Improved Disability, Cognition With Ocrelizumab in MS

Nancy A. Melville

June 04, 2018

NASHVILLE, Tennessee — Treatment with ocrelizumab (Ocrevus, Genentech/Roche) is associated with improving disability and disease activity on MRI for up to 4 years in an open-label extension study of patients with relapsing multiple sclerosis (MS), while important improvements in cognitive deficits among patients at the highest risk for progressive disease are further demonstrated in clinical trial data.

Ocrelizumab, a humanized monoclonal antibody targeting CD20+ B cells, received approval from the US Food and Drug Administration (FDA) in March for the treatment of relapsing MS as well as primary progressive MS in adults. It is the first approved drug on the market for the latter indication.

Approval was based on safety and efficacy findings from the OPERA 1 and OPERA 2 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.

In the nearly identical phase 3 OPERA 1 and OPERA 2 trials, the safety and efficacy of ocrelizumab were demonstrated in relapsing MS, with patients randomly assigned to treatment with intravenous ocrelizumab 600 mg every 24 weeks or subcutaneous interferon β-1a, 44 μg three times weekly for 96 weeks.

After the controlled treatment period, all patients had the option to enter an open-label extension phase, either switching from interferon β-1a to ocrelizumab or continuing to receive ocrelizumab for 2 years.

Of those who entered the open-label phase, more than 89% completed the trial at year 2.

In the first of several updated analyses on the drug presented here at the Consortium of Multiple Sclerosis Centers (CMSC) 2018 Annual Meeting, researchers evaluated the effect of switching to or maintaining ocrelizumab on measures of MS-related disability.

They compared the groups during the course of the blinded and open-label phases, with improvement in disability defined as a reduction in the Expanded Disability Status Scale (EDSS) score of 1.0 or more (if baseline scores were between 2.0 and 5.5) or a reduction of 0.5 points or more (if the baseline EDSS score was >5.5).

In the year before the extension study, the differences between patients receiving ocrelizumab in higher proportions of 24-week confirmed disability improvement and those in the interferon β-1a group (454 [16.8%] vs 419 [13.3%]); however, the difference was not statistically significant (P = .09).

Confirmed disability improvement was also proportionally higher among those who continued receiving ocrelizumab than in those who switched from interferon β-1a in year 1 of the extension study (399 [20.6] vs 366 [16.6%]; P = .089) as well as in year 2 (363 [23.7%] vs 339 [18.9%]; P = .057).

"There was a strong trend for increased likelihood of improvement on disability compared to interferon," first author Robert T. Naismith, MD, Washington University, St. Louis, Missouri, told Medscape Medical News. "Over 4 years, around 20% to 25% of patients on ocrelizumab were noted to improve."

That being said, clinicians should be cautious not to overstate possible improvements, Naismith noted. "I would not necessarily set expectations with patients for an improvement, since this is not a guarantee," he said. "I would tell patients the treatment is designed to keep your disease stable. If they felt better, then that is somewhat of a bonus."

While typical functional symptoms could include weakness or difficult in walking and speech, the study did not assess those factors, Naismith added.

"This analysis included the EDSS score, and did not look at specific functions or domains," he explained, noting that "For future studies, evaluating quality of life, the Multiple Sclerosis Functional Composite, and EDSS functional systems would all be good to include."

Commenting on the research, Corey C. Ford, MD, PhD, a professor of neurology and director of the Multiple Sclerosis Specialty Center at the University of New Mexico in Albuquerque, noted that the findings are important in shedding light on longer-term effects of disease-modifying therapies (DMTs).

"Most clinical trials of MS DMTs show benefit in slowing disability progression or reducing relapses and MRI activity," he told Medscape Medical News. "They are typically 2-year studies, which is a short time in the lifespan of an MS patient."

The 4-year results meanwhile are encouraging in the potential longer-term benefits of the drug. "The disability curves for the ocrelizumab and comparator arm remain separated for 4 years," he noted.

"It is an open-label extension, so the study is no longer blinded," he added. "Overall, this is a very encouraging sign that some patients can actually improve, not just have slower accumulation of disability."

Extension Phase

A separate analysis of the open-label extension phase presented here further showed significant improvements in disease activity and progression in relapsing MS with ocrelizumab treatment, as indicated by lesion activity on MRI.

The analysis showed that in the interferon β-1a group, the adjusted number of T1 gadolinium-enhancing lesions decreased from 0.48 lesions per scan before the switch to ocrelizumab to 0.00 at years 1 and 2 of the open-label extension study.

New or enlarging T2 lesions also significantly declined in the interferon β-1a group, from 2.16 lesions per scan in the year before the switch to 0.33 and 0.08 at years 1 and 2 of the extension study.

