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JC virus urinary excretion and seroprevalence in natalizumab-treated MS patients(23/07/14)

The risk of developing progressive multifocal leukoencephalopathy (PML), as a consequence of infection/reactivation with JC virus (JCV), is consistent in natalizumab-treated multiple sclerosis (MS) patients, with 430 cases of PML reported so far.

The risk of PML is higher in JCV seropositive patients, and it is recommended that only MS patients without JCV antibodies should be enrolled in the treatment postulating that they do not have JCV infection.

We have studied forty-two natalizumab-treated MS patients, and urine and blood were collected monthly for up to 60 months. JCV and BK virus (BKV) DNA presence was verified using quantitative real-time PCR assays, and serum anti-JCV antibodies were measured with the Stratify and/or Stratify DxSelect tests.

JCV and BKV DNA were not found in the blood samples, whereas they were found at least once in the urine of 21 of 42 (50 %) and of 25/42 (59.5 %) patients, respectively. JCV DNA urinary shedding increased up to month 24 of natalizumab treatment (45.2 %), and the effect of time was significant for JCV (p = 0.04), but not for BKV (p = 0.39). JCV viruria and seropositivity did not completely correlate, since three patients shedding JCV DNA in the urine were seronegative according to the serological tests.

The results indicated that natalizumab therapy may increase the rate of JCV urinary shedding. Additionally, we confirmed that the identification of JCV carriers cannot solely rely on serological tests, but sensitive methods for viral DNA detection should be adopted to more precisely identify the truly JCV uninfected cases.

Source: Science Index Copyright © 2014 ScienceIndex.com (23/07/14)

Increased MS relapse rates after Tysabri discontinuation (02/07/14)

Treatment of Relapsing-Remitting Multiple Sclerosis After 24 Doses of Natalizumab -
Evidence From an Italian Spontaneous, Prospective, and Observational Study (the TY-STOP Study)

Marinella Clerico, MD; Irene Schiavetti, BS; Stefania F. De Mercanti, MD; Federico Piazza, MD; Dario Gned, MD; Vincenzo Brescia Morra, MD; Roberta Lanzillo, MD; Angelo Ghezzi, MD; Anna Bianchi, BS; Giuseppe Salemi, MD; Sabrina Realmuto, MD; Patrizia Sola, MD; Francesca Vitetta, MD; Paola Cavalla, MD; Damiano Paolicelli, MD; Maria Trojano, MD; Maria Pia Sormani, BS; Luca Durelli, MD

Abstract

Importance: The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS).

Objective: To evaluate the effect of therapeutic choices on the mean annualised relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS.

Design, Setting, and Participants: The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centres (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab.

Interventions: Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod.

Main Outcomes and Measures: The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year.

Results: No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery.

Conclusions and Relevance This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug.

Trial Registration Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.

Source: JAMA Neurology © 2014 American Medical Association (02/07/14)

Tysabri has an effect on oligoclonal bands in the cerebrospinal fluid of MS patients(26/06/14)

Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: A longitudinal study.

Mancuso R, Franciotta D, Rovaris M, Caputo D, Sala A, Hernis A, Agostini S, Calvo M, Clerici M.

Abstract

Retrospective studies show that natalizumab modifies oligoclonal immunoglobulin (IgG) bands (OCBs) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients.

In this study, we prospectively analyzed both serum and CSF samples from 24 MS patients, before and after 2 years of natalizumab-based therapy. Our results showed complete (55%) or partial (27%) disappearance of the OCBs in CSF samples that were taken after 2 years of therapy.

Intrathecal IgG production, represented by the IgG index and IgGLoc, was also quantitatively reduced. Our data showed that natalizumab substantially modulates both intrathecal polyclonal and oligoclonal IgG production: This effect was much more potent than was previously reported.

Source: Mult Scler. 2014 Jun 16. pii: 1352458514538111. [Epub ahead of print] & Pubmed PMID: 24948690 (26/06/14)

Study suggests MS drug Tysabri treatment can be safely continued past 24 months(13/06/14)

A recent study suggests that treatment with natalizumab (Tysabri) beyond 2 years compared with switching to other drugs can control relapsing-remitting multiple sclerosis (RRMS) with adequate safety.

The longer a patient with RRMS is treated with natalizumab, the greater the risk of developing progressive multifocal leukoencephalopathy (PML), especially in patients who are infected with JC virus after 2 years of monthly treatments.

"Our study provides evidence to support the choice of continuing treatment with natalizumab after the 24th administration," Luca Durelli, MD, from the Department of Clinical and Biological Sciences at the University of Torino and the San Luigi Gonzaga University Hospital in Obassano, Italy, reported here at the 24th Meeting of the European Neurological Society (ENS).

Between 2005 and May 2014, among 125,800 patients with MS treated in the postmarketing setting, 462 cases of PML have been reported, of which 23% were fatal, for an incidence of 3.6 cases/1000 treated. The highest prevalence has been in patients receiving natalizumab for 2 to 3 years.

In this present prospective, multicenter, observational Tysabri discontinuation study after the 24th natalizumab administration (TY-STOP), 130 adult patients with clinically and radiologically stable RRMS were stratified according to their choices of treatment after the 24th dose of natalizumab, 300 mg every 28 days, and observed every 3 months for 1 year.

Treatment options presented to the patients after the 24th natalizumab dose were to continue receiving natalizumab ("continuers"), to start treatment with a different therapy ("switchers"), or to stop any disease-modifying therapy ("quitters").

First-line therapy options were interferon β-1a, interferon β-1b, or glatiramer acetate. Second-line options were fingolimod (since December 2011), natalizumab, or mitoxantrone (only 2 patients).

Of the 130 patients, Professor Durelli reported on 124 (95.4%) who had completed the entire 1-year follow-up, which consisted of 43 (35%) who continued natalizumab and 81 (65%) who interrupted it.

The following baseline characteristics did not significantly differ between the patients who continued natalizumab and those who did not: age, body mass index, age at disease onset, sex, disease duration at baseline, disability scores, annual relapse rates, MRI activity, and disease-modifying therapies before natalizumab initiation.

The as-treated population consisted of 73 (59%) quitters, 16 (13%) switchers, and 35 (28%) continuers.

