FDA Grants Breakthrough Therapy Designation to I-Mab and HI-Bio’s Antibody for Primary Membranous Nephropathy

Rare Daily Staff

The U.S. Food and Drug Administration has granted Breakthrough Therapy Designation I-Mab and HI-Bio’s felzartamab, an investigational CD38 antibody, for the treatment of primary membranous nephropathy (PMN).

“The FDA’s decision to grant felzartamab Breakthrough Therapy designation is recognition of the promising data we have collected to date, as well as an acknowledgement of the need for major advances over available therapies in the treatment of patients with PMN,” said Uptal Patel, chief medical officer of HI-Bio. “We believe that the cellular depletion strategy with felzartamab in PMN is applicable to many more immune-mediated diseases driven by antibodies produced in CD38+ plasma cells. For that reason, we are currently developing felzartamab in multiple diseases including PMN, IgA nephropathy, antibody-mediated rejection and lupus nephritis.”

The FDA granted Breakthrough Therapy designation for felzartamab in PMN based on positive clinical data from M-PLACE, a phase 2 study led by I-Mab partner HI-Bio.

I-Mab has the full rights to develop and commercialize felzartamab for all indications in Greater China which encompasses Mainland China, Hong Kong, Macau, and Taiwan. I-Mab is evaluating felzartamab in oncology and autoimmune diseases.  I-Mab is currently conducting a phase 3 registrational study of felzartamab in combination with lenalidomide and dexamethasone as a second-line treatment for multiple myeloma in China with progression-free survival as the primary endpoint, with a projected read-out in 2024, followed by a planned BLA submission.

The FDA selectively grants Breakthrough Therapy Designation to expedite the development and review of drugs that are intended to treat a serious or life-threatening condition, and preliminary clinical evidence indicates the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).

“This designation represents an important milestone for I-Mab, our partner HI-Bio, and the PMN community as we continue to evaluate felzartamab as an innovative immunotherapy for multiple indications, including cancers and autoimmune diseases,” said Andrew Zhu, president of I-Mab.

Primary membranous nephropathy (PMN) is a rare autoantibody-mediated autoimmune kidney disease and a leading cause of nephrotic syndrome in adults worldwide. Disease onset and diagnosis typically occurs between 40 and 50 years of age, with 80 percent of patients presenting with nephrotic syndrome. PMN is characterized by a thickening of the glomerular basement membrane (GBM) due to the formation and deposition of immune complexes in this space between podocytes and the glomerular endothelium of the kidney. Approximately 80 percent of PMN cases arise due to autoantibodies that recognize the phospholipase A2 receptor (PLA2R) antigen expressed on podocytes. Anti-PLA2R is both a diagnostic and prognostic biomarker, and total aPLA2R antibody level has been shown to be a biomarker for prognosis of outcome in patients with PMN. Other autoantibodies have been identified in patients with PMN including anti-THSD7A, NELL-1 and Sema3B, further supporting the role of antibody-secreting plasma cells in the pathophysiology of PMN. CD38+ long-lived plasma cells and plasmablasts are a main source of autoantibodies. There are no approved therapies for PMN.

Felzartamab is an investigational human monoclonal antibody directed against CD38, a protein expressed on mature plasma cells. The antibody is directed against CD38 on the surface of multiple myeloma cells, which has been characterized as one of the most strongly and uniformly expressed antigens on the surface of malignant plasma cells. According to its suggested mode of action, the antibody recruits cells of the body’s immune system to kill the tumor through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). The antibody does not involve complement dependent cytotoxicity, or CDC, an additional immune mechanism involved in tumor cell killing. Scientific research suggests that an anti-CD38 antibody may have therapeutic potential also in other cancers as well as autoimmune diseases.

Based on a licensing agreement between MorphoSys and I-Mab signed in November 2017, I-Mab owns the exclusive rights for development and commercialization of felzartamab for all indications in Greater China, which encompasses Mainland China, Hong Kong, Macao, and Taiwan. HI-Bio in-licensed felzartamab from MorphoSys in June 2022, and holds exclusive worldwide rights for felzartamab with the exception of Greater China.

Photo: Uptal Patel, chief medical officer of HI-Bio