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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)

Tysabri may inhibit endogenous retro virus in MS(29/07/13)

Natalizumab inhibits the expression of human endogenous retroviruses of the W family in multiple sclerosis patients: a longitudinal cohort study.

Abstract

BACKGROUND: Several viruses were reported as co-factors triggering the pathogenesis of multiple sclerosis (MS), including the endogenous retroviruses of the HERV-W family, that were also proposed as biomarkers of disease progression and therapy outcome.

OBJECTIVE: The objective of this article is to clarify whether in MS patients treatment with natalizumab has effects on MSRV/syncytin-1/HERV-W expression and the possible relationship with disease outcome.

METHODS: Peripheral blood mononuclear cells were collected from 22 patients with relapsing-remitting disease, at entry and after three, six and 12 months of treatment with natalizumab. The cell subpopulations and the expression of MSRVenv/syncytin-1/HERV-Wenv were analyzed by flow cytometry and by discriminatory env-specific RT-PCR assays.

RESULTS: By flow cytometry the relative amounts of T, NK and monocyte subpopulations were shown to remain fairly constant. A relative increase of B lymphocytes was observed at three to six months (p = 0.033). The MSRVenv and syncitin-1 transcripts were reduced at six to 12 months of therapy (p = 0.0001). Accordingly, at month 12, the plasma-membrane levels of the HERV-Wenv protein were reduced (p = 0.0001). B cells, NK and monocytes but not T cells expressed the HERV-Wenv protein. None of the patients relapsed during therapy.

CONCLUSION: Effective therapy with natalizumab downregulates MSRV/syncytin-1/HERV-W expression.

Arru G, Leoni S, Pugliatti M, Mei A, Serra C, Delogu LG, Manetti R, Dolei A, Sotgiu S, Mameli G.
Department of Clinical and Experimental Medicine, University of Sassari, Italy.

Source: Mult Scler. 2013 Jul 22 & Pubmed PMID: 23877972 (29/07/13)

PML not fatal if caught early enough(10/07/13)

All multiple sclerosis patients taking natalizumab (Tysabri) who were diagnosed with progressive multifocal leukoencephalopathy (PML) before symptoms appeared were still alive a year later, researchers said.

In contrast, nearly a quarter of patients in whom PML was diagnosed on the basis of clinical symptoms died, according to Tuan Dong-Si, MD, of Biogen Idec, natalizumab's manufacturer.

They suggested that MRI data for all patients on natalizumab should be examined carefully for signs of PML, including those who are asymptomatic.

The retrospective study of 319 patients developing natalizumab-associated PML worldwide was reported in an abstract presented at the American Academy of Neurology's annual meeting.

PML is a severe brain inflammation resulting from reactivation of latent infection with the JC virus.

The latter is extremely common and causes no symptomatic disease in most people. However, it can become dangerously active in individuals with suppression of certain aspects of their immune function.

PML was first noticed in patients receiving immunosuppressive cancer therapies and then in connection with AIDS. It appeared in multiple sclerosis (MS) patients treated with natalizumab, a monoclonal antibody targeting a leukocyte adhesion factor, shortly after the drug was approved in 2004.

The drug was removed from the U.S. market for 16 months, then relaunched with a strict distribution and registry program. However, PML cases continue to appear. Because of the risk, natalizumab is generally used as second-line therapy for MS.

As of Jan. 1, 2013, a total of 319 cases associated with natalizumab have been tracked by Biogen Idec and its marketing partner, Elan Pharmaceuticals, according to Dong-Si and colleagues.

In their review of records for these cases, the researchers identified 21 in whom PML was diagnosed prior to onset of symptoms, on the basis of routine MRI scans conducted for MS patients.

They found that all 21 were still living 12 months after diagnosis, whereas 228 of the 298 diagnosed with symptomatic PML had survived.

Dong-Si and colleagues also examined data on the trajectory of disability prior to and after PML diagnosis, finding that the patients with early PML diagnosis appeared to fare much better.

In particular, mean Expanded Disability Status Scale (EDSS) scores were substantially higher in the patients diagnosed symptomatically and Karnofsky Performance Scale (KPS) scores were significantly lower, although these data were available for only a minority of patients.

At the patients' last clinic visit prior to diagnosis of PML, mean EDSS and KPS scores were similar between those subsequently diagnosed with asymptomatic versus symptomatic PML (EDSS 3.2 versus 3.8, respectively, P=0.263; KPS 88.0 versus 80.1, respectively, P=0.144).

At diagnosis, EDSS scores were significantly different between the two groups and the KPS scores also had begun to diverge (EDSS 3.6 asymptomatic versus 5.3 symptomatic, P=0.020; KPS 66.7 asymptomatic versus 53.6 symptomatic, P=0.129).

At month 12 post diagnosis, mean EDSS scores had returned to baseline in the asymptomatic group (although data were available for only three of these patients) whereas in the 39 symptomatic PML patients they remained high (3.7 versus 6.5, P=0.066).

KPS scores at month 12 differed significantly, with means of 70.0 in four asymptomatic patients and 46.9 in 50 symptomatic patients (P=0.021).

The study was limited by the small numbers of patients with EDSS and KPS scores available as well as the retrospective design.

PML incidence is expected to decline with screening of MS patients for JC virus exposure prior to natalizumab's initiation, which has only recently become routine.

The study was funded by Biogen Idec and Elan Pharmaceuticals. Dong-Si and other authors are Biogen Idec employees.

Primary source: American Academy of Neurology
Source reference: Dong-Si T, et al "Natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients: survival and functional outcome when asymptomatic at diagnosis" AAN 2013; Abstract P04.268.

Source: Medpage Today © 2013 MedPage Today, LLC (10/07/13)

Early development of anti-natalizumab antibodies in MS patients(20/06/13)

Abstract

The purpose of this study is to monitor the development of anti-natalizumab antibodies to evaluate their first appearance in multiple sclerosis patients, since their presence has been associated with a reduction in the efficacy of the treatment and an increase of adverse events.

A total of 134 multiple sclerosis patients were included in the trial.

Anti-natalizumab antibodies were monthly detected by ELISA up to the first year of treatment and subsequently, a determination was made at 18 months. 15.7 % of the patients were positive, being 7.5 % transiently positive and 8.2 % persistently positive.

The first appearance of anti-natalizumab antibodies occurred after the first month of treatment onset in 72 % of positive patients; 18 % did so after the second month, and 9.7 % after the third month.

Antibodies were never detected for the first time after the fourth infusion.

The development of anti-natalizumab antibodies occurs very early after treatment onset.

This observation should be considered when standardizing the follow up of patients treated with this drug in order to minimize the risks and optimize the treatment.

Oliver-Martos B, Orpez-Zafra T, Urbaneja P, Maldonado-Sanchez R, Leyva L, Fernández O.

Source: Pubmed PMID: 23765090 & J Neurol. 2013 Jun 14 (20/06/13)

JCV test stratifies PML risk in antibody-positive MS(17/06/13)

A quantitative test for antibodies to the JC virus (JCV) stratifies antibody-positive patients with multiple sclerosis (MS) for their risk of contracting progressive multifocal leukoencephalopathy (PML) if they receive natalizumab (Tysabri, Biogen Idec). However, some risk remains even with low antibody levels, and some patients who harbor the virus have proven negative for antibodies, studies show.

Presenting preliminary results of a study here at the 23rd Meeting of the European Neurological Society, Barry Ticho, MD, PhD, vice president of clinical development at Biogen Idec in Cambridge, Massachusetts, commented to Medscape Medical News, "What it would indicate to us right now is that the current levels [of risk] that are ascribed to patients who are JC antibody-positive may not be uniform across that group for those who've not had prior immunosuppressive use."

After 2 years of therapy, approximately 5 per 1000 patients test positive for antibody. But "there's a population that ranges between 30% and almost half of the [antibody-positive] patients who may be at substantially lower risk of PML than is currently ascribed," he said.

PML is an opportunistic viral disease causing inflammation of the white matter of the brain. It is usually fatal. JC virus is normally kept in check by the immune system, but immunosuppressive therapies can compromise this ability. Natalizumab is thought to act by blocking the ability of inflammatory immune cells to migrate across the blood-brain barrier.

In the present study, anti-JCV antibody levels were determined by using the second-generation Stratify (Biogen Idec) JCV enzyme-linked immunosorbent assay (ELISA). Data were from antibody-positive patients from postmarketing sources and natalizumab clinical trials. The ELISA yields an anti-JCV antibody index, which is an optical density measurement of antibody level and is a corollary to antibody titer.

Higher JCV Antibody Levels Precede PML Diagnosis

Patients who were diagnosed with PML (n = 71) had significantly higher JCV antibody index values more than 6 months before the diagnosis compared with patients without a PML diagnosis (n = 2522) (P < .001). Differences in antibody indices occurred only in comparison of patients with (n = 19) and those without (n = 176) a PML diagnosis who had not had prior immunosuppressive therapy; values were higher for patients later diagnosed with PML (P < .001).

For patients who had received immunosuppressive therapy earlier, there was no significant difference in antibody levels between those later diagnosed with PML and those without PML (P = .87).

For JCV antibody–positive patients with no prior immunosuppressant use, the risk for PML increased with longer natalizumab use. For 1 to 24 months of exposure to the drug, the risk was 0.6/1000. With 25 to 48 months of exposure, the risk increased to 5.2/1000, and with 49 to 72 months of natalizumab, the risk was 5.4/1000. Patients who were antibody negative had a risk of 0.07/1000.

For patients with no prior immunosuppressive exposure, antibody index values allowed estimation of PML risk according to the duration of exposure to natalizumab. Patients with lower antibody levels remained at substantially lower PML risk over the course of natalizumab therapy compared with patients with higher antibody levels.

"We know that currently some physicians after 2 years of natalizumab treatment in their antibody-positive patients will take the patients off of drug because of a fear of PML," Dr. Ticho said. "Perhaps for patients who have lower antibody index levels there is another analysis of the benefit-risk that has to be made with respect to both the disease course that those patients have and the fact that their risk of PML may actually be lower than expected right now."

Patients With Low Antibody Levels Still at Risk

Dr. Ticho also noted that some antibody-negative patients seroconvert over time, with an expectation of increased PML risk. "Our data would indicate that depending on what index level they have after they change from negative to positive the change in their PML risk may not be nearly as dramatic as people are expecting," such as going from a risk of 1 per 10,000 to an expected risk of 1 per 500. "But now we see that maybe they're only going from a risk of 1 per 10,000 to maybe a risk of 1 per 1000 or even less."

By 18 months of natalizumab treatment, 96% of 553 previously antibody-negative patients remained negative (87%) or seroconverted to a low antibody index level. The current recommendation is to test patients every 6 months for antibody levels.

Dr. Ticho cautioned that the data are still preliminary and the hypothesis of risk based on antibody levels needs further validation.

Session moderator Ludwig Kappos, MD, professor of neurology and clinical neuroimmunology at the University of Basel and chair of the Department of Neurology at University Hospital in Basel, Switzerland, commented to Medscape Medical News that the study provides a further step in defining the risk of PML and is important for that reason, "but it does not eliminate the risk. You have to understand how the risk is and perhaps also to tailor the other additional measures of surveillance, but it is of course not eliminating the risk."

He said that up to now, tests have shown only whether a patient was positive or negative for antibody, but by judging antibody levels on a continuum and with thresholds for risk, "it shows at least a part of those who are positive may still have a reasonable risk that you would perhaps be ready to take regarding the efficacy of taking the drug and the alternatives." Thus, such a test may open a path for some of the positive patients to get back to or to continue receiving natalizumab therapy.

"Even with more precise risk calculations," Dr. Kappos said, "it's still an individual decision between the treating physician and the patient if they stop treatment or not."

Evolution of JCV Antibody Testing

JCV antibody testing has evolved over the past few years. In 2010, researchers reported development of an ELISA to detect antibodies in serum and plasma, with the hope that the test could be used to confirm the absence of antibodies and therefore facilitate natalizumab treatment of patients at low risk for PML.

In January 2012 the US Food and Drug Administration approved a test so that clinicians could tell whether a patient was positive or negative for the presence of antibodies. Periodic retesting was advised because antibody-negative patients could become infected with JCV over time.

The present risk stratification efforts based on the amount of antibody further refine the risk but are not perfect. Patients with low levels of antibody are still at some risk. And a report in the June 6 New England Journal of Medicine showed that in 1 series, one third of patients with MS who tested negative for anti-JCV antibodies had active JCV viremia. However, it is not practical to test for JCV in the clinic at this time.

