SOUTH PLAINFIELD, N.J.—PTC Therapeutics Inc. announced in July the publication of the results of the ACT DMD trial study of ataluren, the only treatment for the underlying cause of nonsense mutation Duchenne muscular dystrophy (nmDMD), in The Lancet.
“There is a critical need for disease-modifying therapies for this devastating fatal disorder,” states Dr. Craig M. McDonald, lead author and an investigator of ACT DMD, professor of pediatrics and chair of the Department of Physical Medicine and Rehabilitation at the school of medicine of the University of California, Davis. “The data in the publication show that ataluren provides benefit for nmDMD patients who were in the functional range where a treatment benefit can be seen in a one-year trial. The slowing or stabilizing of disease progression and motor function is a highly valuable effect of drug treatment, which likely translates to longer-term benefits.”
Ataluren is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as dystrophin in Duchenne muscular dystrophy.
“This lack of dystrophin [means that] muscle fibers can be damaged with normal activities, and muscle fibers degenerate and are replaced by scar tissue and fat. Patients with DMD lose the ability to walk in their early teens, and experience life-threatening lung and heart complications in their late teens and twenties,” McDonald tells DDNews. “Ataluren allows ribosomal readthrough of premature stop codons, thus enabling production of functional dystrophin that might improve muscle survival and decrease disease progression.”
“Ataluren is licensed in the European Economic Area for the treatment of nmDMD in ambulatory patients aged five years and older under the trade name Translarna. Translarna has been given ‘conditional approval’ in the EU, meaning that the company will continue to provide more evidence about the therapy in the years to come,” McDonald continues. “Every year, the European Medicines Agency (EMA) will review any new information that becomes available. Ataluren in the U.S. currently has an application in for review at the FDA that will hopefully include both ambulatory and non-ambulatory labels for the nmDMD population.
“Future and ongoing trials for ataluren should assess the long-term benefits in patients with nmDMD. The delay in loss of ambulation reported in patients given ataluren will hopefully extend to longer-term benefits in both upper-limb and pulmonary function in non-ambulatory patients with DMD. An evaluation of non-ambulatory patients that have been treated with ataluren shows that they have a reduced rate of pulmonary decline in comparison to natural history DMD patients treated only with steroids. Future research will hopefully identify additional benefits of ataluren in non-ambulatory patients, as the preservation of muscle fibers could translate to relative preservation of arm function and pulmonary function.”
ACT DMD is a multicenter, randomized, double-blind, Phase 3 clinical trial involving 228 patients in 53 sites across 18 countries. Patients with nmDMD were randomized to receive either ataluren 40mg/kg per day or placebo over 48 weeks. The primary endpoint was change from baseline in the six-minute walk test. Treatment effects are more likely to be observed in patients in the transition stage of disease (baseline six-minute walk distance, or 6MWD, of 300 to 400 meters). Analyses of data from prespecified subgroups, including the prespecified subgroup of patients with 6MWD of 300 to 400 meters, were also completed. Key secondary outcome measures were timed-function tests, including time to run or walk 10 meters and the time to ascend or descend four stairs. Exploratory efficacy endpoints were change in physical function as assessed by change in the North Star Ambulatory Assessment, parent-reported health-related quality of life and activities of daily living.
“The six-minute walk test and timed function tests are recommended in guidelines from the EMA and the U.S. FDA for use in clinical trials of DMD, but there are several limitations to their use in a short-duration 48-week trial,” says McDonald. “The 6MWD doesn’t tend to change much over 48 weeks in patients with higher levels of baseline function, and these measures show substantial variability in changes over time in patients with lower baseline function.”
“While we believe treatments such as ataluren preserve muscle fibers and functional abilities in younger stable patients who haven’t entered the transitional decline phase of the disease, it’s difficult to show this benefit over 48 weeks. It likely takes a longer than one-year period of time to demonstrate treatment benefits in younger, more stable patients,” notes McDonald. “Many therapeutic agents have been approved by the FDA and EMA based on improvements in the 6MWD relative to placebo, so the regulatory authorities have a certain amount of comfort with the six-minute walk test when used in placebo-controlled trials. The FDA is increasingly interested in other measures such as the North Star Ambulatory Assessment that has some increased ability to measure benefits over a broader range of patients.”
“The most important finding in ACT DMD was the consistency of large benefits seen across all endpoints when the prespecified transition phase subgroup was assessed. We now know this to be the group of patients where treatment effects can be assessed in a one-year trial when the benefit of a drug is stabilization of DMD disease progression,” McDonald concludes.
