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 Orphan Medicinal Product Designation from the European Medicines Agency (EMA), and 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 SORD Deficiency.
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.
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.
The ACTION-Galactosemia Kids registrational Phase 3 study was designed to evaluate the impact of AT-007 vs. placebo on clinical outcomes over time in 47 children aged 2-17 with Galactosemia.
Biomarker data from the dose range finding pharmacokinetic / pharmacodynamic portion of 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. Additionally, Galactitol was the only biomarker demonstrating correlation with disease severity in pediatric patients with Classic Galactosemia. Higher galactitol levels, but not higher Gal-1p levels, were associated with greater disease severity overall and on each of the four quadrants of CNS function. This data is the first demonstration of correlation of a biochemical biomarker with severity of disease in Galactosemia patients.
Results from the ACTION-Galactosemia Kids study demonstrated clinical benefit of AT-007 on activities of daily living, behavioral symptoms, cognition and tremor. Consistent with prior findings in adult and pediatric populations, AT-007 continued to be safe and well-tolerated throughout the trial period in all age groups (2-17).
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).
Sorbitol Dehydrogenase Deficiency (SORD Deficiency) is a rare, progressive, debilitating hereditary neuropathy that affects peripheral nerves and motor neurons. SORD Deficiency is one of the most common forms of recessive hereditary neuropathy and affects approximately 3,300 patients in the U.S. and 4,000 patients in Europe. The disease is caused by a lack of the enzyme sorbitol dehydrogenase, responsible for the metabolism of sorbitol, which causes sorbitol to accumulate at high levels and become toxic to the body. Intracellular sorbitol accumulation results in significant disability, loss of sensory function, neuromuscular dysfunction, and decreased mobility.
In a pilot study in patients with SORD Deficiency, sorbitol level correlated with disease severity, and AT-007 treatment substantially reduced sorbitol levels by a mean of 66% from baseline. In an animal model of disease, elevated sorbitol resulted in neuronal damage and decline in mobility, and AT-007 treatment prevented the disease phenotype by inhibiting sorbitol production.
The ongoing placebo-controlled Phase 2/3 INSPIRE study is evaluating the impact of AT-007 treatment on sorbitol reduction and clinical outcomes in patients with SORD Deficiency.
In a pre-specified interim analysis of the ongoing Phase 3 INSPIRE trial, AT-007 reduced sorbitol levels by a mean of approximately 52% (or approximately 16,000ng/ml) over 90 days of treatment (p<0.001 vs. placebo) in patients with SORD Deficiency. At baseline, the mean blood sorbitol level of SORD patients was approximately 29,000ng/ml, with a range of approximately 22,000ng/ml-38,000ng/ml. In the INSPIRE trial, a baseline cross-sectional analysis of the relationship between sorbitol level, age (or duration of disease) and clinical outcome measures demonstrated a statistically significant correlation between sorbitol level and key clinical outcome measures, including 10-meter-walk/run speed, 4-stair climb speed, and sit-to-stand test (p<0.05). Taken together with the biology of the disease and strong supportive animal model data, the Company believes that compelling data exists demonstrating that sorbitol reduction is reasonably likely to predict effect on clinical outcomes over time. The Company is working with the FDA to determine the appropriate regulatory path forward, as well as data required for an NDA submission, with the shared goal of bringing a safe and effective treatment to patients with SORD Deficiency as expeditiously as possible.
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.