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Cedars-Sinai Study: Common Drug Restores Blood Flow in Deadly Form of Muscular Dystrophy

Results From 10-Patient Case Study Lead to Phase III Clinical Trial for Patients with Duchenne Muscular Dystrophy

Los Angeles - May 7, 2014 - Cedars-Sinai Heart Institute researchers have found that a commonly prescribed drug restores blood flow to oxygen-starved muscles of boys with Duchenne muscular dystrophy, a genetic muscle-wasting disease that rarely is seen in girls but affects one in 3,500 male babies, profoundly shortening life expectancy. It is the most common fatal disease that affects children.

Muscle weakness begins in early childhood, often causing deformity of the arms, legs and spine. Heart and respiratory muscles often begin to fail before children reach early teen years. Although steroid medications – which often are not well tolerated – and other therapies may ease symptoms and delay the most severe effects, no disease-specific treatment exists, and patients rarely survive into their 30s.

But in this case study of 10 boys with Duchenne muscular dystrophy, also called DMD, a single dose of a drug often prescribed for erectile dysfunction or pulmonary hypertension corrected defective blood vessel mechanisms and restored blood flow to exercising muscles.

"The effects were immediate and dramatic, raising the question: If a single dose restores blood flow to muscle while the drug is in the patient's system, could ongoing tadalafil administration provide sustained benefits, possibly preserve muscle and slow disease progression? If so, this would offer a new therapeutic strategy for DMD, and we have launched a randomized Phase III clinical trial to find out," said Ronald Victor, MD, director of the Cedars-Sinai Center for Hypertension, associate director of clinical research at the Heart Institute and the Burns and Allen Chair in Cardiology Research. He is the senior author of a highlighted article in the May 7 online edition of Neurology.

Duchenne muscular dystrophy results from a genetic defect that eliminates a protein called dystrophin in the membranes of muscle cells. For more than 25 years, Victor has studied DMD and a less aggressive but debilitating variant called Becker muscular dystrophy. This form of muscular dystrophy, usually diagnosed in early adulthood, is caused by a reduction, but not absence, of dystrophin.

Victor led a research team that in 2000 discovered that the blood flow abnormality in the muscles of children with DMD was caused by a loss of nitric oxide, a signaling chemical that normally tells blood vessels to relax during exercise, increasing blood flow and oxygenation.

In studies of mice bred to represent diseases of dystrophin deficiency, the researchers found that drugs prescribed for other disorders of blood vessel function could restore muscle blood flow and enable the animals to exercise more, with less muscle injury. Tadalafil, known by the brand names Cialis and Adcirca, and sildenafil, called Viagra and Revatio, have long been approved by the Food and Drug Administration to treat erectile dysfunction and pulmonary hypertension, a serious illness that restricts blood flow to the lungs.

Translating these findings to a human clinical trial, Victor and his colleagues published in 2012 a study showing that tadalafil fully restored blood flow in eight of nine patients with Becker muscular dystrophy.

In the new study, investigators found that when boys with Duchenne muscular dystrophy performed handgrip exercises, the major artery of the arm and the blood vessels in muscles of the forearm failed to respond the way they did in healthy boys of similar ages, 8 to 13. But when the boys with DMD were given a single dose of tadalafil, normal vessel function and blood flow were restored. Similar results occurred when sildenafil, a drug with a similar mechanism of action on vessels but a different chemical structure, was used in place of tadalafil.

"Steroids and cardiac-protective blood pressure medication are increasingly prescribed at early ages for patients with Duchenne muscular dystrophy in an effort to delay by a few years the most devastating effects of the disease. But these treatments have no effect on the blood vessel dysfunction that prevents muscles from getting the oxygen they need," said Victor. "In contrast, in our study, a single dose of tadalafil or sildenafil had an immediate effect. These are well-studied, well-tolerated drugs that are already on the market. If additional study confirms their benefits, repurposing the drugs for muscular dystrophy patients could quickly transform clinical practice."

This study was funded by a research grant to Victor from Parent Project Muscular Dystrophy (PPMD). Supplemental support was provided by the National Institutes of Health's National Center for Advancing Translational Sciences UCLA CTSI (UL1TR000124). The findings of this PPMD-funded study, together with a clinical trial planning grant to Victor from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U34 AR062893), informed the design of an industry (Lilly)-sponsored Phase 3 multicenter registration trial, which is currently enrolling, to determine whether once daily tadalafil administered orally for 48 weeks lessens the decline in ambulatory ability as measured by the 6-minute walk distance compared to placebo in boys with DMD (NCT01865084). First author Michael Nelson, PhD, is the recipient of research fellowship grants from the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research.

Researchers from the Heart Institute and the Department of Pediatrics at Cedars-Sinai; the Department of Human Genetics, the Department of Pathology and Laboratory Medicine and the Department of Microbiology, Immunology and Molecular Genetics at the David Geffen School of Medicine at UCLA; the Department of Biomathematics at UCLA; the Department of Biostatistics at the UCLA School of Public Health; and the Pennsylvania Muscle Institute in the Department of Medicine at the University of Pennsylvania contributed to the article.

Citation: Neurology, "PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy," available online May 7, 2014.