Amicus Therapeutics said today it plans to submit an NDA for its Fabry disease candidate migalastat in the fourth quarter after the agency, in an unusual about-face, reversed a decision made last year to require an additional Phase III study assessing the drug in gastrointestinal symptoms.

Amicus gained national attention earlier this year when President Donald Trump wove into his February 28 address to Congress the story of the daughter of the company’s CEO. Trump related how the life of 20-year-old Megan Crowley, a Notre Dame sophomore, was saved through a Pompe disease treatment developed by a drug developer founded by her father John F. Crowley, now Amicus’ chairman and CEO.

Crowley’s company at the time, Novazyme Pharmaceuticals, was acquired in 2001 for $137.5 million by Genzyme, which in 2011 was bought by Sanofi for $20.1 billion.

“Our slow and burdensome approval process at the FDA keeps too many advances, like the one that saved Megan’s life, from reaching those in need,” Trump told Congress. “If we slash the restraints, not just at the FDA, but across our government, then we will be blessed with far more miracles like Megan.”

Crowley echoed that argument in a commentary published the following day in the Observer: “The FDA’s regulation of the orphan development process is becoming less flexible, less efficient, and less patient-centered.”

“It is troubling that in recent years, rare disease research is becoming what the Orphan Drug Act sought to change: an enterprise too expensive to justify investment. It takes now orphan drugs as much time to complete Phase III studies (the stage of drug development where efficacy is established) as it does for nonorphans,” Crowley asserted. “At the same time, the average clinical trial cost per patient is 14 times higher for orphan drugs compared to those that are not.”

The FDA about-face comes nearly two weeks since the agency’s Trump-nominated commissioner Scott Gottlieb, M.D., unveiled a plan to step up orphan drug development by eliminating its backlog of requests for orphan designations by September 21, then respond to all new designation requests within 90 days of receipt.

Accelerated Approval Pathway

In a statement issued by Amicus today, the elder Crowley said the NDA will be submitted under the FDA’s Subpart H pathway, created last year to enable accelerated approval of drug candidates indicated for “serious or life-threatening illnesses.”

“This guidance from the FDA marks a tremendous step forward for thousands of people living with Fabry disease in the United States,” CEO Crowley stated. “We are moving ahead expeditiously with our NDA submission and accelerating the U.S. pathway for migalastat. Today is a seminal moment in the development of migalastat and a testament to the dedication and perseverance of the patients, physicians, and employees who have worked so hard on the development of this precision medicine.”

Amicus said it intends to base its NDA on existing data, including reduction in the disease-causing substrate globotriaosylceramide (GL-3), as well as the totality of data from completed clinical studies. Progressive accumulation of GL-3 is believed to lead to the morbidity and mortality of Fabry disease, including pain, kidney failure, heart disease, and stroke, according to the company.

“We believe that we have a robust data package for this NDA submission, and we look forward to advancing toward a planned pathway for U.S. approval for migalastat,” added Jay Barth, M.D., Amicus’ CMO.

Crowley and Amicus have long argued that migalastat should be approved in the U.S. given approvals already granted in the European Union (under the trade name GalafoldTM), Israel, and Switzerland, based on data from the company’s clinical trials, which included the two largest pivotal studies ever completed in Fabry disease. Regulatory submissions for the drug are pending in Japan, Canada, and Australia.

But on November 28, 2016, Amicus acknowledged that the FDA directed the company to generate additional gastrointestinal data in Fabry patients who have an amenable mutation, in order to gain approval of migalastat—something the company said it was prepared to do. Following talks with the FDA, Amicus said it would finalize its clinical protocol, then initiate enrollment in 2017, with data expected in 2019.

“While we believe that the totality of the data from our studies with migalastat support the submission of a NDA today, we acknowledge the FDA's position that accelerated approval based on kidney GL-3 reduction is not currently an option,” Crowley said in a company statement at the time.

Migalastat is an oral precision medicine indicated for Fabry disease in patients who have “amenable” genetic mutations, defined as those that are responsive to therapy with migalastat based on a proprietary in vitro assay. Amicus estimates that 35% to 50% of Fabry patients globally may have amenable genetic mutations.

Migalastat is designed to work by stabilizing the body's own dysfunctional enzyme, so it can clear the accumulated disease substrate in patients who have amenable mutations.

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