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MS TREATMENTS: TYSABRI/NATALIZUMAB
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PostPosted: Sat Aug 08, 2009 7:46 pm    Post subject: Tysabri Webpage info on Tysabri Reply with quote

This seems to be a recent addition to the Tysabri Webpage. At least I was unaware of it till now. You can see it
here.
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PostPosted: Thu Aug 13, 2009 12:43 am    Post subject: Reply with quote

"While the risk was calculated to be 1/1000, it is believed to range from 0.2/1000 to 2.8/1000"

Ummmm... wonder how that is calculated?

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PostPosted: Thu Aug 13, 2009 11:00 am    Post subject: Reply with quote

You're probably talking about this?

Quote:
~There have also been reports of PML in patients who have taken TYSABRI as a monotherapy since TYSABRI was reintroduced to the market in 2006
~An independent committee reviewed over 3000 patients on TYSABRI in clinical trials for the possibility of PML.
~These patients were on therapy for an average of 18 months.
~While the risk was calculated to be 1/1000, it is believed to range from 0.2/1000 to 2.8/1000.
~The absolute risk for PML in patients treated with TYSABRI cannot be precisely estimated.


I don't recall what used to be on their Website, but isn't the risk range (from 0.2/1000 to 2.8/1000) new?

"There have also been reports..." is a bit vague, isn't it?
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PostPosted: Thu Aug 13, 2009 11:48 am    Post subject: Reply with quote

Yeah, quite a bit of it is new.

That range of PML risk ratio must be based on some timeline, like after 6 months through to after 2 yrs of treatment.

2.8:1000 is almost 3 times what they allowed it back on the market with, so I wonder if they are considering limiting it's use for that "demographic"?

Cherie
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PostPosted: Wed Sep 09, 2009 7:46 pm    Post subject: (Abstract) Asymptomatic reactivation of JC virus... Reply with quote

From the New England Journal of Medicine, September 10, 2009:

Quote:
Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab

Yiping Chen, M.D., Ph.D., Evelyn Bord, B.S., Troy Tompkins, B.S., Janice Miller, B.S., Chen S. Tan, M.D., R. Philip Kinkel, M.D., Marion C. Stein, M.D., Raphael P. Viscidi, M.D., Long H. Ngo, Ph.D., and Igor J. Koralnik, M.D.

Background


Progressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus.

Methods

We followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chain-reaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus–related polyomavirus, was used as a control. We determined JC virus–specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences.

Results

After 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P=0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P=0.02). JC virus regulatory-region sequences in blood samples and in most of the urine samples were similar to those usually found in PML. Conversely, BK virus remained stable in urine and was undetectable in blood. The JC virus–specific cellular immune response dropped significantly between 6 and 12 months of treatment, and variations in the cellular immune response over time tended to be greater in patients in whom JC viremia developed. None of the patients had clinical or radiologic signs of PML.

Conclusions


Subclinical reactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis. Viral shedding is associated with a transient drop in the JC virus–specific cellular immune response.



Source Information


From the Divisions of Viral Pathogenesis (Y.C., E.B., T.T., J.M., C.S.T., I.J.K.) and Infectious Diseases (C.S.T.) and the Departments of Neurology (R.P.K., M.C.S., I.J.K.) and Medicine (L.H.N.), Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston; and the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore (R.P.V.).

Address reprint requests to Dr. Koralnik at the Beth Israel Deaconess Medical Center, E/CLS 1005, 330 Brookline Ave., Boston, MA 02215, or at ikoralni@bidmc.harvard.edu


The abstract can be seen here.

The abovementioned study has been discussed at the UK MS Society Website:

Quote:
Researchers discover clues about how PML infects people taking Tysabri

10 September 2009

Research published today in the New England Journal of Medicine has described how progressive multifocal leukoencephalopathy (PML) infection may occur in people taking Tysabri, a drug licensed for use in relapsing remitting multiple sclerosis (MS).


The study, led by researchers at Harvard Medical School, looked at the presence of the human polyoma virus called the JC virus (the virus associated with PML infection) which is present but dormant in about 90% of the population.

The study
Researchers followed 19 people with relapsing remitting MS who were being treated with Tysabri over an 18 month period. They took blood and urine samples three, six, 12 and 18 months into the study and looked for evidence of the JC virus.

Over the course of the study, evidence of the JC virus in the urine and bloodstream increased in people taking Tysabri. The presence of another similar virus called the BK virus did not increase suggesting that taking Tysabri allows the JC virus to evade the immune system.

In addition, the JC virus had undergone mutations that increases it’s chances of infecting the brain.

The authors of the study concluded that taking Tysabri can increase the likelihood that the JC virus can evade the immune system and cause PML infection of the brain but also highlighted several limitations of this research. The study only looked at 19 people and did not include participants who were not taking Tysabri, two limitations that will need to be addressed in future research.

Dr Susan Kohlhaas, Research Communications Officer at the MS Society said, “This research moves us another step forward in characterising serious side effects of an approved treatment for relapsing remitting MS. Larger more comprehensive studies are required to provide further information about how Tysabri increases the risk of developing PML.”




Last edited by agate on Mon Sep 14, 2009 5:28 pm; edited 1 time in total
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PostPosted: Wed Sep 09, 2009 7:50 pm    Post subject: (Summary) Treatment of PML associated w/Tysabri Reply with quote

Summary of a brief report in the same issue of the New England Journal of Medicine (September 10, 2009) as the abstract above:

Quote:
Treatment of Progressive Multifocal Leukoencephalopathy Associated with Natalizumab
Werner Wenning, M.D., Aiden Haghikia, M.D., Jörg Laubenberger, M.D., David B. Clifford, M.D., Peter F. Behrens, M.D., Andrew Chan, M.D., and Ralf Gold, M.D.


SUMMARY

We describe the clinical and therapeutic course of a 52-year-old patient with multiple sclerosis in whom progressive multifocal leukoencephalopathy (PML) developed after 12 months of therapy with natalizumab.

The patient was hospitalized 2 months after the onset of neurologic and psychiatric symptoms and was treated with plasma exchange and immunoadsorption to eliminate natalizumab. After a brief improvement, he became critically ill with an apparent episode of immune reconstitution inflammatory syndrome. Steroid-pulse therapy led to stabilization of the patient's condition and clinically significant recovery.

This case illustrates that prompt diagnosis and treatment may improve the outcome in patients with severe PML associated with natalizumab therapy.


Source Information


From the Neurological Clinic (W.W., P.F.B.) and the Radiological Clinic (J.L.), Ortenau-Klinikum, Offenburg; and the Department of Neurology, Ruhr University Bochum, St. Josef-Hospital Bochum, Bochum (A.H., A.C., R.G.) — both in Germany; and Washington University, St. Louis (D.B.C.).

Address reprint requests to Dr. Gold at the Department of Neurology, Ruhr University Bochum, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, Germany, or at ralf.gold@rub.de.




The summary can be seen here.
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PostPosted: Wed Sep 09, 2009 7:55 pm    Post subject: (Summary) PML after Tysabri monotherapy Reply with quote

And in the same issue of the New England Journal of Medicine as the previous two posts (September 10, 2009) there is this summary of a Brief Report:


Quote:
Progressive Multifocal Leukoencephalopathy after Natalizumab Monotherapy
Hans Lindå, M.D., Ph.D., Anders von Heijne, M.D., Eugene O. Major, Ph.D., Caroline Ryschkewitsch, B.S., Johan Berg, M.D., Tomas Olsson, M.D., Ph.D., and Claes Martin, M.D., Ph.D.


SUMMARY

We describe progressive multifocal leukoencephalopathy (PML) caused by infection with human polyomavirus JC virus in a patient with multiple sclerosis who was treated with natalizumab. The first PML symptoms appeared after 14 monthly infusions of the drug. Magnetic resonance imaging (MRI) showed a presumed multiple sclerosis lesion, and JC virus DNA was not detected on polymerase-chain-reaction (PCR) assay of cerebrospinal fluid. The patient's symptoms worsened, and the diagnosis of PML was established with a more sensitive quantitative PCR assay after 16 infusions of natalizumab. Plasma exchange was used to accelerate clearance of natalizumab.

Approximately 3 weeks after plasma exchange, an immune-reconstitution inflammatory syndrome appeared. JC virus DNA was no longer detectable on quantitative PCR assay, and the patient's symptoms improved.


Source Information

From the Neurology Unit, Division of Internal Medicine (H.L., J.B., C.M.), the Department of Radiology (A.H.), and the Neuroimmunology Unit, Department of Clinical Neuroscience (T.O.), Danderyd Hospital, Karolinska Institutet, Stockholm; and the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.O.M., C.R.).

Address reprint requests to Dr. Lindå at the Division of Neurology, Department of Internal Medicine, Danderyd Hospital, SE-182 88 Stockholm, Sweden, or at hans.linda@ki.se.







The summary can be seen here.
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PostPosted: Thu Sep 10, 2009 8:36 pm    Post subject: (Article) Biogen downplays virus threat w/Tysabri Reply with quote

The NEJM article entitled "Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab" [see above] has prompted a response from Biogen, as reported by Reuters, September 10, 2009:


Quote:
Biogen downplays virus threat with MS drug Tysabri

By Toni Clarke

BOSTON, Sept 10 (Reuters) - Biogen Idec Inc on
Thursday downplayed a report that found its multiple sclerosis treatment Tysabri awakens and strengthens a virus that causes a potentially fatal brain disease.

Evan Beckman, Biogen's senior vice president of Immunology Research and Development, said the biotechnology company has not found any correlation between the level of JC virus in the
blood or urine and the likelihood of a patient's developing the rare brain infection progressive multifocal leukoencephalopathy, or PML.

"We haven't seen any predictive value of this even in
patients who have developed PML," Beckman told investors at the Thomas Weisel Partners Conference in Boston.

The report on Tysabri's potential impact on the JV virus appeared in the New England Journal of Medicine (NEJM).

Beckman noted that the study in the NEJM report was very small and that none of the patients developed PML. He called the results "interesting," but said he is not sure to what extent they can be generalized.

In many ways it would be helpful to Biogen if they could be generalized. The company would benefit from having a blood or urine test that could predict which subset of patients might have a greater risk of developing PML.

...

Dr. Igor Koralnik of Harvard Medical School and Beth Israel Deaconess Medical Center and colleagues studied 19 multiple sclerosis patients just starting Tysabri. Urine samples from the 19 patients showed levels of the JC virus shot up after a
year of taking Tysabri, they noted in the NEJM report.

Beckman said Cambridge, Massachusetts-based Biogen has conducted similar tests on much larger patient groups and has not been able to find a correlation.

The company is examining a myriad of possible factors --from genes to geography -- that might help them understand the elements that come together in a patient who develops PML, since it appears JC virus concentration levels alone are not
predictive.

Tysabri is widely considered to be Biogen's most important product and driver of future growth.

At the end of June, more than 43,000 patients were taking Tysabri. Biogen had originally predicted 100,000 patients would be on the drug by the end of 2010, but physician concerns about Tysabri's safety have caused the company to retract that
prediction. It still says 100,000 is a reasonable target, but not within that time frame.

(Reporting by Toni Clarke, additional reporting by Bill Berkrot in New York, editing by Matthew Lewis)


The article can be seen here.
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PostPosted: Thu Sep 10, 2009 8:43 pm    Post subject: (blog) Tysabri: Virus reactivation & PML treatment Reply with quote

An interesting and informative response to the recent New England Journal of Medicine articles (two of them abstracted above) appears on a blog by Barbara Martin, MD. You can read her comments here.
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PostPosted: Thu Sep 10, 2009 8:57 pm    Post subject: (Article) Remarks by Dr. Igor Goralnik on PML/Tysabri study Reply with quote

The three New England Journal of Medicine articles are provoking quite a lot of response, including attention on lawyers' Websites, incidentally (AboutLawsuits.com and Attorneyatlaw.com).

I won't be posting any of the lawyers' articles but here is an article from Disabled World (September 10, 2009) that contains remarks by Dr. Igor Koralnik, the senior author of one of the studies abstracted above:

Quote:
Brain Disease Virus Found in Natalizumab Treated MS Patients


By Beth Israel Deaconess Medical Center

Virus responsible for deadly brain disease found in MS patients treated with natalizumab - The source of PML, the JC virus, is found to be reactivated in multiple sclerosis patients receiving natalizumab treatment

The virus responsible for PML (progressive multifocal leukoencephalopathy), a rare brain disease that typically affects AIDS patients and other individuals with compromised immune systems, has been found to be reactivated in multiple-sclerosis patients being treated with natalizumab (Tysabri). The findings, led by scientists at Beth Israel Deaconess Medical Center (BIDMC), appear in tomorrow's issue of The New England Journal of Medicine (NEJM).

"This virus – the JC virus, named for the initials of a patient– is found in about 90 percent of the population," explains Igor Koralnik, MD, the study's senior author and director of the Human Immunodeficiency Virus/Neurology Center at BIDMC. "But in healthy individuals the virus lies dormant in the kidneys and causes no problems." Urine samples of healthy individuals may, therefore, show evidence of the benign virus.

But, according to Koralnik, who is also Associate Professor of Neurology at Harvard Medical School and a world leader in the study of PML, among AIDS patients and other patients with compromised immune systems, the JC virus can reactivate and travel to the brain, leading to the development of PML, a destructive brain disorder that may cause numerous neurological symptoms, including dementia, blindness, paralysis, and seizures. There is no cure for PML and more than half of all PML patients die within a year of diagnosis.

Four years ago, PML was diagnosed in two patients who were participating in a clinical trial testing natalizumab, a new drug for the treatment of multiple sclerosis (MS). An autoimmune disease caused by the migration of the immune system's T lymphocytes to the brain, MS results in relapsing and remitting neurologic dysfunction when the T lymphocytes attack the myelin, the insulating sheath that covers the nerves.

"This was the first time we had seen PML develop in patients with multiple sclerosis," notes Koralnik. Because natalizumab, or Tysabri, prevents lymphocytes from crossing the blood-vessel wall, some doctors theorized that it was also providing an opportunity for the dormant PML virus to take hold. "The drug appeared to be something of a double-edged sword," notes Koralnik. "Not only was it keeping dangerous cells from entering the brain, it was also keeping out the protective virus-fighting lymphocytes, thereby leaving patients vulnerable to this dangerous infection.

"If impaired immune surveillance due to natalizumab treatment was responsible for the development of PML, we wanted to find out where in the body the JC virus reactivation was taking place," he adds, explaining that the scientists also wanted to determine whether the reactivated JC virus had the benign molecular composition commonly found in the urine of healthy individuals – or if it had acquired changes typically found only in the brains of patients with PML.

To answer these questions, the scientists enrolled 19 multiple sclerosis patients for a clinical study as they began treatment with natalizumab. They then followed them at intervals of three, six, 12 and 18 months, post-treatment.

Their results showed that measurements of the JC virus in patients' urine increased from 19 percent (before beginning treatment) to 63 percent after 12 months of using natalizumab. Six months later – 18 months after beginning treatment – blood samples further revealed that the virus had additionally entered the blood cells of 60 percent of these patients. (At 12 months of treatment, only one patient had the virus in their blood.)

"These JC virus measures were higher than viral measures found in patients infected with the HIV virus, and similar to measures seen in patients with full-blown PML," explains Koralnik.

The researchers then proceeded to evaluate patients' immune responses against the JC virus, since these immune blood cells play a crucial role in the containment of PML.

"What we saw surprised us," he adds. "Between six and 12 months after beginning the natalizumab treatment, there was a significant drop in the magnitude of patients' immune responses against the virus. Since natalizumab was only supposed to prevent migration of lymphocytes out of the bloodstream – but not directly alter their potency – this finding was quite unexpected."

Finally, he adds, the scientists made another startling discovery: Further analysis showed that among many of the MS patients using natalizumab, the JC virus that was detected in their urine or blood samples had already acquired the signature changes associated with the virus's ability to reach the brain and cause PML.

"This pilot study shows for the first time that natalizumab not only prevents the migration of protective T lymphocytes, but it also directly affects the cells' potency against the JC virus," says Koralnik. "It further tells us that reactivation and transformation of the virus may first occur in the kidney and that once the activated virus spills into the blood it can easily spread to the brain."

Because none of the 19 patients tested developed any symptoms or brain lesions suggestive of PML during the course of the study, the authors do not suggest any change in the management of multiple sclerosis.

"As of July 24, 2009, there was a worldwide total of 13 natalizumab-treated MS patients who had developed PML," he adds. "We hope that the results of our study will stimulate further research, and that monitoring the appearance of the virus in the blood and urine may allow for early identification of natalizumab-treated patients at risk of developing PML."

Reference: This study was supported, in part, by grants from the National Institutes of Health.

Coauthors include BIDMC investigators Yiping Chen, MD, PhD (first author), Evelyn Bord, Troy Tompkins, Janice Miller, Chen Tan, MD, R. Philip Kinkel, MD, Marion Stein, MD, and Long Ngo, PhD; and Raphael Viscidi, MD, of Johns Hopkins University School of Medicine.

BIDMC is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is a clinical partner of the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. ...



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PostPosted: Mon Sep 14, 2009 6:34 pm    Post subject: (Article) 2 more PML cases in MS patients on Tysabri Reply with quote

From the Wall Street Journal, September 15, 2009:

Quote:
Two More Brain-Infection Cases Emerge in Tysabri Patients

By THOMAS GRYTA

Two more cases of a rare brain infection have emerged in users of the multiple-sclerosis drug Tysabri, sold by Biogen Idec Inc. and Elan PLC, the first such incidences since Biogen stopped updating investors of the situation in July.

At that time, Biogen had confirmed 11 cases of progressive multifocal leukoencephalopathy, or PML, since the drug's relaunch in July 2006; Tysabri was pulled from the U.S. market in 2005 because of PML concerns.

A Biogen spokeswoman said the Cambridge, Mass., biotech company is neither commenting on nor confirming the existence of additional cases as long as the PML rate is consistent with the rate of one-in-1,000 patients implied by the label. The new cases appear to be in line with the label's rate.

An editorial published in the New England Journal of Medicine last week revealed a new case that occurred in Europe.

The latest case, also in Europe, was confirmed by Ralf Gold of the Ruhr University Bochum in Germany, who presented the case at the European Committee for Treatment and Research in Multiple Sclerosis that ended Saturday.

Like any public company, Biogen is required to disclose developments deemed material to its business, but the biotech company has said Tysabri's risk profile is accurately detailed in its label after providing weekly updates on new PML cases through July 24, the third anniversary of Tysabri`s relaunch.

Duration of therapy is believed to play a role in Tysabri's PML risk as most cases occurred after patients took the drug for more than a year. Biogen has opposed patients taking treatment breaks--referred to as "drug holidays"--because it can cause MS symptoms to return.

As of June 30, about 43,300 patients were taking Tysabri, with more than 30,000 on it for more than a year, and about 10,000 on it for more than two years.

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.

Wall Street has closely watched the number of cases in gauging Tysabri's sales trajectory because it is the key growth driver for both companies.

Sanford Bernstein analyst Geoffrey Porges said the two new cases "[add] to the dissatisfaction about the company's decision to suspend regular disclosure of the rate of cases, particularly as a large bolus of patients are now reaching what appears to be a point of increased event risk."

Mr. Porges said the new cases were "not necessarily alarming" because the ratio remains below the label-implied rate, but he stressed that there seems to be a connection to PML risk and duration of therapy.

PML re-emerged in Tysabri patients in July 2008, two years after the relaunch, and 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.

Write to Thomas Gryta at thomas.gryta@dowjones.com

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PostPosted: Sun Sep 20, 2009 10:47 am    Post subject: (Editorial & abstract) Rebound after stopping Tysabri? Reply with quote

This editorial was in Neurology, February 2009, 72:392-393.

Quote:


Bound to rebound?
Nicoline Schiess, MD and Peter A. Calabresi, MD

From the Department of Neurology, Johns Hopkins University, Baltimore, MD.

Since it first came to trial, natalizumab (Tysabri) has kept the multiple sclerosis (MS) world in a constant state of flux. Shortly after its initial launch, the appearance of three cases of progressive multifocal leukoencephalopathy (PML), a devastating infection of the CNS caused by the JC virus, resulted in the drug’s withdrawal from the market. Reintroduced in 2006, it is currently in use as monotherapy in thousands of patients worldwide, but four additional cases of PML were recently reported in patients on natalizumab monotherapy for less than 18 months.

While these cases strongly support a mechanistic association between the drug and JC virus reactivation/infection,1 the short-term risk of PML still appears to be quite low (4 confirmed cases out of ~10,000 patients treated for 18 months). Nonetheless, these new cases are concerning and some patients and physicians will choose to discontinue therapy. Several groups have raised the possibility of a rebound effect in cohorts of patients discontinuing natalizumab.2,3 This has led to the concern that stopping natalizumab might lead to a sudden worsening of MS disease. However, rebound was not seen during a 6-month washout period following a phase II placebo-controlled trial with natalizumab.4

Natalizumab is a monoclonal antibody that binds the {alpha}4 integrin chain of the very late activation antigen (VLA)-4 adhesion molecule and blocks mononuclear cell migration and perhaps costimulatory activating signals. The question has been raised as to whether immune cells that are blocked from trafficking build up in the blood persistently during natalizumab therapy, or whether these cells eventually die by attrition and thereby avert the potential for a catastrophic flood of immune cells into the CNS.

In this issue of Neurology, Stüve et al.5 explore the idea of a rebound phenomenon by investigating clinical activity, MRI changes, and immunologic peripheral blood/CSF markers in 23 patients with MS who received natalizumab as part of the AFFIRM and SENTINEL trials. Samples were taken at the time of drug cessation and 14 months later. Reassuringly, most of the patients in this cohort remained clinically and radiographically stable. Immune cell counts in the periphery and CSF still showed natalizumab-mediated effects at 6 months, but returned to normal levels, without any rebound, after 14 months, and no infectious complications occurred. This is encouraging to clinicians treating patients with natalizumab who are concerned about the possibility of a rebound phenomenon upon cessation of the drug. The limitations, however, include a small sample size in which only 21 patients had relapse rates evaluated, 17 had Expanded Disability Status Scale scores, 16 had MRIs, and an even smaller subset had immunologic measurements. Nonetheless, this was a reasonable sample size for such extensive immunologic studies.

