When
Arrowhead suffered its DPC fiasco a year ago, it got a chance to re-prioritize
its pipeline. It therefore caught my
attention that despite the significant theory risk that still persisted, it chose HBV as one of its lead indications.
To wit,
knocking down HBV genes promised to re-awaken the host immune system thought to be exhausted in chronic HBV patients. The HBV surface antigen (HBsAg) had been regarded to be the main culprit for this exhaustion, although other gene products
are now thought to play a role, too.
Previous update suggested long road ahead
When
Arrowhead left off, clinical data had shown robust HBV gene suppression (~1-2log
range) when the RNAi trigger target sites were present (in treatment-naïve e-antigen
positive patients). Curiously, in
e-antigen negative patients where many HBV transcripts lack the ARC-520 target sites,
a modest, protracted anti-HBV response could be observed.
Unfortunately,
data presented this spring at EASL suggested that long, if not chronic
RNAi dosing might be necessary since viral rebounds were seen in all but one
subject once ARC-520 dosing had been stopped after half a year of treatment.
Chronic
dosing, if indeed it can be shown to lead to a reduction of cirrhosis, liver cancer,
and death, is conceivable with a subcutaneously administered RNAi agent. The road, however, to proving such value and broad adoption in the clinic would be harder
and longer compared to demonstrating host control of the virus after a finite treatment period.
New update shows host gaining upper hand
Based on
the latest data presented yesterday at HepDART, including ~8 months of additional follow-up in the same
patients, this may not be the case anymore.
This is because in 50% of the subjects (in 2 out of 3 e-positive and 2 out of 5
e-negative) given ARC-520 along with polymerase inhibitor entecavir, there have
been sustained anti-viral responses after the initial rebound.
In all
cases, HBsAg continued trending down until the last time-point reported, and in
3 of these 4 subjects HBsAg was approaching the limit of detection. Intriguingly,
this was accompanied by a modest spike in liver enzymes, consistent with the
host immune system regaining the ability to spot and remove infected
hepatocytes.
Of note,
the HBsAg declines are more robust (5.0, 3.1, 2.0, and 0.6) and faster than
would be expected based on entecavir treatment alone (~0.5log per year).
Since the
enzyme elevations generally followed on the heels of the viral rebound, it is
possible that treatment cessation and getting HBV to come out of hiding is
actually beneficial. Nevertheless, in the
one subject (patient 01-7985) where there was no viral rebound, ALT values still
rose.
Experimenting with treatment
schedules will therefore be an important component of future HBV trials.
In the
meantime, we can look forward to an update on the same subjects after another
few months. Could it possibly be that we are witnessing the first HBsAg clearances and host control of
HBV brought about by RNAi?
