Five Years of Ocrelizumab Treatment for Relapsing Multiple Sclerosis: Long-Term Benefits and Safety

Table of Contents

• Introduction: Why This Research Matters
• Study Design and Methods
• Patient Characteristics and Participation
• Clinical Results: Relapse Rates and Disability
• MRI Results: Brain Lesion Activity and Volume Changes
• Safety Profile Over 5 Years
• What These Findings Mean for Patients
• Study Limitations
• Recommendations for Patients
• Source Information

Introduction: Why This Research Matters

Multiple sclerosis (MS) is a chronic neurological condition where the immune system attacks the protective covering of nerve fibers. Relapsing multiple sclerosis (RMS) involves periods of new or worsening symptoms followed by recovery periods. Ocrelizumab is a targeted therapy that specifically depletes B cells (a type of immune cell) believed to play a key role in MS progression.

This research followed patients for five years to understand the long-term benefits and safety of ocrelizumab treatment. The study compared patients who started ocrelizumab earlier versus those who switched from interferon therapy after two years. Understanding long-term outcomes is crucial for patients making treatment decisions that may affect their quality of life for years to come.

Study Design and Methods

The study combined data from two identical phase III clinical trials called OPERA I and OPERA II. These were randomized, double-blind studies, meaning neither patients nor researchers knew who received which treatment during the initial phase. After the initial 2-year controlled period, patients entered a 3-year open-label extension where all participants received ocrelizumab.

Patients received either ocrelizumab (600 mg infusions every 24 weeks) or interferon beta-1a (44 μg three times weekly) during the first two years. Those who switched from interferon to ocrelizumab at the start of the extension phase received their first dose as two 300 mg infusions two weeks apart. Researchers tracked multiple outcomes including:

• Annualized relapse rate (number of relapses per year)
• Disability progression confirmed over 24 weeks
• Disability improvement confirmed over 24 weeks
• Brain MRI activity (new lesions and enhancing lesions)
• Brain volume changes over time
• Safety measures and adverse events

The study included 1,656 patients initially, with 1,325 continuing into the extension phase. The clinical cutoff date for this analysis was February 5, 2018, providing up to 5 years of follow-up data.

Patient Characteristics and Participation

The study participants were well-balanced between treatment groups. The average age was approximately 37 years, with about 66% being female. The average Expanded Disability Status Scale (EDSS) score was 2.8 at baseline, indicating mild to moderate disability.

Of the 827 patients originally treated with ocrelizumab, 702 (84.9%) entered the extension phase and 623 (75.3%) completed year 5. Of the 829 patients originally treated with interferon beta-1a, 623 (75.2%) entered the extension phase and 551 (66.5%) completed year 5. Overall, 88.6% of patients who entered the extension phase completed year 5, representing 71% of the originally enrolled population.

Patients received an average of 7.3-7.4 doses of ocrelizumab during the extension phase, with no significant difference between those continuing ocrelizumab versus those switching from interferon.

Clinical Results: Relapse Rates and Disability

Patients who continued ocrelizumab maintained low relapse rates throughout the 5-year period. The annualized relapse rate remained consistently low:

• Year 1: 0.14 relapses per year
• Year 2: 0.13 relapses per year
• Year 3: 0.10 relapses per year
• Year 4: 0.08 relapses per year
• Year 5: 0.07 relapses per year

Patients switching from interferon to ocrelizumab experienced a significant 52% reduction in relapse rate (from 0.20 in year 2 to 0.10 in year 3) that was maintained through years 4 and 5 (0.08 and 0.07 respectively). During the extension phase, there was no difference in relapse rates between the two groups.

The cumulative proportion of patients with 24-week confirmed disability progression was significantly lower in the continuous ocrelizumab group at multiple timepoints:

• Year 2: 7.7% vs 12.0% (p=0.005)
• Year 3: 10.1% vs 15.6% (p=0.002)
• Year 4: 13.9% vs 18.1% (p=0.03)
• Year 5: 16.1% vs 21.3% (p=0.014)

This represents a 31% relative reduction in disability progression at year 5 for patients who started ocrelizumab earlier. The hazard ratio for disability progression during the initial phase was 0.60 (95% CI 0.43-0.84, p=0.003), indicating a 40% lower risk of progression with ocrelizumab.

For disability improvement, patients receiving continuous ocrelizumab showed numerically higher rates of improvement at all timepoints, reaching statistical significance at year 5 (25.8% vs 20.6%, p=0.046).

