71P Phase II/III and efficacy confirmation study of aceneuramic acid for GNE myopathy in Japan

• Published in: Neuromuscular disorders : NMD Vol. 43; p. 104441
• Main Authors: Suzuki, N., Mori-Yoshimura, M., Katsuno, M., Takahashi, M., Yamashita, S., Oya, Y., Hashizume, A., Yamada, S., Nakamori, M., Izumi, R., Kato, M., Warita, H., Tateyama, M., Kuroda, H., Asada, R., Yamaguchi, T., Nishino, I., Aoki, M.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2024
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.434

GNE myopathy is an extremely rare genetic disorder caused by mutations in the GNE gene, resulting in reduced sialic acid synthesis and progressive muscle weakness. So far, no established treatment has been identified. For the replacement therapy of aceneuramic acid, extended-release formulation of aceneuramic acid (SA-ER) tablets have been developed. To evaluate the efficacy and safety of SA-ER for GNE myopathy, phase II/III study and the efficacy confirmation study were performed in Japan. These studies involved patients genetically diagnosed with GNE myopathy, allocated in SA-ER and placebo group (n=16:4 in Ph II/III, and n=10:4 in confirmation study, respectively). The evaluation of efficacy includes the primary endpoint of changes in upper extremity composite (UEC) score, with the secondary endpoint including GNE myopathy functional activity scale (GNEM-FAS). In the phase II/III study, the mean change in UEC at Week 48 was as small as -0.1 ± 3.7 kg in the SA-ER group versus -5.1 ± 3.4 kg in the placebo group with significant difference in two groups (P=0.0013) in the generalized estimating equation test repeated measurement analysis. The least squares mean (LSM) difference (95% CI) between the groups was 4.8 kg (-0.3 to 9.9; P=0.0635). Also, in the efficacy confirmation study, decrease in LSM change in UEC score at Week 48 with SA-ER (-0.115 kg) was numerically smaller as compared with placebo (-2.625 kg), with LSM difference (95% confidence interval) of 2.510 (-1.720 to 6.740) kg. Additionally, plots of GNEM-FAS upper extremity, mobility and total scores separated from each other between the SA-ER group and the placebo group. No clinically significant adverse events were observed in either study. Two sets of trial reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy. Aceneuramic acid received manufacturing and marketing approval in March 2024 following Pharmaceuticals and Medical Devices Agency (PMDA)'s review.