AT-007 found to halve sorbitol levels in SORD deficiency trial

Applied treatment candidate shows benefits for rare CMT disease

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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AT-007, an experimental treatment from Applied Therapeutics, was found to more than halve the levels of a sugar alcohol called sorbitol in people with SORD deficiency, a type of Charcot-Marie-Tooth disease (CMT) in which too much sorbitol causes nerve damage or neuropathy.

Those findings come from a new interim analysis of INSPIRE (NCT05397665), an ongoing Phase 3 clinical trial that’s evaluating the effects of once-daily oral AT-007 versus a placebo in SORD deficiency patients. The study, underway in the U.S. and Europe, involves about 50 people, ages 16-55, with the rare disorder.

“The results of the interim sorbitol analysis are quite compelling, and we believe the reduction in sorbitol level with AT-007 is clinically meaningful,” Riccardo Perfetti, MD, PhD, Applied’s chief medical officer, said in a press release.

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SORD deficiency occurs when the body doesn’t produce enough of an enzyme called SORD, which is short for sorbitol dehydrogenase. This enzyme is responsible for breaking down sorbitol into a simpler sugar called fructose.

Sorbitol is found in many fruits and is also formed by conversion from glucose in the body. Without enough of the SORD enzyme, sorbitol can build up in the body to a toxic level and cause neuropathy.

Symptoms may include pain, difficulty walking, foot deformities, tremors, and muscle weakness.

Also known as govorestat, AT-007 is an aldose reductase inhibitor that works by blocking the conversion of glucose to sorbitol. In so doing, it is expected to prevent the buildup of sorbitol in the body.

In this pilot study, involving eight adults — four men and four women — with SORD deficiency, AT-007 significantly reduced the level of sorbitol in blood by a mean 66% from the study’s start (baseline), the company shared in a scientific poster.

The trial overall is evaluating how well AT-007 works versus a placebo in shortening the time needed to walk or run a distance of 10 meters (about 33 feet). It’s also examining the treatment’s ability to reduce the level of sorbitol in blood from baseline to up to 24 months, or two years.

Additionally, researchers will assess how much fat builds up — or how much muscle is lost — on MRI scans. The Charcot Marie Tooth Functional Outcome Measure is being used to measure functional ability.

The interim analysis revealed that taking AT-007 for 90 days (about three months) reduced the level of sorbitol in blood by a mean 16,000 nanograms (ng)/ml. This was a 52% reduction from the baseline level of 29,000 ng/ml, which ranged from 22,000 ng/ml to 38,000 ng/ml.

“The reduction in sorbitol level seen thus far with AT-007 is impressive, and is predicted to translate into clinical benefit,” said Michael Shy, MD, director of the division of neuromuscular medicine at the University of Iowa Medical Center’s Carver College of Medicine, and a principal investigator in INSPIRE.

So far, AT-007 was found to be safe and tolerated well, according to the company.

INSPIRE will continue in a blinded format at least until a planned 12-month interim analysis. A blinded format means that neither participants nor researchers know who is receiving the medication and whom the placebo.

If the primary clinical outcome measure (the 10-meter-walk or run speed) reaches statistical significance, the trial will be completed and unblinded, meaning everyone involved will know which treatment is being given. If not, the trial will continue in a blinded format for up to 24 months, at which time clinical outcome measures will be assessed again in a final analysis.

Applied joined forces in 2021 with the Charcot–Marie–Tooth Association (CMTA) to identify people with SORD deficiency who might be interested in taking part in future clinical trials through CMTA’s Patients as Partners in Research initiative.

“This is exciting data for patients with SORD Deficiency,” said Amy Gray, the association’s CEO, adding, “We will continue to work closely with Applied Therapeutics and the patient community to ensure that patients have a safe and effective treatment option available for this devastating disease.”

The company is talking with the U.S. Food and Drug Administration to determine what information is needed for a New Drug Application or NDA seeking approval of AT-007.

AT-007 has already received orphan drug designations in the U.S. and Europe for the treatment of galactosemia, a rare metabolic disease, and the congenital disorder glycosylation type Ia (PMM2-CDG).