The study was sponsored by Biogen Idec. Dr. Ticho and all coauthors are employees of the company. Dr. Kappos was not involved in the study and has disclosed no relevant financial relationships.

23rd Meeting of the European Neurological Society. Abstract #O228. Presented June 9, 2013.

Source: Medscape News Today Copyright © 1994-2013 by WebMD LLC (17/06/13)

JCV Test 'Useful But Not Sufficient' to Gauge PML Risk(07/06/13)

A new report raises questions about the reliability of the test for JC virus (Stratify, Biogen Idec) to help determine risk for progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with natalizumab (Tysabri, Biogen Idec).

Eugene O. Major, PhD, from the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland; Elliot Frohman, MD, PhD, from the University of Texas Southwestern Medical Center in Dallas; and Daniel Douek, MD, PhD, from the National Institute of Allergy and Infectious Diseases, report that in their series, one third of patients with MS who tested negative for antibodies to JC virus were found to have active JC viremia.

"Although viremia by itself is not a predictor of the risk of PML, the observation that viremia can occur in patients with negative test results for antibodies to the JC virus raises other issues," the authors write. "The relatively high percentage of patients who had viremia and were seronegative appears to be greater than the false negative rate identified previously. In some of these patients, the same blood sample showed T-cell responses to JC virus proteins but a seronegative test result."

Their findings are published as Correspondence in the June 6 issue of the New England Journal of Medicine.

Before and After Treatment

For this report, Dr. Major and colleagues analyzed plasma samples for JC virus antibodies and viral DNA from 2 cohorts of patients: 26 patients immediately before their first natalizumab infusion and several times over first year of treatment; and 23 patients tested once after more than 24 months of natalizumab treatment.

"Antibody titers and viral DNA were measured by means of an enzyme-linked immunosorbent assay with the use of JC viruslike particles (the Biogen Stratify assay uses similar viruslike particles)," they write. They also used ultrasensitive polymerase chain reaction (PCR) assay specific for JC virus DNA using procedures certified in accordance with the Clinical Laboratory Improvement Amendment.

"The Laboratory of Molecular Medicine and Neuroscience has provided quantitative PCR results that have confirmed the diagnosis of [PML] in approximately half the 370 cases of PML in natalizumab-treated patients with multiple sclerosis," the authors note.

They report that, overall, 17 of the 49 patients (35%) had viremia at some time. Ten of the 26 patients in whom treatment was initiated had viremia; 4 of these were seronegative (antibody titer <2560), and 6 were seropositive (antibody titer ≥2560). Of those patients, 4 had viremia at baseline and 3 were seropositive, the authors write. Seven of 23 patients who received more than 24 infusions had viremia and 2 were seronegative.

One blood sample was obtained from each of the 18 healthy volunteers (6 were seronegative, 12 were seropositive, and none had detectable viral DNA), and a Fisher exact test was used to determine a statistical difference between the treated patients with viremia and the healthy volunteers (P = .003).

"We observed a range in viral titers from 13 to 510 copies of JC virus DNA per milliliter (mean, 43 copies per milliliter) in patients in the initial year of treatment and from 21 to 126 copies (mean, 40 copies per milliliter) in those who received more than 24 infusions," they write. "Of the 17 persons with viremia, 11 were seropositive (65%) and 6 were seronegative (35%)."

"To establish risk-stratification algorithms for PML in patients who receive potent immunomodulatory therapies, a single measurement of viral activity such as a test for antibodies to JC virus may be useful but not sufficient to assess risk," the authors write. "The observation that some patients had viremia and were seronegative provides support for a more comprehensive risk-mitigation strategy involving periodic monitoring over the course of the treatment intervention."

Because of the known risk for PML, natalizumab is available only under a restricted distribution program called the TOUCH Prescribing Program. The prescribing information says testing patients for anti-JV virus antibodies before and during treatment should be considered.

Infection by JC virus is required for the development of PML, the prescribing information notes, but patients who are antibody negative "are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. Therefore, patients with a negative anti-JCV antibody test result should be retested every 6 months."

A patient with a positive antibody test result at any time should be considered anti-JCV antibody positive regardless of the results of any prior or subsequent test, the label notes.

"The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors," the prescribing information notes. "Patients with all three known risk factors (treatment with natalizumab for more than 2 years, prior immunosuppressant treatment and anti-JC virus antibody positivity) have an estimated risk of PML of 11/1,000."

Dr. Major and Dr. Douek have disclosed no relevant financial relationships. Dr. Frohman reports receiving payment for consultancy and as a member of the speakers bureau to Biogen Idec, Teva, Genyme, Abbott Laboratories, Acorda, and Novartis.

Source: N Engl J Med. 2013;368:2240-2241 and Medscape News Today Copyright © 1994-2013 by WebMD LLC (07/06/13)

Natalizumab treatment reduces fatigue in multiple sclerosis(11/04/13)

Abstract

Fatigue is a significant symptom in multiple sclerosis (MS) patients. First-generation disease modifying therapies (DMTs) are at best moderately effective to improve fatigue. Observations from small cohorts have indicated that natalizumab, an antibody targeting VLA-4, may reduce MS-related fatigue. The TYNERGY study aimed to further evaluate the effects of natalizumab treatment on MS-related fatigue.

In this one-armed clinical trial including 195 MS patients, natalizumab was prescribed in a real-life setting, and a validated questionnaire, the Fatigue Scale for Motor and Cognitive functions (FSMC), was used both before and after 12 months of treatment to evaluate a possible change in the fatigue experienced by the patients.

In the treated cohort all measured variables, that is, fatigue score, quality of life, sleepiness, depression, cognition, and disability progression were improved from baseline (all p values<0.0001). Walking speed as measured by the six-minute walk-test also increased at month 12 (p?=?0.0016).

All patients were aware of the nature of the treatment agent, and of the study outcomes.

CONCLUSION: Natalizumab, as used in a real-life setting, might improve MS-related fatigue based on the results from this one-armed un-controlled stud. Also other parameters related to patients' quality of life seemed to improve with natalizumab treatment.

Svenningsson A, Falk E, Celius EG, Fuchs S, Schreiber K, Berkö S, Sun J, Penner IK, For The Tynergy Trial Investigators.

Dept of Pharmacology and Clinical Neuroscience, Umeå University and University Hospital of Northern Sweden, Umeå, Sweden.

Full article 

Source: PLoS One. 2013;8(3):e58643. doi: 10.1371/journal.pone.0058643. and Pubmed PMCID: PMC3605436 (11/04/13)

Low body weight linked to PML risk with natalizumab in MS(04/04/13)

An intriguing new study suggests that low body mass may be associated with an increased risk for developing progressive multifocal leukoencephalopathy (PML) in the setting of therapy with natalizumab (Tysabri, Biogen Idec) for multiple sclerosis (MS).

"Higher PML incidence definitely trends toward lower body weights," said John Foley, MD, a neurologist at Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, Utah.

There is about a 54% excess in PML cases in Europe Union compared with expected cases based on percentage of world-wide use, Dr. Foley pointed out. "The EU/US [European Union/United States] paradox may be at least partially explained actually by the fact that the demographics, at least when using Utah and Swedish controls as surrogates for the US and EU, are very, very different both in age and in weight of those on natalizumab," he told Medscape Medical News.

Natalizumab concentration clearly increases with time, he said, and in this study, high natalizumab concentrations appeared to occur particularly in patients with lower body weight. "High natalizumab saturations correlate best to populations with both low body weight and very high drug level per kilogram. Extended-dose therapy can decrease concentration and saturation as you might expect, and may well be a viable therapy for PML risk reduction."

The findings were presented at the American Academy of Neurology (AAN) 65th Annual Meeting. The study was supported by Biogen Idec/Elan Pharmaceuticals.

Lower Weight, Higher Risk?

Natalizumab is an effective treatment for MS, but the risk for PML is an important issue, considering its use, the study abstract notes. Factors that have already been identified as predictors of PML susceptibility include duration of therapy and positivity for antibodies to the JC virus upon starting therapy.

The so-called EU/US paradox in PML cases has been described previously, he said. If cases were evenly distributed between these regions on the basis of use, there should be approximately 125 cases of PML in the EU. Instead, there have been 193 cases, a 54% excess over expected numbers, much of which has been ascribed previously to an increased use of immunosuppressants in the EU, he noted.

In this study, Dr. Foley looked at pharmacokinetic and pharmacodynamic effects of prolonging the interval between doses of natalizumab as a possible risk mitigation strategy against PML.

He collected demographic and clinical data from a cohort of 301 natalizumab-infusing patients at their clinic and compared their data with an aggregate of such patients worldwide, including a cohort of 38 patients with PML.

Looking at drug concentrations, results showed a tight correlation coefficient between drug saturation of VLA-4 lymphocytes and the concentration per kilogram, ranging from 85% mean saturation to 95% in those with the lowest weight. "This weight relationship was also recognized early on in the natalizumab experience, and actually is in the PI [prescribing information], that higher drug clearance was seen in patients with higher body weight," Dr. Foley noted.

The researchers then stratified saturation by both weight and concentration and found that most patients with saturations of 90% to 95% were in the lower weight category, but they also mapped into the higher concentration category. "When you look at what we called our 'ultra-saturators,' our 95%-plus saturators, here you start seeing stratification into this really high concentration and low-weight group."

On the basis of these findings, he said, "we hypothesized that if increased concentrations and saturations occur in low body weight populations, and are germane to PML risk, then we should see more PML cases in patients with lower body weight."

By collaborating with several other centers, they were able to collect data on 38 patients with PML (almost 12% of the reported cases associated with natalizumab treatment) to look at the weight distribution between EU and US populations. In this PML cohort, the median weight was 64 kg, with a mean of 70 kg across all patients, and no significant difference was seen between the European and US populations in weight distribution among PML cases.

However, at their institution in Salt Lake City, Dr. Foley noted, "our median weight is 78 kilos, 14 kg greater than the average PML case. And in keeping with the theory, we do see in the Swedish cohort, which we are using as a surrogate for the EU population, as being much closer to the PML cohort at 69 kg."

They then divided patients into weight "bins" to try and elucidate the relationship further. In their clinic, 13% of patients fell into the 60 kg or less bin, whereas in the Swedish population of 1127 natalizumab-treated patients, 22% fell into the 60 kg or less bin. "And what we see is there is a striking elevation in PML cases in that lowest-weight category, almost 3-fold different from the US and almost 2-fold different from the combined (EU and US) data," he said.

"The other question is then what happens when you do dose extension, and here we're dose extending from a standard 28 to 30 days, to a 6-week regimen," Dr. Foley concluded. They don't yet have a lot of patients receiving this 6-week regimen, but they saw a significant reduction in mean concentration with the 6-week dosing cycle; in addition, saturation dropped roughly 6.5% in this small cohort.

"In my way of thinking of this, I think you want to avoid these real high saturations for a long time," he said during the discussion.

"Fascinating" Observation

Asked for comment on these findings, Lily Jung Henson, MD, medical director of the Swedish Neuroscience Institute, Seattle, Washington, said she found this potential relationship between lower weight and higher PML risk very interesting.

"It's one of those observations where only time will tell but it's certainly really fascinating," she told Medscape Medical News. The question is, though, which came first, she points out; lower body weight may mean the patients are healthier, or it may mean they are more ill, and therefore more likely to get PML.

"So there are a lot of unknowns, but I think it's just fascinating," she concluded.

The study was supported by Biogen Idec/Elan Pharmaceuticals. Dr. Foley reports having received personal compensation for activities with Biogen Idec, Teva Neuroscience, and Genzyme Corporation as a consultant and research support from Biogen Idec and Novartis. Dr. Jung Henson has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Genzyme Corporation, Novartis, and Pfizer Inc. One of her family members holds stock and/or stock options in Merck & Co Inc. She has received research support from Biogen Idec, Novartis, and Genzyme Corporation.

Source: Medscape Copyright © 1994-2013 by WebMD LLC (04/04/13)

Biogen Idec gains commercial rights of Tysabri from Elan Corporation(04/04/13)

Biogen Idec has completed its purchase of Elan Corporation’s interest in Tysabri (natalizumab) and has gained full strategic, commercial and decision-making rights of Tysabri. The transaction was originally announced on February 6, 2013.

“Full ownership of Tysabri is an important step for Biogen Idec that further solidifies our leadership in MS,” said George A Scangos, Ph.D., chief executive officer of Biogen Idec. “The powerful efficacy of Tysabri makes it an important treatment for many people living with MS and we believe it has a solid growth trajectory for years to come. We are grateful to Elan for more than a decade of collaboration on Tysabri, and for their work to provide a seamless transition as we finalized the transaction.”

