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Abstract：
Long-chain fatty acid oxidation disorders (LC-FAOD) lead to accumulation of high concentrations of potentially toxic fatty acid intermediates. Newborn screening and early intervention have reduced mortality, but most patients continue to experience frequent hospitalizations and significant morbidity despite treatment. The deficient energy state can cause serious liver, muscle, and heart disease, and may be associated with an increased risk of sudden death. Triheptanoin is a medium odd-chain fatty acid. Anaplerotic metabolites of triheptanoin have the potential to replace deficient tricarboxylic acid (TCA) cycle intermediates, resulting in net glucose production as a novel energy source for the treatment of LC-FAOD.
A single-arm, open-label, multicenter Phase 2 safety and efficacy study evaluated patients with severe LC-FAOD evidenced by ongoing related musculoskeletal, cardiac, and/or hepatic events despite treatment. After a four-week run-in on current regimen, investigational triheptanoin (UX007) was titrated to a target dose of 25-35% of total daily caloric intake. Patients were evaluated on several age/condition-eligible endpoints, including submaximal exercise tests to assess muscle function/endurance (12-minute walk test; 12MWT) and exercise tolerance (cycle ergometry), and health related quality of life (HR-QoL). Results through 24weeks of treatment are presented; total study duration is 78weeks.
Twenty-nine patients (0.8 to 58years) were enrolled; most qualified based on severe musculoskeletal disease. Twenty-five patients (86%) completed the 24-week treatment period. At Week 18, eligible patients (n=8) demonstrated a 28% increase (LS mean=+181.9 meters; p=0.087) from baseline (673.4meters) in 12MWT distance. At Week 24, eligible patients (n=7) showed a 60% increase in watts generated (LS mean=+409.3W; p=0.149) over baseline (744.6W) for the exercise tolerance test. Improvements in exercise tests were supported by significant improvements from baseline in the adult (n=5) self-reported SF-12v2 physical component summary score (LS mean=+8.9; p<0.001). No difference from baseline was seen in pediatric parent-reported (n=5) scores (SF-10) at Week 24. Eighteen patients (62%) had treatment-related adverse events, predominantly gastrointestinal (55%), mild-to-moderate in severity, similar to that seen with prior treatment with medium chain triglyceride (MCT) oil. One patient experienced a treatment-related serious adverse event of gastroenteritis. One patient discontinued from study due to diarrhea of moderate severity; the majority of patients (25/29; 86%) elected to continue treatment in the extension period.
In patients with severe LC-FAOD, UX007 interim study results demonstrated improved exercise endurance and tolerance, and were associated with positive changes in self-reported HR-QoL.
A single-arm, open-label, multicenter Phase 2 safety and efficacy study evaluated patients with severe LC-FAOD evidenced by ongoing related musculoskeletal, cardiac, and/or hepatic events despite treatment. After a four-week run-in on current regimen, investigational triheptanoin (UX007) was titrated to a target dose of 25-35% of total daily caloric intake. Patients were evaluated on several age/condition-eligible endpoints, including submaximal exercise tests to assess muscle function/endurance (12-minute walk test; 12MWT) and exercise tolerance (cycle ergometry), and health related quality of life (HR-QoL). Results through 24weeks of treatment are presented; total study duration is 78weeks.
Twenty-nine patients (0.8 to 58years) were enrolled; most qualified based on severe musculoskeletal disease. Twenty-five patients (86%) completed the 24-week treatment period. At Week 18, eligible patients (n=8) demonstrated a 28% increase (LS mean=+181.9 meters; p=0.087) from baseline (673.4meters) in 12MWT distance. At Week 24, eligible patients (n=7) showed a 60% increase in watts generated (LS mean=+409.3W; p=0.149) over baseline (744.6W) for the exercise tolerance test. Improvements in exercise tests were supported by significant improvements from baseline in the adult (n=5) self-reported SF-12v2 physical component summary score (LS mean=+8.9; p<0.001). No difference from baseline was seen in pediatric parent-reported (n=5) scores (SF-10) at Week 24. Eighteen patients (62%) had treatment-related adverse events, predominantly gastrointestinal (55%), mild-to-moderate in severity, similar to that seen with prior treatment with medium chain triglyceride (MCT) oil. One patient experienced a treatment-related serious adverse event of gastroenteritis. One patient discontinued from study due to diarrhea of moderate severity; the majority of patients (25/29; 86%) elected to continue treatment in the extension period.