How can these data be reconciled with the reports of clinical or MRI rebound by Tubridy and Vellinga? The most likely explanation is that short-term treatment with natalizumab, as was characteristic of these two studies, does indeed result in trapping and accumulation of viable activated lymphocytes in the periphery that retain their capacity to cause CNS disease. The Tubridy study only used two doses of natalizumab and in the Vellinga study the effect was driven by patients with short exposures to natalizumab (median of two infusions). In contrast, more prolonged treatment with natalizumab, as was done in the study by Miller et al.4 (6 months) and the phase III trials (120 weeks), probably results in death of the peripheral activated T cells. Thereby, not only is there no rebound, but there may be disease quiescence even upon discontinuing the drug, while new pathogenic immune cells are generated and expanded in the peripheral blood. The persistent leukocytosis seen in the periphery may occur not only through blockade of cell migration, but also due to enhanced egress from the bone marrow. These lymphocytes may not only be less activated through blockade of the costimulatory properties of VLA-4 signaling, but perhaps could even have enhanced regulatory properties. Further immunologic studies examining the presence of Foxp3 T regulatory cells and cytokine profiles will be informative in understanding the mechanisms of this drug’s persistent effects. Ideally, we will be able to develop immunologic biomarkers that would allow clinicians to finesse a balance between the potent immune effects of the drugs and the possibility of rendering patients susceptible to infections.

Overall, these findings are encouraging to the clinician treating patients with natalizumab and suggest that in patients who have been treated for a prolonged period, it is unlikely that there will be a sudden rebound. Whether a drug holiday can be justified based on these data—that it takes more than 6 months for the immune parameters to even normalize—deserves further study. Short-term usage of the drug (e.g., two doses) may be followed by disease rebound and some caution is still advisable in patients who must be discontinued due to early hypersensitivity type reactions or choose to discontinue over concern regarding the risk of PML early on in the course of their treatment.


Disclosure:

Peter A. Calabresi, MD, has received support from the NMSS, NIH, and has received research grants and honoraria from Biogen-IDEC. Dr. Schiess was a National Multiple Sclerosis Society fellow while this manuscript was drafted.



REFERENCES



1. Ransohoff RM. Natalizumab and PML. Nat Neurosci 2005;8:1275.
2. Vellinga MM, Castelijns JA, Barkhoff F, Uitdehaag BMJ, Polman CH. Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated patients. Neurology 2008;70:1150–1151.
3. Tubridy N, Behan PO, Capildeo R et al. The effect of anti-{alpha}4 integrin antibody on brain lesion activity in MS. Neurology 1999;53:466–472.
4. Miller DH, Khan OA, Sheremata WA et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15–23.
5. Stüve O, Cravens PD, Frohman EM et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 2009;72:404–409.


This is the PubMed abstract for the article referred to in the editorial above:

Quote:


Neurology 2009;72:396-401

Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy

O. Stüve, MD, PhD, P. D. Cravens, PhD, E. M. Frohman, MD, PhD, J. T. Phillips, MD, PhD, G. M. Remington, RN, G. von Geldern, MD, S. Cepok, PhD, M. P. Singh, PhD, J. W. Cohen Tervaert, MD, PhD, M. De Baets, MD, PhD, D. MacManus, MD, D. H. Miller, MD, PhD, E. W. Radü, MD, E. M. Cameron, BSc, N. L. Monson, PhD, S. Zhang, PhD, R. Kim, MD, B. Hemmer, MD and M. K. Racke, MD

From the Neurology Section (O.S.), VA North Texas Health Care System, Medical Service, Dallas; Departments of Neurology (O.S., P.D.C., E.M.F., G.M.R., M.P.S., E.M.C., N.L.M.), Immunology (O.S., E.M.C., N.L.M.), Ophthalmology (E.M.F.), and Clinical Sciences (S.Z.), University of Texas Southwestern Medical Center at Dallas; Department of Neurology (O.S., G.v.G., S.C.), Heinrich Heine University Düsseldorf, Germany; Multiple Sclerosis Center at Texas Neurology (J.T.P.), Dallas; Departments of Clinical and Experimental Immunology (J.W.C.T.) and Neurology (M.D.B.), University Hospital Maastricht, The Netherlands; Department of Neuroinflammation (D.M., D.H.M.), Institute of Neurology, Queen Square, London, UK; Institute of Neuroradiology (E.W.R.), Department of Medical Radiology, University Hospital Basel, Switzerland; Biogen-Idec (R.K.), Cambridge, MA; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technische Universität München, Germany; and Department of Neurology (M.K.R.), The Ohio State University Medical Center, Columbus.

Address correspondence and reprint requests to Dr. Olaf Stüve, Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Rd., Dallas, TX 75216 olaf.stuve@utsouthwestern.edu

Objective:

Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy.

Methods:

This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored.

Results:

With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed.

Conclusion:

This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.

Abbreviations:

EDSS = Expanded Disability Status Scale; FDA = Food and Drug Administration; MS = multiple sclerosis; OCB = oligoclonal band; PML = progressive multifocal leukoencephalopathy; VLA-4 = very late activation antigen 4; WBC = white blood cell.
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PostPosted: Tue Sep 22, 2009 6:24 pm    Post subject: (Comment) JC virus reactivation w/Natalizumab Reply with quote

Journal Watch Neurology, September 22, 2009, contains a review of the article by Chen et al., abstracted above on 9/9/09 ("Asymptomatic Reactivation of JC Virus..."):

Quote:
Summary and Comment

JC Virus Reactivation with Natalizumab

A preliminary study shows that JC virus reactivation is common during natalizumab therapy.

Natalizumab, an adhesion-molecule inhibitor, clearly increases the risk for progressive multifocal leukoencephalopathy (PML) associated with JC virus. Natalizumab-associated PML has occurred in patients with multiple sclerosis (MS) and Crohn disease, two conditions not previously associated with the disorder. The precise mechanism or mechanisms by which natalizumab predisposes to PML remain unknown. To identify possible predisposing factors, researchers used quantitative polymerase chain reaction (PCR) on urine, plasma, and peripheral blood mononuclear cell (PBMC) samples prospectively collected from 19 patients with MS before and during 18 months of natalizumab monotherapy.

At baseline, JC virus was not detected in plasma and PBMCs and was present in only 3 of 12 urine samples. At 12 months, urine samples from 9 of 16 patients (56%) were positive for JC virus. At 18 months, 3 of 15 plasma samples (20%) and 9 of 15 PBMC samples (60%) were positive for JC virus. Reactivation of BK virus (a polyoma virus related to JC virus) was absent in urine and blood, suggesting that JC virus reactivation with natalizumab therapy was unique. Sequencing of the regulatory region of the isolated JC virus DNA showed that the neurotropic form of the virus was frequently present. An enzyme-linked immunospot assay showed that plasma levels of JC virus-specific T cells declined, particularly between 6 and 12 months of therapy. This decrease in immune response was greatest in the patients who developed JC viremia. The authors propose that the JC virus reactivation was likely a consequence of this decline in JC virus T-cell levels.

Comment: The development of PML is a stochastic event for which enormous barriers must exist in the normal population: Serologic studies indicate that approximately 70% of the adult population has been infected by JC virus (J Gen Virol 2003; 84:1499), yet the disease was vanishingly rare until the AIDS pandemic. The barriers to PML are likely present at two general levels, one related to the JC virus and the other to the immune system. The virus must be reexpressed from sites of latent infection and be present in a form that is neurotropic, i.e., capable of replicating in glial cells. Concomitantly, the immune system must be impaired and fail to contain the virus. The current findings show that PBMCs of a surprisingly high percentage of patients contain a neurotropic form of JC virus after 18 months of natalizumab therapy. The authors propose that the virus's presence results from a decline in the T-cell response to it, but other possibilities remain equally if not more probable. For instance, the release from the bone marrow of immature B cells containing latent JC virus during natalizumab therapy and upregulation of the virus by transcription factors that drive cell maturation may play significant roles (mAbs 2009; 1 [in press]). This study was small and must be replicated in larger populations. Overall, though, the intriguing results fit well with existing hypotheses regarding why natalizumab increases the risk for PML. The risk for PML becomes most notable after 12 months of natalizumab therapy in patients with JC viremia. Effective strategies for minimizing that risk remain to be developed but might include periodic quantitative PCR for JC virus in PBMCs and periodic fluid-attenuated inversion recovery imaging on cranial MRI to detect early lesions.

— Joseph R. Berger, MD

Dr. Berger is Ruth L. Works Professor and Chairman, Department of Neurology, University of Kentucky College of Medicine, Lexington. He has been a research collaborator and coauthor with one of the study authors and has received grants and research funding from the manufacturer of natalizumab.

Published in Journal Watch Neurology September 22, 2009

Citation(s):


Chen Y et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009 Sep 10; 361:1067.

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PostPosted: Wed Sep 23, 2009 2:59 pm    Post subject: Another new PML case? Reply with quote

I posted about two new PML cases on September 14. The article below seems to be saying that there has been a third case since those two were announced.


From FDAnews Drug Daily Bulletin, September 21, 2009:

Quote:
FDAnews Drug Daily Bulletin
Sept. 21, 2009 | Vol. 6 No. 183



FDA: 13 PML Cases Confirmed in Tysabri Patients

The FDA says there have been 13 confirmed cases of progressive multifocal leukoencephalopathy (PML) in patients taking Biogen Idec and Elan Pharmaceuticals’ Tysabri for multiple sclerosis (MS) in the past three years. Biogen and Elan voluntarily suspended the marketing of Tysabri (natalizumab) in 2005 because of two PML brain infections in patients taking the drug. The drug was reintroduced in July 2006 under a restricted distribution program, and from that point until Sept. 8, 13 PML cases, four of them in the U.S., were confirmed in patients taking the drug as monotherapy for MS, the FDA says in a statement.


The article can be seen here.
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PostPosted: Wed Sep 23, 2009 6:51 pm    Post subject: Reply with quote

From Physician's First Watch, September 21, 2009:

Quote:
Thirteen Confirmed Cases of PML in Patients Taking Tysabri

The FDA has received 13 confirmed reports worldwide of progressive multifocal leukoencephalopathy (PML) in patients taking natalizumab (Tysabri) for multiple sclerosis.

For now, the FDA is not mandating any changes to the drug's label. The agency says that patients taking natalizumab should be monitored closely for PML and other opportunistic infections.

The risk for PML increases with the number of infusions received, the FDA says. In patients who have received 24 or more infusions, the rate of PML ranges from 0.4 to 1.3 per 1000. (The 13 with a PML diagnosis had received an average of 25 natalizumab infusions.)



This article can be seen here.
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PostPosted: Wed Sep 23, 2009 8:51 pm    Post subject: Re: Another new PML case? Reply with quote

agate wrote:
I posted about two new PML cases on September 14. The article below seems to be saying that there has been a third case since those two were announced.


From FDAnews Drug Daily Bulletin, September 21, 2009:

Quote:
FDAnews Drug Daily Bulletin
Sept. 21, 2009 | Vol. 6 No. 183



FDA: 13 PML Cases Confirmed in Tysabri Patients

The FDA says there have been 13 confirmed cases of progressive multifocal leukoencephalopathy (PML) in patients taking Biogen Idec and Elan Pharmaceuticals’ Tysabri for multiple sclerosis (MS) in the past three years. Biogen and Elan voluntarily suspended the marketing of Tysabri (natalizumab) in 2005 because of two PML brain infections in patients taking the drug. The drug was reintroduced in July 2006 under a restricted distribution program, and from that point until Sept. 8, 13 PML cases, four of them in the U.S., were confirmed in patients taking the drug as monotherapy for MS, the FDA says in a statement.


The article can be seen here.


Agate, before they stopped announcing the cases in late July, I had counted 14 at that point in time, including the 3 from the trials. I have only heard about 2 more recently, bringing the total to 16, including the 3 from the trials.

Are you thinking there have been 14 plus the three from the trials ... or how are you reading this?

Cherie
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PostPosted: Wed Sep 23, 2009 10:11 pm    Post subject: Reply with quote

I don't know how to read the most recent reports. I'm confused--and unable to sift through previous ones just now because I'm in the midst of moving.

I'm tempted to wait and see if eventually some reliable source will come along and clear this up about how many Tysabri-related PML cases in MS patients there have been.

The issue is muddied further because sometimes Crohn's patients are thrown into the mix too, apparently....
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PostPosted: Thu Sep 24, 2009 6:47 am    Post subject: Reply with quote

Here's the original 14 (including the trial patients), as per a spreadsheet Lauren was keeping until the end of July:

http://pietynorwit.com/Tytable.htm

Here's Biogen's numbers at the end of July, EXCLUDING the 3 trial patients ... bringing the number to 11 + 3 = 14:

http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9MTEwODd8Q2hpbGRJRD0tMXx...

Here's a recent NMSS summary, that only includes the 13 (no longer 11) since the trials:

http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2104

Good luck on the move.

Cherie
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PostPosted: Thu Sep 24, 2009 5:18 pm    Post subject: Reply with quote

Thanks, Cherie!

Lauren's figures include a Crohn's patient among the trial cases. So really there were only two persons with MS who developed PML when Tysabri was going through trials.

To me this means that, not counting the trials, as of July 27 there were 11 PML cases among MS patients taking Tysabri, and in mid-September two more were announced (since July), making a total of 13, plus the two from the trials = 15.
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PostPosted: Thu Sep 24, 2009 11:43 pm    Post subject: Reply with quote

Yes, that's right. Fifteen, if you count MS patients alone.

There are very, very few Crohn's patients using Tysabri yet, even though it's approved for that disease too. So I think the Crohn's patients often get lumped in with MS patients, for the purpose of counting patients who've tried the drug, as well as those that came down with PML due to this med.

Even the original risk was based on the 3 cases and 3,000 people )1:1000) from the MS + Crohn's trials combined.

Cherie
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PostPosted: Tue Sep 29, 2009 6:34 pm    Post subject: Plasmapheresis for managing Tysabri-related PML risky Reply with quote

From Journal Watch Neurology, September 29, 2009:

Quote:
Summary and Comment

Plasmapheresis for Managing Natalizumab-Associated PML: A Risky Proposition

A severe inflammatory reaction of the brain occurred in two natalizumab-treated MS patients after removal of the drug by plasmapheresis with or without immunoadsorption.


Natalizumab, a monoclonal antibody that binds to integrin receptors on the surface of leukocytes to prevent their migration out of the bloodstream, has been used successfully to treat multiple sclerosis (MS) and Crohn disease. At least 14 patients with MS and one with Crohn disease treated with natalizumab have developed progressive multifocal leukoencephalopathy (PML). PML is a usually deadly demyelinating disease of the nervous system caused by reactivation of JC virus (JCV).

Now, two new case reports describe the management of PML that developed in two patients with MS, one after 12 months (reported by Wenning and colleagues) and another after 14 months (reported by Lindå and colleagues) of natalizumab monotherapy. In the case reported by Lindå, CSF polymerase chain reaction (PCR) in a clinical laboratory was negative for JCV DNA, but quantitative PCR in a research laboratory detected a low copy number. The patients underwent plasmapheresis, either alone or with immunoadsorption, which reduced natalizumab concentration in the blood. However, 3 to 4 weeks later, both patients developed immune reconstitution inflammatory syndrome (IRIS), as evidenced by enlargement and contrast enhancement of PML lesions, appearance of new lesions, and worsening of neurological deficits. After Wenning's patient was treated with both plasmapheresis and immunoadsorption, he had evidence of swelling, mass effect, and midline shift. He developed stupor, was intubated, and was treated with pulse steroids. Both patients improved somewhat and were discharged home but had more-severe neurological deficits than before IRIS developed.

A commentator notes that the original estimate of 1 PML case per 1000 natalizumab recipients appears to be accurate. Because natalizumab promotes the release of immature blood cells from the bone marrow, thereby increasing circulating CD34+ hematopoietic stem cells, the commentator hypothesizes that these cells might be a source of JCV reactivation. The commentator concludes that markers are sorely needed to identify patients at risk for PML but that adapting laboratory testing and clinical options for this task may prove challenging.

Comment:

These two case reports illustrate perfectly the conundrum facing clinicians caring for patients with MS who develop PML during natalizumab treatment. First, diagnosing PML, a disease that causes progressive neurological deficits and white-matter lesions, is extremely challenging in patients with MS, who typically have relapsing and remitting neurological deficits and white-matter lesions. Second, attempting to remove natalizumab from the circulation is worthwhile, as the drug's biological activity lasts approximately 3 months and promoting immune system recovery is the only proven therapy for PML. Yet, removing natalizumab hastened normalization of lymphocyte migration, but it also promoted an intense inflammatory reaction, which was nearly fatal in Wenning's patient and left both patients with more neurological dysfunction than that caused by PML alone. Prophylactic treatment with steroids may be necessary to prevent this iatrogenic complication.

The commentator notes an imbalance between recent cases of PML in Europe (9) and the U.S. (3), which is unsettling. Evidence is lacking that JCV is more virulent in Europe or that Europeans are more susceptible to PML. Detailed publication of the other natalizumab-associated PML cases might reveal whether the European patients had a common factor that the U.S. patients lacked. Furthermore, the hypothesis about CD34+ cells, although attractive, remains to be proven experimentally. Finally, several patients developed PML between 24 and 35 months of therapy. Because few patients have used natalizumab for that long, we don't know whether the risk for PML increases linearly or exponentially after 2 years of treatment and thus whether drug holidays would reduce the risk for PML in this patient population.

— Igor J. Koralnik, MD

Dr. Koralnik is Director, HIV/Neurology Center, Beth Israel Deaconess Medical Center, and Associate Professor of Neurology, Harvard Medical School, Boston. He has received research grant support from the manufacturer of natalizumab.


Citation(s):

Wenning W et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 2009 Sep 10; 361:1075.


Lindå H et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009 Sep 10; 361:1081.

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PostPosted: Sun Oct 04, 2009 10:38 pm    Post subject: (Abstract) Primary CNS lymphoma in MS patient on Tysabri Reply with quote

Something else to be concerned about. From PubMed, October 3, 2009:

Quote:
Ann Neurol. 2009 Jun 29;66(3):403-406.

Primary central nervous system lymphoma in a patient treated with natalizumab

Schweikert A, Kremer M, Ringel F, Liebig T, Duyster J, Stüve O, Hemmer B, Berthele A.
Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

A 40-year-old man with relapsing-remitting multiple sclerosis (MS) developed primary central nervous system lymphoma (PCNSL) after having received 21 doses of natalizumab monotherapy. PCNSL is a disease of the elderly, with the majority of patients being diagnosed in the 7th to 8th decade of life.

Immunodeficiency, iatrogenic immunosuppression, and some autoimmune diseases are known as predisposing conditions, and in these patients PCNSL peaks in the 4th decade. Because there is no increased prevalence of PCNSL in MS, and the patient was otherwise not immunocompromised, an association between natalizumab therapy and PCNSL cannot be ruled out.

PMID: 19798640


The abstract can be seen here.
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PostPosted: Tue Oct 06, 2009 8:27 pm    Post subject: (Article) Tysabri reawakens brain virus Reply with quote

From Forbes.com, October 6, 2009:

Quote:
MS drug Tysabri reawakens brain virus -study


WASHINGTON, Sept 9 (Reuters) - The multiple sclerosis drug Tysabri awakens a virus that causes a rare brain disease, not only suppressing the body's ability to fight it but making the virus stronger, U.S. researchers reported on Wednesday.

But these changes take place even in patients who show no symptoms of the infection -- a finding that suggests scientists still do not fully understand why 13 patients taking Tysabri have developed the potentially fatal brain infection.

Tysabri, known generically as natalizumab, is designed the suppress the immune system which mistakenly attacks nerves in MS patients.

...

Dr. Igor Koralnik of Harvard Medical School and Beth Israel Deaconess Medical Center and colleagues studied 19 multiple sclerosis patients just starting Tysabri.

They were looking for a virus called JC virus.

'This virus, the JC virus named for the initials of a patient, is found in about 90 percent of the population,' Koralnik said in a statement.

'But in healthy individuals the virus lies dormant in the kidneys and causes no problems.'

Urine samples from the 19 patients showed levels of the JC virus shot up after a year of taking Tysabri, Koralnik and colleagues reported in the New England Journal of Medicine.

The virus infected the blood cells of 60 percent of the patients after 18 months, they found.

They confirmed that Tysabri was affecting immune cells called T cells. 'It further tells us that reactivation and transformation of the virus may first occur in the kidney and that once the activated virus spills into the blood it can easily spread to the brain,' Koralnik said.

None of the 19 patients developed any symptoms or brain lesions suggestive of PML, so the researchers do not suggest that patients should stop taking Tysabri.

...
More than 40,000 MS patients take Tysabri.

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PostPosted: Wed Oct 07, 2009 10:33 pm    Post subject: (Abstract) Severe relapses after first Tysabri infusion... Reply with quote

Maybe I'm posting too much gloom-and-doom news about Tysabri, but it's such a comparatively new drug that maybe everybody should keep a careful eye on it....

From Multiple Sclerosis, October 7, 2009:

Quote:
Severe relapses after the first infusion of natalizumab in active relapsing-remitting multiple sclerosis

Francesca Rinaldi1*, Paola Perini2, Massimiliano Calabrese3, Luciano Rinaldi3, and Paolo Gallo3
1 Giustiniani
2 Department of Neuroscience, University Hospital of Padova, Giustiniani 2, 35128, Italy.
3 Department of Neuroscience, University Hospital of Padova

* To whom correspondence should be addressed. E-mail: francyrinaldi@yahoo.com.


Abstract


We describe three patients suffering from a very active form of relapsing–remitting multiple sclerosis (MS), who experienced severe disease worsening, associated with a marked increase in brain inflammation, a few days after the first administration of natalizumab. In line with preclinical studies, our observations suggest that natalizumab, when administered during active disease phases, may worsen disease evolution possibly by modifying the regulatory network in the brain.

