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    You are here : Home » MS Research News » Drugs » Tysabri®

    Tysabri®

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    Tysabri (Natalizumab) is a class of drug known as selective adhesion molecule (SAM) inhibitors. You can find out more about this drug on our Tysabri page.

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

    TysabriBiogen 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

    TysabriAbstract
    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

    TysabriBiogen 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

    TysabriAugust 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

    TysabriAfter 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

    Disease Modifying DrugsMultiple 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

    TysabriHealth 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

    TysabriMultiple 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

    TysabriAccidental 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

    Tysabri 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

    TysabriMultiple 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

    PMLAbstract
    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

    TysabriBiogen 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

    TysabriAbstract

    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

    TysabriAbstract

    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.

    Full Text

    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

    TysabriBiogen 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

    TysabriBiogen 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)

    193 PML cases and one more death in Tysabri MS patients

    TysabriBiogen have released the figures for December for cases of PML and deaths caused by it in Tysabri patients with MS.

    As of December 1, 2011, there have been 193 PML cases, of which 112 have been in the European Economic Area (EEA), 71 in the US and 10 in rest of world (ROW).
    39 of the 193 patients with PML have died.

    In 45 natalizumab-treated MS patients who developed PML and in whom serum samples were available 6-187 months prior to the onset of PML, all 45 patients had anti-JCV antibodies detected.

    Samples were available from 73 patients at the time of PML diagnosis and all 73 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.

    Source: Biogen (19/12/11)

    Fast, accurate test for JC virus benefits patients with MS

    JC VirusA laboratory test developed by scientists at the National Institute of Neurological Disorders and Stroke (NINDS) is helping clinicians around the world in diagnosing a rare and potentially life-threatening brain disease called progressive multifocal leukoencephalopathy (PML). The test, or assay, can quickly and precisely detect trace amounts of the virus responsible for PML.

    In recent years, cases of this little known condition have appeared in some individuals receiving certain types of monoclonal antibody therapies, cutting-edge medications that can successfully treat multiple sclerosis (MS), Crohn’s disease, rheumatoid arthritis and other autoimmune disorders. For medical teams who monitor and safeguard the health of patients on these medications, the NINDS innovation has become an important resource.

    Eugene Major, Ph.D., leads the NINDS team responsible for the assay. He is chief of the Laboratory of Molecular Medicine and Neuroscience (LMMN), part of the NINDS Division of Intramural Research on the Bethesda, Md., campus of the National Institutes of Health.

    Dr. Major’s work focuses on viruses affecting the human nervous system. One of these is the cause of PML: JC virus (so-named after the initials of the patient in whom it was first identified in 1971). This common virus infects an estimated 70 percent of people worldwide, but it is usually rendered harmless by healthy immune system cells. The virus, however, is never cleared entirely from the body; instead it remains latent (inactive) inside hidden reservoirs. If cancer, HIV or other serious conditions weaken immune defenses, JC virus can sometimes reactivate, resulting in PML.

    Both MS and PML are demyelinating diseases, meaning they destroy myelin, the fatty insulation protecting neurons in the brain. In PML the damage progresses much more swiftly, leading to symptoms such as blurred vision, muscle weakness and paralysis. PML can prove fatal within months or even weeks.

    Although there is no treatment for PML, doctors can take steps to help the immune system recognize the viral infection. A rapid diagnosis is critical, and the only conclusive method is to run an assay to confirm the presence of JC virus DNA. As a result, the ultrasensitive NINDS assay has emerged as a key diagnostic asset.

    The NINDS test is based on a quantitative polymerase chain reaction, or PCR (the same technology that sparked a genetics revolution more than three decades ago). “Through PCR we amplify copies of viral DNA from DNA templates isolated from clinical samples,” explained Dr. Major. The result is a highly specific and sensitive gauge capable of returning rapid results.

