OP005: AT-007 significantly reduces toxic galactitol in ACTION-galactosemia kids - the 1st therapeutic interventional clinical trial in children with classic galactosemia

Abstract

Classic Galactosemia (CG) is a rare, autosomal recessive disease where galactose is not metabolized properly due to severe deficiency or absence of the GALT enzyme (galactose-1-phosphate uridyl transferase). At abnormally high levels, galactose becomes an aberrant substrate for the enzyme aldose reductase, resulting in conversion to an abnormal and toxic metabolite, galactitol. Newborn screening and implementation of a galactose-restricted diet has reduced newborn acute symptoms and significantly decreased fatalities. However, despite early dietary intervention, children continue to develop significant morbidities in speech, cognition, behavior, and motor function, which have been shown to progressively worsen with age, as well as cataracts and primary ovarian insufficiency in females. AT-007 is an oral CNS penetrant aldose reductase inhibitor, which prevents conversion of galactose to toxic galactitol, that is in development for the treatment of CG. Reduction in circulating galactitol by AT-007 has been shown to halt the progression of disease in a rat model of Galactosemia. ACTION-Galactosemia Kids is a sequential, two-part, randomized double-blind, placebo-controlled study evaluating the clinical benefit, safety, pharmacokinetics and pharmacodynamics of AT-007 in pediatric patients with CG. Patients were randomized 2:1 to AT-007 or placebo. Disease demographics, genetic variant, and patient history were assessed at baseline. Additionally, functional tests of speech, motor function, cognition and behavior were performed at baseline for all patients enrolled in the clinical study. The primary biomarker study endpoint was reduction in plasma galactitol over a minimum of 30 days of treatment with the target dose of AT-007 vs placebo. Baseline and 30-day plasma galactitol levels were drawn under fasted conditions and evaluated via a validated liquid chromatography-mass spectrometry assay. Baseline galactitol correlation with disease severity was evaluated via a linear model incorporating baseline speech, cognition, behavior and motor skills assessments. Forty-seven patients ranging in age from 2 to 17, were enrolled at 3 US clinical sites in ACTION-Galactosemia Kids across three predefined age groups (2-6 years old; 7-12 years old; 13-17 years old). The patients were predominantly White (98%), had a mean age of 9 and 51% were female/49% male. The most common baseline disease characteristics included learning disorders (∼50%), apraxia (∼40%), anxiety (∼35%), vitamin deficiency (∼30%), tremor (∼20%) and ataxia (∼20%). All the female patients older than 12 had primary ovarian insufficiency. Additionally, ∼10% of the patients suffered from seizures and ∼5% had early onset cataracts. Baseline disease and demographic characteristics were balanced across the placebo and AT-007 treatment groups. Galactitol levels at baseline correlated with total disease severity in this pediatric patient population (p=0.004). Treatment with AT-007 resulted in a 40.2% reduction in galactitol, which was significant when compared with patients on placebo (p<0.001). The reduction in toxic galactitol was consistent among age and dose groups and was not associated with changes in galactose or galacose-1-phosphate (Gal-1p). AT-007 was safe and well tolerated. The biomarker results from ACTION-Galactosemia Kids demonstrates that treatment with AT-007 resulted in a significant reduction of the toxic metabolite galactitol, a biomarker that correlated with disease severity, in pediatric patients with Classic Galactosemia. Treatment of pediatric Galactosemia patients age 2 to 17 with AT-007 was safe and well tolerated.