Cystic Fibrosis Failure Weakens PTC's Duchenne Argument, FDA Says

US FDA sees parallels in ataluren’s development in Duchenne and firm's unsuccessful efforts to find efficacious subsets in cystic fibrosis.

The US FDA used PTC Therapeutics Inc.'s failed development experience with Translarna (ataluren) in cystic fibrosis to buttress its view that the drug should not be approved to treat Duchenne muscular dystrophy absent a new clinical trial.

At a Sept. 28 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, FDA said two unsuccessful trials that tested ataluren in nonsense mutation cystic fibrosis (nmCF) and PTC's subsequent discontinuation of the drug in that indication raise questions about the purported mechanism of action and serve as a cautionary reminder about the hazards of subgroup analyses.

The parallels between the drug's development in nmCF and nonsense mutation Duchenne muscular dystrophy (nmDMD) "are striking," Division of Neurology Products (DNP) Director Billy Dunn said. "A failed initial study, post hoc identification of a promising subgroup accompanied by a similarly reasonable explanation for why that subgroup should derive unique benefit, and a second study designed to evaluate that subgroup of interest that failed."

The ataluren development experience in cystic fibrosis is "a living, breathing example of how subset analyses that looked plausible didn't work out." – FDA's Temple

The CF development program "reminds us that hypotheses derived from exploratory analyses of negative trials, even when they appear to be supported by seemingly logical and plausible explanations, may often be misleading and need to be prospectively tested," Dunn said.

The majority of committee members concluded that while ataluren may be effective in treating dystrophinopathies, particularly DMD, resulting from nonsense mutations in the dystrophin gene, the data are inconclusive and more work would be needed to establish efficacy. (Also see "Patients Can't Clear Translarna's Data Hurdles As PTC Falls Short At FDA Panel" - Pink Sheet, 28 Sep, 2017.)

'Transition Phase' Hypothesis

PTC is developing ataluren, a protein restoration therapy, for treatment of patients with nonsense mutation genetic disorders. The compound is believed to interact with the ribosome, enabling it read through premature nonsense stop signals on mRNA that allow the cell to produce a full-length, functional protein.

FDA convened the advisory committee to consider whether the ataluren efficacy data in nmDMD were adequate to support approval. The NDA, which was filed over protest after two refusal-to-file letters, was based on two randomized, placebo-controlled trials that failed their primary endpoints.

After the failure of Study 007, PTC designed a second trial intended to confirm evidence of benefit in an exploratory subgroup that was identified through post hoc analysis of the 007 study. The second study (020) also missed its primary endpoint. However, PTC again conducted an exploratory analysis to identify a subgroup of patients that appeared to benefit – those with baseline six-minute walking distance (6MWD) of 300-400 meters.

PTC has described this 6MWD baseline range as the "transition phase" of the disease and the most sensitive for assessing changes in muscle decline within 48 weeks, which was the duration of both the 007 and 020 trials.

The company asserted that ataluren's approval was supported by the totality of efficacy evidence and that regulatory flexibility is warranted because nmDMD is a rare disease. However, FDA officials have urged the company to conduct another new study targeting the transition phase subgroup. (Also see "Exondys Revisited? Translarna Brings Efficacy Woes Into US Panel Review" - Pink Sheet, 26 Sep, 2017.)

"We believe an additional study to support the hypothesis-generating findings of those two studies is needed," Dunn said. "This issue is not simply statistical. It is a fundamental concern about the interpretability and persuasiveness of exploratory observations and the importance of experimental designs."

Development Program Parallels

FDA officials said the drug's development in nmCF was a cautionary tale that should inform the advisory committee's consideration of the strength of the efficacy data in nmDMD, because PTC has asserted that ataluren should be able to read through all nonsense mutations regardless of the specific clinical disease.

