Monday, July 20, 2015

Celgene takes PKCθ (PKC theta) inhibitor into the clinic as candidate first in class treatment of psoriasis

This is an extract from UpdatesPlus-Psoriasis, our regular report analyzing breaking development across the field of psoriasis research and development - for further information and sample copies please contact Dr Jon Goldhill
  • The protein kinase C (PKC) family comprises 12 isoforms including T cell modulators, PKCθ and PKCα
  • Both isoforms are anti-inflammatory targets although PKCα inhibition carries a risk of CV AEs
  • PKCθ mediates the response to TCR activation including IL-2 production, cellular expansion, and activation
  • Proof of concept exists to support the development of PKCθ inhibitors for rheumatoid arthritis as knock-out mice do not develop disease in experimental models (Healy et al).  PKCθ inhibition also apparently enhances functionality of rheumatoid arthritis Treg cells (Zanin-Zhorov)
  • Novartis was developing sotrastaurin which inhibits PKCθ with nM potency.  Inhibition was relatively unselective, which likely contributed to the termination of it's development. 
  • Abbvie also reported earlier this year efforts to develop PKCθ inhibitors with low nM potency, but with ≈100-fold selectivity over PKCα.  A representative molecule from this series was active in a model of rheumatoid arthritis however we are unaware of Abbvie advancing this class into the clinic yet
  • Celgene has also previously indicated its involvement in PKCθ inhibitor development and has now opened a Phase 1b study of CC-90005 including the enrollment of psoriasis patients
  • The study is evaluating oral dosing.  Data should be available by Oct 2016.  Although the study is primarily a safety and PK trial, efficacy will also be investigated

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