CMT-HI Upper Limb Subscale Scores Respond to Treatment With Govorestat in Patients With CMT-SORD
Evan Bailey1, Chad Heatwole2, Jennifer Luth1, Catherine Summers1, Samuel Dickson3, Caleb Dayley3, Michael Shy4
1Applied Therapeutics, 2University of Rochester Medical Center, 3Pentara Corporation, 4University of Iowa
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.
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