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Saturday, November 2, 2013 Gilead Lead Chronic HepB Candidate GS-9620 Conceived as a More Patient-Friendly Interferon
As I was reading the latest PK-PD study by Gilead on its lead experimentalchronic HepB drug candidate GS-9620 (Fosdick et al. 2013), itfinally dawned on me that much-touted GS-9620 has been designed to be nothing more than abetter tolerated, more convenient version of an already existing treatmentoption, recombinant interferon. GS-9620is therefore an example of the typical incrementalist Big Pharma value creation strategy. By contrast, if successful, an HBsAgknockdown approach such as with Arrowhead’s ARC520 would bring to healthcareproviders and patients an entirely new, desperately needed treatment option asthe field has become stuck with interferons and RT inhibitors for years.
GS-9620 checks a numberof boxes for an interferon-better
Interferons for the treatment of chronic HepB and HepC is widely regarded as a mixedblessing. In light of its very poortolerability, including flu-like symptoms and depression, patients often opt not to be potentially cured instead of suffering through a year or soof feeling just miserable. Of course, it does not helpthat after all this, the prospects of a (functional) cure still remain depressinglylow in the case of HepB, on the order of 10% for the gold standard HBsAg seroconversion.
Gilead is developing the orally administered, small moleculetoll-like receptor 7 (TLR7) agonist GS-9620 in order to provoke naturalinterferon production along the GI-liver axis without causing systemicexposures with interferon. It is the systemic, body-wide actions of interferon that are responsiblefor its poor tolerability.
This is supported by the PK-PD data in Fosdick et al. that show that while GS9620 isefficiently 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 asthere has not been too much stimulation. Accordingly, it should be possible to get some of the beneficial interferoneffects where it is needed (the liver) without the detrimental systemicexposure.
As a TLR7-specific agonist, GS9620 is also thought to avoidtriggering the type of pro-inflammatory cytokines that you might expect fromTLR activation. In particular, you would wantto steer clear of TNF-alpha to avoidtissue damage and hypersensitivity reactions. Indeed, TNF-alpha is hardly induced in monkeys and humans.
On a related note, the data supporting that TLR7-agonism atleast in primates should specificallyinduce interferon and not TNF-alpha is also good news to efforts aiming tocombine TLR agonism and RNAi gene knockdown as RNA is the natural ligand forTLR7. I do not predict that this willhappen, nor suggest that Arrowhead (or Tekmira) should go down that route, but you couldimagine a modified ARC520 with intentional TLR7 agonism, thus combining the two anti-HBV mechanisms.
Human studies suggestnarrow therapeutic window
While the theory behind GS-9620 is attractive and thepreclinical data apparently supportive of it, the clinical experience thus farsuggests that the development of GS-9620 will not be an easy one. In particular, at least 2mg of the drug wererequired to be able to detect two sensitive biomarkers for interferonproduction, OAS1 and MX1 (Lopatin et al. 2013). The assumptionhere is that you need to be able to observe OAS1 and MX1 in order to have aninterferon benefit in the liver.
However, as doses were escalated, systemic interferon wasdetected in the trial subjects starting at 8mg and coincided with the expected sideeffects. This means that thetherapeutic index for GS-9620 may be as narrow as 2-6mg. Considering not only the inter-species, butalso the considerable intra-species variability of TLR biology in humans, itremains to be seen whether the therapeutic window will be narrowing evenfurther following large multi-national studies.
More value forinnovation
Ultimately, I do feel that GS-9620 may incrementally enhance the treatment experience for chronic HepBpatients: increased tolerability and convenience (oral vs injectable), butlikely only slightly increased cure rates due to improved compliance. This would certainly justify a price tagexceeding 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 bepriced at the same level.
The issue is not just limited to cost, but extends topotential regulatory incentives, including accelerated approval andbreakthrough designation. Don’t expectan orphan designation for a chronic HepB drug though!
And from a business development perspective, just theability alone of ARC520 to rapidly and profoundly down-regulate HBsAg shouldmake it an attractive candidate to be paired with other HepB agents, includingGilead’s GS-9620. |
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发表于 2013-11-3 14:09
