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    You are here : Home » MS Research News » Drugs » Ocrelizumab

    Ocrelizumab

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    Ocrelizumab shows promise in MS

    Roche LogoAn investigational biologic drug that deactivates antibody-producing B cells reduced gadolinium-enhancing T1 lesions in multiple sclerosis patients, potentially offering yet another treatment approach to the disease, researchers said.

    After 24 weeks of the phase II trial, lesion burden as measured by MRI was reduced by 89% in 55 patients treated with a low dose ocrelizumab relative to the 54-patient placebo group (95% CI 68% to 97%), according to Ludwig Kappos, MD, of University Hospital in Basel, Switzerland, and colleagues.

    Lesions were reduced by 96% in 55 patients receiving a high dose of the drug (95% CI 89% to 99%), the researchers reported online in The Lancet.

    The randomized trial also included a fourth arm in which 52 patients received intramuscular interferon-beta-1a (Avonex), a standard treatment for MS. Mean lesion counts during the trial in this group were similar to those seen in the placebo group.

    "Our study shows the effectiveness of B-cell depletion with both ocrelizumab doses in reducing MRI and clinical disease activity, combined with a favorable short-term safety profile," Kappos and colleagues wrote.

    Ocrelizumab is a humanized monoclonal antibody against the CD20 protein that marks activated B cells. It shares this target with rituximab (Rituxan), which has also shown promise in MS and is sometimes used off-label in the condition.

    But rituximab is a chimeric mouse-human globulin and hence potentially more prone to development of neutralizing antibodies. Kappos and colleagues cited data suggesting that ocrelizumab has increased antibody-dependent cell-mediated cytotoxic effects that may make it a better drug for MS.

    The current study is the first to compare ocrelizumab with placebo and interferon-beta in a controlled trial.

    The 218 patients had relapsing-remitting MS with mean duration of about 6 years and mean EDSS disability scores of about 3.3.

    Mean gadolinium-enhancing T1 lesion counts at baseline were 1.6 in the placebo group, 3.9 in the low-dose ocrelizumab group, 2.2 among those assigned to high-dose ocrelizumab, and 2.3 in the interferon group.

    Ocrelizumab was given in two infusions separated by two weeks. The low-dose group received 300 mg in each infusion and the high-dose group was given 1,000 mg per infusion.

    The placebo was given by infusion as well, providing blinding. Interferon, however, was given weekly by intramuscular injection at the standard 30-µg dose and therefore was open-label.

    Primary efficacy outcomes were evaluated after 24 weeks. At that point, all patients received another cycle of treatment with ocrelizumab. The original placebo and interferon groups received two infusions, 14 days apart, of 300 mg of ocrelizumab. The initial low-dose group received a single infusion of 600 mg and the high-dose group received a single dose of 1,000 mg.

    Kappos and colleagues reported safety and limited efficacy data for weeks 24 to 48 in addition to the primary analyses based on the first 24 weeks of treatment.

    Whereas mean gadolinium-enhancing T1 lesion counts -- the study's primary outcome measure -- remained stable through the first 24 weeks in the placebo and interferon groups, they dropped nearly to zero in both ocrelizumab groups (mean 0.6 low dose, 0.2 high dose).

    About 80% of both ocrelizumab groups had lesion counts of zero over weeks 12 to 24, compared with 35% of the placebo group and 48% of the interferon-treated patients.

    A similar pattern was seen for other MRI outcomes, including new gadolinium-enhancing lesions, volume of T2 lesions, and total number of new or enlarging T2 lesions.

    Kappos and colleagues also assessed clinical relapses at week 24 and again at week 48. During the first half of the study, annualized relapse rates were as follows:

    Placebo: 0.64 (95% CI 0.43 to 0.94)
    Interferon: 0.36 (95% CI 0.22 to 0.60)
    Low-dose ocrelizumab: 0.13 (95% CI 0.03 to 0.29)
    High-dose ocrelizumab: 0.17 (95% CI 0.05 to 0.35)
    Annualized relapse rates from week 24 to 48 (at which point all patients were receiving ocrelizumab) ranged from 0.09 to 0.28 with no clear difference between the original assignment groups.

    With one exception, ocrelizumab appeared to have a "benign" safety profile in the study, the researchers indicated.

