PI-050 - COMPARISON OF THE SYSTEMIC EXPOSURE AND PREDICTED INHIBITION OF PHARMACODYNAMIC CYTOKINE RESPONSE BY SYSTEMIC AND LOCALLY ACTING JAK INHIBITORS.

F. Zheng¹, Y. Xiong², J. Shao³, R. Thurmond², L. Madge³, T. Brandt³, T. Beavers³, J. Sendecki⁴, B. Knight⁵, K. Holt³, A. Lo⁶, I. Badagnani⁷, D. Devineni²; ¹Janssen Pharmaceuticals, Somerville, NJ, USA, ²Janssen Pharmaceuticals, Raritan, NJ, USA, ³Janssen Pharmaceuticals, Horsham, PA, USA, ⁴Janssen Pharmaceuticals, Titusville, NJ, USA, ⁵Janssen Pharmaceuticals, San Diego, CA, USA, ⁶Theravance Biopharma, Inc., South San Francisco, CA, USA, ⁷Janssen Pharmaceuticals, South San Francisco, CA, USA.

Background: Tofacitinib, upadacitinib, filgotinib and baricitinib are systemic-acting oral Janus kinase inhibitors (JAKi) that have been approved for several autoimmune diseases, but with black box warnings of immunosuppression and infection risk. Delivery of JAKi to the site of disease is an attractive strategy to minimize systemic adverse events. Topical ruxolitinib and delgocitinib were approved for atopic dermatitis, while oral izencitinib (gut-selective) failed to show efficacy in inflammatory bowel disease. The objective is to compare the systemic pSTAT inhibition between systemic and local JAKi to inform target mediated systemic safety issues.

Methods: PK profiles of JAKi were simulated at therapeutic doses considering inter-individual variability of PK parameters. The concentration-response relationship of JAKi inhibiting the activity of cytokine-induced pSTAT was assessed. Time above IC50 and %inhibition of pSTAT at steady state were computed.

Results: At all doses of izencitinib, the upper 95th percentiles of plasma concentration were below the IC50 for pSTAT inhibition via cytokines (IFNα, IL-6, IL-2, GM-CSF and TPO), suggesting a minimal level of JAK systemic target engagement by izencitinib. Systemic JAKi instead all show substantial time above IC50 and %inhibition of pSTAT response (IFNα, IL-6, IL-2 and TPO). Topical delgocitinib shows much lower systemic exposure and %inhibition of pSTAT than systemic acting JAKi, while topical ruxolitinib shows similar PK and pSTAT inhibition as its oral product.

Conclusion: Low level of predicted systemic JAK inhibition of izencitinib and delgocitinib suggest the potential for an improved safety profile relative to systemic acting JAKi. Topical ruxolitinib was predicted with substantial systemic JAK inhibition and was given the typical JAK class warnings by FDA.