Over the past two decades there has been increased interest in orphan drug development for rare diseases. However, hurdles to clinical trial design for these disorders remain. This phase 1a/1b study addressed several challenges, while evaluating the safety and tolerability of the novel oral molecule KL1333 in healthy volunteers and subjects with primary mitochondrial disease. KL1333 aims to normalize the NAD+:NADH ratio that is critical for ATP production. The trial incorporated innovative design elements with potential translatability to other rare diseases including patient involvement, adaptive design and exploratory objectives, all of which have subsequently informed the protocol of an ongoing phase 2, pivotal efficacy study of KL1333. Results indicate KL1333 is safe and well tolerated, with dose-dependent gastrointestinal side effects, and validate potential novel outcome measures in primary mitochondrial disease including the 30-s Sit to Stand, and the patient-reported fatigue scales. Importantly, the data from the trial support efficacy of KL1333 based on improvements in fatigue and functional strength and endurance. Furthermore, the study highlights the value in using phase 1 studies to capture data that helps optimize later phase efficacy trial design.

中文翻译：

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优化罕见病试验：KL1333 在线粒体疾病成人中的 1a/1b 期随机研究


在过去的二十年里，人们对罕见病的孤儿药开发越来越感兴趣。然而，这些疾病的临床试验设计仍然存在障碍。这项 1a/1b 期研究解决了几个挑战，同时评估了新型口服分子 KL1333 在健康志愿者和原发性线粒体疾病受试者中的安全性和耐受性。KL1333 旨在使对 ATP 产生至关重要的 NAD+：NADH 比率正常化。该试验结合了创新设计元素，并可能可转化为其他罕见疾病，包括患者参与、适应性设计和探索性目标，所有这些都随后为正在进行的 KL1333 的 2 期关键疗效研究的方案提供了信息。结果表明 KL1333 安全且耐受性良好，具有剂量依赖性胃肠道副作用，并验证了原发性线粒体疾病中潜在的新结果指标，包括 30 秒坐立和患者报告的疲劳量表。重要的是，试验数据支持 KL1333 基于疲劳、功能强度和耐力改善的疗效。此外，该研究强调了使用 1 期研究来捕获有助于优化后期疗效试验设计的数据的价值。