Galafold migalastat hydrochloride 123 mg Capsule, 14-count — NDC 71904-100-01 (Billing 71904-0100-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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 [email protected]. 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 wh… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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 [email protected]. 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 a… [Excerpted — this section continues on DailyMed.]

12.3Pharmacokinetics Absorption Following a single GALAFOLD oral dose of 123 mg, the absolute bioavailability (AUC) of migalastat was approximately 75% and the time to peak plasma concentration (t max ) was approximately 3 hours. Plasma migalastat exposure (AUC 0‑∞ and C max ) demonstrated dose‑proportional increases at oral doses from 75 mg to 1250 mg (doses from 0.5 to 8.3‑fold of the approved recommended dosage). Migalastat does not accumulate following administration of 123 mg GALAFOLD every other day.

Effect of Food: Administration of GALAFOLD one hour before a high‑fat (850 calories; 56% from fat) or light meal (507 calories; 30% from fat), or one hour after a light meal, reduced the mean migalastat AUC 0‑∞ by 37% to 42% and C max by 15% to 39% compared to the fasting state [see Dosage and Administration (2.2) ] . Distribution The apparent volume of distribution (V z /F) of migalastat in Fabry patients was approximately 89 L (range: 77 to 133 L) at steady state. There was no detectable plasma protein binding following administration of [ 14 C]‑migalastat in the concentration range between 1 to 100 microM.

Elimination Metabolism: Based upon in vivo data, migalastat is a substrate for uridine diphosphate glucuronosyltransferase (UDPGT), a minor elimination pathway. Excretion: In a mass balance study in healthy male subjects, following oral administration of 123 mg [ 14 C]‑migalastat, approximately 77% of the total radiolabeled dose was recovered in urine and 20% of the total radiolabeled dose was recovered in feces with an overall total recovery of 98% within 96 hours post‑dose. In urine, unchanged migalastat accounted for 80% of the radioactivity, which equates to 62% of the administered dose.

In feces, unchanged migalastat was the only drug‑related component. In plasma, unchanged migalastat accounted for approximately 77% of the plasma radioactivity and three dehydrogenated O‑glucuronide conjugated metabolites, M1 to M3, together accounted for approximately 13% of the plasma radioactivity, none of which comprised more than 6% of the radiolabeled dose. Approximately 9% of the total radioactivity in plasma was unassigned.

Following a single oral dose of 123 mg GALAFOLD, migalastat is cleared from plasma with a mean half‑life (t ½ ) of approximately 4 hours and apparent clearance of

12.5L/hr. Specific Populations Male and Female Patients: The pharmacokinetic characteristics of migalastat were not significantly different between healthy male and female subjects or patients with Fabry disease. Racial or Ethnic Groups: Clinical data indicate no ethnic differences in patient populations studied with migalastat.

Patients with Renal Impairment: In a single‑dose study in subjects with varying degrees of renal impairment, exposure to migalastat (AUC) was increased by 1.2-, 1.8-, and 4.3-fold in subjects with mild (eGFR 60 to 90 mL/min/1.73 m 2 ), moderate (eGFR 30 to 59 mL/min/1.73 m 2 ), and severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ), respectively, while the C max remained unchanged with severity of renal impairment [see Use in Specific Populations (8.6) ] . Drug Interaction Studies In Vitro Studies Migalastat is not a known inhibitor or inducer of cytochrome P450 (CYP450) enzymes, nor is it an inhibitor of BCRP, MDR1, P‑glycoprotein (P‑gp), or BSEP human efflux transporters, or OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2‑K human uptake transporters.

Migalastat is not a substrate of P‑gp, BCRP, MDR1 or MATE1, MATE2‑K, OAT1, OAT3, or OCT2. Migalastat showed low affinity for SGLT1, as both a substrate and an inhibitor, and showed no activity for SGLT2. Clinical Studies: Effects of other Drugs on Migalastat Co‑administration of 190 mg caffeine reduced the mean migalastat AUC 0‑∞ by 55% and C max by 60% compared to without caffeine co‑administration.

The t max of migalastat was not affected by co‑administration of caffeine. No clinically significant pharmacokinetic changes were observed for migalastat… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In Study 1, 31 of 50 patients with amenable GLA variants (18 on GALAFOLD, 13 on placebo) had lyso‑Gb 3 assessments available after 6 months of treatment. The median change from baseline to month 6 in plasma lyso‑Gb 3 (nmol/L) was -2.37 (range -69.7, 1.8) in patients on GALAFOLD and 0.53 (range -21.5, 16.3) in patients on placebo. In the open‑label treatment phase of Study 1, the 13 patients who were initially on placebo for 6 months and who switched to GALAFOLD for another 6 months had a median change in lyso‑Gb 3 (nmol/L) of -2.72 (range -61.1, -0.3).

