Ofatumumab: A potential treatment for relapsing MS?
Treatment with the anti-CD20 monoclonal antibody ofatumumab reduced relapse rate in patients with relapsing multiple sclerosis (MS) compared with the pyrimidine synthesis inhibitor teriflunomide, according to results of the phase III ASCLEPIOS I and II* trials.
“[In the two trials,] both ofatumumab and teriflunomide were associated with low relapse rates [with] the relapse rate … significantly lower with ofatumumab than with teriflunomide,” said the researchers.
Participants in these multinational, double-blind, double-dummy trials were 1,882 patients aged 18–55 years with relapsing MS (≥1 relapse in the 1 year prior, ≥2 in the 2 years prior, or ≥1 MRI-detected gadolinium-enhancing lesion 1 year prior) with EDSS** score 0–5.5. They were randomized to receive either subcutaneous ofatumumab (20 mg Q4W after 20-mg loading doses on days 1, 7, and 14; n=946) or oral teriflunomide (14 mg QD; n=936) for ≤30 months. Patients were followed up for a median 1.6 years.
Annualized relapse rate at trial end was significantly reduced with ofatumumab vs teriflunomide in both ASCLEPIOS I (difference, -0.11, 95 percent confidence interval [CI], -0.16 to -0.06) and ASCLEPIOS II (difference, -0.15, 95 percent CI, -0.20 to -0.09; p<0.001 for both). [N Engl J Med 2020;383:546-557]
In meta-analysis of both trials, fewer patients on ofatumumab than teriflunomide experienced worsening of disability at 3 months (10.9 percent vs 15.0 percent; hazard ratio [HR], 0.66; p=0.002) and 6 months (8.1 percent vs 12.0 percent; HR, 0.68; p=0.01), though improvement in disability at 6 months did not significantly differ between groups (11.0 percent vs 8.1 percent; HR, 1.35; p=0.09).
The mean number of gadolinium-enhancing lesions per T1-weighted MRI scan was lower with ofatumumab vs teriflunomide in ASCLEPIOS I (0.01 vs 0.45) and ASCLEPIOS II (0.03 vs 0.51), which translated to 97 and 94 percent fewer lesions with ofatumumab than teriflunomide in the two trials, respectively (p<0.001 for both).
Annualized rate of new or enlarging lesions on T2-weighted MRI was also lower with ofatumumab than teriflunomide in ASCLEPIOS I (0.72 vs 4.00) and ASCLEPIOS II (0.64 vs 4.15), representing 82 and 85 percent fewer lesions with ofatumumab than teriflunomide (p<0.001 for both).
At month 3, serum neurofilament light chain concentration was significantly reduced in ofatumumab compared with teriflunomide recipients in ASCLEPIOS I (-7 percent; p=0.01) and ASCLEPIOS II (-11 percent; p<0.001). However, annual rate of brain volume loss did not significantly differ between the two treatments.
“This discrepancy between two markers of tissue damage needs further analysis,” said the researchers.
Adverse event (AE) incidence was comparable between ofatumumab and teriflunomide recipients (83.6 percent vs 84.2 percent). The most common (≥10 percent) AEs in ofatumumab recipients were injection-related reactions, nasopharyngitis, headache, injection-site reaction, upper respiratory tract infection (URTI), and urinary tract infection, while in teriflunomide recipients, nasopharyngitis, injection-related reactions, alopecia, URTI, headache, and diarrhoea were most common. Serious AEs occurred in 9.1 and 7.9 percent of ofatumumab and teriflunomide recipients, respectively.
Infections and infestations affected a comparable proportion of ofatumumab and teriflunomide recipients (51.6 and 52.7 percent, respectively), with serious infections occurring in 2.5 and 1.8 percent, respectively. Mild-to-moderate herpes virus-associated infections occurred in 4.9 and 4.2 percent, respectively, while bronchitis occurred in 2.5 and 3.5 percent, respectively.
Injection-related systemic reactions occurred in 20.2 percent of ofatumumab recipients and 15.0 percent of placebo injection recipients in the teriflunomide arm, mostly during the first injection, while injection-site reactions occurred in 10.9 and 5.6 percent, respectively. Five and four neoplasms occurred in ofatumumab and teriflunomide recipients, respectively.
B-cell therapies: The way forward?
The positive outcomes with ofatumumab drew comparisons to another B-cell therapy, ocrelizumab, which was approved by the FDA in 2017 for primary progressive MS. [https://wayback.archive-it.org/7993/20190423192100/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm549325.htm, accessed 16 September 2020]
“Both of these B-cell therapies are astoundingly effective for relapsing MS and offer good options for patients,” said ASCLEPIOS corresponding author Professor Stephen Hauser, Director, UCSF Weill Institute for Neurosciences, University of California, San Francisco, California, US.
“Given the effectiveness we saw in this study with near-complete elimination of inflammation and scarring in myelin-rich areas of the brain, along with the minimal side effects, the use of either of these therapies is most attractive as first-line treatment for most MS patients,” he added.
Despite the positive findings, the researchers cautioned that “the results … do not permit any inferences to be made about the efficacy of ofatumumab [vs] other drugs for MS … considered … more potent than teriflunomide.”