A formulation of ofatumumab (brand name Arzerra) to be injected under the skin (subcutaneous) was found to be safe and effective in the treatment of relapsing-remitting multiple sclerosis (RRMS), even when given at lower doses compared with Arzerra, which is administered intravenously, according to the results of a Phase 2 trial.
Besides offering the possibility of self-administration by the patient, treatment with subcutaneous ofatumumab was seen to effectively reduce the number of brain lesions without leading to severe depletion of immune B-cells, one of the consequences of treatment with intravenous Arzerra.
The study reporting the findings is titled “Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis — The MIRROR study,” and was published in the journal Neurology.
Ofatumumab is a human monoclonal antibody targeting the CD20 molecule, which is found on the surface of B-cells or lymphocytes — key cells of the immune system also implicated in the development of multiple sclerosis.
Arzerra is currently the only approved ofatumumab formulation, indicated for the treatment of chronic lymphocytic leukemia (CLL), a blood cancer that typically develops in B-cells.
By targeting CD20, ofatumumab is able to direct the body’s immune system to fight both normal and cancerous B-cells. The medication is marketed and developed by the Danish biotech company Genmab, under a development and commercialization agreement with Novartis.
The new subcutaneous formulation of ofatumumab showed promising effects in the treatment of RRMS in preclinical studies of animal models.
That, together with positive safety and toxicity data obtained in Phase 1 trials, prompted the launching of a larger Phase 2 study, called MIRROR (NCT01457924), to evaluate the effectiveness and safety of subcutaneous ofatumumab for the treatment of people with RRMS.
The Phase 2 trial was completed in 2013, and top-line results demonstrated a significant reduction in the cumulative number of new brain lesions, according to a Genmab statement.
Now, results on the effectiveness of the drug and its impact on B-cell depletion and repletion over 48 weeks were published.
The study was a multicenter, double-blind, placebo-controlled trial that included 232 RRMS patients. To assess the dose-response effects of the drug, participants were randomized to one of five treatment groups: placebo; ofatumumab 3 mg every 12 weeks; ofatumumab 30 mg every 12 weeks; ofatumumab 60 mg every 12 weeks; or ofatumumab 60 mg every four weeks.
The study’s primary endpoint was the number of new brain gadolinium-enhancing lesions — a contrast-enhanced magnetic resonance imaging method, sensitive for detecting the inflammatory lesions typical of RRMS — assessed at week 12 of treatment.
During treatment, relapses, tolerability, and B-cell counts were measured. Safety monitoring and B-cell repletion were also assessed.
Treatment with subcutaneous ofatumumab significantly reduced the cumulative number of new lesions in patients by 65% for all ofatumumab dose groups, compared with placebo.
Using a similar analysis to that used in earlier studies testing other anti-CD20 antibodies (Rituximab and Ocrevus), researchers estimated that patients receiving a total dose of subcutaneous ofatumumab equal or superior to 30 mg in 12 weeks had a 90% or higher reduction in the number of brain lesions.
Notably, results show that complete B-cell depletion was not necessary for a robust treatment effect, and that an effective reduction of lesions could be achieved at lower doses compared with intravenous ofatumumab.
In addition, no new or unexpected safety findings occurred up to 48 weeks after starting the treatment. The most common adverse event was injection-related reactions (52% in the ofatumumab group and 15% in the placebo group) of mild to moderate severity in 97% of the cases.
“Overall, this study demonstrates that ofatumumab has a high capacity to suppress new brain MRI lesions with subcutaneous administration at considerably lower (and incompletely B-cell depleting) doses compared with those previously studied in patients with MS,” researchers wrote.
“It remains to be seen whether the less profound depletion and faster repletion of B cells achieved with ofatumumab will also translate into a more favorable safety profile,” the team added.