Migalastat Hydrochloride

GALAFOLD is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene ( GLA ) variant based on in vitro assay data [see Dosage and Administration (2.1) and Clinical Pharmacology (12.1) ] . This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. GALAFOLD is an alpha-galactosidase A (alpha-Gal A) pharmacological chaperone indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene ( GLA ) variant based on in vitro assay data. ( 1 , 12.1 ) This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. ( 1 )

Capsules: 123 mg of migalastat in a size “2” capsule with an opaque blue cap and opaque white body with “A1001” printed in black, containing white to pale brown powder. Capsules: 123 mg migalastat. ( 3 )

None. None. ( 4 )

Most common adverse drug reactions ≥ 10% are: headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amicus Therapeutics at 1-877-4AMICUS or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, 139 patients with Fabry disease (79 females, 60 males, 92% Caucasian, ages 16 to 72 years), who were naïve to GALAFOLD or previously treated with enzyme replacement therapy, were exposed to at least one dose of GALAFOLD. Of the 139 patients, 127 patients were exposed to GALAFOLD 123 mg every other day for 6 months and 123 patients were exposed for greater than one year. The clinical trials included one randomized, double-blind, placebo-controlled clinical trial of 6 months duration followed by a 6-month open-label treatment phase (Study 1) [see Clinical Studies (14) ] . A second trial was a randomized, open-label, active-controlled clinical trial of 18 months duration in patients with Fabry disease receiving enzyme replacement therapy who were randomized to either switch to GALAFOLD or continue enzyme replacement therapy (Study 2; NCT01218659). In addition, there were two open-label, long-term extension trials. The most common adverse reactions reported with GALAFOLD (≥ 10%) during the 6-month placebo-controlled, double-blind phase of Study 1 were headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia. Table 1 shows adverse reactions that occurred in at least 5% of patients treated with GALAFOLD during the 6-month placebo-controlled, double-blind phase of Study 1. Table 1: Adverse Reactions* in Patients with Fabry Disease (Study 1) * Adverse reactions were those that occurred in at least 5% of patients treated with GALAFOLD. ** Included urinary tract infection, cystitis, and kidney infection Adverse Reaction GALAFOLD % (N = 34) Placebo % (N = 33) Headache 35% 21% Nasopharyngitis 18% 6% Urinary tract infection** 15% 0 Nausea 12% 6% Pyrexia 12% 3% Abdominal pain 9% 3% Back pain 9% 0 Cough 9% 0 Diarrhea 9% 3% Epistaxis 9% 3% Adverse reactions that occurred in > 5% of patients who received GALAFOLD in the 6-month open-label treatment phase of Study 1, in Study 2, and in the long-term extension trials (N = 115, mean duration of treatment 2.7 years) included those in Table 1 with the addition of vomiting.

6.2 Postmarketing Experience The following adverse reaction has been identified during post-approval use of GALAFOLD. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. General disorder: angioedema

See Full Prescribing Information for clinically significant drug interactions. (7.1)

7.1 Effect of Other Drugs on GALAFOLD Co-administration of GALAFOLD with caffeine decreases migalastat AUC and C max [see Clinical Pharmacology (12.3) ] which may reduce GALAFOLD efficacy. Avoid co-administration of GALAFOLD with caffeine at least 2 hours before and 2 hours after taking GALAFOLD [see Dosage and Administration (2.2) ] .

8.1 Pregnancy Risk Summary There were three pregnant women with Fabry disease exposed to GALAFOLD in clinical trials. As such, the available data are not sufficient to assess drug associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed (see Data ) . The background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There is a study that collects data on pregnant women with Fabry disease, either exposed or unexposed to GALAFOLD. Healthcare providers are encouraged to register patients or obtain additional information by contacting the Pregnancy Coordinating Center at 1-888-239-0758, emailing fabrypregnancy@ubc.com, or visiting www.fabrypregnancyregistry.com. Data Animal Data No adverse developmental effects were observed with oral administration of migalastat to pregnant rats and rabbits during organogenesis at doses up to 26 and 54 times, respectively, the recommended dose based on AUC. No effects on post-natal development were observed following oral administration of up to 500 mg/kg migalastat twice daily to pregnant rats (16 times the recommended dose based on AUC) during organogenesis and through lactation.

8.2 Lactation Risk Summary There are no data on the presence of migalastat in human milk, the effects on the breastfed infant, or the effects on milk production. Migalastat is present in the milk of lactating rats (see Data ). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GALAFOLD and any potential adverse effects on the breastfed infant from GALAFOLD or from the underlying maternal condition. There is a study that collects data on effects of GALAFOLD on lactation for women with Fabry disease and their neonates and infants up to 1 year of age who are exposed through breast milk. Healthcare providers are encouraged to register patients or obtain additional information by contacting the Pregnancy Coordinating Center at 1-888-239-0758, email fabrypregnancy@ubc.com, or visit www.fabrypregnancyregistry.com. Data Animal Data Migalastat concentrations in milk from rats following oral administration of up to 500 mg/kg twice daily (approximately 16 times the recommended human dose based on AUC) was approximately 2.5 times higher than levels in the rat maternal plasma at 4 hours post-dose. The concentration of migalastat in plasma from pups was approximately 11 times lower than the maternal plasma concentrations at 1-hour post-dose.