We suggest that relapsing–remitting MS patients having had a recent relapse should be treated with natalizumab only after achieving complete clinical and radiological remission.


The abstract can be seen here.
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PostPosted: Wed Oct 21, 2009 11:05 pm    Post subject: More on the brain cancer case Reply with quote

Here is a bit more about the brain cancer case mentioned in the October 4 post. This is from the National MS Society, October 15, 2009:

Quote:
Case report: Person treated with Tysabri for MS develops brain cancer (primary central nervous system lymphoma)

A case report of brain cancer (primary central nervous system lymphoma) developing in a person being treated with Tysabri® (natalizumab, Biogen Idec and Elan Pharmaceuticals) has been published. Achim Berthele, MD (Technische Universitate Munchen, Germany) and colleagues report the case in Annals of Neurology (2009:66[3];403 - 406). Based on this single report, it cannot be confirmed that Tysabri caused (or predisposed to) the lymphoma. However, the authors suggest that any development of new or unusual neurological signs or symptoms in a person taking Tysabri should prompt a diagnostic workup for possible complications. Such monitoring is required in people enrolled in the TOUCH risk management program in the U.S.

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.

In the general population, primary central nervous system lymphoma, or PCNSL, is most often diagnosed in the elderly and in individuals whose immune systems have been suppressed by medications or disease. There is no reported increase of PCNSL in individuals who have multiple sclerosis.

Details: A 40-year old man from Germany with relapsing-remitting MS had been treated previously with interferon beta and azathioprine. A previous brain biopsy had shown no signs of lymphoma. He developed partial loss of sensation (hypoanesthesia) on his right side after having received 21 doses of Tysabri. MRI-detected lesions were not typical of multiple sclerosis, prompting tests that led to the diagnosis of primary central nervous system lymphoma.

The authors tested the lymphoma, a high-grade B-cell non-Hodgkin lymphoma, for the presence of Epstein-Barr virus, since this virus has been associated with PCNSL when it develops in immune-suppressed individuals. They found no evidence of the virus in the lymphoma tissues, somewhat reducing the likelihood that the tumor was related to Tysabri-induced immunosuppression.

Comment: “This report underscores the importance of carefully tracking patients on powerful medications like Tysabri and remaining vigilant for new neurologic signs in people on this medication,” said Dr. John R. Richert, executive vice president of research and clinical programs at the National MS Society. It cannot be confirmed from this single report that there is a causal link between Tysabri administration and the occurrence of primary central nervous system lymphoma. However, careful monitoring for new or unusual neurological signs and symptoms in those taking Tysabri, which is required in those enrolled in the TOUCH risk management program in the U.S., should be adequate for detecting possible signs of brain lymphoma.


The report can be seen here.
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PostPosted: Tue Oct 27, 2009 6:39 pm    Post subject: Reply with quote

From Forbes.com, October 27, 2009:

Quote:

Reviving Tysabri

Matthew Herper

The drug's inventor believes a new test might identify people who are less at risk for a deadly side effect.


Worries about a potentially deadly side effect have long impeded sales of the multiple sclerosis drug Tysabri, made by Elan. But now the medicine's inventor says he has created a diagnostic test that might reveal those patients who are less at risk of the side effect. That could increase the market for the drug, which is already a $1 billion seller.

Ted Yednock, a researcher at the South San Francisco labs of Elan, invented the antibody that would become Tysabri in 1992. It offered a new way of curtailing the immune system, which goes haywire in MS and the gastrointestinal ailment Crohn's disease. The drug was approved to treat MS in November 2004.

But only three months after that approval, Tysabri was withdrawn. The immune suppression caused by the drug was allowing a usually dormant virus to infect patients' brains, causing a brain-destroying condition called progressive multifocal leukoencephalopathy (PML). Estimating that the virus occurred in one in 1,000 treated patients, the Food and Drug Administration allowed Tysabri to re-enter the U.S. market in July 2006.

Ever since, Yednock, 52, has been on a quest to understand the virus that causes PML. When Tysabri was pulled, researchers thought that most--90% or more--of human beings were infected with the virus that leads to PML (named JC, after the first two patients to get PML). Yednock says that work done by his team shows that only 50% of patients are infected with the JC virus, meaning that there are many patients for whom Tysabri might bear little PML risk at all.

Even with the specter of PML, 60,900 patients have chosen to take Tysabri, which is given by infusion and is very effective at preventing the brain lesions caused by MS.

Yednock's quest is taking on more urgency, as worries about PML continue to build. The risk of PML rises as patients get more infusions of Tysabri, and as time passes more PML cases are a certainty. On its most recent conference call, executives at Biogen Idec, Elan's partner on the drug, said that the FDA might want to add discussion of this increase to the product's label.

On Oct. 23, European regulators said that 23 cases of PML had been reported, far more than investors had expected. Wall Street analysts who cover Biogen for Bernstein, Deutsche Bank and Oppenheimer all said this could mean the risk of PML had doubled. The FDA-approved labeling for Tysabri puts the risk of PML at 1 in 1,000. With the new cases included, it could be 1 in 400, according to the analyst reports. Most analysts are skeptical that Elan and Biogen-Idec can reach their stated goal of getting 100,000 people on the drug.

Yednock says that the problem with PML testing up until now has been that the JC virus looks a lot like an evolutionary cousin, the BK virus. Antibody tests developed for JC virus were also set off by the BK virus, but BK virus doesn't cause the PML brain infection.

For some patients with JC virus, the virus is excreted in urine. By collecting blood samples from those people, Yednock had a group of patients he knew were infected with JC, allowing him to start developing a test that captured them all.

The test Yednock and his colleagues developed found that something like 50% of the patients have JC virus. There are eight cases of patients who developed PML where Elan and Biogen-Idec have blood samples going back long before the infection happened. All of those cases had JC virus antibodies in their bloodstreams a year before they got PML. "That's a pretty good starting point," says Yednock.

Elan has transferred the assay to a commercial laboratory, a step toward making it available to patients. The test, which uses antibodies to detect the presence of JC virus, could be done with just a saliva sample. It has not been evaluated by regulators or the larger scientific community, but the hope is that doctors might be able to use it to pick which patients are the best candidates for Tysabri therapy.

At a medical meeting Tuesday in San Diego, researchers working with Elan were set to present new analyses of already public clinical trials of Tysabri in Crohn's disease, a condition in which the immune system attacks the intestine, causing bleeding and sometimes requiring surgery. The new analyses show that Tysabri may work best in Crohn's patients who have already failed Crohn's drugs like Remicade, from Johnson & Johnson, and Humira, from Abbott Laboratories.

That's a nice step forward, but the PML risk needs to be clearly established. It would help Tysabri's makers a lot if they could identify patients who aren't at risk at all.





The article can be seenhere.

Emphasis added.


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PostPosted: Wed Oct 28, 2009 7:38 am    Post subject: 24th PML case? Reply with quote

There is some indication of a 24th PML case that was reported just recently, on www.mednous.com:

Quote:
EMEA receives 24th report of PML case linked with Tysabri

Created 26 Oct 2009

There has been a recent surge in new confirmed cases of progressive multifocal leukoencaphalopathy (PML) associated with the multiple sclerosis drug, Tysabri (natalizumab), with the 24th case reported to the EMEA on 25 October.

A spokesman for the European Medicines Agency told MedNous that the latest case was reported to the agency on Sunday. Healthcare professionals, he said, appear to be more aware now than in the past about the need to identify and manage cases of PML in patients being treated with Tysabri. PML is a rare brain infection whose symptoms are similar to those of a multiple sclerosis attack.

Tysabri has been approved in Europe and the US to treat relapsing-remitting multiple sclerosis in patients with high disease activity. There have been only a few reports of PML cases since the drug was authorised for sale. But in recent months, the number has increased.

On 23 October, 2009, the EMEA disclosed that the number of confirmed cases had reached 23. At the same time it announced plans to conduct a review to “discuss any additional measures necessary to ensure the safe use of Tysabri and how to balance the risks to the patients against the benefits of treatment.”

The 24th case was reported two days later.

About 12 of the new cases have been reported in the past two months, indicating that healthcare professionals are now more “sensitized” to the distinction between a multiple sclerosis attack and PML, the spokesman said.

“The review will try and identify what is behind these cases,” he added. There are at least four possible outcomes to the review. They are, that nothing changes; that the labelling of the drug is altered; that the drug is suspended pending further clinical studies, or that the drug is withdrawn from the market. No time limit has been set on the review. Until such time as the review is complete, the drug is considered to have a positive risk-benefit balance.

Tysabri was temporarily suspended from the US market in 2005 after three cases of PML were reported. It was reintroduced there in 2006 with restrictions. The drug was approved for the European market in June 2006. About two years later, in March 2008, the EMEA asked the license holder, Elan Corporation Plc, to alter the drug’s product information to warn about possible liver injury. In August of that same year, it received two reports of PML in patients taking the drug. In September, it requested that the product information be updated to further increase awareness about the risk of PML.

Tysabri is co-marketed by Elan and by Biogen Idec Inc. According to the Wall Street Journal, Biogen is currently in talks with the FDA about possible new amendments to the drug’s label to reflect the increased risk of PML. The risk appears to rise with longer-term use.

As of 30 Sept, an estimated 46,000 people globally were taking the drug, which is a major source of revenue for both Elan and Biogen Idec.


Emphasis added. The highlighted paragraph is the first explanation I've seen for the sudden upsurge in the number of PML cases reported.

The article can be seen here.
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PostPosted: Thu Oct 29, 2009 7:45 pm    Post subject: 24 PML cases now Reply with quote

This is from Reuters, October 30, 2009:


Quote:
UPDATE 1-EU agency reports 24th case of Tysabri infection

* EU regulator says 16 cases in Europe, 8 in U.S., 4 deaths
* Shares in Elan touch year-low; Biogen down 0.7 pct


LONDON, Oct 29 (Reuters) - European regulators reported another case of potentially deadly brain infection in patients taking multiple sclerosis drug Tysabri, taking the worldwide total since 2006 to 24.

There have been four deaths, a spokeswoman for the European Medicines Agency said on Thursday.

The European Union accounts for 14 of the cases of progressive multifocal leukoencephalopathy (PML), with two in Switzerland and eight in the United States.

Last Friday, the agency announced it had begun a review of the drug after reports of 23 cases of PML, sending shares in the drug's makers Biogen Idec Inc and Elan Corp Plc ( sharply lower.

Tysabri was temporarily withdrawn from the market in 2005 after being linked with the disease. It was reintroduced in July 2006 with stricter safety warnings.

Elan fell as much as 3 percent to a new year low on Thursday, before recovering, while Biogen was down 0.7 percent by 1615 GMT. (

Reporting by Ben Hirschler; Editing by David Cowell)


This can be seen here.
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PostPosted: Thu Oct 29, 2009 8:08 pm    Post subject: Reply with quote

I'm going to ask about taking a break if I see my neuro tomorrow. From what I've heard, disease activity starts to return after about six months or so, so it might be worth taking a break.

I read another report that said they're considering having patients take a mandatory drug holiday after a certain number of infusions in Europe where they've had so many cases.
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PostPosted: Fri Oct 30, 2009 8:00 am    Post subject: Reply with quote

wiz, good luck with the neuro. I hope that together you can reach a decision you'll feel comfortable with.

I have you to thank for this information from the National MS Society Website, which you posted on BrainTalk. I'll post it here just in case somebody here hasn't seen it elsewhere because it contains more information about the 24 PML cases than I've seen anywhere else:

Quote:
Oct 29, 2009

Update on Tysabri and PML: Company Releases Details of Cases and Risks

According to information released yesterday by Biogen Idec, there have been 24 confirmed cases of progressive multifocal leukoencephalopathy (PML, a viral infection of the brain that usually leads to death or severe disability) among people who have used Tysabri® (natalizumab, Biogen Idec and Elan Pharmaceuticals) after it became available for prescription in July 2006.

As of the end of September 2009, 60,700 people have used Tysabri worldwide. Although the absolute risk for PML in patients treated with Tysabri cannot be precisely determined, the sponsor has now released data suggesting that the risk increases with increasing time on therapy, starting out lower than the one-in-one thousand level that was estimated at the time of Tysabri’s re-approval in 2006, and rising after two years of infusions to about one in one thousand. There is insufficient information to determine the risk of PML in those who have been on therapy for three years or more. Right now only 2,000 people have been on the therapy for over three years.

This release followed an October 23 announcement from the EMEA, the European equivalent of the U.S. FDA, indicating that one of its advisory committees was launching a review of the risks and benefits of Tysabri in light of the increasing number of new cases of PML.

Signs of PML: Typical symptoms associated with PML progress quickly over days to weeks, and can include:
• personality or behavioral changes
• changes in thinking, memory, and orientation leading to confusion
• onset of seizures, clumsiness or progressive weakness on one side of the body
• disturbances of vision

If individuals taking Tysabri experience new, unusual symptoms, they should contact their prescribing physician immediately. Physicians who need guidelines on the protocol to follow when they have a patient on Tysabri who experiences unusual symptoms should contact Biogen Idec.

Details of Cases: According to the company, the 24 cases of PML have occurred in both men and women who had been given infusions of Tysabri every four weeks for a duration ranging from one year to three and a half years, with an average of two years.

~16 of the cases occurred in Europe, and 8 in the United States
~4 of the 24 died

he degree of disability in the 20 survivors is a wide spectrum: at the milder end, some have recovered enough to return to work, and at the other extreme, some are confined to bed, requiring extensive assistance with activities of daily living, and others were in between this range. Further details of their condition were not provided.
It appears that when PML is detected and treated early, it generally improves outcomes. It is important that individuals taking this drug and their doctors be vigilant in monitoring for any occurrence of new, unusual symptoms that might indicate PML.

Based on these cases, the sponsor stressed that, contrary to prior information, the presence of gadolinium-enhancing lesions on MRI does not exclude the possibility of PML. Likewise, the absence of JC virus DNA in the spinal fluid does not exclude PML.
There has been no characteristic among those who have developed PML that would give substantial clues to who might be more likely to develop it, except that half of the cases had prior histories of having been on immunosuppresive therapies, such as mitoxantrone, and less commonly, azathioprine and methotrexate.

Right now there is no test that can predict who is more likely at risk for developing PML while using Tysabri; in a large company-sponsored study, testing of blood cells, plasma, serum and urine for the causative JC virus in people before and after 48 weeks of Tysabri therapy (Rudick et al, ECTRIMS 2009) did not show any differences in the presence of the virus in those fluids. The results of these studies, performed at the U.S. National Instituties of Health, differ somewhat from an earlier study (N. Engl. J. Med. 361:1067, 2009) suggesting higher virus levels after treatment.

When PML was suspected, Tysabri infusions were halted. There is no specific therapy to treat PML, but the best hope is to reconstitute a person’s immune responses. In most of the 24 cases, once PML was confirmed, Tysabri was removed from their systems with the blood-cleansing treatments of either plasma exchange or immunoadsorption.
During the aftermath of PML, as the immune system begins to recover, a condition called IRIS (immune reconstitution inflammatory syndrome) usually occurs about 4 weeks after the removal of Tysabri from the system. The sponsors suggested that some of the treating physicians found that prompt use of intravenous steroids to treat this brain inflammation led to improvement.

The FDA provides post-marketing safety warnings on Tysabri at this link, although the updated information above is not currently provided.



The article, which includes links that don't show up here, can be seen here.


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PostPosted: Fri Oct 30, 2009 11:28 am    Post subject: Reply with quote

I chose not to get my infusion today. The neuro spoke to me for about an hour. I'm going to go back in three months and talk about whether I want to go back on, or go on something else. I'll check back in later though. I have another appt this afternoon and won't be home until later on.
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Formerly Avonex, Rebif & Copaxone
Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Fri Oct 30, 2009 8:14 pm    Post subject: Reply with quote

I was thinking about doing this since last month and after this past week's events with Biogen, it's what I had to do.

He said that a minimum "drug holiday" would be three months since that's how long it takes to clear from your system. He also said he has no way of knowing if this will help or not and anyone who claims to know that it helps is wrong.

He also said that in one post trial evaluation, patients were given spinal taps and that the T cells were at zero even at six months post drug cessation. So we know it keeps doing what it does for a long time. Everyone will be different of course but I'm hoping I'll be about average in that regard.

He also spoke to me about Cladribine, an oral treatment that should be approved in the spring.

It has a long history since it's a chemo drug that has been used for 18 years, but the MS dose is much smaller and even safer. He said the side effects were negligible in the trials. So I'm thinking about that as a possible replacement therapy. It's hard to believe that a pill is so close to reality.
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Formerly Avonex, Rebif & Copaxone
Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Wed Nov 04, 2009 8:57 pm    Post subject: Reply with quote

Wiz, I am happy in one way ... because of my concern for your longer-term health, but I wonder if you are forgetting how rotten you were feeling before Tysabri?

It might be worth looking back at a few of the forums to see what you were saying a couple of years ago, cause I seem to remember you were not doing particularly well back then ...? scratch

Cherie
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PostPosted: Tue Nov 10, 2009 4:16 pm    Post subject: (Very brief abstract) How Tysabri survived Reply with quote

If anyone has access to Nature Biotechnology, this article might be interesting reading:

From PubMed, November 10, 2009:

Quote:



Nat Biotechnol
. 2009 Nov;27(11):986.

How Tysabri survived
Huggett B.


Most drugs withdrawn from the market because of serious toxicities never make it back. But Biogen Idec succeeded in getting its multiple sclerosis (MS) drug Tysabri reintroduced in less than 16 months.

PMID: 19898447
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PostPosted: Thu Nov 12, 2009 4:17 pm    Post subject: Dr. Timothy Vollmer on Tysabri Reply with quote

From the Rocky Mountain MS Center e-News, November 12, 2009:

Quote:
The Facebook group, Tysabri: As long as my body tolerates it, I'm not scared of PML!, may have a somewhat casual title, but it addresses a very real concern in the MS community: Tysabri and the risk of a brain infection—PML (progressive multifocal leukoencephalopathy)—that it poses.

Biogen Idec., the co-marketers of Tysabri, recently announced that since the FDA approved the therapy in 2004, there have been 24 cases of PML, including 4 deaths. This announcement has brought to light a number of questions and concerns regarding Tysabri, many of which Dr. Vollmer will address in this article.

After first receiving FDA approval in 2004, Tysabri was pulled from the U.S. market when it was linked to three cases of PML. In 2006 it was returned to the market after the safety profile was further explored. Tysabri works by blocking the passage of inflammatory immune cells through the blood brain barrier, thus slowing the progression of MS. The risk of PML is related to the fact that Tysabri may, in fact, work too well. For most people, the immune system would fight off PML without any difficulty, but because Tysabri is designed to fully block the MS immune attack on the brain, it also blocks the immune system’s ability to fight infections in the brain, such as PML. It appears, however, to have little if any problematic effect on other types of infections.


With the recent announcement confirming the increased number of PML cases, other information has become available as well. Of the 24 cases, two-thirds have been in Europe and one-third in the U.S. This is surprising considering that about 60% of exposed patients have been in the U.S. and only 40% in Europe. Why there appears to be a higher risk of PML in European MS patients on Tysabri is unclear. Additionally, the bulk of the cases have occurred in year three of Tysabri treatment. Specifically, in year one the risk is less than 1/30,000; in year two, it is approximately 1/3,000; and in year three the risk increases to approximately 1/800. The risk is real: in addition to the four reported deaths due to PML, mild to severe disability has been reported in those who have survived their bouts with the brain infection.

The above data suggest that the longer patients are treated with Tysabri, the higher the risk of PML. Does that mean that in year four and year five the risk increases? Few patients have reached four and five years of treatment, so we do not yet know the answer. As to the skewing between the number of cases in the U.S. and Europe, European patients may be more likely to have been treated with chemotherapy before beginning Tysabri. Does that mean that chemotherapy treatment increases the risk of PML, as some MS-specialists speculate? That remains unclear, but we do know that most Tysabri patients who develop PML have no history of other immunosuppressant therapies, which makes that hypothesis unlikely.

Despite the risks, Tysabri has proven itself to be a very effective and tolerable MS treatment, with an average efficacy rate of 70% compared to 30% for the first-line agents (Avonex, Betaseron, Copaxone and Rebif). Aside from the concern regarding PML, the therapy’s safety profile is well-developed and positive. According to Dr. Vollmer, were it not for PML, Tysabri would most certainly be a first-line agent for most MS patients. Therefore, one must wonder: what is the future of this effective, yet worrisome, therapy?

Three main possibilities exist, among them that the FDA and the manufacturers may opt to change the label so that Tysabri would be recommended for only 2 years of treatment or less; that research may advance to the point of identifying patients who innately have a higher risk of PML, although to date very few advances have been made in this area; or that Tysabri doses may be changed and/or the therapy used in combination with other treatment agents.

The latter of these three options seems to be, according to Dr. Vollmer, the most likely future path of the therapy (barring what the FDA may do unilaterally). Already a number of experimental avenues have been initiated. By adjusting Tysabri dosage and/or using the therapy in combination, each of these avenues aims to maintain efficacy levels while reducing the risk of PML.

The first possibility is to switch back to an available first-line agent after one to two years of Tysabri therapy. One major consideration with this treatment option, however, is the fact that recent data suggest that when people go off Tysabri, there is a 20% to 50% chance of a rebound effect. This means that disease activity could flair-up above the levels previously experienced by the patient.

According to Dr. Vollmer, it is therefore very important that treatment of this nature be done as a study within an intense safety monitoring program.

One study that is looking at the use of Tysabri in combination with the first-line agent Copaxone is about to be launched at the Rocky Mountain MS Center at Anschutz Medical Campus. These agents are being combined for a 3-month period, and then study participants are continuing solely on Copaxone. The safety of using these therapies in combination was already established in the GLANCE study. This method will be deemed a success or failure based on whether Copaxone is able to maintain a high level of treatment effect. If the treatment approach does not maintain the high level of disease control typical of Tysabri, there is no reason to pursue a larger study to determine if this approach reduces the risk of PML. The current study requires only 100 study participants, whereas a study specifically looking at the risk of PML would require 10,000 study participants or more, making it a huge undertaking.

