Applied Therapeutics recently presented findings from their INSPIRE Phase 2/3 clinical trial of govorestat (AT-007) for the treatment of Sorbitol Dehydrogenase Deficiency, a subtype of Charcot-Marie-Tooth disease, at the Peripheral Nerve Society’s 2025 Annual Meeting in Edinburgh, Scotland. The presented findings included the full 12-month clinical results and highlights from the 18- and 24-month clinical results.
CMT-SORD is a rare axonal subtype of CMT caused by mutations in the SORD gene. These mutations impair the function of an enzyme responsible for breaking down a sugar metabolite called sorbitol, leading to its accumulation. Elevated levels of sorbitol is toxic to the nerve cells and leads to neuromuscular deficits and other symptoms related to the disease.
Govorestat is a small molecule drug that aims to reduce the toxic levels of sorbitol by inhibiting an enzyme responsible for converting sugar into sorbitol.
Some key findings from the 12-month clinical data of the INSPIRE trial include significant lowering of blood sorbitol levels with treatment of govorestat and significant correlations between sorbitol reduction and changes in several functional outcome measures, including the 10-meter walk-run test and the CMT-FOM composite score of the measurements from many functional tests. Patient-reported outcome measures using the CMT-Health Index were also significantly correlated with reduced sorbitol levels and demonstrated significant improvement in the govorestat-treated patients compared to placebo-treated patients. The 10-meter walk-run test, which served as the primary endpoint for this trial, was not statistically significant between govorestat-treated and placebo-treated groups. However, the 10-meter walk-run test has been removed from the CMT-FOM composite score since the initiation of the INSPIRE trial.
Highlights from the 18- and 24-month results include sustained reductions in blood sorbitol levels and sustained improvements in the CMT-Health Index in govorestat-treated patients out to 24 months. Additionally, MRI measurements of the muscle-fat fraction in the lower limbs, which is being explored as a potential biomarker for CMT, showed significant differences at 24-months, suggesting that a slowing of disease progression is occurring at this timepoint. Govorestat remained generally safe and well-tolerated throughout the 24 months of treatment. Despite being unable to observe a significant change in the primary endpoint, the findings from this Phase 2/3 trial show many encouraging improvements in a patient population that previously had no targeted treatment options.
“CMTRF is excited by the results presented by Applied Therapeutics in the treatment of SORD in Charcot-Marie-Tooth disease patients,” said Laura M. MacNeill, CMTRF’s CEO. “These findings offer hope and promise for our patient community, paving the way for more targeted and effective therapies that can significantly improve the quality of life for those affected by this rare condition. Additionally, the positive findings with the CMT-HI and muscle-fat fraction MRI biomarker demonstrate that these may be useful tools for future CMT clinical trials.”
Applied Therapeutics will continue analyzing the results from this trial and remains committed to working with the FDA to determine the appropriate regulatory pathway for a potential drug approval request for govorestat in CMT-SORD in 2025.
Applied Therapeutics is a 2025 Global CMT Research Convention sponsor and will be speaking at the 2025 Global CMT Research Convention in Boston, MA, September 25-27.
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