TY - JOUR
T1 - Aceneuramic Acid Extended Release Administration Maintains Upper Limb Muscle Strength in a 48-week Study of Subjects with GNE Myopathy
T2 - Results from a Phase 2, Randomized, Controlled Study
AU - Argov, Zohar
AU - Caraco, Yoseph
AU - Lau, Heather
AU - Pestronk, Alan
AU - Shieh, Perry B.
AU - Skrinar, Alison
AU - Koutsoukos, Tony
AU - Ahmed, Ruhi
AU - Martinisi, Julia
AU - Kakkis, Emil
N1 - Funding Information:
Dr. Pestronk reports: Travel expenses & honoraria paid by The Myositis Association; Receives revenue related to antibody patent licenses from Athena; Owns stock in Johnson & Johnson; Directs the Washington University Neuromuscular Clinical Laboratory which performs antibody testing; Receives research support from the NIH, Muscular Dystrophy Association, Neuromuscular Research Fund; Insmed, Knopp, Cytokinetics, Biogen Idec, ISIS, Genzyme, GSK, Sanofi & Ultragenyx.
Publisher Copyright:
© 2016 - IOS Press and the authors. All rights reserved.
PY - 2016
Y1 - 2016
N2 - GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. Objective: Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. Methods: A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3 - g/day or 6 - g/day versus placebo was conducted in GNEM subjects (n - = - 47). After the first 24 weeks, placebo subjects crossed over to 3 - g/day or 6 - g/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and safety. Results: Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6 - g/day compared with placebo at Week 24 (LS mean difference 2.33 - kg, p - = - 0.040), and larger in a pre-specified subgroup able to walk ≥200 - m at Screening (3.10 - kg, p - = - 0.040). After cross-over, a combined 6 - g/day group showed significantly better UEC strength than a combined 3 - g/day group (3.46 - kg, p - = - 0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (1.06 - kg, p - = - 0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6 - g/day group compared with a combined 3 - g/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. Conclusions: This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes.
AB - GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. Objective: Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. Methods: A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3 - g/day or 6 - g/day versus placebo was conducted in GNEM subjects (n - = - 47). After the first 24 weeks, placebo subjects crossed over to 3 - g/day or 6 - g/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and safety. Results: Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6 - g/day compared with placebo at Week 24 (LS mean difference 2.33 - kg, p - = - 0.040), and larger in a pre-specified subgroup able to walk ≥200 - m at Screening (3.10 - kg, p - = - 0.040). After cross-over, a combined 6 - g/day group showed significantly better UEC strength than a combined 3 - g/day group (3.46 - kg, p - = - 0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (1.06 - kg, p - = - 0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6 - g/day group compared with a combined 3 - g/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. Conclusions: This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes.
KW - GNE Myopathy
KW - Sialic acid
KW - distal myopathy with rimmed vacuoles
KW - hereditary inclusion body myopathy
KW - myopathy therapy
UR - http://www.scopus.com/inward/record.url?scp=85030419326&partnerID=8YFLogxK
U2 - 10.3233/JND-159900
DO - 10.3233/JND-159900
M3 - Article
C2 - 27854209
AN - SCOPUS:85030419326
SN - 2214-3599
VL - 3
SP - 49
EP - 66
JO - Journal of Neuromuscular Diseases
JF - Journal of Neuromuscular Diseases
IS - 1
ER -