The FIGHT DMD Trial – An FDA Sponsored Study Aimed to Prevent the Cardiomyopathy associated with DMD with an Oral Thromboxane Receptor Antagonist


Pre-Clinical Research

Poster Number: 128


Ines Macias-Perez, PhD, Cumberland Pharmaceuticals

Duchenne muscular dystrophy (DMD) is a rare and fatal disease with no cure. Cardiomyopathy (CM) is the leading cause of death. Thromboxane prostanoid receptor (TPr) activation increases calcium transients in cardiomyocytes, causes arrhythmia, & is pro-fibrotic. We thus hypothesized TPr activation contributes to DMD CM & blockade with the TPr antagonist iferoban may prevent the cardiac phenotype in DMD animal models. Three transgenic mouse models of MD (mdx/utrn double knockout (DKO), 2nd gen mdx/mTR DKO, & delta-sarcoglycan (dSG) KO) were given normal drinking water or water containing 25 mg/kg/day of ifetroban, beginning at weaning. After 6 months (10 weeks for DKO), mice were evaluated for cardiac & skeletal muscle function prior to sacrifice. There was 100% survival of ifetroban-treated mice to the predetermined end point, compared with 60%, 43%, & 90% survival for DKO, mdx/mTR, & dSG KO mice, respectively. Ifetroban improved cardiac output in DKO & mdx/mTR mice, & normalized fractional shortening, ejection fraction, & other parameters in dSG KO mice. TPr antagonism reduced CM and spontaneous death in mouse models of Duchenne and Limb-Girdle MD. These exciting preclinical findings compelled us to design the currently enrolling multicenter, randomized, controlled phase 2 trial to determine the safety and efficacy of oral ifetroban in DMD CM. Our clinical trial is evaluating two doses of daily, oral ifetroban for its potential cardioprotective effect in 48 DMD subjects, 24 with early CM (LVEF > 45%) and 24 with more advanced CM (LVEF 35-45%). Eligible patients receive 12 months of treatment and upon completion, may participate in the optional open-label extension. In addition to quantitative cardiac and respiratory outcomes, the measurable effect of oral ifetroban on muscle strength, daily activity and quality-of-life will be investigated in DMD patients 7 years of age or older. This is the first DMD clinical trial awarded an FDA grant to study an orphan product.