乌鸦传媒

VANCOUVER -- The investigational B-cell monoclonal antibody ocrelizumab beat out interferon at stifling disease activity in multiple sclerosis over 2 years, researchers reported here.

In the OPERA I & II trials, with a significantly larger proportion of patients on the experimental treat achieving no evidence of disease activity (NEDA) (48% versus 29% and 25%, respectively), , of the University of British Columbia in Vancouver, reported at the American Academy of Neurology meeting here.

Ocrelizumab is an anti-CD20+ monoclonal antibody targeting B-cells. Most available immunosuppresive therapies for MS target T-cells, but researchers now theorize that B-cells may also play an important role in MS.

In fact, ocrelizumab would not be the first B-cell targeting therapy used in MS. Some physicians currently use rituximab off-label to treat the condition.

Both rituximab and ocrelizumab are made by Roche/Genentech, which had tested rituximab in both progressive and relapsing-remitting MS with promising results before deciding not to fund further trials. Researchers said that while rituximab is chimeric, ocrelizumab is a fully humanized monoclonal antibody that binds more tightly to its target than the older drug, so infusion reactions and anti-drug antibody responses may be lessened.

NEDA in RRMS

In OPERA I & II, NEDA was a composite of no relapses, no confirmed disability progression, no new or enlarging gadolinium-enhancing T1 lesions, and no new or enlarging T2 lesions.

Patients were randomized to ocrelizumab 600-mg infusion every 24 weeks or to interferon beta three times a week for 96 weeks.

Investigators previously reported a reduction in the annualized relapse rate with ocrelizumab in both trials compared with interferon, with a 46% relative reduction in OPERA I and a 47% relative reduction in OPERA II.

In the latest analysis, they found that significantly more ocrelizumab patients achieved NEDA compared with those treated with interferon (48% versus 29% in OPERA I and 48% versus 25% in OPERA II).

That translated to a 64% to 89% relative increase in preventing disease activity (P<0.0001 for both), Traboulsee said.

When breaking down NEDA by individual component, larger proportions of those on ocrelizumab were:

• Without relapses: about 80% versus 65%
• Without 12-week confirmed disability progression: about 90% versus 85%
• Without gadolinium-enhancing T1 lesions: 90% versus 65%
• Without new or enlarging T2 lesions: 60% versus 38%

"Ocrelizumab for relapsing MS is an extremely important step forward," , of Yale University, who was not involved in the study, told 乌鸦传媒. "The risk of progressive multifocal leukencephalopathy seems to be relatively low. It appears to be, by MRI criteria, the most effective treatment yet."

Hafler said MS clinicians will probably use it as a first-line drug, as long as the safety profile "remains as we've seen."

, of the University of Missouri, who was also not involved in the study, called the drug "very promising" for relapsing MS.

"This changes the way we think about MS as a disease," he told 乌鸦传媒. "Other medications like natalizumab work on T cells, and that is how we have predominantly thought about MS."

No New PPMS Data

Researchers also reported the results of the 732-patient ORATORIO trial during a poster session, but these were not much different from those previously reported at ECTRIMS in Barcelona, Traboulsee said. The drug reduced the relative risk of 12-week clinical disability progression by 24% (HR 0.76, P=0.0321).

The trial enrolled younger patients who'd had a shorter duration of progressive disease than in past progressive MS trials.

"This is the first treatment to crack open the door to show that progressive MS is treatable," Traboulsee told 乌鸦传媒. "Now that we know that the treatment works -- partially, but it works -- we can now better explore why it works and we can improve on that so we get a bigger impact on patients."

Traboulsee noted that "everything is more effective in relapsing MS because we understand the mechanisms better. We are still struggling to figure out why people progress."

Hafler said the effect seen in the ORATORIO trial "was modest at best. We badly need to understand PPMS in its varied forms. Yes, it will probably get approved, and yes, we will use it, but we need to do better."

Govindarajan said it will be an improvement that he will be able to offer progressive MS patients something that has been shown to treat their condition, not just co-occurring symptoms.

"Right now all I can do is provide support," he said. "I don't have much to offer. I can get them a wheelchair. I can give Botox for the spasticity. I can help them with swallowing. But if this medication is shown to work, it can make a difference for these patients."

A Familiar Situation

It remains to be seen whether ocrelizumab beats out rituximab at slowing disease activity in MS, although this is a trial that isn't likely to be done given that Roche/Genentech manufacture both products.

The companies are no strangers to having two competing drugs for a single condition, with one offered at a significantly cheaper price. Roche/Genentech manufacture both bevacizumab (Avastin) and ranibizumab (Lucentis) for a host of ophthalmic conditions, and physicians have long preferred the less costly bevacizumab, especially after studies largely showed equal efficacy and safety profiles between the two.

Whether such a situation will arise with rituximab-ocrelizumab remains speculative, but biosimilars for rituximab are expected to be introduced eventually, at which point market pressures may force Roche/Genentech to drop the price for rituximab.

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