Infection Risk Higher for Ocrevus Than Rituximab, But Cancer Risk Lower

Ocrevus (ocrelizumab), a second-generation anti-CD20 antibody, may be associated with a greater risk of infections. But it carries a lower risk of cancer and immune reactions than first-generation rituximab in people with multiple sclerosis (MS), according to a real-life study.

The higher incidence of infections linked with Ocrevus’ use may result from a potentially different or more extensive depletion of B-cells — the immune system target of anti-CD20 therapies — compared with rituximab, its researchers noted.

Future studies are needed to clarify this, and to better understand the safety differences between these therapies and other second-generation anti-CD20 antibodies, such as Novartis’ recently approved Kesimpta (ofatumumab).

The study, “Adverse event profile differences between rituximab and ocrelizumab: Findings from the FDA Adverse Event Reporting Database,” was published in the Multiple Sclerosis Journal.

B-cells, a type of immune cell that drives inflammation and immune attacks against myelin in MS, are a target of several MS therapies, including those based on antibodies against the CD20 protein found on the surface of B-cells.

While not approved for MS itself, rituximab was the first anti-CD20 antibody used to treat people with the disorder. It is marketed as Rituxan (by Biogen) in the U.S., Canada and Japan, and as MabThera (by Roche’s subsidiary Genentech) in Europe, with other brand names used elsewhere.

Ocrevus, developed by Genentech, is a second-generation anti-CD20 antibody approved for the treatment of primary progressive MS (PPMS) and relapsing MS.

Second-generation anti-CD20 therapies were designed to have lower immunogenicity (the capacity to promote immune reactions against them), and greater effectiveness and tolerability over first-generation treatments.

While the safety and effectiveness of rituximab and Ocrevus in MS patients have been evaluated in several Phase 2 and 3 clinical trials, “their real-world safety profile has not been adequately compared,” the researchers wrote.

A research team in the U.S. set out to compare the safety profile of rituximab and Ocrevus in a real-world setting, using the FDA Adverse Event Reporting System (FAERS) database.

FAERS contains adverse event and medication error reports submitted by healthcare professionals, consumers, and manufacturers. The database is designed to support the FDA’s post-marketing safety surveillance program for therapies.

Although most reports submitted are from the U.S., any country can participate. Each report can include more than one adverse event or side effect, and each is classified automatically into an adverse event category.

The researchers analyzed all eligible reports concerning rituximab and Ocrevus when used as a treatment for MS from 1968 through September 2019.

A total of 623 adverse event reports were filed with rituximab (including 321 unique side effects), and 7,948 with Ocrevus (including 1,271 unique side effects) over this time period.

Patients in rituximab reports were significantly younger (mean age, 43.89 ) than in Ocrevus reports (mean age, 48.76).

Results showed significant differences between each therapy’s adverse event profiles.

Ocrevus was associated with a statistically significant, nearly two times higher, proportion of infections compared with rituximab — 21.93% vs. 11.05% in the rituximab group.

In agreement, urinary tract infections (10.52%) were the most commonly reported adverse event with Ocrevus’ use, and oral herpes showed the highest Ocrevus-adverse event association.

The researchers noted that this higher incidence of infections with Ocrevus was consistent with previous findings, and may be due to a potentially different or more robust B-cell depletion, leading to more profound immunosuppression.

Rituximab was associated with a significantly higher — three times higher — percentage of cancer (4.02% vs. 1.28% in the Ocrevus group) and blood- and lymphatic system-associated adverse events (2.86% vs. 0.91%). A twofold higher proportion of immune-related side effects were also observed in the rituximab group  (2.66%) compared with Ocrevus (1.12%).

The higher number of cancer-related adverse events reported with rituximab “may be partially explained due to over-reporting, although these findings warrant further evaluation in the context of cancer epidemiology,” the researchers wrote.

Infusion-related reactions (4.82%) were the most common adverse events reported with rituximab, and itchy ears showed the therapy’s strongest association with an adverse event.

Rituximab was also associated with a significantly higher proportion of reported serious adverse events (64.8% vs. 56.3% with Ocrevus), and those resulting in death (5.7% vs. 2.1% with Ocrevus).

Researchers noted, however, that the rates of adverse events linked to each therapy were likely to be higher than those reported in FAERS.  Results from this study also may not be generalized, since most adverse events were reported in the U.S.

In addition, “it is possible that [some] AEs [adverse events] associated with rituximab were not reported to the FDA, as it was not an FDA-approved medication,” the team wrote.

The researchers emphasized that further studies are needed to explore and further characterize differences in the adverse event profiles of B-cell-targeting therapies for MS.