Inaxaplin 用于伴有两种变异的蛋白尿性肾病患者。

Inaxaplin for Proteinuric Kidney Disease in Persons with Two Variants.

机构信息

From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.).

出版信息

N Engl J Med. 2023 Mar 16;388(11):969-979. doi: 10.1056/NEJMoa2202396.

DOI:10.1056/NEJMoa2202396

PMID:36920755

Abstract

BACKGROUND

Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 () are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two variants (G1 or G2) are lacking.

METHODS

We used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An G2-homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed.

RESULTS

In preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was -47.6% (95% confidence interval, -60.0 to -31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation.

CONCLUSIONS

Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.).

摘要

背景

携带载脂蛋白 L1()基因毒性获得功能变异的个体发生快速进展性、蛋白尿性肾病的风险增加。尽管已知遗传病因，但针对携带两种变体（G1 或 G2）的个体的蛋白尿性肾病的治疗方法仍缺乏。

方法

我们使用四环素诱导的载脂蛋白 L1 人胚肾（HEK293）细胞来评估小分子化合物 inaxaplin 抑制 APOL1 通道功能的能力。我们使用一种 G2 同源转基因小鼠模型的蛋白尿性肾病来评估 inaxaplin 治疗蛋白尿的效果。然后，我们进行了一项单组、开放标签、2a 期临床试验，其中将 inaxaplin 给予携带两种变体、活检证实的局灶节段性肾小球硬化和蛋白尿（尿蛋白与肌酐比值≥0.7 至<10[均以克为单位测量蛋白和肌酐]，估计肾小球滤过率≥27 毫升/分钟/1.73 平方米体表面积）的参与者。参与者每天接受 inaxaplin 治疗 13 周（前 2 周 15 毫克，后 11 周 45 毫克），同时接受标准治疗。主要结局是在至少 80%的参与者接受 inaxaplin 治疗的情况下，第 13 周时与基线相比尿蛋白与肌酐比值的变化百分比。还评估了安全性。

结果

在临床前研究中，inaxaplin 选择性地抑制了体外的 APOL1 通道功能，并减少了小鼠模型中的蛋白尿。16 名参与者入组了 2a 期研究。在 13 名接受 inaxaplin 治疗且符合用药依从性阈值的参与者中，第 13 周时与基线相比尿蛋白与肌酐比值的平均变化为-47.6%（95%置信区间，-60.0 至-31.3）。在包括所有参与者（无论是否接受 inaxaplin 治疗）的分析中，除了 1 名参与者外，其他参与者均观察到与主要分析相似的降低。不良事件的严重程度为轻度或中度；没有一个导致研究中断。