Further details and updated financial guidance will be provided during Biogen Idec’s upcoming first quarter 2013 earnings announcement.

Biogen Idec says it has the deepest MS pipeline in the industry with compounds that include PLEGRIDY (peginterferon beta-1a); daclizumab high-yield process (DAC HYP) for monthly subcutaneous administration; and an ongoing study with Tysabri as a treatment for secondary progressive multiple sclerosis (SPMS).

Tysabri is approved in more than 65 countries. Tysabri is approved in the United States as a monotherapy for relapsing forms of MS, generally for patients who have had an inadequate response to, or are unable to tolerate, an alternative MS therapy due to the risk of progressive multifocal leukoencephalopathy (PML). In the European Union, it is approved for highly active relapsing-remitting MS (RRMS) in adult patients who have failed to respond to beta interferon or have rapidly evolving, severe RRMS.

Tysabri has advanced the treatment of MS patients with its established efficacy. Data from the phase III AFFIRM trial, which was published in the New England Journal of Medicine, showed that after two years, Tysabri treatment led to a 68 per cent relative reduction (p<0.001) in the annualized relapse rate when compared with placebo and reduced the relative risk of disability progression by 42 to 54 per cent (p<0.001).

Tysabri increases the risk of PML, an opportunistic viral infection of the brain which usually leads to death or severe disability. Infection by the JC virus (JCV) is required for the development of PML and patients who are anti-JCV antibody positive have a higher risk of developing PML. Factors that increase the risk of PML are presence of anti-JCV antibodies, prior immunosuppressant use, and longer Tysabri treatment duration. Patients who have all three risk factors have the highest risk of developing PML. Other serious adverse events that have occurred in Tysabri-treated patients include hypersensitivity reactions (e.g., anaphylaxis) and infections, including opportunistic and other atypical infections. Clinically significant liver injury has also been reported in the post-marketing setting. A list of adverse events can be found in the full Tysabri product labeling for each country where it is approved.

As a result of the acquisition from Elan, Tysabri will be marketed and distributed solely by Biogen Idec.

Source: PHARMABIZ.com Copyright © 2013 Saffron Media Pvt. Ltd (04/04/13)

New Tysabri And Anti-JCV Antibody Stability Data Released(18/03/13)

Biogen Idec and Elan Corporation, plc announced results from several studies of Tysabri(R) (natalizumab) that demonstrate its efficacy compared to other multiple sclerosis (MS) treatments, provide additional data supporting anti-JC virus (JCV) antibody status stability, and suggest better outcomes when progressive multifocal leukoencephalopathy (PML) is detected early. These data will be presented at the 65th Annual Meeting of the American Academy of Neurology (AAN) in San Diego.

"These new data reinforce our belief in the substantial efficacy Tysabri has demonstrated at both the early and advanced stages of relapsing forms of MS," said Alfred Sandrock, M.D., Ph.D., senior vice president, Development Sciences and chief medical officer, Biogen Idec. "We are also encouraged by the consistency in anti-JCV antibody status demonstrated over 18 months, as well as results from our pursuit of additional paths to help mitigate the impact of PML. These combined efforts may allow a more individualized approach when selecting Tysabri  treatment, while helping physicians better understand a patient's benefit-risk profile."

Substantial Tysabri Efficacy Demonstrated Against First-Line Therapies

In an independent statistical analysis led by Timothy Spelman and Helmut Butzkueven, M.D. at the University of Melbourne, with contribution by Fabio Pellegrini and Annie Zhang, Tysabri demonstrated a significantly lower rate of first relapse compared to interferon beta (IFN) and glatiramer acetate (GA). This propensity-matched analysis was conducted using data from two MS patient registries: Tysabri Observational Program (TOP) and MSCOMET. The results indicate that relapses were not only more likely to occur in patients taking IFN and GA, but that they occurred more quickly, when compared to patients taking Tysabri (hazard ratio 2.73, 95 percent confidence interval 2.10-3.55, p<0.001).

-- Comparison of Patients Treated with Natalizumab and Interferon-Beta/Glatiramer Using Propensity-Matched Multiple Sclerosis Registry Data (P01.211) will be available for viewing on Monday, March 18, 2013 from 2:00 to 6:30 p.m. PDT

Anti-JCV Antibody Stability Data Support Risk Stratification Approach

To help physicians better identify the most appropriate patients for Tysabri treatment, Biogen Idec developed a risk stratification approach. This approach assesses each patient's personal benefit-risk profile based on several factors, including anti-JCV antibody status, which was added to the Tysabri EU label in 2011 and the U.S. label in 2012.

An analysis of data from the longitudinal, observational U.S. study of Tysabri-treated patients, STRATIFY-1, demonstrates that anti-JCV antibody status remained consistent in 90 percent of the study population when tested every six months over an 18-month period. Approximately 38 percent of patients tested consistently negative and 52 percent tested consistently positive.

-- Longitudinal Stability of Anti-JC Virus Antibody Status in Multiple Sclerosis Patients: Results of STRATIFY-1 (S30.001) will be presented on Wednesday, March 20, 2013 from 2:00 to 3:45 p.m. PDT

Early PML Detection May Improve Survival

Results from Biogen Idec's ongoing research into PML, an infrequent but serious brain infection, suggest that TYSABRI-treated patients who develop PML and are asymptomatic at time of diagnosis may have improved survival and less functional disability compared with patients who are diagnosed when symptomatic.

This analysis includes preliminary data from four years of case reports and evaluates outcomes in 319 Tysabri-treated patients who developed PML, 21 of whom had no clinical symptoms of PML but were diagnosed based on magnetic resonance imaging (MRI) findings that were consistent with PML and spinal fluid that was positive for the presence of JCV. It shows that survival following PML was 100 percent in the patients without symptoms at diagnosis, compared to 77 percent in the patients with symptoms at diagnosis. Functional outcomes and disability were also better in the asymptomatic group one year after PML diagnosis: the average score on the Karnofsky Performance Scale, which measures functional outcomes, was 70 for asymptomatic patients (meaning the person can care for him/herself), compared to 47 for those with symptoms at diagnosis (meaning the person may be disabled and requires considerable assistance and frequent medical care; p=0.021); and scores on the Expanded Disability Status Scale, which measures disability, were numerically better for asymptomatic patients (3.7 vs. 6.5 p=0.066).

-- Natalizumab-associated Progressive Multifocal Leukoencephalopathy (PML) in Multiple Sclerosis Patients: Survival and Functional Outcome when Asymptomatic at Diagnosis (P04.271) will be available for viewing on Wednesday, March 20, 2013 from 7:30 a.m. - 12:00 p.m. PDT

Source: MarketWatch Copyright © 2013 MarketWatch, Inc (18/03/13)

Early Magnetic Resonance Detection of Natalizumab-Related Progressive Multifocal Leukoencephalopathy in a Patient with Multiple Sclerosis(11/03/13)

Diagnosis of progressive multifocal leukoencephalopathy is usually based on the clinical presentation, on the demonstration of the brain lesions at the magnetic resonance imaging examination, and on the detection of the JC virus DNA in the cerebrospinal fluid with high sensitive polymerase chain reaction.

The role of magnetic resonance imaging specifically in natalizumab-associated progressive multifocal leukoencephalopathy is strengthening, and it is gaining importance not only as an irreplaceable diagnostic tool but also as a surveillance and risk stratifying tool in treated patients.

While other imaging techniques such as computed tomography lack sensitivity and specificity, magnetic resonance performed with morphological and functional sequences offers clinicians the possibility to early identify the stage of the disease and the emergence of an immune reconstitution inflammatory syndrome after natalizumab blood removal plasmapheresis.

Full article 

Source: Case Reports in Radiology (11/03/13)

Early Detection of MS Treatment Complication May Improve Survival(11/03/13)

The drug natalizumab is effective for treating multiple sclerosis (MS), but it increases the risk of a rare but potentially fatal brain infection called progressive multifocal leukoencephalopathy (PML). A study released today that will be presented at the American Academy of Neurology’s 65th Annual Meeting in San Diego, March 16 to 23, 2013, suggests that early detection of PML may help improve survival and disability levels.

The study examined 319 people with MS who were treated with natalizumab and diagnosed with PML. Because of the risk of PML, people taking natalizumab are monitored by their physicians for possible symptoms of the brain infection. The study compared people who had symptoms of PML at the time of diagnosis to people who had no symptoms of the infection, but who were diagnosed with the disease by brain scans and tests in the spinal fluid for the virus that causes the infection. The level of disability for the people in the study was assessed before the PML diagnosis, at the time of diagnosis, and again six months and one year after the diagnosis.

A total of 21 people had no PML symptoms at the time of their diagnosis, while 298 people had symptoms. The preliminary data from the study suggest that people who have no symptoms at diagnosis may have improved survival and less disability than those who had developed symptoms prior to their diagnosis, according to study author Tuan Dong-Si, MD, a medical director with Biogen Idec in Weston, MA.

At the time of PML diagnosis, those people with no symptoms had an average score of 67 on the Karnofsky Performance Scale, which measures disability, while those people with symptoms had a score of 54. A Karnofsky score of 70 indicates that the individual may be able to care for him or herself, but may be unable to carry on normal activities or do active work. A Karnofsky score of 50 indicates that a person may require considerable assistance and frequent medical care. One year after PML diagnosis, the average Karnofsky score of those people with no symptoms at diagnosis was 70, compared to 47 for those with symptoms at diagnosis. Karnofsky scores of less than 50 indicate that the individual may be unable to care for him or herself and may require institutional care or the equivalent.

As of January 1, 2013, all of the 21 people (100 percent) with no symptoms at the time of PML diagnosis were living, compared to 77 percent of the people with symptoms at the time of diagnosis. “These results suggest that the consequences of PML infection can be mitigated by early detection of the disease,” said Dong-Si.

Natalizumab is generally prescribed for people who have not responded to or cannot tolerate other treatments for MS.

The study was supported by Biogen Idec Inc. and Elan Pharmaceuticals.

Source: American Academy of Neurology ©2013 American Academy of Neurology (11/03/13)

Cerebrospinal fluid fetuin-A is a biomarker of active multiple sclerosis(06/03/13)

Summary: In this study from the US, the researchers investigated if fetuin-A is an indicator of disease activity. Fetuin-A is a serum protein secreted mainly from the liver that functions in a wide variety of physiological and pathological processes. It has recently been identified as a potential biomarker in MS, with many functions, including a role in immune pathways.

The researchers found that fetuin-A levels were reduced in CSF one year post treatment with natalizumab. Interestingly, they found that 69% of natalizumab-treated patients overall had decreased fetuin-A levels, which correlates with the known response rate to natalizumab treatment. Fetuin-A was increased in demyelinating lesions and in grey matter within MS brain tissue. In EAE, they found fetuin-A was elevated in degenerating neurons around demyelinating lesions. Also, fetuin-A deficient mice demonstrated delayed onset and reduced severity of EAE symptoms.

Therefore, this study shows that CSF fetuin-A is a biomarker of disease activity and natalizumab response in MS. It raises the possibility that fetuin-A may play a role in the disease process but this needs to be investigated further.

Abstract

BACKGROUND: There is an urgent need for biomarkers in multiple sclerosis (MS) that can reliably measure ongoing disease activity relative to inflammation, neurodegeneration, and demyelination/remyelination. Fetuin-A was recently identified as a potential biomarker in MS cerebrospinal fluid (CSF). Fetuin-A has diverse functions, including a role in immune pathways.

OBJECTIVE: The objective of this research is to investigate whether fetuin-A is a direct indicator of disease activity.

METHODS: We measured fetuin-A in CSF and plasma of patients with MS and correlated these findings to clinical disease activity and natalizumab response. Fetuin-A expression was characterized in MS brain tissue and in experimental autoimmune encephalomyelitis (EAE) mice. We also examined the pathogenic role of fetuin-A in EAE using fetuin-A-deficient mice.

RESULTS: Elevated CSF fetuin-A correlated with disease activity in MS. In natalizumab-treated patients, CSF fetuin-A levels were reduced one year post-treatment, correlating with therapeutic response. Fetuin-A was markedly elevated in demyelinated lesions and in gray matter within MS brain tissue. Similarly, fetuin-A was elevated in degenerating neurons around demyelinated lesions in EAE. Fetuin-A-deficient mice demonstrated delayed onset and reduced severity of EAE symptoms.

