P633 First-in-Human Pharmacokinetic and Safety Study of an Anti-TL1A Antibody, TEV-48574, in Healthy Volunteers and Asthma Patients

Abstract Background TEV-48574 is a human antibody that targets tumor necrosis factor (TNF)-like ligand 1A, also known as TNF superfamily member 15 (TNFSF15). TEV-48574 is in clinical development as a potential treatment for ulcerative colitis (UC) and Crohn’s disease (CD); and has been shown to reduce fibrosis, inflammation, and mortality in animal models of IBD and asthma.1 The main objectives of this phase 1 study were to characterize the pharmacokinetics (PK) and safety of TEV-48574 in healthy subjects and mild asthmatic patients. Methods In the single ascending dose part of the study (SAD), healthy subjects were randomized 6:2 to active and placebo treatment; specifically participants were either administered TEV-48574 single dose (1, 4, 12, 36, 90, 200, 400, or 1000 mg) or placebo by subcutaneous route (SC). In the multiple ascending dose part of the study (MAD) patients with asthma were randomized 9:3 to active and placebo treatment in three cohorts. Cohort 1 received TEV-48574 200 mg Q2W or placebo (days 1, 15, and 29). Cohort 2 received a loading TEV-48574 dose of 800 mg on day 1 followed by 2 maintenance doses of 600 mg on days 15 and 29 (800/600 mg Q2W) or placebo. Cohort 3 received a loading TEV-48574 dose of 2300 mg on day 1 followed by 2 maintenance doses of 1600 mg on days 15 and 29 or placebo. Safety, tolerability, PK, and anti-drug antibody (ADA) levels were assessed at predetermined times. Measurement of total and free TL1A using ligand binding assays will be reported elsewhere. Results TEV-48574 was absorbed slowly with peak concentrations appearing at 72- 96 hours following SAD and MAD administration. It was eliminated gradually in a monophasic manner and the rate of elimination appeared similar across dose levels (Figure 1). Exposures as defined by maximum concentration (Cmax) and area under the curve (AUC) of TEV-48574 increased in a dose-proportional manner with no accumulation. Mean t½ estimates ranged from 6.5 to 9.6 days (Table 1). Administration of TEV-48574 was generally well tolerated at doses up to 2300 mg. ADA-positive responses were observed at doses of 200 mg or lower in 23 of 48 TEV-48574-treated subjects in the SAD portion of the study and in 3 of 27 TEV-48574-treated patients in the MAD portion of the study and were not associated with safety signals. Conclusion TEV-48574 was well tolerated at all tested doses in healthy subjects and participants with asthma, with dose proportional increases in exposure and minimal accumulation after multiple dosing every two weeks. The data support further development of TEV-48574 in patients with IBD. 1. Clarke A. et al. mAbs.2018;10:664-677.