For the intention-to-treat population, after 1 year of observation following the decision to stay on natalizumab or not, there was no significant difference in the mean Expanded Disability Status Scale scores, but the annualized relapse rate had tripled (0.24 ± 0.48 for those remaining on natalizumab vs 0.73 ± 0.85 for those not; P = .004) and the presence of MRI activity in the previous year had doubled (26.8% vs 51.3%, respectively; P = .018).

Results were similar for the as-treated population, with no significant differences in disability scores but a higher annualized relapse rate among quitters and switchers compared with continuers. MRI activity during the follow-up year was higher among quitters but not among switchers compared with continuers.

Professor Durelli said that in the as-treated population, the overall frequency of adverse effects was similar among the patients treated with the different therapies, and "during the period of observation no new safety issues emerged."

Among the continuers, there was 1 case of pyelonephritis and 1 acute myocardial infarction. Among switchers, 1 case of PML occurred in a patient who had been receiving natalizumab for 28 months. The patient made a full recovery after being treated with plasma exchange and mirtazapine.

In no patient who stopped natalizumab did disease activity return worse than it had been before natalizumab therapy.

Professor Durelli concluded that in patients with relapsing-remitting MS, "interruption of treatment with natalizumab after the first 24 courses exposes [patients] to an increased risk of clinical and/or MRI MS disease activity." He added the study results can support a choice of continuing natalizumab beyond 24 months.

Relapse Activity Increase

Session chairman Kjell-Morten Myhr, MD, PhD, professor of neurology at the University of Bergen, Norway, told Medscape Medical News that the study "very well showed the efficacy of Tysabri. When stopping Tysabri and starting them on a less potent treatment, the relapse activity will increase."

Infection with JC virus is a major risk factor for PML in patients treated with natalizumab, and 60% to 80% of adults in the United States and Europe are positive for antibodies to it, indicating exposure. "Of course, it would be best for the treatment of the disease itself continuing with the Tysabri, but it's a difficult issue with the risk of PML," he said.

He commented that he had the impression that the study patients had not been screened for JC virus before natalizumab initiation, probably because screening was not yet available.

"For those that are JC virus negative, there is no reason to stop after 24 months. They should continue," he said. "These patients that could be considered for stopping or switching are JC virus positive after 24 months." In keeping with usual practice, he recommended that JC virus–negative patients be tested every 6 months because they can become infected at any time.

Dr. Myhr said in his experience, when the risks of PML are explained to patients and they elect to continue natalizumab, sometimes they come back in a few months and have decided to switch to another drug because they say that they are continuously thinking about the risk.

"It's difficult for patients to make decisions, and I think they need time to make their decisions. So we really need good biomarkers to differentiate the risk for this serious complication," he said, noting that the JC virus index will be 1 biomarker "to identify those with a low risk but still a risk but lower than those with a high index."

Professor Durelli had no disclosures. Dr. Myhr has received honoraria for lecturing; participation in advisory boards or pharmaceutical company–sponsored clinical trials; and travel support from Allergan, Almiral, Bayer Schering, Biogen Idec, Novartis, Merck-Serono, Roche, and Sanofi-Aventis.

24th Meeting of the European Neurological Society (ENS). Abstract OS1115. Presented May 31, 2014.

Source: Medscape Medical News © 2014 WebMD, LLC (13/06/14)

MS rebound after stopping Tysabri(09/06/14)

Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis.

Gueguen A, Roux P, Deschamps R, Moulignier A, Bensa C, Savatovsky J, Heran F, Gout O.

Abstract

OBJECTIVE: To characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation.

METHODS: Thirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively during and after NTZ, with serial clinical and MRI evaluations. The first relapse occurring after interrupting NTZ was the primary outcome measure. The numbers of gadolinium-enhancing lesions before, during and after NTZ treatment, were compared.

RESULTS: During the year following NTZ cessation, the cumulative probability of relapses was estimated at 52.9% and an unusually high MRI inflammation was noticed. It was defined by a number of gadolinium-enhancing lesions >5 and exceeding the gadolinium lesions existing before NTZ initiation. Rebound of MS activity after NTZ cessation was characterised by association of relapses and unusual MRI inflammation. Cumulative probability of rebound was estimated at 39% and mostly occurring between 3 months and 9?months after interrupting NTZ. Risk of rebound appears related with a higher annualised relapse rate and a lower Expanded Disability Status Scale score before NTZ initiation. Rebound was associated with severe recurring relapses in 9% of the patients.

CONCLUSIONS: This study identifies rebound after NTZ cessation as an association of relapses and high MRI activity.

Source: J Neurol Neurosurg Psychiatry. 2014 May 29. pii: jnnp-2014-307591. doi: 10.1136/jnnp-2014-307591 & Pubmed PMID: 24876183 (09/06/14)

Age and it's effects and response to MS treatment Tysabri(06/06/14)

Age-dependent effects on the treatment response of natalizumab in MS patients.

Matell H, Lycke J, Svenningsson A, Holmén C, Khademi M, Hillert J, Olsson T, Piehl F.

Abstract

BACKGROUND: Natalizumab is approved for treatment of active forms of relapsing-remitting multiple sclerosis (MS) based on a pivotal phase III study comprising patients aged 18-50 years. The effect of natalizumab has not been specifically studied in older patients.

OBJECTIVE: We analyzed age-dependent effects on treatment-related outcome measures in 1872 patients, 189 of whom were aged 50 or more, included in the Swedish post-marketing natalizumab surveillance program.

METHODS: In three MS centers registry data for patients aged >50 years were validated.

RESULTS: At baseline older patients had longer disease duration, higher Expanded Disability Status Scale (EDSS) and lower Symbol Digit Modality Test (SDMT) scores than younger patients. The influence from natalizumab on outcome measures was significantly reduced and 18.7% of patients >50 years stopped treatment for lack of effect compared to 7.7% in the younger age group. At baseline, the cerebrospinal fluid levels of the chemokine CXCL13 and the leukocyte cell count were negatively correlated with age in a smaller subgroup of patients.

CONCLUSION: These results were in agreement with previous findings suggesting that inflammation is more pronounced in younger patients and therefore the beneficial effects of potent anti-inflammatory treatments are subsiding with older ages.