    But the exception was major -- a woman in the high-dose group developed a systemic inflammatory reaction at week 12 that was ultimately fatal. Whether the drug was directly to blame is not yet clear.

    Safety concerns were already lingering over ocrelizumab because of a high rate of opportunistic infections seen in trials of the drug in rheumatoid arthritis. Ocrelizumab's developer, Genentech, stopped that program as a result.

    No opportunistic infections were seen in the current study. Kappos and colleagues noted that their patients were generally younger, in better overall health, and not taking concomitant treatment with steroids or immunosuppressants.

    There have also been no cases of progressive multifocal leukoencephalopathy in the ocrelizumab trials for MS or rheumatoid arthritis, the researchers indicated.

    In an accompanying editorial, two British neurologists argued that all disease-modifying therapies for MS are likely to pose safety concerns.

    Natalizumab (Tysabri), fingolimod (Gilenya), alemtuzumab (Lemtrada), and cladribine each have their own rare but serious side effects that have given clinicians and regulators pause, according to Jeremy Chataway, MD, and David H. Miller, MD, both of University College London.

    "Therapeutic potency will have to be balanced against early or late risk, both known and unknown. The equation is difficult to solve," they wrote.

    Chataway and Miller also highlighted the completely unmet clinical need for therapies that slow or halt progressive MS, noting that clinical trials will be difficult from a pragmatic standpoint.

    They argued that the two- to three-year clinical trial now typical for novel MS drugs will have to be extended to at least five years if the endpoint is -- as it eventually should be -- delay in conversion from relapsing-remitting to progressive disease.

    The trial was funded by Genentech (Roche) and Biogen Idec.

    Kappos reported relationship with Acorda Therapeutics, Actelion Pharmaceuticals Ltd, Advancell, Allozyne, Barofold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, Boehringer Ingelheim, CSL Behring, Geneuro, Genmab, GlaxoSmithKline, Glenmark, Merck Serono, MediciNova, Novartis, sanofi-aventis, Santhera Pharmaceuticals, Shire Plc, Roche, Teva, UCB, Wyeth, the Swiss MS Society, the Swiss National Research Foundation, Europen Union, Gianni Rubato, Roche, and Novartis. Several authors were employees of Genentech/Roche.

    Chataway reported relationships with Novartis, Teva, and Biogen Idec. Miller reported relationships with Biogen Idec, Novartis, GlaxoSmithKline, and Bayer Schering.

    Primary source: Lancet
    Source reference:
    Kappos L, et al "Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial," Lancet 2011; doi:10.1016/S0140-6736(11)61649-8.

    Additional source: Lancet
    Source reference:
    Chataway J, et al "Multiple sclerosis -- quenching the flames of inflammation," Lancet 2011; doi:10.1016/S0140-6736(11)61133-1.

    Source: Medpage Today © 2011 Everyday Health, Inc (01/11/11)

    Ocrelizumab shows effectiveness in Multiple Sclerosis

    Roche LogoRoche Holding AG said Thursday that a phase II showed its experimental drug ocrelizumab maintained significant reduction in disease activity for multiple sclerosis patients for almost two years. Roche said phase III trials underway to investigate ocrelizumab in two forms of MS

    96-week results from a phase II study of ocrelizumab in patients with relapsing-remitting multiple sclerosis (RRMS), the most common clinical form of the disease. The study showed that the significant reduction in disease activity as measured by the total number of active brain lesions and relapses previously reported for 24 weeks, was maintained through 96 weeks.

    The data is being presented today at ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) the world's largest annual international conference devoted to basic and clinical research in multiple sclerosis.

    People with RRMS suffer from relapses and disabling symptoms caused by damage to the central nervous system (the brain, spinal cord and optic nerves) which can significantly affect their quality of life. Symptoms are unpredictable and vary between patients. Most people experience their first symptoms between the ages of 20 and 40.

    Results from the trial showed that during the 24-96 week treatment period no patient who received a dose of 600mg ocrelizumab developed a new or enlarging brain lesions (as measured by MRI). The annualised relapse rate (ARR), the rate of clinical attacks or flare-ups per patient-year, was less than 0.2 attacks per patient per year across the 96-week period. The data also showed that, of the patients who completed the study, two-thirds of the patients in the 600mg group were free of any disease activity (as measured by MRI, relapses or neurological progression) over the 96-week treatment period.

