Novartis Reports New Data Showing 87.8% of RMS Patients on Ofatumumab Achieved No Evidence of Disease Activity in Second Year

Source: Jike Yaowen

On May 27, Novartis announced that the latest data from the Phase 3 ASCLEPIOS trial and the Phase 2 APLIOS trial of ofatumumab were presented at the 6th Congress of the European Academy of Neurology (EAN). The data continue to demonstrate that ofatumumab (OMB157) is a potential novel therapeutic option for patients with relapsing multiple sclerosis (RMS). On February 24 this year, Novartis announced that the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) had accepted its marketing application for the humanized CD20 antibody Arzerra (ofatumumab) for the treatment of patients with relapsing multiple sclerosis (RMS), with the FDA granting priority review status to the application.

ASCLEPIOS I and II were two identical, flexible-duration (up to 30 months), double-blind, randomized, multicenter Phase 3 clinical studies designed to evaluate the safety and efficacy of once-monthly subcutaneous injections of ofatumumab 20 mg versus once-daily oral teriflunomide 14 mg tablets in adults with relapsing multiple sclerosis (RMS). The ASCLEPIOS I and II studies enrolled 1,882 patients with multiple sclerosis (MS), aged 18–55 years, with Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5.5. Trial results demonstrated that, compared with teriflunomide, ofatumumab showed a 34.4% relative risk reduction in confirmed disability worsening (CDW) at 3 months (P=0.002) and a 32.5% relative risk reduction in CDW at 6 months (P=0.012), as per the pre-specified meta-analysis in the ASCLEPIOS trials. Compared with teriflunomide, ofatumumab reduced serum neurofilament light chain (NfL) levels at the first assessment at Month 3. There was no difference between treatment groups in the slope of change in brain volume from baseline. A favorable trend was observed in the endpoint of confirmed disability improvement events over 6 months, but it did not reach statistical significance. The incidence of serious infections and malignancies was similar between the two treatment groups; overall, the safety profile of ofatumumab was comparable to that of teriflunomide. A separate post hoc analysis indicated that ofatumumab might halt new disease activity in patients with RMS. Results showed that, compared with teriflunomide, the odds of achieving NEDA-3 (no relapses, no MRI lesions, and no disability worsening) were more than three times higher with ofatumumab during the first year (0–12 months) (47.0% vs. 24.5% of patients; P<0.001), and more than eight times higher during the second year (12–24 months) (87.8% vs. 48.2%; P<0.001). Ofatumumab is a fully human monoclonal antibody targeting CD20+ B cells, demonstrating superior overall efficacy, good safety and tolerability, and an infection rate similar to that of teriflunomide.

The APLIOS study was a 12-week, open-label, Phase 2 bioequivalence clinical trial designed to determine the extent of B-cell depletion with monthly subcutaneous administration of ofatumumab and to assess the bioequivalence of ofatumumab administered via pre-filled syringe (as used in ASCLEPIOS I and II) versus autoinjector pen in patients with relapsing multiple sclerosis (RMS). Patients were randomized based on injection device and injection site (including abdomen and thigh). B-cell depletion was measured nine times over the 12-week period, and gadolinium-enhancing (Gd+) T1 lesion counts were assessed at baseline and at weeks 4, 8, and 12. Regardless of the injection device or site, monthly 20 mg subcutaneous injections of ofatumumab resulted in rapid, near-complete, and sustained B-cell depletion. By day 7 after the first injection, more than 65% of patients had B-cell counts <10 cells/μL; this proportion reached 94% by week 4 and remained above 95% thereafter. At weeks 4, 8, and 12, ofatumumab treatment reduced the mean number of Gd+ lesions from a baseline of 1.5 to 0.8, 0.3, and 0.1, respectively; the corresponding proportions of patients free of Gd+ lesions were 66.5%, 86.7%, and 94.1%. A separate analysis of the APLIOS trial (n=284) demonstrated that ofatumumab treatment led to rapid and sustained depletion of CD20+ B cells and T cells in patients with RMS. Ofatumumab cleared various B-cell and T-cell subsets, including memory and naïve B cells, as well as T-cell subsets known to exhibit an activated phenotype. However, CD3+ T cells, which do not express the CD20 receptor, were largely unaffected.

Professor Ludwig Kappos of the University Hospital Basel stated, “Achieving no evidence of disease activity (NEDA) is widely recognized as an important treatment goal in multiple sclerosis. These data demonstrate that it is possible to halt new disease activity in relapsing multiple sclerosis (RMS) through B-cell–targeted therapy.” Krishnan Ramanathan, Global Program Head for Neuroscience at Novartis, said, “These results are encouraging and support our belief that, if approved, ofatumumab has the potential to significantly improve the lives of patients with RMS.”

About Ofatumumab

Ofatumumab (OMB157) is a fully human IgG1 kappa monoclonal antibody targeting CD20. The drug has been marketed in the United States for over a decade under the brand name Arzerra® for the treatment of chronic lymphocytic leukemia (CLL). Ofatumumab was initially developed by Genmab and licensed to GlaxoSmithKline. In December 2015, Novartis acquired the rights to Ofatumumab for all indications, including relapsing multiple sclerosis (RMS), from GlaxoSmithKline.

Novartis Seeks to Expand Ofatumumab Label for the Treatment of Multiple SclerosisThe basis for this indication expansion is supported by data from two Phase 3 clinical studies, which demonstrated that patients treated with ofatumumab experienced a significant reduction in relapse rates compared to those treated with teriflunomide. Preclinical studies indicate that ofatumumab exerts its therapeutic effect by potently inducing B-cell lysis and depletion through binding to a unique epitope on the CD20 molecule. As shown in preclinical research, the selective mechanism of action of ofatumumab, combined with subcutaneous administration, allows for precise delivery to lymph nodes and may preserve B cells in the spleen. Monthly dosing of ofatumumab also facilitates rapid B-cell repletion and offers greater flexibility.

About Multiple Sclerosis (MS)

Multiple sclerosis (MS) disrupts the normal functioning of the brain, optic nerves, and spinal cord through inflammation and tissue loss. MS affects approximately 2.3 million people worldwide and commonly presents in three forms: primary progressive MS (PPMS), relapsing-remitting MS (RRMS), and secondary progressive MS (SPMS). SPMS evolves from an initial RRMS course and is characterized by progressive accumulation of neurological disability, with physical and cognitive changes occurring over time, regardless of whether relapses are present. Approximately 85% of patients initially present with relapsing-remitting MS.

References:

[1] Novartis announces new late-breaking ofatumumab data at EAN demonstrating robust efficacy and safety in the treatment of relapsing forms of multiple sclerosis (RMS). Retrieved 2020-05-27, from https://www.globenewswire.com/news-release/2020/05/27/2039066/0/en/Novartis-announces-new-late-breaking-ofatumumab-data-at-EAN-demonstrating-robust-efficacy-and-safety-in-the-treatment-of-relapsing-forms-of-multiple-sclerosis-RMS.html

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