Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis

Abstract

Background and objectives: 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 (SIs) and malignancies were contextualized using multiple epidemiologic sources.

Results: At data cutoff (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% confidence interval) 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 SIs (2.01; 1.81-2.23) and malignancies (0.46; 0.37-0.57), were consistent with the ranges reported in epidemiologic data.

Discussion: 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.

Figure 1. Safety Analyses Populations: Clinical Trials Overview and Patient Exposure as of January 2020

(A) Clinical trials overview and patient exposure. (B) Populations used in the analysis to report different clinical and laboratory safety assessments. Data cutoff: January 2020. Patients received ocrelizumab (OCR) 600 mg by IV infusion every 24 weeks, with the first dose split into two 300 mg infusions given 14 days apart. The exceptions were the controlled treatment period (CTP) of ORATORIO, where all doses were given as split 300 mg infusions, and the phase 2 trial, where in 1 treatment arm the first dose was split into two 1,000 mg infusions administered 14 days apart followed by another 1,000 mg dose at week 24. Prior to each infusion, patients were pretreated with IV 100 mg methylprednisolone (or equivalent), an IV or oral antihistamine, and an optional analgesic/antipyretic. The term “OCR all-exposure” is used to describe the overall clinical trial patient population, whereas the term “phase 3 CTP + open-label extension (OLE)” refers to the patient population from the pivotal phase 3 trials (OPERA 1, OPERA 2, and ORATORIO) and respective OLEs. Boxes are color-coded according to the populations used for respective safety measures, laboratory measures, and immunoglobulin, T cell, and antidrug antibody level measures. ^aPhase 2.^{3 b}OPERA 1 and OPERA 2.^{4 c}ORATORIO.^{5 d}LIBERTO is the long-term extension study to CASTING, ENSEMBLE, and CONSONANCE. As of January 2020, only patients from CASTING were included in LIBERTO (n = 439; patient-years [PY] = 1,155). ALC = absolute lymphocyte count; CTP = controlled treatment period; NK = natural killer; PMS = progressive multiple sclerosis; PPMS = primary progressive multiple sclerosis; RMS = relapsing multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis.

Figure 2. Change in Serum Immunoglobulin G (IgG) Levels and CD3⁺ T-Cell Levels Through Controlled Treatment Period (CTP) and Open-Label Extension (OLE) Period of the Phase 3 Studies

Data cutoff: January 2020. Change in serum levels of IgG from baseline (BL) through the CTP and OLE periods of the pooled OPERA studies (A) and the ORATORIO study (B). Change in CD3⁺ T-cell levels from BL through the CTP and OLE periods of the pooled OPERA studies (C) and the ORATORIO study (D). Data on proportion of patients with immunoglobulin (Ig) levels < lower limit of normal (LLN) shown only until week 312, as data at week 336 are not mature. Data at week 336 on change in T-cell levels are not shown as data are not mature. The proportion of patients randomized to ocrelizumab (OCR) in the OPERA population with IgG levels < LLN was 1.5% at week 96% and 7.7% at week 312 (OCR/OCR data). Similarly, the proportion of patients randomized to OCR in the ORATORIO population with IgG levels < LLN was 1.1% at week 120 and 5.1% at week 312 (OCR/OCR data). ^aIn patients treated with interferon (IFN), an increase in serum IgG levels was observed over a 2-year period. This is consistent with previous findings from other groups. CD = cluster of differentiation; CI = confidence interval; PBO = placebo; RMS = relapsing multiple sclerosis.

Figure 3. Rate of Serious Infections Over 7 years and Association With Immunoglobulin Levels

Data cutoff: January 2020. (A) Yearly rates of serious infections (SIs) in patients with relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS) treated with ocrelizumab (OCR) for a period of up to 7 years, during the controlled treatment period (CTP) and associated open-label extension (OLE) periods of the phase 2 and phase 3 studies, including patients originally randomized to comparator (interferon [IFN]-β-1a or placebo [PBO]) who switched to open-label OCR treatment, plus VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE (PPMS all-exposure only), and LIBERTO (n = 5,680; 18,218 patient-years [PY]). Yearly rates of SIs of patients who received PBO (gray) or IFN-β-1a (purple) during the CTPs are displayed. Due to the event-driven design of ORATORIO, some patients remained on PBO for up to 4 years. (B) Rates of SIs associated with immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) values above or below the respective lower limit of normal (LLN) in patients who received any dose of OCR during the CTP and associated OLE periods of the phase 3 trials (OPERA 1, OPERA 2, and ORATORIO). CI = confidence interval.

Figure 4. Yearly Crude Incidence Rates of all Malignancies and Female Breast Cancer in Ocrelizumab (OCR) All-Exposure Population

Data cutoff: January 2020. Includes patients who received any dose of OCR during the controlled treatment period (CTP) and associated open-label extension (OLE) periods of the phase 2 and phase 3 studies, including patients originally randomized to comparator (interferon [IFN]-β-1a or placebo) who switched to open-label OCR treatment, plus VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. (A) Crude incidence rates of all malignancies from years 1–7, including nonmelanoma skin cancer (NMSC). Crude incidence rate of all malignancies (including NMSC) in the OCR all-exposure population, as of January 2020: 0.46 (0.37–0.57). (B) Crude incidence rates of female breast cancer from years 1–7. Data on yearly crude incidence rates of all malignancies and female breast cancer shown until year 7. Year 7 data are not mature due to limited exposure (543 patient-years [PY] for female breast cancer). AE = adverse event; CI = confidence interval.

Figure 5. Cumulative Standardized Incidence Rates of Malignancies and Comparison With Danish Multiple Sclerosis (MS) Registry and Surveillance, Epidemiology, and End Result (SEER) Database

^aStandardized incidence rates per 100 patient-years (PY) (95% confidence interval [CI]) were derived using a direct standardization method that applies age–sex specific rates to the US population (2010 census), with restriction to the age range of the MS clinical trials (15–59 years). For all malignancies, cases of nonmelanoma skin cancer (NMSC) were excluded from the ocrelizumab (OCR) all-exposure population and from the Danish MS registry to allow a comparison with the SEER database. ^bThe standardized incidence ratio (SIR) (95% CI for Poisson distribution) was calculated as observed number of events/expected number of events. For “OCR-comparison” SIR, SEER database and the Danish MS registry were used as reference populations. For “Danish-comparison” SIR, SEER database was used as reference population. ^cOCR all-exposure population: data represent the follow-up of 5,680 patients covering a period of approximately 7 years (up to January 2020). ^dDanish MS registry: data represent the follow-up of approximately 10,000 patients from 1995 to 2015.^{44 e}SEER database: data cover approximately 27.8% of the US population (based on 2010 census) from 2000 to 2016 (available at: seer.cancer.gov).