Hep B Blog

Arrowhead’s HBV Candidate Requires Further Dose Escalation

It should be noted while numerically the improvement in knockdown from 1mg/kg to 2mg/kg was only 12%, this is likely the result of the apparent high variability at the lower dose level with the increased tightness of the knockdown range at 2mg/kg indicating that the RNAi mechanism is starting to be solidly engaged with the expectation of a steepening dose response going forward.
It should be noted while numerically the improvement in knockdown from 1mg/kg to 2mg/kg was only 12%, this is likely the result of the apparent high variability at the lower dose level with the increased tightness of the knockdown range at 2mg/kg indicating that the RNAi mechanism is starting to be solidly engaged with the expectation of a steepening dose response going forward.

Sadly, we read that Phase 2a data presented by Arrowhead fell short of expectations for their ARC-520 drug to treat chronic hepatitis B. Hopefully dose escalation to 4mg/kg will result in both effective and safe results. However, there are others in the race for the cure, and may the most effective and safe drug soon result in a functional cure for chronic HBV.
~ hepbtalk

 

Harnessing the Power of RNAi Gene Silencing in Quest of a Cure for Chronic Hepatitis B, and the HBV KnockDown blog written by Dirk Haussecker, who believes it’s about time everyone got serious about a functional cure for hepatitis B.  Be sure to visit Dirk Haussecker’s blog !  

Today, we learned about some hard HBsAg knockdown numbers from the phase IIa Hong Kong study of ARC520 in chronically infected HBV patients.  The data relate to the first 2 cohorts in this ongoing dose escalation trial.  Accordingly, the mean HBsAg knockdown at nadir for the starting dose of 1mg/kg was 39% within a range of 22-57%(n=6) while it was 51% within a range of 46-59% for the 2mg/kg cohort (n=6).

ARC520 was given as a single dose to patients already stably on polymerase inhibitor entecavir.

While clearly missing the company’s own guidance of a 1 log reduction at 2mg/kg, the good safety profile-no SAEs at all in the study with all AEs rated to be unrelated to ARC520- in addition to the steepening dose-response curve following 2mg/kg means that ARC520 is far from being out of the HBV knockdown race.  Still, the stock market over-reacted, punishing ARWR stock with a percent decrease that matched the reported knockdowns.

Although even I ended up willing myself into believing that a 70-80% knockdown was possible following a single ARC520 dose of 2mg/kg, revisiting the chimp study which involved 2 doses of ARC520 (first one at 2mg/kg then one at 3mg/kg), it should be noted that at the time the 3mg/kg dose was administered, the HBsAg levels had only declined by 50%…about the same as achieved in the phase IIa study.  It is thus possible that Arrowhead gave the 2nd dose just as HBsAg levels were about to go up again, consistent with the already rebounding levels of HBV DNA and HBeAg in that study.

As a result, my expectations for the single 3mg/kg dose are now 70-75% based on the ~75-80% peak HBsAg knockdown in the chimp study following the 2mg/kg and 3mg/kg doses.  This also means that in order to reach that 1log knockdown goal the company had set for itself, 4mg/kg will most likely be needed.  Importantly, in the concurrent phase I dose-escalating study in healthy volunteers, this quite large amount of drug seemed to be well tolerated and the company is awaiting approval to adopt this dose in the Hong Kong study.

This projection is not much off the 90% knockdown achieved in the ARC-AAT program at 3mg/kg in non-human primates.  The improvement of this 2nd DPC-based candidate about to enter the clinic is possibly explained by progress in the potency of 2-molecule DPC delivery technology.  I add this as today many were confused about what the interim phase IIa results meant for the platform and the value of the company.

Overall, as long as 4mg/kg is an acceptable dose from a tox point-of-view, ARC520 is still in the game to be first-in-class in HBV knockdown.  It would have been much worse if say a 70% knockdown had been reported, but worrisome safety signals emerged.  On the other hand, the continued need for a dose escalation would seem to delay Arrowhead’s broad-based phase IIb study plans, meaning that the competition, in particular Tekmira’s TKM-HBV is coming closer.

At a market cap of ~$400M, the market has almost fully discounted the potential of ARC520 given the $150M+ in cash as well as the IND-ready, first-in-class ARC-AAT for which we can expect solid knockdowns in the clinic.  Interestingly, data for this candidate were selected for an oral presentation at AASLD while the ARC520 data will be in less prestigious poster form. Finally, should the single-molecule DPC which got me excited about the Arrowhead RNAi platform in the first place finally reach the clinic, it would necessitate an upward revision of the value of the company.
Disclosure: Long ARWR.  I sold most of my holdings at $11 and change given the underwhelming results and increasingly negative market reaction, but got back in below $6 when I considered the sell-off to be a gross over-reaction and imminent 3mg/kg data having the potential to surprise the market to the upside from now much lowered expectations.  Add to this ARC-AAT, the platform…

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3 thoughts on “Arrowhead’s HBV Candidate Requires Further Dose Escalation”

  1. Good day , I am a chronic hep B carrier.
    My doctor suggested me to purchase an antiviral drug
    which is Clevudine Revovir. It makes me hesitant to take this drug because I read some information about this ,
    It has an side effect that leads to muscles in abnormal
    function , mutation and some of the patients who took this drug had myopathy cases. I really need a good advice from expert of what antiviral drug or medicine should o take in order to get rid of this deases.
    Here’s my HBV DNA result;
    117 UI/ml
    681 copies/ml

    I will appreciate ure reply through email.
    Thank you.

    1. Cleveudine is not FDA approved in the US, though it is approved in Korea and obviously available elsewhere. Keep in mind that an antiviral will not “cure” your HBV infection. It is used to control and manage a chronic HBV infection. I don’t know if your noted results reflect taking an antiviral for some time, but a viral load of 117/IU/mL is very low. However, if it is low because it is controlled by an antiviral, then that is very different. Abruptly stopping an antiviral can result in flares that care cause damage to the liver. Discussion with a liver specialist is very important to be sure you are making the right decision. However, if you are NOT currently on an antiviral, it would seem that you are in an inactive phase of the virus. You do not mention your ALTs or any other history, but in general, your HBV activity seems low. An antiviral would not typically be recommended for someone that is treatment naive and seems to be in the inactive phase of the virus. Please review recommendations and discuss with a liver specialist.

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