3:21 PM
 | 
Oct 12, 2017
 |  BC Innovations  |  Targets & Mechanisms

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 a strong reduction in HBsAg, as did HBeAg-positive chimpanzees in the companion study. However, patients who were previously treated with nucleoside/nucleotide viral replication inhibitors (NUCs), and patients and chimpanzees who had lost expression of HBeAg, showed limited HBsAg reductions. HBeAg loss can be a consequence of host viral immunity.

"The whole field was thinking that the target was cccDNA, and that's where we all were focused. But it turned out that the integrated DNA was an important source of HBsAg, and in some patients, maybe the vast majority of the HBsAg they make."

Bruce Given, Arrowhead

The key finding in the paper was that HBeAg-negative chimpanzees had low levels of covalently closed circular DNA (cccDNA) -- minichromosomes that were thought to be the primary source of HBV proteins, including HBsAg. Instead, they expressed HBsAg through a truncated version of the virus that had integrated into the host genome, a phenomenon that had been hinted at in the literature but largely ignored by the field.

Arrowhead discovered that transcripts expressed from the integrated DNA lacked regions needed for targeting by ARC-520, enabling the company to develop a new siRNA that could get around the problem.

“The whole field was thinking that the target was cccDNA, and that’s where we all were focused. But it turned out that the integrated DNA was an important source of HBsAg, and in some patients, maybe the vast majority of the HBsAg they make,” said Given....

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