Overview

Amicus Therapeutics (FOLD) is a global patient-centric biotechnology company engaged in the discovery, development and commercialization of a diverse set of novel treatments for patients living with rare metabolic diseases. The cornerstone of its portfolio is migalastat HCl, (also referred to as “migalastat”), an oral precision medicine for people living with Fabry disease who have amenable genetic mutations. Migalastat is currently approved under the trade name GALAFOLD in the European Union (“EU”) and Japan, with additional approvals granted and applications pending in several geographies. During the second quarter of 2018, the company initiated the commercial launch of GALAFOLD in Japan for the treatment of patients, aged 16 and older, with a confirmed diagnosis of Fabry disease and an amenable mutation. GALAFOLD is the first and only oral precision medicine approved for the treatment of Fabry disease in Japan.

The lead biologics program of its pipeline is Amicus Therapeutics GAA (AT-GAA, also known as ATB200/AT2221), a novel, clinical-stage, potential best-in-class treatment paradigm for Pompe disease. The company's Chaperone-Advanced Replacement Therapy (“CHART®”) platform technology is leveraged to develop novel Enzyme Replacement Therapy (“ERT”) products for Pompe disease, Fabry disease, and potentially future other lysosomal storage disorders (“LSDs”). Amicus Therapeutics is also investigating preclinical and discovery programs in other rare diseases including cyclin-dependent kinase-like 5 (“CDKL5”) deficiency. The company believe that its platform technologies and its product pipeline uniquely positions it and drives its commitment to advancing and expanding a robust pipeline of cutting-edge, first- or best-in-class medicines for rare metabolic diseases.

During the first quarter of 2018, the company issued 20,239,839 shares of its common stock through an underwritten offering resulting in net proceeds of $294.6 million after deducting underwriting discounts and commissions and offering expenses payable by it. The company expect to use the net proceeds of the offering for investment in the United States (“U.S.”) and international commercial infrastructure for migalastat HCl, investment in manufacturing capabilities for the ERT ATB200, the continued clinical development of its product candidates, research and development expenditures, clinical and pre-clinical trial expenditures, commercialization expenditures and for other general corporate purposes.

Strategy

The company's strategy is to create, manufacture, test and deliver the highest quality medicines for people living with rare metabolic diseases through internally developed, acquired or in-licensed products and product candidates that have the potential to obsolete current treatments, provide significant benefits to patients, and be first- or best-in-class. In addition to its lead programs in Fabry and Pompe, the company intend to leverage its global capabilities to develop and expand its robust pipeline, with the goal of entering clinical development with one or more programs in 2019. Since the beginning of its last fiscal year, the company made significant progress toward fulfilling its vision to build a leading global biotechnology company focused on rare metabolic diseases.

Highlights of its progress in the first six months of 2018 include:

Commercial success. In the six months ended June 30, 2018, GALAFOLD revenue totaled approximately $38.0 million. Revenue has been generated from outside the U.S., primarily in the EU.Regulatory progress. Received approval for migalastat in Japan and completed global regulatory submissions for migalastat in the U.S. and other key geographies. The FDA has accepted the New Drug Application (“NDA”) for filing under Priority Review, and the Prescription Drug User Fee Act goal date for the FDA decision is August 13, 2018, but there is no guarantee about when the FDA will make any decision concerning the NDA, or when, if ever, FDA approval will be granted.Pompe clinical study. Amicus Therapeutics has reported positive data from a Phase 1/2 clinical study to evaluate Pompe disease patients treated with its novel treatment paradigm AT-GAA.Manufacturing. Successfully scaled manufacture of Pompe biologic engineering batches to commercial scale (1,000L) with capacity plans to enable it to produce sufficient quantities to serve the entire Pompe population as quickly as possible after receipt of applicable regulatory approvals.Financial strength. Total cash, cash equivalents and marketable securities of $552.8 million at June 30, 2018 compared to $358.6 million at December 31, 2017. The current cash position, including proceeds from the February 2018 equity offering and expected GALAFOLD revenues, is sufficient to fund ongoing Fabry and Pompe program operations into at least 2021. Potential future business development collaborations, pipeline expansion, and investment in biologics manufacturing capabilities could impact its future capital requirements.

Commercial Product and Product Candidates

Migalastat for Fabry Disease

Migalastat was approved for use in the EU in May 2016 under the brand name GALAFOLD as a first-line therapy for long-term treatment of adults and adolescents, aged 16 years and older, with a confirmed diagnosis of Fabry disease and who have an amenable mutation. The approved EU label includes 348 Fabry-causing mutations, which represent up to half of all patients with Fabry disease. In the second quarter of 2018, the company initiated the commercial launch of GALAFOLD in Japan. The company currently have an NDA submission under Priority Review in the United States. The Prescription Drug User Fee Act goal date for the FDA decision is August 13, 2018, but there is no guarantee about when the FDA will make any decision concerning the NDA, or when, if ever, FDA approval will be granted. Approvals have also been granted in Israel, Canada, Australia, South Korea, and Switzerland, with additional applications pending in other geographies.

