Long-Term Safety of Ocrelizumab for Multiple Sclerosis: 7-Year Follow-Up Data

Table of Contents

• Introduction: Why This Research Matters
• Study Methods and Patient Population
• Overall Safety Profile
• Detailed Analysis of Specific Risks
• Laboratory Changes and Monitoring
• Real-World Experience and Post-Marketing Data
• Conclusions and Clinical Implications
• Study Limitations
• Patient Recommendations
• Source Information

Introduction: Why This Research Matters

Ocrelizumab (OCR) is an important treatment option for both relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). As a medication that works by selectively depleting certain B-cells while preserving the body's ability to regenerate these cells and maintain existing antibody protection, it represents a significant advancement in MS therapy.

Previous shorter-term studies had established the effectiveness and initial safety profile of ocrelizumab, but until now, comprehensive long-term safety data beyond a few years was limited. This research addresses a critical question for patients and clinicians: how safe is continuous ocrelizumab treatment over many years?

For patients considering or currently using ocrelizumab, understanding the long-term safety profile is essential for making informed treatment decisions. This study provides the most comprehensive safety analysis to date, tracking patients for up to 7 years of continuous treatment.

Study Methods and Patient Population

This analysis combined safety data from 11 different clinical trials, including both the initial controlled periods and the open-label extension phases where all participants received ocrelizumab. The researchers integrated data from 5,680 patients with multiple sclerosis who received at least one dose of ocrelizumab.

The patient population included 4,376 individuals with relapsing MS and 1,304 with primary progressive MS. The median age at treatment start was 38 years for RMS patients and 47 years for PPMS patients, with ages ranging from 18 to 66 years. This represents a broad spectrum of MS patients typically seen in clinical practice.

The total exposure to ocrelizumab amounted to 18,218 patient-years, which is a substantial amount of data for assessing safety signals. More than 50% of patients received at least 5 doses of ocrelizumab, and 28% received at least 10 doses, indicating long-term treatment exposure.

For context, the researchers also included post-marketing data up to July 2020, by which time approximately 174,508 patients had started ocrelizumab treatment globally, with 167,684 initiating treatment after the drug's approval, representing 249,971 patient-years of real-world experience.

Overall Safety Profile

The comprehensive analysis found that ocrelizumab maintained a consistent safety profile throughout the entire 7-year observation period. The rate of all adverse events was 248 per 100 patient-years (with a 95% confidence interval of 246-251), which remained stable compared to earlier phases of the clinical trials.

Serious adverse events occurred at a rate of 7.3 per 100 patient-years (95% CI: 7.0-7.7), which also remained consistent with earlier observations. The treatment discontinuation rate due to adverse events was 3.19% (181 out of 5,680 patients) over up to 7 years, which was actually lower than the comparator rates during the controlled periods (3.35% for placebo and 6.17% for interferon beta-1a over up to 3 years).

The most common reasons for treatment discontinuation included:

• Malignancies (40 cases, which required mandatory discontinuation)
• Infusion-related reactions (33 cases, mostly occurring at the first infusion)
• Infections (27 cases, mostly non-serious)

Fatal outcomes were rare, with 26 reported cases (11 in RMS patients and 15 in PPMS patients) out of 5,680 patients over 18,218 patient-years, representing a rate of 0.14 per 100 patient-years (95% CI: 0.09-0.21). The most frequent causes were suicides (7 cases), infections (4 cases), malignancies (4 cases), and cardiac events (3 cases).

Detailed Analysis of Specific Risks

Infusion-Related Reactions: These remained among the most common adverse events, occurring at a rate of 25.9 per 100 patient-years (95% CI: 25.1-26.6) in the overall population. Importantly, the rate decreased with subsequent infusions, indicating that these reactions are most common during initial treatment.

Infections: Overall infection rates were 76.2 per 100 patient-years (95% CI: 74.9-77.4), with the most common being:

• Urinary tract infections (12.4 per 100 patient-years)
• Nasopharyngitis (common cold, 13.4 per 100 patient-years)
• Upper respiratory tract infections (9.7 per 100 patient-years)
• Bronchitis (3.2 per 100 patient-years)
• Influenza (3.7 per 100 patient-years)

Serious Infections: These occurred at a rate of 2.01 per 100 patient-years (95% CI: 1.81-2.23), with the most common being:

• Urinary tract infections (0.30 per 100 patient-years)
• Pneumonia (0.30 per 100 patient-years)
• Cellulitis (skin infections, 0.14 per 100 patient-years)

Serious herpes virus infections were uncommon (0.03 per 100 patient-years), and no cases of hepatitis B reactivation, cryptococcosis, aspergillosis, listeriosis, toxoplasmosis, or cytomegalovirus infection were reported.

Malignancies: The overall rate of malignancies was 0.46 per 100 patient-years (95% CI: 0.37-0.57). This rate remained consistent with ranges reported in epidemiological data for MS populations, suggesting that ocrelizumab treatment does not significantly increase cancer risk beyond what would be expected in these patients.

