An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis

  • Front Pharmacol. 2022 Nov 16:13:1037983. doi: 10.3389/fphar.2022.1037983.
Alexander Vugler  1 ,  James O'Connell  2 ,  Mai Anh Nguyen  3 ,  Dietmar Weitz  4 ,  Thomas Leeuw  5 ,  Elizabeth Hickford  6 ,  Alexander Verbitsky  7 ,  Xiaoyou Ying  7 ,  Markus Rehberg  8 ,  Bruce Carrington  2 ,  Mark Merriman  1 ,  Andrew Moss  9 ,  Jean-Marie Nicholas  10 ,  Phil Stanley  1 ,  Sara Wright  11 ,  Tim Bourne  12 ,  Yann Foricher  13 ,  Zhaoning Zhu  14 ,  Daniel Brookings  14 ,  Helen Horsley  14 ,  Jag Heer  14 ,  Laurent Schio  13 ,  Matthias Herrmann  5 ,  Srinivas Rao  7 ,  Markus Kohlmann  15 ,  Peter Florian  5
Affiliations
  • 1. Immunology Therapeutic Area, PV Early Solutions, UCB Pharma, Slough, United Kingdom.
  • 2. Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom.
  • 3. Sanofi R&D, TMED Pharmacokinetics Dynamics and Metabolism, Frankfurt am Main, Germany.
  • 4. Sanofi R&D, Drug Metabolism and Pharmacokinetics, Frankfurt am Main, Germany.
  • 5. Sanofi R&D, Type 1/17 Immunology, Immunology & Inflammation Research TA, Frankfurt, Germany.
  • 6. Development Science, PV Early Solutions, UCB Pharma, Slough, United Kingdom.
  • 7. Sanofi R&D, Translation In vivo Models, Cambridge, MA, United States.
  • 8. Sanofi R&D, Translational Disease Modelling, Frankfurt am Main, Germany.
  • 9. Translational Medicine Immunology, PV Early Solutions, UCB Pharma, Slough, United Kingdom.
  • 10. Development Science, Drug Metabolism and Pharmacokinetics, UCB Pharma, Braine-I'Alleud, Belgium.
  • 11. Early PV Missions, PV Early Solutions, UCB Pharma, Slough, United Kingdom.
  • 12. Milvuswood Consultancy, Penn, United Kingdom.
  • 13. Sanofi R&D, Integrated Drug Discovery, Vitry-sur-Seine, France.
  • 14. Global Chemistry, Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom.
  • 15. Sanofi R&D, Early Clinical Development, Therapeutic Area Immunology and Inflammation, Frankfurt am Main, Germany.
PMID: 36467083 DOI: 10.3389/fphar.2022.1037983
Abstract

Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo. With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF.

Keywords
TNF; TNF trimer; immunogenicity; rheumatoid arthritis; small molecule.
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