Source: Mult Scler. 2014 May 27. pii: 1352458514536085. & Pubmed PMID: 24866201 (06/06/14)

Disability progression in patients who switch from Natalizumab to Fingolimod or injectable therapies (31/05/14)

Transitioning from natalizumab to fingolimod was linked to a self-reported worsening of disability in patients with multiple sclerosis, according to data from a North American Research Committee on Multiple Sclerosis (NARCOMS) analysis presented by Stacey Cofield, PhD, at the 2014 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Sixth Cooperative Meeting with Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Cofield is Deputy Director of the CombiRx Statistical and Data Management Center and the NARCOMS Coordinating Center at the University of Alabama-Birmingham (UAB) School of Public Health.

In her presentation, titled “Disability Progression after Switching from Natalizumab to Fingolimod or Injectable Therapies: A NARCOMS Analysis,” Cofield, who is also an associate professor in the Department of Biostatistics at UAB, noted that natalizumab is a highly effective treatment for multiple sclerosis.

“However, the clinical outcomes of natalizumab-treated patients who have switched to other treatments are not well understood,” she noted.

The study was done to compare changes in patient-determined disease steps (PDDS) -- a patient-reported outcome of disability in patients with multiple sclerosis -- between natalizumab-treated patients who remained on natalizumab and patients who switched treatment after a minimum of two years. For the study, researchers collected information on 547 NARCOMS participants who were on at least 2 years of continuous natalizumab treatment.

“Scores from the first survey were compared between participants whose only disease-modifying treatment during follow up was natalizumab and patients who switched to treatment with fingolimod or injectable therapies,” said Cofield.

Injectable therapies included interferon beta or glatiramer acetate.

Adjusted mean PDDS was not different between groups after two years of natalizumab therapy, but at the end of follow up, the mean PDDS increase was 0.31 points for the natalizumab-only group, 0.58 for patients who switched to fingolimod, 0.71 for patients who switched to injectables.

The difference between natalizumab and the injectable therapies groups was significant (P = 0.007).

In addition, there was a difference between groups in the proportion of patients with a greater than one point increase in PDDS (30.8% of the natalizumab-only group, 46.0% of the fingolimod group, and 42.3% of the injectable therapies group; P = 0.03).

On average, patients who switched to treatment with injectable therapies reported larger disability increases than patients who remained on natalizumab.

Age, gender, and starting PDDS were similar in all groups, but median months of total follow up were significantly different (48 months for the natalizumab-only group, 54 months for the fingolimod group, and 60 months for the group that switched to treatment with injectable therapies).

“The study found that age, gender, and starting PDDS were associated with changes in PDDS (P < 0.03) and total follow up was not different between groups after 2 years,” said Cofield.

Switching from natalizumab to fingolimod or injectable therapy was associated with an increased likelihood of reported disability progression.

Since the study included self-reported data, “causality cannot be concluded,” Cofield said.

Source: Copyright HCPLive 2006-2013 Intellisphere, LLC. All Rights Reserved. (31/05/14)

The RESTORE trial: What did we learn about multiple sclerosis?(14/05/14)

RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab. The objectives of RESTORE were to explore the course of MS disease activity and the effects on pharmacokinetic, pharmacodynamic, and immune parameters in patients undergoing an interruption of natalizumab therapy for up to 24 weeks as compared with those in patients remaining on natalizumab. It also assessed the effects of alternate therapies during natalizumab interruption and after restarting natalizumab. Patients with MS receiving natalizumab were randomized into three treatment arms in a 1:1:2 ratio: natalizumab:placebo:alternate immunomodulatory therapy (interferon b-1a, glatiramer acetate or methylprednisolone).

A total of 175 patients were enrolled. At the baseline visit, all patients received a standard 300-mg natalizumab infusion. Starting at week 4, patients randomized to natalizumab or placebo received infusions every four weeks through to week 24 in a double-blind fashion. Patients randomized to other therapies who chose interferon b-1-a (IM IFN-b-1a) or glatiramer acetate (GA) received their first injections on day 0. Patients randomized to other therapies who chose methylprednisolone (MP) received infusions every four weeks starting at week 12. Clinical, MRI, and laboratory evaluations were performed every four weeks during the randomized treatment period starting at week 0, at the time of suspected relapse, and at the final visit. At week 28, patients resumed open-label infusions of natalizumab and stopped placebo or other therapy. Participants were followed for an additional 24 weeks, concluding the study at week 52.

Disease recurred in a large proportion of RESTORE patients who discontinued natalizumab treatment. The safety evaluations were generally consistent with the labeled risk profile for each of the respective marketed products, notably for natalizumab. Natalizumab treatment interruption resulted in occurrence of MRI disease activity as early as 12 weeks, and of clinical disease activity as early as 4–8 weeks, after the last natalizumab dose. Relapses occurring during the first one to three months have also been observed. In RESTORE, GA starting after the last dose of natalizumab and monthly MP starting 12 weeks after the last natalizumab dose did not appear to be effective in disease suppression, as compared with continued natalizumab treatment.

Authors: Karceski S.

Source: MSIF & Neurology. 2014 Apr 29;82(17):e155-7. doi: 10.1212/WNL.0000000000000423 (14/05/14)

New Data for MS drug Tysabri released at AAN annual meeting(01/05/14)

- New Tysabri® analysis shows improved walking speed in significant number of MS patients.

- Additional data show escalation to Tysabri following relapse improves clinical outcomes compared to remaining on or switching between first-line Interferon Beta and Glatiramer Acetate.

Biogen Idec announced that a post hoc analysis of data from the AFFIRM study shows Tysabri® (natalizumab) significantly increased the proportion of relapsing-remitting multiple sclerosis (RRMS) patients with confirmed improvement in walking speed (CIWS) relative to placebo at two years. Additional data from observational registry studies show that switching to Tysabri after experiencing a multiple sclerosis (MS) relapse while taking interferon beta (IFNβ) or glatiramer acetate (GA) reduced the risk of future relapses and treatment discontinuation. These data were presented at the 66th American Academy of Neurology (AAN) annual meeting in Philadelphia, Pa. (April 26-May 3, 2014).

“We know that MS has a significant impact on ambulation – a key concern for many people living with this disease – which is why we analyzed data from AFFIRM to evaluate the potential impact of Tysabri on walking speed,” said Alfred Sandrock, M.D., Ph.D., group senior vice president and chief medical officer at Biogen Idec. “Tysabri was associated with a 20 percent increase in walking speed, a clinically relevant improvement, in a significantly greater number of patients compared to placebo.”

