A funny thing happened while analysts and investors were debating implications of the two-month gap in advisory committee meetings between Duchenne muscular dystrophy (DMD) candidates from Biomarin Pharmaceutical Inc. and Sarepta Therapeutics Inc. PTC Therapeutics Inc., whose DMD candidate, Translarna (ataluren), already has conditional approval in the EU, reported data from its phase III ACT DMD trial suggesting treatment with Translarna can alter the course of DMD disease progression.

But with some caveats.

The randomized, double-blind ACT DMD trial is the largest completed in patients with DMD, according to Cortellis Clinical Trials Intelligence. The study enrolled 228 patients with nonsense mutation DMD at 53 sites across 18 countries. Patients between the ages of 7 and 16 were randomized to Translarna 40 mg/kg per day (n = 114) or placebo (n = 114) over 48 weeks. The primary endpoint was change from baseline in the six-minute walk test (6MWT).

The debut drew a mixed review. Patients in the intent-to-treat population showed a 15-meter benefit (p = 0.213), missing statistical significance. Patients in the pre-specified population with a baseline measurement of 300 to 400 meters on the 6MWT, however, achieved a highly significant benefit of 47 meters (p = 0.007), similar to findings from the company’s phase IIb trial. Moreover, no patients in the pre-specified group who were treated with Translarna lost ambulation (0/47) compared to four patients in the placebo group (4/52) who did.

Shane Kovacs, PTC’s executive vice president, chief financial officer and head of corporate development, said the data were consistent with the evolving understanding of the 6MWT.

“Translarna is an oral small molecule that gets systemic distribution and should touch the systemic muscle tissue – not only the skeletal muscle in the legs but also in the arms, the diaphragm and the cardiac tissue,” he explained. “We’ve shown preclinically that we produce the protein, dystrophin, in all of that tissue. The challenge in conducting clinical studies is that you need to pick an endpoint, and the endpoint today is an ambulatory endpoint, the six-minute walk test, so you’re only studying ambulatory boys.”

The experience in rare diseases is that the label isn’t necessarily limited to the subpopulation that was studied, Kovacs added, because the benefit inferred scientifically should accrue across ambulatory and non-ambulatory patients.

“Clearly, you want to treat these boys, the younger the better,” Kovacs told BioWorld Today. “What you’re trying to do is keep the healthy muscle tissue healthy and maintain its strength. But for older boys who are not ambulatory but can still move their arms and get around that way, you want to be able to preserve that function.”

Craig McDonald, an ACT DMD investigator and professor of pediatrics and chair of the department of physical medicine and rehabilitation at the University of California Davis School of Medicine, said the results showed positive treatment effects across multiple endpoints, validating “our emerging understanding of the optimal patient group in which to demonstrate benefit in the six-minute walk test.” He said the findings were particularly notable given the study’s relatively short time frame.

“These patients show progressive loss of function that occurs over a wide range of muscle groups in various trajectories,” McDonald explained. “The challenge in a study of these patients is to actually choose the endpoints that are going to have the greatest likelihood of showing a clinical benefit in a short trial duration.”

ACT DMD was designed to enroll a broad spectrum of ambulatory DMD patients “in the spirit of the recent FDA draft guidance for Duchenne clinical trials,” he added, with the group mostly likely to see benefit chosen as a pre-specified subgroup.

“With any 48-week Duchenne trial that focuses on an ambulatory population, the six-minute walk distance has been shown to be a responsive and well-validated endpoint,” McDonald pointed out. “In the most optimal treatment population chosen to be able to demonstrate the treatment effect – the group that was pre-specified to be 300 meters to 400 meters – we saw a quite robust effect.”

Equally encouraging, he said, was that key secondary and tertiary endpoints all favored Translarna, including timed function tests (10 meter Run/Walk, 4 Stair Climb, 4 Stair Descend), North Star Ambulatory Assessment test and the Pediatric Outcomes Data Collection Instrument, a quality-of-life measurement for pediatric patients with orthopedic conditions.

In addition, a pre-specified meta-analysis of the combined placebo-controlled ACT DMD and phase IIb trials demonstrated a statistically significant benefit of Translarna across the primary (p = 0.015) and key secondary endpoints.

“What patients and their families desire most are treatments that slow progression of the disease, and the totality of the data in two well-controlled trials showed that Translarna can slow that progression,” McDonald said, mitigating future losses of ambulation, upper limb function and respiratory decline.

ACT DMD confirmed the safety profile of Translarna, which was generally well tolerated, consistent with results from previous studies. More than 500 nmDMD patients have received the drug, which has been in development for more than a decade, including a previous partnership with then-independent Genzyme Corp. during the phase IIb study, which also demonstrated disappointing efficacy results across the entire population. (See BioWorld Today, March 20, 2010.)

‘EVERY EXPECTATION’ OF ANOTHER FDA ADCOM

Following completion of ACT DMD, both placebo and treated patients were given the opportunity to continue on Translarna in an open-label extension study. Ninety-seven percent of the patients who completed ACT DMD, or more than 200 patients, enrolled in the extension study. As additional data are captured over time, “we will likely see continued benefit and even a more robust benefit in comparison to the natural history of the disease,” McDonald predicted.

PTC, of South Plainfield, N.J., said it will submit the findings to the EMA and complete its rolling NDA submission to the FDA – begun last December – by year-end.

Translarna received conditional marketing authorization from the EMA in 2014 for use in ambulatory nmDMD patients 5 and older, ignoring a previous opinion from the Committee for Medicinal Products for Human Use that concluded the phase IIb study failed to show that patients taking oral Translarna performed better on the 6MWT than those on placebo and that other measures “provided only limited supportive evidence of the beneficial effects” of the drug. (See BioWorld Today, May 27, 2014.)

The drug is the only one in clinical development for DMD patients with the nonsense mutation in the dystrophin gene, borne by 10 percent to 15 percent of DMD patients, which causes the cells to stop synthesizing the protein before the process is done.

In recent days, Biomarin, of San Rafael, Calif., and Cambridge, Mass.-based Sarepta disclosed that the FDA advisory committees plan to review their exon-skipping DMD drugs, drisapersen and eteplirsen, not on back-to-back days but on Nov. 24 and Jan. 22, 2016, respectively. Biomarin, which was the first to complete its NDA submission, recently gained additional ground over Sarepta in a patent dispute addressing claims to the use of exon 51 antisense oligonucleotides to treat DMD. (See BioWorld Today, April 29, 2015, and Oct. 2, 2015.)

Given that Translarna targets the same rare disease indication, McDonald said “he had every expectation” that the FDA will convene an advisory committee on the PTC drug, as well.

PTC insisted commercial efforts will accelerate in the EU and begin in the U.S. as it completes regulatory filings for Translarna. Kovacs predicted a 2016 U.S. launch.

“We’re already selling the drug in 13 countries – not only in Europe but in countries in Asia and Latin America,” he said.

On Thursday, the company’s shares (NASDAQ:PTCT) closed at $31.74 for a gain of $1.76. The phase III data were disclosed after the market’s close, and shares initially slumped 17 percent before turning up following the company’s conference call.