Ocrelizumab Benefits in MS Maintained to 96 Weeks

Susan Jeffrey

October 21, 2011

October 21, 2011 (Amsterdam, the Netherlands) — Extension data out to 96 weeks with the still-investigational agent ocrelizumab show no new gadolinium-enhancing lesions since the end of the primary analysis of this phase 2 trial at 24 weeks in patients with relapsing-remitting multiple sclerosis (MS).

The reduction in clinical relapses seen with treatment was also 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]," said David Leppert, MD, from University Hospitals Basel, Switzerland, and F. Hoffman-La Roche Ltd, who presented the results here at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

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.

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 (ENS).

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, they say. 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 (group A), 2000 mg (group B), placebo (group C), or open-label weekly interferon-beta-1a in a dose of 30 μg given intramuscularly (group D).

On the primary endpoint of the study at week 24, both doses of ocrelizumab showed a significant reduction in gadolinium-enhancing T1 lesions, with 89% and 96% relative reductions over placebo, respectively, for the 600- and 2000-mg doses, as well as 80% and 73% reductions in the annualized relapse rates, respectively.

At weeks 24, 48, and 72, all patients were treated with ocrelizumab. Groups A, C, and D received 600 mg/cycle; group B received 1000 mg at weeks 24 and 48 and switched to 600 mg at week 72. A total of 183 patients completed the week 96 treatment.

During weeks 0 to 96, the annualized relapse rate was 0.18 (95% confidence interval [CI], 0.11 - 0.31) for group A and 0.22 (95% CI, 0.13 - 0.35) for group B.

In groups A and B, 67.3% and 76.4% had no relapses and no confirmed progression, as measured by the Expanded Disability Status Scale progression during that period. In those same groups, 78.2% and 80.0% of patients, respectively, were relapse-free.

Only a small number of patients had Expanded Disability Status Scale progression that was sustained for at least 12 weeks at week 96: 12.7% in group A, 7.3% in group B, 13.0% in group C, and 9.3% in group C.

In an exploratory analysis reported here, annualized relapse rates were reduced between weeks 24 and 96 in patients switched from placebo to ocrelizumab (group D), from 0.64 to 0.20 (95% CI, 0.12 - 0.33), and from 0.36 to 0.16 (95% CI, 0.09 - 0.28) in those switched from interferon to ocrelizumab (group C).

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 group B, 1 patient had 1 newly enlarging T2 lesion, and 1 had 2 new lesions at 96 weeks.

Total brain volume was reduced by 1.1% and 1.2% in groups A and B, respectively, between week 12 and week 96.

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 groups A and B, 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."

"We have not yet clarity on what was the initiation of the disease" in that case, Dr. Leppert noted. Whether or not it was directly related to the compound is an open question, he said. "One can certainly say that it's not related to infusion, because it's not an acute or anaphylactic reaction — it happened 12 weeks after the infusion." The patient also had a bee sting that may be related to the initiation of an acute inflammation, he added.

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

Different Mechanism

Asked for comment on these findings, Lily Jung-Henson, MD, medical director of the Swedish Neuroscience Institute Eastside Neurology and chief of staff at the Swedish Issaquah Hospital in Seattle, Washington, was enthusiastic.

"This looks promising," she said, adding that it will be interesting to see whether the results can be maintained in the longer term.

"It's exciting to have a different mechanism of action to offer our patients," she said.

The study was supported by F. Hoffman La Roche Ltd, a member of the Roche Group. Dr. Leppert is an employee and shareholder of F. Hoffmann La Roche Ltd. He is also the director of the University of British Columbia MS/MRI Research Group, which has been contracted to perform central analysis of magnetic resonance imaging scans for therapeutic trials with Angiotech, Bayer, Berlex-Schering, Bio-MS, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences, Sanofi-Aventis, and Transition Therapeutics. He has also acted as a consultant to Genzyme and Novartis. Disclosures for the coauthors appear in the abstract. Dr. Jung-Henson has no conflicts with regard to this study; she is a speaker for Biogen Idec, Serono, Teva, Novartis, and Sanofi-Aventis.

5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS): Abstract P462. Presented October 20, 2011.

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