The second possibility is the use of drug holidays, meaning that patients would be given annual "holidays" from their Tysabri treatment with the goal of reducing the risk of PML. According to Dr. Vollmer, however, the method is racked with concerns, including the above-mentioned disease rebound effect and the possibility of building up neutralizing antibodies to Tysabri. Normally, that risk of developing these antibodies is only 6%, but if patients were to go on and off Tysabri a number of times, that risk could possibly go up and the drug could lose its treatment effect.

Additionally, the fact that there is no evidence that the preclinical phase of PML lasts more than a few weeks or a month, annual "holidays" are not likely to protect against the brain infection. In all actuality, patients would have to take "holidays" on a frequent basis in order to effectively protect against PML, which is not a feasible option.

The third possibility is that after one to two years of monthly treatment, Tysabri infusions could be changed from once a month—as they are currently prescribed—to every other month. The current 300 mg dose is designed to maintain saturation for approximately 6 weeks. If the dose were adjusted and given every 8 weeks, it is possible that on average there would be one week that full blockade of transmigration would not occur and immune surveillance would kick in—meaning that the immune system would function regularly during that week. The thought is that this one week out of 8 of normal immune function might minimize the risk of PML.

Although PML is a very serious risk associated with the agent, Dr. Vollmer stresses that to lose the therapy would be to lose the current MS therapy with the most potential, and that which has shown great efficaciousness. The loss would be a great detriment to the MS community. Because we do not currently know the minimum effective dose of Tysabri, it is critical to explore adjustments in dosage and combination use in order to most effectively and safely treat with Tysabri in the future.

Furthermore, there is a key role that Tysabri patients and their families can play in the fight against PML: educate yourself about the signs associated with the infection, and notify your doctor if you notice any red flags. The best way to minimize the chances of incurring disability from PML is to catch it early. Because patients on Tysabri are usually very stable, psychological and cognitive issues—such as changes in personality or signs of memory loss—can be associated with PML. If you have MS, make sure those around you are on the lookout for any personality or cognitive changes.

It is important that patients and families empower themselves through education regarding the signs of PML and alert medical professionals of any noted changes. Together, we—patients, families, and physicians—can fight PML and find new avenues through which to safely and effectively use Tysabri.











About Dr. Vollmer:
Quote:
Dr. Timothy Vollmer, medical director of the Rocky Mountain MS Center. Dr. Vollmer, widely recognized as one of the world's leading experts on MS, has been working with MS patients for more than 20 years. He joined the Rocky Mountain MS Center in August 2008.
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PostPosted: Thu Nov 19, 2009 12:42 pm    Post subject: PML cases now at 27 Reply with quote

Special thanks to ewizabeth and Cherie for pointing me in the appropriate direction here. From xconomy.com, November 19, 2009:

Quote:

Tysabri, the MS Drug Haunted by Deadly Side Effect, Doesn’t Look So Deadly Anymore

Luke Timmerman 11/19/09

Few doctors knew much about a rare brain infection called PML back in 2005, when two patients on a hot new multiple sclerosis drug from Biogen Idec and Elan died from the side effect. The infection, at the time, was generally considered a death sentence. But now with three years of data from more than 60,000 patients worldwide who have taken natalizumab (Tysabri) under strict monitoring by physicians, a new picture is emerging that shows PML is still very much a serious threat, but that it isn’t nearly as deadly as first feared.

While each and every confirmed case of PML, known formally as progressive multifocal leukoencephalopathy, scares investors in Cambridge, MA-based Biogen (NASDAQ: BIIB) and Ireland-based Elan (NYSE: ELN), I sought to assemble a big picture view of exactly how deadly PML really is when I interviewed Al Sandrock last week. He’s the senior vice president of neurology R&D at Biogen, and an assistant clinical professor of neurology at Harvard Medical School.

...
When the drug came back on the market [in July 2006], its FDA-approved prescribing information contained a prominent warning that about 1 out of every 1,000 patients on the drug were likely to get PML. But that was really just a forecast, and the actual risk-benefit balance for this drug is really a moving target that shifts over time when a new case is confirmed. So I sought to build a simple chart when I spoke to Sandrock that provides a snapshot of PML cases in February 2005, when the drug was pulled off the market because of the PML risk, versus those confirmed as of yesterday. Here’s what I gathered:

[A chart shows that as of February 2005, 3,000 patients were on Tysabri, and there were 3 PMl cases, with 2 deaths. As of November 18, 2009, there were 63,000 patients on Tysabri, and there have been 27 PML cases, with 5 deaths.]

The February 2005 figures came from clinical trial data and formed the foundation for the FDA-required warning of the 1-in-1,000 chance of getting PML. The more recent figures include all the experience of patients who have gotten the drug since it was returned to the market in July 2006. The thing that jumped out at me was the fact that only five of the 27 confirmed patients with PML have died—meaning that the current survival rate stands at over 80 percent.

That curious fact has been buried under a rash of scary headlines this fall, in which the number of cases of PML appears to have gone through a sharp increase. There were 13 cases confirmed in an FDA notice on September 17, and the number climbed to 23 when European regulators issued an update on October 23. The latest tally now stands at 27, Sandrock said in a Nov. 11 interview (and which was confirmed again yesterday by company spokeswoman Naomi Aoki). Based on this evolving body of evidence, the FDA updated the Tysabri prescribing information earlier this month to say that the risk appears to increase as patients stay on the drug for longer periods of time.

But even as more cases get diagnosed, I wanted to know why there hasn’t been a corresponding increase in the number of deaths. The chart shows more than 80 percent of patients diagnosed with PML since the drug came back on the market in July 2006 are still alive. Lots of doctors also want to know what’s happening to those patients who get PML, but still live. Biogen isn’t releasing a patient-by-patient breakdown of what is happening to them all, but its medical affairs staff is answering those questions from physicians, Aoki says.

Some of the patients are severely disabled, Sandrock says, but a few—he wouldn’t say exactly how many of the 27 cases—have recovered and even feel strong enough to return to work. The New England Journal of Medicine recently published an article about one case of PML in which a patient became critically ill with PML, but recovered.

“Back when I trained as resident, we didn’t know much about it, but it was assumed that PML was almost always fatal,” Sandrock says. “But the survival rates appear to have changed. The outcome from PML is not certain death. Some have done well, and others, not so well.”

Of course, this isn’t the only way to look at the PML risk. The drug’s makers and regulators are looking at databases that factor in different variables, like the number of patients who have been on the drug for more than a year, more than two years, more than three years, and so forth. Those figures are what led regulators to add new language to the label that says the risk increases over time. Sandrock emphasized that even though the risk does increase, it’s still within the 1-in-1,000 rate that patients were warned about back in July 2006, even for patients who have been on the drug since shortly after it was brought back to the market. The degree of statistical confidence in the PML risk figure declines over time, because there are fewer patients who have been on the drug for two and three years, Aoki says.

So while the incidence appears to be rising, what has changed that’s keeping PML patients alive? One of the big reasons is the strict monitoring program insisted upon by regulators, Sandrock says.

Now that every physician who treats MS has heard a lot about PML, they are trained to look for telltale signs like changes in cognition, changes in personality, or seizures that are not typical symptoms of an MS patient, Sandrock says. Doctors watch for those signs every time a patient comes in for their monthly IV infusion of the drug. If the side effect is suspected, the doctor will withhold the drug and run an MRI test to look for signs that the cause of PML, the JC virus, has entered the brain. If the MRI shows the virus is there, the doctor then does a spinal tap that can confirm the presence of the virus.

“We think we’re catching the virus early now,” Sandrock says, noting that some cases have been detected with extremely low concentrates of virus in the spinal fluid that only a specialty lab at the National Institutes of Health can detect.

Once the virus is detected, doctors do what is called a “plasma exchange,” which basically means that whatever amount of drug is still circulating in the bloodstream gets washed out through a filtering procedure. Doctors then reconstitute the patients’ immune system, which “clears the virus out,” Sandrock says.

So while early detection has helped lower the risk of death, I wanted to know what else Biogen and Elan think holds promise to bring the fatality rate down even further. Analysts suggested earlier this month that regulators might impose a drug “holiday” for patients who stay on Tysabri for long-periods of time. Sandrock didn’t like the sound of this idea, saying there isn’t data to support the notion that such a step will help lower the risk, while it essentially guarantees that a patient’s disabling MS symptoms will come back. But he did note that the company is looking to conduct a clinical trial to test the idea.

Biogen says it is more interested in developing a blood test that might offer doctors clues as to which individual patients have an elevated risk of getting PML from the start, and which ones are less likely to become infected. The key to determining this could lie in a relatively common lab technology, known as Elisa, that can detect whether a patient has antibodies in the blood made to fight the JC virus that can awaken from a dormant state to cause PML in Tysabri patients. About half of adults are estimated to have these antibodies, which suggest that JC virus is lurking in the body with the potential to become an opportunistic infection in at least some Tysabri patients. The remaining patients are thought to have no JC virus in their systems, and therefore would be considered less likely to get PML, Sandrock says.

Biogen also has a lot of other strategies for minimizing the risk of PML. It is forming a consortium with the makers of other drugs that have been linked to the side effect, such as rituximab (Rituxan), efalizumab (Raptiva), alemtuzumab (Campath), and mycophenolate (Cellcept), Sandrock says. The idea is that accumulating more data in a global database will help each company deal with the issue, Sandrock says.

There are other ideas in the works as well, such as a vaccine to protect against PML—”we’re very excited about that,” Sandrock says—and a potential anti-PML treatment called mephaquin, which is commonly used to treat malaria. A Biogen collaboration with Cambridge, MA-based Alnylam Pharmaceuticals to develop an RNA interference-based treatment for PML has stopped, Sandrock says.

Pressure to show progress with innovative new treatments, vaccines, or drug holidays will surely intensify if the incidence of PML keeps climbing past that 1-in-1,000 benchmark rate as patients stay on the treatment for years. The pressure to figure out how to best manage PML will come from investors, regulators, and from the patients themselves, who want to make sure that they can still get the drug.

“Not a week goes by around here that we don’t hear a story from a patient who has had their life transformed by this treatment,” Sandrock says. “The benefit has been confirmed, by real life stories. And we’ve made a lot of progress at mitigating the risk.”

Luke Timmerman is the National Biotechnology Editor for Xconomy. You can e-mail him at ltimmerman@xconomy.com, call 206-624-2374, or follow him on Twitter at http://twitter.com/ldtimmerman.

Luke Timmerman 11/19/09 12:12 pm



I've shortened the article slightly. The whole article, along with some comments, can be seen here.

Is the author trying to put the best possible face on this PML issue? Are patients supposed to be happy that if they do get PML while on Tysabri, at least their chances of not dying are greater than earlier believed?
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PostPosted: Thu Nov 19, 2009 12:53 pm    Post subject: Reply with quote

My neuro told me that if you get PML and survive, you'll probably wish you had died. He's very blunt about some things and I appreciate it most of the time. He considers PML to be much worse than cancer even.
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PostPosted: Thu Nov 19, 2009 2:45 pm    Post subject: Reply with quote

It doesn't sound like any fun to me, and since so many of its symptoms and signs are the same symptoms and signs often found in MS, I'm not sure how the doctors and patients can sort out which disease is acting up and when.

Even at autopsy they sometimes can't figure out whether it was MS or PML that killed somebody. That one case where the woman's MS diagnosis was called into question was like that.

I suppose to be fair it should be said that the odds of getting PML while on Tysabri are still very, very low.
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PostPosted: Sun Nov 29, 2009 11:04 am    Post subject: Reply with quote

I don't know why he would be confused at the seemingly low "death rate" from PML on Tysabri (20 - 25%) ...

Most people who got PML before were AIDs or organ transplant patients, who had EXTREME immune suppressing disorder (or relied on drugs that caused that). They couldn't just withdraw from the treatment, as they were DEPENDANT on it, and/or they couldn't just "stop" having AIDs.

With Tysabri, they can withdraw the PROBLEM, and "neutralize" the immune system fairly promptly. It seems logical to me that if they can remove the problem quickly, the end result might be better.

But, as Wiz pointed out ... I don't think I'd want to live in the situation that some of these people are in anyway ... and PML IS progressive.

Cherie
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PostPosted: Sun Nov 29, 2009 11:32 am    Post subject: Reply with quote

Also, somewhere in the course of the concern about Tysabri-related PML, wasn't plasmapheresis used with good results? Weren't the experts congratulating themselves that they'd found a way of stopping the PML from getting worse by rapidly removing Tysabri from the system?

There's an article about it here.

Might be another reason why the death rate is lower than expected, it seems to me.
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PostPosted: Mon Dec 14, 2009 6:38 pm    Post subject: 28 PML cases now, according to Reply with quote

Dr. Daniel Kantor, an MD specializing in MS, writing in the blog Neurologique, December 14, states that there have now been 28 PML cases among MS patients taking Tysabri:



http://neurologique.blogspot.com/
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PostPosted: Mon Dec 14, 2009 7:54 pm    Post subject: Reply with quote

You know, it probably doesn't mean anything, but I was starting to feel different and who knows what that means? geek But I was really getting scared to be on it anymore. I'm so glad I'm off of it now.

The Copaxone shots are going great so far and I've had no site reactions at all!!! cheers thumbright

I really worry about others who have been on Tysabri for long periods though. pale
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PostPosted: Tue Dec 15, 2009 12:08 am    Post subject: Reply with quote

Of all of the MS drugs, Copaxone seems to have the least potential to do harm.

Of course, who knows what effects these drugs will have on people after they've been on them 20 or 30 years?
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PostPosted: Tue Dec 15, 2009 12:14 pm    Post subject: Re: 28 PML cases now, according to Reply with quote

agate wrote:
Dr. Daniel Kantor, an MD specializing in MS, writing in the blog Neurologique, December 14, states that there have now been 28 PML cases among MS patients taking Tysabri:



http://neurologique.blogspot.com/


Yeah, I heard about the 28th (31st including the trial patients) too ...

I do not believe it though. At this point, I am highly suspicious that we will not be hearing about the cases until we get another "10+" happening 'all at the same time' again ...

Cherie
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PostPosted: Tue Dec 15, 2009 10:27 pm    Post subject: Reply with quote

As I recall, Dr. Daniel Kantor was the person MS World had reporting on the last neurology conference. I don't know if that means he has access to better information than other people but he might...
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PostPosted: Thu Dec 17, 2009 6:36 pm    Post subject: (Abstract) Decline of chemokines & cytokines in CSF... Reply with quote

From PubMed, December 17, 2009:

Quote:
Mult Scler.

Natalizumab treatment in multiple sclerosis: Marked decline of chemokines and cytokines in cerebrospinal fluid

Mellergård J, Edström M, Vrethem M, Ernerudh J, Dahle C.

Department of Neurology, Linköping Uni. Hosp., Linköping, Sweden/Div. of Clinical Immunology, Unit of Autoimmunity and Immune Regulation,Linköping, Sweden.

Natalizumab exerts impressive therapeutic effects in patients with multiple sclerosis (MS). The proposed main mode of action is reducing transmigration of leukocytes into the CNS, but other immunological effects may also be operative. Cytokines and chemokines are involved in the regulation of inflammatory responses and may reflect the disease process in MS.

The objective of this study was to evaluate the effects of natalizumab treatment on cytokine and chemokine profiles systemically and intrathecally in multiple sclerosis. We used luminex to analyse a panel of cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma, GM-CSF) and chemokines (CXCL9, CXCL10, CXCL11, CCL17, CCL22) in blood and cerebrospinal fluid (CSF) from 31 patients with relapsing MS before and after one year of natalizumab treatment. There was a marked decline in CSF levels of cytokines and chemokines, thus including pro-inflammatory cytokines (IL-1beta, IL-6 and IL-8) as well as chemokines associated with both Th1 (CXCL9, CXCL10, CXCL11) and Th2 (CCL22). Circulating plasma levels of some cytokines (GM-CSF, TNF-alpha, IL-6 and IL-10) also decreased after one year of treatment.

This is the first study to show that natalizumab treatment is associated with a global decline in cytokine and chemokine levels at a protein level. This finding was most pronounced in CSF, in line with the reduced transmigration of cells into CNS, whereas reduction in plasma levels indicates other possible mechanisms of natalizumab treatment.

PMID: 20007431


The abstract can be seen here.
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PostPosted: Sat Dec 19, 2009 3:28 pm    Post subject: (Abstract) Melanoma in MS treated w/Tysabri...coincidence? Reply with quote

From PubMed, December 19, 2009:

Quote:
Mult Scler. 2009 Dec;15(12):1532-3.

Melanoma in multiple sclerosis treated with natalizumab: causal association or coincidence?

Bergamaschi R, Montomoli C.

Multiple Sclerosis Center, Neurological Institute Mondino of Pavia, Italy. roberto.bergamaschi@mondino.it.

We report a relapsing-remitting multiple sclerosis patient who received monthly intravenous natalizumab. After the fifth dose, the patient had a change in a long-standing mole. Ten months later, the mole became ulcerative and was ablated. Histological examination identified a spreading melanoma reaching the lower dermis (Clark level IV).

Considering that at the moment the incidence of melanoma is estimable as about 5 per 100,000 multiple sclerosis person-years treated with natalizumab, and that, in the general population, the incidence of melanoma per 100,000 person-years is more than 10, we may speculate that the occurrence of melanoma during natalizumab treatment in multiple sclerosis is purely a coincidence.

PMID: 20019096 [PubMed - in process]


The abstract can be seen here.
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PostPosted: Wed Jan 06, 2010 11:56 pm    Post subject: Reply with quote

So today Biogen announced the 4 additional cases (28 + 3) that we talked about a few months ago:

http://boston.bizjournals.com/boston/stories/2010/01/04/daily43.html

They are only advising of the cases up to the end of Nov/09 now though.

Strange.

Cherie
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PostPosted: Thu Jan 07, 2010 12:07 am    Post subject: Reply with quote

I noticed that too. Are they being cagey or what?
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PostPosted: Thu Jan 07, 2010 12:12 am    Post subject: Reply with quote

I reckon ... but I have always felt that way about them.

Cherie
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PostPosted: Thu Jan 07, 2010 8:46 am    Post subject: Reply with quote

Guess they can't be blamed for trying in every way they can to protect their interests. Or can they?

Seems as if the public interest ought to enter into the equation when it's a matter of people's health and even their lives....
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PostPosted: Thu Jan 07, 2010 11:06 am    Post subject: (Abstract) JCV detection in MS patients treated w/Tysabri Reply with quote

From PubMed, January 7, 2010:

Quote:
J Neurol. 2010 Jan 7.

JCV detection in multiple sclerosis patients treated with natalizumab

Sadiq SA, Puccio LM, Brydon EW.

Multiple Sclerosis Research Center of New York, 521 West 57th Street, 4th Floor, New York, NY, 10019, USA, ssadiq@msrcny.org.

Natalizumab therapy is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Because the prognosis of established PML is uniformly dismal, identification of highly susceptible patients to the disease may improve outcomes.

We wanted to investigate whether serial plasma and cerebrospinal fluid (CSF) screening for polyomavirus would identify patients with laboratory evidence of viral infection prior to the development of clinical PML.

Two hundred MS patients had pre-treatment CSF/plasma screening for JC virus (JCV) and BK virus (BKV) DNA, and thereafter every six treatments of natalizumab. In all positive patients treatment is stopped (due to potential risk of PML), they have follow-up clinical examinations and plasma/CSF JCV/BKV tests until all evaluations are normal. No patient developed clinical evidence of PML. Eight of the 200 patients had detectable JCV or BKV DNA. Five patients were positive for BKV DNA in the CSF and three patients were positive for JCV DNA (one in plasma, two in CSF).

After cessation of natalizumab treatment, all patients converted to undetectable viral DNA. Screening for JCV in CSF in natalizumab-treated patients could help identify those at heightened risk for developing PML and discontinuing treatment in these patients may abort development of the clinical illness.

PMID: 20052484 [PubMed - as supplied by publisher]




The abstract can be seen here.
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PostPosted: Sat Jan 23, 2010 3:19 pm    Post subject: Better risk-management measures recommended... Reply with quote

From Medical News Today, January 23, 2010:

Quote:
European Medicines Agency Recommends Additional Measures To Better Manage Risk Of Progressive Multifocal Leukoencephalopathy (PML) With Tysabri


The European Medicines Agency has finalised a review of Tysabri (natalizumab) and the risk of progressive multifocal leukoencephalopathy (PML), a rare brain infection caused by the JC virus. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the risk of developing PML increases after two years of use of Tysabri although this risk remains low. However, the benefits of the medicine continue to outweigh its risks for patients with highly active relapsing-remitting multiple sclerosis, for whom there are few treatment options available.

Because it is important that PML is detected early, the Committee recommended that a number of measures be put in place to ensure that patients and doctors are fully aware of the risks of PML. These include: * an update of the product information to add information about the increase in the risk of PML after two years of treatment and additional advice on how to manage patients who show signs of PML; * forms to be signed by patients at the beginning of treatment with Tysabri, and again after two years of treatment, after in-depth discussions about the risk of PML with their doctor.

Measures to minimise the risk of PML were part of the initial marketing authorisation for Tysabri, issued in June 2006. Since then, they have been continuously updated and strengthened to increase awareness of the risk of PML.

The new measures are designed to complement the existing recommendations that patients, and their carers, partners and families should be made aware of the symptoms of PML and that patients should be closely monitored throughout treatment.

Notes

1. Tysabri, from Elan Pharma International Ltd, is used to treat relapsing-remitting multiple sclerosis in patients with high disease activity despite treatment with a beta-interferon or whose disease is severe and progressing rapidly.

2. More information about the review of Tysabri is available in a question-and-answer document.

3. More information about Tysabri is available in the European Public Assessment Report.

Source
European Medicines Agency


The article, with more links, can be seen here.
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PostPosted: Tue Feb 02, 2010 7:05 pm    Post subject: (Abstract) Immune responses to JC virus in PwMS on Tysabri.. Reply with quote

From PubMed, February 2, 2010:

Quote:
Lancet Neurol. 2010 Jan 28.

Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study

Jilek S, Jaquiéry E, Hirsch HH, Lysandropoulos A, Canales M, Guignard L, Schluep M, Pantaleo G, Pasquier RA.

Service of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

BACKGROUND:

Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy (PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment.

METHODS:

We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay.

The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment.

FINDINGS:

We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta.

INTERPRETATION:

Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation.

FUNDING:

Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen
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PostPosted: Fri Feb 05, 2010 7:25 pm    Post subject: (Article) FDA adds new warning on Tysabri label Reply with quote

From Business Week/HealthDay, February 5, 2010:

Quote:
More Doses of MS Drug Raise Risk of Brain Infection

FDA adds new warning on Tysabri label, but says benefits still outweigh dangers

By Amanda Gardner
HealthDay Reporter


FRIDAY, Feb. 5 (HealthDay News) -- In the latest blow to the controversial multiple sclerosis drug Tysabri, the U.S. Food and Drug Administration on Friday announced that it was slapping a new warning on the drug's label.

In an advisory sent to health-care professionals and patients, the FDA warned that the risk of developing progressive multifocal leukoencephalopathy (PML), a rare but deadly brain infection, increases as more infusions are received.

"This is updated information, taking new cases into account," explained Dr. William Sheremata, professor emeritus of neurology at the University of Miami Miller School of Medicine, who gave the drug to the first humans.

European patients account for most of the new cases and many of them might have been taking multiple drugs, raising their risk for PML, he added.

"This is not new information. We've had this information for a couple of months now [but] the labeling in the past did not make a distinction between the time frames that people were on the drugs," said Dr. John Richert, executive vice president for research and clinical programs at the National Multiple Sclerosis Society. "The risk-benefit ratio continues to be about the same as we anticipated since the time the drug was brought back on the market."

Another expert agreed that the clinical picture hasn't been altered by the new label warning.

"I think as long as the medication is being prescribed for the appropriate patient with MS, then the new information we have today is not going to alter medication management," said Dr. Jeffrey Tramonte, director of neurology at the Scott & White University Medical Campus in Round Rock, Texas. "Right now, Tysabri is the most efficacious drug that's ever been approved for the treatment of relapsing-remitting MS, which represents 85 percent of all patients out there who have MS," he said.

"However, it also carries the single most dangerous risk factor, and that's PML," added Tramonte, who only gives Tysabri if his patients have failed or have severe side effects from conventional immunomodulating drugs.

Natalizumab (Tysabri) first received FDA approval in November 2004, only to be pulled from the market three months later after several patients in clinical trials developed PML.

In June 2006, the FDA allowed the drug back on the market, but with strict conditions. According to those revised guidelines, Tysabri can only be administered by approved doctors, at infusion sites and at pharmacies that register and comply with a patient-safety program called CD Touch, designed by drugmaker Biogen Idec and approved by the FDA.

The FDA said the new action was based on reports of 31 confirmed cases of PML as of Jan. 21, 2010.

Information on the risk will also be included in the patient Medication Guide.

However, the FDA did not suggest discontinuing the drug, stating that it "believes that the clinical benefits of Tysabri continue to outweigh the potential risks."

The drug was approved to treat Crohn's disease in early 2008. It is also linked with liver damage. Patients do take the drug long-term, Richert said.

More information

Visit the National Multiple Sclerosis Society for more on this disease.


SOURCES:

John Richert, M.D., executive vice president, research and clinical programs, National Multiple Sclerosis Society, New York City; William Sheremata, M.D., professor emeritus, neurology, University of Miami Miller School of Medicine; Jeffrey Tramonte, M.D., assistant professor, internal medicine, Texas A&M Health Science Center College of Medicine, chief, medicine, and director, neurology, Scott & White University Medical Campus, Round Rock, Texas; Feb. 5, 2010, statement, U.S. Food and Drug Administration



The article can be seen here.
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PostPosted: Sun Feb 07, 2010 10:19 am    Post subject: (Article) Biogen plans 1st study for earlier use of Tysabri Reply with quote

From Dow Jones Newswires, February 5, 2010:

Quote:
Biogen Plans First Study For Earlier Use Of MS Drug Tysabri

NEW YORK -(Dow Jones)- Biogen Idec Inc. (BIIB) is planning the first clinical trial that could lead to use of controversial multiple sclerosis treatment Tysabri, sold with Elan Corp. (ELN), at earlier stages of the disease.

The long-term trial, dubbed Surpass, will measure the effectiveness of Tysabri in patients with active MS that have switched from either Teva Pharmaceutical Industries Ltd.'s (TEVA) Copaxone or Rebif, sold by Pfizer Inc. (PFE) and Germany's Merck KGaA (MRK.XE, MKGAY).

Tysabri is considered a highly effective therapy for MS, and its growth is important to the future of both Elan and Biogen. But its sales have been slower than originally hoped amid concerns about the risk of a rare brain infection that led to its 18-month market withdrawal beginning in 2005. The study comes after Tysabri brought in more than $1 billion in 2009, and it is part of Biogen's push to accelerate Tysabri's growth.

It also comes amid increased competition in MS treatments. Novartis AG (NVS, NOVN.VX) and Germany's Merck KGaA could launch oral treatments for the disease this year, a notable advance compared to the injections and infusions required with current drugs.

The goal of the Surpass trial is to get physicians to use Tysabri when patients aren't responding to their current therapy, rather than switching them to more mainstream therapies.

Beside Copaxone and Rebif, other common options include Biogen's Avonex and Bayer AG's (BAY.XE BAYRY) Betaseron, while Tysabri is generally reserved for patients with very aggressive disease or have no other options.

"We are trying to establish that there is no use in switching around [prior to using Tysabri]," Biogen spokeswoman Naomi Aoki. The company is signing up sites for the trial and has yet to enroll the first of an estimated 1,800 patients.

The study will follow participants for about two years and isn't likely to yield data until 2013 or 2014. If successful, the result should allow Biogen to update Tysabri's label and allow it to market the earlier use to physicians.

-By Thomas Gryta, Dow Jones Newswires


The article can be seen here.
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PostPosted: Wed Feb 17, 2010 10:40 am    Post subject: (Abstract) MS plaque mimicking PML during Tysabri treatment Reply with quote

From PeerViewInstitute Today in General Medicine, February 17, 2010:

Quote:
J Neurol Sci. 2010 Feb 6.

A giant MS plaque mimicking PML during natalizumab treatment

Twyman C, Berger JR.

Associates in Neurology, Lexington, KY, United States.

We describe a patient with a giant MS plaque developing during natalizumab administration whose clinical presentations mimicked PML. This 27-year-old man developed new onset confusion, altered behavior, left hemianesthesia and worsening dysarthria, gait and balance with a new, large, rim-enhancing, temporoparietal subcortical lesion after four infusions of natalizumab. Cerebrospinal JC virus polymerase chain reaction was negative. No neutralizing antibody to natalizumab was detected.

Following discontinuation of natalizumab, plasma exchange, and a single dose of 1000mg of methylprednisolone, he demonstrated clinical and radiographic improvement.

Distinguishing PML from MS may be very difficult in some instances. The frequency with which an aggressive demyelinating disorder due to MS occurs during treatment with natalizumab remains to be determined.

PMID: 20144466 [PubMed - as supplied by publisher]


LinkOut - more resourcesFull Text Sources:
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Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med. 2009 Sep 10; 361(11):1067-74.
[N Engl J Med. 2009]
ReviewThe effects of natalizumab on the innate and adaptive immune system in the central nervous system. J Neurol Sci. 2008 Nov 15; 274(1-2):39-41. Epub 2008 May 12.
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PostPosted: Tue Feb 23, 2010 8:56 am    Post subject: (Abstract) Liver injury in patients on Tysabri Reply with quote

From Peer View Institute, NTK Watch, February 23, 2010:

Quote:
Aliment Pharmacol Ther. 2010 Feb 16.

Review article: clinically significant liver injury in patients treated with natalizumab (TYSABRI)

Bezabeh S, Flowers CM, Kortepeter C, Avigan M.

Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration.

Background:

Natalizumab (Tysabri) is a recombinant monoclonal antibody approved for the treatment of patients with multiple sclerosis (MS) and patients with Crohn's disease (CD). Because of its immunosuppressive effects, natalizumab has been associated with a number of atypical and opportunistic infections.

Methods

The FDA maintains a database of adverse event reports (AERS). We searched the AERS database for reports of serious liver injury associated with natalizumab use from November 2004, when the drug was approved, through June 30, 2008.

Results:


The search resulted in six spontaneously reported postmarketing cases of severe drug-induced liver injury. Four of six patients developed liver injury with elevations of serum transaminases and hyperbilirubinemia after only a single infusion of natalizumab. One of these patients experienced repeated increases of aminotransferases and bilirubin when natalizumab was re-administered.

Conclusions:

Serious hepatic injury may occur in association with natalizumab use. Health professionals should be alerted to possible serious liver injury in patients receiving natalizumab.

PMID: 20163378 [PubMed - as supplied by publisher]




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PostPosted: Mon Mar 08, 2010 7:06 pm    Post subject: 40 PML cases now? Reply with quote

The informal PML reporting Website


http://chefarztfrau.de/?page_id=716

has listed 40 cases of Tysabri-related PML. The most recent one was listed on March 3, a female in Germany who had been taking Tysabri for 25 months.

Before this posting, apparently (February 2010), Biogen Idec/Elan issued a statement to medical professionals. It mentions 31 PML cases.

http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con075954.pdf
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PostPosted: Fri Mar 12, 2010 7:19 pm    Post subject: Reply with quote

The Rocky Mountain MS Center eMS News, March 11, 2010, contains an announcement of a study designed to test whether Tysabri can be delivered subcutaneously in the patient's home instead of by IV at an infusion center. It is an 8-month study, and more details about it are available here.

The study is sponsored by BiogenIdec.
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PostPosted: Thu Mar 18, 2010 6:32 pm    Post subject: 42 cases of PML now (a complete article this time) Reply with quote

From the Dow Jones Newswire via http://www.lloyds.com:

Quote:
Biogen: Now 42 Cases Of Brain Infection In Tysabri Patients

By Thomas Gryta
Of DOW JONES NEWSWIRES


NEW YORK -(Dow Jones)- Biogen Idec Inc. (BIIB) disclosed seven more cases of a rare brain infection in multiple sclerosis patients using Tysabri, which it sells with Elan Corp. (ELN), bringing the total number of cases to 42 as of last Wednesday.


Another patient with the infection has died, bringing the total deaths to nine in patients that have developed progressive multifocal leukoencephalopathy, or PML, according to the Cambridge, Mass., biotech company.


Tysabri is considered a highly effective therapy for MS, and its growth is important to the future of both Elan and Biogen. But its sales have been slower than originally hoped because of concerns about the risk of PML, concerns that led to its 18-month market withdrawal beginning in 2005.


Of the total number of cases, 15 were in the U.S., 24 were in the European Union and three were in other areas. Biogen gave its last update in mid-February.


In January, the Food and Drug administration provided a safety update that noted an increased risk of getting PML as the number of infusions of the medicine increase. The agency concluded that the benefits of the medicine continue to outweigh the risks.


The number of cases is important because if the infection rate climbs too high, sales of the drug may drop.


Tysabri's withdrawal from the market occurred after three patients developed PML. The infection re-emerged in mid-2008, and Biogen provided regular updates about the cases until mid-2009. The company began providing monthly updates last month.


-By Thomas Gryta, Dow Jones Newswires; 212-416-2169; thomas.gryta@dowjones.com







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PostPosted: Fri Mar 19, 2010 10:54 pm    Post subject: (Abstr.) Tysabri + Avonex reduces lesion formation... Reply with quote

From PubMed, March 19, 2010:

Quote:
J Neurol Sci. 2010 Mar 15.

Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis

Radue EW, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Rudick RA, Lublin FD, Weinstock-Guttman B, Wynn DR, Fisher E, Papadopoulou A, Lynn F, Panzara MA, Sandrock AW; for the SENTINEL Investigators.

Medical Image Analysis Center (MIAC), University Hospital Basel, Schanzenstrasse 55, 1st Floor, CH 4031, Basel, Switzerland.

The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here.

Patients received natalizumab 300mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNbeta-1a 30microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p<0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2years (1821.3mm(3) versus 2210.5mm(3); p<0.001), a smaller mean number of new T1-hypointense lesions over 2years (2.3 versus 4.1; p<0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone.

PMID: 20236661


I'm not sure how this squares with the idea that was being bandied about among the experts a while back--to the effect that Tysabri is safe only as monotherapy....
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PostPosted: Sat Mar 20, 2010 7:09 pm    Post subject: (Abstract) Tysabri-associated PML in PwMS... Reply with quote

From PubMed, March 20, 2010:

Quote:
Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases.

Lancet Neurol. 2010 Apr;9(4):438-446

Authors: Clifford DB, Deluca A, Simpson DM, Arendt G, Giovannoni G, Nath A

BACKGROUND:


Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients.

RECENT DEVELOPMENTS:

The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6-80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk.

Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case.

Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML.

WHERE NEXT?:

Diagnosis of natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.

PMID: 20298967
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PostPosted: Sat Mar 20, 2010 7:26 pm    Post subject: (Abstract) PML & other disorders caused by JC virus... Reply with quote

From PubMed, March 20, 2010:

Quote:
Lancet Neurol. 2010 Apr;9(4):425-437.

Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis

Tan CS, Koralnik IJ.

Division of Viral Pathogenesis, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Division of Infectious Diseases, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Medicine, Division of NeuroVirology, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Progressive multifocal leukoencephalopathy (PML) is a rare but often fatal brain disease caused by reactivation of the polyomavirus JC. Knowledge of the characteristics of PML has substantially expanded since the introduction of combination antiretroviral therapy during the HIV epidemic and the development of immune reconstitution inflammatory syndrome (IRIS) in patients with PML.

Recently, the monoclonal antibodies natalizumab, efalizumab, and rituximab-used for the treatment of multiple sclerosis, psoriasis, haematological malignancies, Crohn's disease, and rheumatic diseases-have been associated with PML.

Additionally, the JC virus can also lead to novel neurological disorders such as JC virus granule cell neuronopathy and JC virus encephalopathy, and might also cause meningitis.

The increasingly diverse populations at risk and the recent discovery of the presence of the JC virus in the grey matter invite us to reappraise the pathogenesis of this virus in the CNS.

PMID: 20298966
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PostPosted: Wed Apr 14, 2010 8:47 pm    Post subject: AAN: MS patients need backup when stopping Tysabri Reply with quote

From MedPage Today, April 12, 2010:

Quote:
AAN: MS Patients Need Backup when Stopping Natalizumab

By Ed Susman, Contributing Writer, MedPage Today
Published: April 12, 2010
Reviewed by Ari Green, MD; Assistant Professor, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner


Doctors should discuss risks and benefits of stopping natalizumab therapy, but some form of continued therapy is recommended.



TORONTO -- If multiple sclerosis patients are taken off treatment with natalizumab (Tysabri), their doctors should have a 'Plan B' therapy to prevent relapses and other sequelae, researchers said here.

In reviewing the latest reports on treatment with natalizumab, John Corboy, MD, professor of neurology at the University of Colorado School of Medicine in Denver, noted that one small study from researchers in Texas (Stuve, et al Neurology 2009; 72: 396-401) showed few ill effects as a result of stopping natalizumab.

"They seem to be just fine," Corboy said, "but all these patients were put on interferon or other things."

However, he noted that researchers in Boston observed that if patients are not put on interferon regimens, a significant number on a so-called drug holiday began to show MRI lesions and started having relapses after about 60 to 90 days.

"So if you are going to take someone off natalizumab, you probably should have a plan to substitute something else in order to avoid so-called immune reconstitution inflammatory syndrome and relapses," Corboy said in his presentation at the annual meeting of the American Academy of Neurology here.

The main reason for discontinuing natalizumab, he said, is concern about development of life-threatening progressive multifocal leukoencephalopathy (PML). A lingering concern remains that putting patients on an alternative therapy may not mitigate the risk of PML and allow for recovery of immune surveillance.


"As of March 9 there have been 42 confirmed cases of PML among patients exposed to natalizumab. There has been one case of PML that occurred with less than one year's use of natalizumab. All the other cases occurred with more than a year's use," Corboy said. "Strangely, while most of the use of natalizumab is in the U.S., most of the cases are in Europe for reasons that are not clear."

He said about 58% of the use of natalizumab is in the U.S., but about 70% of the cases of PML have occurred among European patients. Full information on all the patients is not known, but 11 of these individuals have died, he said.

"It may have to do with higher exposure to JC virus or they may have something different about their uses of immunosuppressants. All the patients who had serologies done ahead of time were positive for JC virus prior to starting natalizumab," Corboy said.

The JC virus -- formerly known as papovavirus -- was discovered in 1971 and named after the two initials of a patient with PML. The virus causes PML and other diseases in cases of immunodeficiency.

Corboy suggested that knowing JC virus status would allow clinicians to stratify natalizumab therapy -- perhaps stopping after a year for those patients positive for the virus and continuing longer for virus-negative patients. "There hopefully is going to be a serology test available this year" that will help clinicians determine patients' JC virus status, he said.

He noted that PML risk increases over time. Only one case in 60,000 occurs in the first year, but then cases increase to less than one in 1,000 as infusions increase, he said.

Other complications seen among patients on natalizumab include toxoplasmosis. In addition, two patients have been reported with primary central nervous system lymphoma; whether that is specifically linked to natalizumab is not clear.

Lily Jung, MD, medical director of the neurology clinic and chief of neurology at Swedish Medical Center, Seattle, said that if doctors want to stop natalizumab because of concern over risk of PML, a backup plan is necessary.

"If you look at why patients are started on natalizumab, it is because the first-line disease-modifying therapy has failed or the patients have such aggressive disease that the clinician thinks the benefits of natalizumab outweigh the risks," she told MedPage Today.

"If you stop natalizumab because of fear of PML -- and the risk is debated among neurologists -- you still have to treat the multiple sclerosis."

Jung said that clinicians and patients are caught in a bind because in aggressive disease there are not many viable choices, and there are no guarantees that drugs in the pipeline are going to be any safer than current medications.

---------------------------
Corboy disclosed financial relationships with Orasi, Novartis, Lilly, Peptimmune and Genentech.

Jung reported no financial disclosures.


Primary source: American Academy of Neurology
Source reference:
"2FC.002 Neurology Update I, April 11, 2010" AAN 2010; pp. 132-35.



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PostPosted: Thu Apr 15, 2010 6:16 pm    Post subject: (AAN abstract) Tysabri & risk of melanoma... Reply with quote

Presented at the annual AAN conference in Toronto, April 10-17, 2010:

Quote:
Natalizumab and Risk of Melanoma: A Prospective Follow-Up of Patients Treated by Natalizumab for Multiple Sclerosis

Emeline Castela, Christine Lebrun Frenay, Muriel Laffon, Fanny Rocher, Thierry Passeron, Nice, France

OBJECTIVE:

To follow melanocytic lesions under natalizumab treatment in multiple sclerosis (MS) patients.

BACKGROUND:


Recently, five cases of melanomas complicating natalizumab treatment have been reported. Although they are not definitely related with natalizumab treatment, severity of such potential adverse events requires further investigations.

DESIGN/METHODS:


Prospective follow-up of the cohort of MS patients treated with natalizumab in our center (Nice, France), since March 2008. Clinical dermatologic examination and videodermoscopy were performed every 6 months.

RESULTS:

Forty-two patients were included (31 women and 11 men). The mean age was 35 at inclusion (18-58). The mean delay between the onset of the follow up and the first perfusion was 4.7 months (0-22). To date, examination was performed once for 14 patients, twice (6 months follow-up) for 17 patients, three times (12 months follow-up) for 8 patients and four times (18 months follow-up) for 3 patients. Eighteen patients had fair skin (phototypes I or II). One patient had a familial history of melanoma and one patient had a personal history of melanoma. 156 melanocytic lesions had been examined and followed. Fourteen lesions (9.0%) showed modifications over time. Only 5.8% presented substantial dermoscopical changes. Five lesions were removed. All of them were classified as benign after histological examination.

CONCLUSIONS/RELEVANCE:

Our results showed the same rate of clinical and dermoscopical changes of nevi under natalizumab treatment as compared to the spontaneous evolution of nevi reported in literature. Fundamental data suggest a link between integrin alpha-4 beta-1 and the invasiveness of melanoma but none showed that inhibiting this integrin might promote the transformation of melanocytic lesions.

Thus, we can hypothesize that if natalizumab has an action on melanoma it could only be by promoting the invasiveness of a preexisting melanoma. Our data are consistent with this hypothesis showing no increased modification of nevi under natalizumab treatment.

Category - MS and Related Diseases - Clinical Science

Wednesday, April 14, 2010 7:30 AM

Poster Session III: Multiple Sclerosis and Related Diseases: MRI Diverse (7:30 AM-12:00 PM)
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PostPosted: Thu Apr 15, 2010 6:29 pm    Post subject: (AAN abstract) PML w/Tysabri treatment of MS Reply with quote

Presented at the annual AAN conference in Toronto, April 10-17, 2010:

Quote:
Progressive Multifocal Leukoencephalopathy with Natalizumab Treatment of Multiple Sclerosis

David B. Clifford, Saint Louis, MO, Andrea DeLuca, Rome, Italy, David Simpson, New York, NY, Gabriele Arendt, Duesseldorf, Germany, Gavin Giovannoni, London, United Kingdom, Avindra Nath, Baltimore, MD

OBJECTIVE:

Characterize progressive multifocal leukoencephalopathy (PML) presenting in natalizumab treated multiple sclerosis (MS) patients.

BACKGROUND:

Treatment of MS with natalizumab is complicated by rare cases of PML. These will inform future decisions about risk benefit judgments, early diagnosis, and optimal management.

DESIGN/METHODS:


24 cases reported from the approval of natalizumab in June 2006 to October 27, 2009 from MedWatch records, published reports, and contact with many of the treating physicians were reviewed. Data on the exposed population was obtained from Biogen Idec to estimate risk. Prior treatments, duration of exposure, presenting symptoms, and mode of therapy have been summarized.

