A phase 1, first-in-human, open label, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of stabilized isoamyl nitrite nasal spray in healthy adult participants.

Abstract

Stabilized isoamyl nitrite (SIAN) is a novel small molecule, therapeutic candidate for the treatment of cyanide poisoning. SIAN improves survival and has a demonstrated pharmacodynamic (PD) effect in cyanide challenged nonhuman primates. Here, we report results of phase 1, first-in-human study evaluating the safety, tolerability, pharmacokinetic (PK), and PD of SIAN nasal spray in healthy human subjects (NCT05194358). SIAN was intranasally administered in ascending doses at 2 sites in Texas and Tennessee in the United States. A total of 47 subjects were enrolled across 7 dose cohorts evaluating single doses from 20 to 300 μL. Following the dosing of sentinels in each cohort, safety, PK, and PD data were interpreted by a Safety Monitoring Committee to permit dosing of additional subjects in the cohort or escalation to the next dose level. Isoamyl alcohol peak plasma concentrations were reached within 2 minutes and were highest after a 250 μL dose (125 μL/nostril). This trend was also observed for PD parameters, including a metHB peak at 2 minutes with associated increase in heart rate and systolic and diastolic blood pressure. SIAN was generally well tolerated, no serious or severe drug-related effects were observed, and there were no clinically significant changes in vitals or laboratory parameters. We conclude that SIAN, a potential new treatment for cyanide poisoning, was safe, well tolerated, and showed a relationship between PK and PD parameters at the doses tested. SIGNIFICANCE STATEMENT: This is the first-in-human clinical study to evaluate intranasal stabilized isoamyl nitrite, which was shown to be safe, well tolerated, and to elicit a measurable pharmacokinetic and pharmacodynamic response in healthy human subjects at the doses tested. This study paves the way for investigating stabilized isoamyl nitrite further as a potential emergency treatment for cyanide poisoning.