Efficacy and safety of tozorakimab in moderate-to-severe atopic dermatitis: A Phase 2a randomized controlled trial (FRONTIER-2)

Abstract

Background: Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and eczematous lesions. Tozorakimab is a high-affinity human monoclonal antibody that neutralizes interleukin-33, a broad-acting alarmin cytokine that is over-expressed in keratinocytes of patients with AD.

Objectives: This Phase 2a study (FRONTIER-2; NCT04212169) evaluated the safety and efficacy of tozorakimab in adults with moderate-to-severe AD.

Methods: FRONTIER-2 was a randomized, placebo-controlled, parallel-group, double-blind study conducted from 9 December 2019 to 20 September 2022 at 32 centres across six countries. Patients were randomized 3:1:1:3 to receive placebo, tozorakimab 60 mg, tozorakimab 300 mg or tozorakimab 600 mg by subcutaneous injection once every 4 weeks for four doses. The primary endpoint was percentage change from baseline to Week 16 in the Eczema Area and Severity Index (EASI) score in patients treated with tozorakimab versus placebo. Secondary outcomes included EASI-75 responders (patients achieving ≥75% reduction from baseline in EASI score), Investigator's Global Assessment (IGA) responders (patients achieving an IGA score of 0 or 1), pharmacokinetics, immunogenicity and safety.

Results: Overall, 148 patients were randomized. There was no statistically significant difference in the primary endpoint (60 mg difference of 1.3 [90% confidence interval (CI): -13.7, 16.2], p = 0.888; 300 mg: difference of 5.9 [90% CI: -10.4, 22.1], p = 0.549; 600 mg: difference of - 1.7 [90% CI: -13.4, 10.0], p = 0.807). The proportion of EASI-75 and IGA 0/1 responders at Week 16 was numerically higher in the tozorakimab 600 mg group than in the placebo group (EASI-75: 18.2% vs. 7.1%, p = 0.094; IGA 0/1: 9.1% vs. 1.8%, p = 0.113). Serum pharmacokinetics were dose-dependent, immunogenicity incidence was low and tozorakimab was well tolerated.

Conclusions: FRONTIER-2 did not show a statistically significant difference in the primary endpoint for tozorakimab compared with placebo. However, numerical increases in responder rates were observed.

FIGURE 1

Study design flowchart. The study comprised a screening and TCS/TCI washout period of up to 4 weeks, a 16‐week treatment period and an 8‐week follow‐up period. Q4W, every 4 weeks; SC, subcutaneously; TCI, topical calcineurin inhibitor; TCS, topical corticosteroid.

FIGURE 2

Adjusted mean percentage change from baseline in EASI up to Week 16. Data are from a mixed model with repeated measures analysis, excluding data after study withdrawal or use of rescue therapy (ITT population). EASI, Eczema Area and Severity Index; ITT, intention‐to‐treat; SE, standard error.