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.

中文翻译：

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N-乙酰甘露糖胺 (ManNAc) 在 GNE 肌病患者中的安全性和有效性：一项开放标签的 2 期研究

目的

评估N-乙酰甘露糖胺 (ManNAc) 在 GNE 肌病中的安全性和有效性，这是一种由N-乙酰神经氨酸 (Neu5Ac) 生物合成中的限速酶缺乏引起的遗传性肌肉疾病。

方法

我们进行了一项开放标签、2 期、单中心（美国国立卫生研究院）研究，以评估 12 名 GNE 肌病患者的口服 ManNAc（ClinicalTrials.gov NCT02346461）。主要终点是安全性和生化功效，由血浆 Neu5Ac 和肌膜唾液酸化的变化确定。作为研究扩展的一部分，使用次要结果测量评估临床疗效，并测试疾病进展模型（GNE-DPM）作为疗效分析方法。

结果

与药物相关的不良事件多为胃肠道，无严重不良事件。 与基线相比，在第 90 天观察到血浆 Neu5Ac（+2,159 nmol/L，p  < 0.0001）和肌膜唾液酸化（p = 0.0090）增加。 与自然史相比，观察到上肢力量 ( 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 在 12 (γ = 0.61 [95% CI: 0.09, 1.27]) 和 18 个月 (γ = 0.55 [95% CI: 0.12, 1.02]) 时估计疾病进展减少。

结论

ManNAc 在 GNE 肌病患者中显示出长期安全性、与预期作用机制一致的生化疗效和初步证据临床疗效。