Hope for Patients Diagnosed with Rare, Aggressive Desmoid Fibromatosis
SpringWorks Therapeutics founded by Lara Sullivan, Danielle Lynch, Stephen Squinito, Saqib Islam, and L. Mary Smith, is a clinical-stage biopharmaceutical company that takes a precision medicine approach to acquire, develop, and commercialize life-changing medicine. Their current focus is on patients with rare tumors, hematological cancers, and biomarker-defined metastatic solid tumors.
Nirogacestat is an oral small molecule gamma-secretase inhibitor (GSI) in Phase 3 development for adult patients with desmoid tumors. Desmoid tumors are noncancerous growths that occur in the connective tissue. These tumors are rare with significant morbidity and a high rate of recurrence. Currently, there are no medicines approved for the treatment of desmoid tumors.
The DeFi trial is a Phase 3, randomized controlled trial of Nirogacestat versus placebo for progressing desmoid tumors (DT) in adults. The trial met its primary endpoint of improving progression-free survival (PFS) demonstrating statistically significant improvement for Nirogacestat over placebo, with a 71% reduction in the risk of disease progression (hazard ratio (HR) = 0.29 (95% CI: 0.15, 0.55); p<0.001). The median Kaplan-Meier estimate of PFS was not reached in the nirogacestat arm and was 15.1 months in the placebo arm. PFS was observed across all subgroups (gender, tumor location, prior treatment or surgery, and mutational status). Confirmed objective response rate (complete response + partial response) was 41% with Nirogacestat versus 8% with placebo (p<0.001). The complete response rate was 7% in the Nirogacestat arm and 0% in the placebo arm. The key secondary endpoints of the study, patient-reported outcomes (PRO) were also met. Nirogacestat significantly reduced pain (p<0.001) and significantly improved physical/role functioning (p<0.001) and overall health quality of life (p=0.007).
The median duration of treatment (as of primary analysis on April 7, 2022) was 20.6 months for the Nirogacestat group and 11.4 months for the placebo group. Nirogacestat also demonstrated a manageable safety profile with the most reported adverse events being Grade 1 or 2. The most frequently reported adverse events were diarrhea, nausea, and fatigue.
“DeFi is the largest and most robust Phase 3 trial conducted to date in patients with desmoid tumors and we believe these positive data bring us a step closer toward potentially introducing the first approved therapy for this underserved community. We look forward to completing our full NDA filing package by the end of the year, which will be submitted for review under FDA’s RTOR program,” said Saqib Islam, Chief Officer of SpringWorks Therapeutics. In 2018, SpringWorks Therapeutics received FDA fast-track designation for their trial. This will allow an expedited development and review of the orphan drug. SpringWork Therapeutics also recently announced the dosing of their first patient for a Phase 2 trial evaluating Nirogacestat as a monotherapy in patients with recurrent ovarian granulosa cell tumors. This trial is a multi-center, single-arm, open-label study evaluating the efficacy, tolerability, safety, and pharmacokinetics of Nirogacestat.