Wednesday, December 6, 2017

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?

4 comments:

Anonymous said...

"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."
Could ABUS have already speculated/discovered this? They have already flagged a finite dosage of rnai followed by other drug combinations to include vaccination. Also, once the viral loads are below quantification, do you believe a HBV vaccination would be effective?
Joe

Dirk Haussecker said...

I doubt vaccination (injecting recombinant HBV proteins) will have much impact on the immune system of chronic HBV carriers in this setting. This is because they already seem to have antibodies and T-cells recognizing the virus, but they are either outnumbered (antibodies) or exhausted (T-cells). The name of the game therefore is to re-awaken the existing immune response to the virus.

Anonymous said...

What are your thoughts about possibly using an immune booster as a co-therapy?
On the heels of that news about a single HIV patient and Opdivo--what about using pd-1 blockers or even something from Nektar's pipeline(214)?

Will said...

Hi Dirk, thank you very much for your assay on ARWR. I am now doing due diligence on the company before I make investment. I am a strong believer in the science, but worried about its cash position. ARWR has about 65 million cash now, and spend 68 million last fiscal year. I think the cash burn will increase significantly with the initiation of clinical trials. So it will have to raise money pretty soon, unless there is revenue coming in form somewhere. If offering is needed, is there any near term catalyst(s) available to boost the stock price? Offering at current price seems to be toxic. What is your opinion on the finance part of the company?

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