More Positive Results for Ocrelizumab in Relapsing MS

Pauline Anderson

April 29, 2016

VANCOUVER — A new analysis of studies involving the investigational drug ocrelizumab confirms just how powerful this drug can be in treating patients with relapsing multiple sclerosis (MS), researchers say.

The analysis used NEDA (no evidence of disease activity), a composite of MRI and clinical outcomes, in the OPERA I and OPERA II clinical trials.

These identical phase 3 studies, each of which included about 800 patients, compared ocrelizumab (600 mg given intravenously twice a year) to interferon β-1a (44 μg given subcutaneously three times a week) in patients with relapsing MS.

The new analysis showed that the overall NEDA was 48% for ocrelizumab in the two studies compared with 29% for interferon β-1a in OPERA I and 25% for interferon β-1a in OPERA II.

"There was a 64% to 89% relative increase in preventing disease activity with this new therapy," said Anthony Traboulsee, MD, associate professor, Faculty of Medicine, University of British Columbia, Vancouver, and the MS Society of Canada research chair.

Dr Anthony Traboulsee

Dr Traboulsee presented the results here at the American Academy of Neurology (AAN) 2016 Annual Meeting. The study was funded by F. Hoffman-La Roche Ltd.

Ocrelizumab is a B cell–depleting medication being studied in both relapsing and primary progressive MS (PPMS). Earlier this year, it was granted Breakthrough Therapy Designation for treating PPMS by the US Food and Drug Administration.

Outcomes for efficacy in MS trials traditionally include the relapse rate, typically reported as the annualized relapse rate. Another important clinical element is no disability progression, often measured with the Expanded Disability Status Scale.

Together, these two components make up what is now called NAED.

MRI measurements used to track disease activity include markers of inflammation, such as gadolinium (Gd)-enhancing lesions.

"The ratio is about 10 new MRI lesions for every clinical relapse a patient might have," noted Dr Traboulsee.

Researchers also look at new and enlarging T2 lesions, the advantage here being that T2 images can capture new inflammatory lesions as well as older, more chronic ones.

"If you're only doing an MRI every 6 months or once a year, you might be missing some of the enhancing activity, but it will leave a scar behind and we pick that up as a T2 lesion," said Dr Traboulsee.

Combining these two MRI metrics provides what's called "no evidence of MRI disease activity."

Many in the field believe that putting all four components together — in NEDA — provides an even better picture of the proportion of patients with disease activity.

Indeed, according to Dr Traboulsee, the composite of NEDA has proven value in terms of predicting future clinical disability.

Ocrelizumab is a humanized monoclonal antibody that targets CD20, a protein on the surface of some, but not all, B cells. It's not expressed, for example, on plasma cells or stem cells, and so those cells, which are important for immune function, are not depleted by the drug.

The agent really focuses on, and causes depletion of, cells that affect disease activity in MS, said Dr Traboulsee.

"We think this drug is going to the root of the problem, which is B cells, and knocking them out," Dr Traboulsee told Medscape Medical News.

During his presentation, Dr Traboulsee reviewed what he called the "very impressive" results of the OPERA I and OPERA II trials looking at clinical disease activity, MRI disease activity, and the composite of NEDA.

For example, for OPERA I, the proportion of patients taking ocrelizumab who had no relapses during the 96 weeks of the study was 81% compared with 68% for those receiving interferon. The proportion of patients with no disability progression was 91% vs 84%.

"Combined, we see 76% of patients free of clinical disease activity with ocrelizumab vs 63% for interferon," said Dr Traboulsee.

As for MRI, 95% of ocrelizumab-treated patients had no evidence of T1 Gd lesions vs 73% of interferon recipients. And 62% of patients in the ocrelizumab group were free of new/enlarging T2 lesions compared with 39% in the interferon group.

When both MRI activity and clinical activity were combined, there was an NEDA value of 48% for ocrelizumab compared with 29% for interferon.

The analysis showed a 64% relative increase in NEDA with ocrelizumab vs interferon (P < .0001).

"Wonderful" Consistency

Results for OPERA II were "almost identical," said Dr Traboulsee. NEDA for ocrelizumab was 48% vs 25% for interferon. There was an 89% relative increase in NEDA with ocrelizumab vs interferon (P < .0001).

With both studies, "we get wonderful consistency of results in comparison to the interferon β group," he said. "It gives you a sense that we have made a giant step forward in the past 20 years of treating MS."

Dr Traboulsee called NEDA analyses "a much more conservative way, a more humble way, and a realistic way, of presenting the data."

He showed a slide of NEDA outcomes for ocrelizumab (48% in both OPERA I and OPERAII) alongside those for other MS drugs, including natalizumab (37% in the AFFIRM trial), fingolimod (33% in the FREEDOMS trial), and alemtuzumab (39% in the CARE MS I trial and 32% in CARE MS II).

However, he cautioned about drawing conclusions from cross-trial comparisons because of differences in comparators, patient populations, and definitions of NEDA (eg, the number of MRI scans integrated into the analysis and imputation methods for missing values).

Although infection is a concern with drugs that affect the immune system, "we didn't see any difference in the rate of infection versus interferon, which is remarkable," Dr Traboulsee told Medscape Medical News.

"The degree of response in MS was just outstanding, combined with a beautiful safety signal," he said.

"We are seeing the bar go up higher in terms of effectiveness; we are seeing treatments such as ocrelizumab, which is perhaps twice as effective as interferons."

Ocrelizumab has also been shown to be effective for patients with PPMS. The ORATORIO trial found the drug significantly reduced progression of clinical disability sustained for at least 12 weeks in these patients.

Reached for comment, Daniel Kantor, MD, a neurologist in private practice in Ponte Vedra Beach, Florida; president of the Medical Partnership 4 MS (MP4MS), an advocacy group for neurologists treating patients with MS; and chief medical correspondent for MSWorld, a patient support website, said he's suspicious of NEDA as a measure and suggests it doesn't really add any useful information.

"NEDA is really not powered by clinical findings; it's actually powered by what happens MRI-wise," he told Medscape Medical News. "It's just another way of saying that a drug is strong from an MRI perspective."

When NEDA was first used, said Dr Kantor, "people thought it was a whole new way of looking at things, but it's not a paradigm shift; it's MRI plus."

In the past 5 years, he added, "suddenly NEDA has become an exciting thing to present at scientific meetings."

Dr. Kantor speculated that from the company's perspective, the new analysis "makes sense to do."

"You could argue that it shows better results than the other drugs that we consider high efficacy, which means that it was a winner. It's another positive, another feather in their cap."

Despite his misgivings about the utility of NEDA, Dr Kantor is excited about ocrelizumab itself, which he called "a blockbuster" drug.

"It's a market disruptor; it's going to disrupt the market; it's going to change everything."

The study was supported by F. Hoffman-La Roche Ltd. Dr Traboulsee has received speaker fees and/or advisory board fees from Biogen, F. Hoffman-La Roche Ltd., Genzyme, Serono, and Teva and clinical trial and/or grant support from Biogen, Chugai, Canadian Institute for Health Research, Genzyme, F. Hoffman-La Roche Ltd, Michael Smith Foundation, and MS Society of Canada. Dr Kantor has received speaking fees and research support from Biogen and consulting fees from Genentech/Roche.

American Academy of Neurology (AAN) 2016 Annual Meeting. Clinical Trials Plenary Session. Presented April 20, 2016.

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