Objective: To report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings.

Methods: Safety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections and malignancies were contextualized using multiple epidemiologic sources.

Results: At data cut-off (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient years [PY] of exposure) in clinical trials. Rates per 100 PY (95% CI) of AEs (248; 246–251), serious AEs (7.3; 7.0–7.7), infusion-related reactions (25.9; 25.1–26.6), and infections (76.2; 74.9–77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including serious infections (2.01; 1.81–2.23) and malignancies (0.46; 0.37–0.57), were consistent with the ranges reported in epidemiologic data.

Conclusion: Continuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns in a heterogeneous MS population.

Classification of Evidence: This analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.

Table e-1 - Overview of study designs

Table e-2 - Patients with AEs leading to treatment discontinuation in the OCR all-exposure population^a

Table e-3 - Patients with clinically relevant abnormalities in laboratory values in the phase 3 studies

Table e-4 - NK cell counts during the CTP of the phase 3 studies

Table e-5 - Details of confirmed PML cases outside the clinical trials setting

Table e-6 - Description of serious infections associated with IgG levels < LLN

Table e-7 - Details of breast cancer cases reported in the OCR all-exposure population

Figure e-1 - Change in CD4⁺ and CD8⁺ T cell levels in OPERA and ORATORIO

Figure e-2 - Change in serum IgA and IgM levels in OPERA and ORATORIO