Ofatumumab is an antibody against a protein called CD20, which is found on the surface of certain types of immune cells called B-cells. It being investigated as a treatment for relapsing-remitting multiple sclerosis (RRMS).

Ofatumumab was developed by Danish biotech company Genmab under a co-development and commercialization agreement with Novartis. It is approved by the U.S. Food and Drug Administration (FDA) under the brand name Arzerra to treat chronic lymphocytic leukemia. Besides RRMS, clinical trials are ongoing into its potential to treat other diseases, such as follicular lymphoma.

How does ofatumumab work?

Multiple sclerosis (MS) is an autoimmune disease where the body’s immune system mistakenly attacks and damages the myelin sheath, a protective protein layer that insulates nerve fibers.

The exact mode of action by which ofatumumab alters relapse and remission in MS is still uncertain. Researchers know that the treatment targets B-cells by binding to the CD20 protein found on their surface. It is believed that this leads to a decrease in the number of these immune cells that attack the myelin sheath. 

Ofatumumab in clinical trials

Preclinical studies in animal models produced promising results, which helped developers proceed to Phase 1 clinical trials in healthy volunteers to test the safety of ofatumumab. With positive safety and toxicity findings from these trials, the companies moved forward to Phase 2 and 3 trials.

A pilot Phase 2 trial (NCT00640328) with a small group of 38 RRMS patients was carried out in 2011, testing different doses of ofatumumab for 48 weeks. A considerable reduction in the formation of brain plaques was seen, along with lower numbers of autoimmune B-cells. New plaque formation also appeared to be suppressed. These results were published in the scientific journal Neurology.

These findings paved the way for a second larger, multicenter, double-blind, placebo-controlled Phase 2 trial (NCT01457924) called MIRROR with 232 RRMS patients. Participants were randomized to one of five treatment groups: placebo, 3 mg of ofatumumab every 12 weeks, 30 mg of ofatumumab every 12 weeks, 60 mg of ofatumumab every 12 weeks, or 60 mg of ofatumumab every four weeks. All participants continued in the study for 24 weeks and until B-cell depletion (or destruction).

Results showed that ofatumumab was able to deplete B-cells quickly, depending on the dose and how often it was given, and effectively reduced the formation of new brain plaques relative to placebo. No new or unexpected safety findings were recorded.

Two randomized, double-blind Phase 3 studies, ASCLEPIOS I (NCT02792218) and ASCLEPIOS II (NCT02792231), compared the efficacy and safety of ofatumumab injected under the skin against Aubagio (teriflunomide), an approved MS treatment, in 1,881 RRMS patients. Participants received either ofatumumab every four weeks or Aubagio once daily.

The study assessed the number of confirmed relapses in 12 months, recorded for up to 2.5 years. The disability worsening showed a risk reduction of 34.4% at three months, and 32.5% at six months with ofatumumab, compared with Aubagio. Disability improvement at six months also showed a favorable trend for ofatumumab, but the results were not statistically significant.

Ofatumumab treatment led to a 97.5% relative reduction in the number of T1 lesions in ASCLEPIOS I, and 93.8% in ASCLEPIOS II, compared with Aubagio. These findings led the researchers to conclude that ofatumumab treatment is superior to Aubagio in treating RRMS.

Adverse events occurred in 83.6% of patients on ofatumumab, and in 84.2% of patients receiving Aubagio. There were no significant differences between the two groups in regards to the rate of infections (2.5% with ofatumumab vs. 1.8% with Aubagio) or malignancies (0.5% with ofatumumab vs. 0.3% with Aubagio).

A Phase 3 clinical trial (NCT03650114) is now planned to assess the long-term safety, tolerability, effectiveness, and health outcomes of ofatumumab treatment in patients who participated in a previous study. It is currently recruiting patients at various locations across the world.

The trial will also include a sub-study to evaluate the antibody response to selected vaccines in eligible patients with RRMS. Because ofatumumab leads to B-cell depletion, it can affect patients’ response to vaccinations. Vaccination is not recommended during or shortly after ofatumumab treatment, as it poses a high risk of infection. 

 

Last updated: Nov. 27, 2019

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