Walking Speed Impacted with Tysabri

AFFIRM was a two-year, randomized, multi-center, placebo-controlled, double-blind study of 942 patients with RRMS that evaluated the effect of Tysabri on the progression of physical disability and the rate of clinical relapses. A post-hoc analysis of AFFIRM assessed the impact of Tysabri on the proportion of patients with CIWS compared to placebo. CIWS was defined as greater-than or equal to 20 percent increase in walking speed from baseline in the timed 25-foot walk (T25FW) confirmed 12 weeks later.

Results show that, over the course of two years, CIWS was significantly associated with improvement in patient-reported physical functioning. Treatment with Tysabri increased the proportion of patients with CIWS at year two by 79 percent compared to placebo (Tysabri, 12.3%; placebo 6.9%; p=0.0133). These effects were more significant and occurred earlier in patients with more advanced disability – with CIWS being increased by as much as five-fold compared to placebo at one year.

While many MS clinical trials measure disability progression, which includes a measure of ambulation by the Expanded Disability Status Scale (EDSS), these data from AFFIRM suggest that CIWS may be a more sensitive endpoint in capturing improved ambulation in RRMS patients.

These data were presented in a platform presentation on Tuesday, April 29 at 2:15 p.m. ET:

Natalizumab Treatment Improves Walking Speed in MS Patients: A Post Hoc Analysis of AFFIRM (S4.006)

Efficacy Effect Observed With Switch to Tysabri

Two additional studies used propensity-matched registry data to evaluate the effects of transitioning to Tysabri after an on-treatment relapse while taking INFβ or GA, compared to remaining on, or switching between, INFβ and GA. Results show that switching to Tysabri decreased the risk of future relapses, disability progression and treatment discontinuation for MS patients.

Because there are no randomized clinical trials comparing treatment options for patients with ongoing disease activity, comparisons of propensity-matched data from large observational cohorts are useful to estimate the relative risks associated with treatment decisions in a clinical setting. In these studies, researchers matched patients across three large observational clinical trials: Tysabri Observational Program (TOP), an ongoing observational, open - label, 10 - year prospective study of relapsing - remitting MS (RRMS) patients; MSBase, an ongoing, longitudinal database open to all practicing neurologists worldwide; and MSCOMET, a longitudinal MSBase registry substudy assessing the efficacy of IFNβ and GA in 1,000 patients in 14 countries.

In the first study, researchers matched 759 MS patients who participated in the MSCOMET study to the same number of patients in the TOP. They assessed time to first relapse, treatment discontinuation and disability progression over one year in those who relapsed on IFNβ or GA in the 12 months prior to study entry and either transitioned to Tysabri or stayed on their original first-line therapy. Data show that switching to Tysabri versus remaining on IFNβ or GA after an on-treatment relapse decreased the risk of relapse by 57 percent and reduced the risk of treatment discontinuation by 52 percent. Researchers also analyzed a smaller subset of patients (n=227 patient pairs) to assess disability progression. They found the incidence of three-month confirmed disability progression was lower in patients who transitioned to Tysabri than in those who persisted on IFNβ or GA; however, this difference was not statistically significant, likely due to the small sample size and small number of observed progression events.

In the second study, researchers compared annual relapse rate, treatment discontinuation and disability progression over one year within two subgroups of patients who participated in MSBase and the TOP: subgroup one, patients taking IFNβ who switched to GA compared to those who switched to Tysabri (n=578 for each cohort); and subgroup two, patients taking GA who switched to IFNβ compared to those who switched to Tysabri (n=165 for each cohort). Results show that transitioning to Tysabri treatment versus switching from IFNβ to GA reduced the risk of relapse by 63 percent and discontinuation risk by 62 percent. Transitioning to Tysabri treatment versus switching from GA to IFNβ also reduced the risk of relapse by 53 percent and discontinuation risk by 48 percent. Researchers then combined the subgroups to assess three-month confirmed disability progression; results showed that transitioning to Tysabri versus switching between IFNβ and GA reduced the risk of disability progression by 32 percent.

These data were presented as posters:

Comparative Efficacy of Switching to Tysabri Versus Switching to Interferon-Beta or Glatiramer Acetate after On-Treatment MS Relapse Using Propensity-Matched Registry Data (P3.175) was available for viewing on Tuesday, April 29 from 3:00-6:00 p.m. ET

Comparison of Switching to Tysabri Versus Remaining on Interferon-Beta or Glatiramer Acetate after On-Treatment MS Relapse Using Propensity-Matched Registry Data (P7.208)will be available for viewing on Thursday, May 1 from 3:00-6:00 p.m. ET

Source: MarketWatch Copyright © 2014 MarketWatch, Inc (01/05/14)

New clues to link between MS drug Tysabri and PML(26/03/14)

Researchers report drug mobilises a kind of cell easily infected by a virus that attacks the brain.

Researchers report that they think they have figured out why patients who take the multiple sclerosis drug Tysabri face a high risk of developing a rare, and sometimes fatal, brain infection.

A common virus that can cause the brain disease progressive multifocal leukoencephalopathy (PML) likes to infect and hide in certain blood cells that are triggered to mobilise by Tysabri, the study authors explained. Even more troubling, the researchers discovered that current tests may be missing some who harbour the virus.

"Right now, the risk of PML in patients treated with [Tysabri] for more than two years is about one in 75 patients. That's a very high risk," said study author Eugene Major, a senior investigator at the U.S. National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Md.

"We need to be able to understand why this therapy puts patients at risk. As we further define that, we'll be able to develop better tests and better treatment decisions can be made," Major said.

In PML, the normally harmless "JC virus" attacks the white matter of the brain, stripping nerve cells of their insulation. Without this insulation, nerve cells can't effectively carry brain signals. The disease causes progressive weakness, paralysis, changes in vision and speech, and problems with thinking and memory.

According to the NINDS, 30 percent to 50 percent of patients with PML die within a few months of diagnosis. Those who survive the infection may face permanent disability.

Though most people carry the JC virus, PML is rare. It tends to strike people with suppressed immune function, such as patients with AIDS or those taking powerful immune-suppressing drugs like Tysabri.

The drug has had a troubled history. First approved by the U.S. Food and Drug Administration in November 2004, it was pulled off the market three months later after cases of PML occurred in ongoing clinical trials.

Since Tysabri was allowed back on the U.S. market in 2006 with strict prescribing conditions, more than 440 cases of PML have been reported in patients taking the drug, according to the study background. In 2010, the FDA added a warning about the heightened risk of PML to the drug's labeling.

