Inaxaplin for Proteinuric Kidney Disease in Persons with Two

Animals Humans Mice Apolipoprotein L1 / antagonists & inhibitors Apolipoproteins / genetics Black or African American Creatinine / urine Gain of Function Mutation Genetic Predisposition to Disease Glomerulosclerosis, Focal Segmental / drug therapy HEK293 Cells Proteinuria / drug therapy

Journal

The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562

Informations de publication

Date de publication:
16 Mar 2023
Historique:
entrez: 15 3 2023
pubmed: 16 3 2023
medline: 21 3 2023
Statut: ppublish

Résumé

Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 ( 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 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. Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two

Sections du résumé

BACKGROUND BACKGROUND
Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (
METHODS 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
RESULTS 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 CONCLUSIONS
Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two

Identifiants

DOI: 10.1056/NEJMoa2202396 PMID: 36920755
pubmed: 36920755
doi: 10.1056/NEJMoa2202396
doi:

Substances chimiques

APOL1 protein, human 0
Apolipoprotein L1 0
Apolipoproteins 0
Creatinine AYI8EX34EU

Banques de données

ClinicalTrials.gov
['NCT04340362']

Types de publication

Clinical Trial, Phase II Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

969-979

Investigateurs

Ahmed Aqeel (A)
Vincent Audard (V)
Jean-Jacques Boffa (JJ)
Kate Bramham (K)
Kirk Campbell (K)
Chee Kay Cheung (CK)
Gregorio Cortes-Maisonet (G)
Vimal Derebail (V)
Avrum Gillespie (A)
Laurence Greenbaum (L)
Naimat Khan (N)
Christopher Peter Luscy (CP)
Sreedhar Mandayam (S)
Jill Meyer (J)
Dominic Raj (D)
Dana Rizk (D)
Jeffrey Ryu (J)
James Tumlin (J)
Alexander Velar (A)
Juan Carlos Velez (JC)
Sushrut Waikar (S)
Thomas Wooldridge (T)

Commentaires et corrections

Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2023 Massachusetts Medical Society.

Auteurs

Ogo Egbuna (O)

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.).

Brandon Zimmerman (B)

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.).

George Manos (G)

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.).

Anne Fortier (A)

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.).

Madalina C Chirieac (MC)

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.).

Leslie A Dakin (LA)

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.).

David J Friedman (DJ)

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.).

Kate Bramham (K)

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.).

Kirk Campbell (K)

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.).

Bertrand Knebelmann (B)

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.).

Laura Barisoni (L)

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.).

Ronald J Falk (RJ)

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.).

Debbie S Gipson (DS)

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.).

Michael S Lipkowitz (MS)

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.).

Akinlolu Ojo (A)

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.).

Mark E Bunnage (ME)

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.).

Martin R Pollak (MR)

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.).

David Altshuler (D)

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.).

Glenn M Chertow (GM)

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.).

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Apolipoprotéines L › Apolipoprotéine L1 › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Personnes › Nord-Américains › Groupes de population aux États-Unis › Populations d'origine continentale › Noir ou Africain Américain › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Imidazoles › Créatinine › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation gain de fonction › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Maladies du rein › Néphrite › Glomérulonéphrite › Glomérulonéphrite segmentaire et focale › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Inaxaplin for Proteinuric Kidney Disease in...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations urologiques › Protéinurie › Inaxaplin for Proteinuric Kidney Disease in...