The monoclonal antibody ocrelizumab was recently granted a breakthrough therapy designation by the FDA for the treatment of patients with primary progressive multiple sclerosis (PPMS). Ocrelizumab is the first investigational agent for the treatment of MS to be given this status.
The phase 3 ORATORIO clinical trial randomized 732 patients with PPMS to receive intravenous ocrelizumab 600 mg every 24 weeks or placebo until progression. For the primary end point—the time to onset of 12-week confirmed disability progression—the risk was reduced by 24% with ocrelizumab, and other markers of disease activity were also improved.
After 120 weeks of treatment, significant improvements were observed in a timed 25-foot walk, change in T2 lesion volume from baseline, and the rate of brain volume loss.
Ocrelizumab, which selectively depletes CD20-positive B-cells, also showed efficacy in patients with relapsing-remitting MS in the OPERA study.
At the 2016 ACTRIMS (Americas Committee for Treatment and Research in Multiple Sclerosis) Forum, a subgroup analysis of the ORATORIO clinical trial showed that ocrelizumab is effective in patients with and without T1 gadolinium (Gd)-positive lesions at baseline.
“Ocrelizumab is the first investigational treatment to meet primary and key secondary efficacy end points in a phase 3 PPMS study,” said Jerry S. Wolinsky, MD, Interim Chair, Department of Neurology, the University of Texas Health Science Center at Houston. “The effect was consistent with the improvement seen in the overall population.”
When examined according to T1 Gd enhancement versus no enhancement at baseline, hazard ratios were more favorable for patients with Gd-positive lesions; however, patients with Gd-negative lesions also derived benefit from ocrelizumab. The differences between treatment arms by T1 Gd enhancement, however, were not significant because of a lack of power.
“The confidence intervals cross 1 for both groups, and as you may surmise, they do not lead to statistical significance, but the overall results are similar for the 2 groups,” Dr Wolinsky said.
Because the study lacked power to show significance, no conclusions can be drawn as to which patients may benefit most from this drug, he said.
This subgroup analysis “was an attempt to understand the data better,” Dr Wolinsky explained. “There is still a lot of work to be done to understand if there are subgroups of patients in the study who consistently respond differently from others.”
Researchers are still grappling with the biology of PPMS—trying to understand what is driving the process, what Gd enhancement means in PPMS, and how anti-CD20 molecules and other drugs can affect progression, he said.
Fred D. Lublin, MD, Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center, NY, commented that MS experts have been anxious to see this subgroup analysis, “to know whether [magnetic resonance imaging] activity made a difference or not.”
“It seems that patients did worse if they did not have any, and better if they did, but the power was not there to answer the question,” Dr Lublin said.
The Future of Ocrelizumab
Dr Wolinsky commented on the drug’s breakthrough designation. “First and foremost, this does not assure in any way that ocrelizumab will be approved,” he pointed out.
“What it does say is that the FDA will make every attempt to speed up the process for reviewing the data, for making sure there is open dialogue with the company about whether the data are formatted correctly, whether we have presented all the data they want, about issues they may anticipate…so that we do not wind up in a situation where the decision is protracted because of iterative rounds of asking for more and more information.”
“This designation could not have been made from the OPERA trial [in relapsing-remitting MS], because there are many drugs for this phase of disease, and you cannot say there is an unmet need, but for PPMS, it is clear we do not have anything that the FDA believes is worth using,” Dr Wolinsky said.
Based on the information to date, Dr Wolinsky and Dr Lublin agreed that the FDA lacks grounds for restricting ocrelizumab to patients with Gd-positive lesions. “They could hardly say that one subgroup alone responds,” Dr Wolinsky noted. “The data do not show that.”