Updated Analysis of Ocrelizumab’s Safety

NEW ORLEANS—The safety profile of ocrelizumab in ongoing open-label extension studies in relapsing multiple sclerosis (MS) and primary progressive MS is generally consistent with that observed in controlled clinical trials, according to a report presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). “A slight increase in the rate of serious infections was observed in patients with relapsing MS beyond two years, but the rates remained low,” reported Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel in Switzerland, and colleagues. “This was not observed in patients with primary progressive MS, and additional exposure data are needed to determine if the risk increases with further dosing,” the researchers said. “Incidence rates of malignancies and breast cancer observed with ocrelizumab treatment in MS remain within the range of epidemiologic background data.”

Ludwig Kappos, MD

The safety and efficacy of ocrelizumab previously have been characterized in a phase II study in patients with relapsing-remitting MS and in phase III studies in patients with relapsing MS (OPERA I and OPERA II) and in patients with primary progressive MS (ORATORIO). Results from these trials showed that ocrelizumab reduced clinical and MRI evidence of disease activity, compared with placebo and interferon beta-1a. The most common adverse events associated with ocrelizumab during the double-blind periods of the phase III trials included infusion-related reactions, nasopharyngitis, upper respiratory tract infections, headache, and urinary tract infections. During the double-blind treatment period in the phase III trials in relapsing MS, serious adverse events, serious infections, and malignancies were reported in 6.9%, 1.3%, and 0.5% of ocrelizumab-treated patients, respectively (vs 8.7%, 2.9%, and 0.2% of patients treated with interferon beta-1a). In the phase III trial in primary progressive MS, these events were reported in 20.4%, 6.2%, and 2.3% of ocrelizumab-treated patients (vs 22.2%, 5.9%, and 0.8% of patients who received placebo). Across studies, few patients who received ocrelizumab (in the range of 2% to 4%) had adverse event–related treatment withdrawals.

At the CMSC annual meeting, data from controlled and open-label extension periods of the clinical trials of ocrelizumab in relapsing MS and primary progressive MS were presented.

Upon completion of a double-blind treatment period, patients from all studies were eligible to enter a long-term open-label extension in which they received ocrelizumab treatment. Safety analyses were based on integrated data from the phase II and phase III studies. The primary analysis was based on the clinical cutoff dates of the individual studies (phase II, January 22, 2015; OPERA I, April 2, 2015; OPERA II, May 12, 2015; ORATORIO, July 24, 2015). The present updated analysis includes all patients who received one or more dose of ocrelizumab during the controlled or open-label periods of the phase II and phase III studies (ie, the ocrelizumab all-exposure population) as of January 20, 2016. Additional data cutoffs of June 30, 2016, and September 15, 2016, were presented for malignancies to demonstrate changes with increasing ocrelizumab exposure.

The ocrelizumab all-exposure group included 2,279 patients. Patients’ mean age was 40.1, and 61.3% were female. Time since MS symptom onset was 6.67 years, and time since MS diagnosis was 3.66 years.

Overall Adverse Events

As of January 20, 2016, the majority (81%) of patients who received ocrelizumab experienced at least one adverse event, corresponding to a rate of 242 events per 100 patient-years. The most common adverse events included nasopharyngitis, upper respiratory tract infection, urinary tract infection, infusion-related reactions, and headache. Serious adverse events were reported in 12% of patients, corresponding to 6.97 events per 100 patient-years, and most commonly included infections. Treatment withdrawal because of an adverse event occurred in 3.3% of patients (rate, 1.40 per 100 patient-years) and primarily included infusion-related reactions (0.9%) and events coded as neoplasms (0.6%) or infections (0.4%).

Infections

As of January 20, 2016, 56.9% of the ocrelizumab all-exposure population reported one or more infection with ocrelizumab, corresponding to a rate of 73.6 per 100 patient-years. “These findings are consistent with the 75.6 rate observed at the primary analysis cutoff date,” the researchers reported. Infections were reported at the highest rate following the first dose and declined with subsequent dosing. Infections reported in 5% or more of patients included nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, and influenza. In the ocrelizumab all-exposure population, the rate per 100 patient-years of serious infections (1.80) as of January 20, 2016, was comparable with the rate at the primary analysis cutoff date (1.74). Data for the pooled relapsing MS population showed a slight increase in the rate per 100 patient-years of serious infections (1.45) as of January 20, 2016, compared with the rate at the primary analysis cutoff date (1.08); “however, rates remained low, and further exposure is needed to make any interpretation,” the researchers said.

Among patients with primary progressive MS, the rate per 100 patient-years of serious infections remained stable (2.74) as of January 20, 2016, compared with the rate at the primary analysis cutoff date (2.97). The most common serious infection reported was pneumonia. No infections were identified as opportunistic in nature.

Malignancies

In the MS clinical trial program, an imbalance in the crude incidence of malignancies was observed between the ocrelizumab- and comparator-treated patients, which was associated with a cluster of breast cancer events in the ocrelizumab group. Over time, the crude incidence rate of malignancy per 100 patient-years in the ocrelizumab all-exposure population fluctuated but remained within the epidemiologic range of patients with MS. An observed change in the crude incidence rate of malignancy from June to September is attributed to the crude incidence rate of non-melanoma skin cancer, which increased from 0.090 at the primary analysis cutoff date to 0.145 at the September 15, 2016, data cutoff, due to six new cases of basal cell carcinoma. The crude incidence rate of breast cancer remained stable through the September 15, 2016, data cutoff.

More Recent Developments

In late May 2017, Genentech, the maker of ocrelizumab, notified physicians of the first case of progressive multifocal leukoencephalopathy (PML) in a patient taking ocrelizumab. The case occurred in a JCV-positive patient in Germany who stopped taking natalizumab in February after being on the drug for three years, and received the first dose of ocrelizumab in April. It is unclear whether the PML stemmed from the prior natalizumab treatment or if the switch to ocrelizumab played a role.

—Glenn S. Williams