8.3 Females and Males of Reproductive Potential Infertility The effects of GALAFOLD on fertility in humans have not been studied. Transient and fully reversible infertility in male rats was associated with migalastat treatment at a systemic exposure (AUC) equivalent to the human exposure at the recommended dose. Complete reversibility was seen at 4 weeks after the termination of treatment. Migalastat did not affect fertility in female rats [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use The safety and effectiveness of GALAFOLD have not been established in pediatric patients.

8.5 Geriatric Use Clinical trials of GALAFOLD did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.6 Renal Impairment Migalastat is substantially excreted by the kidneys. Systemic exposure was significantly increased in subjects with severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ). GALAFOLD has not been studied in patients with Fabry disease who have an eGFR less than 30 mL/min/1.73 m 2 . GALAFOLD is not recommended for use in patients with severe renal impairment or end-stage renal disease requiring dialysis. No dosage adjustment is required in patients with mild to moderate renal impairment (eGFR at least 30 mL/min/1.73 m 2 and above) [see Clinical Pharmacology (12.3) ] .

Migalastat is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA ), which is deficient in Fabry disease. This binding stabilizes alpha-Gal A allowing its trafficking from the endoplasmic reticulum into the lysosome where it exerts its action. In the lysosome, at a lower pH and at a higher concentration of relevant substrates, migalastat dissociates from alpha-Gal A allowing it to break down the glycosphingolipids globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb 3 ). Certain GLA variants (mutations) causing Fabry disease result in the production of abnormally folded and less stable forms of the alpha-Gal A protein which, however, retain enzymatic activity. Those GLA variants, referred to as amenable variants, produce alpha-Gal A proteins that may be stabilized by migalastat thereby restoring their trafficking to lysosomes and their intralysosomal activity. In Vitro Amenability Assay In an in vitro assay (HEK-293 assay), Human Embryonic Kidney (HEK-293) cell lines were transfected with specific GLA variants which produced variant alpha-Gal A proteins. In the transfected cells, amenability of the GLA variants was assessed after a 5-day incubation with 10 micromol/L migalastat. A GLA variant was categorized as amenable if the resultant variant alpha-Gal A activity (measured in the cell lysates) met two criteria: 1) it showed a relative increase of at least 20% compared to the pre-treatment alpha-Gal A activity, and 2) it showed an absolute increase of at least 3% of the wild-type (normal) alpha-Gal A activity. The in vitro assay did not evaluate trafficking of the variant alpha-Gal A proteins into the lysosome or the dissociation of migalastat from the variant alpha-Gal A proteins within the lysosome. Also, the in vitro assay did not test whether a GLA variant causes Fabry disease or not. The GLA variants that are amenable to treatment with GALAFOLD, either based on the in vitro assay data or on the concept that synonymous nucleotide changes leading to the same variant alpha-Gal A protein as a confirmed amenable GLA variant are amenable without additional testing, are shown in Table 2 . In patients with multiple identified variants, the amenability assessment of each independent variant may not reflect the overall amenability classification of the combination of variants. The specific variant combination must be present within Table 2 (eg, c.[164A>T; 170A>T]) and on a single chromosome (males and females) to be considered amenable to treatment with GALAFOLD. When multiple variants are identified in a female, it is recommended to consult a clinical genetics professional to determine whether the variants are on a single GLA allele. Inclusion of GLA variants in this table does not reflect interpretation of their clinical significance in Fabry disease. Whether a certain amenable GLA variant in a patient with Fabry disease is disease-causing or not should be determined by the prescribing physician (in consultation with a clinical genetics professional, if needed) prior to treatment initiation. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). If a GLA variant does not appear in Table 2 , it is either non-amenable (if tested) or has not been tested for in vitro amenability. For further information, please contact Amicus Medical Information at 1-877-4AMICUS or medinfousa@amicusrx.com. Table 2: Amenable GLA Variants Based on the In Vitro Assay § Based on available published data, the GLA variant c.937G>T, (p.(D313Y)) is considered benign (not causing Fabry disease). Consultation with a clinical genetics professional is strongly recommended in patients with Fabry disease who have this GLA variant as additional evaluations may be indicated. † Multiple variant combination of two or more different variants on a single GLA allele that informs amenability. ‡ Synonymous variants are listed without testing in the in vitro amenability assay. GLA variant(s) with a different nucleotide change affecting the same amino acid position(s) as the tested GLA variant and predicted to encode the same variant alpha-Gal A enzyme are considered synonymous. ¶ c.761_763delTTG has been previously referred to as c.760_762delGTT. […]