CONCLUSIONS: Our results show that CSF fetuin-A is a biomarker of disease activity and natalizumab response in MS. Neuronal expression of fetuin-A suggests that fetuin-A may play a pathological role in the disease process.

Authors: Harris VK, Donelan N, Yan QJ

Source: Mult Scler. 2013 Feb 25 and Pubmed PMID: 23439582 (06/03/13)

An assay to quantify species-specific anti-JC virus antibody levels in MS patients

Summary: This study looked at developing an assay for the reliable quantification of highly species-specific anti-JCV antibody levels and to compare the results with pre-existing data from the StratifyJCV® test.

The researchers tested the sera of 175 MS patients and matched non-MS-controls for anti-JCV antibodies using glutathione S-transferase-tagged-VP1 as antigen. In order to minimise the cross-reactivity between shared epitopes of JCV-VP1 and BKV-VP1, they pre-absorbed the sera with soluble heterologous VP1 in contrast to StratifyJCV® test as well as measuring the percentage of reduction in antibody reactivity by soluble JCV-VP1 relative to the reduced reactivity after pre-incubation with soluble BKV-VP1 fusion protein.

Results from this study showed good inter-assay agreement with StratifyJCV® test and strong correlation for antibody reactivity. This demonstrates reliable quantification of anti-JCV antibodies, which shows good agreement with results from StratifyJCV® test, which is a qualitative assay. This assay may be used as an additional tool for PML risk assessment.

Abstract

BACKGROUND: The StratifyJCV® test is a qualitative assay to classify MS patients as anti-JC virus (JCV) antibody positive or negative. Quantification of anti-JCV antibody levels in serum and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients might add to the progressive multifocal leukoencephalopathy (PML) risk assessment.

OBJECTIVE: The objective of this study is to test sera of patients in a quantitative anti-JCV antibody assay, and to compare the results with preexisting data from the StratifyJCV® test.

METHODS: Sera of a total of 175 MS patients and matched non-MS-controls were tested for anti-JCV antibodies using glutathione S-transferase-tagged-VP1 as antigen. Antibody reactivity was quantified in arbitrary units using human immunoglobulin as standard.

RESULTS: The comparison of our assay with StratifyJCV® showed good inter-assay agreement (kappa 0.6), and strong correlation for antibody reactivity (r(2) = 0.94). Discordant samples had low-reactive positivity, and a higher proportion (13% vs. 4%) tested positive in the StratifyJCV® test only.

CONCLUSIONS: The method presented is a tool for the reliable quantification of anti-JCV antibodies, which demonstrates good agreement with results from StratifyJCV®. In contrast to StratifyJCV®, we pre-adsorbed all of the sera with BK virus (BKV) VP1 protein to reduce cross-reactivity. This step may account for a higher species-specificity of our assay. As such, our assay might be a promising additional tool for PML risk assessment.

Authors: Warnke C, Pawlita M, Dehmel T

Sources: Mult Scler. 2013 Feb 6. & Pubmed PMID: 23388163 (20/02/13)

Tysabri may be an option for children with Multiple Sclerosis

Off-label treatment with natalizumab (Tysabri) for 20 children with severe multiple sclerosis reduced relapses and brain lesions seen on MRI scans, a retrospective analysis found.

The mean annualized relapse rate while on natalizumab in these patients was 0.4, compared with 3.77 before starting the drug (P<0.001), according to Barbara Kornek, MD, of Austria's Medical University of Vienna, and colleagues.

Also, new T2/fluid attenuated inversion recovery (FLAIR) lesions declined from a mean of 7.8 before natalizumab to 0.5 on the drug (P=0.001), the researchers reported online in JAMA Neurology.

But the treatment was not without adverse events, Kornek and colleagues noted. Half the patients experienced some type of clinical event, including one case each of severe asthenia, laryngeal edema, and anaphylaxis. Two had recurrent infections, although it was not clear that natalizumab was responsible.

Eight of the children also exhibited laboratory abnormalities. Four developed mild anemia, two showed transient elevations in liver enzymes, and two developed hyperbilirubinemia.

In addition, two patients developed high levels of neutralizing antibodies to natalizumab that led to withdrawal of the drug. Three other patients stopped natalizumab after tests showed the presence of antibodies to the JC virus, a strong risk factor for development of progressive multifocal leukoencephalopathy (PML), which can be fatal.

One patient had tested positive for JC virus antibodies before starting natalizumab, but the decision was made to use the drug anyway because of a "highly active disease course." Overall, the researchers found, five of 13 patients tested for JC virus antibodies were positive.

Natalizumab is not currently approved for pediatric use in the U.S. or Europe, but it is sometimes used anyway in children with very severe disease or who do not respond to more conventional disease-modifying treatments.

The 20 children Kornek and colleagues reported on were mostly teenagers and were receiving the drug in 11 clinics in Germany and Austria. In addition to the standard outcomes of relapse rates and MRI lesions, the researchers paid particular attention to development of neutralizing anti-drug antibodies and JC virus antibody status, as these had not previously been studied in a pediatric population.

Mean age at disease onset in these patients was 15.2 (SD 1.3) and the mean age when natalizumab was started was 16.7 (SD 1.1). All but four were girls.

One patient started on natalizumab as first-line treatment, 15 had previously received one disease-modifying treatment, and four had received two.

With a mean of 18 months of disease duration before starting natalizumab, the average number of relapses was 4.3, with 3.1 occurring in the previous year -- numbers that signify highly active disease.

Four of the patients had undergone plasma exchange for a severe, prolonged relapse event.

The mean number of T2/FLAIR brain lesions at pre-natalizumab baseline was 30 (SD 17), with a mean of 2 gadolinium-enhancing lesions.

Mean treatment duration for natalizumab in the analysis was 20 months, during which time 14 of the 20 patients remained relapse-free. Among seven patients on the drug for 2 years or more, four stayed relapse-free.

Only two patients did not show a significant reduction in relapse frequency with natalizumab.

In an analysis combining clinical and MRI results, six of 13 patients with adequate data were deemed to be free of disease activity with natalizumab, insofar as they had no relapses, did not develop new MRI lesions, or show disability progression.

Among 10 patients with complete data for at least 1 year, four were disease-free throughout follow-up.

Most of the patients actually showed some lessening of disability, with a median change in EDSS score of -0.25 points (interquartile range -1.25 to 0.00) relative to baseline, when the group median was 2.0 points.

Kornek and colleagues also looked at the clinical course of patients who had stopped natalizumab either permanently or temporarily. After excluding two who were lost to follow-up after stopping the drug and one who had stopped temporarily during pregnancy, there were nine patients available for this analysis, including eight followed for at least 6 months.

Among those eight, six developed relapses in the first 6 months off natalizumab. The annualized relapse rate among all nine patients showed a strong trend toward increase (mean difference 1.47, 95% CI -0.04 to 2.98, P=0.06).

Overall, Kornek and colleagues concluded that natalizumab "may be safe and effective against MS in pediatric patients with breakthrough disease," but they cautioned that controlled trials are needed to confirm a favourable benefit-risk balance.

The study had no external funding.

Study authors reported relationships with Biogen Idec, Merck Serono, Teva, Bayer Schering, Novartis, Sanofi, UCB, Orion, Solvay, Mundipharma, and Ipsen.

Primary source: JAMA Neurology
Source reference: Kornek B, et al "Natalizumab therapy for highly active pediatric multiple sclerosis" JAMA Neurol 2013; DOI: 10.1001/jamaneurol.2013.923.

Source: MedPage Today © 2013 MedPage Today, LLC. (20/02/13)

Natalizumab in paediatric multiple sclerosis: results of a cohort of 55 cases

Abstract

BACKGROUND: Limited information is available on the use of natalizumab (NA) in pediatric multiple sclerosis (ped-MS) patients.

OBJECTIVE: The purpose of this study was to describe the long-term effects of NA in a large cohort of active ped-MS patients.

METHODS: Patients with definite ped-MS were treated with NA if in the previous year they had experienced at least two relapses or a severe relapse with incomplete recovery while on immunomodulating treatment, or at least two relapses and new magnetic resonance imaging (MRI) lesions regardless of any prior treatment.

RESULTS: The study included 55 patients (mean age: 14.4 years, mean number of relapses: 4.4, pre-treatment mean disease duration: 25.5 months). They received a median number of 26 infusions. Three relapses occurred during the follow-up, one female patient continued to deteriorate in cognitive functioning. Mean Expanded Disability Status Scale (EDSS) scores decreased from 2.7 to 1.9 at the last visit (p<0.001). During the follow-up the majority of patients remained free from MRI activity. Transient and mild clinical adverse events occurred in 20 patients. Mild hematological abnormalities occurred in seven patients. Anti-JCV antibodies were detected in 20/51 tested patients.

CONCLUSIONS: NA was well tolerated in all patients. A strong suppression of disease activity was observed in the majority of patients during the follow-up.

Ghezzi A, Pozzilli C, Grimaldi L, Moiola L, Brescia-Morra V, Lugaresi A, Lus G, Rinaldi F, Rocca M, Trojano M, Bianchi A, Comi G, Filippi M; the Italian MS Study Group.

Source: Mult Scler. 2013 Feb 11 & Pubmed PMID: 23401129 (15/02/13)

MS Patient Dies from Anti-Drug Antibodies

A reaction to anti-natalizumab (Tysabri) antibodies appears to have killed a Swedish woman with multiple sclerosis who received the drug, researchers said.

Significant neurological abnormalities developed after she had received six infusions of natalizumab, and her doctors found that she had extremely high titers of antibodies against the drug, reported Anders Svenningsson, MD, PhD, of Umeå University in Sweden, and colleagues.

Seven months after starting on the drug, she was dead, the researchers wrote online in Neurology. Her physicians ruled out progressive multifocal leukoencephalopathy (PML), a known and frequently fatal side effect of natalizumab therapy.

Svenningsson and colleagues concluded that her death resulted from "rebound neuroinflammation as a result of the development of natalizumab anti-drug antibodies."

Noteworthy was that the patient had shown unusual reactions to the drug starting with the fourth infusion, including chills and fever, they suggested.

"We recommend that repeated moderate to severe infusion reactions in the beginning of natalizumab treatment should prompt the cessation of treatment and assessment for the development of natalizumab anti-drug antibodies," Svenningsson and colleagues wrote.

The patient was first diagnosed with MS in 2001 when she was 32. She was initially treated with interferon-beta-1a, but was switched to natalizumab in November 2007 when MRI scans showed growth in brain lesions. Because the scans did not show contrast enhancement, her doctors determined that her blood-brain barrier remained intact.

Natalizumab was given at the standard dose of 300 mg every 4 weeks by infusion.

The chills and fever that started with the fourth treatment became progressively more severe with subsequent infusions, the researchers indicated. After the sixth, she developed progressive gait abnormalities, ataxia, and significant mental deterioration.

MRI scans showed new hyperintense T2 lesions as well as multiple areas of contrast enhancement. Molecular tests of the patient's cerebrospinal fluid for the JC virus were negative, arguing against PML, which is caused by reactivation of latent JC virus infection.

At that point, she was transferred to a regional hospital. Her disability level progressed to 9 on the EDSS scale, compared with a level of 3 when she started on natalizumab. She was unable to get out of bed and was uncommunicative.

Another MRI scan showed additional contrast-enhancing lesion growth. Brain biopsy results were consistent with acute MS inflammation, Svenningsson and colleagues reported, "with infiltrating activated macrophages as well as signs of blood-brain barrier breakdown."

Most important, anti-natalizumab antibodies were found at a level of 335 mg/L, "among the highest recorded among anti-drug antibody positive patients identified in Sweden," the researchers indicated. The antibodies were predominantly of the IgG3 complement-fixing class.

The woman underwent plasmapheresis and her doctors wanted to perform an autologous stem cell transplant, but her condition was too poor for that, and she died in June 2008.

Autopsy findings showed no evidence of infectious pathogens in the central nervous system. The conclusion was that acute MS inflammation was the cause of her symptoms and eventual death.

Svenningsson and colleagues considered the possibility that the anti-natalizumab antibodies had triggered an anti-idiotype reaction, which could have led to an autoimmune attack on ligands of VLA-4, VCAM-1, and fibronectin. But in vitro studies using serum samples from the patient showed no signs of anti-idiotype reactivity.

Other clinicians have reported cases in which patients worsened while on natalizumab or who showed severe relapses after stopping the drug, Svenningsson and colleagues said, but their case was unusual in its fatal outcome.

The study was funded by ALF, the KI Foundation, and the Swedish Association of Persons with Neurological Disabilities.

