Hung up in the U.S. and overseas, PTC Therapeutics Inc.'s appeal to the FDA regarding the effort with Translarna (ataluren) for nonsense mutation Duchenne muscular dystrophy (DMD) "does not have much of a leg to stand on" in the view of RBC Capital Markets analyst Simos Simeonidis. Wall Street seemed to agree, shearing 40 percent, or $5.30, off the company's shares (NASDAQ:PTCT), which closed Monday at $7.97.

South Plainfield, N.J.-based PTC said the FDA denied the company's first appeal of the refusal-to-file letter issued in February regarding the NDA for Translarna, the company said it would take its case to the agency's next level. Meanwhile, PTC recently participated in an oral explanation meeting before the EMA's Committee for Medicinal Products for Human Use (CHMP) regarding the ongoing annual renewal of its marketing authorization for Translarna, originally granted in August 2014. The CHMP wants more information, and included a request categorized as a "major objection." A spokesperson for the company said PTC would have no comment beyond what's contained in a press release.

In April, Translarna survived intense scrutiny by the National Institute of Clinical and Care Excellence (NICE) to emerge with a recommendation that it is funded under a managed access agreement. This requires PTC to provide a discount to the £220,000 (US$313,000) per-patient, per-year list price and requires that data on how each patient fares be collected over five years, at which point the decision will be reviewed. But a spokesperson for NICE at the time told BioWorld Today that "in the event that the marketing authorization for ataluren is withdrawn by EMA, our guidance would also be withdrawn." (See BioWorld Today, April 19, 2016.)

RBC's Simeonidis said the FDA's move "does not come as a surprise to us," adding that his firm has said previously that "we don't believe this [FDA appeal] effort has much of a chance for success. PTC is basing [at least some of] its arguments for this appeal on the fact that Sarepta's eteplirsen [branded Exondys 51] was approved on arguably weak and incomplete data, a position that we agree with. We have identified this as a potential issue for FDA multiple times in the past, i.e., that other companies with less-than-stellar data sets will now reference Sarepta's data set as a reason to try and get their drugs approved, or at least give them a second chance at a review."

In September, after months of speculation, Cambridge, Mass.-based Sarepta won accelerated approval for eteplirsen plus a rare pediatric disease priority review voucher (PRV) from the FDA for its DMD drug, indicated to treat patients with a confirmed mutation of the DMD gene amenable to exon 51 skipping, which affects about 13 percent of the population with the disease, based on the surrogate endpoint of increased dystrophin in skeletal muscle observed in some patients treated with the drug. The label made clear that clinical benefit was not established during trials and indicated, as is customary with accelerated approvals, that continued approval in the indication may be contingent upon verification of clinical benefit in confirmatory trials. The Federal Register published Monday confirmation that the PRV has been issued. (See BioWorld Today, Sept. 20, 2016.)

CF BID 'HIGH RISK,' TOO

Translarna, for its part, "has failed to show a benefit to patients in two large, randomized, placebo-controlled trials, the second one of which was designed based on the subset of patients that did show a benefit on a post-hoc analysis of the first failed trial," Simeonidis noted. "In addition to the two failed trials in DMD, this compound failed to show a benefit in a third, large, randomized, placebo-controlled trial in an additional indication (cystic fibrosis [CF]). Therefore, while we still disagree with FDA's decision to approve eteplirsen given the weak/incomplete data set, we can at least agree with FDA that we don't know with certainty that it does not help patients. On the other hand, there is strong evidence that PTC's compound does not provide any benefit over placebo and this has been proven in multiple, randomized, placebo-controlled trials, the most rigorous standard in drug development."

At the time of eteplirsen's approval, Jefferies analyst Gena Wang opined that the go-ahead probably didn't mean anything for Translarna. Although the drug is "considered safe, the FDA approval of eteplirsen is mainly based on the marginal increase of dystrophin levels, while PTC does not have any dystrophin data from phase III." Clearance of the Sarepta drug "was based on dystrophin increase in some DMD pts, according to the FDA," she wrote in a report. "Management disclosed that dystrophin level was increased to 0.44 percent of normal level at 48 weeks from 0.16 percent at baseline, which we view as marginal. In contrast, PTC did not have dystrophin data from ataluren phase III in DMD. We continue to see low probability of [Translarna] approval, despite the ongoing appeal."

With the latest news from the FDA and EU, Wang weighed in again. The CHMP's concerns, she pointed out, have to do with "efficacy, overall risk-benefit profile and [the request for the company to] design/conduct an additional clinical trial to provide comprehensive clinical data. Additional concerns related to the primary pharmacology of [Translarna] and label matters were also raised. It would be PTC's responsibility to fully address concerns raised by CHMP," and the company expects a further opinion in the EU by the end of this year, she said, concluding that her firm "continue[s] to see high risk of renewing [Translarna's] EU authorization," and a high risk for the CF readout, due early next year.