    "This demonstration of long-term efficacy of ocrelizumab confirms the compelling benefit demonstrated in the first 24-week treatment period", said Hal Barron, M.D., Head of Global Development and Chief Medical Officer for Roche. "These results indicate a high likelihood of success of the ongoing Phase III program in patients with relapsing-remitting multiple sclerosis. Additionally, a study is underway to evaluate the potential benefit of ocrelizumab in patients with primary progressive multiple sclerosis."

    The safety profile of ocrelizumab over the 96 weeks of the study was consistent with that demonstrated in the earlier 24-week data. No opportunistic infections were reported and the rate of infections (and serious infections) did not increase over the treatment period. Serious infection rates were similar for ocrelizumab 600mg (1.97 events/100 patient/years) and ocrelizumab 1000 mg (1.93 events/100 patient/years) and did not increase with time on ocrelizumab treatment.

    Source: Fox Business ©2011 FOX News Network, LLC (20/10/11)

    Positive mid-stage results for MS drug ocrelizumab

    RocheRoche Holding AG Friday said mid-stage trials of a experimental multiple sclerosis medicine ocrelizumab showed the drug to significantly reduce disease activity in patients with relapsing-remitting multiple sclerosis, raising hopes the medicine could make it to the market and eventually turn into a blockbuster.

    Developed by U.S.-based Biogen Idec Inc (BIIB) and Roche unit Genentech, ocrelizumab was recently abandoned in treating patients suffering from rheumatoid arthritis due to an unfavourable risk profile, raising concerns the drug could be discarded in other indications, a step that would have weakened Roche’s pipeline.

    Roche said that a 24 week phase II trial showed a substantial reduction of brain lesions and the relapse rate of multiple sclerosis patients. When administered at a dose of 2,000 milligrams, the reduction of brain lesions was 96% and at 89% at a dose of 600 milligram when compared to placebo.

    “These efficacy results are amongst the most remarkable seen in a phase II … study, and show that ocrelizumab may have the potential to offer benefits to patients with this disease,” said Professor Ludwig Kappos, lead investigator of the study, from the Department of Neurology, University Hospital Basel, Switzerland.

    The study involved 220 patients, comparing ocrelizumab to placebo in patients with relapsing-remitting multiple sclerosis, the most common form of this autoimmune disease that affects around 1.5 million people worldwide.

    “We are strongly encouraged by these data and the possibility that ocrelizumab could become a new option for patients with multiple sclerosis,” said Hal Barron, Roche’s Chief Medical Officer. “We believe in the potential of ocrelizumab and look forward to exploring it further in the final phase of clinical development.”

    Given these study results, chances for a potential approval are rising and could give Roche a sizable stake in the $10 billion multiple-sclerosis market even though ocrelizumab is administered via infusions, albeit only about twice a year depending on the treatment methodology. Earlier this year, cross-town rival Novartis AG received approval to market its multiple sclerosis drug Gilenya, which is administered orally in pill form.

    Given this easy regime, Gilenya is expected to reach peak sales of more than $ 3 billion, and could, according to analysts, give Novartis a lead over competitors such as Irish drug maker Elan Corp. PLC, U.S.-based Biogen Idec Inc. and Germany’s Merck KGaA, whose drugs have to be administered more often via injections and infusions.

    “The data still lacks a few missing pieces, but if it is what it looks like … ocrelizumab has a … strong efficacy profile, especially in relapse rates,” said Vontobel pharma analyst Andrew Weiss.

    Source: Adjmediator's Blog (13/11/10)

    Biogen, Genentech amend deal on MS drug

    Biogen LogoBiogen Idec Inc. and Genentech said Thursday they amended their development agreement on a potential multiple sclerosis treatment.

    Genentech, a unit of Swiss drug developer Roche, will now have responsibility for the further development of ocrelizumab in multiple sclerosis and will fund all the costs going forward. Biogen will receive tiered, double-digit royalties on U.S. sales that will approximate its current 30 percent interest in the compound.

    Ocrelizumab recently completed a midstage study with positive results.

    The companies are already partners on the drug Rituxan and said the sale of ocrelizumab will not impact that current profit-sharing deal.

