Exploratory pharmacodynamics and efficacy of PF-06817024 in a Phase 1 study of patients with chronic rhinosinusitis and atopic dermatitis

Abstract

PF-06817024 is a humanized antibody against interleukin-33 that has the potential to inhibit type 2 inflammation. An exploratory analysis of the pharmacodynamics and clinical effects of single and repeat doses of PF-06817024 was assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and patients with moderate-to-severe atopic dermatitis (AD), respectively, as part of a Phase 1, first-in-human study. Rhinosinusitis symptoms were improved, and nasal polyps were decreased in size following treatment with PF-06817024 in patients with CRSwNP. In patients with AD, PF-06817024, in aggregate, reduced disease severity and improved symptoms, as demonstrated by greater percentage decrease from baseline in Eczema Area and Severity Index (EASI) scores and reduced pruritus numerical rating scores, compared with placebo. The efficacy in AD appeared to be bimodal with a sub-group of participants exhibiting high levels of improvement (EASI75 and EASI90) for a sustained period of time after dosing. In patients with CRSwNP, a consistent trend of decrease in eosinophil levels was observed in the PF-06817024 group, compared with placebo. Further research would be needed to confirm the clinical benefit and safety of PF-06817024 as a treatment for allergic diseases. Trial registration ClinicalTrials.gov, NCT02743871. Registered 15 April 2016, https://clinicaltrials.gov/study/NCT02743871?term=NCT02743871&rank=1 .

Keywords: Anti-IL-33 antibody; Atopic dermatitis; Biomarkers; Chronic rhinosinusitis with nasal polyps; Efficacy; Pharmacodynamics; Phase 1.

Fig. 1

Percentage change from baseline in efficacy endpoints at Day 61 in patients with CRSwNP (placebo-corrected)^a Note: baseline is defined as the last measurement prior to first dosing. Circle represents LSM of percentage change from baseline in comparing with placebo. The estimate and CI were calculated based on ANCOVA analysis with independent variable of treatment groups and baseline result. Only asthmatic patients completed the ACQ-5. NPS data shown are for bilateral score. Lund-Mackay CT score was assessed by two expert reviewers; scores shown here are those from expert reviewer 1. Bars represent 80% CIs ^an=11 for UPSIT, SNOT-22, NPS, and Lund-Mackay CT score in the PF-06817024 group; n = 7 for ACQ-5 in the PF-06817024 group; n = 9 for UPSIT, SNOT-22, NPS, and Lund-Mackay CT score in the placebo group; and n = 7 for ACQ-5 in the placebo group ACQ-5, 5-item version of the Asthma Control Questionnaire; ANCOVA, analysis of covariance; CI, confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; CT, computerized axial tomography; LSM, least squares mean; NPS, nasal polyp score; SNOT-22, 22-item Sino-nasal Outcome Test;UPSIT, University of Pennsylvania Smell Identification Test

Fig. 2

Longitudinal percentage change from baseline in EASI scores in patients with AD Note: baseline is defined as the last measurement prior to the first dosing. MMRM contains fixed factors of baseline EASI, treatment, study day, inverse study day, treatment by study day, and treatment by inverse study day and random factor of subject AD, atopic dermatitis; CI, confidence interval; EASI, Eczema Area and Severity Index; IV, intravenous; LSM, least squares mean; MMRM, mixed model repeated measures