D3.418 - A Phase 1b Study of Lesigercept, a Long-acting High-affinity IgETrap-Fc Fusion Protein: Safety, Tolerability, PK, and PD in Atopic Healthy and Allergic Subjects

IgE-mediated pathways are key drivers of allergic inflammation, and therapeutic strategies that more effectively neutralize free IgE may provide enhanced clinical benefit. Lesigercept has shown marked and durable suppression of serum-free IgE in atopic subjects and patients with chronic spontaneous urticaria. This Phase 1b study aimed to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of lesigercept in atopic healthy subjects and subjects with allergic diseases.

In this Phase 1b study, healthy subjects with atopy, with or without mild allergic diseases, were enrolled into Cohorts 1–4. Subjects were randomized into sequential cohorts: Cohorts 1, 2, and 4 received lesigercept (0.75 mg/kg Q2W, 3 mg/kg Q4W, and 6 mg/kg Q8W, respectively) or placebo in a 6:1 ratio; Cohort 3, with high baseline total IgE, received lesigercept 6 mg/kg Q4W, placebo, or omalizumab 300 mg Q4W in a 6:1:6 ratio. Cohort 5 enrolled subjects with moderate-to-severe atopic dermatitis and received lesigercept 6 mg/kg Q2W or placebo in a 2:1 ratio, to explore clinical and PD effects of the lesigercept in atopic dermatitis. All cohorts were followed for a total of 141 days.

A total of 46 subjects were enrolled, of whom 41 completed the study. Baseline characteristics were well-balanced across treatment groups. In Cohorts 1-4, treatment-related adverse events (TRAEs) occurred in 8.0% (2/25), 33.3% (2/6) and 40.0% (2/5) of subjects in the lesigercept, omalizumab and placebo group, respectively. In Cohort 5, TRAEs occurred in 33.3% (2/6) of the lesigercept group, with no events occurring in the placebo group. No discontinuations due to adverse events or drug-related serious adverse events occurred. Following multiple administrations, lesigercept exposure increased dose-dependently across dose groups, in line with previous observations. Across all cohorts, lesigercept showed a dose-dependent decrease in serum free IgE levels and a tendency toward longer free IgE suppression with increasing dose levels. In Cohort 3, the median duration during which serum free IgE levels remained below 25 ng/mL was 15 days with lesigercept, compared to none (0 days) with placebo and omalizumab (both p < 0.05).

Lesigercept demonstrated a favorable safety profile as well as therapeutic potential with greater and longer-lasting suppression of serum-free IgE levels than omalizumab after multiple doses, consistent with prior clinical trials.