Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III program

Abstract

Objective: The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA).

Methods: This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented.

Results: Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3-4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, -1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03-3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups.

Conclusions: In placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX.

Trial registration: STAGE ClinicalTrials.gov NCT00406419 SCRIPT ClinicalTrials.gov NCT00476996 FILM ClinicalTrials.gov NCT00485589 FEATURE ClinicalTrials.gov NCT00673920.

Conflict of interest statement

Competing Interests: This study was funded by F. Hoffmann-La Roche, the employer of Carmen Martin, Laurie Millar, Helen Travers, and Elena Fisheleva. Helen Travers holds stock in Roche. PE has provided expert advice and undertaken clinical trials for Pfizer, Merck Sharpe Dome, Abbvie, UCB, Roche, BMS and Novartis. WR has served as a consultant for Roche. PPT has served as a consultant for Roche/Genentech and became an employee of GlaxoSmithKline after completion of this work. TD has served as a consultant for Roche and has received speakers' bureau honoraria from Roche. EO has received research funding from Abbvie, Genentech, Pfizer, UCB and Vertex, consultancy fees from Abbvie, Crescendo, Genentech, Janssen, Pfizer and UCB, and speakers' bureau honoraria from Abbvie, Crescendo and UCB. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Patient disposition flow diagram of pooled safety population.

Figure 2. Rates of serious infectious events (SIEs) in the double-blind, placebo-controlled periods.

Multiple occurrences of the same event in one individual were counted multiple times. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo; pt-yrs, patient-years.

Figure 3. Fixed-effects meta-analysis of incidence rate differences in serious infectious events (SIEs).

(A) OCR200+MTX; (B) OCR500+MTX. The pooled rate difference accounts for study and is weighted according to the inverse of the estimated variance. These analyses are based on patients with at least one event (does not count all events). Zero indicates no difference, and a positive value indicates that ocrelizumab (OCR) is worse. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo.

Figure 4. Rates of serious infectious events (SIEs) by region.

(A) STAGE; (B) SCRIPT; (C) FILM. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo. “Asia” includes China, Hong Kong, Indonesia, Malaysia, Philippines, Republic of Korea, Singapore, Taiwan, Thailand and Japan; “Other” includes North and South America, Europe and South Africa.

Figure 5. Cumulative probability of B-cell repletion in each clinical trial.

(A) STAGE; (B) SCRIPT; (C) FEATURE and (D) FILM. B-cell repletion was defined as a return of CD19+ levels to baseline or 80 cells/µL, whichever was lower. Data summarized under the PBO/OL OCR500+MTX, OCR200/OL OCR500+MTX and OCR500/OL OCR500+MTX treatment groups are OL data only. The x-axis represents the number of weeks since the first infusion of the last course of OCR. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; OL, open-label; PBO, placebo.