Nirogacestat (Gamma Secretase Inhibitor)
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Nirogacestat is an investigational oral, selective, small molecule gamma secretase inhibitor (GSI) in Phase 3 clinical development as a monotherapy for adult patients with progressing desmoid tumors and is being evaluated in multiple studies as a potential cornerstone of BCMA combination therapy for patients with multiple myeloma.
Nirogacestat (gamma secretase inhibitor)
Gamma secretase is a protease complex that cleaves multiple transmembrane proteins, including Notch. When dysregulated, Notch can play a key role in activating pathways that contribute to desmoid tumor growth.
Gamma secretase has been shown to cleave BCMA, a therapeutic target that is specifically expressed on multiple myeloma cells. We believe that by inhibiting gamma secretase with nirogacestat, membrane-bound BCMA can be preserved on the surface of myeloma cells, thereby increasing target density while simultaneously reducing levels of soluble BCMA, which may interfere with the activity BCMA-directed therapies. Combining nirogacestat with BCMA-targeted therapies may increase their activity and improve outcomes for multiple myeloma patients. SpringWorks is advancing nirogacestat as a potential cornerstone of multiple myeloma combination therapy across modalities in collaboration with industry-leading BCMA therapy developers.
Nirogacestat is an investigational product currently in clinical development that has not been approved by the U.S. Food and Drug Administration (FDA); the safety and efficacy of nirogacestat have not been established.
Nirogacestat in desmoid tumors
Desmoid tumors are rare, aggressive soft-tissue tumors characterized by locally invasive growth, significant morbidity, and high rates of recurrence. There are currently no FDA-approved therapies for the treatment of desmoid tumors.
Nirogacestat has been studied in over 200 subjects and clinical activity has been observed in patients with desmoid tumors in Phase 1 and Phase 2 trials. Importantly, this clinical activity was shown to be independent of the type and number of prior lines of therapy received as well as the specific underlying mutation driving desmoid tumor growth.
SpringWorks is conducting a global, randomized, double-blind, placebo-controlled Phase 3 clinical trial (the DeFi trial) to evaluate the efficacy, safety, and tolerability of nirogacestat in adult patients with progressing desmoid tumors (NCT03785964).
Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.
Nirogacestat in multiple myeloma
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.
B-cell maturation antigen (BCMA) is a cell surface protein that is highly and specifically 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.
We believe that 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 interfere with BCMA-directed therapies. Together, these mechanisms combine to potentially enhance the activity of BCMA-directed therapies and improve outcomes for multiple myeloma patients.
Nirogacestat’s ability to significantly enhance the activity of BCMA-directed therapies has been observed in several preclinical models of human multiple myeloma.
In preclinical models of multiple myeloma, nirogacestat significantly enhanced the activity of BCMA-directed therapies across therapeutic modalities.
Nirogacestat is being developed as a cornerstone of combination in BCMA therapies
Eight ongoing collaborations with industry-leading developers of BCMA-targeted therapies
Read more in these key publications
- Messersmith, WA, Shapiro GI, Cleary JM, et al. A Phase I, Dose-Finding Study in Patients with Advanced Solid Malignancies of the Oral γ-Secretase Inhibitor PF-03084014. Clinical Cancer Research. 2014; 21(1):60-7. doi:10.1158/1078-0432.CCR-14-0607.
- Villalobos, VM, Hall F, Jimeno A, et al. Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF-03084014, an Oral Gamma Secretase Inhibitor. Annals of Surgical Oncology, 2017;(3):768-775. doi:10.1245/s10434-017-6082-1.
- Kummar, S, Coyne GO, Do KT, et al. Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). Journal of Clinical Oncology. 2017;35(14):1561-1569. doi:10.1200/jco.2016.71.1994.
- Shang, H, Braggio D, Lee YJ, et al. Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors. Cancer. 2015;121(22):4088-96. doi:10.1002/cncr.29564.
- Takahashi T, Prensner JR, Robson CD, Janeway KA, Weigel BJ. Safety and efficacy of gamma-secretase inhibitor nirogacestat (PF-03084014) in desmoid tumor: Report of four pediatric/young adult cases. Pediatric Blood & Cancer. 2020;67(10). doi:10.1002/pbc.28636.
- Gronchi, A, Kasper, B, et al. The Management of Desmoid Tumours: A Joint Global Consensus-Based Guideline Approach for Adult and Paediatric Patients. European Journal of Cancer, 2020;(127):96-107. doi: 10.1016/j.ejca.2019.11.013.
- Anneberg M, Svane H, Fryzek J, et al. The Epidemiology of Desmoid Tumors in Denmark. Cancer Epidemiology. 2022; 77:1-7. doi.org/10.1016/j.canep.2022.102114.
GSI + BCMA Combination Therapy
- Laurent, SA, Hoffmann FS, Kuhn P-H, et al. γ-secretase directly sheds the survival receptor BCMA from plasma cells. Nature Communications. 2015;6(1):7333. doi:10.1038/ncomms8333.
- Pont, MJ, Hill T, Cole GO, et al. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019;134(19):1585-1597. doi:10.1182/blood.2019000050.
- Cowan, AJ, Pont, M, Sather BD, 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;134(supplement_1):204. doi:10.1182/blood-2019-129405.
- Eastman, S, Shelton, C, Gupta I, Krueger J, Blackwell C, Bojczuk. Synergistic Activity of Belantamab Mafodotin (anti-BCMA immuno-conjugate) with PF-03084014 (gamma-secretase inhibitor) in Bcma-Expressing Cancer Cell Lines. Blood. 2019;134(supplement_1):4401. doi:10.1182/blood-2019-123705.
- Green, DJ, Pont, M, Cowan AJ, 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;134(supplement_1):1856-1856. doi:10.1182/blood-2019-129582.