A combination of three factors seems to put patients at highest risk: treatment with Tysabri for more than two years; receiving other kinds of immune-suppressing medications; and testing positive for antibodies to the JC virus.

To find out why the drug carries such a high risk of PML, researchers collected blood samples from two groups of MS patients -- those just starting treatment with Tysabri, and those who had been on the drug for more than two years. They compared those samples to blood taken from healthy volunteers.

The investigators were looking for a particular type of cell in the blood -- a kind of stem cell that turns into white blood cells called B-cell lymphocytes.

"Turns out in these MS patients treated with [Tysabri], the number of these blood stem cells is three- to 10-fold higher than you'd see normally under normal physiologic conditions," Major said.

"JC virus is able to infect these blood stem cells as they become a B lymphocyte," he explained. His working theory has been that these infected B lymphocytes then carry the infection into the brain.

To test that theory, the researchers wanted to see if they could find traces of the JC virus in circulating blood stem cells.

And they did. Of 26 patients who were just starting treatment with Tysabri, 50 percent had traces of the JC virus in their circulating blood stem cells. Of 23 patients who had taken the drug for more than two years, 44 percent had JC virus DNA in more than one kind of blood stem cell type. In contrast, only 17 percent of the 18 healthy volunteers had signs of the JC virus in those cells.

"It was somewhat surprising to us that quite a high percentage of individuals had detectable viral DNA in these blood stem cells," Major said.

But what isn't exactly clear is how this could affect their risk of developing PML. Most patients who tested positive for JC virus had only a few copies of the virus, suggesting that they were still at low risk of infection. Patients who had taken the drug for more than two years had higher virus counts than those who were just starting treatment.

"We need to look at additional patients, and follow them for a long period of time," Major said.

Perhaps most concerning, 10 study participants had evidence of the JC virus in their blood but tested negative for antibodies to it. That suggests current tests for the virus may be missing some patients who could be at high risk for PML infection, the authors explained.

An expert who was not involved in the study, which was published online March 25 in the journal JAMA Neurology, said the findings left some questions unanswered.

"Clearly, Tysabri seems to engender the release of JC virus-containing cells from the bone marrow," said Dr. Gary Birnbaum, a neurologist and director of the Multiple Sclerosis Treatment and Research Center in Golden Valley, Minn. "This could explain why risks of PML are high in patients on this drug," he noted.

"What isn't clear is why the risk escalates dramatically after two years, since JC virus-bearing cells emerge early in the course of treatment," Birnbaum pointed out.

Additionally, Birnbaum said it was "disquieting" that researchers found evidence of the JC virus in patients who then tested negative for antibodies to it.

"Thus, testing individuals for exposure to JC virus by measuring antibodies to the virus may be insufficient to fully assess their risks for developing PML," he said.

Source: WebMD ©2005-2014 WebMD, LLC (26/03/14)

Australian regulator finds no definite melanoma link for Tysabri(19/03/14)

Australia’s Therapeutic Goods Administration (TGA) revealed today that it is monitoring reports of melanoma in patients being treated with natalizumab and encourages consumers and health professionals to report all such cases.

Natalizumab, Biogen Idec’s blockbuster drug Tysabri, which generated global in-market sales of $1.7 billion last year) is used to treat patients with relapsing-remitting multiple sclerosis to delay the progression of physical disability and reduce the frequency of relapse.

Melanoma is potentially life-threatening and Australia has one of the highest incidence rates of this condition in the world.Three cases of melanoma in patients being treated with natalizumab have been reported to the TGA.

An ongoing TGA review of this issue has found insufficient evidence to show a definite link between natalizumab and melanoma. However, given the high incidence of melanoma in Australia, this remains an issue of concern for the TGA.

Source: The Pharma Letter © The Pharma Letter Limited 2014 (19/03/14)

Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results(21/02/14)

Abstract

BACKGROUND: Clinical trials established the efficacy and safety of natalizumab. Data are needed over longer periods of time and in the clinical practice setting.

OBJECTIVE: To evaluate long-term safety of natalizumab and its impact on annualised relapse rate and Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting multiple sclerosis (RRMS).

METHODS: The Tysabri (natalizumab) Observational Program (TOP) is an open-label, multinational, 10-year prospective study in clinical practice settings.

RESULTS: In this 5-year interim analysis, 4821 patients were enrolled. Follow-up for at least 4 years from natalizumab commencement in 468 patients and at least 2 years in 2496 patients revealed no new safety signals. There were 18 cases of progressive multifocal leucoencephalopathy reported, following 11-44 natalizumab infusions. Mean annualised relapse rate decreased from 1.99 in the 12 months prior to baseline to 0.31 on natalizumab therapy (p<0.0001), remaining low at 5 years. Lower annualised relapse rates were observed in patients who used natalizumab as first MS therapy, in patients with lower baseline EDSS scores, and in patients with lower prenatalizumab relapse rates. Mean EDSS scores remained unchanged up to 5 years.

CONCLUSIONS: Interim TOP data confirm natalizumab's overall safety profile and the low relapse rate and stabilised disability levels in natalizumab-treated patients with RRMS in clinical practice.

TRIAL REGISTRATION NUMBER: NCT00493298.

Butzkueven H1, Kappos L, Pellegrini F, Trojano M, Wiendl H, Patel RN, Zhang A, Hotermans C, Belachew S; on behalf of the TYSABRI Observational Program (TOP) Investigators.

Source: J Neurol Neurosurg Psychiatry. 2014 Feb 14. doi: 10.1136/jnnp-2013-306936. & Pubmed PMID: 24532785 (21/02/14)

HIV drug may help in PML(31/01/14)

A relatively simple way to make progressive multifocal leukoencephalopathy (PML) more survivable appears to have worked in a multiple sclerosis patient taking natalizumab (Tysabri).

Before telling you what that remedy is, first let's go over what happens in PML. Those already familiar with it and a related condition called IRIS can skip over this part.

PML is a severe brain inflammation arising from reactivation of latent infection with the so-called JC virus, which is common in the general population. This reactivation usually results from some type of immunosuppression -- PML has been seen in conjunction with cancer chemotherapy, HIV infection, and with certain drugs targeting particular immune-system components.

Although natalizumab has attracted the most attention recently for PML risk, the condition has been linked to other drugs, including rituximab (Rituxan), fingolimod (Gilenya), and others.

