2. Academic Validation
  3. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases

Small-molecule factor B inhibitor for the treatment of complement-mediated diseases

  • Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7926-7931. doi: 10.1073/pnas.1820892116.
Anna Schubart 1,  Karen Anderson 2 3,  Nello Mainolfi 2 4,  Holger Sellner 1,  Takeru Ehara 2 5,  Christopher M Adams 2,  Aengus Mac Sweeney 1 6,  Sha-Mei Liao 2,  Maura Crowley 2,  Amanda Littlewood-Evans 1,  Sophie Sarret 1,  Grazyna Wieczorek 1,  Ludovic Perrot 1,  Valérie Dubost 1,  Thierry Flandre 1,  Yuzhou Zhang 7,  Richard J H Smith 7,  Antonio M Risitano 8,  Rajeshri G Karki 2,  Chun Zhang 2,  Eric Valeur 1 9,  Finton Sirockin 1,  Bernd Gerhartz 1 10,  Paulus Erbel 1,  Nicola Hughes 1,  Thomas M Smith 2,  Frederic Cumin 1,  Upendra A Argikar 2,  Börje Haraldsson 1,  Muneto Mogi 2,  Richard Sedrani 1,  Christian Wiesmann 1,  Bruce Jaffee 2,  Jürgen Maibaum 1,  Stefanie Flohr 1,  Richard Harrison 1 11,  Jörg Eder 12
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • 2 Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • 3 Ophthalmology, Biogen, Cambridge, MA 02142.
  • 4 Kymera Therapeutics, Cambridge, MA 02139.
  • 5 PeptiDream Inc., Kawasaki-shi, 210-0821 Kanagawa, Japan.
  • 6 Drug Discovery Biology, Idorsia Pharmaceuticals Ltd., 4123 Allschwil, Switzerland.
  • 7 Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
  • 8 Department of Clinical Medicine and Surgery, Bone Marrow Transplantation Program, Federico II University, 80138 Naples, Italy.
  • 9 Medicinal Chemistry, Cardiovascular, Renal & Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, 431 83 Mölndal, Sweden.
  • 10 Protein Sciences, Abcam PLC, CB4 0GZ Cambridge, United Kingdom.
  • 11 Institute of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN Cardiff, United Kingdom.
  • 12 Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland; [email protected].
PMID: 30926668 DOI: 10.1073/pnas.1820892116
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.

Keywords

alternative pathway; complement; drug discovery; factor B; nephropathy.

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