Shares of PTC Therapeutics Inc. (NASDAQ:PTCT) hit a record low of $5.29 on Tuesday after the company further detailed the FDA's refusal to accept a new drug application (NDA) for its Duchenne muscular dystrophy (DMD) candidate, Translarna (ataluren), saying that, in the agency's view, "both the phase IIb and (phase III) ACT DMD trials were negative and do not provide substantial evidence of effectiveness."

In addition, the agency "characterized certain of the company's adjustments to the ACT DMD study as post hoc and therefore not supportive of effectiveness" and criticized the NDA for not containing adequate information regarding the abuse potential of Translarna, a requirement for new molecules that cross the blood-brain barrier.

Although PTC sought to cheer investors with the prospects of growing Translarna sales in Europe and elsewhere, wary equity analysts saw little to like in the company's discussion of the FDA's refuse to file (RTF) letter. The picture was made gloomier yet by a pricing and reimbursement dispute in Germany that left PTC expecting to delist Translarna from the country's pharmacy ordering system.

"We have little conviction in the stock pending more clarity on the U.S. path forward after the recent RTF from FDA, and the EU market opportunity on heels of the German pricing dispute for Translarna," wrote Cowen and Co.'s senior biotechnology analyst, Ritu Baral, who downgraded her firm's rating of PTC shares to "market perform" from "outperform."

RBC Capital Markets' senior biotech analyst, Simos Simeonidis, expressed similar doubts, noting that his firm doesn't "see a path forward for ataluren in the U.S., other than starting a new phase III trial" and that "Germany is not only the largest country where the drug was being sold but it also serves as reference pricing for the rest of Europe."

PTC has already requested a meeting with the FDA to discuss a path forward after which "we'll be in a better position to update you," Stuart Peltz, the company's CEO and co-founder, told investors during a Monday afternoon call to discuss the company's fourth quarter and full 2015 earnings. (See BioWorld Today, Feb. 24, 2016.)

Shares closed at $5.55 on Tuesday, down 30.5 percent for the day and 92.1 percent since one year ago.

As it seeks to determine next steps with the FDA, the company is waiting for the EMA's Committee for Human Medicinal Products (CHMP) to decide whether to make permanent its conditional approval of Translarna in the European Union, granted in August 2014. To support that decision, the EMA asked PTC to complete and submit the final results of the ACT DMD trial. With that step completed in January, the CHMP is reviewing the ACT DMD data. PTC expects to have a decision by midyear on the application to remove the condition from its marketing authorization.

While the primary efficacy endpoint in the intent-to-treat population of the ACT DMD trial did not achieve statistical significance, PTC said it still believes that "the totality of clinical data" from that study and its prior phase IIb trial support the clinical benefit of Translarna for the treatment of nonsense mutation DMD. It's unclear what could happen to the conditional approval if the CHMP takes the FDA's lack of conviction in that argument to heart.

A further problem for PTC is its failure to see eye to eye with the German Federal Association of the Statutory Health Insurances (GKV-SV) on pricing and reimbursement. According to PTC's chief commercial officer, Mark Rothera, GKV-SV requested a 57 percent discount on Translarna on top of a 7 percent mandatory rebate, an ask that "would take us into an unsustainable and unrealistic price level for Translarna," he said. As an alternative, patients and doctors may be able to access Translarna through a reimbursed importation pathway, PTC said.

A discussion with the U.K.'s National Institute for Health and Care Excellence sounds to be going somewhat better, yielding what the company called "great progress outlining a managed access agreement."

Peltz said Monday that while PTC remains committed to the goal of obtaining regulatory approval for the therapy in the U.S., it is working it parallel to expand the footprint of Translarna's regulatory approvals from its current 23 countries to at least 35 countries this year, a feat that could help it generate ex-U.S. DMD revenue that it projects could be between $65 million to $85 million in 2016.

PTC finished 2015 with approximately $339 million in cash and cash equivalents and is far from short on ideas for what's next for Translarna. Peltz reported that the company saw "overwhelmingly strong demand from physicians and patients" who wanted to participate in the phase III ACT cystic fibrosis (CF) trial. The trial completed enrollment in November with about 280 patients and is expected to be complete by the end of this year, with top-line data expected in early 2017. PTC has already submitted an application to add nonsense mutation CF to the existing label for Translarna in Europe.

"Resilience," he said, "has been one of our key values since I founded PTC in 1998 and our team continues to work diligently to bring Translarna to patients globally."