What the post-approval confirmatory trial might look like and the outcome of a likely FDA advisory committee meeting are among the questions that remain for investors in Amicus Therapeutics Inc., but news of a clearer – and potentially faster – regulatory path for its Fabry disease therapy in Europe as well as the U.S. provided Wall Street with plenty of cause for optimism.

"The full approval, which would be potentially with the current dataset, does not appear to be the best path forward" in the U.S. with the oral small-molecule chaperone migalastat, Chief Medical Officer Jay Barth said during a conference call. Amicus held a type C meeting with the FDA earlier this week.

"We think the quickest way to get the drug approved is through subpart H [accelerated approval], with one of the surrogate endpoints that we have been discussing, with the commitment to do an additional study post-approval, and that is the context," Barth said. "The whole meeting really was in that context." Fabry disease – an inherited, progressive, disorder that is caused by mutations in the GLA gene, located on the X chromosome, which directs the making of an enzyme called alpha-galactosidase A – afflicts an estimated one in every 40,000 to 60,000 males, though females may carry the faulty gene and develop symptoms as well.

Shares of Cranbury, N.J.-based Amicus (NASDAQ:FOLD) ended Thursday at $12.46, up $3.11, or 33.3 percent. The company said it expects to file for approval in Europe during the second quarter of this year (rather than midyear, as previously planned) and in the U.S. during the second half of the year.

Leerink Partners LLC analyst Joseph Schwartz was "highly encouraged that the FDA is open to considering several potential surrogate endpoints" used in the trials, including globotriaosylceramide substrate reduction, lessened cardiac mass and stabilized kidney function as determined by glomerular filtration rate.

The agency also has promised to examine the "totality of the data" – a pledge that's especially important since the drug missed its original primary endpoint in one of two pivotal trials, known as Study 011, though it yielded improvements associated with good Fabry outcomes.

"As of late, the FDA has provided orphan drug sponsors very transparent guidance pre-filing, and has not been hesitant to tell companies not to file when it believes that their data sets are not ready," Schwartz noted in a research report, citing the experiences of such companies as Monmouth Junction, N.J.-based Insmed Inc. and Sarepta Therapeutics Inc., of Cambridge, Mass. "This renders the FDA's positive guidance to Amicus even more meaningful, we believe, leading us to increase our probability of approval to 85 percent from 60 percent."

CEO John Crowley clarified on the call that "the plan, then, under this pathway would be that we would gain approval based on subpart H, and be on the market in the same way that Fabrazyme was approved under subpart H, we think with a very distinct label and certainly the same product profile. Once the phase IV [trial] is complete, we could then apply to convert to full approval." Fabrazyme (agalsidase beta), from Sanofi SA unit Genzyme, was approved in 2003 – the first drug to win marketing clearance for Fabry disease. Data with migalastat in the pair of pivotal trials, Study 011 and Study 012, rolled out in April and August of last year. (See BioWorld Today, April 25, 2003, April 30, 2014, and Aug. 21, 2014.)

The accelerated strategy followed by a phase IV trial, "if you remember years back, was the Fabrazyme plan, the difference being that they failed their phase IV," Crowley said. "But the drug was allowed to remain on the market and it has been on the market for nearly 12 years now, based only on the subpart H approval."

'GIFT' FROM THE FDA

Crowley said the company talked with the FDA about several potential protocols for the phase IV trial, and the agency "actually proposed that we consider gastrointestinal [GI] endpoints. Although cardiac disease is the most frequent killer of people with Fabry disease, followed by the kidney aspects of the disease, the most debilitating and life-limiting aspects of the disease are these severe GI symptoms."

Analysts also wanted to know more about labeling for migalastat, and whether the compound would be limited to treatment-naïve patients or would include enzyme replacement therapy "switch" patients as well.

"In Europe, given the nature of the discussions and the submissions, we expect a very broad label [based on data] from both of our studies to support switch patients as well as naive patients," Crowley said. "And we also had a very good discussion with the team in Europe last week that leads us to believe very strongly that this will be for all amenable mutations, not just those that were studied in our study." In the U.S., he said, "I don't believe we have got into that level of detail" during the type C meeting. Barth said that was true, but "the indication we are seeking is a broad one that is for treatment of Fabry disease, not specifically for naive or switch, so [the label] would be inclusive."

The latest nod from regulators "certainly accelerates our plans [for building infrastructure] in Europe," Crowley said. Bradley Campbell, chief operating officer, added that recruiting in Europe is "well under way, and this meeting if anything fast forwards that timeline, which is great. We have a number of great candidates for the European Union general manager position, and we will continue to build out that team over the course of the next months. With this U.S. feedback, we will also begin the U.S. team recruiting in earnest, and we expect to be able to move very quickly, especially given the number of firms over the last five years in the rare disease space who have done this. So there is, I think, a very rich talent pool out there to draw from, which is great." Medical outreach efforts are expanding, too, as Amicus works with consultants on positioning migalastat.

Cowen and Co. analyst Ritu Baral predicted a positive advisory panel meeting in 2016. He pointed out Amicus' belief that it will need to have the phase IV trial designed and under way by the time action is taken on a new drug application.

"We view the FDA's suggestion of a phase IV trial around GI symptom improvement as a gift from the agency," Baral wrote in a research report, because in Study 011, GI symptoms improved significantly with migalastat vs. placebo at six months, and they "can be improved within 12 months of treatment and with low data variability, especially compared to renal function." Baral said he was "buoyed" by the progress so far, adding that key opinion leaders have told his team "they would switch some subtype of Fabry patient to migalastat on approval."