Meanwhile, patients who continued receiving ocrelizumab maintained low numbers of the lesions in the extension study, and their brain atrophy levels from the core study baseline were also lower than in the interferon β-1a group in terms of whole brain volume change, cortical grey matter volume change, and white matter volume change (all P < .01 with the exception of cortical grey matter volume change in year 1, which was P = .16).

"Switching from interferon β-1a to ocrelizumab at the start of the open-label extension period was associated with rapid and robust reductions in MRI disease activity," the authors, led by Anthony Traboulsee, MD, from the University of British Columbia, Vancouver, Canada, concluded.

"Patients initially randomized to ocrelizumab maintained lower whole brain, white matter and cortical grey matter tissue loss after 4 years of continuous treatment compared to those initiating ocrelizumab 2 years later."

Ford commented that these MRI findings are valuable in gauging the nature of the drug's effects.

"Reductions in the rate of brain atrophy are very important in assessing the effectiveness of MS DMTs in clinical trials," he explained. "Atrophy as an individual measure is more difficult to implement because of natural fluctuations in atrophy measures in individuals and the generally slow rate at which is develops, but group data for specific DMTs is very supportive that the drugs reduce MS activity and preserve brain tissue."

In terms of clinical implications, however, the results are less clear, Ford added.

"Many factors play into disability, and atrophy is not a perfect surrogate marker of patient function or quality of life," he said. "Unfortunately, MS can strike very sensitive, eloquent brain regions causing significant disability, even with only modest or normal levels of brain atrophy."

Cognitive Impairment  

Finally, in a separate analysis of the pooled OPERA I and OPERA II trials, researchers focused on changes in cognitive deficits in patients with relapsing MS who were at an increased risk for progressive disease, marked by greater increases in cognitive impairment.

In the analysis, 186 patients in the ocrelizumab group and 180 in the interferon β-1a group were identified as being at an increased risk for progressive disease, defined as having a baseline EDSS score of 4 or greater and a pyramidal Kurtzke Functional Systems Score of 2 or greater.

Patients in the ocrelizumab group showed significantly greater mean improvements from baseline Symbol Digit Modalities Test (SDMT) scores over 96 weeks (ocrelizumab 6.2 [1.2]) vs interferon β-1a (2.6 [1.2]; P = .023).

Among those who had SDMT impairment at baseline (ocrelizumab: n = 116, mean [standard error] SDMT score of 27.9 [1.0]; interferon β-1a: n = 107, mean SDMT score of 28.2 [0.9]), the mean improvements from baseline were also greater over 96 weeks in the ocrelizumab group (10.5 [1.4]) than in the interferon β-1a group (6.0 [1.4]; P = .011).

Furthermore, a greater proportion of patients treated with ocrelizumab showed improvements of 4 points or more in SDMT scores by 48 weeks compared with those in the interferon β-1a group (51.2% vs 39.4%; P = .040), and the benefits of ocrelizumab were more likely to be maintained at 96 weeks (62.2% vs 46.5%; P = .009).

"It's previously been shown that ocrelizumab has a positive impact on cognitive processing speed as measured by SDMT and [in the new analysis] we extend these findings to patients at increased risk of progressive disease, as defined by EDSS and baseline cognitive impairment," lead author Ralph H. Benedict, PhD, a professor with the Department of Neurology at the University of Buffalo's Jacobs School of Medicine & Biomedical Sciences, New York, said in presenting the findings.

"The positive effect of ocrelizumab is most evident in patients at an increased risk of progressive disease, and the assessments based on validated SDMT responder thresholds indicate that the statistically significant effects of ocrelizumab on cognitive performance are clinically meaningful to patients."

The studies were sponsored by Genentech/Roche. Naismith's disclosures include relationships with Acorda, Genentech (speakers' bureau); Alkermes, Biogen, EMD Serono, Genzyme, Novartis, Teva (consulting fee). Benedict's disclosures include relationships with AbbVie, Genentech Inc, Novartis, Roche, Teva (consulting fee); Biogen (consulting fee, research support); EMD Serono (CME); Genzyme (consulting fee, contracted research, research support); Mallinckrodt (research support); and Psychological Assessment Resources Inc (royalty). Corey Ford has received research funding from Genentech/Roche and Genzyme/Sanofi Aventis but has not done any recent consulting work with either and is not on any speaker's bureaus.

Consortium of Multiple Sclerosis Centers (CMSC) 2018 Annual Meeting. Abstracts DX64, DX67, and DX45. Presented May 31 and June 1, 2018.

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