Abstract Details

Title CMT-HI Upper Limb Subscale Scores Respond to Treatment With Govorestat in Patients With CMT-SORD

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S2 - Updates on Motor Neuron and Peripheral Nerve Disorders (2:12 PM-2:24 PM)

Poster/Presentation
Number 007

Objective To evaluate the effects of sorbitol reduction on disease burden in Charcot-Marie-Tooth Sorbitol Dehydrogenase deficiency (CMT-SORD).

Background Biallelic loss of function in the Sorbitol Dehydrogenase (SORD) enzyme results in a hereditary neuropathy (CMT-SORD), caused by an accumulation of sorbitol in blood and tissues. Govorestat, a CNS-penetrant aldose reductase inhibitor, is being evaluated as a potential treatment for patients with CMT-SORD. The CMT-HI is a well-validated outcome designed to measure disease burden in CMT patients.

Design/Methods

INSPIRE is a randomized, double-blind, placebo-controlled, multicenter study that assessed the safety and efficacy of long-term administration of govorestat in patients with CMT-SORD. Patients were randomized 2:1 to govorestat 20 mg/kg/day or placebo for up to 24 months. Sorbitol levels were serially evaluated and patient reported disease burden was quantified using the CMT-HI and its subscales at baseline and Months 12 and 24.

Results

Fifty-six patients with CMT-SORD were randomized. Mean age was 34.4 (± 11) years. Twenty-six patients (46.4%) had the biallelic homozygous mutation c.757 delG (p.A253Qfs*27). Baseline mean whole blood sorbitol level was 29,978 ng/mL (± 5074). Govorestat was safe and well-tolerated and resulted in a lowering of sorbitol of ~37% that was maintained through 24 months. Govorestat treatment resulted in statistically significant improvements in CMT-HI total scores at Month 12 that were sustained through Month 24. In addition, statistically significant improvements in the CMT-HI’s Shoulder and Arm Function Subscale Scores and Hand and Finger Function Subscale Scores were seen at Months 12 and 24 respectively. An improvement in both Subscale Scores was associated with a reduction in sorbitol levels at Month 12.

Conclusions CMT-SORD is a severe progressive neuropathy caused by excess sorbitol. As a disease-specific outcome measure, the CMT-HI and its subscales are capable of detecting a reduction in disease burden in response to govorestat during a longitudinal trial.

Authors/Disclosures
Evan Bailey, MD PRESENTER	Mr. Bailey has received personal compensation for serving as an employee of Applied Therapeutics, Inc. Mr. Bailey has stock in Applied Therapeutics, Inc.
Chad R. Heatwole, MD, FAAN (University of Rochester Medical Center)	Dr. Heatwole has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Virginia Commonwealth University. Dr. Heatwole has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Legal Med. Dr. Heatwole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. Dr. Heatwole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Heatwole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Swan Bio. Dr. Heatwole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Harmony. Dr. Heatwole has received personal compensation in the range of $0-$499 for serving as a Consultant for Iris. Dr. Heatwole has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Recursion. Dr. Heatwole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity Biosciences. Dr. Heatwole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lupin. Dr. Heatwole has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neurocrine. Dr. Heatwole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Heatwole has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for New York Central Mutual. Dr. Heatwole has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Penn Prop and Gas. The institution of Dr. Heatwole has received research support from Department of Defense. The institution of Dr. Heatwole has received research support from Novartis. The institution of Dr. Heatwole has received research support from MJFF. The institution of Dr. Heatwole has received research support from FARA. The institution of Dr. Heatwole has received research support from NIH. The institution of Dr. Heatwole has received research support from University of Miami. The institution of Dr. Heatwole has received research support from MDA. Dr. Heatwole has received intellectual property interests from a discovery or technology relating to health care.
Jennifer Luth	Jennifer Luth has received personal compensation for serving as an employee of Applied Therapeutics.
Catherine Summers	No disclosure on file
Samuel Dickson (Pentara Corporation)	Mr. Dickson has nothing to disclose.
Caleb Dayley	Mr. Dayley has received personal compensation for serving as an employee of Pentara Corporation.
Michael E. Shy, MD, FAAN (University of Iowa)	Dr. Shy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Shy has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for DTx Pharma. The institution of Dr. Shy has received research support from NIH. The institution of Dr. Shy has received research support from Muscular Dystrophy Association. The institution of Dr. Shy has received research support from Charcot Marie Tooth Association. The institution of Dr. Shy has received research support from Applied Therapeutics.

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