    A 2009 case study in The New England Journal of Medicine(1) documented the NINDS assay’s strengths. Investigators at Sweden’s prestigious Karolinska Institute suspected PML in an MS patient treated with natalizumab, a monoclonal antibody drug. The patient was experiencing muscle problems, and brain scans revealed that his white matter lesions had grown larger.

    The medical team took precautions, withdrawing the drug from the patient’s blood and conducting local PCR tests to verify if this was PML. At the same time the investigators also sent samples of the patient’s cerebrospinal fluid to Dr. Major for additional testing.

    According to the published report, even though the initial tests in Sweden had been negative for JC virus (with criteria at less than 200 copies per milliliter), the results from quantitative PCR assay at NINDS confirmed borderline positivity (at 10 copies per milliliter). The analysis validated the doctors’ suspicions. Their prompt response helped the patient recover with fewer neurological deficits than expected.

    Dr. Major had worked previously on a similar international collaboration. In 2005 he served on a task force investigating PML cases among natalizumab-treated MS patients (a role he continues to this day). As part of that study, he and NIH colleagues analyzed tissue samples from more than 3,000 patients in clinical trials around the world. (2)

    The data aided U.S. and European regulatory agencies assessing natalizumab’s record. The medication, which had been temporarily removed from the market, was reintroduced in 2006. Manufacturers of monoclonal antibody therapies and doctors alike now closely watch patients for any complications related to treatment.

    Today, Dr. Major’s team continues to assist global efforts to track PML. The LMMN analyzes nearly 1,000 patient samples per year, according to NINDS medical technologist Caroline Ryschkewitsch.

    NINDS conducts the tests free of charge. Dr. Major considers it part of his lab’s translational research mission. “Our work extends from developing new technologies to enhance our basic understanding of disease mechanisms to translating that knowledge into diagnostics and therapeutic strategies to treat patients,” he said.

    Dr. Major also continues to investigate underlying reasons for JC virus reactivation. In an article published in conjunction with the Karolinska case study, he mapped out a possible connection.(3)

    Some monoclonal antibodies modify properties of immune system cells. Natalizumab specifically disrupts their ability to bind with cell surface proteins, potentially facilitating the extravasation (forcing out) of certain cells from bone marrow tissue, one of the likely harbors of latent JC virus. This process might enable viral particles to escape their reservoirs and make their way to the brain to cause PML.

    Pursuing PML’s disease mechanisms remains an important scientific challenge, along with developing new drug treatments or vaccines, according to a 2010 article by Dr. Major.(4) Underscoring this point, a recent study published by Dr. Major’s lab demonstrated lingering neurological disability in several natalizumab-treated MS patients.(5) The findings suggest that JC virus can persist for years even after treatment has been halted.

    Dr. Major remains committed to improving and broadening access to the assay. He had the test independently validated and certified through the U.S. Clinical Laboratory Improvement Amendments (CLIA). The program ensures quality standards for lab procedures.

    NIH also recently licensed the assay technology, making it commercially available for scientists anywhere in the world. “This will expand opportunities for collaboration,” said Dr. Major. “We hope the assay continues to be an important resource wherever it’s needed.”

    By Gregory Roa, NINDS

    REFERENCES:
    1. Lindå H, von Heijne A, Major EO, Ryschkewitsch C, Berg J, Olsson T, Martin C. "Progressive multifocal leukoencephalopathy after natalizumab monotherapy." The New England Journal of Medicine. 2009 Sep 10;361(11):1081-7

    2. Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, Curfman B, Miszkiel K, Mueller-Lenke N, Sanchez E, Barkhof F, Radue EW, Jäger HR, Clifford DB. "Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy." The New England Journal of Medicine. 2006 Mar 2;354(9):924-33

    3. Major EO. "Reemergence of PML in natalizumab-treated patients--new cases, same concerns." The New England Journal of Medicine. 2009 Sep 10;361(11):1041-3.