RESULTS:

Risk of PML increases with duration of exposure through the first three years of treatment. (Incidence/ 1000 patients with 1-12 infusions, 13-24 infusions, and 25-36 infusions (95% CI) of 0.035 (0.00,0.19), 0.34 (0.14, 0.69), 1.34 (0.75, 2.21)) Duration of exposure to onset of symptoms has been 12 - 80 months (median 25). Presenting symptoms include change in cognition, personality, and motor performance.

Clinical diagnosis was established in all cases. In more than half, JC viral loads in the CSF were <500 copies. MR scans in some showed gadolinium contrast enhancement at diagnosis. Management has routinely employed plasma exchange. Exacerbation of symptoms has occurred with apparent immune reconstitution inflammatory syndrome (IRIS) within days to weeks following plasma exchange. Treatments used included corticosteroids, mirtazapine, mefloquine, IVIG.

Four deaths occurred, associated with higher JC viral titers, or lesions in critical brain regions.

CONCLUSIONS/RELEVANCE:

Experience with natalizumab-associated PML demonstrates that [for?] up to three years the incidence increases with duration of exposure, with an incidence of approximately 1:1000 in patients treated for 2 to 3 years. Diagnosis requires clinical vigilance, reliable, sensitive quantitative JC PCR test, and broadened criteria for MR recognition of PML lesions, including contrast enhancement. Universal IRIS reactions require aggressive management with corticosteroids.

Category - Infections/AIDS/Prion Disease - Other

Wednesday, April 14, 2010 9:00 AM

Plenary Session: Contemporary Clinical Issues (9:00 AM-12:00 PM)



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PostPosted: Fri Apr 16, 2010 3:11 pm    Post subject: Total PML cases at 46, 11 deaths as of April 6 Reply with quote

From www.nasdaq.com, April 15, 2010:

Quote:

Biogen: Total PML Cases At 46, Deaths At 11 As Of April 6



By Thomas Gryta, Of DOW JONES NEWSWIRES

NEW YORK -(Dow Jones)- Biogen Idec Inc. disclosed four more cases of a rare brain infection in multiple sclerosis patients on Tysabri, which it sells with Elan Corp., bringing the total number of cases to 46 as of April 6.

The Cambridge, Mass., biotech company also reported two additional deaths in patients that have developed progressive multifocal leukoencephalopathy, or PML, bringing the total to 11.

Tysabri is considered a highly effective therapy for MS, and its growth is important to the future of both Elan and Biogen. But its sales have been slower than originally hoped amid concerns about the risk of PML that led to its 18-month market withdrawal beginning in 2005.

"The overall global rate generally falls within the 1-in-1,000 rate previously seen in clinical trials," Biogen spokeswoman Naomi Aoki said. That rate is what is implied on the drug's label.

Shares of Biogen recently traded down 1.2% to $54.33, while Elan's American depositary shares dropped 3.6% to $7.78. Biogen is scheduled to report first- quarter results Tuesday and Elan will do the same Wednesday.

Of the new cases, 17 were in the U.S., 26 were in the European Union and three were in other areas.

Biogen provides monthly updates on the number of PML cases, giving its last update in mid-March.

A patient's risk of getting PML increases with the number of monthly infusions that he or she receives, something that the Food and Drug Administration highlighted in a January safety update. The agency concluded that the benefits of the medicine continue to outweigh the risks.

The most recent update translates to about 1.33 cases per 1,000 patients on the drug for between two and three years. That figure has dropped for the past two months, coming in at 1.36 in mid-March and at 1.56 in mid-February.

The incidence is about 0.33 case per 1,000 patients in those using it for one to two years, and it is almost nonexistent in patients using less than a year.

The number of cases is important because if the infection rate climbs too high, sales of the drug may drop.

For patients on the drug for a year or longer, the rate is 1.1 cases per 1, 000, but rises to 1.53 per 1,000 for those on the drug for two years or longer.

Tysabri's withdrawal from the market occurred after three patients developed PML. The infection re-emerged in mid-2008, and Biogen provided regular updates about the cases until mid-2009. The company began providing monthly updates in mid-February.

-By Thomas Gryta, Dow Jones Newswires; 212-416-2169; thomas.gryta@dowjones.com




I was providing the link but now the link no longer works. I'm getting "Page not found." However, the informal PML reporting site, chefarztfrau, lists the 46 cases as of this month--26 in the EU, 17 in the US, and 3 in other areas.
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PostPosted: Tue Apr 20, 2010 6:12 pm    Post subject: (Article) Biogen races to create test for JC virus Reply with quote

From the San Francisco Chronicle, April 9, 2010:

Quote:

Biogen Races to Create Test for Brain Disease Linked to MS Drug




By Elizabeth Lopatto

Biogen Idec Inc. wants to take the fear out of prescribing its multiple sclerosis treatment Tysabri with a test that can tell patients their odds of getting a deadly brain illness from the drug.

The screening tool could be marketed as early as 2011 if clinical trials involving 9,000 people, set to start this year, show a low rate of false findings, said Naomi Aoki, a spokeswoman for the Cambridge, Massachusetts-based biotechnology company. The test is designed to detect the JC virus that causes progressive multifocal leukoencephalopathy, or PML, a brain-cell destroyer that can lead to disability and death.

...

If the test works, it is "absolutely a game changer," said Patricia O'Looney, vice president of biomedical research at the New York-based National Multiple Sclerosis Society, in a telephone interview. "If Biogen can validate it, that takes out the guessing game."

...

'Longer-Term Positive'

It's too early to set a dollar amount on the potential gain in drug sales based on such a test until the clinical trials are completed said Geoffrey Meacham, an analyst for J.P. Morgan in New York, in a telephone interview. A successful test that determines Tysabri is safe to use in some patients would be "a longer-term positive" for the company, he said.

...

Behind Goal

Since the therapy returned to the market in 2006, the company hasn't reached its goal to have 100,000 patients use it by the end of 2010. Tysabri is used by about 48,800 patients as of the end of 2009, according to Biogen. The company backed away from the goal last year, after a fifth patient developed PML.

About 200 new cases of multiple sclerosis are diagnosed weekly in the U.S., according to the National Institutes of Health. Patients, at first diagnosis, typically are prescribed Biogen's Avonex; Rebif, made by Darmstadt, Germany-based Merck KGaA; Betaferon, made by Bayer AG, of Leverkusen, German; and Copaxone, by Israel-based Teva Pharmaceutical Industries Ltd.

While less effective than Tysabri, these drugs all carry fewer side-effects, Meacham said.

Biogen plans two clinical trials to determine the rates of false positives and false negatives. For patients who test positive, the risk of PML will be about 1 in 500, said Robert Fox, a neurologist at the Cleveland Clinic in Ohio. For those who test negative, though, the risk is "quite low," Biogen's Sandrock said.

MS Millions

...

PML 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.

In February, the FDA updated Tysabri's labeling to clarify its risks. The number of infections and deaths from PML remains about 1 in 1,000 overall. The rate is higher outside the U.S., with 2 of every 1,000 patients contracting the illness. The reason for the difference is unknown, the FDA said.

Antibody Presence

The test is designed to detect the presence of an antibody to the JC virus in the blood of patients, signaling that the patient has been infected.

With a false-negative rate of 2 percent, patients who are free of the virus would lower their risk of getting the brain disorder PML to 1 in 25,000 for the first three years of their Tysabri therapy, wrote analyst Joshua Schimmer of Leerink Swann, in a March 25 note to investors.

Since a patient may become infected with the JC virus at any time (it is passed through the air), part of Biogen's task in its clinical trials is to determine how many patients become infected over time. This determination changes the odds that any one patient may get the disease.

Probably about 1 to 2 percent of patients will be infected yearly, Sandrock said.

Antibody Reliability

Eugene Major, a researcher at the National Institutes of Health in Bethesda, Maryland, said that when the NIH and others tested for the presence of the virus, rather than antibodies, they found that at least 70 percent of the population probably is infected. The company, based on antibody testing, has put that number at 50 percent.

"They're underestimating the number of people who've been exposed," Major said in a telephone interview. "We have strong evidence that the overwhelming majority, especially after the third and fourth decade, have been exposed."

Biogen is looking at other biological signs of PML risk that may be incorporated to improve the test, Sandrock said. In those who test positive, Biogen is testing for markers to further determine which patients are at high risk, Sandrock said. Those markers may include certain genes that increase the risk of a brain infection, or viral mutation that allows JC virus to live in brain tissue.

"We know a lot about the benefits of Tysabri, and we know something about the risk," said Sandrock. "If we can be specific about an individual's risk versus an individual's benefit, that would help patients make better-informed treatment decisions. Patients want to know, 'what's my risk?'"

--Editors: Angela Zimm, Lisa Rapaport



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PostPosted: Sat May 08, 2010 6:57 pm    Post subject: (Abstract) Early EEG changes in Tysabri-associated PML Reply with quote

From Multiple Sclerosis, May 7, 2010:

Quote:
Early changes on electroencephalography in natalizumab-associated progressive multifocal leucoencephalopathy

Ingo Kleiter1*, Michael Schröder1, Ralf Lürding1, Gerhard Schuierer2, David B. Clifford3, Ulrich Bogdahn1, Andreas Steinbrecher4, and Peter Pöschl1

1 Department of Neurology, University Medical Center Regensburg, Universitätsstraße 84, 93053 Regensburg, Germany
2 Center of Neuroradiology, University Medical Center and Bezirksklinikum Regensburg, Universitätsstr. 84, 93053 Regensburg, Germany
3 Department of Neurology and Medicine, Washington University, 660 S. Euclid Ave, St.Louis, MO 63110, USA
4 Dept. of Neurology, Uni. Medical Center Regensburg, Universitätsstraße 84, Germany/Dept. of Neurology, Helios Med. Center Erfurt, Nordhäuser Straße 74, Germany



* To whom correspondence should be addressed. E-mail: ingo.kleiter@klinik.uni-regensburg.de.


Progressive multifocal leucoencephalopathy has become a growing concern in natalizumab-treated multiple sclerosis patients. Here, we describe a 35-year-old patient who was treated with 34 infusions of natalizumab before complaining about visual deterioration. MRI was non-diagnostic and JC virus testing initially was negative.

Electroencephalography showed severe slowing of the right hemisphere, and neuropsychological testing revealed right frontal and temporal deficits. The diagnosis of progressive multifocal leucoencephalopathy was established 2 months later by typical MRI presentation and detection of JC virus DNA in the cerebrospinal fluid. Functional neurological deficits may precede imaging features and should prompt early consideration of progressive multifocal leucoencephalopathy.



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PostPosted: Mon May 17, 2010 12:44 pm    Post subject: (Abstract) Hydrocephalus during Tysabri treatment Reply with quote

From PeerViewInstitute, May 17, 2010:

Quote:
Neurol Sci. 2010 May 8.

Hydrocephalus during natalizumab treatment

Zecca C, Städler C, Gobbi C.

Servizio Cantonale di Neurologia, Ospedale Civico, via Tesserete 46, 6903, Lugano, Switzerland, chiara.zecca@eoc.ch.


Natalizumab is a humanized monoclonal antibody recently approved for multiple sclerosis treatment. Although generally well tolerated and efficacious in multiple sclerosis treatment, it raised concerns after the occurrence of some cases of progressive multifocal leucoencephalopathy in exposed patients.

Extensive and prolonged use of natalizumab could unmask further unexpected side effects. We describe the case of a woman suffering from multiple sclerosis who experienced an acute tetra-ventricular hydrocephalus soon after the beginning of immunomodulating treatment with natalizumab. The patient was also affected with a VIII cranial nerve Schwannoma treated with stereotactic radiosurgery 2 years before, with subsequent clinical and radiological stabilization.

The strict temporal correlation between clinical worsening and natalizumab therapy points to a possible triggering role of the drug in the pathogenesis of hydrocephalus in our patient. Treating neurologists should be aware of this possible complication in selected subsets of patients.

PMID: 20454819


The abstract can be seen here.
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PostPosted: Sat May 22, 2010 7:10 pm    Post subject: PML underdiagnosed in MS patients in Tysabri? Reply with quote

The Lancet Neurology, June 2010 (vol. 9, issue 6 p. 564) has an interesting exchange in the Letters section:

Quote:
PML: underdiagnosed in MS patients on natalizumab

Israel Steiner
Department of Neurology, Rabin Medical Center, Petach Tikva, 49100, Israel

I read with interest the comprehensive Rapid Review by Clifford and colleagues1 on progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) who were treated with natalizumab, but their analysis did not seem to take into account the possibility that, at present, PML is underdiagnosed. The most important fact that supports this possibility is the disparity in incidence between Europe and the USA. Of 28 patients who were diagnosed with PML up to December, 2009, 18 were European and only ten were from the USA, even though the number of patients who received natalizumab was much higher in the USA. The authors suggest that this discrepancy might be attributed to an increased use of immunosuppressant therapies in European patients with MS, but the data do not seem to support this explanation. Of the 26 patients in whom information on previous therapies is available, 14 of 16 European patients and nine of ten US patients had previous therapies. The relative number of patients who received only immunomodulatory drugs in both groups is also similar. Therefore, there seems to be no noticeable difference in previous therapies between the two groups.

Identification of early PML in patients with active MS is sometimes challenging. A patient with MS with a known active course and receiving natalizumab therapy might present with new symptoms and signs, and imaging might disclose a relevant new demyelinating lesion. If this patient is not deemed to be responding to natalizumab therapy but instead having an MS relapse, treatment will be stopped and the patient switched to an alternative therapy. Without PCR analysis of the CSF, stringent follow-up, and, when required, brain biopsy, diagnosis of PML will be missed. This omission is particularly relevant because cessation of natalizumab therapy might be associated with an arrest of PML progression.

Therefore, under the current surveillance protocol,2 many cases of PML might go undiagnosed and the true incidence of this devastating side-effect underappreciated. Several protocol amendments might reduce this risk: patients who are scheduled to receive natalizumab should have their CSF examined for the JC virus before initiation of therapy and at regular intervals thereafter;3 every clinical relapse under natalizumab therapy should be regarded as a possible presentation of PML and assessed accordingly; and only established and validated laboratories should be used to evaluate CSF viral load.

I have no conflicts of interest.

References

1 Clifford DB, DeLuca A, Simpson DM, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010; 9: 438-444.

2 Biogen Idec. The TYSABRI TOUCH Prescribing Program. http://www.tysabri.com/tysbProject/tysb.portal/_baseurl/threeColLayout/SCSRepository/en_US/tysb/home/treatment-with-tysabri/touch-prescribing-program.xml. (accessed April 2, 2010).

3 Sadiq SA, Puccio LM, Brydon EW. JCV detection in multiple sclerosis patients treated with natalizumab. J Neurol 201010.1007/s00415-009-5444-4. published online Jan 7.



The authors reply (in the same issue, pp. 565-565.

Quote:
PML: underdiagnosed in MS patients on natalizumab — Authors' reply

David B Clifford a, Avindra Nath b

We thank Steiner for his comments; however, we believe that it is unlikely that progressive multifocal leukoencephalopathy (PML) is underdiagnosed in the setting of natalizumab therapy. Steiner's main argument about the effect of previous therapy might stem from different definitions of chemotherapy for multiple sclerosis. The use of previous chemotherapy (excluding interferons and glatiramer acetate) in Europe was twice that of patients on natalizumab in the USA (22% vs 12%; Bozic C, Biogen Idec, personal communication). Assuming such therapy increases the risk for developing PML, this could be consistent with the increased number of cases in Europe compared with those in the USA. Of 16 European cases of PML, nine (56%) had received previous chemotherapy. In the USA, five of ten cases of PML (50%) had received chemotherapy. The proportion of patients with a history of chemotherapy who developed PML after treatment with natalizumab is similar, but the number of patients at risk was higher in Europe (22%), which might explain the higher number of PML cases in that population.
We agree that recognition of PML in patients with multiple sclerosis (MS) is challenging, and hope that our Rapid Review1 will encourage active assessment of any new lesion in a patient on natalizumab. We believe that it is unlikely that PML would be mistaken for MS in these patients. If a patient with PML was misdiagnosed and continued to receive natalizumab treatment, then the PML would progress and would reliably force an alternative diagnosis. Cases in which natalizumab has been withdrawn have clearly indicated that withdrawal is followed by vigorous immune reconstitution inflammatory syndrome (IRIS) that exacerbates the signs and symptoms over several months, and would also be likely to necessitate reassessment of the diagnosis. If the IRIS reaction was mild and easily responded to corticosteroids, confusion of PML with MS could be more likely.

Any differences in incidence between Europe and the USA are also unlikely to be due to geographic differences in diagnostic skills or effort. Risk management programmes in both regions provide extensive education about the risk of PML with natalizumab treatment, and we believe that neurologists have gained an increased awareness of this complication recently. Uniform administration of natalizumab in a few specifically trained infusion centres with monthly surveillance of patients is required in the USA, but not in Europe, and should if anything enhance the detection of PML in the USA.

We disagree with the contention that routine CSF examination for the JC virus at baseline would contribute to better risk assessment. Even in patients with active PML, it is difficult to confirm the diagnosis with CSF examination because of very low JC viral loads in at least half of these patients. The CSF is negative for the JC virus in patients without active PML lesions, and repeating lumbar puncture at frequent intervals is an impractical screening method for early diagnosis. We agree, however, that every clinical relapse while on natalizumab treatment must be considered as a possible PML case, and careful assessment including MRI of the brain and examination of the CSF is appropriate. As we pointed out in our Rapid Review, CSF examination should be done with a reliable and sensitive PCR assay.

DBC has advisory board membership with Genzyme and has received consultancy fees from Biogen Idec, Genentech, Pfizer, and Millennium (all <$10 000 per year). He has received travel expenses from and has grants or grants pending with Biogen Idec. AN has received consultancy fees from Biogen Idec.

References

1 Clifford DB, DeLuca A, Simpson DM, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010; 9: 438-446.

a Department of Neurology, Washington University in St Louis, St Louis, MO, USA
b Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
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PostPosted: Wed Jun 16, 2010 7:42 pm    Post subject: Now 55 PML cases (6 more as of June 7) Reply with quote

From MSNewsChannel.com, June 16, 2010:

Quote:
Wednesday, June 16

Biogen Reports 6 More Brain Infection Cases In Tysabri Users(Posted By: Josi Creek)



-Biogen Idec Inc. (BIIB) disclosed six more cases of a rare brain infection in multiple sclerosis patients on Tysabri, which it sells with Elan Corp. (ELN), bringing the total number of cases to 55 as of June 7.

The Cambridge, Mass., biotech company reported no additional deaths in patients that have developed progressive multifocal leukoencephalopathy, or PML, keeping the total at 11.

Tysabri is considered a highly effective therapy for MS, and its sales growth is important to the future of both Biogen and Elan. But sales have been slower than first anticipated because of concerns about the risk of PML, which led to the drug's 18-month market withdrawal beginning in 2005.

The overall global rate of PML infection is about 0.77 per 1,000 patients, Biogen said, which falls within the 1-in-1,000 rate previously seen in clinical trials and implied on the drug's label.
Shares of Biogen added 23 cents Wednesday to $48.35, while the American Depositary Shares of Elan slid 11 cents to $5.04.

Of the 55 cases Biogen reported, 20 were in the U.S., 32 in the European Union and three in other areas.

Biogen provides monthly updates on the number of PML cases in patients taking Tysabri.

A patient's risk of getting PML increases with the number of monthly infusions that he or she receives, something the Food and Drug Administration highlighted in a January safety update. The agency concluded that the benefits of the medicine continue to outweigh the risks.

The most recent monthly update translates to a rate of 1.24 cases per 1,000 for patients on the drug for a year or longer, but rises to 1.76 per 1,000 for those on the drug at least two years.

The rate of incidence is about 0.35 cases per 1,000 patients on the drug for between one and two years and 1.47 per 1,000 for those taking the drug between two and three years.


The article can be seen here.
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PostPosted: Wed Jun 23, 2010 5:43 pm    Post subject: (Abstract) Early EEG changes in Tysabri-related PML Reply with quote

From Multiple Sclerosis, June 1, 2010:

Quote:
Early changes on electroencephalography in natalizumab-associated progressive multifocal leucoencephalopathy

Ingo Kleiter
Department of Neurology, University Medical Center Regensburg, Germany, ingo.kleiter@klinik.uni-regensburg.de

Michael Schröder

Department of Neurology, University Medical Center Regensburg, Germany

Ralf Lürding

Department of Neurology, University Medical Center Regensburg, Germany

Gerhard Schuierer

Center of Neuroradiology, University Medical Center and Bezirksklinikum Regensburg, Germany

David B Clifford

Department of Neurology and Medicine, Washington University, USA

Ulrich Bogdahn

Department of Neurology, University Medical Center Regensburg, Germany

Andreas Steinbrecher

Department of Neurology, University Medical Center Regensburg, Germany/Department of Neurology, Helios Medical Center, Erfurt, Germany

Peter Pöschl

Department of Neurology, University Medical Center Regensburg, Germany

Progressive multifocal leucoencephalopathy has become a growing concern in natalizumab-treated multiple sclerosis patients. Here, we describe a 35-year-old patient who was treated with 34 infusions of natalizumab before complaining about visual deterioration. MRI was non-diagnostic and JC virus testing initially was negative.

Electroencephalography showed severe slowing of the right hemisphere, and neuropsychological testing revealed right frontal and temporal deficits. The diagnosis of progressive multifocal leucoencephalopathy was established 2 months later by typical MRI presentation and detection of JC virus DNA in the cerebrospinal fluid.

Functional neurological deficits may precede imaging features and should prompt early consideration of progressive multifocal leucoencephalopathy.






Multiple Sclerosis, Vol. 16, No. 6, 749-753 (2010)



The abstract can be seen here.
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PostPosted: Tue Jun 29, 2010 1:13 pm    Post subject: (Abstract) Swedish Tysabri MS surveillance study Reply with quote

From PeerView Institute, June 29, 2010:

Quote:


Neurol Sci. 2010 Jun 16.