Amicus Therapeutics has launched GALAFOLD in several European countries, including France, Germany, Italy, Spain, and the UK, on a commercial basis, as well as in select other countries through reimbursed EAPs. Amicus Therapeutics has been granted pricing and reimbursement in 19 countries. The company plan to continue to launch GALAFOLD in additional countries during 2018.

As an orally administered monotherapy, migalastat is designed to bind to and stabilize an endogenous alpha-galactosidase A (“alpha-Gal A”) enzyme in those patients with genetic mutations identified as amenable in a GLP cell-based amenability assay. Migalastat is an oral precision medicine intended to treat Fabry disease in patients who have amenable genetic mutations and, at this time, it is not intended for concomitant use with ERT.

Patients with Fabry disease have an inherited deficiency of the alpha-Gal A enzyme that would normally degrade the lipid substrate globotriaosylceramide in the lysosome. Genetic mutations that cause changes in the amino acid sequence of alpha-Gal A result in an unstable enzyme that does not efficiently fold into its correct three-dimensional shape and cannot be trafficked properly in the cell, even if it has the potential for biological activity. Migalastat is an oral small molecule pharmacological chaperone that is designed to bind to and stabilize a patient’s own endogenous target protein. This is considered a precision medicine because migalastat targets only patients with GLA mutations or variants amenable to migalastat.

Amicus Therapeutics has completed two Phase 3 global registration studies of migalastat monotherapy. Amicus Therapeutics has reported Phase 3 data in both treatment-naïve patients (“Study 011”) and ERT-switch patients (“Study 012”). Results from these studies have shown that treatment with migalastat results in reductions in disease substrate, stability of kidney function, reductions in cardiac mass, and improvement in gastrointestinal symptoms in patients with GLA mutations or variants amenable to migalastat in a validated GLP amenability assay.

Next-Generation Therapies for Fabry Disease

Amicus Therapeutics is committed to continued innovation for all people living with Fabry disease. For people living with Fabry disease who have non-amenable mutations or variants, which are not suitable for migalastat as a monotherapy, its strategy is to advance next-generation therapies such as its proprietary Fabry-ERT co-formulated with migalastat or other innovative technologies that the company continue to evaluate.

Amicus Therapeutics is leveraging its CHART® technology and advanced biologics capabilities to move forward with a proprietary Fabry ERT for co-formulation with migalastat. Master cell banking has been completed, process development work has commenced, and initial preclinical studies have been completed to potentially advance this novel co-formulation toward the clinic in 2019.

Novel ERT for Pompe Disease

Amicus Therapeutics is leveraging its biologics capabilities and CHART® platform to develop Amicus Therapeutics GAA (AT-GAA, also known as ATB200/AT2221), a novel treatment paradigm for Pompe disease. AT-GAA consists of a uniquely engineered rhGAA enzyme, ATB200, with an optimized carbohydrate structure to enhance lysosomal uptake, administered in combination with a pharmacological chaperone, AT2221, to improve activity and stability. The company acquired ATB200 as well as its enzyme targeting technology through its purchase of Callidus. ATB200 is its first biologic to enter clinical development.

The pharmacological chaperone, AT2221 is not an active ingredient that contributes directly to GAA substrate reduction but instead acts to stabilize ATB200. The small molecule pharmacological chaperone AT2221 binds and stabilizes ATB200 to improve the uptake of active enzyme in key disease-relevant tissues, resulting in increased clearance of accumulated substrate, glycogen.

In preclinical studies, AT-GAA demonstrated greater tissue enzyme levels and further substrate reduction compared to the currently approved ERT for Pompe disease (alglucosidase alfa).

Amicus Therapeutics is engaged in ongoing collaborative discussions with U.S. and EU regulators regarding a registration-directed study for approval, manufacturing activities, and the best and fastest pathway forward for AT-GAA. A scientific advice meeting with the European Medicines Agency (“EMA”) was held in the second quarter of 2018. The scientific advice authorities from the EMA indicated that the current clinical package is not sufficient for a Conditional Marketing Authorization Application at this time. The company intend to continue a dialogue on a potential pathway for conditional approval with the EMA authorities in 2019. In the U.S., ongoing interactions for this program include a Type C meeting scheduled to occur in the third quarter of 2018. The company expect to provide an FDA update following the receipt of written minutes from this meeting. The company continue to believe that the evolving regulatory path will include a series of further iterative discussions with regulators as the program advances and as additional data is collected.