With natalizumab-related PML, the death rate has been about 20%, and many patients who have survived show permanent neurocognitive deficits. Consequently, clinicians want to treat it aggressively. The normal treatment is plasmapheresis, in order to remove natalizumab (which has a long half-life) from circulation as quickly as possible, restoring immune function and suppression of the JC virus.

Unfortunately, the sudden removal of natalizumab often triggers a condition called immune reconstitution inflammatory syndrome (IRIS), which is practically as dangerous as PML. Many of the deaths and persistent deficits attributed to PML actually are a consequence of IRIS.

Amit Bar-Or, MD, of McGill University in Montreal, and colleagues reported in the New England Journal of Medicine this week that oral maraviroc (Selzentry), a CCR5 chemokine receptor antagonist for treating certain forms of HIV infection, helped a 49-year-old woman with MS avoid IRIS following plasmapheresis. The woman had undergone plasmapheresis because she had developed PML while taking natalizumab.

The treatment had two inspirations. One was bench research that implicated the CCR5 receptor as important to immune cell populations that contribute to IRIS. The other was a 2009 case report from France in which an HIV patient who developed PML and IRIS (which can paradoxically develop in HIV patients in the absence of plasmapheresis) responded well to maraviroc, which had been administered because it was supposed to have vague "immunomodulating properties."

Bar-Or and colleagues started the woman on maraviroc shortly after plasmapheresis. For 2 months, she showed no "clinical or imaging evidence of overt IRIS," they wrote.

She then stopped taking the maraviroc for 5 days, at which point she developed clear neurocognitive symptoms and showed IRIS-like features on brain MRI scans. Her doctors restarted the maraviroc and the symptoms and brain lesions abated, but she was left with some mild but permanent cognitive deficits.

It's too early to say whether maraviroc will become a standard part of PML treatment. On the other hand, for clinicians with PML patients on their hands, it seems likely that many if not most will give maraviroc a try -- given the risks of not trying.

Several authors of the report had relationships with pharmaceutical companies that sell MS drugs, including natalizumab's manufacturer, Biogen Idec. None reported a relationship with maraviroc's manufacturer, ViiV Healthcare.

Source: MedPage Today © 2014 MedPage Today, LLC (31/01/14)

IgM antibody identifies good candidates for natalizumab(09/10/13)

Researchers in Spain have identified lipid-specific antibody bands in the cerebrospinal fluid (CSF) that are associated with an aggressive presentation of multiple sclerosis (MS), and patients with these antibodies seem to have a much lower risk for progressive multifocal leukoencephalopathy (PML) with natalizumab therapy (Tysabri, Biogen Idec).

"The presence of lipid-specific IgM bands in the CSF signals patients with aggressive disease and highly activated immune systems," said Luisa Villar, PhD, Hospital Ramón y Cajal, Madrid, Spain. "We seem to be able to lower the immune system in patients in whom it is highly activated without inducing immunosuppression. So natalizumab is safe to use in this population, and these are the very patients who need this strong drug.

"About one third of MS patients test positive for IgG antibodies," she added. "These patients generally have highly active disease, with many relapses. Beta-interferons don't work well for these patients and so they need a stronger drug right from the start. Therefore natalizumab is a good treatment option for these patients," Dr. Villar told Medscape Medical News. "And now we have shown that natalizumab is actually very safe in this group too. Our cohort of patients, some of whom have been treated for 5 years, have an extremely low risk of developing PML."

Dr. Villar says her hospital now routinely tests for IgM in all new patients with MS. "If positive, I would recommend natalizumab as first-line therapy. I am trying to urge other hospitals in Spain to do the same."

She explained that the IgM antibodies are targeted against lipids and they recognize myelin in the axons of neurons, which is extremely rich in lipids.

Dr. Villar presented their findings at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

In her presentation, Dr. Villar noted that IgM antibodies are believed to have a role in the pathology of MS. "Most patients with IgM bands in the CSF show suboptimal response to beta-interferon, but a good response to natalizumab, with 90% of inhibition of relapse rate and stabilization or improvement of EDSS [Expanded Disability Status Scale] score in most cases."

The aim of the current study was to explore the risk for PML in patients with and without these IgM antibody bands. The study involved 365 patients treated with natalizumab, of whom 240 tested positive for IgM. There were 22 cases of PML reported.

Results showed that IgM antibodies were detected in 70% of patients in the group who did not get PML but in only 1 (4%) of those who did get PML.

"We now have data on 365 patients on natalizumab," she said. "Of these, 240 are positive for IgM and in this group there has only been 1 case of PML. In the 120 patients who are IgM negative there were 21 cases of PML. These data are absolutely significant."

She added that patients who developed PML had a much longer disease duration when they started natalizumab therapy, but the duration of natalizumab treatment in both groups was similar.

Upon analysis of JC virus (JCV) antibody status (the virus that causes PML), about half the patients who did not develop PML and all but 1 patient who developed PML were found to be JCV positive.

Dr. Villar reported that the presence of IgM antibodies lowered the risk for PML in patients positive for JCV antibodies to that of patients who tested negative for JCV antibodies.

When asked for a possible explanation of these observations, Dr. Villar noted that patients who test positive for IgM antibodies also have very high levels of CD4 lymphocytes.

"They have highly inflammatory disease, with 20 times more CD4 lymphocytes than IgM-negative patients before treatment with natalizumab." She suggested that in patients with such highly inflammatory disease, the immune system is so activated that the patient is protected against the development of immunosuppression with natalizumab.

Dr. Villar has received speaking honoraria from Bayer Schering Pharma, Merck Serono, Biogen-Idec, Teva Pharmaceuticals, sanofi-aventis, and Novartis.

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Abstract 180. Presented October 4, 2013.

Source: Medscape Copyright © 1994-2013 by WebMD LLC (09/10/13)

Tysabri may be possible for more MS patients with new test(08/10/13)

A blood test for L-selectin expression on circulating immune cells may identify multiple sclerosis patients who could safely receive natalizumab (Tysabri) despite past exposure to the JC virus, a small study presented here suggested.

All MS patients taking natalizumab who developed the rare but life-threatening brain inflammation called progressive multifocal leukoencephalopathy (PML) in the study had very low levels of L-selectin expression, which was not seen in other patients who did not develop PML or in controls, said Heinz Wiendl, MD, of the University of Muenster in Germany.

