A phase 1 study investigating DX-2930 in healthy subjects

Abstract

Background: DX-2930 is a human monoclonal antibody inhibitor of plasma kallikrein under investigationfor long-term prophylaxis of hereditary angioedema. Objective: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of DX-2930 in healthysubjects. Methods: A single-center, double-blinded study was performed in 32 healthy subjects randomized 3:1 toreceive a single subcutaneous administration of DX-2930 or placebo within 1 of 4 sequential, ascending dosecohorts (n = 8 each): 0.1, 0.3, 1.0, or 3.0 mg/kg. Results: No dose-limiting toxicity was observed. Headache was the most commonly reported treatmentemergent adverse event (AE), occurring at a rate of 25% in the DX-2930- and placebo-treated groups; nonewere severe and all resolved. There were no serious AEs, discontinuations owing to an AE, or deaths. Twosubjects had a severe AE reported as related to treatment by the blinded investigator; the 2 AEs wereasymptomatic creatinine phosphokinase elevations of 902 U/L in 1 subject receiving 0.1 mg/kg DX-2930 and1,967 U/L in 1 subject receiving placebo. For the 0.1-, 0.3-, 1.0-, and 3.0-mg/kg dose groups, respectively,mean maximum plasma concentrations were 0.6, 1.4, 5.6, and 14.5 mg/mL and mean elimination half-liveswere 20.6, 16.8, 17.6, and 21.2 days. Exploratory biomarker assays, involving ex vivo activation of the kallikreinpathway, showed dose- and time-dependent inhibition of plasma kallikrein, with evidence of sustainedbioactivity consistent with the pharmacokinetics profile. Conclusion: A single administration of DX-2930 in healthy subjects up to doses of 3.0 mg/kg was welltolerated without dose-limiting toxicity. Pharmacokinetic and pharmacodynamic data provide evidencefor a long-acting biological effect relevant to long-term prophylaxis for hereditary angioedema withC1-inhibitor deficiency.Trial Registration: ClinicalTrials.gov identifier: NCT01923207.