A Way Forward in Treating Primary-Progressive Multiple Sclerosis?

By: Thomas Crocker
Wednesday, June 1, 2016

The lack of a medication to treat primary-progressive multiple sclerosis (PPMS) is a source of frustration for clinicians and patients. The results of a recent phase 3 study of the drug ocrelizumab may be cause for hope.

An estimated 400,000 Americans have MS, according to the National Multiple Sclerosis Society. Data show approximately 85 percent of individuals diagnosed with MS have relapsing-remitting MS (RRMS) at the time of diagnosis. Inflammation is the hallmark of RRMS, as immune cells launch inflammatory assaults against myelin and nerve fibers. Individuals experience flare-ups of symptoms, followed by periods of remission.

Approximately 15 percent of individuals with MS are initially diagnosed with PPMS. Several factors make PPMS more difficult to diagnose than RRMS, according to Claire Riley, MD, Assistant Professor of Neurology and Director of the Multiple Sclerosis Clinical Care and Research Center at Columbia University. These include fluctuations in the disease course of PPMS that can mask progression, as well as a bias among clinicians toward diagnosing RRMS, which is more treatable than PPMS.

“One factor that makes [treating PPMS] challenging is that we’ve developed a lot of treatments that focus on inflammatory activity,” Dr. Riley says. “While there is some inflammatory activity in people with PPMS, it seems like there are also degenerative changes going on — loss of [whole-brain] volume, loss of neurons. I think these degenerative diseases are much more challenging mechanistically to interfere with. Understanding why particular cells are vulnerable and helping them survive is ... a tough nut to crack.”

Researchers also face methodological hurdles.

“Studies [focused on] PPMS have suffered from their placebo group not progressing fast enough to show a difference, even when you think one might exist,” Dr. Riley says. “And so the expense of running a study that’s long enough ... is astronomical.”

B Cells to the Fore

The South San Francisco biotechnology company Genentech, a member of the Roche Group, may have at least a partial answer to the treatment puzzle posed by PPMS, in the form of ocrelizumab.

“In people with RRMS and PPMS, areas where the brain is inflamed and nerve cells are losing their insulation and support often contain a high number of CD20-positive B cells,” says Peter Chin, MD, Principal Medical Director, Global Neuroscience Development at the Roche Group. “Ocrelizumab is designed to selectively target CD20-positive B cells. [These] cells are a specific type of immune cell thought to be a key contributor to myelin and axonal nerve damage, which can result in disability in people with MS. Based on preclinical studies, ocrelizumab binds to CD20 cell surface proteins expressed only on certain B cells, and not on stem cells or plasma cells, and therefore important functions of the immune system may be preserved.”

In late 2015, Genentech released findings from three randomized, double-blind Phase 3 studies of ocrelizumab. Two of the studies — OPERA I and OPERA II — focused on RRMS. The studies tested the efficacy and safety of ocrelizumab compared with that of interferon beta-1a, a widely prescribed drug for relapsing forms of MS. Compared with interferon beta-1a, ocrelizumab reduced study participants’ annualized relapse rate by nearly 50 percent during the two-year study period and delayed confirmed disability progression at both the 12- and 24-week markers by about 40 percent. The drug’s safety was similar to interferon beta-1a’s.

The third study, ORATORIO, measured ocrelizumab’s efficacy and safety against placebo in 732 individuals with PPMS. The study was event-driven rather than constrained by a preset duration; it concluded only when all participants had received either ocrelizumab or placebo for 120 weeks, and the study reached a total confirmed disability progression benchmark. Findings of ocrelizumab’s efficacy compared with placebo included:

  • A 25 percent reduction in risk of progression of clinical disability sustained for at least 24 weeks
  • A 29 percent reduction in time to complete the Timed 25-Foot Walk test over 120 weeks
  • A 17.5 percent reduction in whole-brain volume loss over 120 weeks

Ocrelizumab also reduced the volume of hyperintense T2 lesions by 3.4 percent over 120 weeks; placebo increased the volume of these lesions by 7.4 percent. Ocrelizumab’s safety profile was similar to placebo’s.

“For decades, trial after trial has failed to show the benefit of any medicine for people with PPMS,” Xavier Montalban, MD, PhD, Chair of the Scientific Steering Committee of the ORATORIO study and Professor of Neurology and Neuroimmunology at Vall d’Hebron University Hospital and Research Institute in Barcelona, Spain, said in a news release from Genentech. “Now, for the first time, we have a positive Phase 3 study result for people with this debilitating form of the disease.”

During the first half of 2016, Genentech planned to seek regulatory approval for ocrelizumab to treat both RRMS and PPMS.

Cautious Optimism

Dr. Riley, who was not involved with the ocrelizumab studies, thinks clinicians and patients can be hopeful about the findings, as long as they have a realistic outlook.

“It’s very appealing to have a drug that has data in both [RRMS and PPMS] because you could potentially hedge your bets a bit [as a clinician],” Dr. Riley says. “You could say, ‘I think this is probably PPMS, but maybe that was a relapse back then,’ and so ... we have an agent that potentially works for both. Knowing that this B-cell-directed therapy has efficacy in each form of the disease ... is sort of opening new doors for us thinking about the role of B cells.

“I am enthusiastic about [the findings], but I don’t think [ocrelizumab] is going to work for everyone,” she continues. ”None of our medicines does. People who have had severe impairment are unlikely to see reversal of their impairment. It’s just important to have realistic expectations.”