He and his colleagues at the Muenster MS clinic have begun to implement the test in patients, he told attendees at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting, using a cutoff of 30% of circulating T cells positive for L-selectin (also known as CD62L).

So far, 10 patients had levels consistently below the cutoff in repeat testing. Four stopped natalizumab after counseling, Wiendl said. One developed PML, and five others are still taking the drug but with no sign of PML so far.

A larger validating study is now underway, with 342 patients accrued so far, Wiendl said.

PML results from reactivation of latent infection with the JC virus, which is common in the general population. It has been a particular problem with natalizumab, appearing shortly after the drug was approved in 2004 and forcing it off the U.S. market until its manufacturer implemented a strict risk evaluation and mitigation strategy.

Current recommendations call for JC virus serological testing in patients prior to starting natalizumab and periodically while on the drug to detect new infections. Although a positive test is not an absolute contraindication for the drug -- it remains the standard of care for patients showing aggressive MS activity in patients taking first-line therapies -- it is to be prescribed cautiously.

PML risk in patients with JC virus infection is increased with prior immunosuppressive therapy and duration of natalizumab treatment beyond 2 years.

Natalizumab mainly targets the alpha-4 integrin protein, an adhesion molecule, as is L-selectin. Studies of T cells in blood and cerebrospinal fluid (CSF) taken from 381 patients treated at the Muenster clinics showed that alpha-4 integrin expression in CSF T cells was essentially nil in natalizumab-treated patients.

But because some type of adhesion molecule action is necessary for T cells to enter CSF, Wiendl said, the finding indicated that an alternative pathway must exist, prompting the attention to L-selectin.

Among patients with long-term natalizumab therapy who did not develop PML, a mean of 40.2% of their peripheral blood CD4-positive T cells expressed L-selectin, whereas in the eight patients who later developed PML and for whom pre-PML blood samples were available, the average was 4.6% (P<0.0001), Wiendl said.

He told MedPage Today that the most obvious use of an L-selectin test would be to identify patients with past JC virus exposure on natalizumab with relatively high T-cell expression of L-selectin, since so far they appear to be at low risk for PML.

But he noted that JC virus-negative patients could benefit as well, because their risk of PML is not zero. JC virus serology tests may miss patients with recent infection or may simply be wrong; and the condition can be caused by other viruses.

Currently, he said, the group is beginning to test patients when they have received 18 natalizumab infusions, and then every 6 months. (He said the test "is very laborious.") In patients with L-selectin positivity in less than 30% of CD4-positive T cells, a switch to other therapies is considered.

Session co-moderator Fred Lublin, MD, of Mount Sinai School of Medicine in New York City, told MedPage Today that it was too early to say how much promise the technology held. "Not enough data," he said.

Wiendl agreed, even though his clinic is already using the test to help guide treatment management in patients. "We need four-digit numbers [of patients] to really validate it."

The study had no commercial funding.

Wiendl reported relationships with Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, Teva, and Novo Nordisk.

Primary source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference: Schneider T, et al "Dynamic biomarkers for clinical efficacy and individual PML prevention under natalizumab therapy" ECTRIMS 2013; Abstract 232.

Source: MedPage Today © 2013 MedPage Today, LLC (08/10/13)

New Tysabri data show earlier treatment & longer-term use result in significant reductions in MS disease activity(03/10/13)

Biogen Idec announced results from several new analyses of Tysabri(R) (natalizumab) data that demonstrate its effectiveness in reducing multiple sclerosis (MS) disease activity. This effect was particularly significant in people with relapsing MS who initiated treatment when they had lower Expanded Disability Status Scale (EDSS) scores as well as in those who have been treated for more than two years. These data will be presented at the 29(th) Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Copenhagen, Denmark from 2-5 October.

"These analyses build upon a growing body of evidence that demonstrates greater clinical benefits for people with MS when Tysabri is initiated earlier in the course of the disease, as well as when Tysabri is used for a longer duration in appropriate patients," said Alfred Sandrock, M.D., Ph.D., group senior vice president, Development Sciences and Chief Medical Officer, Biogen Idec.

More Patients Demonstrated No Evidence of Clinical or MRI Disease Activity with Earlier Tysabri Use

AFFIRM was a two-year, randomized, multi-center, placebo-controlled, double-blind study of 942 patients evaluating the effect of Tysabri on the rate of clinical relapses and the progression of disability as measured by at least a one-point worsening in EDSS score sustained for three months.

A post-hoc analysis of AFFIRM was undertaken to determine which baseline characteristics were associated with patients showing no evidence of clinical or MRI disease activity (defined as no relapse, no 12-week sustained EDSS progression, and no gadolinium-enhancing [Gd+] or new/enlarging T2-hyperintense lesions) at two years. A greater proportion of Tysabri patients were found to have no evidence of clinical or MRI disease activity compared to those on placebo in all sub-groups analyzed with the beneficial effect being significantly greater in patients with an EDSS score of <3.0 versus >= 3.0 at baseline.

Fewer and Less-Severe Relapses with Tysabri

An additional sub-analysis of AFFIRM assessed the effectiveness of Tysabri on reducing relapse severity and recovery from relapse compared to placebo. Observations from this sub-analysis showed that patients treated with Tysabri experienced less-severe relapses, as measured by EDSS score changes during the relapse and residual deficits following relapse.

These data will be presented in the poster session titled, "Immunomodulation/Immunosuppression," on Friday, 4 October at 3:45 p.m. -- 5:00 p.m. CET:

-- Effects of natalizumab treatment on freedom from disease activity by baseline characteristics in AFFIRM (poster 519)

-- Natalizumab reduces the disabling amplitude of multiple sclerosis relapses and improves post-relapse residual disability (poster 524)

Clinical Benefit of Tysabri Improves Beyond Two Years of Treatment

An analysis of data from the Tysabri Observational Program (TOP), an ongoing observational, open-label, 10-year prospective study of relapsing-remitting MS (RRMS) patients, assessed patients who have been treated with Tysabri for at least four years. The analysis found that patients with less disability at baseline (EDSS score of <3.0 at baseline) had a significantly greater reduction in 12 month sustained disability progression in months 25-48 compared with months 0-24. Additionally, annualized relapse rates (ARR) in patients treated with Tysabri decreased from 2.03 at baseline to 0.19 during months 0-24 and 0.18 during months 25-48 (p<0.0001).

