Functional Cure of Chronic Hepatitis B: RNAi Therapeutics May Be the Only Game in Town (Part II)

Today, I will explain why I believe that ARC520, the chronic HBV drug candidate by Arrowhead Research, is particularly well suited to exploit the unique potential of RNAi to deliver a functional cure for many people suffering from chronic HBV.   For the basic rationale of using RNAi gene silencing to treat HBV, the reader is referred to the previous blog entry.

ARC520 is Highly Potent

As illustrated in this week’s publication of preclinical data on ARC520 (Wooddell et al. 2013), ARC520 promises to be a particularly potent example for therapeutic RNAi gene knockdown.  90% and more knockdowns were routinely observed for all HBV proteins.  What is more, the protein for which knockdown is most important according to the underlying immune reactivation hypothesis, the Hepatitis B surface Antigen (HBsAg), seems exceptionally susceptible to RNAi with multi-log gene knockdowns for this target.  Equally important, the masked melittin-like peptide component of DPC, expected to be dose limiting, was very well tolerated at 10mg/kg in non-human primates, the highest dose tested in the publication.  Such an amount was considerably more than what was required for achieving maximal knockdowns.

HBV is also an example for which the high knockdown potency of DPC (and SNALP) sets it apart from other potential competing RNAi Therapeutics approaches for HBV, including a GalNAc-siRNA conjugate-based one, which lack knockdown potencies adequate for such a viral applications.   At this moment, I do not exclude Tekmira to become interested in HBV as well, especially with their UsiRNAs and MV-RNAs which they probably consider to be free from the Alnylam-imposed target restrictions.

ARC520 Fits into Current Standard of Care

At the AsiaTides meeting in Tokyo that I have just attended (btw, you’d be amazed how much serious RNAi Therapeutics development work is going on in Japan, China, and South Korea), Dr. Lewis from Arrowhead Research presented drug-drug interaction data for ARC520 and Entecavir, the current standard of care Nuc for HBV.  These interaction studies performed in mouse models of HBV are important since ARC520 would initially likely be used in combination with current standard of care (probably also interferons).  In fact, the distinct mechanisms of actions of Nucs, interferons and RNAi Therapeutics would neatly complement each other.  Importantly, ARC520 did not impair Entecavir-mediated suppression of viral replication nor did Entecavir impair the 2-3 log-fold viral protein suppression by ARC520.

Moreover, the data which include 80% knockdown following a single administration after 3 months in non-human primates (Factor VII surrogate gene), clearly support once-monthly dosing.  Given that ARC520 is not intended as a chronic therapy, it should thus easily fit into current treatment regimes. 

ARC520 May Be Foundation for HBV Franchise

ARC520 is administered by intravenous infusion.  In terms of dose escalation and achieving maximal potency, this is positive since solubility and injection volume issues do not apply.  However, there is the obvious opportunity for Arrowhead to enhance the value of their HBV franchise by developing a subcutaneously administered follow-on candidate, thus capitalizing on their progress with the protease-sensitive DPCs.  This would broaden the target population and extend market exclusivities.

Risk-Reward

For a small biotech company like Arrowhead Research, the enormity of the HBV opportunity also comes with its challenges.  The complex course of chronic HBV and probably also the various genotypes mean that clinical development will be equally complex- and costly.  I have followed with horror the many billions Vertex Pharmaceuticals invested on developing their HCV drug after the first exciting phase I proof-of-concept data were reported.  Ultimately, Vertex shareholders that had invested before the phase I validation, only made a 3x return taking on all the risk, and those that jumped onto the bandwagon after the results did not see much appreciation after 6-7 more years, despite of the fact that clinically pretty much everything went according to plan.

Part of the expense, however, was also driven by the fear of the emerging competition in HCV leading to a capital intensification of clinical development.  Except for competing RNAi Therapeutics candidates enabled by similarly potent liver-directed knockdown technologies (perhaps SNALP), I do not see such intense competition emerging for ARC520. 

Another risk for Arrowhead is that while the immune reactivation hypothesis is attractive and supported by clinical data correlating HBsAg seroconversion with preceding loss of HBsAg, the remaining uncertainty may make ARC520 unsuitable for a small platform company to wager its entire future on it.  By contrast, a Big Pharma may be willing to take on the risk if it agrees with the hypothesis simply because the market opportunity is so large.  Witness how much capital is being spent on the amyloid hypothesis in Alzheimer’s Disease or the good HDL-cholesterol hypothesis in cardiovascular disease.

Therefore, at the right time and for the right price, also depending on factors such as clinical data, share price performance, and the availability of non-dilutive funding opportunities, the HBV franchise should be partnered.  The issuance of the patentcovering the protease-sensitive DPCs which are amenable to subcutaneous administration could be an important piece in this puzzle.  After all, with manufacturing much less of an issue with DPC 2.0, you don’t have much to sell unless you control the IP.