On February 27, 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 the U.S. Food and Drug Administration (FDA) has accepted the Company’s New Drug Application (NDA) for nirogacestat, an investigational gamma secretase inhibitor, for the treatment of adults with desmoid tumors (Press release, SpringWorks Therapeutics, FEB 27, 2023, View Source [SID1234627747]). The NDA was granted Priority Review and has been given a Prescription Drug User Fee Act (PDUFA) action date of August 27, 2023. The FDA’s Priority Review designation is given to investigational medicines that treat a serious condition and offer significant improvements in safety or effectiveness. In addition, the FDA has stated that it is not currently planning to hold an advisory committee meeting to discuss the application.
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"People with desmoid tumors can experience severe pain and other debilitating morbidities, and we are excited by the opportunity to potentially transform the standard of care for these patients," said Saqib Islam, Chief Executive Officer of SpringWorks. "The acceptance of our NDA for nirogacestat with Priority Review represents a significant milestone in our ambition to provide the first approved therapy for patients with desmoid tumors. We look forward to working closely with the FDA during the review process and remain focused on ensuring that we are well-positioned to expeditiously serve the desmoid tumor patient and the physician communities following approval."
The NDA is being reviewed under the FDA’s Real-Time Oncology Review (RTOR) program and is based on the previously announced positive results from the Phase 3 DeFi trial, a global, randomized, double-blind, placebo-controlled trial evaluating nirogacestat in adult patients with desmoid tumors. The FDA 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. Nirogacestat has also received Orphan Drug designation from the FDA for the treatment of desmoid tumors.
About the DeFi Trial
DeFi (NCT03785964) is a global, randomized (1:1), double-blind, placebo-controlled Phase 3 trial evaluating the efficacy, safety and tolerability of nirogacestat in adult patients with progressing desmoid tumors. The double-blind phase of the study randomized 142 patients (nirogacestat, n=70; placebo n=72) to receive 150 mg of nirogacestat or placebo twice daily. Key eligibility criteria included tumor progression by ≥20% as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) within 12 months prior to screening. The primary endpoint was progression-free survival, as assessed by blinded independent central review, or death by any cause. Secondary and exploratory endpoints included safety and tolerability measures, objective response rate (ORR), duration of response, changes in tumor volume assessed by magnetic resonance imaging (MRI), and changes in patient-reported outcomes (PROs). DeFi includes an open-label extension phase, which is ongoing.
About Desmoid Tumors
Desmoid tumors are rare, aggressive, locally invasive, and potentially morbid tumors of the soft tissues.1,2 While they do not metastasize, desmoid tumors are associated with a high rate of recurrence.2,3,4 Sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis, these soft tissue tumors can be serious, debilitating, and, in rare cases when vital structures are impacted, they can be life-threatening.2,5
Desmoid tumors are most commonly diagnosed in patients between the ages of 20 and 44 years, with a two-to-three times higher prevalence in females.4,6,7,8 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.7,8,9
Historically, desmoid tumors were treated with surgical resection, but this approach has become less favored due to a high recurrence rate after surgery.1,4,10 There are currently no FDA-approved therapies for the treatment of desmoid tumors.
About Nirogacestat
Nirogacestat is an 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. Nirogacestat is an investigational drug for which safety and efficacy have not been established.
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 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 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.
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.