Laboratory Changes and Monitoring

The study carefully tracked laboratory parameters to understand how ocrelizumab affects various blood components over time:

Lymphocyte Counts: Treatment with ocrelizumab resulted in an approximate 15% decrease in absolute lymphocyte counts between baseline and week 12, likely due to the expected depletion of B-cells. These levels then remained stable throughout treatment.

T-Cells: Flow cytometry analysis showed decreases of ≤6% in CD3+ T-cell populations by week 2, primarily driven by reduction in CD8+ T-cells rather than CD4+ T-cells. These levels gradually recovered to baseline during the extension periods.

Neutrophils: Most patients maintained neutrophil levels within normal range. The proportion with marked neutropenia (absolute neutrophil count <1.5 × 10⁹/L) was 4.4% with ocrelizumab versus 18.2% with interferon beta-1a in the RMS trials.

Immunoglobulins: The study found important changes in antibody levels:

• IgM levels decreased by an average of 55.8% (mean reduction of 0.78 g/L)
• IgG levels decreased at an average rate of 0.33 g/L per year (2.99% per year)
• IgA levels showed a similar gradual decline

Despite these reductions, the proportion of patients with immunoglobulin levels below the lower limit of normal remained relatively low (7.7% for IgG at week 312 in the OPERA population).

Real-World Experience and Post-Marketing Data

As of July 2020, post-marketing data from approximately 174,508 patients who started ocrelizumab treatment globally showed consistency with the clinical trial findings. The fatality rate in real-world settings was slightly higher at 0.28 per 100 patient-years (95% CI: 0.26-0.31) compared to the clinical trial setting, which is expected given the broader, less selected patient population in real-world use.

Regarding progressive multifocal leukoencephalopathy (PML), a serious brain infection that can occur with some immunosuppressive treatments, no cases were reported in the clinical trials as of July 2020. However, 9 confirmed cases were reported outside of clinical trials, 8 of which were considered "carryover" cases from previous treatments with other immunosuppressive medications.

This suggests that the risk of PML with ocrelizumab appears to be low, particularly in patients who haven't previously been on highly immunosuppressive therapies.

Conclusions and Clinical Implications

This comprehensive 7-year safety analysis provides reassuring data for patients considering or currently using ocrelizumab for multiple sclerosis. The research demonstrates that continuous ocrelizumab treatment for up to 7 years in clinical trials, followed by more than 3 years of broader real-world use, maintains a favorable and manageable safety profile.

No new safety concerns emerged with longer treatment duration, which is particularly important for a chronic condition like MS that requires long-term therapy. The rates of serious infections and malignancies remained consistent with expected ranges in the MS population, suggesting that these risks are not significantly increased by ocrelizumab treatment.

The gradual decline in immunoglobulin levels observed over time warrants ongoing monitoring, but the clinical significance of this finding requires further study, as the rates of serious infections did not show a corresponding increase over time.

Study Limitations

While this study provides extensive safety data, several limitations should be noted. The use of open-label extension data and historical controls for comparison means this is considered Class III evidence, which is not as robust as randomized controlled trial data.

The patient population in clinical trials may not fully represent all MS patients in clinical practice, as trials typically exclude patients with certain comorbidities or more advanced disease. The post-marketing data helps address this limitation but comes with its own challenges in terms of consistency and completeness of reporting.

Additionally, while 7 years represents substantial follow-up time, even longer-term data will be needed to fully understand the safety profile over decades of treatment, which may be relevant for younger MS patients who might use the medication for many years.

Patient Recommendations

Based on this extensive safety analysis, patients using ocrelizumab can be reassured about its long-term safety profile. However, several important recommendations emerge:

1. Continue regular monitoring: Regular blood tests to monitor lymphocyte counts, neutrophil counts, and immunoglobulin levels remain important throughout treatment.
2. Report infections promptly: While most infections were not serious, patients should report any signs of infection to their healthcare providers promptly, especially given the modest increase in serious infection risk.
3. Adhere to infusion premedication: The decreasing rate of infusion reactions with subsequent infusions supports continuing the standard premedication regimen before each infusion.
4. Maintain routine cancer screenings: The malignancy rate remained consistent with expected rates in MS patients, emphasizing the importance of age-appropriate cancer screenings regardless of treatment.
5. Discuss concerns with your neurologist: Any concerns about long-term treatment should be discussed with your healthcare team, who can help balance the benefits of disease control against potential risks.

This research reinforces that ocrelizumab remains an important treatment option for both relapsing and primary progressive multiple sclerosis with a consistent long-term safety profile.

Source Information

Original Article Title: Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis

Authors: Stephen L. Hauser, MD, Ludwig Kappos, MD, Xavier Montalban, MD, PhD, MBA, Licinio Craveiro, MD, PhD, Cathy Chognot, PhD, Richard Hughes, MD, Harold Koendgen, MD, PhD, Noemi Pasquarelli, PhD, MSc, Ashish Pradhan, MD, Kalpesh Prajapati, MSc, MPhil, and Jerry S. Wolinsky, MD

Publication: Neurology 2021;97:e1546-e1559. doi:10.1212/WNL.0000000000012700

Note: This patient-friendly article is based on peer-reviewed research and aims to accurately represent the original study findings while making them accessible to non-specialist readers.