Phase 1 clinical trials of DAS181, an inhaled sialidase, in healthy adults

Abstract

DAS181, (study drug, Fludase®) was developed for treatment of influenza and parainfluenza infections. Delivered by inhalation, DAS181 cleaves sialic acid receptors from respiratory epithelial cells. Treatment of influenza for three days with DAS181 reduced viral shedding. To increase deposition in the upper airways and decrease systemic absorption, the particle size was increased to 10μm. We conducted two Phase I trials with three cohorts, randomized 2:1, active drug to placebo. The initial cohort got a single 20mg dose of DAS181, or placebo; the second, 20mg DAS181 or placebo for 10days, and the third got 20mg of DAS181 or placebo for 3days. Formulations differed slightly in their excipients. Subjects in the 1- and 3-day cohorts completed dosing without serious adverse events. Two subjects in the 10-day cohort stopped at Day 9 after developing respiratory and systemic symptoms, and a third experienced a decrease in FEV1 (Forced Expiratory Volume in 1s) after the 9th dose and a further decline after the 10th dose. Plasma DAS181, in the 10-day cohort, peaked and began falling before the last dose. Antibodies, predominately IgG with neutralizing activity, were detected in 15/18 subjects by Day 30. The highest IgG concentrations were in the 10-day cohort. The respiratory adverse events occurring after seven days and rapid drug clearance during continued dosing are consistent with the induction of DAS181 antibodies. This could preclude use of this medication for longer than seven days or for repeated courses. (These studies have been registered at ClinicalTrials.gov under registration Nos. NCT 00527865 and NCT 01651494.).

Trial registration: ClinicalTrials.gov NCT00527865 NCT01651494.

Keywords: DAS-181; Influenza; Parainfluenza; Sialidase.

Copyright © 2015 Elsevier B.V. All rights reserved.

Figures

Figure 1

CXR of subject 2006 obtained after the 9th dose of DAS181 showing a left lower lobe infiltrate.

Figure 2

IgG and IgA levels in serum of subjects before, 30 days after and 90 days after receiving DAS181 by inhalation for 1, 3 or 10 days. IgG and IgA levels are arbitrary units based on a standard curve of dilutions of a serum with high titers. The lower limit for each assay is shown by the horizontal hatched line: 0.2 for IgG titers and 0.1 for IgA titers. Subject number followed by “P” = placebo recipient Three subjects in the 10-day cohort stopped dosing early: Subject 2007 after the 4th dose for psychiatric symptoms considered to be treatment-unrelated, Subject 2009 (identified by **) after the 9th dose for prolonged wheezing and coughing, and Subject 2006 (identified by *) after the 9th dose for a hypersensitivity pneumonitis syndrome.