On May 30, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported that it has achieved full enrollment in its Phase 2 trial evaluating nirogacestat, an investigational gamma secretase inhibitor, as a monotherapy in patients with recurrent ovarian granulosa cell tumors (OvGCT) (Press release, SpringWorks Therapeutics, MAY 30, 2023, View Source [SID1234632220]). SpringWorks expects to report initial data from the trial in 2024.
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OvGCT account for approximately 5% of all ovarian cancers and are the most common subtype of ovarian sex cord tumors, representing 70% of all cases. Nearly all OvGCT harbor a mutation in the FOXL2 gene and preclinical studies have demonstrated that OvGCT cell lines are susceptible to gamma secretase inhibition.1,2
"While early-stage OvGCT can be managed with surgery, nearly half of patients experience post-surgical recurrence, and once these tumors recur, there are limited treatment options and no FDA-approved therapies," said Saqib Islam, Chief Executive Officer of SpringWorks. "We are very pleased to have fully enrolled this trial well ahead of our projections, which we believe is a testament to the high unmet need that remains for patients living with OvGCT who are in need of a rational, targeted, oral therapy to treat their tumors. We look forward to continuing to work closely with our investigators and to reporting initial data from this study next year."
The Phase 2 trial (NCT05348356) is a multi-center, single-arm, open-label study evaluating the efficacy, tolerability, safety, and pharmacokinetics of nirogacestat in recurrent OvGCT. The target enrollment for the study was approximately 40 participants, with people receiving 150mg of nirogacestat twice daily. The study enrolled participants with recurrent OvGCT who had received one or more prior lines of systemic therapy. The primary endpoint of the trial is objective response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Secondary endpoints include progression-free survival, overall survival, duration of response, safety and tolerability, and quality of life assessments.
About Ovarian Granulosa Cell Tumors
Ovarian granulosa cell tumors (OvGCT) are a rare ovarian cancer subtype that are usually slow-growing tumors. OvGCT account for approximately 5% of all ovarian cancers and are the most common subtype of ovarian sex cord stromal tumors. At the time of diagnosis, patients typically present with severe abdominal pain, abdominal distension, and abnormal or postmenopausal bleeding alongside a large pelvic or abdominal mass.3
OvGCT are most commonly diagnosed in women during the perimenopausal/early postmenopausal period with a median age of diagnosis of 50 years.3 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.4,5 Prognosis for patients with advanced disease is poor, with a 10-year survival rate of approximately 25%.6
There are currently no FDA-approved therapies for patients with OvGCT. While early-stage disease can be managed with surgery, approximately 45% of patients experience post-surgical recurrence,7 and once these tumors recur, those with advanced disease often receive off-label systemic therapy, including chemotherapy.
About Nirogacestat
Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors. SpringWorks is also evaluating nirogacestat as a potential treatment for patients with ovarian granulosa cell tumors and for patients with multiple myeloma as part of several B-cell maturation agent (BCMA) combination therapy regimens in collaboration with leaders in industry and academia. Nirogacestat is an investigational drug for which safety and efficacy have not been established.
The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for nirogacestat for the treatment of adults with desmoid tumors, which is being reviewed under the FDA’s Real-Time Oncology Review program. The NDA was granted Priority Review designation and has been given a Prescription Drug User Fee Act (PDUFA) action date of August 27, 2023. The FDA also granted Fast Track and Breakthrough Therapy Designations to nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. In addition, 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.
Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to growth of desmoid and ovarian granulosa cell tumors. Gamma secretase has also been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain (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. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has several collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities. SpringWorks has also formed research collaborations with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA-directed therapies using a variety of preclinical multiple myeloma models.