Researchers throughout the world continue to work towards improved treatments for Duchenne muscular dystrophy (DMD). In response to recent advancements in the lab, the Muscular Dystrophy Association has published their Fall 2014 drug development update, highlighting the most prominent and promising DMD research and drug development.
Translarna (ataluren), a protein restoration therapy being developed by PTC Therapeutics, received conditional approval in Europe this past August for use in ambulatory patients ages five and up suffering from genetic-caused DMD, also known as premature stop codons or nonsense mutations. The association had granted PTC Therapeutics $1.5 million funding for the development of the stop codon read-through drug.
In addition, the company has announced the completion of patient enrollment for a phase 3 trial to study Translarna, with results planned for the second half of the next year. The study is a large-scale, 48-week, multinational trial, and the company expects the data from it to support the drug’s approval in both the United States and the European Union. The phase 2b trial assessed the safety and efficacy of Translarna in male patients with nonsense mutation DMD, and the results revealed its effectiveness in reducing the decline in the distance the patients were able to walk in six minutes.
British biotechnology company Summit PLC also announced last month that their experimental oral drug therapy, which is being developed with the support of the MDA, has had positive results in its phase 1b trial in male DMD patients. The study revealed the drug SMT C1100’s safety and ability to reduce blood levels of enzymes related to muscle damage. The drug is an atropin modulator that increases the levels and distribution of the muscle protein utrophin, which is related to the disease. Controlling the levels and distribution of utrophin within muscle fibers can help compensate for part of the dystrophin protein loss caused by DMD, according to previous studies. In addition, utrophin modulators are designed to be effective regardless of the DMD-causing genetic mutation. The results of the phase 1b trial were presented at the World Muscle Society meeting last October, and the company said it was working on additional utrophin-altering compounds.
Last July, ReveraGen Biopharma, another drug development company supported by the MDA, also reported that its experimental DMD compound VBP15 was beginning testing in healthy subjects, and that the company expected to continue studies with DMD patients. The drug has been designed to provide the same benefits of corticosteroid medications on DMD-affected muscles, but with less harsh side effects, such as weight gain, growth slowing, and mood changes.
A study authored by the MDA grantee Eric Hoffman and colleagues and recently published at the Journal of Cell Biology, demonstrated the ability of VBP15 in reducing the formation of scar tissue in the muscles. In addition, the researchers discovered in mice that neighbor fibers, which were injured in 10-day intervals, can experience conflict signaling, becoming confused, and creating scars instead of regenerating. When treated with prednisone or VBP15, the healing process was able to resynchronize, which the researchers believe provides important information on the muscle’s ability to heal.
Sarepta Therapeutics is currently enrolling patients for its phase 3 trial to study the experimental DMD drug eteplirsen, developed to target and block a section of genetic instructions for the dystrophin protein exon 51. The drug is expected to make a functional, albeit short version of the missing dystrophin protein in DMD-affected cells. Even though the company was planning on submitting a new drug application to the U.S. Food and Drug Administration (FDA) this year, the FDA recently asked for more data and trials about the drug, delaying the process at least until the middle of next year.
“We understand that this news is disappointing to the DMD community, and we feel the same sense of urgency that our families do when it comes to finding effective treatments,” explained the MDA’s chief medical and scientific officer, neurologist Valerie Cwik, M.D. “We hope this development will not significantly delay the process as the FDA ensures eteplirsen is safe and effective before it is brought into the clinic.”
Sarepta is now working to meet the criteria required by the FDA and is going to submit an application for an accelerated approval pathway, an option offered by the agency to accelerate the development of new drugs. In addition, the company is also studying other exon-skipping compounds that target the 53, 45, 50, 44, 52, and 8 exons of the dystrophin gene. The company expects to be able to develop these studies, which are not yet clinical trials, into DMD treatments.
The Dutch biotechnology company Prosensa also submitted a new drug application for its DMD drug called drisapersen to the FDA this past October using the accelerated approval method. In addition, the company also announced that it was planning on submitting a marketing authorization application to the European Medicines Agency (EMA) for conditional approval at the beginning of next year. The drug is designed to target exon 51 of the dystrophin gene for the treatment of DMD patients.
Last September, the company began the re-administration of drisapersen in their ongoing trials in both North America and Europe after having stopped due to discouraging preliminary results. The phase 3 trial conducted in 2003 failed its intentions to demonstrate the drug effectiveness on tests of walking distance or motor function at 48 weeks, compared to placebo. However, two new phase 2 trials revealed different and more encouraging results that influenced the company’s decision to start re-administering patients.
These above mentioned drug development profiles are among those that the MD Association considers to be the most promising for bringing new, commercially-available therapies to the DMD patient population in the near future.