Journal article
Small-molecule factor B inhibitor for the treatment of complement-mediated diseases
Proceedings of the National Academy of Sciences - PNAS, Vol.116(16), pp.7926-7931
04/16/2019
DOI: 10.1073/pnas.1820892116
PMCID: PMC6475383
PMID: 30926668
Abstract
Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number of diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead to complement-driven nephropathies. Here we describe the discovery of a highly potent, reversible, and selective small-molecule inhibitor of factor B, a serine protease that drives the central amplification loop of the AP. Oral administration of the inhibitor prevents KRN-induced arthritis in mice and is effective upon prophylactic and therapeutic dosing in an experimental model of membranous nephropathy in rats. In addition, inhibition of factor B prevents complement activation in sera from C3 glomerulopathy patients and the hemolysis of human PNH erythrocytes. These data demonstrate the potential therapeutic value of using a factor B inhibitor for systemic treatment of complement-mediated diseases and provide a basis for its clinical development.
Details
- Title: Subtitle
- Small-molecule factor B inhibitor for the treatment of complement-mediated diseases
- Creators
- Anna Schubart - Novartis (Switzerland)Karen Anderson - Biogen (United States)Nello Mainolfi - Akebia Therapeutics (United States)Holger Sellner - Novartis (Switzerland)Takeru Ehara - Peptidream (Japan)Christopher M Adams - Novartis (United States)Aengus Mac Sweeney - Idorsia (Switzerland)Sha-Mei Liao - Novartis Institutes for BioMedical Research, Cambridge, MA 02139Maura Crowley - Novartis Institutes for BioMedical Research, Cambridge, MA 02139Amanda Littlewood-Evans - Novartis (Netherlands)Sophie Sarret - Novartis (Switzerland)Grazyna Wieczorek - Novartis (Switzerland)Ludovic Perrot - Novartis (Switzerland)Valérie Dubost - Novartis (Switzerland)Thierry Flandre - Novartis (Switzerland)Yuzhou Zhang - University of IowaRichard J H Smith - University of IowaAntonio M Risitano - Federico II University HospitalRajeshri G Karki - Novartis Institutes for BioMedical Research, Cambridge, MA 02139Chun Zhang - Novartis Institutes for BioMedical Research, Cambridge, MA 02139Eric Valeur - Novartis (Switzerland)Finton Sirockin - Novartis (Switzerland)Bernd Gerhartz - Novartis (Switzerland)Paulus Erbel - Novartis (Switzerland)Nicola Hughes - Novartis (Switzerland)Thomas M Smith - Novartis Institutes for BioMedical Research, Cambridge, MA 02139Frederic Cumin - Novartis (Switzerland)Upendra A Argikar - Novartis Institutes for BioMedical Research, Cambridge, MA 02139Börje Haraldsson - Novartis (Switzerland)Muneto Mogi - Novartis Institutes for BioMedical Research, Cambridge, MA 02139Richard Sedrani - Novartis (Switzerland)Christian Wiesmann - Novartis (Switzerland)Bruce Jaffee - Novartis Institutes for BioMedical Research, Cambridge, MA 02139Jürgen Maibaum - Novartis (Switzerland)Stefanie Flohr - Novartis (Switzerland)Richard Harrison - Novartis (Switzerland)Jörg Eder - Novartis (Switzerland)
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.116(16), pp.7926-7931
- DOI
- 10.1073/pnas.1820892116
- PMID
- 30926668
- PMCID
- PMC6475383
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- R01 DK110023 / NIDDK NIH HHS
- Language
- English
- Date published
- 04/16/2019
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984627196402771
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