Study authors reported relationships with Biogen Idec, Bayer-Schering, Baxter Medical, Sanofi, and Merck Serono.

Primary source: Neurology

Source reference: Svenningsson A, et al "Fatal neuroinflammation in a case of multiple sclerosis with anti-natalizumab antibodies" Neurology 2013; DOI: 10.1212/WNL.0b013e3182840be3.

Source: Medpage Today © 2013 MedPage Today, LLC (12/02/13)

Biogen to Pay Elan $3.25 Billion for Full Tysabri Rights

Biogen Idec Inc. agreed to acquire partner Elan Corp.’s stake in the multiple sclerosis drug Tysabri for $3.25 billion in cash plus future royalties.

The deal gives Biogen all rights to the product, and the company will pay royalties to Elan, Dublin-based Elan said in a statement today. The companies had been splitting profit equally on the medicine, which generated $1.6 billion in sales in 2012.

The deal ends speculation that Biogen would buy Elan and transforms the Irish company into an investment vehicle in search of assets to buy in health care. Elan’s experimental drug for Alzheimer’s disease failed in late-stage trials last year, leaving Tysabri as the company’s single major product.

“This move gives us a chance to reinvest a fair amount of capital across a whole host of assets and helps us redefine and reposition the whole company,” Elan Chief Executive Officer Kelly Martin said in an interview. The company seeks a “balanced portfolio of assets” that would include products already on the market and experimental medicines, he said.

Elan rose 5.6 percent to 8.15 euros at 8:10 a.m. in Dublin. The stock has fallen 26 percent in the past year through yesterday. Biogen rose 1.1 percent yesterday to close at $157.36 in New York. The shares have gained 29 percent in the 12 months through yesterday.

Royalty Payments
Under the terms of the deal, Weston, Massachusetts-based Biogen will pay Elan 12 percent of global net sales of Tysabri for the first year; 18 percent on annual sales of as much as $2 billion and 25 percent on sales of more than $2 billion. Elan has said Tysabri sales may reach $2.5 billion to $3 billion by 2016, Eric Schmidt, an analyst with Cowen & Co., wrote in a research note. He estimated $1.9 billion by 2017.

Tysabri was left as Elan’s single major product after the experimental Alzheimer’s drug bapineuzumab failed to improve cognitive or functional ability in patients in late-stage studies. In December, Elan spun off its drug discovery unit into a company called Prothena Corp. Elan sold its Elan Drug Technologies unit to Alkermes Plc in 2011. Elan’s future actions will be guided by the company’s “assessment of business opportunities,” Martin said in the statement. “We are enthusiastic about the market opportunities around the globe and remain flexible and creative about the manner in which we would participate in those opportunities.”

Source: Bloomberg ©2013 BLOOMBERG L.P. (06/02/13)

Applications for first-line use of Tysabri in anti-JCV antibody negative patients with MS announced

Biogen Idec and Elan Corporation, plc have announced that they have submitted applications to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) requesting updates to the Tysabri® (natalizumab) labels. The applications request an expanded indication that would include first-line use for people living with certain relapsing forms of multiple sclerosis (MS) who have tested negative for antibodies to the JC virus (JCV). A formal assessment of both applications is ongoing.

These submissions are supported by risk stratification data and a risk algorithm that enables physicians and individuals living with MS to make informed decisions when considering treatment with Tysabri. If approved, a first-line label will allow all appropriate anti-JCV antibody negative patients to consider Tysabri early in the course of treatment, regardless of the level of disease activity or prior treatment history. TYSABRI is a highly efficacious treatment that has been shown to slow disability progression by 42 – 54 percent and reduce annualized relapse rates by 68 percent.

“Our anti-JCV antibody test, STRATIFY JCV®, helps to determine the most appropriate patients for TYSABRI and the data collected to date supports our recent filing for first-line use,” said Alfred Sandrock, M.D., Ph.D., senior vice president, Development Sciences and Chief Medical Officer, Biogen Idec. “Many appropriate patients are already benefiting from TYSABRI. A first line approval would allow people with MS access to a highly efficacious treatment earlier in the course of the disease, potentially leading to better outcomes. This is an important consideration for people with MS who may want or need more efficacy.”

Currently in the U.S., due to an increased risk of an opportunistic viral infection, progressive multifocal leukoencephalopathy (PML), Tysabri is generally recommended for people living with relapsing forms of MS whose disease is not responding to, or who are unable to tolerate, an alternative therapy regardless of JCV status. In the EU, TYSABRI is approved for highly active relapsing-remitting MS (RRMS) in adult patients who have failed to respond to beta interferons or have rapidly evolving, severe RRMS.

“Tysabri is an important treatment option for thousands of people living with MS,” said Hans Peter Hasler, chief operating officer, Elan Corporation, plc. “We are excited about these filings and the potential to make TYSABRI available as a treatment option for more individuals early in the course of their disease.”

Source: Business Wire © 2010 - 2012 Postmedia Network Inc. (16/01/13)

Lethal Multiple Sclerosis relapse after natalizumab withdrawal

Abstract

Natalizumab dramatically reduces relapses in patients with active multiple sclerosis (MS), but it may induce progressive multifocal leukoencephalopathy (PML). A rebound of MS or an immune reconstitution inflammatory syndrome (IRIS) were described after natalizumab withdrawal, even in the absence of PML.

Very few data concerning the potential severity and the neuropathology of this event are available.

We report the case of a 50-year-old patient with MS who developed a fulminating relapse 3 months after stopping natalizumab, leading to death despite intensive care and immunosuppressive therapy. Radiologic and neuropathologic findings provide interesting data regarding the nature of the rebound.

Rigau V, Mania A, Béfort P, Carlander B, Jonquet O, Lassmann H, Camu W, Thouvenot E.

Source: Pubmed PMID: 23100404 & Neurology. 2012 Oct 24 (01/11/12)

Tysabri trial to evaluate use in secondary progressive MS

Biogen Idec and Elan Corporation announced a global Phase 3b study that is being conducted to evaluate the effectiveness of Tysabri as a treatment for secondary-progressive multiple sclerosis (SPMS).

The Ascend study is part of an ongoing commitment of both Biogen Idec and Elan to find ways to improve the well-being of patients with multiple sclerosis. Ascend (A Study to Characterize the Efficacy of Natalizumab on Disability in SPMS) is a double-blind, placebo-controlled study with SPMS patients being randomized to receive either Tysabri 300 mg or placebo intravenously every four weeks for 96 weeks. A global study, Ascend is expected to enroll approximately 850 patients in 15 countries.

Study participants will be between the ages of 18 and 58, with a diagnosis of SPMS for at least two years; an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, MS Severity Score of four or higher; documented, confirmed evidence of disease progression, independent of clinical relapses during the one-year prior to enrollment; and naïve to Tysabri treatment.

“The Ascend trial is investigating whether treatment with Tysabri may prevent worsening in walking, hand movement and daily functioning in these patients,” explains Aaron Miller, MD, member of the Ascend advisory board.

"One hypothesis behind the development of SPMS is that disease progression is a result of chronic inflammation in the brain tissue trapped behind the blood-brain-barrier. This causes destruction of the myelin sheath, which protects the coating around nerve fibers, as well as the progressive loss of nerve cells, which can lead to disability in MS patients,” says Richard Reynolds, professor of Cellular Neuroscience, Imperial College, London. “Preliminary data suggest that Tysabri may hinder this inflammation in the brain and reduce SPMS-related disease progression; therefore, further investigation of this hypothesis is warranted."

Source: Advantage Business Media © Copyright 2012 Advantage Business Media (25/08/12)

7 more cases of PML and one more death for Tysabri MS patients

August 2012 Tysabri PML update that was made available to physicians:

As of August 1, 2012, there have been 271 PML cases, of which 162 have been in the European Economic Area (EEA), 97 in the US and 12 in rest of world (ROW).

As of August 1, 2012, 59 of the 271 patients with PML have died.

As of August 1, 2012, in 85 natalizumab-treated MS patients who developed PML and for whom serum samples were available 6-187 months prior to the onset of PML. Of these 85 patients:

83 (98%) tested anti-JCV antibody positive at all time points where samples were available for testing;

1 patient (1%) tested anti-JCV antibody negative 9 months prior to PML diagnosis and anti-JCV antibody positive 6.5 months prior to PML diagnosis;

1 patient (1%) tested anti-JCV antibody negative 9 months prior to PML diagnosis; no additional samples were available.

As of August 1, 2012, samples were available from 112 patients at the time of PML diagnosis and all 112 tested positive for anti-JCV antibodies.

In addition, one sample, collected from a patient at the time of PML diagnosis following a cycle of plasma exchange (PLEX) tested negative for anti-JCV antibodies.

Because this sample was collected immediately following PLEX, and PLEX removes antibodies from the circulation, the information obtained from this sample is unreliable.

One patient tested anti-JCV antibody positive two months before PML diagnosis. Previously, the patient had tested anti-JCV antibody negative 15 months prior to PML diagnosis, indicating that they had been exposed to the JC virus at some point between the two tests.

Source: Elan (20/08/12)

Natalizumab interruption results in a high rate of MRI and clinical MS disease activity recurrence

After a 24-week cessation of natalizumab treatment, a high rate of magnetic resonance imaging (MRI) and clinical disease activity recurs in patients with multiple sclerosis (MS) according to new research.

Natalizumab treatment duration has been associated with the development of progressive multifocal leukoencephalopathy (PML), a rare but often lethal and untreatable disorder of the central nervous system, characterized by large white-matter lesions that occur in immunocompromised patients. The RESTORE study was designed to investigate the effects of natalizumab interruption on MS disease activity.

Robert Fox, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic in Ohio, and colleagues conducted the randomized, partially placebo-controlled exploratory RESTORE study. The objective was to evaluate the effects of a 24-week treatment interruption on MS disease activity in 175 patients who had been relapse-free after treatment with natalizumab for a year or more and had no gadolinium-enhancing (Gd+) lesions on baseline MRI scan.

Patients received either natalizumab, placebo or, in an open-label fashion, an alternative immunomodulatory therapy, such as interferon beta-1a (IFNbeta-1a), glatiramer acetate, or methylprednisolone. Rescue treatment with natalizumab or high-dose corticosteroids was allowed if patients experienced a clinical relapse, 1 new Gd+ lesion over 0.8 cubic centimeters in volume, or 2 or more Gd+ lesions.

Overall, 26 percent of patients continued to receive natalizumab, 24 percent received placebo, and 50 percent received an alternative immunotherapy. The majority receiving alternative immunotherapy received methylprednisolone (61 percent), compared with 19 percent each who received IFNbeta-1a or glatiramer acetate. A total of 30 percent of patients, all treated with placebo or alternative immunotherapies, were rescued with natalizumab.

MRI rescue criteria were met for 44 percent of placebo-treated patients, 7 percent of IFNbeta-1a patients, 53 percent of glatiramer patients, and 40 percent of patients rescued with methylprednisolone. No patients who continued to receive natalizumab met MRI rescue critiera. Clinical relapse was observed in 4 percent of natalizumab patients compared with 15 to 29 percent of patients in other arms.

“RESTORE data confirm a high rate of MRI and clinical MS disease activity recurrence after natalizumab cessation. MRI scans helped identify patients with recurring disease activity during natalizumab interruption; the majority of activity was seen at 16-20 weeks,” the authors concluded.

This research was supported by Biogen Idec Inc and Elan Pharmaceuticals, Inc.

Source: HCPLive Copyright HCPLive 2006-2011 Intellisphere, LLC (11/06/12)

MS patients' risk tolerance may change in a year

Multiple sclerosis (MS) patients reported that they may change their minds about the acceptability of risk associated with disease-modifying therapies in as little as 1 year, a researcher said here.

More than 20% of MS patients queried about their tolerance of treatment-associated risk gave substantially different answers than they did in an identical survey a year earlier, said Sneha Ramesh, PhD, of the Cleveland Clinic.

The findings suggest that MS patients on treatments that pose serious risks, such as natalizumab (Tysabri), which has been linked to a life-threatening form of brain inflammation, should have regular discussions with clinicians about whether treatment risks continue to be acceptable.

Ramesh presented the survey results in a poster session at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

The new findings were from a follow-up to a survey of risk tolerance reported last year by the same researchers.

That survey, conducted with more than 5,000 patients in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry, found that only about one-third of patients were willing to tolerate the risks associated with natalizumab.

The chief risk for natalizumab treatment is progressive multifocal leukoencephalopathy (PML), which can result from reactivation of latent JC virus infection in the brain triggered by the drug's targeted suppression of immune function.

