Ocrelizumab Reduces Wheelchair Use in Primary Progressive MS

September 24, 2019

STOCKHOLM — Long-term data from the ORATORIO trial of ocrelizumab (Ocrevus, Genentech/Roche) in patients with primary progressive multiple sclerosis (PPMS) show that, after 6.5 years of follow-up, disability progression outcomes favored those on earlier continuous treatment with the drug versus delayed initiation.

This included a 42% reduced risk of becoming confined to a wheelchair in patients who started on ocrelizumab compared with those in the original placebo group.

The latest data from the trial were presented at last week's 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019.

"These latest results show that the benefits of ocrelizumab in reducing disability progression in patients with PPMS were durable with up to 6.5 years of follow up," ORATORIO lead investigator Jerry Wolinsky, MD, University of Texas Health Science Center at Houston, concluded.

"Personally I would like to say that this is the first time that has shown positive results in any controlled trial in PPMS yet alone durability of those results out to 6.5 years. It will be some time before these results can be challenged," he added.

The ORATORIO trial enrolled 732 patients with PPMS and randomized them to receive ocrelizumab or placebo in a 2:1 ratio. After the randomized phase had established benefit of the drug, patients were continued on open-label active treatment, with the open-label part of the study starting 140 to 240 weeks after randomization.

Results at 6.5 years showed that patients in the original ocrelizumab group had less disability progression sustained for at least 24 weeks than the original placebo group as ascertained by several different measures including: 1) an increase in Expanded Disability Status Scale (EDSS) score of least 1 point or an increase of > 0.5 points if baseline EDSS was under 5.5; 2) an increase of > 20% in the timed 9-hole peg test; 3) an increase of > 20% in the timed 25-foot walk test; and 4) time to wheelchair (confirmed EDSS > 7).

Table. Disability Progression for Earlier Versus Later Ocrelizumab

Endpoint HR (95% CI) P value
Increase in EDSS 0.72 (0.58 - 0.89) .002
Increase in timed 9-hole peg test 0.65 (0.50 - 0.86) .002
Increase in timed 25-foot walk 0.77 (0.64 - 0.94) .010
Time to wheelchair (EDSS > 7) 0.58 (0.38 - 0.89) .011
HR = hazard ratio; CI = confidence interval


"This is an open label extension with no continued control group so one has to be careful about interpreting the results but it was very impressive to see that what we saw in the double-blind phase in terms of benefit of ocrelizumab created a difference between the two groups which remained out to 6.5 years," Wolinsky commented to Medscape Medical News.

"This serves to show that even when you move people over from the placebo group to ocrelizumab just a few years later from randomization they don't catch up," he said.

"This is a slowly moving disease. I would hope that we could stop that progression just with a very potent anti-inflammatory but we may need something more," Wolinsky noted. "But what this shows is that what we've learned from studies in relapsing remitting MS and clinically isolated syndrome is the earlier you start the drugs the more potent any one of them looks because there is less damage. The same thing is true in PPMS," he added.

Which Patients Benefit?

Commenting for Medscape Medical News, Robert Fox, MD, Cleveland Clinic, cochair of the session at which the study was presented, said the results were "interesting and thought provoking on the long-term benefit of the drug."

"I would like to see how much of that long-term benefit was driven by patients with active inflammation at baseline," Fox added. "We know the initial results were significantly impacted by those who had active inflammation so I would like to see a similar subgroup analysis of this dataset in those patients with gadolinium enhancing lesions versus those without at baseline to see if this again was driven by the anti-inflammatory component in the subset of patients with inflammation or was this a broader based effect.

"While these results give encouragement that there is durable benefit," he said, "there are still unanswered questions about which patients will benefit as it was quite a select patient population that were enrolled into the trial — younger patients with earlier active disease. Knowing how to apply these results to broader base of progressive MS patients is still unknown particularly those with longer disease duration and who are older."  

Other experts had similar opinions.

Tobias Derfuss, MD, University Hospital Basel, Switzerland, said: "It's good to see a continued effect out to 6 years, but the effect size is quite small. The group still progresses but more slowly than those originally on placebo."

Derfuss pointed out that ocrelizumab works best in the subgroup of patients who have more signs of inflammation, which he estimated may only be about 20% of the PPMS population. "But as it is the only drug available for PPMS, all patients want it, and it can be hard to know if it is working in individual patients as all these patients generally progress, especially as the MRI is quite silent in these patients."

ECTRIMS president, Bernhard Hemmer, MD, Technical University of Munich, Germany, pointed out that this type of extended analysis always has to be interpreted carefully, as there could have been unbalanced dropouts between the two groups, which could lead to self-selection of patients who are responders.

He noted that in Germany it is just the subgroup of younger PPMS patients with some evidence of inflammatory activity that tend to get ocrelizumab. "I am hesitant to treat patients over 50 as there isn't any evidence of effectiveness and the risk of adverse effects increases with age," he said.

Wolinsky said that based on previous failures in PPMS trials, "we tried to recruit the earliest patients that we could and to make absolutely sure they had oligoclonal bands — not because we thought they needed it for the diagnosis, but those patients can progress faster; and we also wanted younger patients because age matters unfortunately. That's how we set it up and that helped us get a clear treatment effect."

"Physicians are loathe to label patients primary progressive because we haven't had anything that would work, so this is a major breakthrough. Period. And yes, we are treating them and we are making a difference," he added. "In some ways, the magnitude of the containment of the progression is almost as high as it is in relapsing disease. We have shown that there are 42% less wheelchair bound people in the group who started the drug at the beginning compared to those who had delayed treatment, and no one wants to go in a wheelchair."

On the applicability of these results to the broader PPMS population, Wolinsky added: "I would say that if patients have something to lose and are showing evidence of actively progressing this is well worth a try."

The ORATORIO study was funded by Roche. Wolinsky has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities with AbbVie, Actelion, Alkermes, BrainStorm Cell Therapeutics, Biogen, Bionest, Celgene, Clene Nanomedicine, EMD Serono, Forward Pharma A/S, GeNeuro, GW Pharma Ltd, MedDay Pharmaceuticals, Otsuka, PTC Therapeutics, Novartis, Roche/Genentech and Sanofi Genzyme; royalties are received for outlicensed monoclonal antibodies through UTHealth from the Millipore Corporation.

35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019: Abstract 159. Presented September 12, 2019.

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