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Three Year Safety Experience in Children Treated with Govorestat for Classic Galactosemia

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
Classic Galactosemia is an autosomal recessive metabolic disease resulting in an inability to metabolize the sugar galactose. Newborn screening and implementation of a galactose-restricted diet have substantially decreased mortality.  However, despite dietary adherence, patients continue to develop significant long-term neurological and behavioral complications.

Methods:
The AT-007-1002 clinical study was a double-blind placebo-controlled trial evaluating the safety and clinical efficacy of govorestat (AT-007) in children with Classic Galactosemia age 2-17 years old.   Govorestat is an oral CNS penetrant Aldose Reductase Inhibitor (ARI) which prevents conversion of galactose to galactitol; galactitol is the toxic metabolite responsible for long-term complications in Galactosemia.  Children enrolled in the study were randomized 2:1 to govorestat or placebo for 18 months and continued to adhere to the galactose-restricted diet throughout the clinical study.  Patients who were randomized to govorestat in the trial could transition into an Expanded Access Program to continue to receive open-label govorestat after completion of the clinical trial.  These patients have now completed 3 years of continuous exposure to govorestat. Adverse events and laboratory values were collected in the EAP by their treating physician every 3 months and reported to the central database.  Summary data was reported by system organ class, severity and relatedness.

 

Results:
26 of the 31 patients originally randomized to govorestat in the AT-007-1002 clinical study completed 18 months of treatment (5 discontinued during the trial).  Of these 26, 23 enrolled in the EAP and have completed 3 years of continuous treatment.  The safety profile of govorestat in the EAP was consistent with the findings from the AT-007-1002 study. There have been no discontinuations in the EAP for any reason. No adverse event occurred in more than one patient, and no AEs were considered to be drug-related in the EAP.  In the AT-007-1002 study, a small number of patients 5/31 (16%) experienced ALT/AST elevations >3X ULN. These elevations were transient, reversible, not associated with any clinical symptoms, and there were no concurrent increases in bilirubin or cases of Hy’s law. These elevations occurred within the first 6 months of treatment and were identified via routine lab monitoring.   In the additional 18 months of govorestat exposure during the EAP, there were no additional cases of ALT/AST elevations, including none in the patients who experienced ALT/AST elevations during the AT-007-1002 study. 

Conclusion:
Govorestat was safe and well tolerated in both the AT-007-1002 clinical trial and the EAP.  Long-term exposure to govorestat over 3 years of treatment was safe and well tolerated in Classic Galactosemia patients.

 

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