Clinical trial
Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies

https://doi.org/10.1016/j.msard.2019.01.044Get rights and content

Highlights

  • IRRs were common in the ocrelizumab clinical trials.

  • Most IRRs were mild to moderate in severity.

  • IRRs were most frequent with the first infusion and decreased subsequently.

  • Nearly all patients received 100-mg (or equivalent) methylprednisolone infusions.

  • Additional pretreatment, especially with antihistamines, reduced IRR frequency.

Abstract

Background

Ocrelizumab is an infusible humanized monoclonal antibody that selectively depletes CD20+ B cells. Infusion-related reactions (IRRs) were summarized from the OPERA I, OPERA II, and ORATORIO trials for relapsing and primary progressive multiple sclerosis (MS).

Methods

OPERA I and OPERA II were identical, randomized, double-blind, active-controlled trials that enrolled patients with relapsing MS (RMS). Patients in the ocrelizumab group initially received two 300-mg intravenous (IV) infusions separated by 14 days (on Days 1 and 15); subsequent doses were administered as single 600-mg IV infusions. Ocrelizumab-treated patients also received subcutaneous (SC) placebo injections 3 times weekly. Patients in the active comparator group received SC injections of IFN β-1a 3 times weekly, as well as placebo infusions on Days 1 and 15 and Weeks 24, 48, and 72. ORATORIO was a randomized, parallel-group, double-blind, placebo-controlled study that enrolled patients with primary progressive MS (PPMS). As in the OPERA studies, patients in the ocrelizumab group initially received two 300-mg infusions separated by 14 days; however, ORATORIO patients continued to receive this divided-dose regimen throughout the study. The ORATORIO control group received IV placebo. Prior to each infusion, all patients in the OPERA and ORATORIO studies were pretreated with 100 mg IV methylprednisolone; additional prophylactic treatment with analgesics, antipyretics, and/or an IV or oral antihistamine was optional. IRRs were defined as adverse events that occurred during or within 24 h of IV infusion of ocrelizumab or placebo.

Results

Safety analyses included 1651 patients with RMS from OPERA I and OPERA II (ocrelizumab, n = 825; IFN β-1a, n = 826) and 725 patients with PPMS from ORATORIO (ocrelizumab, n = 486; placebo, n = 239). Across studies, IRRs were reported in 34.3% (vs 9.7% with IFN β-1a) and 39.9% (vs 25.5% with placebo) of ocrelizumab-treated patients in the pooled OPERA and ORATORIO populations, respectively. The majority of IRRs were mild to moderate in the OPERA (ocrelizumab, 92.6%; IFN β-1a, 98.8%) and ORATORIO (ocrelizumab, 96.9%; placebo, 93.4%) studies. IRRs most commonly occurred with the first infusion. Severe IRRs were reported in 2.4% of ocrelizumab-treated patients in the OPERA studies (vs 0.1% with IFN β-1a) and 1.2% of ocrelizumab-treated patients in ORATORIO (vs 1.7% with placebo). Two serious IRRs occurred across the OPERA studies, both of which occurred with the initial infusion. The first event occurred in an IFN β-1a-treated patient in association with the initial infusion of IV placebo and consisted of severe balance disorder, dizziness, flushing, and hypoesthesia. The second event was a life-threatening reaction (bronchospasm) that occurred in an ocrelizumab-treated patient 15 min after the infusion started. Frequently reported IRR symptoms included pruritus, rash, throat irritation, and flushing. Premedication use, particularly antihistamines, was associated with fewer IRRs.

Conclusion

Findings from the OPERA I, OPERA II, and ORATORIO trials show that IRRs were the most frequently reported adverse events with ocrelizumab, were mostly mild to moderate in severity, were reduced with appropriate pretreatment, and decreased with subsequent dosing. IRRs that did occur were effectively managed through infusion rate adjustment and symptomatic treatment.

