March 23, 2011 -- Exciting findings from an early-stage clinical trial offer new hope to patients with Duchenne's muscular dystrophy, the most common but incurable and devastating form of muscular dystrophy.
Patients who received three months of weekly injections with PRO051 had a modest improvement in their ability to walk, reports a research team led by Judith C. van Deutekom, PhD, vice president for discovery at Prosensa Therapeutics, which funded the study.
"The patients are still on the product, and anecdotal evidence suggests they are functioning better in daily life," van Deutekom tells WebMD.
Duchenne's muscular dystrophy (DMD) is a very common form of the disease, striking about one in every 3,500 boys worldwide. It's a recessive genetic defect, carried by mothers but almost always striking boys.
The defect is in the gene coding for dystrophin, a protein with a major role in muscle function. Normal dystrophin acts like a shock absorber for muscle cells. The defective dystrophin in DMD leads to muscle damage and degeneration, says muscular dystrophy expert Roger W. Kula, MD, head of the neuromuscular clinic at North Shore-Long Island Jewish Health System.
"Duchenne's patients have progressive wasting of muscle," Kula, who was not involved in the PRO051 study, tells WebMD. "The disease affects walking at age 2 to 5 years, confines patients to wheelchair by age 9 to 12, and results in death from age 20 to 30. It is horrible."
Different patients with DMD have different mutations in the gene that codes for dystrophin. One of the most common mutations -- seen in about 13% of DMD patients -- is at a site called exon 51. PRO051 is a string of nucleic acids called an antisense oligonucleotide.
When the body is decoding the dystrophin gene, the drug causes the mRNA that is "reading" the gene to skip over the mutated exon 51. The result is a dystrophin protein that isn't exactly normal, but which works well enough. Muscular dystrophy patients who have naturally occurring dystrophin like this have a much milder form of the disease known as Becker's muscular dystrophy.
In their study, van Deutekom and colleagues enrolled 12 DMD patients at an average age of 9 years. In the first phase of the study, they gave increasing doses of the drug to sets of three patients. There were no serious safety issues, and patients given higher doses showed evidence of making functional dystrophin.
This led to a second phase in which all 12 patients received weekly abdominal injections of PRO051 at the highest dose tested.
"We noticed a modest improvement, which is quite remarkable for patients with this disease, in the distance they can walk in six minutes," van Deutekom says. "The dystrophin probably accumulated over time in their muscles and led to the observed improvement."
Three of the patients improved their walking distance by 213 feet or more. That may not seem like much. But in just the six to 15 months between the first and second phases of the study, these patients' six-minute walking ability had declined by 121 feet.
"This is exciting, but it is not going to be for everyone with DMD," Kula says. "But the exciting thing is, if the technology works out, you can generate drugs for different DMD mutations. That is the wave of the future."
Indeed, van Deutekom says that is exactly what her company is doing. PRO051 should work for patients with DMD mutations on or very near exon 51. Now in the works are similar drugs targeting exons 44, 45, 52, 53, and 55.
PRO051 is not the only drug candidate in clinical trials. A U.S. company, AVI BioPharma, is testing a similar exon-51-skipping antisense oligonucleotide called AVI-4658. Promising findings -- but not clinical improvement -- was reported last October from early clinical trials of AVI-4658.
Van Deutekom and colleagues report their findings in an early online release of the New England Journal of Medicine.