Abstract
Aims
Aloxistatin (E64d) is a membrane‐permeable cysteine protease inhibitor prodrug that is converted by esterases to the active metabolite E64c (loxistatin). This first‐in‐human study evaluated the safety, tolerability and pharmacokinetics of single ascending doses of inhaled E64d in healthy volunteers.
Methods
In this randomized, double‐blind, placebo‐controlled phase 1 trial, 47 healthy male volunteers contributed 48 study participations across six dose cohorts. Thirty‐six treatment assignments were to E64d and 12 to placebo. Study medication was administered by inhalation using a breath‐triggered mesh nebulizer. Safety assessments included adverse events, pulmonary function, gas exchange, cardiovascular parameters, and laboratory variables. Plasma concentrations of E64d and E64c were characterized following inhalation.
Results
No serious adverse events occurred, no adverse event was classified as severe and no participant discontinued because of an adverse event. Ten adverse events occurred following E64d and four following placebo; one mild event of mucosal dryness was considered treatment related. No clinically relevant changes were observed in pulmonary, cardiovascular, or laboratory safety assessments. E64d appeared rapidly and transiently in plasma, with a median T
max
of 3 min. E64c showed sustained systemic exposure, with median T
max
values of approximately 15–20 min and an elimination half‐life of approximately 30–40 min across evaluable dose levels. Dose proportionality was not formally assessed.
Conclusions
Single ascending doses of inhaled E64d were generally well tolerated in healthy male volunteers. Inhalation resulted in rapid, transient systemic exposure to E64d followed by measurable formation of E64c. These findings provide a safety and pharmacokinetic basis for further investigation of inhaled aloxistatin.