Exposure-response characterisation of tildrakizumab in chronic plaque psoriasis: pooled analysis of three randomised controlled trials.

AIMS: In this exposure-response analysis, the dosing regimen for tildrakizumab, an antibody for treating moderate-to-severe chronic plaque psoriasis, was determined using data from three randomised controlled trials (P05495/NCT01225731: phase 2b, N=355; reSURFACE 1/NCT01722331: phase 3, N=772; reSURFACE 2/NCT01729754: phase 3, N=1090). METHODS: A maximum drug effect (Emax ) logistic-regression exposure-efficacy model was used to describe the week 12 Psoriasis Area and Severity Index (PASI) responses with average concentration of tildrakizumab during weeks 1-12 (Cavg12 ) as exposure metric. The impact of covariates (eg. body weight, region) was tested. Exposure-safety, longitudinal pharmacokinetic-pharmacodynamic (PK-PD) and risk-benefit analyses were also conducted. RESULTS: At week 12, Emax was estimated at 62.2%, 37.9% and 14.6% of responders for PASI75/90/100, respectively. Exposure-response curves plateaued at exposures >5 mug mL(-1) . Heavier subjects had a lower response rate to placebo as measured by PASI75/90/100 than lighter subjects. PASI100 placebo response was less in subjects with higher baseline PASI score and older age. Simulated week 12 PASI75 increased by 90 kg) may benefit from a higher dose (200-mg Q12W).