Clinical Trials of Muscular Dystrophy Therapies for Heart Dysfunction Underway

Current drug development approaches for muscular dystrophy have focused mainly on loss of walking ability and do little for heart dysfunction, which often lead to premature death in patients suffering Duchenne and Becker muscular dystrophies (DMD and BMD). Attempts to develop therapies targeting heart dysfunction are underway, however, with clinical trials planned or ongoing.

PhaseBio, a biopharmaceutical company focusing on metabolic and cardiopulmonary disorders, is preparing a clinical trial of PB1046, a drug targeting DMD-associated cardiomyopathy, planned to commence in the second half of 2016. The drug has been developed using the naturally occurring vasoactive intestinal peptide (VIP) as a blueprint.

In a mouse model of DMD, PB1046 slowed the progress of heart dysfunction by protecting against damage caused by muscle contraction. It also prevents formation of fibrosis in the muscles – a key factor in DMD treatment, and could be used to complement exon-skipping treatments.

While VIP is a potent substance, it does not have the necessary properties to be used in a drug preparation. With PB1046, PhaseBio has worked around these difficulties producing a substance that has shown good safety and tolerability results in two Phase 1 studies.

“While current treatments and products in development have focused on support of respiratory function and the prevention of loss of skeletal muscle function, cardiomyopathy and resultant heart failure is becoming more widely recognized as a leading cause of death in DMD patients. The majority of patients will develop progressively worsening cardiomyopathy, with their only treatment options being repurposed heart failure medications and/or glucocorticoids, which haven’t been shown to extend the lives of DMD patients. There is a clear need for new treatment alternatives for all aspects of this debilitating disease, for use alone or in combination, to provide better overall outcomes,” PhaseBio CEO Jonathan Mow told Muscular Dystrophy News.

In December last year, the drug received Orphan Drug Designation by the U.S. Food and Drug Administration (FDA), and PhaseBio is now getting ready to launch a two-part Phase 2a clinical trial of PB1046 in DMD.

The first four-week part of the study will target non-DMD patients older than 18 with ischemic and non-ischemic left ventricle dysfunction. The second part will focus on DMD and BMD patients, older than 18, with cardiac dysfunction. If successful, the trial will be followed by a longer pivotal study in a similar patients with cardiomyopathy.

Meanwhile, Capricor Therapeutics recently initiated a Phase 1/2 clinical trial of its lead candidate CAP-1002. The treatment employs donated heart stem cells called cardiosphere-derived stem cells (CDC) for therapy, and the first patient received the therapy in February.

The study, called HOPE, plans to enroll 24 patients with DMD-related cardiomyopathy in a randomized, multi-center study, which will evaluate the safety and efficacy of CAP-1002.

The treatment, recently reported successful in adult patients with heart failure, infuses heart stem cells directly into the coronary artery of patients, and is intended as a once-weekly injection.

In a press release covering the treatment of the first DMD patient, Capricor CEO Linda Marbán said: “We are thrilled to have initiated the HOPE-Duchenne clinical trial. CAP-1002 is to our knowledge the only clinical stage therapy intended to reduce fibrosis and scar in hearts affected by DMD. One of our goals with our CDCs is to target orphan diseases with cardiac implications, and DMD cardiomyopathy is our first target along these lines. We are hopeful that CAP-1002 may be a big step forward as a treatment option for DMD cardiomyopathy, which at present is a progressive disease with poor therapeutic options.”