Introduction

Infusion-related reactions (IRRs) are frequently observed with the administration of monoclonal antibody (mAb) treatment. Several pathogenic mechanisms have been proposed for mAb-associated IRRs, including cytokine release syndrome and immunoglobulin E- and immunoglobulin G-mediated hypersensitivity reactions (Maggi et al., 2011, Picard and Galvao, 2017). Massive cytokine release is thought to occur as a result of complement-mediated lysis triggered by the binding of the mAb to the target cell (Maggi et al., 2011). Hypersensitivity reactions can occur throughout the course of treatment and can produce anaphylaxis or anaphylaxis-like reactions (Maggi et al., 2011, Brown and Torabi, 2011). In most cases, however, IRRs are unlikely to be driven by hypersensitivity, as evidenced by the decrease in IRR frequency with subsequent infusions, reduction and/or elimination of symptoms with premedication, and infusion rate adjustments (Brown and Torabi, 2011). Typically, IRRs occur during or within a few hours of infusion, although symptoms may be delayed for up to 24 h and may vary in severity (Lenz, 2007).

Ocrelizumab, an infusible humanized mAb that selectively depletes CD20+ B cells, is approved by the US Food and Drug Administration for the treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) (US Food and Drug Administration, 2017) and by the European Commission for RMS and early PPMS (F. Hoffmann-La Roche Ltd, 2018). Results from phase 3 studies in either RMS (OPERA I [NCT01247324], OPERA II [NCT01412333]) (Hauser et al., 2017) or PPMS (ORATORIO [NCT01194570]) (Montalban et al., 2017) showed that ocrelizumab was effective at reducing clinical and magnetic resonance imaging activity compared with interferon beta-1a (IFN β-1a) and placebo (Hauser et al., 2017, Montalban et al., 2017). Similar to findings from clinical trials of other mAb treatments (Cohen et al., 2012, Rudick et al., 2006), IRRs were among the most common adverse events (AEs) reported with ocrelizumab in the OPERA I, OPERA II, and ORATORIO trials (Hauser et al., 2017, Montalban et al., 2017). An understanding of the overall infusion experience in ocrelizumab-treated patients can help to reduce the occurrence and impact of IRRs and optimize patient outcomes.

Section snippets

Phase 3 study designs and ocrelizumab dosing regimen

Details of the OPERA I, OPERA II, and ORATORIO study designs were previously described and are summarized in Fig. 1a (Hauser et al., 2017; Montalban et al., 2017). Briefly, patients were assigned to receive ocrelizumab 600 mg via IV infusion every 24 weeks. In OPERA, the initial ocrelizumab dose was administered as two 300-mg infusions separated by 14 days, followed by single 600-mg infusions thereafter, whereas in ORATORIO ocrelizumab was consistently administered as a divided dose separated

Overview of IRRs

Safety analyses included 1651 patients with RMS from OPERA I and OPERA II (Hauser et al., 2017) who received up to 5 infusions and 725 patients with PPMS from ORATORIO (Montalban et al., 2017) who received 10–12 infusions. An overall summary of the most frequent IRRs is shown in Table 1.

The majority of IRRs were mild to moderate in both the OPERA (ocrelizumab, 92.6%; IFN β-1a, 98.8%) and ORATORIO (ocrelizumab, 96.9%; placebo, 93.4%) studies. Severe IRRs were reported in 2.4% of

Summary of ocrelizumab experience

In the phase 3 trials of ocrelizumab in patients with RMS and PPMS, IRRs were among the most common AEs. The majority of events occurred during the infusion and were primarily mild to moderate; 1 life-threatening IRR (bronchospasm) occurred in an ocrelizumab-treated patient, which resolved on the same day after appropriate treatment. In addition, IRRs were most common with the first dose and decreased in frequency with subsequent doses over time.

Across trials, the initial dose of ocrelizumab

Conclusions

Findings from the OPERA I, OPERA II, and ORATORIO trials showed that IRRs were the most frequently reported AEs with ocrelizumab and were commonly mild to moderate. The frequency of IRRs was highest with the first dose and decreased with subsequent infusions. Prophylaxis reduced the likelihood of IRRs, and few patients were discontinued from the study due to IRRs. IRRs were effectively managed through infusion rate adjustment and symptomatic treatment.

Experience is currently lacking to evaluate

Data sharing statement

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Acknowledgments

Editorial assistance was provided by Liz LaFlamme and Angela Morris of Health Interactions, Inc.

Funding

This work was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Conflict of interest disclosures

L Mayer has received consulting fees from Biogen, Genentech, Inc., Genzyme and Novartis.

L Kappos’ institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards for trials sponsored by Actelion, Addex, Almirall, Bayer HealthCare Pharmaceuticals, CLC Behring, F. Hoffmann-La Roche Ltd and Genentech,

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