DAS181 Biology

Sialic Acid Biology

Sialic acids are a type of nine-carbon sugars that occur at the end of sugar chains attached to glycoproteins, glycolipids, and glycosaminoglycans.  The most common sialic acid in humans is N-acetylneuraminic acid (Neu5Ac) and its derivatives, and it can be connected to sugar chains by several different linkages, with α2,3- and α2,6-linkages particularly relevant for human infectious disease.  Certain viruses and bacteria can bind to sialic acids as a requirement for entry and infection of cells.

Influenza viruses typically have preference for binding to sialic acids with either α2,3- or α2,6-linkages, with the specific preference of one over the other dependent on the influenza subtype.  Parainfluenza viruses show selectivity with parainfluenza virus type 1 (PIV1) recognizing sialic acids with α2,3-linkages, and parainfluenza virus type 3 (PIV3) recognizing sialic acids with α2,3- or α2,6-linkages.

A New Class of Antiviral

Ansun recognized the difficulty of targeting respiratory viral infections by traditional direct-acting antivirals where rapid viral mutation may result in resistance and the loss of treatment activity. A whole new class of drug was needed. In response we developed an innovative approach for fighting respiratory viruses by targeting the host receptor instead of the virus.

This has led to the creation of DAS181, a first-in-class recombinant sialidase protein designed to remove sialic acids located on the surface of epithelial cells lining the human respiratory tract.  These sialic acids are naturally present on cell surfaces and are needed by some viruses for viral entry into cells. Cleavage of sialic acids lining the respiratory tract, while harmless to the patient, destroys a factor critical to viral infection. It inactivates the mechanism for viral entry and infection, interrupting the virus lifecycle and giving patients the chance to recover.

DAS81 is a bifunctional recombinant protein fusing a cellular anchoring domain to an sialidase enzymatic domain. The sialidase domain cleaves sialic acids while the anchoring domain is intended to improve retention on cell surfaces. DAS181 hydrolyzes sialic acids with alpha-2,3, alpha-2,6, and alpha-2,8 linkages, and offers potential stoichiometric advantage over antagonist treatments. Cleavage of sialic acids is non-reversible but temporary because host tissues regenerate sialic acids over the course of days.

While influenza and parainfluenza viruses are known to exhibit specificity for sialic acids with different linkages resulting in host tropism, DAS181 activity cleaves the relevant linkages for all human PIV and influenza viruses. This host-targeting mechanism of action is a novel, first-in-class potential therapy meeting a substantial unmet medical need.

Parainfluenza viruses (PIV) are dependent on binding to sialic acids to initiate infection of ciliated cells in the upper respiratory tract.  Replication in these cells can result in the spread of the infection to neighboring cells along the the respiratory tract.  PIV infection is the second most common cause acute respiratory tract infections among children less than 5 years old and it is estimated to cause approximately 18% of all cases of croup.  There is no approved treatment for childhood croup by PIV.  Among healthy adults, PIV infections are usually mild, self-limited upper respiratory tract infections characterized by typical cold symptoms.  However, in immunocompromised patients the virus is much more likely to progress to infect the lower respiratory tract.  In these patients, up to 50% will develop viral pneumonia where mortality rates are reported to range from 25% to 55% within 30 days.  Presently, there is neither a vaccine to prevent nor a drug to treat PIV infection.

DAS181 is formulated for delivery to the pulmonary surface by dry powder inhalation or nebulization.  In a Phase 2 clinical trial for the treatment of lower tract PIV infection in immunocompromised patients, promising results were observed in an objective and clinically meaningful measure of lung function.  These data are the basis for the U.S. FDA granting Breakthrough Therapy designation to DAS181.  DAS181 is currently being evaluated in a Phase 3 trial in the same population.