Caroline Helwick

February 22, 2016

NEW ORLEANS — A subgroup analysis of the phase 3 ORATORIO trial in primary progressive multiple sclerosis (PPMS) showed that ocrelizumab has efficacy in patients with and without T1 gadolinium-positive (Gd+) lesions at baseline.

The effect was consistent with the improvement seen in the overall population, according to Jerry Wolinsky, MD, from the University of Texas Health Sciences Center at Houston.

"Ocrelizumab is the first investigational treatment to meet primary and key secondary efficacy endpoints in a phase 3 PPMS study," Dr Wolinsky noted.

Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. It recently showed efficacy in the ORATORIO study of PPMS and in the OPERA study among patients with relapsing-remitting MS.

When the results of ORATORIO were examined according to T1 Gd enhancement vs no enhancement at baseline, hazard ratios were more favorable for Gd+ patients, however, gadolinium-negative (Gd–) patients also derived benefit from ocrelizumab. The differences between treatment group by T1 Gd enhancement, however, did not show statistical significance because of a lack of power. The subgroup analysis, Dr Wolinsky emphasized, "was an attempt to understand the data better."

"There's still a lot of work that has to be done to understand if there are subgroups of patients in the study who consistently respond differently than others," he said.

Breakthrough Designation

The phase 3 ORATORIO trial randomly assigned 732 patients with PPMS 2:1 to ocrelizumab, 600 mg intravenously, every 24 weeks until progression, or to placebo. Patients were required to have an elevated IgG index, two or more oligoclonal bands, Expanded Disability Status Scale Score of 3.0 to 6.5, and age 18 to 55 years.

On the basis of the positive results of the trial, the US Food and Drug Administration (FDA) granted breakthrough therapy designation for ocrelizumab in PPMS on February 16, 2016, making it the first investigational agent for MS to be given this status.

ORATORIO found that for the primary endpoint — time to onset of 12-week confirmed disability progression — risk was reduced by 24% with ocrelizumab (P = .0321), compared with placebo, and other markers of disease activity were also improved. After 120 weeks of treatment, significant improvements were observed in timed 25-foot walk (P = .04), change in T2 lesion volume from baseline (P < .0001), and rate of brain volume loss (P = .02).

Here at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016, a meeting on PPMS, Dr Wolinsky presented this subgroup analysis.

He pointed out that the characteristics of patients in ORATORIO were mostly similar to those of other large trials in PPMS (PROMISE, OLYMPUS, INFORMS), with a few important differences. They were slightly younger (mean age, 44.6 vs 48.8 - 51.5 years) and had a higher proportion of patients with Gd+ lesions (26.4% vs 13.4% - 24.5%).

"So our question, was, to what extent did baseline enhancement activity have an effect on the overall outcomes of this study?" he said.

For the key disability endpoints, the results for Gd+ and Gd– groups were consistent with the findings for the overall population, he reported.

Table. Confirmed Disability Progression With Ocrelizumab vs Placebo

Endpoint Overall Population HR (95% CI) (n = 731) T1 Gd+ Lesions HR (95% CI) (n = 193) T1 Gd– Lesions HR (95% CI) (n = 533)
Time to onset of 12-wk confirmed disability progression 0.76 (0.59 - 0.98) 0.65 (0.40 - 1.06) 0.84 (0.62 - 1.13)
Time to onset of 24-wk confirmed disability progression 0.75 (0.58 - 0.98) 0.67 (0.40 - 1.14) 0.81 (0.59 - 1.10)

CI = confidence interval; HR = hazard ratio.


"The confidence intervals cross 1 for both groups, and as you might surmise they do not lead to statistical significance, but the overall results are similar for the two groups," Dr Wolinsky said.

Commenting on the better hazard ratios for the Gd+ versus Gd– patients, he emphasized that ocrelizumab appeared beneficial in both subgroups. "There clearly are effects occurring in those who are Gd-negative at baseline, or at least patterns that are very much in the same direction for every endpoint we looked at," he said.

Similar findings were made for change in T2 hyperintense lesion volume from baseline to week 120, for the subgroups and the overall population. For the overall population, a 7.4% increase was observed in the placebo group, while a 3.4% decrease was seen after treatment with ocrelizumab (P < .0001). A similar pattern was observed for both Gd subgroups.

Mean change in whole brain volume from week 24 to week 120 was a 17.5% relative reduction (P = .0204) for the whole population, again with similar patterns observed in the subgroups.

Dr Wolinsky reiterated that the study was not powered to show statistical significance, and therefore no conclusions can be drawn as to which patients might benefit most from this drug. 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.

"This is one of the smaller of the large PPMS studies, but it is one in which we are trying to disentangle these things as best we can," he said. "The baseline Gd-positive group is larger than in some of the other studies but still not large enough for answers."

He said the next step is to evaluate new lesion activity and relapses on-study, "which don't happen often in PPMS but do always happen to some degree in our trials," he said.

The Data "We've Been Waiting for"

Fred D. Lublin, MD, the Saunders Family Professor of Medicine and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai School of Medicine, New York, commented that Dr Wolinsky presented "what we've been waiting to see, the subset analysis, to see whether activity made a difference or not."

"It seems that patients did worse if they didn't have any, and better if they did, but the power was not there to answer the question," Dr Lublin said.

Nevertheless, he maintained that the subgroup analysis of ORATORIO "is giving us some information that needs to be confirmed in other studies so that we can better identify the individuals with progressive disease who will respond to an anti-inflammatory agent, if that's how this agent is working."

When asked how neurologists should respond to patients with PPMS who will undoubtedly be requesting ocrelizumab, Dr Lublin responded, "Yes, this is going to be an issue, but I don't know if we will ever have data to answer it," that is, to select patients most likely to respond.

Dr Lublin also offered that there appear to be insufficient data for the FDA to restrict use of ocrelizumab to certain subsets.

Dr Wolinsky reported financial relationships with Genentech, Novartis, F. Hoffmann-La Roche, Genzyme, Teva Pharmaceuticals, AbbVie, Actelion, Alkermes, Athersys, EMD Serono, Forward Pharma, and XenoPort. Dr. Lublin reported financial relationships with Actelion, Accorda, Bayer, Biogen Idec, EMD Serono, Forward-Pharma, Genentech, Genzyme, Johnson & Johnson, MedImmune, Novartis, Receptos, Revalesio, Roche, Sanofi-Aventis, Questcor, Teva, XenoPort, Abbvie, Toyama, BBB Technologies, Akros, and Cognition Pharmaceuticals.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016. Abstract LB1.3. Presented February 19, 2016.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.