last case of PML that the company plans to announce on its website. Biogen said on its earnings conference call earlier this month that it would in future communicate new cases by word of mouth to physicians and patient advocacy groups.



The article can be seen here.

More info here. The patient is in the US and had been on Tysabri for 29 months:
Quote:

Biogen Reports New PML Case In Final Weekly Tysabri Update


By George Stahl
Of DOW JONES NEWSWIRES

NEW YORK -(Dow Jones)- Biogen Idec Inc. (BIIB) reported another case of a rare brain infection in users of the multiple sclerosis drug Tysabri in the company&apos;s final weekly update Friday.

The latest patient represents the 11th case of progressive multifocal leukoencephalopathy, or PML, since the drug's relaunch in July 2006 and the fourth announced over the past seven updates. Tysabri - sold with Ireland's Elan Corp. (ELN) - was pulled from the U.S. market in 2005 because of PML concerns.

The total [number] of cases remains below the risk rate on Tysabri's label, Biogen has said. However, the recent increase raises questions as to whether now is the time to stop the updates and adds to concerns that patients may stop taking Tysabri for a time to avoid developing the infection.

Duration of therapy is believed to play a role in Tysabri's PML risk, but such breaks - referred to as "drug holidays" - are opposed by Biogen and could hurt sales of a key growth driver for the company.

Biogen shares, which rose 39 cents to $48.98 in the regular session, were unchanged after hours. Elan shares, meanwhile, fell 3% after hours to $7.41 but remained above its $7.34 close Thursday, thanks to a 4.1% gain during the regular session.

In the latest confirmed case, the patient took Tysabri for 29 doses, continuing a trend as those in the last six reported cases have each had therapy for two years or longer.

The latest patient was located in the U.S. This is notable because it is only the third such U.S. patient. Eight of the previous 10 cases have occurred overseas, and it is unknown why that has been the case.

The PML incidence remains below the long-projected risk of one in 1,000 patients developing the infection. After the previous case, a Jefferies & Co. research note last month put the revised PML incidence at one in 2,490 after 12-month Tysabri therapy; one in 1,400 after 18-month therapy; and one in 680 after 24-month therapy.

Tysabri receives strong support from patients and doctors because of the drug's perceived effectiveness. That support has remained steady because patients are well aware of the PML risk before they start taking Tysabri for the otherwise debilitating disease of MS.

Nonetheless, the number of PML cases has frustrated Biogen's aim of making Tysabri into a blockbuster drug. The company has invested in treatments for PML and ways to mitigate the infection - once thought to be almost always fatal - and in persuading doctors that PML's risk in Tysabri patients is less severe and less likely. Of the 11 confirmed cases since the relaunch, one has died.

Biogen began issuing weekly updates in January after receiving criticism for its previous policy of disclosing new cases through 8-K filings with the Securities and Exchange Commission. From the start, Biogen had determined July 24 would be the final date because it was around the third anniversary of Tysabri's relaunch, by which time the company expected the risk/benefit profile to be clearer.

Tysabri was pulled from the U.S. market in 2005 after three initial cases, including two deaths.

The Food and Drug Administration allowed Tysabri to be reintroduced in 2006 because of the drug's effectiveness in fighting the degenerative disease, and under monitoring rules and a prohibition on using it in combination with other MS drugs. The system was aimed at reducing PML incidence.

Tysabri sales rose 27% to $187.6 million in Biogen's recently reported second quarter. Tysabri's price also increased, by 5.8% over a year ago, to roughly $30,000 a year. About 43,300 patients are now taking Tysabri, up from 40,000 in March.


-By George Stahl, Dow Jones Newswires; 212-416-2182; george.stahl@dowjones.com





The article can be seen here.
Back to top
View user's profile Send private message
agate
Site Admin


Joined: 17 May 2006
Posts: 5694
Location: Oregon

PostPosted: Tue Aug 04, 2009 4:13 pm    Post subject: (Abstract) PML in patients treated w/monoclonal antibodies Reply with quote

From PubMed, August 4, 2009:

Quote:
Lancet Oncol. 2009 Aug;10(8):816-24.

Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project

Carson KR, Focosi D, Major EO, Petrini M, Richey EA, West DP, Bennett CL.
Department of Internal Medicine, Division of Medical Oncology, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.

Progressive multifocal leucoencephalopathy (PML) is a serious and usually fatal CNS infection caused by JC polyoma virus. CD4+ and CD8+ T lymphopenia, resulting from HIV infection, chemotherapy, or immunosuppressive therapy, are the primary risk factors. The immune modulatory monoclonal antibodies rituximab, natalizumab, and efalizumab have received regulatory approval in the USA and Europe for treatment of non-Hodgkin lymphoma, rheumatoid arthritis, and chronic lymphocytic leukaemia (Europe only); multiple sclerosis and Crohn's disease; and psoriasis, respectively.

Efalizumab and natalizumab administration is associated with CD4+ T lymphopenia and altered trafficking of T lymphocytes into the CNS, and rituximab leads to prolonged B-lymphocyte depletion. Unexpected cases of PML developing in people who receive these drugs have been reported, with many of the affected individuals dying from this disease. Herein, we review clinical findings, pathology, epidemiology, basic science, and risk-management issues associated with PML infection developing after treatment with these monoclonal antibodies.

PMID: 19647202


The abstract can be seen here.
Back to top
View user's profile Send private message
Display posts from previous:   
Post new topic   Reply to topic    msspeaks Forum Index -> MS - RESEARCH, ARTICLES, ABSTRACTS, DISCUSSION All times are GMT - 7 Hours
Goto page Previous  1, 2, 3, 4  Next
Page 2 of 4

 
Jump to:  
You can post new topics in this forum
You can reply to topics in this forum
You can edit your posts in this forum
You can delete your posts in this forum
You cannot vote in polls in this forum
Create your own free forum now!
Terms of Service Purchase Ad Removal Forum Archive Report Abuse