Three Year Safety Experience in Children Treated with Govorestat for Classic Galactosemia
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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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.
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.