In patients with severe LC-FAOD, UX007 interim study results demonstrated improved exercise endurance and tolerance, and were associated with positive changes in self-reported HR-QoL.
摘要：
长链脂肪酸氧化紊乱(LC-FAOD)导致高浓度的潜在毒性脂肪酸中间体的积累。新生儿筛查和早期干预降低了死亡率，但尽管接受了治疗,大多数患者仍频繁住院,且发病率显著.缺乏能量的状态会导致严重的肝脏，肌肉，还有心脏病,并可能与猝死风险增加有关。三庚酸甘油酯是一种中等的奇数链脂肪酸。三庚酸的反转录代谢物有可能取代缺乏的三羧酸（TCA）循环中间体，产生净葡萄糖作为治疗LC-FAOD的新型能源。
单臂，开放标签，多中心2期安全性和有效性研究评估了严重LC-FAOD患者的持续相关肌肉骨骼，心脏,和/或肝事件，尽管治疗。在对当前方案进行为期四周的磨合后，研究性三庚酸甘油酯(UX007)的目标剂量为每日总热量摄入的25-35%.对患者进行了几个符合年龄/条件的终点评估，包括亚最大运动测试，以评估肌肉功能/耐力（12分钟步行测试；12MWT）和运动耐量（周期测功），和健康相关的生活质量（HR-QoL）。提供了24周治疗的结果；总研究持续时间为78周。
29名患者（0.8至58岁）入选，最合格的患者是严重的肌肉骨骼疾病。25名患者（86％）完成了24周的治疗期。在第18周,合格的患者(n=8)在12MWT距离中显示从基线(673.4米)增加28%(LS平均值=+181.9米;p=0.087)。在第24周,对于运动耐量测试,合格的患者(n=7)显示产生的瓦特比基线(744.6W)增加60%(LS平均值=+409.3W;p=0.149)。运动测试的改善得到了成人（n=5）自我报告的SF-12v2身体成分汇总评分（LS平均值=8.9；p<0.001）的显着改善。在第24周,在儿科父母报告的(n=5)评分(SF-10)中没有观察到与基线的差异。18例患者（62%）有治疗相关的不良事件，主要是胃肠道（55％），严重程度为轻度至中度，与以前用中链甘油三酯（MCT）油处理时看到的相似。一名患者经历了与治疗相关的严重不良事件胃肠炎。一名患者因中度腹泻而停止研究；大多数患者（25/29;86％）选择在延长期内继续治疗。
重度LC-FAOD患者，UX007中期研究结果表明，运动耐力和耐力得到了改善，并与自我报告的HR-QoL的积极变化相关。
单臂，开放标签，多中心2期安全性和有效性研究评估了严重LC-FAOD患者的持续相关肌肉骨骼，心脏,和/或肝事件，尽管治疗。在对当前方案进行为期四周的磨合后，研究性三庚酸甘油酯(UX007)的目标剂量为每日总热量摄入的25-35%.对患者进行了几个符合年龄/条件的终点评估，包括亚最大运动测试，以评估肌肉功能/耐力（12分钟步行测试；12MWT）和运动耐量（周期测功），和健康相关的生活质量（HR-QoL）。提供了24周治疗的结果；总研究持续时间为78周。
29名患者（0.8至58岁）入选，最合格的患者是严重的肌肉骨骼疾病。25名患者（86％）完成了24周的治疗期。在第18周,合格的患者(n=8)在12MWT距离中显示从基线(673.4米)增加28%(LS平均值=+181.9米;p=0.087)。在第24周,对于运动耐量测试,合格的患者(n=7)显示产生的瓦特比基线(744.6W)增加60%(LS平均值=+409.3W;p=0.149)。运动测试的改善得到了成人（n=5）自我报告的SF-12v2身体成分汇总评分（LS平均值=8.9；p<0.001）的显着改善。在第24周,在儿科父母报告的(n=5)评分(SF-10)中没有观察到与基线的差异。18例患者（62%）有治疗相关的不良事件，主要是胃肠道（55％），严重程度为轻度至中度，与以前用中链甘油三酯（MCT）油处理时看到的相似。一名患者经历了与治疗相关的严重不良事件胃肠炎。一名患者因中度腹泻而停止研究；大多数患者（25/29;86％）选择在延长期内继续治疗。
重度LC-FAOD患者，UX007中期研究结果表明，运动耐力和耐力得到了改善，并与自我报告的HR-QoL的积极变化相关。
