Amicus Therapeu?cs John F. Crowley Chairman 8: CEO CONFIDENTIAL May 16, 2017 Scott Gottlieb, M.D. Commissioner United States Food and Drug Administration BUILDING W01 ROOM 2228 10903 New Hampshire Avenue Silver Spring, MD 20993-002 via overnight deiivery Dear Dr. Gottlieb: I hope that this letter finds you well and settling into your new role as FDA Commissioner. I would like to bring two items to your attention briefly regarding our programs in Pompe and Fabry diseases. First, write to share some exciting news in Pompe. As you will note from the attached press release, Amicus announced publicly on Monday of this week positive functional, biomarker and safety data from the initial patients in our Pompe Phase 1/2 Study. in this study, we are investigating the safety and efficacy of our novel, highly-glycosylated recombinant enzyme replacement therapy (ATBZOO), co-administered with an oral, small molecule pharmacological chaperone (AT2221). We are studying both treatment-naive and treatment- experienced patients who have been treated with the current standard of care, Lumizyme, for several years. The results to date show robust effects on biomarkers and functional outcomes in both patient groups, including patients who became non-ambulatory while on Lumizyme. We will collect further data over the coming months in a total of 20 patients in this study. If these data continue to show such marked improvements in this broad range of patients, we would expect to file an application for Breakthrough Therapy Designation for this program. indeed, given the significant unmet needs of people living with Pompe disease, including my own children, we would welcome the opportunity for the program to establish a new paradigm for rapid development, review and potential approval for enzyme replacement therapies in rare, devastating disorders. We will work closely with the Division in this regard. It is our hope that the FDA will use its accumulated experience with the success of these enzyme-replacement drugs to streamline the process here. Second, I would like to make you aware of the current status of our oral, small molecule precision medicine for Fabry disease known as ?migalastat.? Migalastat received full approval in the EU in 2016 (following a unanimous CHMP recommendation) for the treatment of all Fabry patients age 16 and older with an amenable mutation. In over a decade of clinical development of this novel small molecule, we have accumulated over 600 patient-years of data. Recently, migalastat also received full approval from NICE in the UK, the fastest that any rare disease medicine has ever been approved by NICE. 1 Cedar Brook Drive Cranbury, NJ 08512 T: 609-662-2000 F: 609-662-2001 Migalastat has also been approved in Switzerland and applications are pending in 6 other countries based on existing data. The application in Japan for full approval, based on the existing data, will be submitted next month. Indeed, no agency outside the United States has asked for any additional studies or data. In contrast, last fall, the Gastroenterology and Inborn Errors Products Division at FDA (DGIEP) advised Amicus that we must conduct a third Phase 3 study for US. approval, by investigating the drug?s effects on gastrointestinal of Fabry disease (which had been studied successfully in a prior Phase 3 study of migalastat, though not as a primary endpoint). On March we met with Dr. Janet Woodcock, Dr. Julie Bietz and other senior CDER leaders to discuss the status of this program. In March we also advised DGIEP that following a global feasibility survey, we have concluded that a further Phase 3 study of gastrointestinal is not feasible in a reasonable amount of time (estimated 5-7 years to complete). As a result of Dr. Woodcock?s request at the March 13th meeting, on April 19"h we submitted to the DGIEP, Dr. Woodcock, and senior CDER leadership, the attached briefing document, which includes important new data on the cardiac benefits of migalastat, new long term data on the stabilization of renal function, further data on the positive effects of migalastat in males with classic Fabry disease, and patient narratives and experience with migalastat.(PIease see pages 7-15 of this Briefing Document for an executive summary). We noted in the Briefing Document specifically that Amicus now intends to submit an NDA for migalastat for the treatment of patients with Fabry disease and amenable mutations, based on existing data. We specifically asked two questions: 1. Does the Agency agree that an additional Phase 3 study is not required for NDA submission? 2. Does the Agency agree to review an NDA for migalastat? Our understanding is that the DGIEP will provide a Center Briefing directly to Dr. Woodcock. Please know that Dr. Woodcock has provided exceptionally thoughtful, science driven and patient centric leadership throughout this process and we have complete confidence in her oversight. As we have shared with Dr. Woodcock, it would be extremely helpful for this program and for patients to receive clarity on the above questions from FDA as soon as reasonably possible. Patients with Fabry disease continue to suffer and die in the United States; the unmet medical need remains great. We are committed to move most expeditiously to submit the NDA once we have clarity on the above. Thank you for your attention to these matters and for your extraordinary sacrifice in serving in this important role. Very sincerely, John F. Crowley Chairman CEO Amicus Therapeutics, Inc. Enclosures: 1. Amicus Press Release of May 15, 2017 2. Migalastat Briefing Document (IND 068456) CC: Janet Woodcock, M.D. 1 Cedar Brook Drive Cranbury, NJ 08512 T: 609?662-2000 F: 609-662-2001