At the time of the survey, the PML risk was believed to be about 1 in 1,000, although recent research has indicated wide variability depending on patients' exposure to the JC virus, previous immunosuppressant therapy, and duration of natalizumab treatment.

Participants were asked about two scenarios, both involving risks of serious consequences: one mirroring natalizumab, in which the benefit was given as 68% fewer relapses, 42% less disability progression, and 90% lower MRI lesion burden, but with the possibility of PML.

The other was a hypothetical scenario of a complete, permanent MS cure that carried a risk of instant, painless death.

Participants were asked to indicate their highest acceptable risk, from 3:4 up to 1:1,000,000.

In the original survey, 34% of patients said they would accept a 1:1,000 risk of PML for the natalizumab-like treatment. The same percentage also said they would accept a 1:1,000 risk for the complete MS cure.

About 3,800 participants repeated the survey a year later with the same two scenarios. Ramesh and colleagues continued to use the 1:1,000 risk acceptability as the threshold for "tolerant" versus "intolerant" of treatment risk.

Although it was common to give somewhat different answers in the two surveys, Ramesh and colleagues only counted those that reflected changes from tolerant to intolerant, or vice versa.

Responses in the second survey indicated that 79% of participants remained in their original risk-tolerance category for natalizumab and 77% were in the same category for the complete cure.

Of those who changed their minds substantially about the natalizumab scenario, about 60% went from tolerant to intolerant of the 1:1,000 risk.

The NARCOMS data also included information on whether patients were actually taking natalizumab at the time of the surveys.

There were 70 patients who said they were taking the drug during the first survey but had stopped by the time of the second survey. Another 82 began natalizumab therapy during the interim.

Change in risk tolerance did not appear to be the dominant factor in either treatment decision, Ramesh said. Of the 70 who stopped taking natalizumab, only 16 had shifted from tolerant to intolerant of the 1:1,000 risk. Likewise, just 26 of the 82 who started the drug between surveys had changed from intolerant to tolerant.

Among 251 patients who were on natalizumab at the time of both surveys, 28 had a change of mind about the risk (about half in each direction) and six said in both surveys that they would not accept the 1:1,000 risk, Ramesh reported.

Of the 333 patients taking natalizumab at the second survey, 32 indicated that they would not accept the 1:1,000 risk of PML.

Across the entire sample, Ramesh and colleagues found that participants had become less tolerant of risk. For the natalizumab scenario, the median at the first survey was 1:10,000, but this shifted to 1:100,000 in the second survey.

The only factor associated with an increased acceptability of risk was an increase in self-reported disability, Ramesh said.

She said the findings should demonstrate to clinicians that risk tolerance is dynamic.

The study was supported by the CMSC and the National Multiple Sclerosis Society.

Ramesh declared she had no relevant financial interests. Other investigators reported relationships with Alexion, Abbott, Allozyne, Bayer, Coronado Biosciences, Novartis, Genzyme, Klein-Buendel, Nuron Biotech, Diogenix, Celgene, Receptos, Somnus, Teva, Biogen, Eli Lilly, Medivation, Avanir, St. Louis University, and Questcor.

Primary source: Consortium of Multiple Sclerosis Centers-Americas Committee for Treatment and Research in Multiple Sclerosis

Source reference: Ramesh S, et al "Does risk tolerance to multiple sclerosis therapies change over time? A NARCOMS survey" CMSC-ACTRIMS 2012; Abstract DX76.

Source: Medpage Today © 2012 Everyday Health, Inc. (06/06/12)

Health Canada approves updates to Tysabri product monograph to include anti-JC virus antibody status

Health Canada has approved a product monograph change for Tysabri® that will help enable individual benefit risk assessment for patients with multiple sclerosis (MS). The new label identifies anti-JC virus (JCV) antibody status as a risk factor for developing an uncommon, but serious, brain infection known as progressive multifocal leukoencephalopathy (PML). This marks the third risk factor identified to help physicians and people with MS have more confidence in their treatment decisions when considering Tysabri, a highly effective treatment for relapsing remitting forms of MS.

"This label change marks an important advance in assisting people with MS and their physicians to make better informed decisions concerning the challenges of balancing effectiveness with safety," said Dr. Virender Bhan, Director, Dalhousie MS Research Unit, Halifax, Nova Scotia. "Tysabri is an important treatment option for appropriate patients so the ability to confidently address PML risk stratification may allow for earlier treatment to reduce the frequency of clinical exacerbations and delay the progression of physical disability."

Infection with the JC virus (JCV) is required for the development of PML. The new label states that anti-JCV antibody negative status indicates that exposure to the JC virus has not been detected, while patients who are anti-JCV antibody positive have a higher risk of developing PML. Patients who are anti-JCV antibody positive, have received prior immunosuppressant (IS) therapy and have received treatment with Tysabri for more than two years have the highest risk of developing PML.

"Tysabri has benefited thousands of patients worldwide who are living with multiple sclerosis, an often devastating disease affecting people in the prime of their lives," said Paul Petrelli, General Manager, Biogen Idec Canada Inc. "Biogen Idec's use of novel research and scientific expertise has allowed us to gain a better understanding of the benefit-risk profile for Tysabri. Our development of a risk stratification algorithm and subsequent efforts to support the commercial availability of anti-JCV antibody testing reflect our commitment to providing patients and their physicians with additional guidance to help them make more personalized treatment decisions."

Biogen Idec's quantitative risk stratification algorithm, which was presented at a number of major international medical meetings, shows that patients who were anti-JCV antibody positive were at an increased risk for developing PML with varying degrees of risk depending on prior IS use and Tysabri treatment duration. Irrespective of MS treatment, approximately 55 per cent of MS patients are anti-JCV positive.

The Canadian label update follows the U.S. Food and Drug Administration and the European Commission approvals of anti-JCV antibody status as an additional factor to aid in stratifying patients at risk for developing PML. Through the third quarter of 2011, globally there have been approximately 59,000 anti-JCV antibody tests administered commercially and through clinical trials.

Source: Digital Journal copyright © 1998-2012 digitaljournal.com (23/05/12)

MS drug Tysabri leukoencephalopathy risk factors identified

Multiple sclerosis patients taking natalizumab are at higher risk of developing progressive multifocal leukoencephalopathy (PML) if they are positive for the anti-JC virus antibodies, have been treated with immunosuppressants, and have been treated with natalizumab for longer periods, according to a study published in the May 17 issue of the New England Journal of Medicine.

Gary Bloomgren, M.D., and colleagues from Biogen Idec in Weston, Mass., estimated the risk of PML based on the presence of anti-JC virus antibodies, use of immunosuppressants, and treatment length in 212 confirmed cases of PML from a cohort of 99,571 patients treated with natalizumab (2.1 cases per 1,000 patients).

The researchers found that 54 patients who had samples available before diagnosis were all positive for anti-JC antibodies. The PML risk was lowest in patients negative for anti-JC virus antibodies (0.09 cases or less per 1,000 patients). The risk was highest in patients positive for anti-JC virus antibodies who had taken immunosuppressants before starting treatment and were treated for 25 to 48 months (11.1 cases per 1,000 patients).

"Positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increased duration of natalizumab treatment, alone or in combination, were associated with distinct levels of PML risk in natalizumab-treated patients with multiple sclerosis," Bloomgren and colleagues conclude.

The study was funded by Biogen Idec and Elan Pharmaceuticals. All of the authors disclosed financial ties to Biogen Idec.

Abstract

BACKGROUND
Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment. We quantified the risk of PML in patients with multiple sclerosis, according to the presence or absence of three risk factors: positive status with respect to anti–JC virus antibodies, prior use of immunosuppressants, and increasing duration of natalizumab treatment.

METHODS
We used data from postmarketing sources, clinical studies, and an independent Swedish registry to estimate the incidence of PML among natalizumab-treated patients with multiple sclerosis, according to positive or negative status with respect to anti–JC virus antibodies, prior or no prior use of immunosuppressants, and duration of treatment (1 to 24 months vs. 25 to 48 months). Blood samples were available for anti–JC virus antibody testing from 5896 patients with multiple sclerosis and from 54 patients with multiple sclerosis who were treated with natalizumab and in whom PML later developed.

RESULTS
As of February 29, 2012, there were 212 confirmed cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000 patients). All 54 patients with PML for whom samples were available before the diagnosis were positive for anti–JC virus antibodies. When the risk of PML was stratified according to three risk factors, the risk of PML was lowest among the patients who were negative for anti–JC virus antibodies, with the incidence estimated to be 0.09 cases or less per 1000 patients (95% confidence interval [CI], 0 to 0.48). Patients who were positive for anti–JC virus antibodies, had taken immunosuppressants before the initiation of natalizumab therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk (incidence, 11.1 cases per 1000 patients [95% CI, 8.3 to 14.5]).

CONCLUSIONS
Positive status with respect to anti–JC virus antibodies, prior use of immunosuppressants, and increased duration of natalizumab treatment, alone or in combination, were associated with distinct levels of PML risk in natalizumab-treated patients with multiple sclerosis. (Funded by Biogen Idec and Elan Pharmaceuticals.)

Gary Bloomgren, M.D., Sandra Richman, M.D., Christophe Hotermans, M.D., Meena Subramanyam, Ph.D., Susan Goelz, Ph.D., Amy Natarajan, M.S., Sophia Lee, Ph.D., Tatiana Plavina, Ph.D., James V. Scanlon, Pharm.D., Alfred Sandrock, M.D., and Carmen Bozic, M.D.

Source: N Engl J Med 2012; 366:1870-1880May 17, 2012 NEJM.org Copyright © 2012 & Doctors Lounge Copyright © 2001-2012 Doctors Lounge (17/05/12)

Tysabri appears OK for expectant mothers with MS

Accidental fetal exposure to natalizumab did not appear associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age in pregnant multiple sclerosis patients, according to small studies presented here.

Based on data from an MS and pregnancy registry in Germany, seven babies born to MS patients were exposed to natalizumab (Tysabri) during the third trimester and two were found to have profound anemia at birth, but both recovered and all the infants in the group are now healthy, said Kerstin Hellwig, MD, from St. Josef Hospital/Ruhr University in Bochum, at the annual meeting of the American Academy of Neurology.

Women with MS are often advised to discontinue disease-modifying drugs prior to conceiving -- Hellwig noted that current recommendations call for suspension of natalizumab therapy 3 months prior to a planned pregnancy -- but accidental exposure still occurs.

In the national registry, Hellwig said 62 pregnancies were recorded in which exposure to natalizumab occurred at some time point during gestation. Of those babies, 48 babies were born healthy. One boy was born with an extra digit that was successfully amputated at age 1. There were eleven spontaneous miscarriages that occurred, there was one tubal pregnancy, and one women who electively terminated the pregnancy.

"From our study it appears that accidental exposure to natalizumab in the first trimester does not appear to cause major risk to the children," she said. "There might be some minor risks but we cannot observe them at the present because we have small numbers of patients."

In a second study, Ellen Lu, a PhD candidate at the University of British Columbia in Vancouver, and colleagues conducted a literature review through August 2011 and found 15 studies that identified 761 interferon-beta, 97 glatiramer acetate (Copaxone), and 35 natalizumab exposed pregnancies.

They reported that compared with unexposed pregnancies, fair to good quality prospective cohort studies reported that interferon-beta exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth, but not low birth weight, cesarean delivery, congenital anomaly, or spontaneous abortion.

While there were fewer studies of fair quality available for glatiramer acetate and natalizumab, neither drug was associated with lower mean birth weight, congenital anomaly, preterm birth or spontaneous abortion.

However, they cautioned that the quality of all the studies ranged from poor to good and most studies were limited by small sample sizes. Also, few studies examined long-term developmental outcomes in children who were exposed in utero.

Lu said the jury is still out on recommendations for newer agents such as fingolimod (Gilenya). "There is no clear signal of harm with these newer drugs," she said. "If women are exposed to these drugs, we don't think we should recommend that they terminate their pregnancy, but they should try to come off the drug."

Hellwig stressed the importance of counseling female MS patients about the possible consequences of MS drugs. In her study, 40% of the women experienced MS relapse while off natalizumab during pregnancy. "There does appear to be a protective effect of pregnancy on MS patients, but that protective effect is not complete," she explained.

She pointed out that if severe MS activity occurs during the pregnancy, and the mother takes natalizumab during the last trimester, the babies require close watch after birth. "I would continually monitor the mother, and would closely follow the children for 2 years," she said.

