Nirogacestat (Gamma Secretase Inhibitor)
Nirogacestat is an oral, selective, small molecule, gamma secretase inhibitor (GSI) in Phase 3 clinical development for patients with desmoid tumors. Gamma secretase is a protease complex that cleaves, or divides, multiple transmembrane protein complexes, including Notch, which, when dysregulated, can play a role in activating pathways that contribute to desmoid tumor growth.
Gamma secretase has also been shown to directly cleave BCMA, a therapeutic target that is highly expressed on multiple myeloma cells. By inhibiting gamma secretase with nirogacestat, membrane-bound BCMA can be preserved, thereby increasing target density while simultaneously reducing levels of soluble BCMA, which may serve as decoy receptors for BCMA-directed therapies. Together, these mechanisms combine to potentially enhance the activity of BCMA therapies and improve outcomes for multiple myeloma patients. SpringWorks is seeking to advance nirogacestat as a cornerstone of multiple myeloma combination therapy in collaboration with industry leaders who are advancing BCMA therapies.
Desmoid tumors are rare and often debilitating and disfiguring soft tissue tumors. There are currently no FDA-approved therapies for the treatment of desmoid tumors.
Nirogacestat has been generally well tolerated in over 200 patients and clinical activity was observed in desmoid tumor patients enrolled in Phase 1 and Phase 2 trials independent of prior lines of therapy and underlying mutation.
- A Phase 1 study was conducted in 64 patients with advanced solid tumors, of which there were seven evaluable patients who had a diagnosis of desmoid tumor. Of these seven patients, five had an objective tumor response (defined as > 30% tumor reduction).
- A Phase 2 open-label, investigator-initiated study sponsored by National Cancer Institute (NCI) enrolled 17 desmoid tumor patients. Sixteen patients were evaluable for tumor response. Five patients had a confirmed partial response and 11 had stable disease. Some patients also experienced improvements in symptom severity.
- Nirogacestat was generally well tolerated in both of these studies. In the Phase 1 study the mean time on therapy was four years and approximately 59% of the Phase 2 patients remained on therapy for at least two years. One desmoid tumor patient in the combined trials discontinued treatment due to an adverse event. The most common adverse events in the Phase 2 study were diarrhea, skin disorders and hypophosphatemia.
SpringWorks is conducting a global Phase 3, double-blind, placebo-controlled clinical trial (the DeFi trial) to evaluate nirogacestat in adults with progressing desmoid tumors.
The U.S. FDA has granted nirogacestat Orphan Drug Designation for the treatment of desmoid tumors and Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. In addition, the European Commission granted Orphan Drug Designation for nirogacestat for the treatment of soft tissue sarcoma.
Multiple myeloma is the second most common hematologic malignancy in the U.S., accounting for approximately 10 percent of all hematologic cancers. There are approximately 130,000 patients in the U.S. living with multiple myeloma, with an estimated 27,000 new patients each year in the U.S. whose disease comes back after a period of remission (relapsed) or who will not respond to available treatments (refractory).
B-cell maturation antigen (BCMA) is a cell surface protein universally expressed on multiple myeloma cells. BCMA has emerged as a promising target in multiple myeloma across several therapeutic modalities. Gamma secretase directly cleaves membrane-bound BCMA. By inhibiting gamma secretase with nirogacestat, membrane-bound BCMA can be preserved, thereby increasing target density while simultaneously reducing levels of soluble BCMA, which may serve as decoy receptors for BCMA-directed therapies. Together, these mechanisms combine to potentially enhance the activity of BCMA therapies and improve outcomes for multiple myeloma patients.
Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma.
MECHANISM OF ACTION OF NIROGACESTAT + BCMA THERAPY (ADC SHOWN)
SpringWorks is collaborating with industry-leading BCMA developers to advance potentially best-in-class combinations using nirogacestat:
- In June 2019, SpringWorks signed a clinical collaboration with GlaxoSmithKline (GSK) to evaluate nirogacestat in combination with GSK’s investigational antibody-drug conjugate (ADC), belantamab mafodotin, in patients with relapsed or refractory multiple myeloma.
- In January 2020, SpringWorks signed a clinical collaboration with Allogene Therapeutics to evaluate nirogacestat in combination with ALLO-715, Allogene’s investigational BCMA allogeneic chimeric antigen receptor T cell (AlloCAR T ™) therapy.
- Villalobos, V., et al. Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF-03084014, an Oral Gamma Secretase Inhibitor. Annals of Surgical Oncology, 2017.
- Kummar, S., et al. Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). J Clin Oncol. 2017 May 10;35(14):1561-1569. Epub 2017 Mar 28.
- Shang, H., et al. Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors. Cancer. 2015 Sep 08. 121: 4088-4096.
- Messersmith, W., et al. A Phase I, Dose-Finding Study in Patients with Advanced Solid Malignancies of the Oral γ-Secretase Inhibitor PF-03084014. Clin Cancer Res. 2015 Jan 1.
GSI + BCMA Combination Therapy
- Laurent, Sarah A., et al. γ-secretase directly sheds the survival receptor BCMA from plasma cells. Nature Communications. 2015 June 11.
- Pont, Margot J., et al. γ-secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019 Sept 26.
- Cowen, A. J., Pont, M., et al. Efficacy and Safety of Fully Human Bcma CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase Bcma Surface Expression in Patients with Relapsed or Refractory Multiple Myeloma. Blood. 2019 November 13.
- Eastman, S., Shelton, C., et al.Synergistic Activity of Belantamab Mafodotin (anti-BCMA immuno-conjugate) with PF-03084014 (gamma-secretase inhibitor) in Bcma-Expressing Cancer Cell Lines. Blood. 2019 November 13.
- Green. D. J., Pont, M., et al.Response to Bcma CAR-T Cells Correlates with Pretreatment Target Antigen Density and Is Improved By Small Molecule Inhibition of Gamma Secretase. Blood. 2019 November 13.