Safety and pharmacokinetics of inhaled aloxistatin: A first‐in‐human phase 1 dose escalation trial
Year: 2026
Type: article
Study designs: Randomized Controlled Trial, Clinical Trial
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.
DOI: 10.1002/bcp.70858
Authors: Sebastian Fähndrich, Franziska Friedrich, Daniel Soriano, Jona Gjeloshi, Björn C. Frye, Xuan Phuoc Nguyen, Lydia Herbstritt, Caroline von Spee‐Mayer, Britta Lang, Fabrice Nollevaux, Andreas Hoheisel, Dorothee Winterberg, Armin Braun, Thomas Epting, Christine Contini, Karl Winkler, Thomas Reinheckel, Franziska C. Trudzinski, Gernot Rohde, Daiana Stolz, Robert Bals, Martin J. Hug, Sebastian Wirtz, Christoph Peters, Carolin Jenkner
Institutions: University of Freiburg, University Medical Center Freiburg, Novadip (Belgium), Fraunhofer Institute for Toxicology and Experimental Medicine, German Center for Lung Research, Philipps University of Marburg, Universitätsklinikum Gießen und Marburg, Helmholtz Centre for Infection Research, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,780
OpenAlex ID: W7219595039