SpringWorks Therapeutics, a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, and GlaxoSmothKline have entered into a clinical trial collaboration agreement to evaluate SpringWorks’ investigational gamma secretase inhibitor (GSI), nirogacestat, in combination with GlaxoSmithKline’s investigational anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC), belantamab mafodotin (formerly GSK2857916), in patients with relapsed or refractory multiple myeloma.

Multiple myeloma is the second most common blood cancer in the United States and while it is generally considered as treatable, the disease is not curable. In many instances the disease becomes refractory to available treatments, hence ongoing research into new treatments remains vital.[1]

Multiple myeloma is not a common cancer but is the second most common blood cancer after non-Hodgkin lymphoma in the United States. The lifetime risk for multiple myeloma is about 1 in 132. This year, an estimated 32,110 adults (18,130 men and 13,980 women) in the United States will be diagnosed with multiple myeloma. [1] It is estimated that 12,960 deaths (6,990 men and 5,970 women) from this disease will occur this year.[1]

Improving treatment
Gamma secretase is an enzyme that cleaves multiple transmembrane proteins, including BCMA. As evidenced in publications and preclinical experiments, treatment with a GSI, including nirogacestat, can increase BCMA cell surface expression levels on multiple myeloma cells, potentially improving the activity of BCMA-targeted therapies, including BCMA ADCs.[2]

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Nirogacestat is an investigational, oral, selective, small molecule gamma-secretase inhibitor in Phase III clinical development for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth. In June 2018, the FDA granted Orphan Drug designation for nirogacestat for the treatment of desmoid tumors, and in November 2018, the FDA granted Fast Track designation for nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.

In addition, gamma secretase has been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain, or ECD, from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. [3] Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma.

Belantamab mafodotin is an investigational anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) in Phase II clinical development for patients with relapsed/refractory multiple myeloma and other advanced hematologic malignancies expressing BCMA. The drug includes a humanised anti-B cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent Monomethyl Auristatin F via non-cleavable linker. The linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using technology licensed from BioWa.

Breakthrough Therapy Designation
In 2017, belantamab mafodotin was awarded Breakthrough Therapy designation from the U.S. Food and Drug Administration and PRIME designation from the European Medicines Agency; these designations are intended to facilitate development of investigational medicines that have shown clinical promise for conditions where there is significant unmet need.

“While significant advances have been made in treating multiple myeloma over the past decade, a significant unmet need remains for patients who have relapsed or are refractory to available treatments,” noted Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics.

“We are delighted to enter into this agreement with GlaxoSmithKline, who also invested in our recent Series B financing, and we look forward to exploring the potential benefit of nirogacestat and belantamab mafodotin for multiple myeloma patients. With this collaboration, we are pleased to further expand on our strategy in building our targeted oncology portfolio with another industry leader.”

Under the terms of the agreement, GlaxoSmithKline will sponsor and conduct the adaptive Phase Ib study to evaluate the safety, tolerability and preliminary efficacy of the combination, and will assume all development costs associated with the study. GlaxoSmithKline and SpringWorks Therapeutics will also form a joint development committee to manage the clinical study.

Belantamab mafodotin currently in clinical development in patients with relapsed/refractory multiple myeloma and other advanced hematologic malignancies expressing BCMA.

[1] Multiple Myeloma: Statistics. Cancer.Net Online. Last accessed June 1, 2019. [Article]
[2] Laurent SA, Hoffmann FS, Kuhn PH, Cheng Q, Chu Y, Schmidt-Supprian M, Hauck SM, et al. γ-Secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun. 2015 Jun 11;6:7333. doi: 10.1038/ncomms8333. [Article]
[3] Chen H, Li M, Xu N, Ng N, Sanchez E, Soof CM, Patil S, Udd K Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells. Leuk Res. 2019 Jun;81:62-66. doi: 10.1016/j.leukres.2019.04.008. Epub 2019 Apr 18. [Article]

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