Nieves Velez de Mendizabal(1), Emmanuel Chigutsa(1), Michael Heathman(1), Siak-Leng Choi(2), Laiyi Chua(2), Stuart Friedrich(1), Kimberley Jackson(3)
(1) Eli Lilly and Company, Indianapolis, IN, USA; (2) Lilly-NUS Centre for Clinical Pharmacology, Singapore; (3) Eli Lilly and Company, Windlesham UK
Objectives: The Psoriasis Area and Severity Index (PASI) score is a clinical tool for evaluating the severity and extent of psoriasis and the score ranges from 0 (no disease) to 72 (most severe disease). Ixekizumab is a monoclonal antibody that selectively binds and neutralizes interleukin 17A and has shown high levels of efficacy in the treatment of psoriasis [1]. The aim of this work is to describe and quantify the effect of ixekizumab on the PASI percent improvement from baseline scores (PASI 50/75/90/100) over time in patients with moderate to severe plaque psoriasis using a longitudinal PKPD model.
Methods: Data up to Week 32 from a Phase 2 study (N=141 patients), and data up to Week 60 from a Phase 3 study (N=1296) were included in the analysis. Phase 2: Ixekizumab was administered subcutaneously (SC) at doses from 10 to 150 mg at weeks 0, 2, 4, 8, 12, and 16. Phase 3: Ixekizumab 80mg SC was dosed every 2 or 4 weeks (Q2W or Q4W) during an induction period (up to Week 12). A starting dose of 160 mg was administered at Week 0. Responders to ixekizumab at Week 12 were randomly assigned to 80 mg Q4W, Q12W, or placebo, while nonresponders (ixekizumab and placebo) received 80mg Q4W. Responders to placebo remained on placebo or until relapse when they were switched to 80mg Q4W. Sequential PKPD model was conducted using NONMEM 7.3. Posthoc ixekizumab concentrations and area under the curve (AUC) estimates from a population PK model were used as the exposure inputs to an indirect latent variable response PKPD model.
Results: The developed model is able to simultaneously describe PASI 50/75/90/100 over time. The drug effect was best described by two different components: (i) an Emax model on the Type III indirect latent variable response model, with EC50=1.47 µg/mL; (ii) a direct effect of AUC on the logit model for cumulative probabilities (proportional odds model) defined as EMAXD×log(AUC+1) where EMAXD=0.419. The placebo effect was included as a direct effect on the logit model with a sigmoidal time function, described with parameters, PL50=1.67 weeks and PLMAX=1.23. The PKPD model described the data well when evaluated using the treatment adaptive simulations which mimicked the complexity of the Phase 3 adaptive study design.
Conclusions: The developed latent variable indirect response PKPD model well described the time course of PASI percent improvement in patients with moderate to severe plaque psoriasis.
References:
[1] Griffiths CE, et al. UNCOVER-2 and UNCOVER-3 investigators. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015 Aug 8;386(9993):541-51.
Reference: PAGE 25 () Abstr 6042 [www.page-meeting.org/?abstract=6042]
Poster: Drug/Disease modeling - Other topics