POS1266 A PHASE IA, RANDOMIZED STUDY TO EVALUATE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF SINGLE ASCENDING DOSES OF RO7303509, AN ANTI-TGFΒ3 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS

Background Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. [1] However, treating fibrotic diseases with systemic pan-TGFβ inhibitors has demonstrated unacceptable toxicities. [2,3] In human lung liver tissue, the skin of patients sclerosis, elevated TGFB3 gene expression suggests its use as a more specific therapeutic target. [2,4] RO7303509, high-affinity, TGFβ3-specific, humanized immunoglobulin G1 (IgG1) monoclonal antibody, is being developed potential anti-fibrotic therapy. Objectives To evaluate RO7303509 safety, tolerability, pharmacokinetics, pharmacodynamics. Methods This phase 1a, randomized, double-blind trial ( ISRCTN13175485 ) healthy adult volunteers (HVs) consisted 6 cohorts that evaluated single doses placebo or administered intravenously (IV; 50 mg, 150 240 mg) subcutaneously (SC; 675 1200 mg). The follow-up period was 12 weeks. Throughout study, we monitored frequency severity adverse events (AEs) plasma concentrations. We also measured TGFβ pathway biomarkers, including serum periostin cartilage oligomeric matrix protein (COMP), by immunoassay. Results study enrolled 49 HVs, 18–73 years old, median baseline weight 79 kg. Twenty-seven subjects (55%) were male; 8 (16%) Black African American, 1 (2%) Asian, multiracial, 39 (80%) White; Hispanic Latino. Ten (28%) RO7303509-treated reported 24 AEs, (31%) placebo-treated AEs. All AEs Grade except for one 2 AE hyperamylasemia (unrelated) 1200-mg SC cohort. most frequent related to drug injection site reactions (1200 mg SC: 4 placebo) infusion-related (240 IV: placebo). Median times maximum concentration (T max after IV 1–2 hours 5–7 days, respectively. Geometric mean half-lives (t 1/2 dosing ~23 days. Maximum concentrations (C area under curve from time 0 infinity (AUC 0-inf values appeared increase proportionally across all tested adjusting observed subcutaneous bioavailability 73%. No positive anti-drug antibodies (ADAs) at baseline; subject (2.8%; IV) ADAs timepoint (Day 15). clear pharmacodynamic effects biomarkers COMP upon TGFβ3 inhibition. Conclusion well tolerated up without any dose-limiting toxicities, ≥3 serious deaths, clinically significant vitals/ ECG changes. addition favorable safety profile, dose-proportional exposure dose range administration supports further development using repeat-dosing regimens. half-life every four lack an effect on likely indicates inactive during homeostasis, which targeting this may have profile. These data support treatment diseases. References [1]Morikawa M, et al. Cold Spring Harb Perspect Biol 2016;8:a021873. [2]Sun T, Sci Transl Med 2021;13(605):eabe0407. [3]Rice LM, J Clin Invest 2015;125:2795−807. [4]Kaundal U Arthritis Rheumatol 2022; 74 (suppl 9). Acknowledgements would like thank who participated clinical staff assisted trial. Disclosure Interests Lyrialle Han Shareholder of: Roche, Employee Genentech, Inc., member Roche group, Samira Jamalian Lin Pan X. Rebecca Sheng Xiaoyun Yang Xiaoying Sharmeen Hassan Sharareh Monemi Allayah Stillwell Sara Glickstein Kunder group.