Inhaled Anti-IL-4rα Single-domain Antibody Significantly Reduces FeNO in Moderate-to-Severe Asthma Patients: A Phase 2a Proof-of-Concept Study

Abstract Rational: Asthma is a prevalent chronic inflammatory airway disease that poses significant social and economic burdens. Currently, all authorized biologics for asthma treatment are administered systemically. LQ036 is an inhalable, homogeneous, bivalent single-domain antibody (sdAb) for asthma treatment by targeting IL-4Rα. Two Phase I clinical trials have been completed in 112 healthy volunteers from Australia and China, demonstrating a favorable safety profile and excellent tolerability. Notably, no significant differences were observed in the pharmacokinetic profiles between Caucasian and Chinese populations. A dose-dependent pharmacokinetic-pharmacodynamic correlation validated the essential proof-of-mechanism, advancing LQ036 into clinical studies in asthma patients. Methods: This multicenter, randomized, double-blind, placebo-controlled Phase IIa proof-of-concept (POC) study aimed to evaluate the effect of LQ036 (12 mg, once daily via nebulization) on the airway biomarker fractional exhaled nitric oxide (FeNO), by comparing the change from baseline with placebo over a 28-day treatment period and 14-day follow-up. The study participants were adults with T2-high, uncontrolled moderate-to-severe asthma, defined by FEV1% Pred ≥ 40% and < 80%, ACQ-5 ≥ 1.5, blood eosinophils ≥ 150 cells/μL and FeNO ≥ 35 ppb, on the treatment of stable medium-to-high dose ICS plus LABA regimen as the standard of care. Results: A total of 19 patients were randomized into two groups: LQ036 (n=12) and placebo (n=7). In the LQ036 group, the percentage change in FeNO from baseline was -29.8% on Day 7, -40.5% on Day 14, -41.1% on Day 28, and -26.8% on Day 42. Among them, the reduction on Day 14 was statistically significant compared with the placebo group (-9.1%, p < 0.05). Change form baseline in FEV1 was 149 ml on Day 7, 253ml on Day 14, 236 ml on Day 28, and 164 ml on Day 42. No serious adverse events (SAEs) related with LQ036 reported. Notably, the incidence of anti-drug antibodies (ADA) in the LQ036 group was 0%. Conclusions: LQ036 significantly improved the airway inflammation in asthma, as evidenced by a marked inhibition in FeNO. This improvement occurred with a rapid onset as early as Day7 and was sustained throughout at least one month of treatment and two weeks after discontinuation. LQ036 was well tolerated without SAEs or incidence of ADA. These findings provide strong supports for the further clinical development of LQ036, warranting further evaluation of its clinical efficacy and safety in the following clinical trials.