AT-007 is an investigational, novel Aldose Reductase Inhibitor (ARI) being developed for the treatment of several rare diseases. AT-007 is a potent and selective compound, which crosses the blood brain barrier into the Central Nervous System (CNS penetrant). AT-007 has received both Orphan Drug and Pediatric Rare Disease designations from the FDA for the treatment of Galactosemia, a rare metabolic disease, and Phosphomannomutase 2 Deficiency – a Congenital Disorder of Glycosylation (PMM2-CDG).

AT-007 is currently in pivotal-stage development for treatment of Galactosemia and will move into clinical studies for SORD Deficiency and PMM2-CDG in 2021.

AT-007 for Galactosemia

AT-007 is a once-daily oral compound that inhibits the enzyme Aldose Reductase. Aldose Reductase plays a crucial role in the pathogenesis of Galactosemia.

Galactosemia is a rare, slowly progressing metabolic disease caused by a genetic inability to break down the sugar galactose. Aldose Reductase converts galactose into galactitol, a toxic metabolite that builds up in tissues and organs and can cause long-term disease complications. Galactosemia has no known cure or approved treatment.

We believe AT-007 has the potential to be the first and only approved treatment for Galactosemia.

AT-007 was evaluated in a Phase 1/2 Registrational Study (ACTION-Galactosemia) of adult patients with Galactosemia. The study confirmed that AT-007 was safe and well tolerated. AT-007 decreased levels of galactitol, a key biomarker of Aldose Reductase function, in all treated patients without increasing galactose levels or levels of other galactose metabolites (such as Gal1P). The reduction in galactitol was rapid, beginning on the first day of treatment, and sustained over one month of treatment; dose-dependent; and statistically significant at the higher doses of 20 & 40 mg/kg. At the 20 mg/kg dose, an approximately 50% reduction in galactitol was observed compared to baseline levels. The pharmacokinetic results showed that AT-007 plasma concentrations increased linearly in a dose-dependent manner and support once-daily dosing.

In June 2020, the company initiated the ACTION-Galactosemia Kids registrational pediatric clinical study. The study consists of a dose range finding pharmacokinetic/pharmacodynamic study to determine the optimal dose of AT-007 in children, followed by a biomarker-based assessment of galactitol reduction. A long-term clinical outcomes study will follow post-NDA submission to provide long-term safety data.

Full biomarker data from the pediatric ACTION-Galactosemia Kids study demonstrated a substantial reduction in mean plasma galactitol of 40%, which was statistically significant (p<0.001) vs. placebo.  Reduction in plasma galactitol was rapid and sustained, with no impact on levels of galactose or Gal-1p, and was similar across dose groups.  AT-007 was safe and well tolerated in children of all ages (2-17). 

Additionally, analysis of the 47 children in the ACTION-Galactosemia Kids study demonstrated a clear correlation between baseline galactitol level and baseline clinical functional outcomes. Children with higher plasma galactitol levels displayed greater disease severity vs. children with lower plasma galactitol levels at baseline. This data is the first demonstration of correlation of a biochemical biomarker with severity of disease in Galactosemia patients.

AT-007 for SORD Deficiency and PMM2-CDG

AT-007 has transformative therapeutic potential in two additional rare diseases that currently have no approved therapies: sorbitol dehydrogenase deficiency (SORD) and phosphomannomutase 2 deficiency – a congenital disorder of glycosylation (PMM2-CDG).

SORD Deficiency is a progressive hereditary neuropathy that is caused by a deficiency in the sorbitol dehydrogenase enzyme, which results in toxic levels of sorbitol. Recent research in animal and cell models suggests that treatment with an Aldose Reductase Inhibitor (ARI) may provide therapeutic benefit in SORD Deficiency. Applied Therapeutics intends to initiate a clinical study in 2021.

PMM2-CDG is the most common congenital disorder of glycosylation and presents with a range of debilitating systemic and CNS complications. As a result of reduced activity of the PMM2 enzyme, patients with PMM2-CDG have imbalances in sugar metabolism pathways, including Aldose Reductase activity. Initial data in fibroblast cell lines derived from patients with PMM2-CDG demonstrates that AT-007 increases PMM2 activity and may provide therapeutic benefit in PMM2-CDG patients. Applied Therapeutics plans to initiate a clinical study in PMM2-CDG patients in 2021.