Deborah Brauser

March 06, 2017

ORLANDO — Further research from three phase 3 trials of ocrelizumab (Ocrevus, La Roche) for multiple sclerosis (MS) showed no increased risk for serious infections, while patient-reported outcomes showed significant benefits.

The findings were presented in two posters here at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2017.

The first included patients with relapsing MS (RMS) from the two almost-identical OPERA 1 and 2 trials and those with primary progressive MS (PPMS) from the ORATORIO trial. Although the patients with RMS receiving ocrelizumab had numerically more common colds (nasopharyngitis) and upper respiratory tract infections (URTIs) than those receiving interferon β-1a (IFNβ-1a), they had fewer serious infections.

The ORATORIO patients with progressive MS who were receiving the study drug had similar rates of serious infection as those receiving placebo. They also had higher rates of any infection, but the investigators note that this may be because the group had a higher mean disability level and were older. Two deaths, due to pneumonia and aspiration pneumonia, occurred among these patients. Investigators felt the deaths were not related to treatment, but review by an independent monitoring committee struck by the sponsor found otherwise.

The second analysis, which assessed only the ORATORIO participants, showed higher mental well-being scores in those receiving ocrelizumab than in those receiving placebo, as well as significantly reduced fatigue.

"They certainly were functioning better in terms of things that are nontrivial for the patient," coinvestigator Jerry S. Wolinsky, MD, director of the MS Research Group at the University of Texas Health Science Center in Houston, told Medscape Medical News.

Dr Jerry S. Wolinsky

The main results from the three phase 3 trials, which were published recently in the New England Journal of Medicine, have been submitted to the US Food and Drug Administration (FDA). The highly anticipated Prescription Drug User Fee Act date to review the Biologics License Application for the treatment is set for March 28.

"I have a hard time second guessing the FDA, but I cannot believe that they would do anything but approve, based on the OPERA 1 and OPERA 2 studies," Dr Wolinsky said.

"If they don't approve for primary progressive MS, then they don't quite understand how hard it is to achieve outcomes in this patient population," he said. Still, "I hope that we get this approved for both [RMS and PPMS] patients."

Investigating Infection Concerns

The original OPERA 1 and OPERA 2 trials each included approximately 800 patients with RMS who received 600 mg of intravenous ocrelizumab every 6 months for 96 weeks or 44 μg of subcutaneous IFNβ-1a (Rebif, EMD Serono) three times weekly.

In the original ORATORIO trial, 732 patients with PPMS received 600 mg of intravenous ocrelizumab every 24 weeks for at least 120 weeks or matching placebo.

The patient population in ORATORIO was older at baseline than that in the OPERA studies (mean age, 44.5 vs 37.2 years, respectively) and had a higher Expanded Disability Status Scale (EDSS) score (4.7 vs 2.8).

Infection analyses showed higher rates of any type for the ocrelizumab group but more than double the rate of serious infections in the interferon group.

Table 1. Infection Rates in Combined OPERA Studies

Outcome Ocrelizumab IFNβ-1a
Any infection (%) 58.4 52.4
Serious infection (%) 1.3 2.9
Nonserious infection-related withdrawals (n) 2a 0
Total infection rates per 100 patient-years 84.5 67.8
Serious infection per 100 patient-years 0.8 1.8

aDue to cellulitis and urinary tract infection.

 

The most frequently reported symptoms in the ocrelizumab vs IFNβ-1a groups were URTI (15.2% vs 10.5%) and nasopharyngitis (14.8% vs 10.2%). However, most cases "were mild to moderate and most patients recovered while remaining on the study drug," note the investigators.

Herpesvirus-associated infections were also reported in 5.9% and 3.4% of the groups, respectively. All but one of these cases were mild or moderate. The exception was a patient in the OPERA 1 ocrelizumab group, who had a severe genital herpes simplex infection leading to hospitalization, but the event resolved with antiviral treatment.

Table 2. Infection Rates in ORATORIO

Outcome Ocrelizumab Placebo
Any infection (%) 69.8 67.8
Serious infection (%) 6.2 5.9
Nonserious infection-related withdrawals (%) 0.8 1.3
Total infection rates per 100 patient-years 71.7 73.8
Serious infection rates per 100 patient-years 3.0 2.9

 

The ocrelizumab group had higher rates of influenza than the placebo group (11.5% vs 8.8%) and greater rates of URTI (10.9% vs 5.9%). But their rates of nasopharyngitis and urinary tract infection were lower (22.6% vs 27.2% and 19.8% vs 22.6%, respectively).

Oral herpes was the only herpes type significantly more common in the active treatment group (2.3% vs 0.4%).

No opportunistic infections occurred in any study, and there were no infection-related deaths in OPERA.