    4. Major EO. "Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies." Annual Review of Medicine. 2010;61:35-47.

    5. Ryschkewitsch CF, Jensen PN, Monaco MC, Major EO. "JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab." Annals of Neurology. 2010 Sep;68(3):384-91.

    Source: National Institute of Neurological Disorders and Stroke (01/11/11)

    Progressive multifocal leukoencephalopathy associated with natalizumab in paediatric MS

    TysabriBackground: In the pediatric Multiple Sclerosis (MS) population large and controlled studies on safety and efficacy of Natalizumab have not yet been performed. In literature there have been no cases of Natalizumab-related Progressive Multifocal Leukoencephalopathy (PML) reported in paediatric population with MS.

    Case Report: A 14-year-old girl presented in October 2009 diplopia, gait ataxia, vomiting and impaired mentation, preceded by asthenia, fever and left sensory loss lasting for 3 days, 1 month earlier. MRI showed a diffuse leukoencephalopathy with large lesions in brainstem, semioval centers and spinal cord with diffuse gadolinium enhancement. The IgG Index was increased. After treatment with i.v. Methylprednisolone (MP) she improved.

    Initial diagnosis was ADEM. In December 2009 she presented behavioural changes, ataxia, strabismus and urinary incontinence. Brain MRI showed new large lesions with ring enhancement. She was treated with MP and high dose i.v. immunoglobulins for 5 days without efficacy. She underwent 3 Mitoxantrone (8 mg/sqm) monthly infusions and then 8 plasma exchanges, with partial recovery only in mental function. MRI showed new demyelinating areas with ring enhancement. A 10 d MP course was followed by improvement in motor and mental functions; apraxia and urinary incontinence persisted.

    Final diagnosis was of malignant MS. She was treated with monthly Natalizumab infusions from May 2010 to December 2010, with partial efficacy. Antibodies against Natalizumab were negative. Her parents refused autologous bone marrow transplantation.

    In February 2011 the girl had a clinical relapse with stable MRI. She was treated with Natalizumab (one infusion) and i.v. MP. Brain MRI in March 2011 showed new areas in left frontal lobe, some subcortical with enhancement. The girl had further deterioration in cognitive function. Test for JC virus antibodies was positive. Assuming a diagnosis of PML Natalizumab was stopped and lumbar puncture was performed. PCR for JC virus DNA revealed over 140 copies and diagnosis of PML was confirmed.

    Conclusions: This case of paediatric MS is extremely aggressive and no treatment was really effective to stabilize the disease. The girl had a cognitive impairment from the beginning of the disease and worsening of it is the only signal of PML. Further studies are needed to assess the efficacy and safety of Natalizumab in paediatric MS population and to identify clinical and radiological parameters for early diagnosis of PML.

    M di Ioia, D. Farina, G. De Luca, D. Travaglini, V. Di Tommaso, E. Pietrolongo, A. Lugaresi (Chieti, IT)

    Maria Di Ioia is involved in clinical trials of Merck Serono S.A – Geneva and Teva Neuroscience Deborah Farina has received researcher grant from: Merck Serono S.A. – Geneva, Biogen-Dompè and is involved in clinical trials of the same company, plus GlaxoSmithKline, Biogen-Dompé, Bayer Schering, Novartis and Teva. Giovanna De Luca has received a researcher grant from: Merck Serono S.A. – Geneva and is involved in clinical trials of the same company, plus GlaxoSmithKline, Biogen-Dompé, Bayer Schering, Novartis and Teva. Daniela Travaglini is involved in clinical trials of GlaxoSmithKline, Biogen-Dompé, Bayer Schering, Merck-Serono, Novartis and Teva. Valeria Di Tommaso is involved in clinical trials of GlaxoSmithKline, Biogen-Dompé, Bayer Schering, Merck-Serono, Novartis and Teva. Erika Pietrolongo is involved in clinical trials of Merck-Serono, Novartis, Sanofi-Aventis and Teva. Alessandra Lugaresi has received research and travel support or speaker fees from Biogen-Dompé, Bayer Schering, Merck-Serono, Novartis, Sanofi-Aventis and Teva.