Swedish natalizumab (Tysabri) multiple sclerosis surveillance study

Piehl F, Holmén C, Hillert J, Olsson T.

Department of Clinical Neuroscience, Karolinska Institutet, 171 76, Stockholm, Sweden, fredrik.piehl@ki.se.


A post-marketing surveillance program was implemented to monitor the safety and open-label efficacy of natalizumab since its launch in Sweden August 2006. Patients are registered in the Swedish multiple sclerosis (MS)-registry that has a nationwide coverage using a standardized follow-up that includes EDSS, MSSS, SDMT, MSIS-29, and recording of adverse events (AEs).

As of 31 January, 2010, 1,115 patients had been included, of which 363 were treated >/=24 months. Dropout rate was 10%, mainly due to planned pregnancy.

Serious AEs were rare, but included three cases of progressive multifocal leukoencephalopathy (PML), none of which had received previous immunosuppressive therapy. All analyzed clinical outcome parameters showed significant improvements compared to baseline for patients exceeding 24 months of treatment.

Our results demonstrate good general tolerability and sustained efficacy of natalizumab for patients with severe MS, though the risk of PML remains a concern.

PMID: 20556456
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PostPosted: Mon Jul 12, 2010 5:54 pm    Post subject: (Abstract) Successful management of PML... Reply with quote

From Archives of Neurology, July 12, 2010:

Quote:
Successful Management of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy and Immune Reconstitution Syndrome in a Patient With Multiple Sclerosis

Alexandra Schröder, MD; De-Hyung Lee, MD; Kerstin Hellwig, MD; Carsten Lukas, MD; Ralf A. Linker, MD; Ralf Gold, MD

Objective

To describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis.

Design

Case report.

Setting

University hospital.

Patient

A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions.

Interventions

Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids.

Results

After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML.

Conclusions


In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.


Author Affiliations:

Departments of Neurology (Drs Schröder, Lee, Hellwig, Linker, and Gold); and Radiology (Dr Lukas), St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.





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PostPosted: Fri Jul 16, 2010 5:22 pm    Post subject: Total PML cases now 58, with one new death Reply with quote

From PharmaTimes, July 16, 2010 (this is part of a longer article about Elan):

Quote:
Three more cases of PML with Tysabri

...Meantime, in their monthly update, Elan and partner Biogen Idec announced that there were a further three cases of the brain infection progressive multifocal leukoencephalopathy confirmed in June linked to use of their multiple sclerosis blockbuster Tysabri,(natalizumab). This brings the total to 58.

This is a lower number of cases than the previous month (six); however, one more patient has died, bringing that total up to 12. Interestingly, Mr Hunter noted, the incidence rate in patients on the drug for two years or over has moderated slightly this month, slipping to 1.71 per 1,000 for patients that have received 24 or more infusions (down from 1.76) and 1.46 (was 1.50) for patients on 30 or more infusions.

He added that for the first time, the companies have been able to provide data on patients on 42 or more infusions, where the rate is 1.07 per 1,000, but with “very wide confidence intervals (0.29 to 2.74), undoubtedly because of low patient numbers”. He concluded that this is a more encouraging set of data points than last month, with the increase in cases lower than average and incidence rate dipping.



The article can be seen here.

According to chefarztfrau, the Website where a tally is being maintained informally, of the 3 new cases, one is in Switzerland and the other two are in the US. No information yet on the location of the most recent death.
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PostPosted: Sun Jul 18, 2010 5:17 pm    Post subject: (Rocky Mtn. MS Center) Tysabri, JC virus & PML Reply with quote

From the Rocky Mountain MS Center e-MS News, July 16, 2010:

Quote:
Tysabri, JC Virus and PML
Dr. Augusto Miravalle, Rocky Mountain MS Center at Anschutz Medical Campus

Since its initial release in 2004, Tysabri (generic name Natalizumab) has become the therapy choice of many people with MS. This, undoubtedly, is because the treatment option has a 70% efficacy rate—compared to around 30% for other therapies—and is often prescribed when a patient’s MS is quite aggressive or they’ve failed on other medications. Many people on Tysabri report that the therapy makes them feel better, and helps to control and subdue flare-ups. It is, for many, a breath of fresh air—the monthly injections seem quite manageable compared to daily or weekly injections.

All that being said, continuing safety concerns exist around Tysabri, namely because of the possible development of a brain infection, called progressive multifocal encephalopathy (PML), which is caused by the JC virus (JCV). In general terms, this brain infection causes lesions similar to the ones seen in MS. Although there are no typical symptoms suggestive of PML, severe deterioration of cognitive functions and personality changes are among the most common presentations.

Because Tysabri works by blocking the entrance of the immune cells into the brain, the risk of PML might be greater in patients receiving Tysabri. In individuals with healthy and active immune systems, there is little or no concern about PML because the body naturally fights off the infection. With a suppressed immune system, however, that natural fighting ability is weakened.

One thing that physicians and researchers do know is that some individuals are at higher risk for PML than others. One main risk factor for PML is the presence of JCV. It is estimated that between 40 and 60% of people have JCV, which they generally contract during childhood or adolescence. Symptoms of JCV—if there are any—resemble those of the common cold.

For most of the population, JCV poses no significant health risk and given the widespread presence of the virus, there are not clear strategies to decrease the exposure to this infection. For individuals on immunosuppressants such as Tysabri, however, the virus could be problematic. To date, there are no validated tests that can demonstrate the presence of JCV infection in PML cases, despite the possible connection.

In order to better understand the role of JCV in PML, MS researchers have begun to move forward with studies specifically looking at markers for JCV infection. These studies, named STRATIFY I & II, aim specifically at identifying individuals with JCV. These studies will help researchers and treating physicians weigh the benefit of Tysabri versus the risk of PML.

JCV will be tested through a simple blood test, which will register anti-JCV antibodies if the virus is present. It remains unclear exactly what a positive or negative JCV test result will mean. In order to thoroughly answer these questions, researchers first have to gather study material, analyze it, and then deduce the results. Only then will the link between JCV and PML for MS patients on Tysabri be better understood.










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PostPosted: Wed Jul 28, 2010 10:46 am    Post subject: (Abstract) Tysabri drug holiday in MS--poorly tolerated Reply with quote

From PubMed, July 28, 2010:

Quote:

Ann Neurol. 2010 Jul 26.

Natalizumab drug holiday in multiple sclerosis: Poorly Tolerated

Killestein J, Vennegoor A, Strijbis EM, Seewann A, van Oosten BW, Uitdehaag BM, Polman CH.

Department of Neurology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.

It has been suggested that natalizumab-associated progressive multifocal leukoencephalopathy may be prevented by structured interruptions of treatment. Evidence supporting such a drug holiday is not yet available.

Here we present initial observations in 10 multiple sclerosis patients who were stringently monitored up to 6 months after discontinuation of the infusions. Cumulatively, a combination of clinical relapse and new and/or enhanced lesions on magnetic resonance imaging had occurred in 7 of 10 patients.

Although numbers are small, our data suggest that in patients who were switched to natalizumab because of disease activity despite first-line treatment, a natalizumab drug holiday without reinstatement of alternate disease-modifying therapy is poorly tolerated.

PMID: 20661928


The abstract can be seen here.
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PostPosted: Fri Aug 06, 2010 10:29 am    Post subject: (Abstract) Effectiveness, safety of Tysabri for RRMS Reply with quote

From PubMed, August 6, 2010:

Quote:
Farmacia Hospitalaria. 2010 Aug 2.

[Assessment of the effectiveness and safety of natalizumab for treating relapsing-remitting multiple sclerosis.]
[Article in Spanish]

Fernández-Megía MJ, Casanova B, Magraner MJ, Font-Noguera I, Poveda-Andrés JL.

Servicio de Farmacia, Hospital Universitario La Fe, Valencia, España.


OBJECTIVE:

Assessing the effectiveness and safety of natalizumab for treating relapsing-remitting multiple sclerosis in a tertiary hospital.

METHOD:

Observational, prospective study of adult patients treated with natalizumab from May 2007 until February 2009.

TREATMENT:

300mg natalizumab every four weeks. Response criteria: assessment of disease progression, appearance of flare-ups and assessment of magnetic resonance images. Adverse reactions during treatment with natalizumab were recorded.

RESULTS:

Thirty patients (73% female); average age 34+/-8.4 years; mean baseline EDSS 3.4+/-1.3; number of flare-ups in the past year 2.1+/-1.2. Treatment was discontinued in five patients, due to refusal in one case, ineffectiveness in two cases and anaphylaxis in the other two cases. Fourteen patients completed one year of treatment with satisfactory results. A lower EDSS score by 36%, 47%, 31%, 54% and 28% was obtained at 3, 6, 9, 12 and 15 months of treatment respectively. The prevalence of relapse-free patients was 94%, 76% and 54% at 3, 6 and 12 months. MRI imaging studies in 11 patients one year after they began treatment showed no new lesions. Two patients suffered severe anaphylactic shock and another one had an outbreak of urticaria. The presence of neutralising antibodies was the reason for suspending treatment in 6.6% of the patients.

CONCLUSIONS:

The treatment's effectiveness and safety in our patient group suggest that natalizumab is a treatment for refractory patients or those with aggressive types of multiple sclerosis, although we do not yet know about its long-term effects and the evolution of the appearance of neutralising antibodies.

PMID: 20685144


The abstract can be seen here.
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PostPosted: Mon Aug 09, 2010 7:31 pm    Post subject: (Abstract) Tysabri & PML: ...can it be avoided? Reply with quote

From Archives of Neurology, August 9, 2010:

Quote:
Natalizumab and Progressive Multifocal Leukoencephalopathy
What Are the Causal Factors and Can It Be Avoided?


Clemens Warnke, MD; Til Menge, MD; Hans-Peter Hartung, MD; Michael K. Racke, MD; Petra D. Cravens, PhD; Jeffrey L. Bennett, MD, PhD; Elliot M. Frohman, MD, PhD; Benjamin M. Greenberg, MD, MSc; Scott S. Zamvil, MD, PhD; Ralf Gold, MD; Bernhard Hemmer, MD; Bernd C. Kieseier, MD; Olaf Stüve, MD, PhD


Arch Neurol. 2010;67(8):923-930. doi:10.1001/archneurol.2010.161

Natalizumab (Tysabri) was the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS). After its initial approval, 3 patients undergoing natalizumab therapy in combination with other immunoregulatory and immunosuppressive agents were diagnosed with progressive multifocal leukoencephalopathy (PML). The agent was later reapproved and its use restricted to monotherapy in patients with relapsing forms of MS. Since reapproval in 2006, additional cases of PML were reported in patients with MS receiving natalizumab monotherapy.

Thus, there is currently no convincing evidence that natalizumab-associated PML is restricted to combination therapy with other disease-modifying or immunosuppressive agents. In addition, recent data indicate that risk of PML might increase beyond 24 months of treatment.





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PostPosted: Wed Aug 18, 2010 7:54 pm    Post subject: 5 new PML cases - total now 63 Reply with quote

There have been 5 more PML cases in connection with
Tysabri, bringing the total to 63. You can read more about it here.
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PostPosted: Tue Aug 24, 2010 10:42 pm    Post subject: (Article) Test for patients at most risk of PML Reply with quote

From Boston Business Journal, August 24, 2010:

Quote:
Biogen research may reduce Tysabri risk

Biogen Idec is reporting promising early data for a potential test to help determine which patients taking [the]multiple sclerosis drug Tysabri are at greatest risk for developing a rare but serious brain infection.

Biogen and its partner, Ireland-based Elan Corporation plc, announced data has been published in the Annals of Neurology on an assay to detect antibodies to a virus known to be associated with the brain infection, known as progressive multifocal leukoencephalopathy.

The goal is to develop a test that could be used to determine which patients might be most at risk for developing PML, to alert patients and doctors to potential risks, and to improve clinical management of MS patients.

“These data support our ongoing clinical studies to assess the clinical utility of this assay and our commitment to further mitigating the rare risk of PML in Tysabri-treated patients,” Dr. Alfred Sandrock, senior vice president of neurology research and development at Biogen Idec, said in a statement.

More than 60,000 patients have taken Tysabri since the drug’s reintroduction in July 2006. Tysabri’s warning labels said the anticipated incidence rate of PML is one in 1,000, and Biogen said the current rate is still below that.

The number of cases is rising because the longer patients take the drug, the greater the risk of developing the infection, Biogen has said.

The company took Tysabri off the market between February 2005 and July 2006 because of concerns about the risk of PML. Tysabri sales reached $1 billion in 2009.




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PostPosted: Wed Sep 08, 2010 11:00 pm    Post subject: (Abstract)Tysabri dosage suspension--helping or hurting? Reply with quote

From PubMed, September 8, 2010:

Quote:


Ann Neurol. 2010 Sep;68(3):395-9.

Natalizumab dosage suspension: Are we helping or hurting?

West TW, Cree BA.

Multiple Sclerosis Center, University of California at San Francisco, San Francisco, CA.


The risk of developing progressive multifocal leukoencephalopathy increases with the duration of treatment with natalizumab. Planned dosage interruptions have been proposed as a means of decreasing cumulative risk.

The clinical consequences of dosage interruption were evaluated in a single center cohort of natalizumab-treated patients. Medical records were reviewed for 84 patients identified with multiple sclerosis who received 12 or more infusions of natalizumab at an academic multiple sclerosis center. Eighty-one percent (68/84) underwent a dosage interruption, and 19% (16/84) had no interruption in natalizumab treatment.

Of those with a treatment interruption, 27.9% (19/68) experienced a clinical relapse within 6 months of the suspension, whereas none of the patients with ongoing treatment experienced a flare during months 12 to 18 of treatment (p = 0.017, Fisher exact test). Survival analysis showed that Kaplan-Meier curves comparing dosage interruption to ongoing treatment diverged (p = 0.025). Median time from treatment interruption to relapse onset was 3 months. No clinical predictors associated with an increased risk of developing flares during dosage interruption were identified.

Among the 19 patients who had a flare, 7 had severe flares, with a mean number of 16 Gad+ lesions on brain magnetic resonance imaging (range, 6-40). Their median Expanded Disability Status Scale at natalizumab interruption was 3.0 and increased to 6.0 during the flare (p = 0.0008).

Natalizumab dosage interruption is associated with clinical flares and return of radiographic inflammatory disease activity. Some of these flares can be clinically severe, with a high number of contrast-enhanced lesions, suggesting a possible rebound of disease activity.

PMID: 20818793


The abstract can be seen here.
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PostPosted: Fri Sep 10, 2010 9:11 pm    Post subject: (Abstr.) Risk perception in PwMS on Tysabri & neuros Reply with quote

From PubMed, September 10, 2010:

Quote:


Mult Scler. 2010 Sep 8.

Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists

Heesen C, Kleiter I, Nguyen F, Schäffler N, Kasper J, Köpke S, Gaissmaier W.

Institute of Neuroimmunology and Clinical MS Research (INiMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.


Background:

Natalizumab is associated with the potentially life-threatening side-effect progressive multifocal leukoencephalopathy (PML). Little is known about patients' and physicians' risk estimates and attitudes towards natalizumab treatment.

Methods:

Consecutive natalizumab-treated patients (n = 69) and neurologists (n = 66) in two centres and cooperating private practices received an evidence-based three-page information leaflet about natalizumab-associated PML and an evaluation sheet.

Results:

After reading the information, patients were significantly more likely than physicians to intend continuation of natalizumab treatment and willing to accept higher risks of PML: 49% of physicians would stop treatment at a PML risk of 2 : 10,000 or lower, while only 17% of patients would do so (p < 0.001). This difference could not be explained by risk calculation abilities or lack of understanding. Both groups overestimated natalizumab treatment effects.

Conclusion:

Patients had a significantly worse perception of multiple sclerosis as a malignant disease. We conclude that patients were willing to accept a higher risk of PML than neurologists. Coherent with their perception of risks and benefits, patients were also more willing to continue treatment. Open information about treatment-related risks is appreciated and might support shared decision making.

PMID: 20826527


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PostPosted: Tue Sep 14, 2010 6:53 pm    Post subject: 5 more PML cases--total now 68, with 2 new deaths Reply with quote

From Nasdaq.com, September 14, 2010:

Quote:
Biogen: Five More Cases of Brain Infection In Tysabri Patients


By Thomas Gryta, Of DOW JONES NEWSWIRES

NEW YORK -(Dow Jones)- Biogen Idec Inc. (BIIB) disclosed five more cases of a rare brain infection in multiple sclerosis patients on Tysabri, which it sells with Elan Corp. (ELN), bringing the total number of cases to 68 as of Sept. 2.

The Cambridge, Mass., biotech company reported that the number of deaths among patients that have developed the infection--known as progressive multifocal leukoencephalopathy, or PML--rose by two to 14.

Sales of Tysabri are important to the future of both Elan and Biogen. The drug is considered a highly effective therapy for multiple sclerosis, but its growth has been slower than originally hoped due to concerns about the risk of PML that led to the drug's temporary withdrawal beginning in 2005.

The infection re-emerged among Tysabri patients in mid-2008, and Biogen provides monthly updates about the number cases.

The overall global PML rate is about 0.90 per 1,000 patients, the company said, which falls within the 1-in-1,000 rate previously seen in clinical trials and implied on the drug's label.

As of June 30, 52,700 patients were using the drug around the world. In total, about 71,400 patients have used the drug since its launch.

Of the total PML cases, 28 were in the U.S., 36 were in the European Union and four were in other areas. The company didn't disclose the distribution of the 14 patient deaths.

The number of cases is important because if the infection rate climbs too high, the drug's sales growth may drop. Regulators have said that they watch the cases, but have concluded that the benefits of the medicine to MS patients outweigh the risks.

Tysabri is usually used in MS patients who don't respond to earlier therapy or in patients with aggressive cases of the disease, and is distributed under a strict risk-management plan that monitors patients for PML.

The risk of the infection increases with the number of monthly infusions that a patient receives. The incidence rate appears to drop after 30 months of use, but Biogen views the drop as inconclusive, because there aren't enough patients to have confidence in that finding.

The most recent data update translates to a rate of 1.42 cases per 1,000 for patients on the drug for a year or longer, but rises to 1.86 per 1,000 for those on the drug for two years or longer.

Looked at another way, the rate is about 1.46 cases per 1,000 patients on the drug for between two and three years. The incidence is about 0.39 case per 1,000 patients in those using it for one to two years, and it is essentially nonexistent in patients using it for less than a year.

...

-By Thomas Gryta, Dow Jones Newswires; 212-416-2169; thomas.gryta@dowjones.com





The article can be seen
here.
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PostPosted: Sat Sep 18, 2010 6:33 pm    Post subject: Balancing the risks of Tysabri dosing holidays (ANA) Reply with quote

From Doctor's Guide, September 18, 2010 (also see the September 8 post in this thread):
Quote:


"Balancing the Risks of Natalizumab Dosing Holidays: Presented at ANA"

By Fred Gebhart SAN FRANCISCO

A new study may help clinicians balance the risks and potential benefits of suspending natalizumab dosing in patients with relapsing multiple sclerosis (MS), according to research presented here at the 135th Annual Meeting of the American Neurological Association (ANA). There is no clear answer, said Timothy West, MD, University of California San Francisco (UCSF) Multiple Sclerosis Center, San Francisco, California, on September 15. Continuing dosing appears to increase the risk for developing progressive multifocal leucoencephalopathy (PML).

Suspending dosing to reduce the risk of PML may contribute to an increased risk for MS flares. "There is a clear risk to these patients for developing PML from continuing use of natalizumab," Dr. West said. "But if you suspend dosing, about 30% of your patients will flare. Some of them will have an uncharacteristically severe flare."

Natalizumab is a humanised monoclonal antibody that is effective in treating relapsing MS. It has been shown to decrease the relapse rate, reduce TC and gadolinium-enhancing (Gd+) lesions on magnetic resonance imaging (MRI), and slow the progression of disability. The problem is that longer treatment is associated with an increased risk for developing PML. The estimated risk for developing PML is 1 in 50,000 after 12 infusions, 1 in 3,000 after 24 infusions, and 1 in 750 after 36 infusions. Many clinicians use planned dosing interruptions of 3 to 6 months to reduce the cumulative risk for PML. During a phase 2 trial of the natalizumab, patients on active drug and placebo showed no difference in Gd+ lesions 3 months after discontinuation. Another observational cohort showed an increase in cerebrospinal fluid oligoclonal bands and intrathecally synthesised immunoglobulin G 6 months after cessation of natalizumab.

No data show that treatment suspension can restore immunological function to the degree needed to influence the risk of PML, Dr. West noted, but it has become common practice. Researchers conducted an observational study through chart review of all patients at the UCSF MS Center who had received at least 12 natalizumab infusions. Patients were identified via the Tysabri Outreach United Commitment to Health (TOUCH) program mandated by the US Food and Drug Administration and implemented by the manufacturer. Observational data were censored at 6 months because patients whose treatment was interrupted typically have restarted natalizumab or some other disease-modifying treatment in place of natalizumab by then. The researchers identified 187 patients who had received natalizumab, of whom 84 met the inclusion criteria. Within the inclusion group, 68 patients had a treatment interruption and 16 did not. Of the 68 patients who had a drug holiday, 4 received another disease-modifying therapy during the natalizumab dosing suspension. None of the 4 patients had a clinical flare or an observed increase in MRI activity during the observation period. Patients had a median of 18 infusions before dosing suspension. Among the 16 patients who did not have a dosing interruption, none had a clinical flare during the observation period. Of the 68 patients who had a drug holiday, 19 (28%) had a clinical relapse within the 6-month period ([P = .017). The median time from dosing interruption to flare was 3 months (range 1-6 months). Seven of the 19 patients (10.3%) who flared had unusually severe flares, Dr. West said. These patients had nearly a 3-point increase in median Expanded Disability Status Scale score, many Gd+ lesions, and limited recovery of neurological function.

"You want to exercise extra vigilance with patients if you suspend dosing," Dr. West said. "Most of our flares happened at 3 months or later, so you may want to consider an extra clinic visit around that time. You may also want to consider some other disease-modifying therapy during dosing suspension. The reality is that nobody knows for sure."