"Tysabri has advanced the treatment of RRMS patients with its established efficacy," Sandrock added. "This analysis is encouraging because it provides new insight into the use of Tysabri beyond two years and suggests that effects of treatment are even better with longer use in appropriate patients."

These data will be presented in the poster session titled, "Long-Term Treatment Monitoring," on Friday, 4 October at 3:30 p.m. -- 5:00 p.m. CET:

-- Disease activity and disability progression decrease beyond 2 years on natalizumab in relapsing MS patients in the Tysabri(R) (natalizumab) Observational Program (poster 1050)

Source: The Wall Street Journal ©2013 Dow Jones & Company, Inc (03/10/13)

Biogen Idec, Elan facing suits over MS drug side effects(10/09/13)

Despite living with multiple sclerosis since 1997, Kimberley A. Yout kept a busy schedule, working full time as a money manager for a Boston bank and modeling in her spare time.

That changed on Aug. 28 of last year when Yout, 45, was diagnosed with a rare brain infection that developed as a side effect of Tysabri, a drug she took for six years to keep her MS in check. Yout’s speech became slurred, her gait unsteady, and her future uncertain.

“I was a very successful businesswoman,” said Yout, who lives in Hanover. “Today, I can’t even balance my checkbook, I can’t use an ATM, I can’t see out of one eye. I had to move back in with my mother. I’ve lost my independence. I’ve lost everything.”

Now, she is suing the two companies that marketed Tysabri — Biogen Idec Inc. of Weston and the Irish drug maker Elan Pharmaceuticals Inc. — in Middlesex Superior Court in Woburn. Her complaint, filed Friday, alleges they failed to adequately warn patients of the risks some face from prolonged use of Tysabri.

The lawsuit is one of at least a half-dozen pending in Massachusetts and federal courts in three other states. In each case, plaintiffs are seeking more than $1 million in punitive damages from Biogen Idec and Elan on behalf of patients or their families. After taking Tysabri, the patients developed progressive multifocal leukoencephalopathy, known as PML, an infection of the brain’s white matter that can cause death or severe disability.

Many doctors consider Tysabri highly effective in slowing the progression of relapsing forms of MS, a neurodegenerative disease, in adults for whom other drugs have stopped working. That’s why many of them take it, despite the risks.

Biogen Idec has been working to move beyond nearly a decade of controversy over Tysabri. Last year, it altered the drug’s label to include new safety information and introduced blood tests to help doctors identify patients’ risk level for PML. But the new suit and those pending are again raising questions about the drug’s safety.

Tysabri was approved by the Food and Drug Administration in 2004. But Biogen Idec and Elan pulled it from the market in 2005 after several PML cases, two of which resulted in death. The companies reintroduced the drug in 2006, with the approval of regulators, along with a “risk management” program that trains physicians prescribing Tysabri and requires them to monitor patients monthly under strict guidelines.

The approval for Tysabri, despite its chance of causing brain infections, was not unique. Regulators sometimes allow potentially dangerous drugs on the market if the disease they seek to ameliorate is severe, and they determine the benefits outweigh the risks.

“Based on the available information to date, the FDA continues to believe that the benefits of taking Tysabri outweigh the potential risks,” said FDA spokeswoman Stephanie Yao.

In recent years, Tysabri has become Biogen Idec’s second-largest-selling therapy, generating 2012 revenue of $1.6 billion, and is used by about 118,000 patients globally. But cases of PML continue to turn up in the United States and around the world. As of August, there were 395 confirmed cases of Tysabri-associated PML, including 92 deaths, according to Biogen Idec’s data.

Biogen Idec spokeswoman Kate Niazi-Sai declined to address Yout’s complaint specifically, citing company policy. More generally, she defended Tysabri and Biogen Idec’s response to the brain infection.

“We take PML very seriously,” Niazi-Sai said. “And we’re doing everything we can to educate doctors and patients on the benefits of Tysabri and also the risks. Tysabri is extremely effective for MS, but it’s got to be the right choice for patients in consultation with their physicians.”

Biogen Idec’s studies, resulting in the tests to gauge PML vulnerability, identified three risk factors for MS patients, Niazi-Sai said. The company found those most susceptible to the infection have taken immunosuppressant drugs previously, have used Tysabri for at least two years, or have contracted the JC virus. That virus is latent in as much as half of the general population, but is almost always suppressed by the immune system. Immunosuppressant drugs, such as Tysabri, can compromise the immune system, allowing the virus causing PML to replicate in the brain.

Elan sold its interest in Tysabri to Biogen Idec earlier this year for $3.2 billion, but still collects royalties. A representative of Elan declined to discuss the lawsuit. “The company doesn’t comment on matters of litigation,” said Jamie Tully, a New York-based spokesman.

Yout’s lawsuit levels six charges against the two companies, including failure to warn patients of Tysabri’s risks and negligent and fraudulent misrepresentation of the drug in product information.

“Tysabri was unaccompanied by adequate warnings of the risk of PML, either known or reasonably scientifically knowable at the time of distribution,” her suit alleges.

“It’s important for patients to know the risks of taking this kind of drug,” said Sofia E. Bruera, a Houston lawyer representing Yout and other MS patients who lodged state and federal complaints against Biogen Idec and Elan in Massachusetts, New York, New Jersey, and Utah. “Our clients weren’t adequately warned about the risks, and it ruined their lives.”

One of the other cases filed in Middlesex Superior Court involves Marla Fair, 40, a Greenfield, Ind., woman who was diagnosed with MS in 2002 and five years later began taking Tysabri. Two years after that, she was diagnosed with PML. Today, Fair walks with a cane and uses a wheelchair outside the home. Monday through Friday, she lives with her parents in Frankton, Ind., about 35 miles from her own home, while her husband, Terry, works in an auto parts plant to help pay for her 24-hour care.

“When she tries to talk to you, she’ll say things in a backward manner,” Terry Fair said of his wife. “They did not warn us that the longer you take this drug, the more likely you are to get PML. . . . I just want to get my wife home. I’m not looking to win a billion dollars or anything. I just want them [Biogen Idec and Elan] to help me take care of her.”

Yout and Terry Fair contend Tysabri should not be on the market, arguing that despite its benefits, the risks to some patients can be devastating.

“It’s like playing Russian roulette,” Fair said.

Source: The Boston Globe © 2013 THE NEW YORK TIMES COMPANY (10/09/13)