First-in-human, randomized dose-escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PF-06480605 in healthy subjects

Abstract

Aims: Human genetic, tissue expression, proteomics, transcriptomics and nonclinical studies implicate tumour necrosis factor α-like ligand 1A (TL1A) as a novel target in inflammatory bowel disease (IBD). PF-06480605, a fully human immunoglobulin G1 monoclonal antibody, targets TL1A. This first-in-human, Phase 1, dose-escalation study assessed safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of intravenous (IV) and subcutaneous (SC) PF-06480605 in healthy subjects (NCT01989143).

Methods: Ninety-two subjects were randomized to single ascending doses (SAD), PF-06480605 1 mg, 3 mg, 10 mg, 30 mg, 100 mg, 300 mg, 600 mg or 800 mg IV, or multiple ascending doses (MAD), PF-06480605 3 × 500 mg IV, or 3 × 30 mg, 3 × 100 mg, or 3 × 300 mg SC every 2 weeks for three doses, or placebo. Safety, tolerability, pharmacokinetics, immunogenicity profiles and total TL1A, anti-drug antibody (ADA) and neutralizing antibody (NAb) levels were assessed at pre-determined times.

Results: PF-06480605 SAD up to 800 mg IV and MAD up to 300 mg ×3 SC and 500 mg ×3 IV were well tolerated. Overall, there were 45 and 44 treatment-emergent adverse events in SAD and MAD cohorts, respectively, and no deaths or serious adverse events. PF-06480605 exposure generally increased dose-dependently. ADA and NAb levels did not impact safety, pharmacokinetics, or pharmacodynamics at higher doses. Target engagement was demonstrated through dose-dependent differences in serum total soluble TL1A concentrations for PF-06480605 vs placebo cohorts.

Conclusions: PF-06480605 was generally well tolerated, and binding of soluble TL1A was maintained throughout the dose interval, supporting further study of PF-06480605 in patients with IBD and other inflammatory conditions.

Keywords: Phase 1; clinical trials; inflammation; monoclonal antibodies; pharmacodynamic; pharmacokinetic.

© 2019 The British Pharmacological Society.

Figures

Figure 1

Study schedule for the SAD and MAD cohorts. Arrows indicate when MAD dosing begins in relation to SAD dosing. Progression to higher MAD SC doses could proceed as follows: for progression to 100 mg SC, review of safety/tolerability data (up to day 8) and PK data (up to day 3) of the 300 mg single IV dose, cumulative safety/tolerability and PK data from previous IV dose cohorts and safety/tolerability data of the 30 mg SC cohort was required; for progression to 300 mg SC, review of cumulative safety/tolerability and PK data up to 600 mg IV, safety/tolerability and PK data of the 30 mg SC cohort and safety/tolerability data from the first (up to day 14) and second (up to day 7) 100 mg SC doses was required; for progression to 500 mg IV, review of cumulative safety/tolerability and PK data up to 800 mg IV, safety/tolerability data from the first (up to day 14) and second (up to day 7) 300 mg SC doses was required. IV, intravenous; MAD, multiple ascending doses; SAD, single ascending doses; SC, subcutaneous

Figure 2

Median serum PF‐06480605 concentration‐time profiles following SAD and MAD doses. Panels show semi‐logarithmic scales. IV, intravenous; MAD, multiple ascending doses; SAD, single ascending doses; SC, subcutaneous

Figure 3

Median total sTL1A in (a) SAD and (b) MAD cohorts. Interquartile ranges are presented in Table S1. IV, intravenous; MAD, multiple ascending doses; SAD, single ascending doses; SC, subcutaneous; sTL1A, soluble tumour necrosis factor α‐like ligand 1A