Ocrelizumab Benefits Early and 'Quite Persistent' in MS
BOSTON — Onset of efficacy is fairly rapid with the humanized monoclonal antibody ocrelizumab (Ocrevus, Genentech/Roche) for patients with relapsing multiple sclerosis (RMS), and the benefits are long-lasting — even for those who switch from other treatment — suggest further findings from the phase 3 OPERA trials.
In "pooled relapse endpoint analysis" from cohorts in the OPERA 1 and OPERA 2 studies, patients who were randomly assigned to receive 600 mg of intravenous (IV) ocrelizumab had a significantly reduced annualized relapse rate (ARR) at 96 weeks compared with those who received thrice-weekly 44-Ág doses of interferon ▀-1a (IFN▀-1a; Rebif, EMD Serono).
But the onset of treatment efficacy began within the first 8 weeks of treatment, with a significant 54.9% reduction in relapse rate.
Lead author, Stephen L. Hauser, MD, chair of the Department of Neurology at the University of California, San Francisco (UCSF), and director of the UCSF Weill Institute for Neuroscience, presented the results here at the American Academy of Neurology 2017 Annual Meeting (AAN).
During the same session, Robert T. Naismith, MD, Washington University, St. Louis, Missouri, presented preliminary, end-of-the-first-year findings from an open-label extension (OLE) phase for pooled OPERA participants.
As expected, the patients who kept using ocrelizumab had continued benefits, but so also did those who switched over to the treatment from their originally assigned treatment of IFN▀-1a — with reductions in ARR and T1 and T2 lesions.
"What's exciting about both presentations is that we now understand that the efficacy determined by patient experience begins very early. And the open-label extension data are also very encouraging," Dr Hauser later told Medscape Medical News.
"The rather dramatic effects of ocrelizumab on markers of relapsing disease activity, both clinical and MRI activity, continue to be present and are quite persistent," he said.
Early, Continued Reductions in ARRs
In March, the US Food and Drug Administration approved ocrelizumab for the treatment of both RMS and primary progressive MS in adults. The approval was based on safety and efficacy findings from the two OPERA trials — as well as the phase 3 ORATORIO trial. Main results for all three studies were published in December 2016 in the New England Journal of Medicine.
The primary endpoint in the OPERA studies, which each included about 800 patients with RMS, was reduction in ARR. Those in OPERA 1 who received IV ocrelizumab for 96 weeks had a 46% lower ARR compared with the patients who received subcutaneous IFN▀-1a.
In OPERA 2, the study treatment group had a 47% lower ARR than did the IFN▀-1a group. The rate was reduced by 46.5% in the pooled studies' ocrelizumab group over 96 weeks of treatment compared with the pooled IFN▀-1a group (P < .001).
In addition, the study treatment "significantly reduced ARR" within 8 weeks — and continued through weeks 12, 24, and 48, reported Dr Hauser.
TABLE. Adjusted AARs for Pooled Ocrelizumab vs IFN ß-1a
|Treatment Time Period||Adjusted ARR||P Value|
|8 wk||0.12 vs 0.27||.005|
|12 wk||0.17 vs 0.33||.002|
|24 wk||0.18 vs 0.30||<.001|
|48 wk||0.16 vs 0.30||<.001|
Ocrelizumab also "significantly reduced the probability of first protocol-defined relapse" compared with IFN▀-1a by 8 weeks (P = .01) and at all other time periods measured, Dr Hauser said.
This included significant reductions at 16 weeks (P = .001) and 24 weeks (P = .002), as well as at 48, 72, and 96 weeks (all P < .001).
Also, a treatment effect was observed on B-cell counts, "which were reduced to negligible levels by 2 weeks," and it had a rapid onset of effect on brain MRI.
Overall, "the rapid onset of the ocrelizumab effect has implications for patients switching from other therapies," said Dr Hauser.
"We know that continuation of some therapies may occasionally be associated with rebound disease severity. So it's helpful to have a [treatment] that will potentially prevent that rebound when one is switching," he added to Medscape Medical News.
After completion of the randomized phase of the OPERA trials, all participants were invited to enter an OLE phase, which is scheduled to last about 5 years. Of those in the pooled group who were originally receiving ocrelizumab, 93.6% continued treatment for at least 48 additional weeks, as did 93.7% of those who had originally received IFN▀-1a.
Preliminary results for this patient population showed that the IFN▀-1a switchers "experienced ARR outcomes consistent with those of patients who received continuous ocrelizumab," write the investigators.
At year 2 of the core/original study, the ocrelizumab continuers had an unadjusted ARR of 0.128, which was reduced to 0.106 at the end of OLE year 1. For the IFN▀-1a switchers, the ARRs were 0.212 and 0.100, respectively.
The switchers also had reductions in T1 gadolinium-enhancing lesions (mean number per MRI scan, down from 0.48 to 0.01) and new/enlarging T2 lesions (from 2.17 to 0.37).
The continuers had a mean number of T1 and T2 lesions per MRI scan of 0 and 0.09, respectively, at the end of OLE year 1, "demonstrating the sustained benefit of ocrelizumab treatment," said Dr Naismith.
"Additional data from the OPERA 1 and OPERA 2 open-label phase are forthcoming, including metrics of disease progression," he added.
Official session discussant Ellen M. Mowry, MD, associate professor of neurology and epidemiology at Johns Hopkins University in Baltimore, Maryland, noted that the OLE report had "very encouraging data," which were reminiscent of other observational studies.
One of the challenges, though, is that "patients may feel like they're on a stronger med" during open-label studies, and reports of treatment-related adverse events may be lower, she added.
Regarding the rapidity-of-onset presentation by Dr Hauser, Dr Mowry called it "nice" and said that "we owe it to our patients to find high-level therapy that takes effect in a faster time frame."
But she cautioned that there are several differences between real-world patients with MS and those participating in studies. These include that the former often have less rapid access to care and more challenging concomitant conditions to consider when selecting MS treatment, such as pregnancy; and these comorbidities may influence adherence and even outcomes.
The OPERA trials were funded by F. Hoffman-LaRoche. Dr Hauser reported serving on the board of trustees for Neurona and on scientific advisory boards for Annexon, Symbiotix, and Bionure, and he has received travel reimbursement and writing assistance from F. Hoffman-LaRoche for meetings and presentations.
American Academy of Neurology 2017 Annual Meeting (AAN). Abstracts S31.002 and S31.004. Presented April 26, 2017.
Ocrelizumab Benefits Early and 'Quite Persistent' in MS. Medscape. May 18, 2017.
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