Cumberland Pharmaceuticals Gears up for Phase II Clinical Trial

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 disease," explained Ines Macias-Perez, PhD, principal scientist for Cumberland Pharmaceuticals. She added the drug is being developed for several other indications recognized as unmet medical needs, as well.

"We were studying it originally for pulmonary arterial hypertension," 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. Typically diagnosed between the ages of three and five and affecting one in 3,500 to 5,000 male children, DMD is a fatal neuromuscular disease caused by a genetic mutation that prevents 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 evaluating ifetroban in mouse models of DMD. They hypothesized TP signaling contributes to DMD-associated cardiomyopathy since activation of TP can create fibrosis in the heart, and therefore blocking TP signaling with ifetroban might decrease the cardiac fibrosis and dysfunction, which could ultimately help 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, a former clinician at Vanderbilt and 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 Muscular Dystrophy" appeared in the December 2019 issue of the Journal of American Heart Association.

Although the Phase II trial hasn't yet begun recruiting, Macias-Perez said the first site at Children's National in Washington, D.C., will begin this month. The plan, she continued, is to have six to nine sites across the country participate to quickly enroll 48 DMD patients. The boys in the study must be at least seven years old and have stable heart disease. Although this is the first ifetroban trial for DMD patients, Macias-Perez noted the safety profile of ifetroban is well established with more than two dozen clinical trials, including Cumberland Pharmaceutical's ongoing trials in scleroderma and aspirin-exacerbated respiratory disease (AERD).

"We worked with families, patient advocacy groups and caregivers to help us design a study that focuses most importantly on the patient and their families," Macias-Perez said. For this reason, she continued, study participants only have to visit the clinician at least three times within a 12-month period to minimize the burden of travel. Additionally, a travel stipend will be provided for those traveling more than 50 miles to the clinical sites in an effort to keep participation from becoming a financial burden.

"Cumberland also designed a new method of measuring ifetroban pharmacokinetics for the DMD trial using a finger-stick method that can be done at home. We were informed during the study design review process that traditional methods using multiple blood draws over 24 hours is a challenge for DMD patients and their families," said Macias-Perez. "The patient families also told us that having the option of continuing on ifetroban after completing the trial is important to them when considering participation on a clinical trial. We changed our protocol to include an optional, open-label extension for all patients that complete the initial 12 months of treatment.

"Incorporating patient feedback into our DMD trial design has added greater value and meaning. We are so grateful to our DMD community for their support of our clinical trial," she added.

A.j. Kazimi

"This new program is an excellent strategic fit for our company given our mission to develop new medicines that address unmet medical needs," said Cumberland Pharmaceuticals CEO A.J. Kazimi. "As ifetroban may uniquely address the heart failure associated with this deadly disease, we very much appreciate the FDA grant support of our novel treatment for these critically ill patients."

He added, "The FDA's involvement through the Orphan Drug Grant is the first time they have gotten involved with DMD from a financial support standpoint." Kazimi said it is exciting the FDA believed this was the right program, the right product and the right clinical sites to move forward.

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