PII-004 - PHASE 1 DEVELOPMENT OF RAVAGALIMAB, AN ANTI CD40 MONOCLONAL ANTIBODY, TO SUPPORT DOSE SELECTION FOR PHASE 2.

S. Bhatnagar¹, S. Hao¹, K. Hew¹, A. Nader¹, M. Ismail², T. Doan¹, A. Lazar³, M. Mohamed¹, W. Liu¹; ¹Abbvie Inc., North Chicago, IL, USA, ²University at Buffalo, Getzville, NY, USA, ³AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Rhineland-Palatinate, Germany.

Background: Ravagalimab (RAV) is a humanized monoclonal antibody that binds to CD40, a receptor with elevated expression in chronic inflammatory diseases, with the potential to disrupt the signaling pathway that results in a reduction of T cell activation, secretion of pro-inflammatory cytokines, and tissue damage.

Methods: Phase 1 development of RAV consisted of a single ascending dose (SAD; N = 63), multiple ascending dose (MAD; N = 16), an Asian pharmacokinetic (PK; N = 72), and a pharmacodynamic (PD; N = 39) study. These studies evaluated the safety, tolerability, PK, PD, and immunogenicity of subcutaneously (SC) and intravenously (IV) administered RAV in healthy subjects, which informed dose selection for future development.

Results: All regimens tested in the Phase 1 studies were generally safe and well tolerated. RAV serum exposures increased in a more than dose-proportional manner across the dose range of 50 mg to 300 mg SC and 50 mg to 600 mg IV, with a half-life of 4 to 11 days. RAV exposures in Japanese subjects were 47% – 87% higher than those in Caucasian subjects at a dose of 300 mg SC but similar between the two groups at 600 mg IV. Although doses ≥ 50 mg SC/IV maintained a receptor occupancy (RO) of ~90% for at least two weeks after the last dose, subjects dosed with 100 mg SC still elicited an immune response to keyhole limpet haemocyanin (KLH) antigen, while a single 300 mg SC dose markedly suppressed the immune response until Day 29, after which the response rebounded. The PD data helped inform a dosing frequency of every other week (EOW). Treatment emergent anti-drug antibodies were present across all studies, with no apparent impact on PK or safety.

Conclusion: The totality of the data from the Phase 1 studies supported studying 300 mg SC EOW in Phase 2.