Elarekibep, an inhaled Anticalin protein, targets IL-4Rα locally: first-in-human randomized phase 1 trials of a novel potential therapeutic class in asthma

Background Elarekibep (AZD1402/PRS-060) is an Anticalin, a new class of inhaled therapeutic proteins, which has been engineered to inhibit interleukin-4 receptor α-subunit (IL-4Rα) signalling, a key target in asthma. Methods Two phase 1 randomized, first-in-human, dose-escalating, single-blind studies (NCT03384290; NCT03574805) investigated single ascending doses (SADs) or multiple ascending doses (MADs) of elarekibep compared with placebo. In the SAD study, healthy participants received a single inhaled dose of elarekibep 0.1–160 mg, intravenous doses of 1 mg or 2 mg, or matched placebo. In the MAD study, participants with mild asthma and elevated fractional exhaled nitric oxide (FeNO) received inhaled doses of elarekibep 0.2–60 mg or placebo twice daily for 10 or 17 days (single dose on day 10 in all but one cohort), continuously or intermittently. Results In total, 148 participants were enrolled across both studies. No safety concerns were reported. Treatment-emergent adverse events were experienced by 34.7% (elarekibep, 35.2%; placebo, 33.3%) and 81.6% (elarekibep, 75.9%; placebo, 95.5%) of SAD and MAD study participants, respectively. Elarekibep was absorbed after inhalation, with dose-related increases in systemic exposure detectable with doses greater than or equal to 6 mg. In both studies, systemic exposure resulted in decreased levels of phosphorylated signal transducer and activator of transcription 6, a biomarker for systemic IL-4Rα target engagement. In the MAD study, rapid reductions of FeNO were demonstrated with doses greater than or equal to 2 mg, indicating pulmonary target engagement. Conclusions Elarekibep was well tolerated in both studies and demonstrated pulmonary and systemic target engagement. Elarekibep was investigated further in a phase 2a study (NCT04643158). Trial registration NCT03384290. Registered 26 November 2017, https://clinicaltrials.gov/ct2/show/NCT03384290 . NCT03574805. Registered 2 July 2018, https://clinicaltrials.gov/ct2/show/NCT03574805 .