TY - JOUR
T1 - Phase 1 clinical trials of DAS181, an inhaled sialidase, in healthy adults
AU - Zenilman, Jonathan M.
AU - Fuchs, Edward J.
AU - Hendrix, Craig W.
AU - Radebaugh, Christine
AU - Jurao, Robert
AU - Nayak, Seema U.
AU - Hamilton, Robert G.
AU - McLeod Griffiss, J.
N1 - Funding Information:
This work was supported by Public Health Service Contract No. HHSN272200800026 from the National Institute of Allergy and Infectious Diseases, J.McL.Griffiss, PI. Dr. Jeffrey Blumer reviewed the manuscript and provided excellent advice.
Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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 10 μm. We conducted two Phase I trials with three cohorts, randomized 2:1, active drug to placebo. The initial cohort got a single 20 mg dose of DAS181, or placebo; the second, 20 mg DAS181 or placebo for 10 days, and the third got 20 mg of DAS181 or placebo for 3 days. 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 1 s) 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.)
AB - 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 10 μm. We conducted two Phase I trials with three cohorts, randomized 2:1, active drug to placebo. The initial cohort got a single 20 mg dose of DAS181, or placebo; the second, 20 mg DAS181 or placebo for 10 days, and the third got 20 mg of DAS181 or placebo for 3 days. 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 1 s) 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.)
KW - DAS-181
KW - Influenza
KW - Parainfluenza
KW - Sialidase
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U2 - 10.1016/j.antiviral.2015.09.008
DO - 10.1016/j.antiviral.2015.09.008
M3 - Article
C2 - 26391974
AN - SCOPUS:84942859853
VL - 123
SP - 114
EP - 119
JO - Antiviral Research
JF - Antiviral Research
SN - 0166-3542
ER -