Japanese Phase 1 Study for Global Development of Anti-TL1A Antibody PF-06480605: A Randomized, Placebo-Controlled, Single-Ascending Dose Study

Abstract

PF-06480605, a fully human IgG1 monoclonal antibody targeting tumor necrosis factor α-like ligand 1A (TL1A), has demonstrated acceptable safety and the potential as an effective treatment for inflammatory bowel disease in phase 1/2a studies. To facilitate future clinical development in Japan and China, a Japan local phase 1 study was designed in consultation with the Japan regulatory authority. In addition to fulfilling Japan regulatory requirements, this study will bring operational efficiency and speed to global and China development by evaluating PF-06480605 in Japanese healthy adults prior to a China local phase 1 study as required by the China regulatory authority. This phase 1, randomized, double-blind, placebo-controlled, single-dose escalating study investigated the safety, tolerability, immunogenicity, pharmacokinetics (PK), and pharmacodynamics of PF-06480605 in Japanese healthy adults assigned to receive a single subcutaneous (SC) dose of PF-06480605 150 mg (N = 6), 450 mg (first-in-human dose level, N = 6), or placebo (N = 4). PF-06480605 was well tolerated and absorbed slowly with a median T_max of 217.5 h for both 150 and 450 mg doses. Mean t_1/2 was 18.4 and 19.1 days for 150 and 450 mg, respectively. Exposure parameters showed dose proportionality. No ethnic differences in PF-06480605 PK were observed. Serum TL1A levels increased in a dose-dependent manner. Immunogenicity was high with 100% of anti-PF-06480605 antibody formulation. This study satisfied the Japan regulatory requirements, while the favorable tolerability and PK of 450 mg SC in Japanese contributed to a waiver of the 150 mg SC cohort in the China local phase 1 study. NCT04269538.

Keywords: China; Japan; MHLW; PF‐06480605; PMDA; TL1A; first‐in‐Japanese; first‐in‐human; pharmacodynamic; pharmacokinetic.

FIGURE 1

Median serum PF‐06480605 concentration‐time profiles by treatment group following subcutaneous injection of PF‐06480605 (150 or 450 mg). Open circles and triangles represent median serum concentrations in the PF‐06480605 150 and 450 mg groups, respectively. Upper and lower panels are linear and semilog scales, respectively. Lower limit of quantification is 20.0 ng/mL. Summary statistics are calculated by setting concentration values below the lower limit of quantification to zero.

FIGURE 2

Individual and geometric mean serum PF‐06480605 dose‐normalized AUC_14day (upper panel) and C _max (lower panel) values following subcutaneous injection of PF‐06480605 150 or 450 mg. Closed circles represent the geometric mean, and open circles represent individual values. Abbreviations: AUC_14day , area under the concentration‐time curve from time 0 to 14 days postdose; C _max, maximum concentration.

FIGURE 3

Median serum sTL1A concentration‐time profiles by treatment group following subcutaneous injection of PF‐06480605 (150 or 450 mg) or placebo. Open circles, triangles, and diamonds represent median serum sTL1A concentrations in the PF‐06480605 150 mg, PF‐06480605 450 mg, and placebo groups, respectively. Lower limit of quantification is 40.0 pg/mL. Summary statistics are calculated by setting concentration values below the lower limit of quantification to zero. Abbreviations: STL1A, soluble tumor necrosis factor α‐like ligand 1.