Treatment of Single Patient With <scp>PMM2</scp> ‐Congenital Disorder of Glycosylation With Govorestat ( <scp>AT</scp> ‐007), an Aldose Reductase Inhibitor

Aldose reductase inhibitors (ARI) have been identified as a potential treatment for phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG), a serious condition for which no treatments are approved. We treated a single patient for 36 months 30 months of age at enrollment, under a single-patient investigational new drug expanded access request, with govorestat (AT-007), a novel, highly selective, once daily, brain penetrant ARI at a starting dose of 1 mg/kg oral suspension, which was escalated to 30 mg/kg. The primary endpoint was safety. Secondary assessments included liver transaminases, factor XI, antithrombin III, and whole blood and urine sorbitol. Clinical outcomes were also assessed, including Nijmegen Pediatric CDG Rating Scale (NPCRS), Bayley Scales of Infant Development, and Vineland Adaptive Behavioral Scale. Govorestat was well tolerated; no adverse effects were noted. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels improved from a pre-treatment 12-month average of 205 and 268 U/L to 63 and 68 U/L, respectively, averaged over 36 months of govorestat treatment at 30 mg/kg. Antithrombin III and factor XI fluctuated with illness throughout the study period but overall increased by 60%-100%, approaching the normal range (> 83% activity) at the 5 mg/kg dose. Whole blood sorbitol decreased in a dose-dependent fashion, normalizing at the 30 mg/kg dose. The NPCRS improved by 9 points (46%) over the course of treatment. In conclusion, our patient tolerated govorestat without safety concerns. Improvements in liver transaminases, clotting factors, and whole blood sorbitol were observed along with improvements in clinical measures. These findings support further study of govorestat as a potential treatment for PMM2-CDG.