On September 29, 2022 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 the first patient has been dosed in a Phase 2 trial evaluating nirogacestat, SpringWorks’ investigational gamma secretase inhibitor, as a monotherapy in patients with recurrent ovarian granulosa cell tumors (Press release, SpringWorks Therapeutics, SEP 29, 2022, View Source [SID1234621551]).
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Ovarian granulosa cell tumors 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 ovarian granulosa cell tumors harbor a mutation in the FOXL2 gene and preclinical studies have demonstrated that ovarian granulosa cell tumor cell lines are susceptible to gamma secretase inhibition.1,2
"The science behind this study is exciting because Notch signaling, a key target of gamma secretase inhibitors, is involved in the expression of FOXL2, which is an integral component of granulosa cell development, proliferation, and function," said Panos Konstantinopoulos, M.D., Ph.D., Director of Gynecological Oncology Translational Research at Dana-Farber Cancer Center and Harvard Medical School and the Principal Investigator of the Phase 2 trial. "Without any FDA-approved therapies, there is a high unmet need for patients with recurrent ovarian granulosa cell tumors and I look forward to evaluating nirogacestat in this important study."
"Over the course of their disease, patients with ovarian granulosa cell tumors may experience severe abdominal pain associated with a large pelvic or abdominal mass, requiring surgery and subsequent systemic therapy," said Saqib Islam, Chief Executive Officer of SpringWorks. "We are pleased to be developing a much-needed therapy for these patients and are encouraged by this new, meaningful opportunity for nirogacestat."
The Phase 2 trial (NCT05348356) is a multi-center, single-arm, open-label study evaluating the efficacy, tolerability, safety, and pharmacokinetics of nirogacestat in patients with recurrent ovarian granulosa cell tumors. The study will enroll approximately 40 patients who will receive 150mg of nirogacestat twice daily. Eligible patients will have recurrent ovarian granulosa cell tumors and will have 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. Surgery is currently the mainstay of initial treatment, however, the risk of recurrence is high for those with advanced disease and off-label systemic therapy, including chemotherapy, is often used.
About Nirogacestat
Nirogacestat is an investigational, oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors and in Phase 2 clinical development for ovarian granulosa cell tumors. 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.
In addition, gamma secretase has been shown to directly cleave membrane-bound B cell maturation antigen (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 eight collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies, three bispecific antibodies and a monoclonal antibody. 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.
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. SpringWorks plans to submit a New Drug Application (NDA) to the FDA in the second half of 2022, which will be submitted for review under the FDA’s Real-Time Oncology Review (RTOR) program.