RARE Daily

Applied Therapeutics Reports Positive Results in Ongoing Late-State SORD Study

February 16, 2023

Rare Daily Staff

Applied Therapeutics reported positive sorbitol reduction data from an interim analysis of its global phase 3 INSPIRE trial evaluating its experimental therapy AT-007 to treat the genetic neuropathy SORD deficiency.

SORD deficiency (also called SORD neuropathy or CMT-SORD) is a hereditary axonal neuropathy caused by mutations in the sorbitol dehydrogenase gene, leading to an inability to metabolize the sugar sorbitol, and resulting in accumulation of high levels of toxic sorbitol, which causes motor neuron degeneration and loss of mobility and motility.

AT-007 (govorestat) is a central nervous system penetrant aldose reductase inhibitor in development for the treatment of several rare neurological diseases, including galactosemia, SORD deficiency, and PMM2-CDG. AT-007 blocks conversion of glucose to sorbitol, and has previously been shown to reduce sorbitol levels in an open-label pilot study in patients with SORD Deficiency.

In clinical trials, AT-007 significantly reduced plasma galactitol levels vs. placebo in adults and children with galactosemia. AT-007 is currently being studied in a phase 3 clinical outcomes trial in children ages 2-17 with galactosemia, as well as a long-term open-label study in adults with galactosemia.

In a pilot study in adults with SORD deficiency, AT-007 significantly reduced blood sorbitol levels. AT-007 is currently being studied in the phase 3 INSPRIRE trial investigating biomarker efficacy and clinical outcomes in adults and children 16 years and older with SORD deficiency. The drug has been generally safe and well tolerated in all clinical studies to date.

In a pre-specified interim analysis of the ongoing phase 3 INSPIRE trial, AT-007 reduced sorbitol levels by a mean of approximately 52 percent over 90 days of treatment in patients with SORD Deficiency.

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.

The INSPIRE study will continue in blinded format to the 12-month interim clinical outcomes assessment. If the primary clinical outcome measure (10-meter-walk/run) reaches statistical significance at 12 months, the study will be completed and unblinded. If not, the study will continue in blinded format to 24 months, where clinical outcomes will be assessed again in a final statistical analysis. AT-007 continues to be safe and well tolerated to date.

“The role of sorbitol in disease pathogenesis in SORD Deficiency is clear,” said Michael Shy, director of the Division of Neuromuscular Medicine at Carver College of Medicine at University of Iowa Medical Center, and principal investigator on the INSPIRE phase 3 trial. “The reduction in sorbitol level seen thus far with AT-007 is impressive, and is predicted to translate into clinical benefit.”

Photo: Michael Shy, director of the Division of Neuromuscular Medicine at Carver College of Medicine at University of Iowa Medical Center

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