She said that additional safety data of natalizumab exposure during pregnancy are needed to exclude any major teratogenic or pro-abortive risks.

Hellwig disclosed commercial interests with Bayer Pharamceuticals, Schering AG, Biogen Idec, Merck Serono, Teva Neuroscience, Aventis Phramceuticals Corporation, Novartis, and Serono.

The German MS and pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Teva Sanofi Aventis, and Novartis.

Primary source: American Academy of Neurology

Source reference: Lu E, et al. "Disease-Modifying Drugs for Multiple Sclerosis in Pregnancy: A Systematic Review" AAN 2012;abstract P06.188. Additional source: American Academy of Neurology

Source reference: Hellwig K, et al. "Natalizumab and Pregnancy – Results from the German MS and Pregnancy Registry" AAN 2012;abstract P06.187.

Source: MedPage Today © 2012 Everyday Health, Inc (02/05/12)

New Tysabri data presented at AAN Meeting

Biogen Idec and Elan Corporation announced findings from several studies of Tysabri(R) (natalizumab) evaluating its long-term safety and efficacy in the treatment of multiple sclerosis (MS) across the course of disease and impact on MS-related symptoms such as fatigue. These data, as well as data relating to the companies' risk stratification algorithm as a way to help enable individual benefit risk assessment for patients with MS, were accepted for presentation at the 64th Annual Meeting of the American Academy of Neurology (AAN).

"We continue to build on the extensive data we have for Tysabri and are committed to studying its long-term use and potential effect on symptoms like fatigue, which MS patients struggle with every day," said Douglas E. Williams, Ph.D., executive vice president of Research and Development at Biogen Idec. "Our research is aimed at discovering additional ways Tysabri can help physicians and patients best manage the symptoms of MS and make informed and personalized treatment choices."

Long-Term Observational Study of Tysabri

Initial results from the Tysabri Observational Program (TOP) indicate that post-baseline annualized relapse rates (ARR) after four years for patients receiving Tysabri therapy decreased from 1.99 at baseline to 0.28 (p<0.0001); disability, as measured by the Expanded Disability Status Scale (EDSS), remained stable over time. TOP is an ongoing open-label, multicenter, observational study designed to assess long-term outcomes in patients with relapsing-remitting MS (RRMS) in Europe, Australia, and Canada. TOP is expected to enroll more than 4,500 patients who will be followed for 10 years.

Neither reduction in ARR nor stabilization of a patient's EDSS was affected by the type of treatment they were using before initiating Tysabri therapy. However, ARR were lowest in immunosuppressant (IS) therapy-naive patients and highest in patients who had used IS therapy (p<0.0001).

The incidence and type of serious adverse events (SAEs) seen in these patients after long-term use was consistent with Tysabri's known safety profile. There were no significant differences by baseline treatment history in the incidence of SAEs, infection-related SAEs, or progressive multifocal leukoencephalopathy (PML) during Tysabri therapy, although there was a trend of higher incidence of PML in patients with prior IS use.

"TOP may help provide insight into the potential impact current treatment may have on long term efficacy and safety outcomes with Tysabri," said Professor Ludwig Kappos, MD, chair of Neurology, Research Group Leader Clinical Neuroimmunology and Neurobiology, Department of Biomedicine, University Hospital, Basel, Switzerland. "The reduction of MS relapse and stable disability progression that we observed with Tysabri in the TOP study across naive and previously treated patients was sustained after four years of treatment."

Risk-Stratification Initiatives

Biogen Idec and Elan developed a quantitative risk stratification algorithm to help physicians and people with MS have more confidence in their treatment decisions when considering Tysabri. The algorithm provides guidance for physicians and patients about the varying degrees of PML risk associated with Tysabri treatment. The variables impacting PML risk are: anti-JCV antibody status, prior IS use, and Tysabri treatment duration.

"We are pleased to be able to offer MS patients and their physicians an approach for assessing the potential benefit-risk with Tysabri," said Ted Yednock, executive vice president and head of Global Research, Elan. "A significant advancement in this area is the inclusion of anti-JCV antibody status in the Tysabri label as a risk factor for developing PML, as well as the commercial availability of the STRATIFY JCV(TM) blood test. Use of this approach for risk stratification is supported by data presented at AAN."

PML risk was quantified by assessing more than 92,000 MS patients from Tysabri post-marketing sources and clinical studies; through September 2011 there were 159 cases of PML among this patient population and data show PML risk was lowest in anti-JCV antibody negative patients (no PML cases occurred in anti-JCV antibody negative patients; with the inclusion of one hypothetical anti-JCV antibody negative case, the risk is less-than or equal to 0.10 cases per 1,000 patients treated). PML risk was highest in patients with all three risk factors: anti-JCV antibody positive status; prior immunosuppressant use; and 25-48 months of Tysabri treatment (10.6 cases per 1,000 patients treated). The use of anti-JCV antibody status in this algorithm marks the first time a safety biomarker for risk stratification has been used to inform treatment decisions in MS and these data will be updated during the AAN presentation.

A separate study, STRATIFY-2, an ongoing, longitudinal, observational U.S. study, is the largest data set to date to analyze anti-JCV antibody seroprevalence among MS patients. Baseline anti-JCV antibody testing results from more than 35,000 MS patients who were either receiving or considering treatment with Tysabri showed that the overall prevalence of anti-JCV antibodies was 53.5 percent (95% confidence interval [ci]:53.0%--54.0%), which is consistent with the prevalence of anti-JCV antibodies observed in MS patients in other clinical research. Interim results from STRATIFY-2 demonstrated prospectively that the PML incidence in Tysabri-treated anti-JCV antibody negative patients was significantly lower than that in anti-JCV antibody positive patients (anti-JCV negative = 0, CI: 0--0.34; anti-JCV positive=1.02, CI: 0.53--1.78 [p=0.0004]). Final data from STRATIFY-2 will further characterize PML risk in anti-JCV antibody negative and positive patients.

Tysabri Impact on MS-related Fatigue

Initial findings from the TYNERGY study (Effects of Tysabri Over 12 Months on MS Related Fatigue in Patients with RRMS) show that Tysabri treatment was associated with improved MS-related fatigue. TYNERGY was a multicenter, 12-month clinical follow-up study conducted to evaluate the effect of Tysabri on MS-related fatigue in patients with RRMS. Fatigue is considered the most common symptom of MS, impacting 75-95 percent of patients. Further, 50-60 percent of MS patients report fatigue as one of their most disabling symptoms, which can contribute to cognitive and physical difficulties.

In the study, researchers measured MS-related fatigue at 0 and 12 months via the Fatigue Scale for Motor and Cognitive Functions (FSMC). Results indicate that treatment with Tysabri impacted fatigue in patients with RRMS as evidenced by a median reduction of the FSMC score by 9.0 points (p<0.0001), which corresponds to an improvement from severe to moderate fatigue. Both the motor and the cognitive components of the FSMC showed similar improvement (p<0.0001). Researchers noted that these first results are promising but need further validation.

Data highlighted in this press release is featured in the following poster and platform presentations at the AAN annual meeting:

-- Long-Term Safety and Efficacy and Association between Baseline Treatment History and Postbaseline Relapses in Multiple Sclerosis Patients Treated with Natalizumab in the Tysabri Observational Program (TOP) (P04.134) was presented on Wednesday, April 25, 2012

-- Updated Incidence of Progressive Multifocal Leukoencephalopathy in Natalizumab-Treated Multiple Sclerosis Patients Stratified by Established Risk Factors (S41.001) --presented by Dr. Gary Bloomgren on Thursday, April 26, 2012 from 1:00 to 1:15 p.m. CDT

-- Anti-JCV Antibody Prevalence in Patients with Relapsing Multiple Sclerosis Receiving or Considering Treatment with Natalizumab: Baseline Results of STRATIFY-2 (S41.002) -- presented by Dr. Sandra Richman on Thursday, April 26, 2012 from 1:15 to 1:30 p.m. CDT

-- Natalizumab Reduces Fatigue as Measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC)--First Results from the TYNERGY trial (P07.081) -- available for viewing on Thursday, April 26, 2012 from 2:00 to 6:30 p.m. CDT

Source: Market Watch Copyright © 2012 MarketWatch, Inc (27/04/12)

Patients dropping MS drug Tysabri face relapse risk

Multiple sclerosis patients treated with natalizumab were more likely to discontinue therapy after learning of a positive JCV antibody result, only to see a higher risk for relapse, according to a small, single-center study reported here.

Of nine patients who discontinued natalizumab (Tysabri) after learning their antibody result, which indicated a heightened risk for progressive multifocal leukoencephalopathy (PML) -- a rare but life-threatening event -- five relapsed within 6 months, said Denise Cheng, RN, of Winthrop Comprehensive MS Care Center in Mineola, N.Y.

These patients may have assumed their MS was no longer active, as opposed to a continuing disease process that was suppressed by the natalizumab treatment, Cheng said at the American Academy of Neurology's annual meeting.

Four of the five patients resumed natalizumab after relapsing, she added. Three of them, as well as another patient who had persisted with substitute therapy despite the relapse, remained worse in terms of functional status than before natalizumab was initially discontinued.

PML, which is caused by reactivation of latent JC virus infection, has been seen in about 0.1% of MS patients receiving natalizumab. The risk is very low in patients without previous infection, but is more than 1% in patients with JC virus who take the drug for more than 2 years, and are taking other immunosuppressant agents.

In January, the FDA approved a serological test for JC virus exposure to be used in patients taking or considering natalizumab therapy.

Patients are now routinely tested for JCV antibodies before starting on natalizumab, with the risks and potential benefits explained to those with positive results, Cheng explained.

But patients already taking natalizumab are now being offered the test, and their decision-making and clinical outcomes are a matter of significant interest to neurologists.

She reported results in 71 patients at Winthrop tested for JCV antibody. Of these, 39 were negative and continued on natalizumab. There were two relapses during 6 months of follow up.

Among the 32 with positive test findings, 23 decided to stay on natalizumab, Cheng said. One of these suffered a relapse during follow up.

Of the nine patients who switched away from natalizumab, seven chose injectable drugs including interferon-beta products, glatiramer acetate (Copaxone), or rituximab (Rituxan). Two chose the oral drug fingolimod (Gilenya).

Cheng said patients underwent a three-month washout period after stopping natalizumab.

The four who did not relapse all had picked injectable agents for the substitution, Cheng said.

Both of the patients choosing fingolimod had relapses, including one who stayed with it even after suffering a relapse.

"She refused, absolutely refused, to go back on an injectable," Cheng said.

The other patient choosing fingolimod could not tolerate the drug and had stopped it after 6 weeks and he had a mild relapse 2 weeks later.

Most of the relapsed patients had good results with natalizumab before discontinuing. One had a mild relapse after 20 infusions, and another experienced a moderate relapse after 11 infusions. The other three had no relapse while on the drug.

She suggested that it would be helpful to have an objective test to show that natalizumab is still exerting an effect in patients without clinical or radiological signs of disease. Such a test, she said, might "prevent the false conclusion that the MS had become quiescent."

For patients considering natalizumab treatment, Cheng added, the JC virus antibody test was a valuable tool. Negative results in her clinic do not seem to make patients more likely to start the drug, she said, but it definitely increases the comfort level in those who do.

The study had no external funding.

Cheng reported having received payments from Biogen Idec, Bayer, and the MSAA

Primary source: American Academy of Neurology

Source reference: Gottesman M, et al "JCV antibody status: patient decision making and clinical course" AAN 2012; Abstract P02.140.

Source: MedPage Today © 2012 Everyday Health, Inc (26/04/12)

Antibody to α4 integrin suppresses natural killer cells infiltration in CNS

Abstract

Natalizumab inhibits the influx of leukocytes into the central nervous system (CNS) via blockade of alpha-4 subunit of very late activation antigen (VLA)-4.

The association of natalizumab therapy with progressive multifocal leukoencephalopathy (PML) suggests a disturbance of CNS immune surveillance in a small percentage of Multiple Sclerosis (MS) patients exposed to the medication.

Natural killer (NK) cells are known to play an important role in modulating the evolution of different phases of this lymphocyte mediated disease, and we investigated the effects of natalizumab on the NK cell phenotype and infiltration in the CNS in experimental autoimmune encephalomyelitis (EAE), a murine model of MS.

Our data show that both resting (from naïve mice) and activated (from EAE mice) NK cells express high levels of VLA-4, and anti-VLA-4 antibody treatment significantly decreases NK cells frequency in the CNS of EAE mice. Moreover, we find that anti-VLA-4 possibly impairs NK cells migratory potential, since unblocked VLA-4 expression levels were downregulated on those NK cells that penetrate the CNS.

