Novartis' Once-Monthly Subcutaneous CD20 Monoclonal Antibody Ofatumumab Nears Approval in China for Relapsing Multiple Sclerosis

On December 16, the marketing application (acceptance number: JXSS2000049) for Novartis' CD20 inhibitor Ocrelizumab has entered the administrative approval stage and is expected to be approved soon.

Source: NMPA Official Website

Ofatumumab, a fully human antibody targeting CD20, was initially developed by GlaxoSmithKline (GSK) and Denmark's Genmab. In October 2009, it was approved by the FDA for use in combination with chlorambucil as a first-line treatment for previously untreated patients with chronic lymphocytic leukemia (CLL) who are not suitable for fludarabine-based therapy. Its trade name is Arzerra. Subsequently, it was also approved for extended treatment of patients with relapsed or progressive CLL who have achieved complete or partial remission after receiving at least two prior therapies. In September 2016, it was further approved for use in combination with fludarabine and cyclophosphamide for patients with relapsed CLL.

Novartis subsequently acquired the relevant rights to the drug. In August 2020, ofatumumab was approved for a new indication by the FDA as a subcutaneous injection for the treatment of relapsing multiple sclerosis (RMS), including clinically isolated syndrome in adults, relapsing disease, and active secondary progressive disease, under the brand name Kesimpta. The medication is administered once a month via subcutaneous injection, allowing patients to self-administer at home. In November 2020, Novartis' ofatumumab was submitted for production in China for the first time, with the same indication for relapsing forms of multiple sclerosis in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

According to a press release previously issued by Novartis, Ofaatumab is the first B-cell targeted therapy that can be self-administered once a month at home by patients using the Sensoready autoinjector pen, providing convenience for disease management. After its submission for marketing approval in China, it was included in the priority review process.

Results published in the New England Journal of Medicine in August 2020 showed that ofatumumab, compared with the approved oral therapy in the control group, significantly reduced patients' annualized relapse rate (ARR) and confirmed disability progression, and decreased active or new brain lesions. Data revealed that, compared with the active control group, ofatumumab reduced ARR by 50.5% and 58.8% respectively in the two trials involving MS patients.

CD20 (Cluster of Differentiation 20) is a transmembrane phosphoprotein located on the surface of B lymphocytes. Evidence suggests that the killing of B-cell-derived tumors by anti-CD20 monoclonal antibodies is associated with three mechanisms of action: antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct effects caused by the binding of the antibody to the CD20 molecule, including inhibition of cell growth, alteration of the cell cycle, and apoptosis.

The world's first anti-CD20 monoclonal antibody is Roche's rituximab (trade name: Mabthera). Since its approval in 1997, multiple anti-CD20 monoclonal antibodies have been approved globally. However, these anti-CD20 monoclonal antibodies differ significantly in structure and indications. Additionally, based on the degree of humanization and Fc fragment modification, anti-CD20 monoclonal antibodies can be roughly divided into three generations: the first generation mainly consists of chimeric or murine antibodies represented by rituximab; the second generation comprises humanized antibodies represented by ofatumumab; and the third generation of anti-CD20 monoclonal antibodies is represented by obinutuzumab, whose antibody Fc fragment has undergone glycosylation modification.

Among them, the global sales of Rituximab have been in the TOP10 list in recent years. In 2019, its global sales reached 6.86 billion US dollars, ranking 10th in the global drug sales in 2019, but affected by biosimilars, it decreased by 4.0% year-on-year. In addition, according to the Insight database, currently in China, the rituximab biosimilars from Henlius and Innovent Biologics have been approved.

In addition, obinutuzumab (Gazyva), developed by Genentech under Roche, is the next-generation product of the blockbuster drug Rituxan. It was approved by the FDA in 2013 for use in combination with chlorambucil as a first-line treatment for CLL. Later, it was also approved for use in combination with chemotherapy to treat follicular lymphoma (FL) and advanced FL, as well as in combination with Imbruvica for the treatment of CLL/small lymphocytic lymphoma (SLL).

Currently, among the drugs under research targeting CD20, there are 2 in the marketing application stage, 8 in Phase III clinical trials, and 7 in Phase I clinical trials, indicating a highly competitive landscape.