The 18 patients who were treated with GALAFOLD for 6 months and then continued GALAFOLD in the open‑label treatment phase of Study 1 for an additional 6 months had no further changes in plasma lyso‑Gb 3 . In Study 2, 46 of 56 patients with amenable GLA variants (31 on GALAFOLD, 15 on enzyme replacement therapy (ERT)) had lyso‑Gb 3 assessments available after 18 months of treatment. The median change from baseline to month 18 in plasma lyso‑Gb 3 (nmol/L) was 0.53 (range -2.27, 28.3) in patients on GALAFOLD and -0.03 (range -11.9, 2.57) in patients on ERT.

Cardiac Electrophysiology At a dose approximately 8 times the recommended dose, GALAFOLD did not prolong the QT interval to any clinically relevant extent.

14 CLINICAL STUDIES Study AT1001‑011 (referred to as Study 1; NCT00925301) included a 6‑month randomized, double‑blind, placebo‑controlled phase followed by a 6‑month open‑label treatment phase and a 12‑month open‑label extension phase. Patients received 123 mg GALAFOLD orally every other day taken without consuming food 2 hours before and 2 hours after each dose to give a minimum 4‑hour fast [see Dosage and Administration (2.2) ] . A total of 67 patients with Fabry disease who were naïve to GALAFOLD and enzyme replacement therapy (ERT) or were previously treated with ERT (agalsidase beta or non‑U.S. approved agalsidase alfa) and had been off ERT for at least 6 months were randomized in a 1:1 ratio to receive either GALAFOLD 123 mg every other day or placebo for the first 6 months.

In the second 6 months, all patients were treated with GALAFOLD. Results - Patients with Fabry Disease with Amenable GLA Variants Of the 67 enrolled patients, 50 patients (32 females, 18 males) had amenable GLA variants based on the in vitro amenability assay [see Clinical Pharmacology (12.1) ] . The median age of this population was 45 years (range from 16 to 68 years old); 65 were White (97%), and 2 were other racial group (3%).

The major efficacy outcome measure of the average number of GL‑3 inclusions per kidney interstitial capillary (KIC) in renal biopsy samples was assessed by light microscopy before and after treatment. Efficacy was evaluated after 6 months of treatment in 45 of 50 patients with amenable GLA variants (29 females and 16 males) and with available histology data both at baseline and month 6. Of the 45 evaluable patients, 25 received GALAFOLD (18 females, 7 males) and 20 received placebo (11 females, 9 males).

The proportion of patients with ≥ 50% reduction from baseline in the average number of GL‑3 inclusions per KIC and the median changes from baseline in the average number of GL‑3 inclusions per KIC after 6 months of treatment in Study 1 are shown in Table 3 . Table 3: Changes from Baseline to Month 6 in Average Number of GL‑3 Inclusions per KIC in Adults with Fabry Disease with Amenable GLA Variants in Study 1 (N = 45) GALAFOLD n/N (%) with ≥ 50% reduction Median change from baseline (range) Placebo n/N (%) with ≥ 50% reduction Median change from baseline (range) All patients (N = 45) 13/25 (52%) -0.04 (-1.94, 0.26) 9/20 (45%) -0.03 (-1.00, 1.69) Females (N = 29) 8/18 (44%) -0.02 (-0.46, 0.26) 5/11 (46%) -0.03 (-0.35, 0.10) Males (N = 16) 5/7 (71%) -1.10 (-1.94, -0.02) 4/9 (44%) -0.03 (-1.00, 1.69) Patients with baseline GL-3 ≥ 0.3 (N = 17; 9 males, 8 females) 7/9 (78%) -0.91 (-1.94, 0.19) 2/8 (25%) -0.02 (-1.00, 1.69) Patients with baseline GL-3 < 0.3 (N = 28; 7 males, 21 females) 6/16 (38%) -0.02 (-0.10, 0.26) 7/12 (58%) -0.05 (-0.16, 0.14) Results - Patients with Fabry Disease with Non‑Amenable GLA Variants Of the 67 enrolled patients in Study 1, 17 patients had non‑amenable GLA variants.

These patients had no change from baseline in the average number of GL‑3 inclusions per KIC after 6 months of treatment.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis The carcinogenic potential of migalastat was assessed in a 2‑year study in rats and a 26‑week study in Tg.rasH2 mice. In the 2‑year rat study, migalastat was not tumorigenic at oral doses of up to 600 mg/kg twice daily (24 times the recommended dose based on AUC). In the 26‑week study in Tg.rasH2 mice, migalastat was not tumorigenic at oral doses of up to 1000 mg/kg/day in males and 500 mg/kg/day in females.

Mutagenesis Migalastat was negative in the bacterial mutagenicity (Ames) assay, in vitro cell mutation assay in L5178Y mouse lymphoma TK +/- cells, and in vivo micronucleus assay in rats. Impairment of Fertility Oral administration of up to 12.5 mg/kg migalastat twice daily in rats (equivalent to the human AUC at the recommended dose) produced a significant decrease in male fertility. This effect was completely reversed after four weeks of recovery.

Female fertility was not affected.