BACKGROUND Achondroplasia is a genetic skeletal condition that results in disproportionately short stature and medical complications throughout life. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia. METHODS In this phase 2 dose-finding study, we evaluated the safety and efficacy of oral infigratinib in children with achondroplasia between the ages of 3 and 11 years. A total of 72 children were enrolled in five sequential cohorts to receive daily infigratinib at doses of 0.016 mg per kilogram of body weight (cohort 1), 0.032 mg per kilogram (cohort 2), 0.064 mg per kilogram (cohort 3), 0.128 mg per kilogram (cohort 4), and 0.25 mg per kilogram (cohort 5) for 6 months, followed by 12 months of extended treatment in which the dose in cohorts 1 and 2 could be escalated to the next ascending level at months 6 and 12. The primary safety outcome was the incidence of adverse events that led to a decrease in the dose or discontinuation of infigratinib. The primary efficacy outcome was the change from baseline in the annualized height velocity. RESULTS During treatment, all the children had at least one adverse event, most of which were mild or moderate in severity; none resulted in treatment discontinuation. In cohort 5, an increased annualized height velocity was observed, which persisted throughout the duration of the study, with a mean change from baseline at 18 months of 2.50 cm per year (95% confidence interval [CI], 1.22 to 3.79; P = 0.001). The mean change from baseline in height z score was 0.54 (95% CI, 0.35 to 0.72) relative to an untreated achondroplasia reference population at 18 months; the mean change from baseline in the upper-to-lower body segment ratio was -0.12 (95% CI, -0.18 to -0.06). CONCLUSIONS The administration of oral infigratinib did not result in any apparent major safety signal and increased the annualized height velocity and z score and decreased the upper-to-lower body segment ratio at 18 months of treatment in cohort 5. (Funded by BridgeBio Pharma; PROPEL2 ClinicalTrials.gov number, NCT04265651.).

中文翻译：

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口服 Infigratinib 治疗儿童软骨发育不全症。


背景 软骨发育不全是一种遗传性骨骼疾病，会导致一生中不成比例的身材矮小和医疗并发症。Infigratinib 是一种口服生物可利用的 FGFR1-3 选择性酪氨酸激酶抑制剂，正在开发用于治疗软骨发育不全。方法 在这项 2 期剂量探索研究中，我们评估了口服 infigratinib 在 3 至 11 岁软骨发育不全儿童中的安全性和有效性。共有 72 名儿童被分为 5 个连续队列，接受每日 infigratinib，剂量为 0.016 毫克/公斤（队列 1）、0.032 毫克/公斤（队列 2）、0.064 毫克/公斤（队列 3）、0.128 毫克/公斤（队列 4）和 0.25 毫克/公斤（队列 5），持续 6 个月，然后是 12 个月的延长治疗，其中队列 1 和队列 2 的剂量可以升级到下一个上升级别在第 6 个月和第 12 个月。主要安全性结局是导致 infigratinib 剂量减少或停药的不良事件的发生率。主要疗效结果是年化身高速度相对于基线的变化。结果 治疗期间，所有患儿均至少发生 1 次不良事件，其中大多数为轻或中度严重程度;没有导致治疗中断。在队列 5 中，观察到年化身高速度增加，并在整个研究期间持续存在，18 个月时相对于基线的平均变化为每年 2.50 厘米（95% 置信区间 [CI]，1.22 至 3.79;P = 0.001）。相对于 18 个月时未经治疗的软骨发育不全参考人群，身高 z 评分相对于基线的平均变化为 0.54 （95% CI，0.35 至 0.72）;上半身与下半身节段比率相对于基线的平均变化为 -0.12 （95% CI，-0.18 至 -0.06）。 结论 在队列 5 中，口服 infigratinib 的给药未导致任何明显的主要安全信号，并增加了年化身高、速度和 z 评分，并降低了上下半身节段比值。（由 BridgeBio Pharma 资助;PROPEL2 ClinicalTrials.gov 号，NCT04265651.）。