A phase 1 study investigating DX-2930 in healthy subjects.

Autor:	Chyung Y; Dyax Corp, Burlington, Massachusetts. Electronic address: ychyung@dyax.com., Vince B; Vince & Associates Clinical Research, Overland Park, Kansas., Iarrobino R; Dyax Corp, Burlington, Massachusetts., Sexton D; Dyax Corp, Burlington, Massachusetts., Kenniston J; Dyax Corp, Burlington, Massachusetts., Faucette R; Dyax Corp, Burlington, Massachusetts., TenHoor C; Dyax Corp, Burlington, Massachusetts., Stolz LE; Dyax Corp, Burlington, Massachusetts., Stevens C; Dyax Corp, Burlington, Massachusetts., Biedenkapp J; Dyax Corp, Burlington, Massachusetts., Adelman B; Dyax Corp, Burlington, Massachusetts.
Jazyk:	angličtina
Zdroj:	Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology [Ann Allergy Asthma Immunol] 2014 Oct; Vol. 113 (4), pp. 460-6.e2. Date of Electronic Publication: 2014 Jun 26.
DOI:	10.1016/j.anai.2014.05.028
Abstrakt:	Background: DX-2930 is a human monoclonal antibody inhibitor of plasma kallikrein under investigation for long-term prophylaxis of hereditary angioedema. Objective: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of DX-2930 in healthy subjects. Methods: A single-center, double-blinded study was performed in 32 healthy subjects randomized 3:1 to receive a single subcutaneous administration of DX-2930 or placebo within 1 of 4 sequential, ascending dose cohorts (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 treatment emergent adverse event (AE), occurring at a rate of 25% in the DX-2930- and placebo-treated groups; none were severe and all resolved. There were no serious AEs, discontinuations owing to an AE, or deaths. Two subjects had a severe AE reported as related to treatment by the blinded investigator; the 2 AEs were asymptomatic creatinine phosphokinase elevations of 902 U/L in 1 subject receiving 0.1 mg/kg DX-2930 and 1,967 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 μg/mL and mean elimination half-lives were 20.6, 16.8, 17.6, and 21.2 days. Exploratory biomarker assays, involving ex vivo activation of the kallikrein pathway, showed dose- and time-dependent inhibition of plasma kallikrein, with evidence of sustained bioactivity consistent with the pharmacokinetics profile. Conclusion: A single administration of DX-2930 in healthy subjects up to doses of 3.0 mg/kg was well tolerated without dose-limiting toxicity. Pharmacokinetic and pharmacodynamic data provide evidence for a long-acting biological effect relevant to long-term prophylaxis for hereditary angioedema with C1-inhibitor deficiency. Trial Registration: ClinicalTrials.gov identifier: NCT01923207. (Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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