MRI Results: Brain Lesion Activity and Volume Changes

MRI results showed dramatic differences in disease activity. Patients continuing ocrelizumab maintained near-complete suppression of new brain lesions throughout the 5-year period:

Gadolinium-enhancing lesions (indicating active inflammation): - Year 2: 0.017 lesions per scan - Year 3: 0.005 lesions per scan - Year 4: 0.017 lesions per scan - Year 5: 0.006 lesions per scan

New or enlarging T2 lesions (indicating new disease activity): - Year 2: 0.063 lesions per scan - Year 3: 0.091 lesions per scan - Year 4: 0.080 lesions per scan - Year 5: 0.031 lesions per scan

Patients switching from interferon to ocrelizumab showed almost complete suppression of MRI activity after switching: - Gadolinium-enhancing lesions dropped from 0.491 at year 2 to 0.007 at year 3 - New T2 lesions dropped from 2.583 at year 2 to 0.371 at year 3

Brain volume changes showed significant benefits for continuous ocrelizumab treatment. At year 5, patients treated continuously with ocrelizumab experienced significantly less brain volume loss compared to those who switched from interferon: - Whole brain volume: -1.87% vs -2.15% (p<0.01) - Gray matter volume: -2.02% vs -2.25% (p<0.01) - White matter volume: -1.33% vs -1.62% (p<0.01)

The proportion of patients with no evidence of disease activity (NEDA - no relapses, disability progression, or new MRI lesions) was significantly higher in the continuous ocrelizumab group both during the initial phase (48.5% vs 27.8%, p<0.001) and over the entire 5-year period (35.7% vs 19.0%, p<0.001).

Safety Profile Over 5 Years

The safety analysis included all patients treated with ocrelizumab over the 5-year period. The overall incidence of adverse events was consistent with previous reports, and no new safety signals emerged with prolonged treatment.

The most common adverse events included: - Upper respiratory tract infections: 47.0 events per 100 patient-years - Urinary tract infections: 16.7 events per 100 patient-years - Nasopharyngitis: 15.5 events per 100 patient-years - Headache: 14.5 events per 100 patient-years

Serious adverse events occurred at a rate of 10.2 events per 100 patient-years. The most common serious adverse events were: - Infections: 2.6 events per 100 patient-years - Nervous system disorders: 1.4 events per 100 patient-years - Neoplasms: 0.8 events per 100 patient-years

There were 12 deaths during the study (0.5 events per 100 patient-years), none of which were considered related to ocrelizumab by the investigators. The incidence of serious infections was 2.6 events per 100 patient-years, and the incidence of malignancies was 0.8 events per 100 patient-years.

What These Findings Mean for Patients

This 5-year study provides strong evidence that early and continuous treatment with ocrelizumab provides sustained benefits for relapsing multiple sclerosis patients. The data show that starting ocrelizumab earlier leads to better long-term outcomes compared to starting with interferon and switching later.

Patients who began ocrelizumab earlier experienced significantly less disability progression over 5 years (16.1% vs 21.3%), representing a 31% relative reduction. They also maintained near-complete suppression of new brain lesions and experienced less brain volume loss, which is important since brain atrophy is correlated with long-term disability in MS.

The safety profile remained consistent over 5 years, with no new safety concerns emerging. This is particularly important for patients considering long-term treatment options.

Study Limitations

While this study provides valuable long-term data, it has several limitations. The study is rated as Class III evidence because the initial treatment randomization was disclosed after patients entered the extension phase, which could potentially introduce bias.

The extension phase was open-label, meaning both patients and doctors knew they were receiving ocrelizumab, which could influence reporting of outcomes. Additionally, patients who discontinued treatment were not included in the later analyses, which might affect the results if those who discontinued had different outcomes.

The study compared ocrelizumab against interferon beta-1a, which is not the most potent MS therapy available today. Comparisons against other high-efficacy therapies would be valuable for future research.

Recommendations for Patients

Based on this research, patients with relapsing multiple sclerosis should consider:

1. Discuss early treatment with high-efficacy therapies like ocrelizumab with their neurologist, as earlier intervention appears to provide better long-term outcomes
2. Understand the long-term benefits of continuous treatment, including reduced disability progression and fewer new brain lesions
3. Be aware of the safety profile and monitor for infections while on treatment
4. Maintain regular follow-up with their healthcare team to monitor treatment response and any potential side effects
5. Consider participating in clinical trials to help advance our understanding of long-term MS treatments

Patients should have open discussions with their healthcare providers about treatment options, considering both the potential benefits and risks of different therapies.

Source Information

Original Article Title: Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension

Authors: Stephen L. Hauser, MD, Ludwig Kappos, MD, Douglas L. Arnold, MD, Amit Bar-Or, MD, Bruno Brochet, MD, Robert T. Naismith, MD, Anthony Traboulsee, MD, Jerry S. Wolinsky, MD, Shibeshih Belachew, MD, PhD, Harold Koendgen, MD, PhD, Victoria Levesque, PhD, Marianna Manfrini, MD, Fabian Model, PhD, Stanislas Hubeaux, MSc, Lahar Mehta, MD, and Xavier Montalban, MD, PhD

Publication: Neurology 2020;95:e1854-e1867. doi:10.1212/WNL.0000000000010376

Clinical Trial Identifiers: NCT01247324/NCT01412333

This patient-friendly article is based on peer-reviewed research published in Neurology, the official journal of the American Academy of Neurology.