Mining the negatives
Arrowhead mined its non-responder data and found its next HBV drug candidate
By investigating why its discontinued siRNA candidate against hepatitis B caused only weak responses in certain patients, Arrowhead Pharmaceuticals Inc. has upended a dogma about the virus’ genetics that has been clouding drug design and developed a new therapeutic strategy it plans to take to the clinic next year.
The findings not only provide a case study for finding new opportunities in non-responder populations, but highlight yet another example of a field making incorrect assumptions based on the limitations of its most accessible animal models.
In a study published in Science Translational Medicine last month, Arrowhead synthesized data from its Phase II trial of ARC-520, an siRNA designed to degrade the entire transcriptome of wild-type hepatitis B virus (HBV), and a companion study of the compound in chimpanzees.
Arrowhead COO Bruce Given told BioCentury the company decided to launch the chronically infected chimpanzee study alongside the clinical trial to help it dissect the molecular mechanisms behind patient responses and non-responses.
The clinical study’s primary endpoint was depth and duration of HBsAg reduction through day 85.
Christine Esau, director of translational biology at the RNA medicines company Arcturus Therapeutics Inc., told BioCentury HBsAg reduction has been the main goal of nucleic acid-based HBV therapies. “HBsAg is one of the primary mechanisms the virus uses to suppress the immune response, and it has been undruggable using small molecules so far.”
In the Phase II trial, patients who were treatment-naïve and tested positive for a different HBV antigen, HBeAg, achieved