This week, Amicus announced that the FDA has requested additional data from Amicus in order for the agency to consider approving migalastat for the treatment of Fabry disease. More specifically, the agency wants to see data showing the safety and efficacy of migalastat in patients who have an amenable mutation and gastrointestinal (GI) symptoms.
Amicus further noted that some of the additional data that may be required for migalastat approval include:
• Randomized, 12-month, placebo-controlled pivotal "cross-over" study in treatment naïve Fabry patients who have an amenable mutation and GI symptoms
• Crossover study design provides sufficient powering with a small number of patients (~35 patients planned)
• Primary endpoint to assess diarrhea based upon established FDA irritable bowel syndrome (IBS) guidance
• Amicus is working with FDA to finalize the clinical protocol and plans to initiate enrollment in 2017, with data expected in 2019
• Upon successful NDA filing, the review will be based upon these new data and the totality of the data from all prior migalastat studies
• Intermediate Expanded Access Program (EAP) planned to ensure short-term access to migalastat for U.S. patients who are currently on ERT and meet EAP requirements
• U.S. patients currently enrolled in ongoing clinical extension studies will continue to receive migalastat
In other words, Amicus likely has to do another clinical trial before getting the drug approved.
Since the announcement on Monday, Amicus’ stock has dropped approximately 30% to $6.00 a share.
Migalastat's Regulatory Journey
The path to gain approval of migalastat has been a rocky one. In 2012, data from Amicus’ clinical trial testing the efficacy of migalastat in Fabry patients did not meets its primary endpoint and many (i.e., investors) were not optimistic. However, further analysis indicated that patients with ‘amenable mutations’ were more responsive to migalastat and since then, the data has been more optimistic. Amenable mutations are defined as having an absolute increase of 3% of wild type alpha-Gal A enzyme activity and a relative increase of 20% when exposed to migalastat in a cell-based in vitro assay. It is estimated that approximately 30% to 50% of the Fabry population has mutations that are amenable to migalastat.
Never Say Never
In a press release
, John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics “While we believe that the totality of the data from our studies with migalastat support the submission of a new drug application today, we acknowledge the FDA's position that accelerated approval based on kidney GL-3 reduction is not currently an option. We have thus defined a plan to collect additional GI data to support full approval for migalastat that we believe is feasible in a reasonable amount of time and with a high likelihood of success based on positive GI data generated in our previous Phase 3 Study 011.”
What is Fabry Disease?
Fabry disease is an X-linked lysosomal storage disorder that leads to excessive deposition of glycosphingolipids throughout the body. Skin, eye, kidney, heart, brain, and peripheral nervous system are highly vulnerable. Fabry disease is caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A) which degrades specific lipids in lysosomes, including globotriaosylceramide (GL-3). The accumulation of GL-3 is believed to cause the various symptoms of Fabry disease.
Symptoms do appear in childhood but often go undiagnosed for several years. As the disease progressive, most patients with Fabry disease die in their fourth or fifth decade due to complications arising from renal or cardiovascular problems.