Clinical Pharmacology Corner: FDA Approves GALAFOLD (Migalastat)

FDA Approves GALAFOLD (Migalastat) 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

On August 10, 2018, the U.S. Food and Drug Administration (FDA) approved GALAFOLD (migalastat) 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. 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.

The approved recommended dosage regimen of GALAFOLD is 123 mg orally once every other day at the same time of day. GALAFOLD should be taken on an empty stomach. Food should not be consumed at least 2 hours before and 2 hours after taking GALAFOLD to give a minimum 4 hours fast. GALAFOLD should not be taken on 2 consecutive days. Additional information regarding dosage and administration can be found in the full prescribing information linked below.

GALAFOLD is indicated for patients with an amenable GLA variant that is interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. 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).

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) 

• MOA: Migalastat is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by 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-Gb₃). The GLA variants which are amenable to treatment with GALAFOLD, based on in vitro assay data can be found in the full prescribing information linked below.
• General PK: 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.
• 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 was approximately 3 hours.
• Effect of Food: Administration of GALAFOLD one hour before a high-fat (850 calories; 56% from fat) or light (507 calories; 30% from fat) meal, or one hour after a light meal, reduced the mean migalastat AUC_0-∞ by 37% to 42% and C_max by 15% to 39%.
• Distribution: The apparent volume of distribution 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 [¹⁴C]-migalastat in the concentration range between 1 to 100 microM.
• Elimination: Following a single oral dose of 123 mg GALAFOLD, migalastat is cleared from plasma with a mean half-life of approximately 4 hours and apparent clearance of 12.5 L/hr.
• Metabolism: Based upon in vivo data, migalastat is a substrate for uridine diphosphate glucuronosyltransferase (UDPGT), a minor elimination pathway.
• Excretion: Following oral administration of 123 mg [¹⁴C]-migalastat, approximately 77% of the total radiolabeled dose was recovered in urine (80% unchanged which equates to 62% of the administered dose) and 20% in feces (unchanged) with an overall total recovery of 98% within 96 hours post-dose. In plasma, approximately 77% of the plasma radioactivity was unchanged, 13% attributable to three conjugated metabolites, and approximately 9% was unassigned.
• PD: In adults with a confirmed diagnosis of Fabry disease and an amenable GLA variant based on in vitro assay data patients receiving the recommended dosage of GALAFOLD, the median change from baseline to month 6 in plasma lyso-Gb₃ (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, the patients who were initially on placebo for 6 months and switched to GALAFOLD for another 6 months had a median change in lyso-Gb₃ (nmol/L) of -2.72 (range -61.1, -0.3). The patients who were treated with GALAFOLD for 6 months and then continued GALAFOLD in the open-label treatment phase for an additional 6 months had no further changes in plasma lyso-Gb₃.

Drug Interactions

Migalastat is not an inhibitor or inducer of cytochrome P450 (CYP450) enzymes. Migalastat is not an inhibitor of BCRP, MDR1, P-glycoprotein (P-gp), BSEP human efflux transporters, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K human uptake transporters. Migalastat is not a substrate of P-gp, BCRP, MDR1, 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.

Use in Specific Populations

The pharmacokinetics of migalastat were not significantly different between healthy male and female subjects, patients with Fabry disease, or racial/ethnic groups studied.

Patients with Renal Impairment
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 m² and above). In a single-dose study, migalastat AUC in subjects with mild (eGFR 60 to 90 mL/min/1.73 m²), moderate (eGFR 30 to 59 mL/min/1.73 m²), and severe (eGFR less than 30 mL/min/1.73 m²) renal impairment increased by 1.2-, 1.8-, and 4.3-fold, respectively. The C_max remained unchanged with severity of renal impairment.

Efficacy and Safety

Efficacy of GALAFOLD for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable GLA variant based on in vitro assay data was demonstrated in a clinical trial, which 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. The major efficacy outcome measure was the average number of GL-3 inclusions per KIC in renal biopsy samples assessed by light microscopy before and after treatment. Additional information regarding efficacy trial can be found in the full prescribing information linked below.

The most common adverse drug reactions reported with GALAFOLD (≥ 10%) are headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia.
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Full prescribing information is available at https://go.usa.gov/xUtGF.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.