    Source: 5th Joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis Amsterdam, The Netherlands 19.10.2011 - 22.10.2011 (31/10/11)

    MS relapses seen after Tysabri drug holiday

    TysabriIn patients with relapsing-remitting multiple sclerosis (MS), interrupting treatment with natalizumab (Tysabri, Biogen) often leads to relapse, a new study shows.

    The findings "confirm a high rate of recurrence" of magnetic resonance imaging (MRI)-defined and clinical MS disease activity starting at approximately week 12, during a 24-week interruption of natalizumab therapy, a study team notes.

    "Clearly, the risk of return of disease activity during treatment interruption is notable, even with the alternative immunomodulatory therapies used in this study," Robert J. Fox, MD, neurologist and medical director of the Mellen Center for MS at the Cleveland Clinic, Ohio, and leader of the study team, said in his presentation here at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

    If an interruption is still desired, the researchers recommend monthly MRIs starting 3 months, or certainly 4 months, after the last natalizumab dose could be considered, "although the practicality of monthly MRI obviously needs to be factored in," he added. "Rescue therapy if gadolinium lesions appear or the patient has a clinical relapse could be considered as well."

    The RESTORE Study

    Natalizumab is a monoclonal antibody that inhibits leukocyte migration across the blood–brain barrier. It is thought to reduce inflammation in the central nervous system and has been approved worldwide for the treatment of relapsing-remitting MS.

    After US Food and Drug Administration approval in 2004, natalizumab was temporarily withdrawn from the market in 2005 after being linked with progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the central nervous system associated with the John Cunningham (JC) virus. The drug was reintroduced in the United States in 2006 with stricter safety warnings and monitoring programs.

    A test for antibodies for the JC virus is currently in development. In addition to JC virus positivity, an increasing time receiving natalizumab has also emerged as a risk factor for PML, leading researchers to hypothesize that a temporary interruption of natalizumab treatment might decrease PML risk. "However, that needs to be balanced out with the risk of return of the underlying MS disease activity," Dr. Fox points out.

    The Randomized Treatment Interruption of Natalizumab (RESTORE) trial is a randomized, partially placebo-controlled study designed to evaluate the effect of a 24-week interruption in natalizumab treatment. Presented here were preliminary data from an interim analysis of the study focusing on MS disease activity.

    The aims were, first, to determine the relative time course of return of MS disease activity during natalizumab interruption, and second, to determine whether an alternative immunomodulatory treatment could modify disease activity after a temporary treatment interruption. "It's important to recognize that RESTORE was not designed, nor was it powered, to detect the effect of a temporary natalizumab treatment interruption on the development of PML," Dr. Fox noted.

    The trial compares continued natalizumab treatment with placebo or with switching therapy to interferon beta-1a, glatiramer acetate, or methylprednisolone. The first 2 groups were double-blind, whereas in the third group, the preferred alternative agent could be chosen by the neurologist in consultation with the patient. After 24 weeks, all patients returned to treatment with natalizumab and were followed-up to week 52.

    If disease activity occurred, including clinical relapse and/or new gadolinium-enhancing lesions, rescue treatment with high-dose corticosteroids and/or natalizumab could be initiated. Clinical disease activity was defined by the blinded neurologist, but "the bar was set relatively low," Dr. Fox said, as either an increase in the overall Expanded Disability Status Scale or an increase in any other functional system subscale. MRI disease activity also qualified as a return of disease activity, defined as 1 gadolinium-enhancing lesion of 0.8 cm3 or larger, or 2 gadolinium lesions of any size.

    Eligible patients were relapse-free during natalizumab treatment for the preceding 12 months or longer before randomization, and did not have gadolinium-enhancing lesions on screening brain MRI.

