• Ogo Egbuna, Brandon Zimmerman, George Manos, Anne Fortier, Madalina C Chirieac, Leslie A Dakin, David J Friedman, Kate Bramham, Kirk Campbell, Bertrand Knebelmann, Laura Barisoni, Ronald J Falk, Debbie S Gipson, Michael S Lipkowitz, Akinlolu Ojo, Mark E Bunnage, Martin R Pollak, David Altshuler, Glenn M Chertow, and VX19-147-101 Study Group.
• 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.).
• N. Engl. J. Med. 2023 Mar 16; 388 (11): 969979969-979.

BackgroundPersons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) 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 APOL1 variants (G1 or G2) are lacking.MethodsWe 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 APOL1 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 APOL1 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 m2 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.ResultsIn 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.ConclusionsTargeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.).Copyright © 2023 Massachusetts Medical Society.

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