A Safety Evaluation of DAS181, a Sialidase Fusion Protein, in Rodents

Abstract

DAS181 is a novel inhaled drug candidate blocking influenza virus (IFV) and parainfluenza virus (PIV) infections through removal of sialic acid receptors from epithelial surface of the respiratory tract. To support clinical development, a 28-day Good Laboratory Practices inhalation toxicology study was conducted in Sprague-Dawley rats. In this study, achieved average daily doses based on exposure concentrations were 0.47, 0.90, 1.55, and 3.00 mg/kg/day of DAS181 in a dry powder formulation. DAS181 was well tolerated at all dose levels, and there were no significant toxicological findings. DAS181 administration did not affect animal body weight, food consumption, clinical signs, ophthalmology, respiratory parameters, or organ weight. Gross pathology evaluations were unremarkable. Histological examination of the lungs was devoid of pulmonary tissue damage, and findings were limited to mild and transient changes indicative of exposure and clearance of a foreign protein. DAS181 did not show any cytotoxic effects on human and animal primary cells, including hepatocytes, skeletal muscle cells, osteoblasts, or respiratory epithelial cells. DAS181 did not cause direct or indirect hemolysis. A laboratory abnormality observed in the 28-day toxicology study was mild and transient anemia in male rats at the 3.00 mg/kg dose, which is an expected outcome of enhanced clearance of desialylated red blood cells resulting from systemic exposure with DAS181. Another laboratory observation was a transient dose-dependent elevation in alkaline phosphatase (ALP), which can be attributed to reduced ALP clearance resulting from increased protein desialylation due to DAS181 systemic exposure. These laboratory parameters returned to normal at the end of the recovery period.

DAS181 treatment of severe parainfluenza type 3 pneumonia in a lung transplant recipient

“…Our patient tolerated DAS181 well. During treatment with DAS181, it is common to see a mild increase in alkaline phosphatase levels, thought to be related to delayed clearance secondary to systemic protein desialylation ; this was seen in our patient, and promptly resolved after discontinuation of the drug. No other toxicity was evident.…”

“…DAS181, a novel sialidase fusion protein, cleaves sialic acid‐containing receptors used by PIV and influenza to bind to respiratory epithelial cells . DAS181 has in vitro and in vivo activity against both PIV and influenza , and has been shown to be safe in an animal model and in phase‐1 human trials. Recently, Chen et al.…”

The use of sialidase therapy for respiratory viral infections

“…Repeated daily exposures of inhaled DAS181 for 28 days at achieved doses of up to 3.00 mg/kg/day were well tolerated, and clinical signs were not affected by treatment with DAS181. Minimal but significant decreases in red blood cells, haematocrit and hemoglobin were identified, together with an increased reticulocyte count, in keeping with a mild anemia; systemic absorption from the respiratory tract was estimated at 2% (Larson et al, 2011). In this A B study there was also a 3-fold increase in alkaline phosphatase (ALP) from the liver, which was attributed to diminished clearance, owing to competition for the asialoglycoprotein receptor.…”

Clinical potential of DAS181 for treatment of parainfluenza‐3 infections in transplant recipients

“…The patient had an elevated PTT during his treatment course to a maximum of 49.2 s 2 days after completing DAS181 treatment. His alkaline phosphatase (ALK) was also transiently elevated to a maximum of 184 units/L 5 days after starting DAS181 therapy, a known phenomenon resulting from a decreased rate of ALK clearance . No other adverse effects of DAS181 treatment were observed during his treatment course or at his subsequent follow‐up visits.…”