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
  • 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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