Ifetroban for Treating DMD-Associated Cardiomyopathy Cumberland Pharmaceuticals Gears up for Phase II Clinical Trial By CINDY SANDERS
Last fall, the U.S. Food and Drug Administration (FDA) announced $15 million in grant funding in support of 12 new clinical trials through the Orphan Products Clinical Trials Grant Program funded by Congress. The grants aim to determine the benefit of various treatment options for patients with rare diseases. Cumberland Pharmaceuticals, a Nashville-based specialty pharmaceutical company, received $1 million as one of the 12 recipients to help fund a new Phase II clinical trial studying the use of ifetroban to treat cardiomyopathy associated with Duchenne Muscular Dystrophy (DMD). Ifetroban is a potent antagonist of the thromboxane prostanoid (TP) receptor, which has various functions including smooth muscle contraction, platelet aggregation and inflammation. “It is not currently approved by the FDA but is a candidate for orphan drug status because DMD meets the U.S. definition of
a rare diseased,” explained Ines MaciasPerez, PhD, principal scientist for Cumberland Pharmaceuticals. She added the drug is being developed for several other indications recog- Ines Macias-Perez, nized as unmet mediPhD cal needs, as well. “We were studying it originally for pulmonary arterial hypertension, or PAH,” Macias-Perez continued, “and found ifetroban could prevent fibrosis in the heart.” That observation led the publicly traded company, which has successfully brought a number of other drugs to market to treat a range of unmet needs, to consider ifetroban as a possible therapy for DMD patients. Affecting one in 3,500 to 5,000 male children, DMD is a fatal neuromuscular disease caused by a genetic mutation preventing the body from producing dystrophin, which is
critical for muscles to function properly. Characterized by muscle weakness and the progressive loss of muscle, cardiomyopathy leading to arrhythmias and heart failure has emerged as the leading cause of death in DMD patients. “DMD is a devastating X-linked disease affecting primarily boys and leads to losing their ability to walk between ages eight and 12, respiratory failure and cardiomyopathy at any age, and inevitably premature death in their 20s or early 30s,” explained Macias-Perez. “Many other drug development efforts are focused on restoring dystrophin and prolonging ambulation. With no specific cardiac treatments to extend life, our study aims to address this unmet need using a new therapeutic strategy for patients with DMD.” Cumberland Pharmaceuticals is working in collaboration with scientists at Vanderbilt University Medical Center to evaluate ifetroban in mouse models of DMD. They believed TP signaling contributes to DMD-associated cardio-
myopathy since activation of TP could create fibrosis in the heart. Therefore, blocking TP signaling with ifetroban might decrease the cardiac fibrosis and dysfunction, thereby helping those with the disease live longer. Results of the preclinical studies affirmed those conclusions with all mice in the ifetroban arm surviving to the end of the study compared to 60 percent, 43 percent and 90 percent in the various mouse models treated with placebo. Additionally, TPr antagonism improved cardiac output in two models of severe DMD and increased ejection fraction while decreasing fibrosis in the third. The team from Vanderbilt, Cumberland Pharmaceuticals and Indiana University School of Medicine – where Larry Markham, MD, primary investigator on the ifetroban trial is located – recently published these successful results. “Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscu(CONTINUED ON PAGE 12)
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