Harnessing the Power of RNAi Gene Silencing in a Quest of a Cure for Chronic Hepatitis B, and the HBV KnockDown blog written by Dirk Haussecker, who believes it’s about time everyone got serious about a functional cure for hepatitis B.
As I was reading the latest PK-PD study by Gilead on its lead experimental chronic HepB drug candidate GS-9620 (Fosdick et al. 2013), it finally dawned on me that much-touted GS-9620 has been designed to be nothing more than a better tolerated, more convenient version of an already existing treatment option, recombinant interferon. GS-9620 is therefore an example of the typical incrementalist Big Pharma value creation strategy. By contrast, if successful, an HBsAg knockdown approach such as with Arrowhead’s ARC520 would bring to healthcare providers and patients an entirely new, desperately needed treatment option as the field has become stuck with interferons and RT inhibitors for years.
GS-9620 checks a number of boxes for an interferon-better
Interferons for the treatment of chronic HepB and HepC is widely regarded as a mixed blessing. In light of its very poor tolerability, including flu-like symptoms and depression, patients often opt not to be potentially cured instead of suffering through a year or so of feeling just miserable. Of course, it does not help that after all this, the prospects of a (functional) cure still remain depressingly low in the case of HepB, on the order of 10% for the gold standard HBsAg seroconversion.
Gilead is developing the orally administered, small molecule toll-like receptor 7 (TLR7) agonist GS-9620 in order to provoke natural interferon production along the GI-liver axis without causing systemic exposures with interferon. It is the systemic, body-wide actions of interferon that are responsible for its poor tolerability.
This is supported by the PK-PD data in Fosdick et al. that show that while GS9620 is efficiently taken up in the GI tract, it does not make it out of the liver into the systemic circulation. Moreover, despite local interferon production somewhere along the GI-liver tract, interferon itself seems to be largely contained locally as long as there has not been too much stimulation. Accordingly, it should be possible to get some of the beneficial interferon effects where it is needed (the liver) without the detrimental systemic exposure.
As a TLR7-specific agonist, GS9620 is also thought to avoid triggering the type of pro-inflammatory cytokines that you might expect from TLR activation. In particular, you would want to steer clear of TNF-alpha to avoid tissue damage and hypersensitivity reactions. Indeed, TNF-alpha is hardly induced in monkeys and humans.
On a related note, the data supporting that TLR7-agonism at least in primates should specifically induce interferon and not TNF-alpha is also good news to efforts aiming to combine TLR agonism and RNAi gene knockdown as RNA is the natural ligand for TLR7. I do not predict that this will happen, nor suggest that Arrowhead (or Tekmira) should go down that route, but you could imagine a modified ARC520 with intentional TLR7 agonism, thus combining the two anti-HBV mechanisms.
Human studies suggest narrow therapeutic window
While the theory behind GS-9620 is attractive and the preclinical data apparently supportive of it, the clinical experience thus far suggests that the development of GS-9620 will not be an easy one. In particular, at least 2mg of the drug were required to be able to detect two sensitive biomarkers for interferon production, OAS1 and MX1 (Lopatin et al. 2013). The assumption here is that you need to be able to observe OAS1 and MX1 in order to have an interferon benefit in the liver.
However, as doses were escalated, systemic interferon was detected in the trial subjects starting at 8mg and coincided with the expected side effects. This means that the therapeutic index for GS-9620 may be as narrow as 2-6mg. Considering not only the inter-species, but also the considerable intra-species variability of TLR biology in humans, it remains to be seen whether the therapeutic window will be narrowing even further following large multi-national studies.
More value for innovation
Ultimately, I do feel that GS-9620 may incrementally enhance the treatment experience for chronic HepB patients: increased tolerability and convenience (oral vs injectable), but likely only slightly increased cure rates due to improved compliance. This would certainly justify a price tag exceeding that of current interferons. However, when comparing it to an agent like ARC520 which could transform the treatment of chronic HepB, it is difficult to see how the two agents would be priced at the same level.
The issue is not just limited to cost, but extends to potential regulatory incentives, including accelerated approval and breakthrough designation. Don’t expect an orphan designation for a chronic HepB drug though!
And from a business development perspective, just the ability alone of ARC520 to rapidly and profoundly down-regulate HBsAg should make it an attractive candidate to be paired with other HepB agents, including Gilead’s GS-9620.