In 2014, PTC disclosed negative results from a Phase III trial in nmCF. "The applicant argued that the data from this trial suggested trends towards effectiveness and stated that the collective data from the trial, including retrospective and subgroup analyses, supported the conclusion that ataluren was active and showed clinically meaningful improvements over placebo," FDA's meeting briefing document states.

PTC reported that a post hoc analysis suggested patients who did not receive aminoglycoside antibiotics appeared to gain the most benefit, and it theorized that such drugs interfere with ataluren's activity. The company tested this hypothesis in a second Phase III trial that excluded patients who were taking chronic inhaled aminoglycosides.

In March, PTC reported that this second trial, which had been enriched on the basis of an exploratory subgroup analysis in the first trial, also failed to achieve its primary or secondary endpoints. The company also announced it would discontinue ataluren's development for nmCF. (See sidebar for Scrip story.)

Given ataluren's purported mechanism of action, the failure to demonstrate efficacy in another disease setting defined by nonsense mutations "lowers the prime expectation of efficacy in other conditions," DNP Clinical Reviewer Veneeta Tandon said. "In addition, these results highlight the importance of the need to prospectively test even seemingly very logical theories from exploratory analyses of negative trials."

Joe McIntosh, PTC's senior vice president and head of clinical development, challenged FDA's view that parallels could be drawn between the efficacy data in the nmCF and nmDMD development programs.

CF is an entirely different disease, McIntosh said, noting that the cystic fibrosis transmembrane conductance regulator (CFTR) protein has to be trafficked and activated in the membrane to be functional. In CF, there are two competing nonsense mutations, in contrast to the single mutation in DMD, McIntosh said.

"We did show in Phase II that we did replace CFTR," he said. "The question is can you replace enough to reverse the trajectory of the disease?"

Center for Drug Evaluation and Research Deputy Director for Clinical Science Robert Temple, who also serves as acting deputy director of the Office of Drug Evaluation I, said the CF experience is further reason for being cautious because, as in the DMD trials, "a perfectly plausible subset finding didn't really work out."

"There are two issues here," Temple said. "One is does it make you worry about the whole mechanistic explanation here? … The other is it's a living, breathing example of how subset analyses that looked plausible didn't work out."

Long-Term Study Underway

While FDA believes another study is needed before ataluren can be approved in DMD, the agency commended PTC's initiation and design of a new, long-term trial that will serve as a post-approval commitment for the drug's approval in the EU.

Study 041 is a randomized, double-blind, placebo-controlled, 72-week study comparing the efficacy and safety of ataluren to placebo, followed by a 72-week open-label extension. The primary endpoint is the six-minute walk test, with secondary endpoints including time function tests and the North Star Ambulatory Assessment.

"The study will be conducted in countries across North America, Latin America, Eastern Europe and Asia/Pacific," PTC's briefing document states. " A total of 250 nmDMD patients (age five and older) with a baseline 6MWD >150 meters are expected to enroll. While the study will enroll a broad patient population, similar to that of Study 020, only a subset of patients – those entering or in the transition phase – will be included in the primary endpoint analysis."

Results from PTC's new, long-term trial with refined enrollment criteria are not expected until 2021.

"We are pleased to see that the applicant has recently initiated recruitment into an additional long-term trial, Study 041, that is informed by the information gleaned from study 007 and 020," Dunn said.

"It is also notable that the enrollment criteria for Study 041 have been even further refined from those used for the exploratory analyses of Study 020, which speaks to the continually evolving nature of the understanding of how best to enrich clinical trials in DMD," he said.

The problem for PTC, however, is that the Study 041 results are not expected to be available until 2021. This means that if FDA once again decides that ataluren is not approvable for nmDMD based on the currently available data, PTC would not be able to count on the Study 041 results for a near-term approval in the US.

FDA also appears to have closed the door on accelerated approval as an option for ataluren. (Also see "How Accelerated Approval Works – And How It Doesn't" - Pink Sheet, 28 Sep, 2017.)