Oral Thromboxane Receptor Antagonist Demonstrates Significant Cardiac Benefit in 12-Month Phase 2 Trial in Duchenne Muscular Dystrophy Patients

Topic:

Clinical Trials

Poster Number: LB440

Author(s):

John Jerry Parent, MD, MSCR, Indiana University School of Medicine, Larry W. Markham, MD, Indiana University School of Medicine, Jonathan H. Soslow, MD, MSCI, Vanderbilt University Medical Center, Erica J. Carrier, PhD, Vanderbilt University Medical Center, James D. West, PhD, Vanderbilt University Medical Center, Breanne H.Y. Gibson, PhD, Cumberland Pharmaceuticals, Andrew T. Abad, PhD, Cumberland Pharmaceuticals, Byron Kaelin, RN, BSHS, Cumberland Pharmaceuticals, Ingrid Anderson, PhD, Cumberland Pharmaceuticals, Leo Pavliv, RPh, MBA, Cumberland Pharmaceuticals, Ines M. Macias-Perez, PhD, Cumberland Pharmaceuticals

Duchenne muscular dystrophy (DMD) is a rare and fatal disease for which there is no cure. The leading cause of death in DMD patients is cardiomyopathy (CM) marked by progressive tissue damage and fibro-fatty replacement of cardiomyocytes. Aberrant thromboxane prostanoid receptor (TPr) activation has been implicated in dysfunctional calcium handling and profibrotic signaling in DMD CM. Preclinical studies have demonstrated a cardioprotective effect for TPr antagonist ifetroban in DMD mouse models.

The safety and efficacy of oral ifetroban in DMD CM was evaluated in a 12-month randomized, placebo-controlled phase 2 clinical trial. A total of 41 DMD subjects were randomized to receive placebo (N=11), low-dose (100 mg, N=12), or high-dose ifetroban (300 mg, N=18) daily for 12 months (NCT03340675). Cardiac efficacy was measured by change from baseline in left ventricular ejection fraction (LVEF). High-dose ifetroban-treated subjects experienced a 1.8% increase (+/- 5.4) in LVEF whereas placebo-treated subjects experienced a 1.5% (+/- 3.3) decline in LVEF over 12 months, consistent with known progression of DMD CM. LVEF remained unchanged over 12 months with low-dose ifetroban treatment. A planned control group of 24 DMD patients (6 placebo, 18 propensity-matched by age, baseline LVEF, and DMD therapies from a contemporary FDA funded DMD natural history study) showed a 3.6% (+/- 4.1) decline in LVEF over 12 months. Overall, the between group difference in LVEF change for high-dose and placebo was 3.3% and 5.4% (p=0.002) comparing high dose with matched natural history patients. Transcriptomic profiling identified several peripherally-expressed potential biomarkers that changed with ifetroban treatment and corresponded with improved LVEF. There were no serious or unexpected drug-related events.

Over 12 months, ifetroban was well-tolerated with a clinically significant benefit in cardiac function, highlighting its potential for therapeutic use in DMD CM. Long-term follow-up is ongoing in an optional open-label extension with high-dose ifetroban.