Friday, October 12, 2018

AASLD Abstract Continues to Support Promise of ARO-HBV, but with a Twist

Yesterday, Arrowhead revealed the abstract for data on its new HBV RNAi drug candidate to be presented at the big annual Liver Meeting in November (AASLD).  The data continue to support highly potent knockdown of not only the surface antigen (HBsAg), but also other HBV components.

Dose response issues

When Arrowhead announced initial first-in-patient knockdown data from its 3rd generation HBV RNAi candidate ARO-HBV, I found it suspicious for them to only reveal data for the 100mg and 200mg cohorts although more data was available at the time.  Curiously, the new data seem to suggest that there was no apparent benefit from going higher than 100mg in dose, at least when dosed with the current monthly frequency. 

Whether there is significantly worsening safety with increasing dose remains to be seen.

HBeAg positive/negative dichotomy

Similarly (but not as earth-shattering for sure) to the history of a prior HBV RNAi candidate by the company before, ARC-520, however, Arrowhead was able to learn more about its drug candidate as they went along in the study.  In particular, the first dose escalation cohorts (100, 200, 300, and 400mg monthly x3) encompassed a mix of HBeAg positive and negative patients, with 13 out of 16 being HBeAg negative.    

When Arrowhead then decided the last 2 cohorts to be just HBeAg positive, a remarkable increase in drug response was observed: whereas it took the predominantly HBeAg-negative patients 70-90 days to achieve 1.5log reductions in HBsAg, it looks like the pure HBeAg-positive patients only take 30-40 days to achieve the same.

Ergo, the reason why no clean dose response had been seen in the first cohorts is best explained by the fact that they were mixed and at that small cohorts.

Trigger choice likely explanation

ARO-HBV comprises 2 RNAi triggers: one that targets all (intact) HBV mRNA (X trigger) and one that makes sure the surface antigen is hit (S trigger) even in those patients with integrated HBV.  These typically lose the corresponding DNA element targeted by the X trigger during integration.

In the early days of RNAi, there was some controversy about the usefulness of using 2 or more triggers against the same target in terms of knockdown potency and specificity.  When I first started to practice RNAi in the lab in 2003, it was my experience that when you combined a very potent trigger with a less potent one, the knockdown was less than with the highly potent one alone.  As a result, I am a firm believer in the concept of RNAi trigger competition.

In the case of ARO-HBV it means that in HBeAg negative patients that have lost the X-trigger DNA, there will be one sterile/inactive trigger somewhat blunting the potency of the active one.

HBV biology is certainly complex and downstream events could also account for final knockdown differences.  Accordingly, in the HBeAg-only cohorts  it appears from the early observations that the nuc-experienced patients that in previous studies corresponded to patients that had lost the X-trigger-targeted elements by study enrollment not only responded as well, but in fact slightly better than the nuc-na├»ve patients.  It will therefore be important to learn more about their HBV integration status at AASLD to confirm or disprove the competition theory.

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By Dirk Haussecker. All rights reserved.

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