DOP118A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of the p40xTL1A bispecific antibody PF-07261271 in healthy participants.

Abstract Background There is an unmet need for more effective therapies in inflammatory bowel disease (IBD). A single drug that blocks multiple distinct pathogenic pathways may offer therapeutic benefit superior to current monotherapies. PF-07261271, a bispecific antibody targeting both the p40 subunit of interleukin-12/23 and tumor necrosis factor-like cytokine 1A (TL1A), is being investigated as a potential new IBD therapy. This study evaluates the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the p40xTL1A bispecific antibody PF-07261271 (now RO7837195) in healthy participants. Methods This phase 1, randomized, double-blind, placebo-controlled study assessed single ascending doses (SAD; intravenous 30–100-300-1000 mg) and multiple doses (MD; subcutaneous 300 mg once every 4 weeks) of PF-07261271 in healthy adults. Safety, PK, immunogenicity and exploratory PD serum biomarkers (total soluble TL1A sTL1A and p40) were evaluated. Results Thirty-five participants were enrolled (Part A: SAD, N = 27; Part B: MD, N = 8). PF-07261271 was generally safe and well tolerated; all treatment-emergent adverse events were mild/moderate (Table 1). Following peak serum concentration, there was a multi-phase decline with a trend towards increased terminal half-life at the higher doses. For the MD cohort, the estimated bioavailability of PF-07261271 administered subcutaneously was 48%. Dose-dependent increases from baseline in serum total sTL1A and p40 levels were observed in participants receiving PF-07261271, demonstrating target engagement. There was no apparent impact of anti-drug antibodies on safety, PK or PD parameters. Conclusion PF-07261271 demonstrated p40 and TL1A target engagement and a favorable safety profile. Further studies are warranted to evaluate its safety and efficacy in patients with IBD. References: 1.Targownik LE, Benchimol EI, Bernstein CN, et al. Combined biologic and immunomodulatory therapy is superior to monotherapy for decreasing the risk of inflammatory bowel disease-related complications. J Crohns Colitis. 2020;14(10):1354-1363. doi: 10.1093/ecco-jcc/jjaa050. 2.Caron B, Netter P, Danese S, Peyrin-Biroulet L. Bispecific antibodies for the treatment in inflammatory bowel disease: an avenue worth exploring? Expert Opin Biol Ther. 2022;22(8):951-953. doi: 10.1080/14712598.2022.1985999. 3.Jairath V, Danese S, D’Haens G, et al. Phase 1b study of SOR102, a novel, orally delivered bispecific anti-TNF/anti-IL-23 domain antibody in patients with mild to severe ulcerative colitis. J Crohns Colitis. 2025;19:i62-i63. doi: 10.1093/ecco-jcc/jjae190.0031. Conflict of interest: Sapone, Anna: Shareholder Neelakantan, Srividya: Pfizer stockholder Banfield, Christopher: Consulting Hung, Kenneth: Pfizer Affiliation at the time the study was conducted Shareholder Pradhan, Vivek: Shareholder Zhao, Yuxi: Shareholder Parsons-Rich, Dana: Shareholder Lee, Grace: Shareholder Johnson, Bryce: Shareholder Peeva, Elena: Shareholder Michael, Vincent: Shareholder Clerin, Valerie: Shareholder