2026 American Academy of Neurology Abstract Website

Francis Rossignol¹, Christopher Coffey⁴, Merit Cudkowicz⁵, LUMY SAWAKI-ADAMS², Amy Tsou², Richard Barohn⁶, Miriam Freimer⁷, Nuria Carrillo¹, Timothy Leonard⁵, David Klements⁵, Dixie Ecklund⁴, Maxine Koepp⁴, Michele Costigan⁴, Emily Roberts⁴, Elizabeth Klingner⁴, Charlie Choi⁴, Dosten Kopenhauszen⁴, Melanie Quintana⁸, Farah Khandwala⁸, Eric Henninger⁹, William Gahl¹, Marjan Huizing¹, Joseph Shrader³, Galen Joe³, Alessandro Noseda¹⁰, Giuseppe Testa¹⁰, Anthony Amato¹¹
¹National Human Genome Research Institute, ²National Institute of Neurological Disorders and Stroke, ³Clinical Center, National Institutes of Health, ⁴Department of Biostatistics, University of Iowa, ⁵Department of Neurology, Massachusetts General Hospital, ⁶University of Missouri, ⁷The Ohio State University, ⁸Berry Consultants, ⁹Alira Health AG, ¹⁰Leadiant Biosciences, ¹¹Brigham and Women's Hospital

Objective:

To evaluate the efficacy of N-acetylmannosamine (ManNAc) administration in individuals with GNE myopathy to slow the progression of muscle strength decline as compared to placebo.

Background:

GNE myopathy is a rare, autosomal recessive muscle disease caused by deficiency of the UDP-GlcNAc 2-epimerase / ManNAc kinase enzyme, in the sialic acid synthesis pathway. This disorder presents initially in young adults with anterior tibialis weakness, that then progresses to involve skeletal muscles throughout the body, relatively sparing the quadriceps. Hyposialylation of muscle glycans is thought to play a key role in the pathophysiology. ManNAc, a sialic acid precursor, has shown evidence of increased sialic acid production and improved muscle sialylation in preclinical and clinical (phase I/II) studies.

Design/Methods:

A randomized, double-blind, placebo-controlled trial of ManNAc was conducted. Participants were randomized 2:1 to receive ManNAc 4g TID or erythritol for at least 24 months. Maximum voluntary isometric contraction as measured by the Quantitative Muscle Assessment system and compared to the GNE Myopathy Disease Progression Model, was the primary outcome measure. Other endpoints included patient-reported outcomes and other functional measures.

Results:

Fifty-four (54) participants received either ManNAc (n=37) or placebo (n=17). Baseline demographic characteristics were similar between both arms, but the ManNAc treatment arm was significantly weaker at baseline for several muscle groups. Primary endpoint analysis showed no difference between ManNAc and placebo on muscle strength decline. Per protocol analysis slightly favors ManNAc but is not statistically significant. Negative results were also observed on secondary and exploratory endpoints. ManNAc was well-tolerated but there was an increase in flatulence and ophthalmic adverse events.

Conclusions:

ManNAc failed to demonstrate a significant benefit on the rate of muscle strength decline in GNE myopathy. This suggests greater complexity in pathophysiology, as supplementation therapy alone does not appear to be sufficient to reduce disease progression.