Ocrelizumab Results in MS Published

Susan Jeffrey

October 31, 2011

October 31, 2011 — Results of a phase 2 trial of ocrelizumab treatment in patients with relapsing-remitting multiple sclerosis (MS) show that both doses studied significantly reduced the total number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) at 24 weeks vs placebo.

Both the 600-mg and 2000-mg doses studied reduced clinical relapses, with no apparent separation between doses, and extension data in this report out to 48 weeks suggested sustained efficacy, the researchers note.

"The similarly pronounced effects of B-cell depletion with both ocrelizumab doses on MRI and relapse-related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-term trials," the researchers, with first author Ludwig Kappos, MD, from University Hospital, Basel, Switzerland, conclude.

The results were published online November 1 in The Lancet.

The primary analysis of this study at 24 weeks was presented at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Gothenburg, Sweden, in October 2010, and reported by Medscape Medical News at that time. Data to 72 weeks were presented at the 21st Meeting of the European Neurological Society, and most recently, results out to 96 weeks were presented at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) in Amsterdam, the Netherlands.

The reduction in clinical relapses seen with treatment was maintained from week 24 to week 96, with subsequent infusions at 24-week intervals. In addition, patients who switched from placebo to ocrelizumab at the end of the blinded phase of the trial had similar reductions in the clinical measures of disease.

"Phase 3 has started; we are recruiting in 1 study for primary progressive [MS] and 2 studies...for relapsing forms of [MS]," David Leppert, MD, who is also from University Hospitals Basel, and F. Hoffman-La Roche Ltd, and who presented the results at ECTRIMS/ACTRIMS, told Medscape Medical News.

The phase 3 program, called ORCHESTRA, includes the 2 relapsing-remitting MS trials, called OPERA I and II, and the primary progressive MS trial, called ORATORIO.

Humanized Antibody

There is increasing evidence that B-cells play a role in the pathogenesis of MS through antibody-dependent and antibody-independent mechanisms, the authors note. Rituximab, an anti-CD20 monoclonal antibody that selectively reduces CD20-positive B-cells, showed "proof of concept" efficacy in MS in phase 1 and 2 investigations. Ocrelizumab is a recombinant humanized version of rituximab meant to provide some advantages in potency, tolerability, and safety for the long term.

In May 2010, the companies stopped a phase 3 program of ocrelizumab in rheumatoid arthritis because of safety issues in that generally older population, including serious infections (some of which were fatal) and opportunistic infections.

In MS, however, results of this phase 2 investigation of ocrelizumab were positive.

The study included 220 patients with relapsing-remitting MS who, for the main analysis, were randomly assigned 1:1:1:1 to receive intravenous ocrelizumab on days 1 and 15, for a total dose of 600 mg or 2000 mg; placebo; or open-label weekly interferon-beta-1a in a dose of 30 μg, given intramuscularly. All groups were double blinded except the patients in the interferon beta-1a group, who were rater masked, the researchers note.

A total of 218 (99%) of the 220 patients received at least 1 dose of ocrelizumab. Of these, 204 patients (93%) completed 24 weeks of the study, and 196 (89%) completed 48 weeks.

On the primary endpoint of the study at week 24, intention-to-treat analysis showed that both doses of ocrelizumab displayed a significant reduction in gadolinium-enhancing T1 lesions, with 89% (95% confidence interval [CI], 68% - 97%; P < .0001) and 96% (95% CI, 89% - 99%; P < .0001) relative reductions over placebo, respectively, for the 600- and 2000-mg doses. Reductions of 80% and 73% in the annualized relapse rates, respectively, also were seen.

In exploratory analyses, both the 600-mg and the 2000-mg ocrelizumab groups were better than interferon beta-1a for the reduction of gadolinium-enhancing lesions.

"We noted serious adverse events in 2 of 54 (4%; 95% CI 3.0 – 4.4) patients in the placebo group, 1 of 55 (2%; 1.3 – 2.3) in the 600 mg ocrelizumab group, 3 of 55 (5%; 4.6 – 6.3) in the 2000 mg group, and 2 of 54 (4%; 3.0 – 4.4) in the interferon beta-1a group," the authors write.

Week 96 Results

Since these newly published data were first reported, further extension data on ocrelizumab have become available. At week 24, the end of the primary analysis, patients in the initial placebo group, the 600-mg ocrelizumab group, and the interferon beta-1a groups received ocrelizumab 600 mg; participants in the 2000-mg group received 1000 mg, but were switched to 600 mg at week 72.

At weeks 24, 48, and 72, all patients were treated with ocrelizumab. A total of 183 patients completed the week 96 treatment. Dr. Kappos and colleagues reported that during weeks 0 to 96, the annualized relapse rates were 0.18 (95% CI, 0.11 - 0.31) and 0.22 (95% CI, 0.13 - 0.35) for those initially receiving the 600- and 2000-mg doses, respectively, in the original trial.