    Also, Biogen will increase its share of the losses and profits related to the development and sales of GA101 in the US to 35 percent from 30 percent. GA101 is aimed at treating chronic lymphocytic leukemia and non-Hodgkin lymphoma. Once that drug reaches certain sales milestones, Biogen's share of the profits of Rituxan will decrease to 35 percent from 40 percent.

    Source: Bloomberg ©2010 Bloomberg L.P. (22/10/10)

    Roche, Biogen report one death in MS drug trial

    RocheRoche Holding AG and Biogen Idec Inc reported data from a mid-stage trial of their experimental multiple sclerosis drug ocrelizumab on Friday that showed one patient died of an inflammatory condition.

    Data presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) showed that the drug reduced disease activity by a significant amount as measured by the number of brain lesions and relapse rate. But some side effects were greater in the ocrelizumab arm than in the placebo arm.

    In May, Roche of Switzerland and Biogen of Cambridge, Massachusetts, said they would discontinue studies of the drug as a treatment for rheumatoid arthritis after a safety monitoring board ruled that the risk outweighed the benefit in the RA population.

    The decision followed reports of serious infections, some of which were fatal, as well as opportunistic infections -- or infections that do not normally occur in healthy people.

    The companies said that in the latest 220-patient MS trial no opportunistic infections were reported, and they said no causal link had been established between ocrelizumab and the patient death from systemic inflammatory response syndrome (SIRS). Roche said exhaustive analysis showed the condition in this case was not sparked by an infection, even though it sometimes can be.

    There were no cases of SIRS in the placebo group or among patients who received the lower of the two doses of ocrelizumab. However, 1.8 percent of patients -- or one out of 55 -- who took the higher dose developed the condition.

    Infusion-site reactions such as swelling were higher in the ocrelizumab group than in the placebo group -- with 34.5 percent of those taking the lower dose and 43.6 percent taking the higher dose experiencing a reaction compared with 9.3 percent in the placebo group. The reactions were in general mild to moderate, the companies said, and the reports decreased during the second infusion.

    In general, the companies said, the serious side effect profile was similar in all treatment groups, with the drug showing strong efficacy.

    The total number of brain lesions detected by magnetic resonance imaging (MRI) in the study was reduced by 96 percent in the higher-dose group and 89 percent in the lower-dose group compared with placebo.

    "We are strongly encouraged by these data and the possibility that ocrelizumab could become a new option for patients with MS," said Dr. Hal Barron, chief medical officer at Roche. "We believe in the potential of ocrelizumab and look forward to exploring it further in the final phase of clinical development."

    Patients will be treated for up to 96 weeks, receiving ocrelizumab infusions every 24 weeks.

    Source: Reuters © Copyright 2010 Thomson Reuters (20/10/10)

    Positive results from ocrelizumab phase II RRMS study

    Roche LogoRoche and Biogen Idec announced 24-week results from a phase II study of ocrelizumab in patients with relapsing-remitting multiple sclerosis (RRMS), the most common form of the disease.

    Ocrelizumab demonstrated a significant reduction in disease activity as measured by brain lesions and relapse rate. Patients with RRMS suffer from relapses and disabling symptoms caused by nerve damage which can significantly affect their quality of life.

    “These efficacy results are amongst the most remarkable seen in a phase II RRMS study, and show that ocrelizumab may have the potential to offer benefits to patients with this disease”

    Reductions in total number of brain lesions detected by magnetic resonance imaging (MRI) scans (the primary endpoint of the study) were highly significant at 96% for 2000mg ocrelizumab and 89% for 600mg ocrelizumab compared to placebo. Disease activity was also measured by reduction in annualized relapse rate (ARR), the rate of attacks or flare-ups per patient-year. At week 24, ARR was significantly lowered versus placebo with a reduction of 73% for ocrelizumab 2000mg and 80% for ocrelizumab 600mg.

    "These efficacy results are amongst the most remarkable seen in a phase II RRMS study, and show that ocrelizumab may have the potential to offer benefits to patients with this disease," said Professor Ludwig Kappos, lead investigator of the study, from the Department of Neurology, University Hospital Basel, Switzerland.