Two ORATORIO patients in the ocrelizumab group died: one of pneumonia and the other of aspiration pneumonia. Although investigator judgement found them to be unrelated to treatment, review by an independent data monitoring committee found the opposite.

"Both patients had an EDSS score of 6.5 prior to death and reported no prior concomitant use of immunosuppressants," write the investigators.

"The bottom line is: We don't think that, at least from what we saw in these trials for both relapsing and progressive disease, infections have been a major problem so far," Kottil Rammohan, MD, professor of neurology at the University of Miami, Florida, said during his presentation.

Dr Kottil Rammohan

Patient Outcomes

For the ORATORIO patient-outcome analysis, the Short Form-36 (SF-36) quality-of-life scale and the Modified Fatigue Impact Scale (MFIS) were administered at baseline and at weeks 48 and 120.

Results showed no significant difference in decline on the physical domain of the SF-36 after treatment with ocrelizumab vs placebo. However, the mental component summary score domain was significantly improved at week 120 (P = .0006).

Compared with placebo, these patients also reported reduced overall fatigue on the MFIS (P = .0009) and better scores for fatigue-related physical (P = .01) and psychosocial (P = .04) functioning.

Although both treatment groups reported increased cognitive fatigue, smaller increases were reported by the ocrelizumab group (P < .04).

"I think this supports that the patients actually are experiencing some things that make them do better," said Dr Wolinsky. "And it's not just what we, as neurologists, are using as our conventional endpoints for studies."

"Interesting to See How It Plays Out"

"Surprisingly, it's been difficult to demonstrate benefit from a patient's perspective in clinical trials," ACTRIMS President-Elect Jeffrey A. Cohen, MD, Cleveland Clinic Neurological Institute-Mellen Center, Ohio, told Medscape Medical News.

Dr Jeffrey A. Cohen

Reasons include patient difficulty with assessing their performance after receiving the treatment in comparison to not having received it or compared with other people, said Dr Cohen, who was not involved with this research.

"So I've tended to not pay a lot of attention to patient-reported outcomes," he admitted, noting that they're important if dramatic benefit is shown on disease activity but with very poor patient-noted outcomes, "which suggests that there are a lot of side effects."

Or if there isn't much change on objective measures but patients report that they're doing much better, questions arise whether there were some placebo effect," he noted.

"In general, the fact that the patient-reported outcomes went in the same direction as the objective measures [of ocrelizumab] underscores the benefit on the disease activity and the general tolerability. Patients felt well and their MS was benefitted," said Dr Cohen.

He also applauded the findings in the infection analysis. "There was very little, if any, change in severe infections, serious infections, or rate of infections. So that is actually quite reassuring," he said. "It probably reflects the fact that many aspects of immune function are left preserved."

One caveat he noted is that "we'll have to wait and see" what happens with long-term therapy. In addition, a concern has been raised about the potential for breast cancer. "I would say that signal is still uncertain, but it's something we'll be paying attention to," said Dr Cohen.

As for the FDA's upcoming decision, he said, "I think all of us would be very surprised if this doesn't get approved, and I think it's going to be a very popular medication."

That said, he noted that the drug will foster debate between escalating therapy (starting with a safe but modestly effective treatment and changing if it's inadequately effective) or starting with one that's more potent from the beginning.

"Previously, our concern has been safety and tolerability with the more potent agents. But this agent is going to force that debate because there's been very little safety or side effect issues with it," said Dr Cohen. "It'll be interesting to see how that plays out."

The trials were funded by F. Hoffmann-La Roche. Dr Rammohan has received honoraria for participating in advisory boards and consulting for Acorda, Biogen, EMD Serono, Genentech/F Hoffman-La Roche, Genzyme, and Teva; and has received honoraria for consulting, serving on steering committees, and speaking at scientific symposia by the Rector of Heinrich-Heine University Düsseldorf from Bayer, Biogen, GeNeuro, Genzyme, Merck Serono, MedImmune, Novartis, Octapharma, Opexa, F Hoffmann-La Roche, Teva, and Sanofi. Dr Wolinsky has served on advisory boards, served on data monitoring or steering committees, or held consulting agreements from AbbVie, Alkermes, Bayer HealthCare, Clene Nanomedicine, Celgene, Forward Pharma A/S, MedDay, Novartis, Roche/Genentech, Sanofi Genzyme, Takeda, and Teva Pharmaceuticals. Dr Cohen reported that although he was involved with some premarketing studies for ocrelizumab, he had no involvement in the OPERA and ORATORIO trials. He is also involved in some studies for another CD-20 monoclonal antibody.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2017. Abstract P045, presented February 23, 2017. Abstract P171, presented February 24, 2017.

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