FDA Delays U.S. Review Decision for Novartis’ Ofatumumab sBLA in Relapsing Multiple Sclerosis by Three Months

Compiled by Keke

Novartis and its partner Genmab announced on June 2 that the U.S. FDA has extended the review timeline for the supplemental Biologics License Application (sBLA) for ofatumumab (OMB157), a targeted B-cell therapy for self-administration by patients with relapsing multiple sclerosis (RMS). The FDA, which had initially scheduled its approval decision for June, has now postponed the deadline to September.

On February 24 this year, Novartis announced that regulatory authorities in the United States and Europe had accepted the marketing application for ofatumumab for the treatment of adult patients with relapsing RMS. The European Union plans to issue an approval decision in the second quarter of this year and has not indicated any need for delay so far.

This application is based on the positive results from the Phase 3 ASCLEPIOS I and II clinical trials, which evaluated the efficacy and safety of monthly subcutaneous injections of 20 mg ofatumumab versus once-daily oral administration of 14 mg teriflunomide (Aubagio®, Sanofi) in patients with relapsing multiple sclerosis (RMS). In both trials, ofatumumab demonstrated superior efficacy compared to Aubagio. As assessed by the annualized relapse rate (ARR), the ofatumumab treatment groups showed a highly significant and clinically meaningful reduction in patient relapse rates. Meanwhile, the key secondary endpoint of time to confirmed disability progression (CDP) was not met.

Compared with Aubagio treatment, the ofatumumab group:

ARR was reduced by 50.5% (0.11 vs. 0.22) and 58.5% (0.10 vs. 0.25), respectively (p < 0.001 for both studies);

Significant inhibition was observed in both Gd-enhancing T1 lesions and new or enlarging T2 lesions, indicating that new inflammatory activity was completely suppressed;

In the pre-specified pooled analysis, the relative risk of CDP was reduced by 34.4% at three months (p=0.002) and by 32.5% at six months (p=0.012);

The safety profile was consistent with the results of previous Phase II clinical trials.

Furthermore, Novartis completed the APLIOS, an open-label Phase 2 clinical study, to determine the bioequivalence of subcutaneous ofatumumab administered via pre-filled syringes (as used in ASCLEPIOS I and II) and autoinjector pens in patients with relapsing multiple sclerosis (RMS). The results demonstrated that ofatumumab provides a highly effective B-cell therapy, enabling patients to self-administer the treatment at home using an autoinjector pen.

Ofatumumab is a fully humanized anti-CD20 monoclonal antibody indicated for relapsing multiple sclerosis (RMS), targeting an epitope distinct from that of rituximab. Compared with rituximab, ofatumumab binds more tightly to CD20 and exhibits a lower dissociation rate. As demonstrated in preclinical studies, ofatumumab is believed to exert its effects by binding to a unique epitope on the CD20 molecule, thereby inducing potent B-cell lysis and depletion. Its selective mechanism of action and subcutaneous administration enable precise drug delivery to lymph nodes involved in multiple sclerosis (MS) where B-cell depletion is required, while preserving B cells in the spleen. Once-monthly dosing of ofatumumab allows for rapid B-cell reconstitution and offers greater flexibility.

Ofatumumab was initially developed by Genmab and licensed to GlaxoSmithKline (GSK). In December 2015, GSK sold the rights to all indications of this drug to Novartis. The drug received approval from the European Medicines Agency (EMA) in June 2010, from the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) in April 2010, from Health Canada in August 2012, and was first approved by the US Food and Drug Administration (FDA) on April 17, 2014. It was approved for use in combination with chlorambucil as first-line treatment for patients with previously untreated chronic lymphocytic leukemia (CLL) who are not suitable for fludarabine-based therapy, under the brand name Arzerra. Subsequently, it was also approved by the US FDA and the European EMA for the treatment of patients with relapsed CLL.

If the new indication is approved, ofatumumab has the potential to become the preferred treatment for a broad population of patients with relapsing multiple sclerosis (RMS), and it would be the first B-cell therapy administered via monthly subcutaneous injection that allows for easy patient initiation and self-management. The launch of ofatumumab is also likely to challenge Roche’s blockbuster multiple sclerosis (MS) drug, Ocrevus. In 2019, Ocrevus achieved annual sales of CHF 3.71 billion (a year-on-year increase of 57%), accounting for approximately 40% of the US MS market share. However, in clinical practice, physicians tend to prefer prescribing medications that patients can self-administer; therefore, Novartis places significant importance on the launch of ofatumumab’s new indication and its subsequent market potential.

The delayed approval of ofatumumab in the United States may be related to inherent mechanistic limitations of the drug. It is reported that anti-CD20 monoclonal antibodies can lead to immune suppression in patients. Previous studies have also shown that the most common adverse reactions (incidence >10%) associated with ofatumumab include lower respiratory tract infections (including pneumonia), upper respiratory tract infections, rash, anemia, and neutropenia. During the COVID-19 pandemic, the use of such medications places patients at increased risk. Some countries have already recommended that patients with multiple sclerosis (MS) postpone treatment with Ocrevus.

Reference source: FDA extends review of Novartis' ofatumumab filing in relapsing MS