Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study

Nuria Carrillo; May C Malicdan; Petcharat Leoyklang; Joseph A Shrader; Galen Joe; Christina Slota; John Perreault; John D Heiss; Bradley Class; Chia-Ying Liu; Kennan Bradley; Colleen Jodarski; Carla Ciccone; Claire Driscoll; Rebecca Parks; Scott Van Wart; Levent Bayman; Christopher S Coffey; Melanie Quintana; Scott M Berry; Marjan Huizing; William A Gahl

doi:10.1038/s41436-021-01259-x

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Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study

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Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study

Nuria Carrillo, May C Malicdan, Petcharat Leoyklang, Joseph A Shrader, Galen Joe, Christina Slota, John Perreault, John D Heiss, Bradley Class, Chia-Ying Liu, …

Genetics in medicine, Vol.23(11), pp.2067-2075

11/2021

DOI: 10.1038/s41436-021-01259-x

PMCID: PMC8553608

PMID: 34257421

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Abstract

Purpose: To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. Methods: We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. Results: Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. Conclusion: ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

Details

Title: Subtitle: Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study
Creators: Nuria Carrillo
May C Malicdan
Petcharat Leoyklang
Joseph A Shrader
Galen Joe
Christina Slota
John Perreault
John D Heiss
Bradley Class
Chia-Ying Liu
Kennan Bradley
Colleen Jodarski
Carla Ciccone
Claire Driscoll
Rebecca Parks
Scott Van Wart
Levent Bayman
Christopher S Coffey
Melanie Quintana
Scott M Berry
Marjan Huizing
William A Gahl
Resource Type: Journal article
Publication Details: Genetics in medicine, Vol.23(11), pp.2067-2075
DOI: 10.1038/s41436-021-01259-x
PMID: 34257421
PMCID: PMC8553608
NLM abbreviation: Genet Med
ISSN: 1098-3600
eISSN: 1530-0366
Language: English
Date published: 11/2021
Academic Unit: Biostatistics
Record Identifier: 9984214663002771

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