The full study design is described in the companion publication of safety, tolerability, PK, and PD [18]. Briefly, the assessment of clinical effect and biomarkers of PF-06817024 were exploratory endpoints in a Phase 1, randomized, double-blind, placebo-controlled study that assessed the safety, tolerability, PK, and immunogenicity of PF-06817024 in healthy participants (Part 1), participants with CRSwNP (Part 2), and participants with AD (Part 3) (ClinicalTrials.gov, NCT02743871). The current brief report describes the results of exploratory analyses of signs of the clinical effect of PF-06817024 in participants with CRSwNP and AD. In Part 2 of the study, participants with CRSwNP were randomized (1:1) to receive a single intravenous (IV) dose of PF-06817024 300 mg or placebo. Participants were followed for > 211 days after the single dose, divided into a treatment period of 2 days, a follow-up period of 211 days, and an extended follow-up period thereafter, defined by the PK profile. In Part 3 of the study, participants with moderate-to-severe AD were randomized to receive repeat doses of PF-06817024 or placebo at a ratio of 2:1, although actual recruitment was closer to a ratio of 3:1, resulting in a mixed randomization ratio. The dosing regimen in Part 3 consisted of a single 600 mg IV loading dose, followed by three IV doses of 300 mg every 4 weeks. This dosing regimen was guided by emerging total IL-33 clinical data suggesting that higher and more frequent (monthly) dosing may be needed clinically than that predicted by in vitro antibody affinity assays for continuous, high level, suppression of IL-33 levels; a detailed rationale of the dosing regimens has been provided previously [18]. The defined treatment period was 113 days, with a standard follow-up period of 337 days, and an extended follow-up period thereafter. The extended follow-up period for both parts of the study was necessitated by the extended half-life of PF-06817024 (83–94 days) observed in Parts 1 and 2 of the study. For all parts of this study, blood samples were collected before dosing and at time points specific for the participant cohort as described previously [18]. All parts of this study were participant- and investigator-blinded.

The study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation of Good Clinical Practice Guidelines.

Participants aged 18–65 years with a body mass index (BMI) of 17.5–35 kg/m2 and a total body weight of > 50 kg with a history of CRSwNP were eligible for inclusion if they had: a minimum bilateral nasal polyp score (NPS) of 5 out of a maximum score of 8 and the presence of at least two of the following symptoms prior to screening: nasal blockade/obstruction/congestion, nasal discharge, facial pain/pressure, and reduction or loss of smell; were otherwise healthy (comorbid, controlled asthma with a forced expiratory volume in 1 s [FEV1] > 60% predicted was permitted). Participants were excluded from the study if they had received anti-IgE or anti-IL-5 therapy within 130 days prior to screening, had a 22-item Sino-nasal Outcome Test (SNOT-22) score < 7, or had undergone any nasal surgery within 6 months before screening.

Participants aged between 18 and 75 years with a BMI of 17.5–40 kg/m2 and a total body weight of > 50 kg were eligible for inclusion if they had: a clinical diagnosis of chronic AD (for at least 1 year prior to Day 1) with an inadequate response to treatment with topical medications; moderate-to-severe AD, defined as having an affected body surface area (BSA) ≥ 10%, investigator global assessment (IGA) ≥ 3, and Eczema Area and Severity Index (EASI) score ≥ 12 at screening and baseline visits; were otherwise healthy (comorbid, controlled asthma with an FEV1 > 60% predicted was permitted). Participants were excluded if they had evidence of skin conditions such as psoriasis, seborrheic dermatitis, or lupus; had received systemic corticosteroids within 4 weeks prior to the first dose of the study drug; or had received dupilumab within 4 months of the first dose of the study drug or another anti-IL-4 and/or anti-IL-13 targeted therapies within 6 months of the first dose of the study drug.

The pharmacologic effect of PF-06817024 was assessed by measuring the change from baseline in several serum biomarkers, including IL-5, IgE, chemokine (C-C motif) ligand 17 (CCL17), chemokine (C-C motif) ligand 26 (CCL26), circulating eosinophils, basophils, and ILC2s in participants with CRSwNP; and IgE, CCL17, and high-sensitivity C-reactive protein (hsCRP) in patients with AD.

In addition, exploratory measures of clinical effect of the single dose and multiple doses of PF-06817024 were also assessed in the CRSwNP and AD patient cohorts, respectively. In participants with CRSwNP, Lund-Mackay computerized axial tomography (CT) score [19], NPS [20], University of Pennsylvania Smell Identification Test (UPSIT) [21], the SNOT-22 score [22], and 5-item version of the Asthma Control Questionnaire (ACQ-5; asthmatic patients only) [23] were monitored. In participants with AD, the percentage change from baseline in the total EASI score, EASI50/75/90, affected BSA, IGA, and Scoring Atopic Dermatitis (SCORAD) were monitored. The change from baseline in patient-reported outcomes (PROs), including pruritus numerical rating scale, patient-oriented eczema measure, Dermatology Life Quality Index, Hospital and Anxiety Depression Scale, and ACQ-5 (asthmatic patients only) were also assessed.

All efficacy data were listed and summarized separately by part, and biomarker data were summarized descriptively. For Part 2 in patients with CRSwNP, as these were exploratory endpoints, no formal hypothesis testing was performed in this study. However, post-hoc efficacy and biomarker analyses were conducted, with least squares means (LSMs) and 80% confidence intervals (CIs) calculated based on analysis of covariance with independent variable of treatment groups and baseline result. Binary variables were summarized by the number of responders and the number of participants with data.

In Part 3, a mixed model for repeated measures (MMRM) analysis of change from baseline and percentage change from baseline in EASI scores was performed, with LSMs and 90% CIs presented for Day 113, the pre-specified landmark time point for assessment of clinical effect. The model included percentage change from baseline as the dependent variable and baseline EASI, treatment, study day, inverse study day (1/study day), treatment by study day, and treatment by inverse study day as fixed effects. Study day and inverse study day were included as continuous variables (not as class variables) and used the observed day (not the scheduled day). The MMRM analyses were performed in R using the lme package and included a random subject effect and a first-order autoregressive correlation over time. To understand the data generated by the pre-specified statistical analyses, additional post-hoc analyses were conducted.