Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study.
Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study.
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DOI：
10.1038/s41436-021-01259-x
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Gahl WA
中科院分区：
文献类型：
--
作者：
Carrillo N;Malicdan MC;Leoyklang P;Shrader JA;Joe G;Slota C;Perreault J;Heiss JD;Class B;Liu CY;Bradley K;Jodarski C;Ciccone C;Driscoll C;Parks R;Van Wart S;Bayman L;Coffey CS;Quintana M;Berry SM;Huizing M;Gahl WA
评价n -乙酰氨基甘露糖胺（ManNAc）治疗GNE肌病的安全性和有效性。GNE肌病是一种由n -乙酰神经氨酸（Neu5Ac）生物合成限速酶缺乏引起的遗传性肌肉疾病。我们开展了一项开放标签、2期、单中心（NIH， USA）研究，评估12例GNE肌病患者口服甘露聚糖（ManNAc）的疗效（ClinicalTrials.gov NCT02346461）。主要终点是通过血浆Neu5Ac和肌上皮唾液化变化确定的安全性和生化疗效。作为研究扩展的一部分，使用次要结局指标评估临床疗效，并测试疾病进展模型（GNE-DPM）作为疗效分析方法。药物相关不良事件以胃肠道为主，无严重不良事件发生。与基线相比，在第90天观察到血浆Neu5Ac （+2,159 nmol/L, p < 0.0001）和肌上皮唾液化（p = 0.0090）增加。与自然病史相比，上肢力量（p = 0.0139）、下肢力量（p = 0.0006）和成人肌病评估工具（p = 0.0453）的下降速度较慢。使用GNE-DPM估计疾病进展减少在12个月（γ = 0.61 [95% CI: 0.09, 1.27]）和18个月（γ = 0.55 [95% CI: 0.12, 1.02]）。ManNAc显示长期安全性，生化疗效与预期作用机制一致，初步证明其对GNE型肌病的临床疗效。
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. 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. 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. ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.
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影响因子：
3.4
作者：
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