Duchenne muscular dystrophy (DMD) is a rare and fatal disease affecting approximately 1 in every 3,500 live male births across all races and cultures with no cure. DMD results in loss of ambulation, respiratory failure, cardiomyopathy (CM), and premature death. CM is now the leading cause of death in DMD. Limited ambulation in DMD patients often masks typical symptoms of heart failure, allowing unchecked CM disease progression. Without aggressive screening in DMD, the first manifestation of CM can be irreversible heart failure or sudden cardiac death. Our group and others have shown activation of the thromboxane prostanoid receptor (TPr) located on platelets, immune cells, smooth muscle and cardiomyocytes contributes to deleterious effects in the heart. Further, TPr blockade with the potent and selective TPr antagonist, ifetroban, prevents cardiac fibrosis, improves cardiac function and mortality in multiple animal models of DMD CM. Isoprostanes (IP) activate the TPr and are elevated in DMD. Not only are they the most reliable marker for assessing oxidative stress, IP are mediators of vascular dysfunction. They perpetuate the inflammatory response to oxidant injury, which may play a key role in DMD CM pathogenesis. Our overall goal is to determine the safety and efficacy of ifetroban to support its approval for the treatment of DMD CM, a rare condition where no current therapy exists thereby directly serving the Orphan Products Development?s mission. The proposed clinical study aims to determine the safety, pharmacokinetics and efficacy of oral ifetroban in patients with DMD CM. 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. This randomized, placebo-controlled, multicenter phase 2 trial is designed to test the central hypothesis that TPr signaling promotes cardiac inflammation and drives IP overproduction contributing to DMD CM, thereby perpetuating the inflammatory response which leads to cardiac fibrosis and vascular dysfunction.
Aim 1 will determine the safety and efficacy of ifetroban, an oral TPr antagonist, as treatment for DMD CM. A network of pediatric cardiologists with DMD and cardiac imaging expertise at the largest DMD centers in the country will expedite enrollment for this rare disease. The same imaging equipment and standardized cardiac imaging protocol will be used to compare cardiac imaging data across centers.
Aim 2 will determine the effect of TPr blockade on protein expression and CMR structures. Specimens and imaging will be used to determine the effects of TPr blockade on skeletal muscle and CM disease progression. Successful completion of this phase 2 trial will help support the approval of ifetroban for treatment of DMD CM. Study outcomes will provide the necessary information for design of the pivotal phase 3 study to have the greatest impact on reducing death and disability in patients with DMD.
Heart muscle disease is now the leading cause of death in patients with Duchenne muscular dystrophy (DMD), a rare and fatal condition. The central objective of this proposal is to test a novel targeted drug product, ifetroban, for safety and efficacy in the treatment of DMD heart muscle disease, an unmet medical need. Successful clinical outcomes from this study will support the clinical development and approval of ifetroban for treating DMD heart muscle disease and improving the quality of life in children and men with DMD.