In these groups, 67.3% and 76.4%, respectively, had no relapses and no confirmed progression on the Expanded Disability Status Scale during the 96 weeks, and 78.2% and 80.0%, respectively, were relapse-free.

Remarkably, at week 96 there were no new gadolinium-enhancing T1 lesions, indicating acute disease activity, in any group, and very few T2 lesions, indicating permanent damage. In the group first given the 2000-mg dose, 1 patient had 1 newly enlarging T2 lesion, and 1 had 2 new lesions at 96 weeks.

In terms of safety, the authors report there was no imbalance in the total number of serious adverse events across all groups over the course of 96 weeks.

Serious infection rates were similar for the groups first treated with ocrelizumab, at 1.97 (95% CI, 0.49 - 7.98) and 1.93 (95% CI, 0.48 - 7.71) events/100 patient-years, and did not increase with ocrelizumab retreatment. Infusion-related reactions were more common after the first infusion, but decreased to placebo levels in subsequent infusions.

The most serious adverse event remains the death of a patient in the 2000-mg group at week 14, the authors point out, "as a consequence of complicated systemic inflammatory response syndrome and a prolonged hospital course."

There have been no further such safety issues out to 96 weeks, however, including no cases to date of progressive multifocal leukoencephalopathy.

"Our findings show that ocrelizumab rapidly suppresses inflammatory activity as depicted by contrast enhancing lesions in frequent MRIs, and by clinical relapses," the authors conclude in the current Lancet report. "With caution needed when results are compared between different trials, the effect size in our study on MRI and relapse activity compares favorably with established treatments, and to most of the other compounds in development. In the observation period of 48 weeks, this rapid and pronounced effect was associated with a benign safety profile."

A "Difficult Equation"

In a linked commentary, Jeremy Chataway, PhD, from the National Hospital for Neurology and Neurosurgery, University College London Hospitals National Health Service Foundation Trust and Imperial College London, United Kingdom, and Professor David Miller, MD, from the National Hospital for Neurology and Neurosurgery, University College London Hospitals National Health Service Foundation Trust and Institute of Neurology, also at University College London, discuss issues surrounding powerful immunological drugs such as ocrelizumab and others now in development.

"The therapeutic successes so far in [MS] should be celebrated, and provide detailed mechanistic insights into an enigmatic disease that affects more than 1 million people worldwide," they write. "However, perhaps not surprisingly with powerful immunological drugs, serious adverse events have been noted."

Progressive multifocal leukoencephalopathy, for example, is an "unwelcome intruder" in the phase 4 study of natalizumab, they note. The current overall risk is about 1.5 per 1000 and is affected by length of exposure, John Cunningham virus seropositivity, and previous immunosuppression. For fingolimod, the first oral agent approved for MS, cardiac bradyarrthymias, macular edema, and fatal herpes infection possibly resulting from past steroid use have emerged, they write. For alemtuzumab, issues have been seen with idiopathic thrombocytopenic purpura, Goodpasture's syndrome, and thyroid dysfunction.

The success of the oral agent cladribine, with a 60% reduction in annualized relapse rate, they point out, was not enough to convince the US Food and Drug Administration or European Medicines Agency to grant licenses because of safety concerns, including an increased rate of herpes zoster and perhaps malignancy, they add. Now, findings from the current study "show the unusual event of a systemic inflammatory response syndrome, resulting in the death of one patient — the association with ocrelizumab remains unclear."

"For new drugs that are highly effective for prevention of relapses but that are also more risky, what should be done when phase 3 studies that typically last for 2 years are completed (which has yet to happen for ocrelizumab) and the drugs receive regulatory approval?" Dr. Chataway and Dr. Miller ask. MS is a disease of relatively young people who can expect to be treated for 20 years before secondary progression begins, the main cause of long-term disability that occurs after inflammation subsides and progressive axonal damage becomes evident.

It is not clear whether these drugs should be used very early and aggressively in clinically isolated syndrome or early relapsing-remitting MS to completely abolish the inflammation, or with gradual escalation, depending on individual disease activity, they add.

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

The study was supported by F. Hoffman-La Roche Ltd and Biogen Idec Inc. Dr. Kappos reports he has received grant support through the University Hospital Basel from 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 Foundations. Disclosures for coauthors appear in the article. Dr. Chataway reports he has been an investigator in clinical trials sponsored by Novartis, Teva, and Biogen. Dr. Miller reports he has received honoraria from Biogen Idec, Novartis, GlaxoSmithKline, and Bayer Schering, as well as research grant support for doing MRI analysis in MS trials sponsored by GlaxoSmithKline, Biogen Idec, and Novartis.

Lancet. Published online November 1, 2011. Abstract

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