Clinicians Practice Caution with Ocrelizumab's Approval

DECEMBER 29, 2017
Kevin Kunzmann
multiple sclerosis, ocrelizumab, Ocrevus, genentech, 2017, fda, approval, MSThis story is part of MD Magazine's Year-End Recap series.

The US Food and Drug Administration’s (FDA) approval of ocrelizumab (Ocrevus) for the treatment of both relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS) made history in March.

Genentech’s monoclonal antibody became the first disease-modifying therapy (DMT) approved for treating PPMS. Though it’s difficult to disparage a much-needed development in the field of MS, many clinicians have reacted cautiously to ocrelizumab’s approval.

John Corboy, MD, professor and vice chair, Department of Neurology at the University of Colorado Anschutz Medical Campus, told MD Magazine that ocrelizumab’s trial data was “not surprising, unique, or groundbreaking.”

“If you look at data for any numbers of studies for PPMS, or even secondary primary progressive MS, they all show the same thing: If you treat someone with an immune suppressive therapy, then the patients will drive benefits from those therapies,” Corboy said. “But the older the patient is and the longer they have had the disease, the less likely they are to benefit from those therapies.”

Corboy was referencing the demographics in pivotal phase 3 trials which led to the approval of ocrelizumab for 2 forms of MS. In the 2 studies comparing its efficacy and safety in RRMS patients versus interferon beta-1 (OPERA 1, OPERA 2), the mean patient age in the treatment population were 37.1 and 37.2 years old, respectively.

In the phase 3 trial comparing ocrelizumab in PPMS patients versus placebo (ORATORIO), the mean patient age in the treatment population was 44.7 years old.

In an interview earlier this year, Clyde Markowitz, MD, director, MS Center, University of Pennsylvania, also shared reticence to ocrelizumab’s approval for PPMS.

“I think at this point we’re excited about it, but the results were not blockbluster results,” Markowitz told MD Magazine. “But it is better than anything else we’ve tested to date.”

What’s become more clear in the past decade of PPMS research is that it’s a very complex disorder, Corboy said. It is both a neurodegenerative disorder and an inflammatory condition, and inflammation occurs in patients at a younger age.

“Sometimes, it’s the right patient, at the right time,” Corboy said. “And that’s the key. A 35-year-old PPMS patient is not the same as a 75-year-old with PPMS. It’s just not the same situation.”

Corboy also noted that ocrelizumab data benefitted from a substantially larger patient population than that of similar monoclonal antibody rituximab. The combined patient groups of OPERA 1 (821), OPERA 2 (835), and ORATORIO (732) totaled 2,388 participants.

As opposed to the RRMS-related trials, ORATORIO randomly split patients with PPMS 2:1 between intravenous 600 mg ocrelizumab (488) and placebo (244).

Patients were administered treatment ever 24 weeks, for at least 120 weeks and until a prespecified number of disability progression events were confirmed by researchers. The study’s primary endpoint was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis.

A lesser rate of ocrelizumab patients (32.9%) reported disability progression at week 12 than placebo patients (39.3%; 95% CI, 0.59 to 0.98, P = 0.03). At week 24, 29.6% of ocrelizumab patients reported disability progression, versus 35.7% with placebo (P = 0.04).

Even more substantially, brain lesion volume on T2-weighted magnetic resonance imaging had decrease 3.4% for ocrelizumab patients, and increase 7.4% for placebo patients (P <0.001) at week 120. Brain-volume loss was 0.90% for ocrelizumab patients, versus 1.09% with placebo (P = 0.02).

Results that show ocrelizumab’s ability to limit central nervous system (CNS) damage plays into Corboy’s projection that MS treatment will turn to a “cocktail of DMTs and repair therapies all at the same time, used as early as possible to limit the immunology and neurologic damage of MS.”

Stephen Krieger, MD, associate professor at Mount Sinai Hospital, told MD Magazine earlier this year that ocrelizumab’s differing results for both RRMS and PPMS means a different conversation for a patient other either condition.

“And in primary progressive patients, it’s a more tempered conversation to think about what they can expect from a medicine that may slow down the disability for them, and also all the safety issues we have to think about there, too,” Krieger said.

It was a historic moment in the clinical history of MS, but experts are not regarding ocrelizumab’s approval for PPMS as the end-all solution. Rather, it could be the start of change — the first progressive MS therapy, and among the first treatments to focus on CNS protection.

“Potentially, the biggest frame-shift in how we think of treating MS is in the implementation of those therapies involved in repair,” Corboy said.

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