Mitochondrial disease is a group of rare conditions, with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive and oxidative distress modulator, selectively inhibiting microsomal prostaglandin E1 synthase activity. This Phase 2b program, aiming at evaluating sonlicromanol in adults with m.3243A>G mutation and primary mitochondrial disease, consisted of a randomized controlled (RCT) study (dose-selection) followed by a 52-week open-label extension study (EXT, long-term tolerability, safety, and efficacy of sonlicromanol). Patients were randomized (1:1:1) to receive 100- or 50-mg sonlicromanol, or placebo twice daily (bid) for 28 days with ≥2-week wash-out period between treatments. Patients who completed the RCT study entered the EXT study wherein they received 100-mg sonlicromanol bid. Overall, 27 patients were randomized (24 RCT patients completed all periods). 15 patients entered the EXT, and 12 patients were included in the EXT analysis set. All patients reported good tolerability and favourable safety, with pharmacokinetic results comparable to the earlier Phase 2a study. The RCT primary endpoint (change from placebo in the attentional domain of cognition score [IDN: visual identification, Cogstate]) did not reach statistical significance. Using a categorisation of the subject's period baseline a treatment effect over placebo was observed if their baseline was more affected (p=0.0338). Using this approach, there were signals of improvements over placebo in at least one dose in the Beck Depression Inventory (BDI, p=0.0143), Cognitive Failure Questionnaire (CFQ, p=0.0113), and the Depression subscale of the Hospital Anxiety and Depression Scale (p=0.0256). Statistically and/or clinically meaningful improvements were observed in the patient- and clinician-reported outcome measures at the end of the EXT study (Test of attentional performance [TAP] with alarm, p=0.0102; TAP without alarm, p=0.0047; BDI somatic, p=0.0261; BDI Total, p=0.0563; SF12 physical component score, p=0.0008). Seven of nine domains of RAND-Short form-36 like SF-36 pain improved (p=0.0105). Other promising results were observed in Neuro QoL-Fatigue-SF (p=0.0036), MiniBESTest (p=0.0009), McGill Pain Questionnaire (p=0.0105), EQ-5D-5L-VAS (p=0.0213) and EQ-5D-5L-index (p=0.0173). Most patients showed improvement in the 5× sit-to-stand test. Sonlicromanol was well-tolerated and demonstrated a favourable benefit/risk ratio for up to one year. Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domains. Long-term treatment showed more pronounced changes from baseline.

中文翻译：

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2b 期计划在 m.3243A>G 突变引起的线粒体疾病患者中使用 sonlicromanol。


线粒体疾病是一组罕见的疾病，迄今为止还没有批准的治疗方法，除了 Leber 遗传性视神经病变。迫切需要缓解线粒体疾病症状的治疗方案。Sonlicromanol 是一个很有前途的候选者，因为它积极改变与线粒体疾病相关的关键代谢和炎症途径。Sonlicromanol 是一种还原和氧化痛苦调节剂，选择性抑制微粒体前列腺素 E1 合酶活性。该 2b 期计划旨在评估 sonlicromanol 在患有 m.3243A>G 突变和原发性线粒体疾病的成人中的疗效，包括一项随机对照 （RCT） 研究（剂量选择）和一项为期 52 周的开放标签扩展研究（EXT、sonlicromanol 的长期耐受性、安全性和有效性）。患者被随机分配 （1：1：1） 接受 100 或 50 mg sonlicromanol 或安慰剂，每天两次 （bid），持续 28 天，两次治疗之间有 ≥2 周的清除期。完成 RCT 研究的患者进入 EXT 研究，其中他们接受了 100 毫克 sonlicromanol bid。总体而言，27 例患者被随机分组 （24 例 RCT 患者完成了所有时期）。15 例患者进入 EXT，12 例患者纳入 EXT 分析集。所有患者均报告了良好的耐受性和良好的安全性，药代动力学结果与早期的 2a 期研究相当。RCT 主要终点 （与安慰剂相比，认知注意力领域评分的变化 [IDN： visual identification， Cogstate]）未达到统计学意义。使用受试者的经期基线分类，如果他们的基线受到更大的影响，则观察到治疗效果优于安慰剂 （p=0.0338）。 使用这种方法，在贝克抑郁量表 （BDI， p=0.0143）、认知失败问卷 （CFQ， p=0.0113） 和医院焦虑和抑郁量表的抑郁分量表 （p=0.0256） 中，至少有一个剂量的改善信号优于安慰剂。在 EXT 研究结束时，在患者和临床医生报告的结果测量中观察到具有统计学和/或临床意义的改善（带警报的注意力表现测试 [TAP]，p=0.0102;TAP 无警报，p=0.0047;BDI 体细胞，p=0.0261;BDI 总计，p=0.0563;SF12 物理成分评分，p=0.0008）。RAND Short form-36 的 9 个结构域中的 7 个，如 SF-36 疼痛得到改善 （p=0.0105）。在 Neuro QoL-Fatigue-SF （p=0.0036）、MiniBESTest （p=0.0009）、麦吉尔疼痛问卷 （p=0.0105）、EQ-5D-5L-VAS （p=0.0213） 和 EQ-5D-5L-index （p=0.0173） 中观察到其他有希望的结果。大多数患者在 5× 坐-站测试中表现出改善。Sonlicromanol 耐受性良好，并在长达一年内显示出良好的收益/风险比。Sonlicromanol 在基线时受到影响时对患者有效，这在各种临床相关领域中都可见。长期治疗显示与基线相比变化更明显。