Two phase 3 clinical trials showing impressive results with the new subcutaneously-delivered, B-cell depleting multiple sclerosis anti-CD20 mononclonal antibody ofatumumab (Arzerra) have now been published in The New England Journal of Medicine.
The ASCLEPIOS I and II clinical trials were first presented, and reported by Medscape Medical News, at last year’s European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting.
Ofatumumab is currently available for the treatment of chronic lymphocytic leukemia. Approval applications for its use in MS are under review by the US Food and Drug Administration, the company notes, “with an action expected by September 2020.”
The drug will provide competition for ocrelizumab (Ocrevus), the first B-cell depleting anti-CD20 drug approved for MS, which became available in 2017.
The main difference between the two products is the route of administration. Ocrelizumab is given as an IV infusion every 6 months, which requires medical supervision; by contrast, ofatumumab is administered by monthly subcutaneous injection, which can be done by the patient at home.
The ASCLEPIOS I and II trials were led by Stephen Hauser, MD, University of California San Francisco, and Ludwig Kappos, MD, University Hospital, Basel, Switzerland.
In the two double-blind, double-dummy, randomized ASCLEPIOS trials, a total of 946 patients were assigned to receive ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) and 936 to receive oral teriflunomide (14 mg daily) for up to 30 months.
After a median follow-up of 1.6 years, the primary outcome (annualized relapse rates) were 0.11 in the ofatumumab group vs 0.22 in the teriflunomide group in trial 1 (P < .001) and 0.10 vs 0.25 in trial 2 (P < .001).
In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15% with teriflunomide (hazard ratio [HR], 0.66; P = .002). Disability worsening confirmed at 6 months occurred in 8.1% of ofatumumab patients vs 12% of those on teriflunomide (HR, 0.68; P = .01), and disability improvement confirmed at 6 months was seen in 11% of the ofatumumab group vs 8.1% of the teriflunomide group (HR, 1.35; P = .09).
In ASCLEPIOS I, the mean number of gadolinium-enhancing lesions per T1-weighted MRI scan was 0.01 with ofatumumab and 0.45 with teriflunomide (97% lower number of lesions with ofatumumab, P < .001); in ASCLEPIOS II, the corresponding numbers were 0.03 and 0.51, respectively (94% lower with ofatumumab, P < .001).
The mean number of new or enlarging lesions per year on T2-weighted MRI was 0.72 with ofatumumab and 4.00 with teriflunomide in the first trial (82% lower number of lesions with ofatumumab, P < .001); corresponding values in ASCLEPIOS II were 0.64 and 4.15, respectively (85% lower with ofatumumab, P < .001).
Serum neurofilament light chain concentration was lower in the ofatumumab group than in the teriflunomide group by 7% at month 3, by 27% at month 12, and by 23% at month 24 in ASCLEPIOS I. Corresponding differences in ASCLEPIOS II were 11%, 26%, and 24%.
However, despite greater reductions in neurofilament light chain concentrations with ofatumumab, change in brain volume did not differ significantly between the two treatments. “This discrepancy between two markers of tissue damage needs further analysis,” the authors say.
Adverse events were reported by similar numbers of patients in the two groups. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15% in the teriflunomide group (placebo injections). Serious adverse events were reported in 9.1% of the patients treated with ofatumumab and 7.9% of those treated with teriflunomide. Serious infections occurred in 2.5% and 1.8% of patients respectively.
Appendicitis was reported in 8 patients who received ofatumumab and in 2 who received teriflunomide.
“The reason for the observed imbalance in appendicitis as an adverse event with ofatumumab is unknown, and no signal for appendicitis has been observed with ofatumumab treatment in phase 2 studies in multiple sclerosis and other autoimmune indications or with other anti-CD20 therapies in multiple sclerosis,” the researchers comment.
“Larger and longer trials are required,” the authors conclude, “to determine the long-term effect and risks of ofatumumab as compared with other disease-modifying treatments, including other anti-CD20 monoclonal antibodies.”
The ASCLEPIOS trials were funded by Novartis. Hauser reports receiving travel reimbursement and writing assistance from Roche and Novartis for CD20-related meetings and presentations. Kappos reports grants from Novartis to his institution, during the conduct of the trial. Some other coauthors are employees of Novartis.
N Eng J Med. Published online August 6, 2020. Abstract