Supplementary Material for: Safety and Tolerability of the APOL1 Inhibitor, Inaxaplin, Following Single- and Multiple-ascending Doses in Healthy Adults

Introduction
Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD.

Methods
We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs.

Results
A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs.

Discussion/Conclusion
Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.

## 引言
具有毒性的功能获得性载脂蛋白L1（Apolipoprotein L1, APOL1）变异体可诱发蛋白尿性肾病，此类疾病统称为APOL1介导肾病（APOL1-mediated kidney disease, AMKD）。尽管接受标准治疗，AMKD患者仍会加速进展至终末期肾病。两项APOL1变异体被确定为AMKD的遗传病因，这推动了伊沙普林（inaxaplin）的研发——它是一种APOL1通道活性抑制剂，可降低AMKD患者的蛋白尿水平。

## 方法
本研究开展两项1期临床试验，评估健康受试者单次递增剂量（single-ascending doses, SAD）与多次递增剂量（multiple-ascending doses, MAD）给予伊沙普林后的安全性、耐受性与药代动力学特征。在单次递增剂量队列中，受试者被随机分配接受单次剂量的伊沙普林（剂量范围7.5mg至165mg）或安慰剂。在多次递增剂量队列中，受试者被随机分配接受每日给药的伊沙普林（每日剂量范围15mg至120mg）或安慰剂，疗程为14天。本研究基于不良事件（adverse events, AEs）、临床实验室检测指标、心电图（electrocardiograms, ECGs）与生命体征，评估伊沙普林的安全性与耐受性。

## 结果
两项研究的单次递增剂量与多次递增剂量队列中共随机入组178名受试者，平均年龄36.7岁，男性占比94.9%。伊沙普林组与安慰剂组的任意不良事件发生率相近，分别为24.6%与22.7%。所有不良事件均为轻度或中度，无严重不良事件发生。头痛是最常见的不良事件：伊沙普林组发生率为10.4%，安慰剂组为2.3%。无药物相关的治疗中断事件，且实验室检测指标、心电图与生命体征未出现具有临床意义的异常变化趋势。

## 讨论与结论
单次给药剂量最高达165mg、每日多次给药剂量最高达120mg且疗程为14天时，伊沙普林具有良好的安全性与耐受性。该结果与已完成的2a期概念验证研究中伊沙普林展现出的良好安全性特征一致。综上，上述研究结果支持在正在开展的2/3期关键性临床试验中进一步评估伊沙普林，将其作为AMKD患者潜在的精准治疗药物。