The full data from the ASCLEPIOS I and II trials suggest that the Novartis agent ofatumumab is superior to teriflunomide in reducing annualized relapse rates and other measurements of disease progression in MS.
Stephen L. Hauser, MD
According to the full data publication from the phase 3 ASCLEPIOS trials (NCT02792218; and NCT02792231), among patients with multiple sclerosis (MS), treatment with 20-mg subcutaneous injections of ofatumumab (also known as OMB157; Novartis) is associated with lower annualized relapse rates (ARRs) than with 14-mg oral tablet of teriflunomide (Aubagio; Sanofi).1
All told, the ARRs for patients with MS were reduced by 51% (ofatumumab: 0.11; teriflunomide: 0.22; difference, −0.11; 95% CI, −0.16 to −0.06; P <.001) and 58% (ofatumumab: 0.10; teriflunomide: 0.25; difference, −0.15; 95% CI, −0.20 to −0.09; P <.001) in the ACLEPIOS I and II trials, respectively, with both differences achieving statistical significance (P <.001 for both).
“The ASCLEPIOS studies found that ofatumumab produced a significant reduction in new inflammation, as well as fewer clinical relapses and progression events,” said Stephen L. Hauser, MD, director, UCSF Weill Institute for Neurosciences; professor of neurology, UCSF School of Medicine; and co-chair of the steering committee for the ASCLEPIOS I and II studies, in a statement.2 “Ofatumumab represents a potential new option for RMS patients with greater efficacy compared to teriflunomide, a comparable safety profile, and the convenience of once monthly self-administration without the need for infusions.”
All told, the trials randomized 946 patients to the ofatumumab—a subcutaneous anti-CD20 monoclonal antibody that selectively depletes B cells—and 936 to teriflunomide—an oral inhibitor of pyrimidine synthesis that reduces T-cell and B-cell activation.
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Pre-specified meta-analysis showed that the risk of 3-month and 6-month confirmed disability worsening (CDW) were reduced by 34% (P = .002) and 32% (P = .01), respectively. In the pooled data, the percentage of patients with 3-month CDW was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio [HR], 0.66; P = .002), and at 6 months was 8.1% and 12.0%, respectively (HR, 0.68; P = .01). At 6 months, the percentage of patients with confirmed disability improvement at 6 months was 11.0% and 8.1% (HR, 1.35; P = .09), respectively.
There was also a significant reduction of both gadolinium enhancing (Gd+) T1 lesions observed, with a 97% and 94% relative reduction in ASCLEPIOS I and II, respectively (P <.001 for both). There was an 82% and 85% relative reduction in new or enlarging T2 lesions in ASCLEPIOS I and II, respectively (P <.001 for both).
“ASCLEPIOS I and II demonstrate the efficacy and safety of ofatumumab and its potential to become a first-choice treatment option that offers RMS patients the flexibility as they continue to live their lives,” said Krishnan Ramanathan, Neuroscience Global Program Head at Novartis. “Ofatumumab is a testament to our commitment to advance science and investigate potential treatments that reimagine care and address significant unmet needs at all parts of the RMS journey.”
A secondary end point assessed showed a superiority for ofatumumab in the reduction of neuroaxonal damage as well, with the ofatumumab group showing a 7% lower concentration of neurofilament light chain (NfL) at 3 months (P = .01), 27% lower at 12 months, and 23% lower at 24 months in ASCLEPIOS I. The corresponding differences in ASCLEPIOS II were 11% (P <.001), 26%, and 24%, respectively.
The Novartis agent also demonstrated a similar safety profile to teriflunomide, with the frequency of serious infections and neoplasms being comparable between treatment groups. Injection-related reactions occurred in 20.2% of the ofatumumab group and in 15.0% of the teriflunomide group. Additionally, nasopharyngitis, headache, injection-site reaction, upper respiratory tract infection and urinary tract infection were the most commonly observed adverse events (AEs) with ofatumumab, occurring in ≥10% of patients. Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.
Novartis recently announced in June that the FDA delayed its regulatory decision on ofatumumab, originally expected sometime that month, to September 2020. The decision was speculated to be associated with the ongoing delays associated with the coronavirus disease 2019 pandemic. The FDA accepted the supplemental biologics license application with priority review in February 2020 with data in hand from the head-to-head ASCLEPIOS trials.3,4
The fully human anti-CD20 monoclonal antibody is already approved in the US and Europe as first-line treatment for chronic lymphocytic leukemia (CLL) and recurring CLL. It is marketed under the name Arzerra.
Recently, in a NeurologyLive Peers & Perspectives segment, Matthew J. Baker, MD, shared his thoughts on results from the APLIOS bioequivalence study and treatment of appropriate patients with ofatumumab for relapsing MS in the future with Jeffrey M. Kaplan, MD. Check out that conversation below.
1. Hauser SL, Bar-Or A, Cohen JA, et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020;383:546—557. doi: 10.1056/NEJMoa1917246.
2. Novartis announces NEJM publication of Phase III ASCLEPIOS trials demonstrating superior efficacy of ofatumumab in patients with relapsing multiple sclerosis [press release]. East Hanover, NJ. Novartis. Published August 5, 2020. Accessed August 10, 2020. https://www.prnewswire.com/news-releases/novartis-announces-nejm-publication-of-phase-iii-asclepios-trials-demonstrating-superior-efficacy-of-ofatumumab-in-patients-with-relapsing-multiple-sclerosis-301107052.html
3. Novartis provides update on FDA review of ofatumumab, a self-administered, targeted B-cell therapy for patients with relapsing multiple sclerosis [press release]. Novartis. June 2, 2020. Accessed August 5, 2020. https://www.novartis.com/news/media-releases/novartis-provides-update-fda-review-ofatumumab-self-administered-targeted-b-cell-therapy-patients-relapsing-multiple-sclerosis
4. Novartis announces FDA and EMA filing acceptance of ofatumumab, a novel B-cell therapy for patients with relapsing forms of multiple sclerosis (RMS) [press release]. Novartis. February 24, 2020. Accessed August 5, 2020. https://www.globenewswire.com/news-release/2020/02/24/1988939/0/en/Novartis-announces-FDA-and-EMA-filing-acceptance-of-ofatumumab-a-novel-B-cell-therapy-for-patients-with-relapsing-forms-of-multiple-sclerosis-RMS.html