    The 175 patients enrolled in the study were randomly assigned to the treatment groups in a 1:1:2 ratio. They were also stratified by country and by disease activity before the start of natalizumab therapy, and dichotomized into high (≥2 relapses in the year before natalizumab therapy) or low (0 or 1 relapses) groups. Of those randomly assigned to receive the other therapy, about half of the patients chose methylprednisolone, and the rest were split between interferon-beta-1a and glatiramir acetate. Dr. Fox emphasized, however, that the study was also not powered to detect differences between these other therapies.

    Of patients who continued to receive natalizumab, none met the criteria for return of MRI disease activity compared with 44% of the patients receiving placebo, 7% of patients receiving interferon-beta-1a, 40% of patients receiving methylprednisolone, and 53% of patients receiving glatiramir acetate. Perhaps not surprisingly, those with high disease activity before starting natalizumab were more likely to have it return after interruption.

    Kaplan-Meier curves suggested that first return of MRI-defined disease activity occurred at around 12 weeks, "and around weeks 16 to 20, we really see the up-tick in patients who were going to have return of disease activity, and then it flattened out somewhat after week 20," Dr. Fox noted.

    Despite no MRI activity, 2 of the patients who had continued to receive natalizumab had a clinical relapse during the trial. Relapses occurred in 17% of patients receiving placebo, and in between 15% and 29% of patients receiving the other therapies. Again, relapses were more common in those with higher disease activity before natalizumab therapy.

    Kaplan-Meier curves on time to relapse showed that relapses occurred later in the randomized period for patients receiving natalizumab compared with those receiving other therapies or placebo. Several patients randomly assigned to receive the other therapies had early return of disease activity clinically, despite not yet having a return of MRI-defined disease activity, Dr. Fox noted. "And to me this suggests that perhaps there was a reverse placebo or nocebo effect in at least a portion of the patients."

    When the researchers combined time to first clinical relapse or meeting MRI criteria for return of disease activity, curves again showed an increase between weeks 16 and 20.

    There was a sense of some delay in the return of disease activity among those receiving interferon-beta-1a as an alternative therapy, Dr. Fox noted, "although the sample sizes are very small." Those patients receiving interferon also tended to have lower disease activity before natalizumab therapy. Monthly methylprednisolone, in contrast, appeared not to be effective in suppressing disease activity, at least at the doses used here, he noted.

    Rescue therapy with natalizumab tended not to be used for early signs of disease activity return, and the 2 patients who had relapses despite receiving natalizumab did not return to open-label therapy until the end of the trial. "But again, it was in the area of 20 weeks when patients opted for the rescue therapy," Dr. Fox said.

    Patients Rescued With Natalizumab

    Agent

    %

    Natalizumab

    0

    Placebo

    63

    Interferon beta-1a

    21

    Glatiramer Acetate

    47

    Methylprednisolone

    42

    "Not Surprising"

    Reached for comment, David M. Clifford, MD, from the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, who was not involved in the study, said he is not surprised that interrupting natalizumab led to relapse.

    "This is exactly what was expected. It has been my view that treatment interruption was not rational, and indeed might well put patients at risk for disease progression with no real expectation on my part that it would reduce risk of PML," Dr. Clifford told Medscape Medical News.

    "While these data are suboptimal in number, they certainly seem to confirm that interruption will often result in recurrent MS in a relatively short time frame," he added.

    Ralf Gold, MD, professor and chair, Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany, gave a talk on the last day of the conference on the clinical highlights presented, and touched on these results from RESTORE.

    Natalizumab is an important agent for patients with active disease, but given the potential risks with longer treatment duration, he said, "it's clear some patients who are stable may like to discontinue after 2 years, and maybe switch, and this was addressed by this study."

    The main result "doesn't come as a surprise," he said. "All of us know in active patients after 3 months, it starts again, and those on natalizumab remained stable." Although the numbers were small, Dr. Gold noted, "surprisingly, the interferon patients also stayed stable."