The article can be seen here.
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PostPosted: Fri Oct 01, 2010 11:11 pm    Post subject: (Abstr.) Effect of Tysabri on cognitive function in RRMS Reply with quote

From Peer View Institute/PubMed, September 30, 2010:

Quote:
Neurol Sci. 2010 Sep 25.

The effect of natalizumab on cognitive function in patients with relapsing-remitting multiple sclerosis: preliminary results of a 1-year follow-up study

Mattioli F, Stampatori C, Capra R.

Clinical Neuropsychology Unit, Spedali Civili of Brescia, Via Nikolajewka, 13, 25123, Brescia, Italy, flaviacaterina.mattioli@gmail.com.


The objective of the study was to assess the [effect of natalizumab] on the course of cognitive impairment in patients with relapsing-remitting multiple sclerosis (MS).

Patients with active relapsing-remitting MS (n = 17) were treated with natalizumab for 1 year. The quasi control group included patients (n = 7) with clinically stable MS. Assessment of disease course [expanded disability status scale (EDSS); number of relapses] and neuropsychological impairment [Wisconsin card sorting test (WCST); controlled oral word associations; verbal/non-verbal memory tests; paced auditory serial addition test] was conducted at baseline and after 1 year.

Natalizumab-treated patients experienced significantly fewer relapses compared with the previous year (P < 0.05). At 1-year follow-up, EDSS score was unchanged and neuropsychological assessments of memory/executive functions showed a significant improvement in natalizumab-treated patients (all P < 0.05). No changes were observed in the quasi control group.

This preliminary study suggests that natalizumab could be effective in ameliorating cognitive functions in patients with active relapsing-remitting MS, over 1-year follow-up.

PMID: 20872033
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PostPosted: Mon Oct 11, 2010 8:31 pm    Post subject: 2 more PML cases? Reply with quote

According to the chefarztfrau Website, whose author claims to have information from internal sources, there are two new PML Tysabri-related PML cases.

Case #69 - 9/14/10 - Poland, female, 34 doses

Case #70 - 10/3/10 - USA, female, 55 doses

http://chefarztfrau.de/?page_id=716
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PostPosted: Wed Oct 13, 2010 9:21 am    Post subject: IRIS in MS patients after stopping Tysabri Reply with quote

From PubMed, October 13, 2010:

Quote:


Arch Neurol. 2010 Oct 11.

Immune Reconstitution Inflammatory Syndrome in Patients With Multiple Sclerosis Following Cessation of Natalizumab Therapy

Miravalle A, Jensen R, Kinkel RP.

University of Colorado, Denver (Dr Miravalle); Department of Neurology, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark (Dr Jensen); and Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Dr Kinkel).

OBJECTIVE:

To assess clinical consequences of temporary natalizumab dosage suspension.

DESIGN:

Prospective cohort study.

SETTING:

Multiple sclerosis (MS) center at an academic medical center in the United States.

PATIENTS:

Thirty-two patients with MS who had received at least 12 consecutive natalizumab infusions.

MAIN OUTCOMES MEASURES:

Recurrent MS disease activity, defined as a clinically documented exacerbation with objective findings and/or the development of 1 or more new gadolinium-enhancing lesions on magnetic resonance imaging.

RESULTS:

Thirty-eight percent of patients with relapsing-remitting and secondary progressive MS experienced relapses during therapy interruption or shortly after restarting natalizumab therapy (9 of 24 and 3 of 8, respectively), but relapses were severe with unusually widespread evidence of inflammatory activity on magnetic resonance imaging in several patients with secondary progressive MS with greater inflammatory disease activity prior to starting natalizumab therapy. Imaging and cerebrospinal fluid findings in these cases were suggestive of an immune reconstitution inflammatory syndrome. Overall, relapses occurred more often in younger patients with fewer natalizumab infusions prior to therapy interruption. The number of gadolinium-enhancing lesions at the time of relapse after therapy interruption was modestly correlated with the number of gadolinium-enhancing lesions prior to starting natalizumab therapy (r = 0.51; P = .45). Prior disease control resumed after reinstitution of natalizumab therapy in all patients.

CONCLUSIONS:

In this cohort of patients with MS who had disease refractive to multiple therapeutics before starting natalizumab treatment, magnetic resonance imaging and clinical disease activity returned, often aggressively, following discontinuation of natalizumab therapy. These findings suggest we should consider strategies to minimize the risk of immune reconstitution inflammatory syndrome after natalizumab discontinuation.

PMID: 20937940


The abstract can be seen here.

I thought Tysabri wasn't being given to people with SPMS, and yet this article indicates otherwise....
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PostPosted: Wed Oct 20, 2010 10:31 am    Post subject: (ECTRIMS) Clinical outcomes in PML assoc'd w/Tysabri Reply with quote

Presented at the ECTRIMS conference in Sweden, October 15, 2010:

Quote:
Overview of clinical outcomes in cases of natalizumab-associated progressive multifocal leukoencephalopathy

P. Vermersch, J. Foley, R. Gold, L. Kappos, T. Olsson, C. Bozic, S. Richman (Lille, FR; Salt Lake City, US; Bochum, DE; Basel, CH; Stockholm, SE; Cambridge, US)

Background:

As of March 2010, 67,000 multiple sclerosis (MS) patients have been treated with natalizumab, corresponding to 97,000 patient-years. While natalizumab’s efficacy is well known, a small number of patients experience progressive multifocal leukoencephalopathy (PML), a rare opportunistic CNS infection caused by JC virus.

Objective:

Identify variables associated with survival and functional status in the first 35 postmarketing cases of natalizumab-associated PML.

Methods:

Between January and March 2010, treating physicians provided Karnofsky scores and clinical status updates on motor and cognitive function and activities of daily living. Data were supplemented by the natalizumab global safety database.

PML cases were categorised by survival outcome (fatal/nonfatal) and functional status (mild/moderate/severe disability).

Results:

At the time of analysis, 25/35 (71%) PML patients survived. Nonfatal cases were younger (median: 40 vs 54 years), had lower EDSS scores prior to PML (median: 3.5 vs 5.5) and shorter time from symptom onset to diagnosis (mean: 44 vs 63 days) compared with fatal cases.

Most (86%) nonfatal cases had unilobar/multilobar disease whereas most (70%) fatal cases had widespread disease on MRI. Gender, MS duration, natalizumab exposure, prior immunosuppressant use, and CSF JCV DNA load at diagnosis were generally similar between the 2 groups.

In all cases, natalizumab dosing was withheld. In the majority of cases, PML was treated by rapid removal of natalizumab using plasma exchange or immunoadsorption (92%, fatal cases; 100% nonfatal cases).

Immune reconstitution inflammatory syndrome (IRIS) was reported in 91% of cases; most were treated with corticosteroids (pulse and continuous steroid regimens were reported). Twelve of 25 nonfatal cases (48%) had >=6 months of follow-up after PML diagnosis and were more likely to be clinically stable. In these patients, 33% had mild disability, 33% had moderate disability, and 33% had severe disability based on Karnofsky scores.

Conclusions:

Natalizumab-associated PML has a higher survival rate compared with PML in other populations. Functional status in survivors ranges from mild to severe disability. Risk factors for mortality include longer time from symptom onset to diagnosis and widespread disease on brain MRI at diagnosis.

These data suggest that earlier diagnosis through enhanced clinical vigilance and aggressive clinical management of PML and IRIS may improve survival.


For more information on a Karnofsky score, see
here.

The abstract can be seen here.
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PostPosted: Thu Oct 21, 2010 7:35 pm    Post subject: 2 more cases of PML definite--total now 70 Reply with quote

I posted about this on October 11, but here is more definite information about the two additional cases of PML, bringing the total to 70.

Quote:
Biogen reports more brain infections in MS patients

By Toni Clarke


BOSTON (Reuters) - Two more patients taking Biogen Idec Inc's multiple sclerosis drug Tysabri have developed a potentially deadly brain infection known as PML, the company said on Wednesday.

The Cambridge, Massachusetts-based biotechnology company said in its latest monthly update that as of October 1, there have been 70 confirmed cases of PML, up from 68 as of September 2.

Of those, 14 have died and 56 are alive with varying degrees of disability ranging from mild to severe. There were no additional deaths in October.

Tysabri, which Biogen sells in partnership with Irish drugmaker Elan Corp Plc, is an important growth driver for both companies, and is battling for share of an increasingly competitive market.

U.S. regulators recently approved the first oral MS drug, Gilenya, made by Novartis AG, which, while not as effective as Tysabri, is more convenient, since Tysabri must be infused roughly once a month.

Genzyme Corp, which recently reported five-year follow-up data from its experimental MS drug Campath, shows even greater efficacy than Tysabri but also carries worrisome side effects.

Tysabri was temporarily withdrawn from the market in 2005 after it was linked with PML, but reintroduced in 2006 with stricter safety warnings. Since its reintroduction, the overall incidence of PML, based on the 70 cases, is estimated to be 0.91 per 1,000 patients, up from 0.90 in September.

As of June 30, about 71,400 patients had received Tysabri since it was launched.

Biogen is developing a test that it hopes will be able to identify patients at higher risk for developing PML. In the meantime, the risk has been shown to increase with duration of therapy.

For patients who received more than 24 infusions of the drug, the rate of PML was 1.87 per 1,000 patients in October, up from 1.86 in September. The rate for patients receiving between 13 and 24 infusions was 0.38 per 1000, down from 0.39 in September. For patients who received between 25 and 36 infusions, the rate was 1.44 per 1,000, down from 1.46 in September.

(Reporting by Toni Clarke; Editing by Gary Hill)



The article can be seen here.
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PostPosted: Mon Oct 25, 2010 6:08 pm    Post subject: (ECTRIMS) Indolent course of PML during Tysabri treatment Reply with quote

Presented as a poster session at the ECTRIMS conference in Sweden, October 15, 2010:

Quote:
Immunomodulation 2

Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in multiple sclerosis

A. Vennegoor, M.P. Wattjes, E. van Munster, R.L. Kriekaart, B.W. van Oosten, F. Barkhof, J. Killestein, C.H. Polman (Amsterdam, 's Hertogenbosch, NL)

Objective:

To report a case which shows that the presentation of natalizumab-associated progressive multifocal leucoencephalopathy (PML) can be indolent and protracted, with a relatively mild disease course, even in the absence of immediate immune reconstitution.

Background:

PML has developed in over 40 MS patients treated with natalizumab. In almost all of these patients, PML presented as an aggressive disease with a short interval between first symptoms and diagnosis.

Case report:

In September 2002, a 30-year-old previously healthy woman presented with walking problems. Neurological examination showed a bipyramidal syndrome. MRI of the brain and spinal cord showed multiple T2-weighted white matter lesions. A diagnosis of a clinically isolated syndrome suggestive of a first episode of MS was established.

She used Interferon beta-1a and Glatiramer Acetate without success.

In March 2007 she started with natalizumab. She had no clinical exacerbations since and routine MRI of the brain one year later showed no active lesions. A second MRI in February 2009 was initially interpreted as showing no new lesions. In retrospect, subtle and diffuse abnormalities were visible in cortical and subcortical areas.

Since June 2009 she suffered from progressive cognitive problems. Therefore a new MRI was performed in October 2009, showing a new lesion and progression of the diffuse abnormalities. In November 2009 she developed an acute delirium. Due to the suspicion of PML, natalizumab was discontinued. At the moment the CSF results on JC virus load confirmed the diagnosis PML, the patient’s condition had spontaneously improved. Because of this and the last infusion being given more than 2 months ago, we decided not to treat the patient with plasma exchange or immunoabsorption.

Discussion:

Most remarkable is the extremely protracted and indolent course of PML. Whereas clinical symptoms probably existed at least 3 to 6 months before diagnosis, we could see subtle MRI abnormalities already 9 months before diagnosis. Another remarkable feature is the relatively mild disease severity even though another 9 natalizumab infusions were given after the initial MRI manifestations.

In our opinion, this case report shows that in a MS patient treated with natalizumab clinical and radiological vigilance is extremely important, because PML can present as an indolent disease with a protracted course which remains relatively benign for many months despite continued treatment with natalizumab.


The abstract can be seen here.
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PostPosted: Sun Nov 07, 2010 2:13 pm    Post subject: PML cases now at 71? Reply with quote

The chefarztfrau Website that lists PML cases related to Tysabri has listed a 71st case as of 10/18/10, in the US, a woman, after 22 doses. You can see her on YouTube though she's speaking Italian.
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PostPosted: Tue Nov 09, 2010 5:43 pm    Post subject: (Abstract) 2nd case report of melanoma & Tysabri in Ital Reply with quote

From PeerView Institute NTK Watch, November 9, 2010:

Quote:

Neurol Sci. 2010 Nov 5.

Association of melanoma and natalizumab therapy in the Italian MS population: a second case report

Laroni A, Bedognetti M, Uccelli A, Capello E, Mancardi GL.

Multiple Sclerosis Center, Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy.

There is debate about a possible association between natalizumab treatment and higher risk of melanoma. Here we report a case of melanoma in a patient who developed melanoma after 77 infusions of natalizumab, without known risk factors.

Pharmacovigilance programs of new drugs can help to monitor adverse events in patients at risk.

PMID: 21052756
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PostPosted: Wed Nov 17, 2010 8:13 pm    Post subject: PML cases now total 75 Reply with quote

A report from NASDAQ Dow-Jones Newswires (November 17, 2010) reveals that the total number of PML cases in patients on Tysabri is now 75. There has been one more death, bringing the total to 15.
Quote:


Biogen: 5 More Cases Of Brain Infection In Tysabri Patients

By Thomas Gryta, Of DOW JONES NEWSWIRES

NEW YORK -(Dow Jones)- Biogen Idec Inc. (BIIB) disclosed five more cases of a rare brain infection in multiple sclerosis patients on Tysabri, which it sells with Elan Corp. (ELN), bringing the total number of cases to 75 as of Nov. 2.

The Weston, Mass., biotech company also reported an additional death among patients that have developed the infection--known as progressive multifocal leukoencephalopathy, or PML--a number that is now 15.

The number of PML cases is important because if the infection rate climbs too high, the drug's sales growth may drop. Regulators have said that they watch the cases, but have concluded that the benefits of the medicine to MS patients outweigh the risks.

The overall global PML rate is about 0.96 per 1,000 patients, a company spokeswoman said, which still falls within the 1-in-1,000 rate previously seen in clinical trials and implied on the drug's label. But the rate has been rising, and multiple Wall Street analysts raised concern about the trend on Wednesday as the MS market is becoming increasingly competitive.

"Given this PML rate increase, we expect it to cross the 1/1000 incidence threshold sometime during the next two months," Barclays Capital analyst Jim Birchenough said in a note to clients.

Food and Drug Administration officials weren't immediately available for comment.

Sales of Tysabri are important to the future growth of Biogen and Elan. There is hope that the development of a blood test may better determine the chances of patients contracting PML. Although the overall risk of the infection is small, the test may make patients and physicians more comfortable with using the drug.

Tysabri is considered to be a highly effective therapy for multiple sclerosis, but its growth has been stunted by concerns about PML. The drug was temporary withdrawn from the market beginning in 2005 and relaunched in 2006 with a strict access plan that monitors every patient using the drug.

Meanwhile, the MS treatment market is getting increasingly competitive, something that Wall Street believes could put some pressure on Tysabri and Biogen as a whole. Biogen get most of its revenue from MS treatments Avonex and Tysabri, and hasn't launched a new drug since the approval of Tysabri in 2004.

Novartis AG's (NVS) Gilenya, the first oral therapy for the disease, was recently approved, and numerous other therapies are in development.

Earlier this month, Biogen unveiled a sweeping restructuring plan that cuts costs--including facility closings and layoffs--and focuses the company on developing neurology treatments and defending its current franchise of MS drugs.

The moves came after a business review by new Chief Executive George Scangos, who joined the company in July.

As of Sept. 30, 55,100 patients were using the drug around the world. In total, about 75,500 patients have used the drug since its launch.

Of the total PML cases, 33 were in the U.S., 38 were in the European Union and four were in other areas.

The risk of the infection increases with the number of monthly infusions that a patient receives, but that rate appears to drop after 30 months of use. Biogen views the drop as inconclusive, because there aren't enough patients at the longer duration to have enough confidence in that finding.

The most recent data update translates to a rate of 1.49 cases per 1,000 for patients on the drug for a year or longer, but rises to 1.97 per 1,000 for those on the drug for two years or longer.

Looked at another way, the rate is about 1.49 cases per 1,000 patients on the drug for between two and three years. The incidence is about 0.37 case per 1,000 patients in those using it for one to two years, and it is essentially nonexistent in patients using it for less than a year.

-By Thomas Gryta, Dow Jones Newswires; 212-416-2169; thomas.gryta@dowjones.com




The article can be seen here.


Cases 70 through 74 are in the USA, according to the informal reporting site chefarztfrau.
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PostPosted: Wed Dec 08, 2010 5:58 pm    Post subject: (Abstr.) Course of RRMS before, during, after Tysabri Reply with quote

From PubMed, December 8, 2010:

Quote:
Mult Scler. 2010 Dec 6.

Course of relapsing-remitting multiple sclerosis before, during and after natalizumab

Kaufman MD, Lee R, Norton H.

MS Center, Carolinas Medical Center, 1010 Edgehill Road North, Charlotte, NC 28207, USA.

The consequences of interruption of natalizumab treatment are incompletely known. The objective was to assess the confirmed annualized relapse rates for patients preceding initiation, during and following suspension of natalizumab therapy.

A chart review was conducted and data were analyzed using the Generalized Estimating Equations. During natalizumab therapy the confirmed annualized relapse rate was 0.08, compared to 0.52 (p = 0.0003) during the prior 12 months and to 0.35 (p = 0.0032) during the following 3 to 24 months. Similar results were found when confirmed and unconfirmed were analyzed.

To conclude, following cessation of natalizumab therapy disease activity rapidly returned to pre-natalizumab levels.

PMID: 21135017
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PostPosted: Thu Dec 16, 2010 6:51 pm    Post subject: 4 new PML cases, 1 new death for Tysabri patients Reply with quote

Biogen has announced 4 new PML cases in MS patients on Tysabri, and one new death. From Reuters, December 16, 2010:

Quote:
Biogen reports four more Tysabri cases, one death

* 79 confirmed PML cases as of Dec. 2, with 16 deaths

* Estimated incidence of PML per 1000 patients is 1.0


NEW YORK Dec 16 (Reuters) - Four more patients taking Biogen Idec's (BIIB.O) multiple sclerosis drug Tysabri have developed the serious brain infection known as PML and one of them died, according to the biotechnology company's monthly update.

The four new confirmed cases of potentially fatal progressive multifocal leukoencephalopathy, or PML, were detected between Nov. 2 and Dec. 2, the company said. That brought the total number of confirmed cases as of Dec. 2 to 79, with 16 deaths.

Biogen, which markets the drug with Ireland-based partner Elan Corp Plc (ELN.I), said the rate of PML cases per 1,000 patients has edged slightly higher to 1.0 from 0.96 and is likely due to more patients being on the drug for more than two years.

The chances of contracting PML tend to increase the longer a patient is on the drug, which is considered the most important growth driver for Biogen and Elan. The incidence of PML cases per 1,000 patients who have received between 1 to 12 infusions of Tysabri is just 0.01, but that rises to 2.05 at more than 24 infusions, according to Biogen's statistics.

...

(Reporting by Bill Berkrot. Editing by Robert MacMillan)



The entire article can be seen here.
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PostPosted: Wed Dec 22, 2010 7:04 pm    Post subject: (Abstract) Axon damage in relapsing MS markedly reduced... Reply with quote

From NTK Watch (PeerView Institute), December 22, 2010:

Ann Neurol. 2010 Oct 28. [

Quote:
Axonal damage in relapsing multiple sclerosis markedly reduced by natalizumab

Gunnarsson M, Malmeström C, Axelsson M, Sundström P, Dahle C, Vrethem M, Olsson T, Piehl F, Norgren N, Rosengren L, Svenningsson A, Lycke J.

Department of Neurology, Örebro University Hospital, Örebro, Göteborg.

OBJECTIVE:

The impact of present disease-modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and reactive astrogliosis is still unclear. Therefore, we studied the effect of natalizumab treatment on the release of 2 brain-specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients.

METHODS:

CSF samples from 92 patients with relapsing forms of MS were collected in a prospective manner prior to natalizumab treatment and after 6 or 12 months. In 86 cases, natalizumab was used as second-line DMT due to breakthrough of disease activity. The levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were determined using highly sensitive in-house developed enzyme-linked immunosorbent assays.

RESULTS:

Natalizumab treatment led to a 3-fold reduction of NFL levels, from a mean value of 1,300 (standard deviation [SD], 2,200) to 400 (SD, 270) ng/l (p < 0.001). The later value was not significantly different from that found in healthy control subjects (350ng/l; SD, 170; n = 28). Subgroup analysis revealed a consistent effect on NFL release, regardless of previous DMT or whether patients had relapses or were in remission within 3 months prior to natalizumab treatment. No differences between pre- and post-treatment levels of GFAP were detected.

INTERPRETATION:

Our data demonstrate that natalizumab treatment reduces the accumulation of nerve injury in relapsing forms of MS. It is anticipated that highly effective anti-inflammatory treatment can reduce axonal loss, thereby preventing development of permanent neurological disability.

PMID: 21154414 [PubMed - as supplied by publisher]

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PostPosted: Fri Dec 24, 2010 6:51 pm    Post subject: New information, possibly 3 new cases Reply with quote

The chefarztfrau Website, which seems to have access to internal sources, is listing 3 more PML cases:

#80 - Female, 29 months on Tysabri, Germany
#81 - Female, 34 doses of Tysabri, USA
#82 - Male, 50 doses, Poland

There is added information for cases 75-79:

#75 - Female, 33 months on Tysabri, Germany
#76 - Female, 49 doses of Tysabri, Hungary
#77 - Female, 49 doses, USA
#78 - Male, 25 months on Tysabri, Germany
#79 - Female, 24 months on Tysabri, Australia

http://chefarztfrau.de/?page_id=716
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