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 for adult patients with progressing desmoid tumors and in Phase 2 clinical development for patients with ovarian granulosa cell tumors.
Nirogacestat is also being evaluated in multiple studies as a potential cornerstone of BCMA combination therapy for patients with multiple myeloma.
Nirogacestat (gamma secretase inhibitor)
Gamma secretase cleaves multiple transmembrane proteins, including Notch, that are believed to play a role in activating pathways that contribute to growth of desmoid and ovarian granulosa cell tumors.
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.
A global, randomized, double-blind, placebo-controlled Phase 3 clinical trial (the DeFi trial) is evaluating the efficacy, safety, and tolerability of nirogacestat in adult patients with progressing desmoid tumors (NCT03785964). In September 2022, positive data from the Phase 3 DeFi trial were presented at the ESMO Congress 2022, and in March 2023, data from the trial were published in the New England Journal of Medicine.
A New Drug Application for nirogacestat in the treatment of adults with desmoid tumors is currently under review by the U.S. Food and Drug Administration (FDA). Nirogacestat has received Orphan Drug Designation from the 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 ovarian granulosa cell tumors
Ovarian granulosa cell tumors (OvGCT) account for approximately 5% of all ovarian cancers and are the most common subtype of ovarian sex cord stromal tumors. It is estimated that there are 1,500 to 2,000 new cases diagnosed per year in the U.S., and an estimated prevalence of approximately 10,000-15,000 patients with OvGCT in the U.S. There are no FDA-approved therapies for patients with OvGCT. SpringWorks is conducting a Phase 2 trial to evaluate the efficacy, tolerability, safety, and pharmacokinetics of nirogacestat for the treatment of patients with recurrent OvGCT (NCT05348356) .
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
Ongoing collaborations with industry-leading developers of BCMA-targeted therapies
Read more in these key publications
- Gounder M et al. Nirogacestat, a Gamma-Secretase Inhibitor for Desmoid Tumors. N Engl J Med 2023; 388:898-912. doi: 10.1056/NEJMoa2210140
- Riedel RF, Agulnik M. Evolving strategies for management of desmoid tumor. Cancer. June 2022. doi:10.1002/cncr.34332
- Coyne GO, Kummar S, Steinberg, SM, et al. Extended progression-free survival and long-term safety of nirogacestat in patients with desmoid tumors. [abstract] In: Journal of Clinical Oncology 2022 40:16_suppl, 11545-11545
- 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.
Ovarian granulosa cell tumors
- Irusta G, Pazos MC, Abramovich D, De Zúñiga I, Parborell F, Tesone M. Effects of an inhibitor of the γ-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN). Biol Reprod. 2013;89(1):9. doi: 10.1095/biolreprod.113.108100.
- Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J. Clin Oncol. 2003;21 (6):1180-9. doi: 10.1200/JCO.2003.10.019.
- Shah SP, Kobel M, Senz J, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med. 2009;360(26):2719–29. doi: 10.1056/NEJMoa0902542.
- Torre LA, Trabert B, Desantis CE, et al. Ovarian Cancer Statistics, 2018. CA Cancer J Clin. 2018; 68(4): 284–296. doi:10.3322/caac.21456.
- Gershenson DM, Okamoto A, Ray-Coquard I. Management of Rare Ovarian Cancer Histologies. J. Clin Oncol. 2019;37(27):2406-2415. doi:10.1200/JCO.18.02419.
- Li J, Bao R, Peng S, Zhang C. The Molecular Mechanism of Ovarian Granulosa Cell Tumors. J Ovarian Res. 2018;11(1):13. doi:10.1186/s13048-018-0384-1.
- Vanorny DA, Mayo KE. The Role of Notch Signaling in the Mammalian Ovary. Reproduction (Cambridge). 2017;153(6):R187-R204. doi:10.1530/REP-16-0689.
- Dridi M, Chraiet N, Batti R, et al. Granulosa cell tumor of the ovary: A retrospective study of 31 cases and a review of the literature. Int J Surg Oncol. 2018:1-4. doi:10.1155/2018/4547892.
GSI + BCMA combination therapy
- Chen H, Yu T, Lin L, et al. γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation. Blood Cancer J. 2022;12(8). doi:10.1038/s41408-022-00716-3.
- 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.