    "We are strongly encouraged by these data and the possibility that ocrelizumab could become a new option for patients with MS," commented Hal Barron, M.D., executive vice president, Product Development and chief medical officer. "We believe in the potential of ocrelizumab and look forward to exploring it further in the final phase of clinical development."

    Both ocrelizumab doses were generally well tolerated and no opportunistic infections were reported. Serious adverse events (SAEs) were similar in all treatment groups. Infusion-related events during first infusion, predominantly mild to moderate, were more common with ocrelizumab (34.5% and 43.6%) than placebo (9.3%). However, these reports decreased during the second ocrelizumab infusion and were comparable to those initially reported with placebo.

    Source: Roche Inc. and Biogen Idec (16/10/10)

    Deaths overshadow ocrelizumab trials in MS

    RocheSwiss drugmaker Roche AG and Biogen Idec Inc. are discontinuing development of ocrelizumab in patients with rheumatoid arthritis (RA), after an infection-related safety signal was observed in Phase III testing, resulting in the death of some patients.

    Results from the program will be made available at a medical forum, the companies said, without divulging the specific type of infection or the number of affected study patients.

    Roche and Biogen have said that the infections were serious, some of which were fatal, and others were opportunistic infections.

    The FDA had placed a clinical hold on the studies prior to the companies' ultimate decision to stop development in RA. Last year Biogen had stopped its Phase III program of ocrelizumab in lupus patients.

    Despite the severe safety concerns a Phase II study of ocrelizumab is ongoing in patients with relapsing-remitting multiple sclerosis, and data from that study will be submitted for presentation this autumn at the European Committee for the Treatment and Research in Multiple Sclerosis conference in Sweden.

    Roche was taking the lead on the development of ocrelizumab in RA, while Biogen Idec was contributing financial support.

    Biogen Idec spokeswoman Amy Reilly said the company has not disclosed the costs of the ocrelizumab RA program.

    Roche representatives in Basel, Switzerland, could not be reached immediately for comment.

    Ocrelizumab, which was discovered by Biogen, was in four Phase III studies known as SCRIPT, FILM, FEATURE, and STAGE.

    The most recent analysis included available safety and efficacy data from the SCRIPT Phase III study in patients with previous inadequate response to TNF-inhibitors and safety data from the Phase III FILM study in patients who were methotrexate-naïve.

    The troubles in the ocrelizumab RA program surfaced in March, when Roche and Biogen Idec suspended treatment.

    That decision came after an independent RA and lupus data and safety monitoring board for ocrelizumab concluded that the safety risk outweighed the benefits observed in those patient populations, based on an infection-related safety signal.

    Source: Bioworld copywrite AHC Media LLC (21/05/10)

    IV ocrelizumab shows promise in phase II study in relapsing-remitting Multiple Sclerosis

    MS MRIRoche and Biogen Idec announced that the experimental monoclonal antibody ocrelizumab, given intravenously, significantly reduced disease activity as measured by MRI (magnetic resonance imaging) scans in a phase II study of 220 people with relapsing-remitting MS.

    Ocrelizumab binds to a molecule (CD20) on the surface of B cells and depletes them from the circulation. B cells are immune cells that make antibodies and may play a role in the immune attack on brain and spinal cord tissues in multiple sclerosis. The drug is a humanized version of rituximab, a mouse antibody to CD20 that has previously shown benefit in people with relapsing-remitting MS.

    In the aspects of this phase II study participants were randomly assigned to receive one of two treatment regimens and observed for 24 weeks, with plans for observing them for up to 96 weeks. Participants received repeated intravenous infusions of one of three different dose regimens of ocrelizumab or inactive placebo) or intramuscular injections of Avonex®.

    The main objective of this study was to determine whether ocrelizumab was effective in reducing MS disease activity compared with placebo, as observed on MRI at 12, 16, 20, and 24 weeks. The companies report that ocrelizumab "showed a strong effect with a highly statistically significant reduction" in signs of disease activity.

    The companies are continuing to analyze the data, and plan to provide a full report at an upcoming medical meeting, including the results of secondary endpoints - which include relapse rate and the appearance of new disease activity - and safety information. Since this was a phase 2 study, additional research will be needed to further determine this drug's safety and efficacy.

    Source: MSS Canada (10/12/09)

    © Multiple Sclerosis Resource Centre (MSRC)

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