Results of the ACTION-Galactosemia Kids Study to Evaluate the Effects of Govorestat in Pediatric Patients with Classic Galactosemia

Abstract

To evaluate the pharmacodynamic effects and clinical outcomes of orally administered once-daily govorestat (AT-007), a central nervous system penetrant aldose reductase inhibitor, the double-blind placebo-controlled ACTION-Galactosemia Kids study (NCT04902781) randomly assigned 47 participants (2-17 years old) with Classic Galactosemia to 18 months of govorestat or placebo (2:1) treatment. Mean change in galactitol was compared between the treatment groups at each post-baseline timepoint using a t-test, with a mixed model for repeated measures (MMRM) analysis as a sensitivity analysis. Changes from baseline in clinical outcomes were compared between treatment groups also using a t-test with two different MMRM models as sensitivity models, one including baseline clinical outcome score. The pharmacodynamic effect of govorestat was assessed by correlating galactitol level at 3 months with change from baseline in clinical measures at 18 months using a Pearson correlation. Govorestat treatment resulted in a rapid and sustained reduction in plasma galactitol. Govorestat treatment stabilized or improved clinical measures of behavior, daily living skills, adaptive skills, cognition, tremor, and fine motor skills, which declined over time in the placebo group. Govorestat treatment did not demonstrate a benefit compared with placebo on speech outcomes or gross motor skills, which improved in both treatment groups over 18 months. Govorestat was safe and well tolerated, with adverse events well balanced between the active and placebo groups. Aldose reductase inhibition with govorestat represents a potential opportunity to lower galactitol and improve clinical outcomes in children with Classic Galactosemia.

Keywords: AT‐007; Classic Galactosemia; aldose reductase; govorestat; pediatric.

Figure 1

Participant disposition.

Figure 2

Forest plots of the composite primary endpoint and components of this primary endpoint with change in primary endpoint over time. (a) Forest plot displaying the primary endpoint global statistical test and sensitivity analyses to the primary endpoint including cognition and 9‐Hole‐Pegboard Test (9HPT). (b) Forest plot displaying individual components of the primary endpoint (Behavior Assessment System for Children Activities of Daily Living [BASC‐ADL], Behavior Assessment System for Children Behavioral Symptoms Index [BASC‐BSI], Oral and Written Language Scales‐Oral Expression [OWLS‐OE], and Oral and Written Language Scales‐Listening Comprehension [OWLS‐LC]); components of the sensitivity analyses to the primary endpoint (National Institute of Health Cognition Battery [NIH‐CB] and NIH Motor Battery 9HPT); and key secondary endpoints (BASC social skills, withdrawal, adaptability, Adaptive Skills Index [ASI], attention deficit hyperactivity disorder [ADHD] probability index, and functional impairment index; NIH Motor Battery standing balance test; and tremor). Brackets show 95% confidence intervals (CI). *Variables were reversed so that higher scores represented improvement. ^†Archimedes Spiral Drawing test for tremor was multiplied by 10 to match the scales of the other tests. (c) Change over time in z‐scores for the composite primary endpoint and sensitivity analyses including cognition and fine motor skills from baseline to 6, 12, and 18 months.

Figure 3

Mean change from baseline to 6, 12, and 18 months for the govorestat and placebo treatment groups on age‐standardized rests. (a) Behavior Assessment System for Children Activities of Daily Living (BASC‐ADL). (b) Behavior Assessment System for Children Behavioral Symptoms Index (BASC‐BSI). (c) Oral and Written Language Scales‐Oral Expression (OWLS‐OE). (d) Oral and Written Language Scales‐Listening Comprehension (OWLS‐LC). (e) National Institute of Health Cognition Batter (NIH‐CB). (f) 9‐Hole‐Pegboard Test (9HPT). (g) BASC social skills. (h) BASC withdrawal. (i) BASC adaptability. (j) BASC adaptive skills. (k) BASC attention deficit hyperactivity Disorder (ADHD) probability index. (l) BASC functional impairment index. (m) NIH standing balance test. (n) Tremor (not age standardized). For all graphs, error bars show standard error (SE).

Figure 4

Pearson correlations showing galactitol level (ng/mL) at Month 3 compared with change in clinical outcomes from baseline to 18 months. (a) Behavior Assessment System for Children Activities of Daily Living (BASC‐ADL). (s) Behavior Assessment System for Children Behavioral Symptoms Index (BASC‐BSI). (c) Oral and Written Language Scales‐Oral Expression (OWLS‐OE). (d) Oral and Written Language Scales‐Listening Comprehension (OWLS‐LC). (e) National Institute of Health Cognition Batter (NIH‐CB). (f) 9‐Hole‐Pegboard Test (9HPT). (g) BASC social skills. (h) BASC withdrawal. (i) BASC adaptability. (j) BASC adaptive skills. (k) BASC attention deficit hyperactivity disorder (ADHD) probability index. (l) BASC functional impairment index. (m) NIH standing balance test.

Figure 5

Exit interview results. Results shown as improvement (green), no change (light grey), or worsening (dark grey) from the caregiver perspective. All results are shown as percentages of participants in the treatment group.