Continuous Early Ocrelizumab Provides Greater Sustained Benefits in Primary Progressive MS

Stephen L. Hauser, MD

Results from the ongoing, long-term open-label extension of the phase 3 ORATORIO study (NCT01194570) demonstrated that earlier and continuous treatment with ocrelizumab (Ocrevus; Genentech) provided sustained benefits on measures of disease progression in patients with primary progressive multiple sclerosis (MS) compared with patients switching from placebo.¹ 

Senior author Stephen L. Hauser, MD, director, UCSF Weill Institute for Neuroscience, and colleagues found that the proportion of patients with progression of disability measures was lower for those who initiated ocrelizumab early than for those initially receiving placebo for most of the measures of 24-week confirmed disability progression across 6.5 study years of follow-up.

The measures included Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), ≥20% increase in time to perform the Timed 25-Foot Walk (T25FW), composite progression defined as the first confirmed occurrence of any of these 3 individual measures, and time to require a wheelchair (EDSS ≥7). 

The proportion of patients with significantly lower EDSS scores was higher in those receiving continuous ocrelizumab (64.8%) than in those switching to ocrelizumab (51.7%), a difference of 13.1% (95% CI, 4.9–21.8; P = .0018) after the full follow-up. Similar results were seen on 9HPT (30.6% vs 43.1%; difference, 12.5 [95% CI, 4.1–20.9]; P = .0035), T25FW (63.2% vs 70.7%; difference, 7.5 [95% CI, –0.3 to 15.2]; P = .058), and composite progression (73.2% vs 83.3%; 95% CI, 3.6–16.6; P = .0023). 

Additionally, time to require a wheelchair was observed in 11.5% of those who received continuous ocrelizumab treatment compared to 18.9% of those who switched, for a difference of 7.4% (95% CI, 0.8–13.9; P = .0274). 

“Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis,” Hauser and colleagues concluded.

READ MORE: Ocrelizumab Shows Range of Benefits for Spectrum of Patients With Multiple Sclerosis​

The hazard ratio [HR] for patients receiving continuous ocrelizumab compared with those switching to ocrelizumab for time-to-first 24-week confirmed disability progression over all phases of the study was 0.72 (95% CI, 0.58–0.89; P = .0021). For the composite measure, the HR was 0.73 (95% CI, 0.61–0.88; P = .0006). Likewise, the HR for those receiving continuous therapy on the 9HPT was 0.65 (95% CI, 0.50–0.86; P = .002), on the T25FW was 0.77 (95% CI, 0.64–0·94; P = .0101), and 0.58 (95% CI, 0.38–0.89; P = .0112) for the time-to-requiring a wheelchair.

The analysis included 544 (74%) of the 732 participants who completed the double-blind period to Week 144. Among those, 527 (97%) entered the open-label extension phase, 451 (86%) of which are still currently enrolled in the ongoing open-label extension. Eligible participants were randomized 2:1 to receive either an intravenous infusion of 600-mg ocrelizumab (2 infusions of 300 mg, 14 days apart) or placebo every 24 weeks for at least 120 weeks until a prespecified number (n = 253) of disability events occurred. 

The rate of adverse events (AEs) over the entire period in the ocrelizumab all exposure population was 238.09 (95% CI, 232.71–243.57) per 100 patient-years and serious AEs was 12.63 (95% CI, 11.41–13.94) per 100 patient-years. Infection, which occurred at a rate of 4.13 (95% CI, 3.45–4.91) per 100 patient-years was the most common serious AE observed.

“Moreover, safety and tolerability were similar in participants with primary progressive multiple sclerosis compared with those with relapsing-remitting multiple sclerosis in the OPERA studies, despite the patient cohort being older with greater disability,” Steve Cohen, MD, director of the Mellen Center for MS Treatment and Research, Cleveland Clinic, wrote in a related editorial.² 

Using conventional magnetic resonance imaging (MRI) measures, researchers found that the percent change from baseline in T2 lesion volume was lower in those who initiated ocrelizumab early (0.45%) than in those initially receiving placebo (13%; P <.001). Similar results were found in T1 hypointense lesion volume (36.68% vs 60.93%; P <.001). 

Investigators noted that patients who had switched from placebo to ocrelizumab had almost complete and sustained suppression of MRI T2 lesion activity from study year 2.5 to study year 6.5. No significant differences in the rates of whole brain, cortical grey matter, or white matter volume loss were observed between the continuous and delayed ocrelizumab groups. 

Although not deemed significant, patients treated continuously with ocrelizumab had numerically lower rates of brain atrophy compared to those who switched, measured by a change from the double-blind baseline in whole brain volume (adjusted rate, –3.077% vs –3.366%; P = .13) and cortical grey matter volume (adjusted rate, –2.525% vs –2.642%; P = .38). 

Ocrelizumab was approved for the treatment of relapsing forms of MS, including clinically isolated syndrome, as well as secondary progressive and primary progressive disease in 2017. The drug, which is delivered via intravenous infusion every 6 months following a loading dose, had updates to its drug label with new safety information earlier this year in January.³ 

The investigators noted that further research is needed to investigate how the potential benefits of the study might be improved upon, particularly over longer time periods. 

Cohen added, “Several important questions remain. Can we extrapolate these results in primary progressive multiple sclerosis to secondary progressive multiple sclerosis…? Are there rare or late adverse events that have not yet been seen? What is the clinical significance of the decrease in immunoglobulin concentrations, and how should patients with low immunoglobulin concentrations be managed?” 

REFERENCES
1. Wolinsky JS, Arnold DL, Brochet B, et al. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomized, placebo-controlled, phase 3 trial. Lancet Neurol. Published online October 29, 2020. doi: 10.1016S1474-4422(20)30342-2
2. Rose DR, Cohen JA. Long-term ocrelizumab in progressive multiple sclerosis. Lancet Neurol. Published online October 29, 2020. doi: 10.1016/S1474-4422(20)30399-9
3. Drug Safety-related Labeling Changes (SrLC). US FDA. January 15, 2020. accessdata.fda.gov/scripts/cder/safetylabelingchanges/index.cfm. Accessed November 2, 2020.