MO068EFFICACY AND SAFETY OF MIGALASTAT, AN ORAL PHARMACOLOGICAL CHAPERONE FOR FABRY DISEASE: RENAL FINDINGS FROM TWO RANDOMIZED PHASE 3 STUDIES (FACETS AND ATTRACT)

Abstract

Fabry disease is an X-linked disorder of lysosomal α-galactosidase A (a-Gal A) deficiency, leading to substrate accumulation, multiorgan disease, and progressive decline in renal function. Accumulation of globotriaosylceramide (GL-3) in the kidney is a known consequence of Fabry disease. We examined whether administration of Migalastat, an oral pharmacological chaperone that induces proper folding of specific mutant forms of a-Gal A and increases trafficking to lysosomes, helps stabilize renal function in patients with Fabry disease. Two randomized phase 3 studies were conducted for Migalastat 150 mg every other day. FACETS (011, NCT00925301) was a 24-month trial, including a 6-month double-blind, placebo-controlled period, in 67 enzyme replacement therapy (ERT)-naive patients. ATTRACT (012, NCT01218659) was an active-controlled, 18-month trial in 57 ERT-experienced patients with a 12-month openlabel extension (OLE). Efficacy analyses focused on patients with amenable mutations (FACETS, n = 50; ATTRACT, n = 53). A post hoc analysis examined the eGFR annualized rate of change from baseline in the range of 60 to <90 or >90 mL/ min/1.73 m2; the range of 30 to <60 mL/min/1.73 m2 was not included due to the low number of patients in this group. In FACETS, analyses revealed statistically significant reductions in kidney interstitial capillary GL-3 from months 0 to 6 (placebo-controlled; P = .008) and months 6 to 12 (P = .014). Over 24 months, the annualized rate of change in eGFRCKD-EPI ± SD with Migalastat was -0.3±4.2 mL/ min/1.73 m2. The annualized rate of change ± SD for eGFR in the range of 60 to <90 mL/min/1.73 m2 (-0.8 ±4.16) was comparable to the rate in the range of ≥90 mL/min/1.73 m2 (0.2 ± 4.11). During the 18-month controlled period of ATTRACT, the annualized means ± SD for eGFR for Migalastat (-0.40 ± 4.3) and ERT (-1.03 ± 7.4) were comparable. The annualized rates of change in eGFR ± SD in the range of 60 to <90 mL/min/1.73 m2 for Migalastat and ERT were -0.2 ± 5.32 and -7.3 ± 15.90, respectively; the annualized rates in the range of ≥90 mL/min/1.73 m2 were -2.0 ± 2.15 and -2.1 ± 5.30. Predefined renal events occurred in 24% and 33% of patients on Migalastat and ERT, respectively. During the 12-month OLE, eGFR remained stable. In FACETS and ATTRACT, renal function remained stable with Migalastat across patient subgroups. Migalastat has promise as a first-in-class oral chaperone for patients with Fabry disease with amenable mutations. This is an encore abstract.