New Arrowhead Data Shows RNAi Ratting Out HBV

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?