Effectiveness of Ocrelizumab in Primary Progressive Multiple Sclerosis: A Multicenter, Retrospective Real-World Study

Background and Research Motivation

Multiple sclerosis (MS) is a chronic, complex, inflammatory, and degenerative demyelinating disease primarily affecting the central nervous system (CNS). It can lead to neurological impairments in the spinal cord, brainstem, optic nerves, cerebellum, and cerebrum. Primary progressive multiple sclerosis (PPMS), a relatively rare MS subtype, accounts for 10–15% of patients. It is characterized by a progressive course from onset, often accompanied by pronounced motor impairments, cerebellar ataxia, and brainstem symptoms. This subtype is considered a highly disabling condition with significant unmet medical needs.

Despite advances in MS therapies, current treatments show limited efficacy in slowing disability progression for PPMS patients, particularly those with lower disease activity or prolonged disease duration. Ocrelizumab, a recombinant humanized monoclonal antibody selectively targeting CD20-expressing B cells, demonstrated therapeutic potential for PPMS during its initial development. However, the ORATORIO phase III trial primarily focused on patients under 55 years old with an Expanded Disability Status Scale (EDSS) score ≤6.5. Data on older patients or those with longer disease durations are lacking.

This study aims to evaluate the clinical effectiveness of ocrelizumab in real-world settings, particularly in PPMS patients who do not meet ORATORIO trial eligibility criteria.

Research Methods

This multicenter, retrospective study was conducted by MS treatment centers across Italy, collecting data from PPMS patients treated with ocrelizumab between May 2017 and June 2022. Patient data were obtained from the Italian Multiple Sclerosis Registry and the MA30130 program database.

Patient Grouping and Data Analysis

1. Group Classification:

   • ORATORIO Group: Patients meeting ORATORIO trial criteria (e.g., age 18–55, EDSS 3.0–6.5, disease duration within specified limits).
   • Non-ORATORIO Group: Patients not meeting the above criteria.

2. Data Analysis:

   • Inclusion criteria encompassed adult patients who had received at least four treatment courses and undergone at least three EDSS evaluations.
   • Kaplan–Meier analysis was used to estimate the cumulative risks of EDSS worsening over 12 and 24 months.
   • Cox proportional hazard models were employed to identify factors influencing disability progression.

Key Findings

Baseline Characteristics and Distribution

A total of 589 patients were included in the study, with 149 (25.3%) in the ORATORIO group and 440 (74.7%) in the Non-ORATORIO group. Non-ORATORIO patients were older (mean age: 52.1 vs. 42.4 years, p < 0.001) and had longer disease durations (mean: 157.2 vs. 68.4 months, p < 0.001).

Risk of Disability Progression

1. Overall Analysis:

   • No significant differences were found between the ORATORIO and Non-ORATORIO groups in terms of EDSS worsening at 12 or 24 months (p > 0.05).
   • Patients aged over 65 showed a higher risk of disability progression (HR = 2.51, 95% CI 1.07–3.65, p = 0.01).

2. Subgroup Analysis:

   • Patients over 65 years exhibited significantly higher rates of EDSS worsening at 12 and 24 months compared to younger age groups (43.6% vs. 9.5%, p < 0.001).
   • Disease duration >10 years showed no significant impact on disability progression compared to shorter durations (p > 0.05).

3. Disease Activity:

   • No significant differences in treatment outcomes were observed based on the presence of clinical relapses or MRI activity at treatment initiation.

Multivariate Analysis

Age was identified as an independent predictor of disability progression. Patients over 65 years were at significantly higher risk of EDSS worsening, while EDSS score and disease duration at baseline were not significant predictors.

Study Implications and Value

1. Scientific Contribution:

   • This study is the first to evaluate ocrelizumab’s effectiveness in real-world PPMS patients outside the ORATORIO trial criteria, filling a critical knowledge gap.
   • It provides insights into the impacts of age, disease duration, and activity on treatment outcomes, offering valuable data for future treatment guidelines.

2. Clinical Relevance:

   • Ocrelizumab may benefit PPMS patients under 65 years old, regardless of ORATORIO eligibility.
   • Treatment decisions for older patients should carefully weigh the risks and benefits, considering potential immunosenescence-related efficacy reductions.

3. Limitations and Future Directions:

   • The retrospective design may introduce selection bias.
   • EDSS’s limitations (e.g., inadequate assessment of cognitive or upper extremity function) highlight the need for more comprehensive evaluation metrics.
   • Prospective studies are recommended to further evaluate long-term safety and efficacy, particularly in older populations.

Conclusion

As the first disease-modifying therapy approved for PPMS, ocrelizumab demonstrated significant potential for disability progression mitigation in real-world settings. This study supports expanding its use to selected PPMS patients who do not meet ORATORIO trial criteria, particularly those under 65 years old. Future research should address its safety and efficacy in older patients to optimize personalized treatment strategies.