These data suggest that treatment with antibody to VLA-4 may alter immune surveillance of the CNS by impacting NK cell functions and might contribute to the understanding of the mechanisms leading to the development of PML in some MS patients.

Source: J Neuroimmunol. 2012 Apr 13. Copyright © 2012 Elsevier B.V. All rights reserved & Pubmed 22503411 (25/04/12)

212 PML cases and 46 deaths in Tysabri MS patients as of March 1st 2012

Biogen Idec have released the latest figures for PML cases and deaths following Tysabri infusions for Multiple Sclerosis

As of March 1, 2012, there have been 212 PML cases, of which 122 have been in the European Economic Area (EEA), 80 in the US and 10 in rest of world (ROW). 46 of the 212 patients with PML have died.

In 54 natalizumab-treated MS patients who developed PML and in whom serum samples were available 6-187 months prior to the onset of PML, all 54 patients had anti-JCV antibodies detected.

Samples were available from 86 patients at the time of PML diagnosis and all 86 tested positive for anti-JCV antibodies.

In addition, one sample, collected from a patient at the time of PML diagnosis following a cycle of plasma exchange (PLEX) tested negative for anti-JCV antibodies. Because this sample was collected immediately following PLEX, and PLEX removes antibodies from the circulation, the information obtained from this sample is unreliable.

One patient tested anti-JCV antibody positive two months before PML diagnosis. Previously, the patient had tested anti-JCV antibody negative 15 months prior to PML diagnosis, indicating that they had been exposed to the JC virus at some point between the two tests.

Source: Biogen Idec (16/03/12)

Immunological markers of optimal response to natalizumab in Multiple Sclerosis

Abstract

Objective To explore cell subsets and molecules that changed specifically in patients with multiple sclerosis (MS) who had an optimal response to natalizumab. Natalizumab is a monoclonal antibody that inhibits the migration of activated immune cells to the central nervous system. It shows high efficacy in modifying the natural history of MS and induces freedom of disease activity in about 40% of treated patients with MS.

Design Prospective study of intrathecal immunoglobulin synthesis and cerebrospinal fluid lymphocyte subsets in patients with MS before and 1 year after beginning treatment with natalizumab. We monitored clinical and magnetic resonance imaging activity during a median time of 2 years.

Setting Two tertiary hospitals from the Spanish National Health Service.

Patients A total of 23 patients with MS.

Main Outcome Measures The differences between patients free of disease activity and patients with active disease during treatment.

Results Of the 23 patients, 10 (43.5%) remained free of disease activity during follow-up. The remaining 13 patients (56.5%) had relapses or new lesions despite natalizumab therapy. We did not find differences in demographic variables or clinical data between both groups prior to natalizumab therapy. All patients showed a decrease in cerebrospinal fluid CD4+ cells regardless of their response to treatment. Conversely, only patients free of disease activity showed a decrease in local IgM and, to a lesser extent, in IgG synthesis. They also showed lower percentages of B cells, particularly of CD5+ and plasmablast subsets that virtually disappeared after treatment with natalizumab.

Conclusion These data indicate that inhibition of intrathecal antibody synthesis is associated with a complete therapeutic response to natalizumab in patients with aggressive MS.

Luisa M. Villar, PhD; María I. García-Sánchez, PhD; Lucienne Costa-Frossard, MD; Mercedes Espiño, PhD; Ernesto Roldán, PhD; Dolores Páramo, MD; Miguel Lucas, PhD; Guillermo Izquierdo, MD; José C. Álvarez-Cermeño, MD

Source: Arch Neurol. 2012;69(2):191-197. doi:10.1001/archneurol.2011.971 © 2012 American Medical Association (14/02/12) Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab

Abstract

Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS).

Treatment with natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV).

We searched PubMed and used current data from the natalizumab global safety database to assess risk factors and quantify the risk of PML.

Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in natalizumab-treated patients.

With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV.

The availability of this assay provides an additional option for risk stratification of PML in patients using or considering natalizumab therapy.

Recommendations for clinical management of patients with MS and use of natalizumab are provided based on the presence of these three risk factors.

The identification of risk factors that increase the likelihood of PML in natalizumab-treated patients can facilitate benefit–risk discussions between health care professionals and patients.

Continued research and data collection will further develop our understanding of PML and the mechanisms by which these risk factors contribute to its development.

Per Soelberg Sørensen, Antonio Bertolotto, Gilles Edan, Gavin Giovannoni, Ralf Gold, Eva Havrdova, Ludwig Kappos, Bernd C Kieseier, Xavier Montalban, Tomas Olsson

Source: Multiple Sclerosis Journal Copyright © 2012 by SAGE Publications (13/02/12)

ASCEND study to evaluate the effectiveness of Tysabri in secondary progressive MS

Biogen Idec today announced a global Phase 3b study, ASCEND, that is being conducted to evaluate the effectiveness of Tysabri as a treatment for secondary-progressive multiple sclerosis (SPMS). According to the National Multiple Sclerosis Society, approximately half of all people initially diagnosed with relapsing-remitting multiple sclerosis (RRMS) - the most common form of multiple sclerosis (MS) - will transition to SPMS within 19 years.

Patients with RRMS typically experience unpredictable relapses; the time between relapses is characterised by full or partial recovery and a lack of disease progression. SPMS is characterized by a steady progression of nerve damage, symptoms and disability, but the exact reasons for the progression are unknown. The potential for greater disease burden in SPMS typically includes decreased mobility, impaired activities of daily living, loss of independence and reduced quality of life.

"There are limited treatment options available to people living with SPMS and there is a high unmet need for effective therapies," said Aaron Miller, M.D., member of the ASCEND advisory board; Medical Director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis; and Co-Director of the Multiple Sclerosis Care Center at Maimonides Medical Center in Brooklyn, New York. "The ASCEND trial is investigating whether treatment with Tysabri may prevent worsening in walking, hand movement and daily functioning in these patients."

"One hypothesis behind the development of SPMS is that disease progression is a result of chronic inflammation in the brain tissue trapped behind the blood-brain-barrier. This causes destruction of the myelin sheath which protects the coating around nerve fibres, as well as the progressive loss of nerve cells, which can lead to disability in MS patients," said Professor Richard Reynolds, Professor of Cellular Neuroscience, Imperial College, London; and Scientific Director of the UK Multiple Sclerosis Society Tissue Bank. "Preliminary data suggest that Tysabri may hinder this inflammation in the brain and reduce SPMS-related disease progression; therefore, further investigation of this hypothesis is warranted."

The ASCEND study is part of the ongoing commitment of both Biogen Idec and Elan to find ways to improve the well-being of patients with multiple sclerosis.

About the ASCEND Study

ASCEND (A Study to Characterise the Efficacy of Natalizumab on Disability in SPMS) is a double-blind, placebo-controlled study with SPMS patients being randomized to receive either Tysabri 300 mg or placebo intravenously every four weeks for 96 weeks. A global study, ASCEND is expected to enroll approximately 850 patients in 15 countries.

Study participants will be between the ages of 18 and 58, inclusive, with a diagnosis of SPMS for at least two years; an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, inclusive; MS Severity Score of 4 or higher; documented, confirmed evidence of disease progression, independent of clinical relapses during the one-year prior to enrollment; and naive to Tysabri treatment.

The primary endpoint is to investigate whether treatment with Tysabri slows the accumulation of disability not related to relapses in subjects with SPMS.

Secondary endpoints are:

-- The proportion of subjects with consistent improvement in Timed 25-foot Walk (T25FW);

-- The change in subject-reported ambulatory status as measured by the 12-Item MS Walking Scale (MSWS-12);

-- The change in manual ability based on the ABILHAND questionnaire;

-- The impact of Tysabri on subject-reported quality of life using the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical);

-- The change in whole brain volume between the end of study and week 24 using MRI; and

-- The proportion of subjects experiencing progression of disability as measured by individual physical EDSS system scores.

ASCEND is ongoing and actively enrolling patients.

Source: Biogen Idec and Elan Corporation, plc (26/01/12)

FDA updates Tysabri® label to include anti-JC virus antibody status as a PML risk factor and clears safety screen

Biogen Idec and Elan Corporation, plc announced that the U.S. Food and Drug Administration (FDA) has approved a product label change for Tysabri that will help enable individual benefit risk assessment for patients with multiple sclerosis (MS). The new label identifies anti-JCV antibody status as a risk factor for developing an infrequent but serious brain infection known as progressive multifocal leukoencephalopathy (PML).

This marks the third risk factor identified to help physicians and people with MS have more confidence in their treatment decisions when considering Tysabri, a highly effective treatment for relapsing forms of MS.

“This label change marks an important advance in assisting people with MS and their physicians to make better-informed decisions concerning the challenges of balancing effectiveness with safety,” said Dr. Nicholas LaRocca, Vice President Heath Care Delivery and Policy Research at the National MS Society. “We are encouraged by the proactive role that Biogen Idec and Elan are taking in addressing PML risk stratification.”

Infection with the JC virus (JCV) is required for the development of PML and the new label states that anti-JCV antibody negative status indicates that exposure to the JC virus has not been detected. Patients who are anti-JCV antibody positive have a higher risk of developing PML. Patients who are anti-JCV antibody positive, have received prior immunosuppressant (IS) therapy and received treatment with Tysabri for more than two years have the highest risk of developing PML.

“Tysabri has benefited thousands of patients worldwide who are living with multiple sclerosis, an often devastating disease affecting people in the prime of their lives,” said George Scangos, Ph.D., Chief Executive Officer, Biogen Idec. “Biogen Idec and Elan’s use of novel research and scientific expertise has allowed us to gain a better understanding of the benefit-risk profile for Tysabri. Our development of the risk stratification algorithm and subsequent efforts to support the commercial availability of anti-JCV antibody testing reflect our commitment to providing patients and their physicians with additional guidance to help them make more personalized treatment decisions.”

The label update was based on analysis of data from Biogen Idec’s and Elan's quantitative risk stratification algorithm, which was presented at a number of major international medical meetings, including the American Academy of Neurology's annual meeting in April, 2011. In the analysis, patients who were anti-JCV antibody positive were at an increased risk for developing PML with varying degrees of risk depending on prior IS use and Tysabri treatment duration. Irrespective of MS treatment, approximately 55 percent of MS patients are anti-JCV positive.

“We welcome the inclusion of PML risk stratification in the U.S. label as it significantly supports our aim to provide the information patients and physicians need to make a more informed treatment decision,” said Kelly Martin, Chief Executive Officer, Elan. “This further confirms the utility of the anti-JCV antibody status, which along with prior IS use and treatment duration enables the identification of differing levels of risk.”

The U.S. label update follows the European Commission approval of anti-JCV antibody status as an additional factor to aid in stratifying patients at risk for developing PML in the Summary of Product Characteristics for Tysabri in the European Union. Through the third quarter of 2011, globally there have been approximately 59,000 anti-JCV antibody tests administered commercially and through clinical trials.

The Food and Drug Administration also approved a new diagnostic test to help identify patients who have an increased risk of developing a rare brain infection while taking Biogen Idec's multiple sclerosis drug Tysabri.

Tysabri is one of a handful of drugs used to control multiple sclerosis, a debilitating disease in which the body attacks its own nervous system. Prescribing of the drug has been tightly controlled by the FDA because of a rare infection that causes inflammation of the brain, known as multifocal leukoencephalopathy, or PML. Currently there is no treatment or cure for PML, which usually causes death or severe disability.

The newly approved Stratify JCV test is designed to detect a common virus that increases the likelihood of developing the brain infection. The John Cunningham virus is harmless in most people, but can become dangerous in patients taking immune system-suppressing drugs like Tysabri.

Doctors can use the results of the blood-based test, combined with facts about the patient's medical history, to determine whether they are at risk of developing the brain infection. Other factors that influence a patient's risk include how long they've been taking Tysabri and whether they've previously taken other medications that weaken the immune system.

The test was developed by Quest Diagnostics.

Tysabri was temporarily pulled from the market shortly after its launch in 2005 after three patients taking the drug developed PML. FDA allowed the drug back on the market the following year but under a restricted distribution program. Only doctors and pharmacies registered with the company's distribution program are permitted to prescribe and dispense the drug.

Biogen, based in Weston, Mass., sells Tysabri through a partnership with Elan Corp., an Irish drugmaker.

Source: Seatlle Pi © 2012 Hearst Communications Inc. & Bradenton Herald © 2012 Bradenton Herald (23/01/12)