AB0379 DOSE-DEPENDENT SUPPRESSION OF T CELL-DEPENDENT ANTIBODY RESPONSE IN HEALTHY VOLUNTEERS BY KPL-404, AN ANTI-CD40 MONOCLONAL ANTIBODY, SUPPORTS CHRONIC DOSING STUDY IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background An unmet need remains in patients with failure and/or inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARD-IR) Janus kinase inhibitors (JAKi-IR). The CD40/CD40L (CD154) costimulatory pathway is linked inflammation and joint destruction RA via production of autoantibodies inflammatory mediators. KPL-404 a humanized IgG4 antibody engineered bind CD40 without triggering Fc effector functions (Muralidharan, 2019), which are known have been associated thromboembolic events seen the first generation CD40L-targeting therapies. In first-in-human Phase 1 single ascending dose study, 52 healthy volunteers received doses administered either subcutaneously (SC) or intravenously (IV) no dose-limiting safety findings, infectious episodes, toxicities (Samant, 2021). study demonstrated that 10 mg/kg IV, full receptor occupancy (RO) was observed through day 71, there complete suppression T-cell dependent (TDAR) keyhole limpet hemocyanin challenge on re-challenge 29 57. With 5 SC, RO 43, TDAR at least 29. Complete ADA KPL-404, an independent indicator target engagement, also while serum concentrations were above approximately 0.1 0.2 µg/mL continued for 50 days 57 after SC IV administration, respectively. Objectives Using nonclinical data, identify chronic dosing regimens anticipated yield PK sub-therapeutic, therapeutic, supra-therapeutic ranges be utilized Multiple Ascending Dose 2 Study. Methods A model used simulate multiple scenarios, including: 2.5, 5, qwk, q2wk, q4wk, as well q4wk. optimal schedules by generating 1000 virtual subjects using typical parameter estimates between-subject variability included. Results Following all predicted achieve interval at/above 2.5 q2wk. At q2wk (starting level), simulated steady-state 8-week data sub-therapeutic range most 31- 18-fold margin relative preclinical NOAEL dose. 100% therapeutic range, indicating potential practical efficacious level. supratherapeutic range. These results support (MAD) design, lead-in comprised 3 Cohorts 2, (each randomized 6:2) Proof-of-Concept phase (Cohort 4) 48-60 1:1:1 mg/kg, placebo ongoing will evaluate efficacy (Disease Activity 28 joints C-reactive protein [DAS28-CRP]), safety, PK, pharmacodynamics (PD) escalating levels compared moderate severe (bDMARD-IR JAKi-IR). allows flexibility optional cohorts including additional subpopulations identified based clinical biomarkers. Conclusion Inhibition CD40-CD154 co-stimulatory interaction holds promise management spectrum autoimmune diseases. prolonged absorption/excretion capable suppressing extended periods allowing use intervals irrespective dosing. analyses supported design assessing RA. References [1]Muralidharan S et al. 2019. Poster Keystone Symposia [2]Samant M Arthritis Rheumatol. 2021; 73(suppl 10) Disclosure Interests Anastassia Papandrikopoulou Shareholder of: Kiniksa Pharmaceuticals Corp., Employee Gerd Rüdiger Burmester Speakers bureau: Abbvie, Amgen, BMS, Lilly, MSD, Pfizer, Roche, Sanofi, Consultant Kiniksa, Fang Alan Kivitz Gilead Sciences, Inc., GlaxoSmithKline, Novartis, Sanofi,, AbbVie, Celgene, Flexion, Genzyme, Merck, UCB, Horizon, Boehringer Ingelheim, Janssen, SUN Pharma Advanced Research, Moses Njenga Arian Pano Costantino Pitzalis Abbott/AbbVie, Astra- Zeneca/MedImmune, Janssen/J&J, Roche/Genentech/Chugai, UCB.,, Astellas, Astra-Zeneca/MedImmune, CelGene, Grunenthal, GSK, Roche / Genentech Chugai, UCB., Grant/research from: Manoj Samant Steve Schmitz Madeline Spiers Eben Tessari John Ziemniak Pharmaceuticals, Ltd., F. Paolini Corp.