HBV test kitchen
How far industry is from assembling a functional cure in HBV
Early results for HBV monotherapies are pointing the way toward combinations that could deliver a functional cure. What remains unknown is how many components, and which ones, will prove necessary to eliminate remnants of the virus that persist on standard of care.
Data on combinations that add a single MOA to standard of care will begin to read out over the next 18 months. More complex combinations, including cocktails combining novel mechanisms, are a few years away.
In the meantime, several companies will be reporting data on monotherapies that could give hints about the contribution different mechanisms could make to a cocktail.
The backbone of all the combination approaches are nucleoside analogs, which are SOC but must be given for a lifetime. These drugs reduce viral DNA in the blood, but they do not eradicate circular DNA (cccDNA) reserves in hepatocytes. Neither do they combat systemic immune suppression caused by HBV surface antigen (HBsAg). As a result, the virus breaks through if treatment is stopped or interrupted.
“I think we could see new drugs out there in the next four to five years that will have a big impact on patients.”
Johnson & Johnson, Roche and Arbutus Biopharma Corp. expect that routing out the virus will require inhibition of all three of these pathways, plus immune stimulation. The initial goal is to get viral DNA and HBsAg to undetectable levels with 12 months of treatment (see “HBV Tool Kit”).
“If you have less reverse transcriptase, less surface antigen and less core, you don’t have the components necessary for the virus to assemble and replicate,” said Lawrence Blatt, co-lead of the Infectious Diseases & Vaccines therapeutic area at Johnson & Johnson’s Janssen Research & Development unit.
“If you can reduce those factors being produced by the virus to block the body’s innate immune response and at the same time stimulate an immune response, you can tip the balance to viral clearance,” he added.
All three companies are still testing the individual components of their quad cocktails in monotherapy studies.
The most advanced is an siRNA therapy from Arbutus that is designed to block viral mRNA translation of HBsAg. It will have Phase II monotherapy data this year and will move into combination trials with SOC this year.
The biotech also plans to start a novel-novel combination trial in 2018.
An alternative to the quad hypothesis holds that a functional cure could be achieved with a simpler approach that adds only one new MOA to SOC.
In this camp are Replicor Inc.