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Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants.

Publication ,  Journal Article
Egbuna, O; Zimmerman, B; Manos, G; Fortier, A; Chirieac, MC; Dakin, LA; Friedman, DJ; Bramham, K; Campbell, K; Knebelmann, B; Barisoni, L ...
Published in: N Engl J Med
March 16, 2023

BACKGROUND: Persons 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. 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 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. 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 APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.).

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Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

March 16, 2023

Volume

388

Issue

11

Start / End Page

969 / 979

Location

United States

Related Subject Headings

  • Proteinuria
  • Mice
  • Humans
  • HEK293 Cells
  • Glomerulosclerosis, Focal Segmental
  • Genetic Predisposition to Disease
  • General & Internal Medicine
  • Gain of Function Mutation
  • Creatinine
  • Black or African American
 

Citation

APA
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Egbuna, O., Zimmerman, B., Manos, G., Fortier, A., Chirieac, M. C., Dakin, L. A., … VX19-147-101 Study Group, . (2023). Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants. N Engl J Med, 388(11), 969–979. https://doi.org/10.1056/NEJMoa2202396
Egbuna, Ogo, Brandon Zimmerman, George Manos, Anne Fortier, Madalina C. Chirieac, Leslie A. Dakin, David J. Friedman, et al. “Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants.N Engl J Med 388, no. 11 (March 16, 2023): 969–79. https://doi.org/10.1056/NEJMoa2202396.
Egbuna O, Zimmerman B, Manos G, Fortier A, Chirieac MC, Dakin LA, et al. Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants. N Engl J Med. 2023 Mar 16;388(11):969–79.
Egbuna, Ogo, et al. “Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants.N Engl J Med, vol. 388, no. 11, Mar. 2023, pp. 969–79. Pubmed, doi:10.1056/NEJMoa2202396.
Egbuna O, Zimmerman B, Manos G, Fortier A, Chirieac MC, Dakin LA, Friedman DJ, Bramham K, Campbell K, Knebelmann B, Barisoni L, Falk RJ, Gipson DS, Lipkowitz MS, Ojo A, Bunnage ME, Pollak MR, Altshuler D, Chertow GM, VX19-147-101 Study Group. Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants. N Engl J Med. 2023 Mar 16;388(11):969–979.

Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

March 16, 2023

Volume

388

Issue

11

Start / End Page

969 / 979

Location

United States

Related Subject Headings

  • Proteinuria
  • Mice
  • Humans
  • HEK293 Cells
  • Glomerulosclerosis, Focal Segmental
  • Genetic Predisposition to Disease
  • General & Internal Medicine
  • Gain of Function Mutation
  • Creatinine
  • Black or African American