    This finding raises an interesting hypothesis, he said: If disease is "silenced" for 1 or 2 years by natalizumab, it may be possible that alternative therapies could then be used. "At least it's important, and we'll learn a lot about this study from further biomarkers."

    The study was supported by Biogen Idec Inc and Elan Pharmaceuticals, Inc. Several of the study authors have disclosed financial relationships with Biogen Idec and Elan and other pharmaceutical companies. Four of the authors are employed by Biogen Idec. Dr. Clifford has disclosed no relevant financial relationships.

    5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS): Abstract 150. Presented October 22, 2011.

    Source: Medscape Today Copyright © 1994-2011 by WebMD LLC. (24/10/11)

    Tysabri PDUFA date extended by FDA

    TysabriBiogen Idec and Elan Corporation, plc announced that the U.S. Food and Drug Administration (FDA) has extended the initial PDUFA date for its review of the supplemental Biologics License Application (sBLA) for Tysabri(R) (natalizumab).

    The sBLA was submitted in December 2010 to update the Prescribing Information for Tysabri to include anti-JC virus antibody status as a factor to help stratify the risk of progressive multifocal leukoencephalopathy (PML) in the Tysabri-treated population. The 3 month extension is a standard extension period.

    The FDA has indicated that the extension of the PDUFA date is needed to allow time for review of the changes being incorporated into the Risk Evaluation and Mitigation Strategies (REMS) program for Tysabri, to be consistent with the anticipated Prescribing Information.

    Biogen Idec and Elan are working with the FDA to help facilitate a timely review of the REMS changes and the sBLA.

    Source: Medpage Today © 2011 Everyday Health, Inc (20/10/11)

    2 out of 3 patients report discontinuing Tysabri without doctors' advice

    TysabriIn the first report of a series on Multiple Sclerosis (MS) disease modifying therapies (DMTs), PatientsLikeMe reveals that nearly two-thirds (64%) of patients who report discontinuing the use of Tysabri (n=323) did not cite "doctor's advice" as a reason.

    "Side effects too severe" and "did not seem to work" topped the other reasons cited by patients. The report goes on to reveal that patients stop Tysabri due to side effect severity less frequently than patients who discontinue other DMTs for that same reason. The PatientsLikeMe report is the first of five in a series focusing on how patients are experiencing and evaluating DMTs in the real world.

    "People with MS and other conditions have become much more than just consumers of prescription medications, they are now customers who wield a high level of influence on treatment decisions," says David S. Williams III, Chief Marketing Officer at PatientsLikeMe. "The goal is maximizing health outcomes for patients. Clinicians can use the real-world insights from this report to collaborate better with patients in treatment planning while manufacturers can use them to better design adherence programs to reduce inappropriate discontinuation."

    This 40-page report -- titled "Does Tysabri patient experience in the real world justify its value?" -- analyzes the experiences of more than 12,000 MS patients who are taking, or have taken, Tysabri or other DMTs.

    In the report, PatientsLikeMe evaluates:

    • Tysabri Price vs. Value: Is this drug appropriately priced given real-world evidence regarding efficacy and side effects?
    • The Patient Voice in Treatment Discussions: Of the 4,083 patient conversations mentioning one or more MS DMTs from January-June this year, Tysabri commanded 27% share of patient voice. What percentage of Tysabri-related discussions were focused on progressive multifocal leukoencephalopathy (PML) or JCV (John Cunningham virus) antibodies?
    • Efficacy and Side Effects: More than half (55%) of the 500 Multiple Sclerosis patients who have taken and evaluated Tysabri experienced "moderate" to "major" efficacy compared to interferon therapies which average 33% moderate to major efficacy.

    Source: Market Wire Copyright 2011 Marketwire, Inc. (22/09/11)

    © Multiple Sclerosis Resource Centre (MSRC)

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