Throughout 2017, the company reported a cascade of interim data from a Phase 1/2 clinical study, ATB200-02, to investigate its novel Pompe treatment paradigm in Pompe patients. The primary objective was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics (“PD”) of AT-GAA for an 18-week primary treatment period followed by a long-term extension. The three patient cohorts, enrolling 20 total patients across all cohorts, are ambulatory ERT-switch patients (Cohort 1), non-ambulatory ERT-switch patients (Cohort 2), and ERT-naïve patients (Cohort 3).

As of its interim analysis reported in October 2017, patients who completed six months of treatment with AT-GAA showed improvements in the six-minute walk test ("6MWT") distance and other measures of motor function, stability or increases in forced vital capacity ("FVC"), and further reductions in biomarkers of muscle damage and disease substrate, with consistent results reported in initial patients who completed nine months of treatment.

On February 8, 2018 the company reported additional interim data from its clinical study ATB200-02 at the 14th Annual WORLD Symposium. Highlights included safety and tolerability data in all 20 patients (maximum of 20+ months of treatment) as well as PD data (muscle damage biomarker and disease substrate biomarker) for all 20 patients (15 ERT-switch patients and 5 ERT-naïve patients). To date, adverse events have been generally mild and transient. AT-GAA has resulted in a low rate of infusion-associated reactions (IARs) following 550+ infusions (three events of IARs in two patients; < 1% of all 550+ infusions with an IAR). The clinical pharmacokinetic profile has been consistent with previously reported preclinical data. Treatment with AT-GAA resulted in persistent and durable reductions in creatine kinase and urine hexose tetrasaccharide across all patient cohorts out to month 12.

As of the last interim analysis in February 2018, data on functional outcomes are available for 19 of the 20 patients enrolled (one patient dropped out of the extension study due to travel burden and family considerations). Muscle function improved in 16 of 19 patients at month 9. Muscle function improved in 10 out of 10 patients with available data at month 12. Mean 6MWT improved in both ERT-naïve and ERT-switch patients with continued benefit observed out to month 12. All 5 ERT-naïve patients showed increases in 6MWT distance at all time points out to month 12. The ERT-naïve patients showed mean increases of 41.8 meters at month 6 (n=5), 63.5 meters at month 9 (n=5), and 86.8 meters at month 12 (n=2). Of the 10 ERT-switch patients, 8 patients showed increases in 6MWT distance and two patients showed decreases at month 9. All eight of the ERT-switch patients with available data at month 12 showed increases in 6MWT distance. The ERT-switch patients showed mean increases of 23.9 meters at month 6 (n=10), 24.5 meters at month 9 (n=10), and 57.4 meters at month 12 (n=8). Other motor function tests generally showed mean improvements consistent with 6MWT distance. Three of the four non-ambulatory ERT-switch patients showed improvements in upper extremity strength (which includes elbow and shoulder) from baseline to month 9, as measured by quantitative muscle testing and manual muscle testing. Pulmonary function improved in ERT-naïve patients and was generally stable in ERT-switch patients. In ERT-naïve patients, mean absolute change in FVC was +4.2% at month 6 (n=5), +6.2% at month 9 (n=5), and +6.0% at month 12 (n=2). In ERT-switch patients mean absolute change in FVC was -1.3% at month 6 (n=9), -1.7% at month 9 (n=9), and -3.1% at month 12 (n=7). Overall, other pulmonary tests of maximal inspiratory pressure, a measure of inhalation, and maximal expiratory pressure, a measure of exhalation, were stable or increased in both ERT-naïve and ERT-switch patients.

CDKL5

Amicus Therapeutics is researching a potential first-in-class protein replacement therapy approach for CDKL5 deficiency in preclinical studies. CDKL5 is a gene on the X-chromosome encoding the CDKL5 protein that regulates the expression of several essential proteins for normal brain development. Genetic mutations in the CDKL5 gene result in CDKL5 protein deficiency and the disorder manifests clinically as persistent seizures starting in infancy, followed by severe impairment in neurological development. Most children affected by CDKL5 deficiency cannot walk or care for themselves and may also suffer from scoliosis, visual impairment, sensory issues, and gastrointestinal complications.

Strategic Alliances and Arrangements

The company will continue to evaluate business development opportunities as appropriate that build stockholder value and provide it with access to the financial, technical, clinical, and commercial resources necessary to develop and market pharmacological chaperone therapeutics, ERTs, and other technologies or products with a focus on rare metabolic diseases. Amicus Therapeutics is exploring potential collaborations, alliances, and other business development opportunities on a regular basis. These opportunities may include the acquisition of preclinical-stage, clinical-stage or marketed products so long as such transactions are consistent with its strategic plan to develop and provide therapies to patients living with rare and orphan diseases and support its continued transformation from a development-stage company into a commercial biotechnology company.