P0932The First-in-Class SIK3 Inhibitor O3R-5671 Demonstrates Optimal Pharmacokinetics and Potent and Sustained Pharmacodynamic Activity in Human Participants

Abstract Background Treatment options for inflammatory bowel disease (IBD) are limited by low remission rates and loss of response. Most therapies target single pathogenic pathways and while combinations of biologics targeting different pathogenic cytokines can increase clinical remission rates, dosing schedules are inconvenient. Salt-inducible kinases (SIKs), a subfamily of serine/threonine kinases in the AMP-activated protein kinase (AMPK) family, act as key regulators of immune cell signaling. Three SIK isoforms exist: SIK1, SIK2 and SIK3. SIK inhibitors targeting multiple isoforms have been investigated in the clinic. Although there were signals of activity in patients with ulcerative colitis and psoriasis, limited efficacy and safety concerns related to SIK1 and SIK2 inhibition and poor target coverage hampered their development. O3R-5671 is a potent and selective SIK3 inhibitor that inhibits cytokines including TNFa, IL-23 and IL-12, which is designed to avoid off-target effects of first-generation SIK inhibitors. The prodrug, O3R-5671-PRO, was engineered to optimize PK and target coverage. Methods In the ongoing Phase 1 study (randomized, placebo-controlled, double-blind), 40 healthy male participants have received single or multiple ascending doses of O3R-5671-PRO or a placebo. PK samples were drawn pre-dose and post-dose and analyzed by LC-MS/MS. PD samples were drawn simultaneously and whole blood was stimulated with LPS for 20 hours prior to TNFa quantification in plasma by MSD V-PLEX immunoassay. Results At the time of writing, PK and PD data were available for 5mg, 10mg, 25mg and 35mg SAD cohorts. O3R-5671 levels reached Cmax in each of the cohorts approximately 4-6 hours post-dose. O3R-5671 demonstrated a long half-life of between 25-30 hours and low inter-subject variability. In each of the cohorts, TNFa release was maximally inhibited between 4 and 8 hours post dose. In the 25mg cohort, TNFa release was inhibited by ≈90% at 8 hours and 75% at 24 hours. PK and PD plots are shown in the figure below. Conclusion O3R-5671 is a potent and selective SIK3 inhibitor that inhibits pathogenic cytokines including TNFa, IL-23 and IL-12. After single doses, it has demonstrated an attractive PK profile and potent TNFa inhibition in highly translational PD assay. Full PK and cytokine analyses from all available SAD and MAD cohorts will be presented. As O3R-5671 is expected to strongly inhibit IL-23 and IL-12 on top of TNFα, a high response rate is expected in IBD patients. Conflict of interest: Kolb, Fabrice: Employment Passier, Paul: Employment: 3D-PharmXchange Nijholt, Diana: Employment- 3D-pharmXchange Yadav, Lokesh: Employment: 3D-phasrXchange Von Rongen, Anne: Employment- 3D-pharmXchange Petkova, Magdalena: Employment- Onco3R Therapeutics Van Riet, Camille: Employment- SGS Lodeweyckx, Thomas: Employment- SGS Raboisson, Pierre: Employment- Onco3R Therapeutics Dr. Gallivan, John-Paul: No conflict of interest