1. In preclinical studies, inaxaplin selectively inhibited apolipoprotein L1 (APOL1) in vitro and reduced proteinuria in a APOL1 G2-homologous transgenic mouse model of proteinuric kidney disease.
2. In a following phase 2a clinical study, 13 participants treated with inaxaplin had a significant reduction in urinary protein-to-creatinine ratio at week 13.
Evidence Rating Level: 3 (Average)
Study Rundown: The presence of two APOL1 variants confers a higher risk for proteinuric chronic kidney disease. These toxic gain-of-function variants may enhance APOL1 channel function leading to podocyte damage. The standard of care for patients with focal segmental glomerulosclerosis and two APOL1 variants, including diuretics, renin-angiotensin-aldosterone system inhibitors, and glucocorticoids, has a poor efficacy and safety profile. In this study, the efficacy of inaxaplin, an APOL1 channel selective inhibitor, for reducing proteinuria, a predictive marker of progression to end-stage kidney disease, was characterized in preclinical and phase 2a clinical studies. In cellular assays, inaxaplin bound directly to APOL1 protein and blocked APOL1 protein channel in a concentration-dependent manner. In a transgenic mouse model of APOL1-mediated kidney disease, inaxaplin administration significantly reduced the mean interferon gamma-induced urinary albumin-to-creatinine ratio. For the clinical study, adult patients with two APOL1 variants and biopsy-proven focal segmental glomerulosclerosis received inaxaplin treatment for 13 weeks and were followed for an additional 28 days. No placebo control was included. For the primary outcome, there was a reduced urinary protein-to-creatinine ratio at week 13 in both nephrotic and subnephrotic-range patients. One patient did not have a reduction despite having 100% adherence to treatment. All adverse events related to the treatment were mild or moderate in severity. As limitations, this study had a small sample size, short duration, and no placebo control.
Click here to read the study in NEJM
In-Depth [randomized controlled trial]: The mechanism and efficacy of inaxaplin were assessed in preclinical and clinical studies. In the preclinical phase, inaxaplin action was assessed in human embryonic kidney cell lines expressing APOL1 variants and transgenic homozygous APOL1 G2 variant mouse models of kidney disease. In cellular assays assessing thallium ion flux, a surrogate for potassium ion flux, inaxaplin bound directly to APOL1 protein and blocked the channel function of APOL1 in a concentration-dependent manner. In animal studies, prophylactic administration of inaxaplin significantly reduced the urinary albumin-to-creatinine ratio by 74.1% compared to control saline after interferon gamma-induced kidney dysfunction. In the phase 2a clinical trial, 16 adult patients with two APOL1 variants and biopsy-proven focal segmental glomerulosclerosis received inaxaplin treatment for 13 weeks and were followed for an additional 28 days. Three patients did not have at least 80% adherence and were not included in the primary outcome analyses. For the primary outcome, a mean change in the urinary protein-to-creatinine ratio of -47.6% (95% Confidence Interval [CI], -60.0 to -31.3) was observed at week 13 in both nephrotic- and subnephrotic-range groups. One patient did not have a reduction despite having 100% adherence to treatment. Nine patients underwent a further 12 weeks follow-up after treatment for urinary protein-to-creatinine ratio monitoring. The mean urinary protein-to-creatinine ratio increased from -47.6% to -30.1% by week four after treatment. For the safety profile, 15 patients had at least one adverse event, the most common of which were headaches, back pain, and nausea. Two serious adverse events occurred in one participant (deep-vein thrombosis and uterine leiomyoma), which were deemed unrelated to inaxaplin. This study provides initial evidence that targeted inhibitors of APOL1 function could reduce proteinuria for patients with related genetic risk factors.
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