Tuesday, August 12, 2014

Dose of ARC520 HBV Drug Candidate to be Increased to 3mg/kg

Today, Arrowhead Research reported preliminary phase IIa safety and efficacy results of ARC520 in patients infected with HBV.  The goal of this study is to determine the level of viral knockdown, especially HBsAg, following a single dose of ARC520.

Efficacy in-line with animal studies

The results for the 1mg/kg and 2mg/kg cohorts indicate that knockdowns are in-line with what has been seen with 2 molecule DPC-enabled RNAi in non-human primates, including the HBV-infected chimpanzee.  The company could not be more specific about numbers since it is still a blinded study and the knockdown curves apparently haven’t stabilized yet after 8 weeks in the 2mg/kg cohort suggesting remarkably prolonged pharmacology.

In the chimp study, HBV load in serum was reduced by 1log at 2mg/kg, but determination of the HBsAg knockdown following a single administration was complicated by the fact that Arrowhead gave a second dose of ARC520 of 3mg/kg before the HBsAg knockdown at 2mg/kg had leveled off.  With 2 doses of 2mg/kg and 3mg/kg 2 weeks spaced apart, the final knockdown was ~80%.  This level of knockdown was likely an underestimate of the true efficacy of ARC520 since one of the two siRNAs was a mismatch and the chimp had very high viremia to start with.  For the non-human primate study with ARC-AAT, Arrowhead’s new development candidate for alpha-1 antitrypsin, the knockdown with a single dose of 1.5mg/kg was ~75%.

Taken together, I expect that the knockdown at 2mg/kg to be somewhere around 70-75%.

Arrowhead extending to higher doses

While this level of HBsAg knockdown in such a short period of time, would be superior to anything before in the HBV space, for comfort and competitive reasons, it is not all that exciting.  What is more exciting is that Arrowhead is doing what I’ve always said they should be doing, namely testing higher doses than 2mg/kg.

This is because for 2-molecule DPC-RNAi, it is the amount of the endosomolytic peptide that is rate-limiting for knockdown efficacy. As shown in animal model after animal model (e.g. Wooddell et al. 2013), the efficacy achieved with 2mg/kg was well below maximal knockdown efficacy.  However, when slightly extending the dose to 3mg/kg or 4mg/kg, the depth of knockdown increases tremendously. 

In the case of ARC-AAT for example, a 75% knockdown at 1.5mg/kg became a knockdown of 90% at 3mg/kg, which was the same knockdown as with 6mg/kg indicating that a plateau had been reached.  In the case of HBV, the plateau, based on 6mg/kg endosomolytic peptide was a virtual elimination of HBsAg in the serum.

Despite the various genes and doses, the picture is that the dose-response becomes very steep soon after 2mg/kg.  Whether it is 3mg/kg or 4mg/kg is another question.  Arrowhead is currently gearing up for these doses following phase I extension studies in healthy volunteers,   

The most important news today therefore is that 3mg/kg in healthy volunteers was as well tolerated as 1mg/kg and 2mg/kg before (4mg/kg in the works).  Indeed, it was even better tolerated since the skin reactions disappeared with the transient use of an oral anti-histamine. 

Results from the 3mg/kg cohort in this dose-finding study should be presented at or around AASLD in November. Stay tuned.


kss said...

They left out ALT data. Seroconversion in these patients will be augured by "therapeutic hepatitis." I am happy for their data, and await phase 2b, but still so many hurdles. Will these patients clear? High risk for mutant selection. Will they break through in 6 months? A liver biopsy with some IHC and ISH would be so profoundly helpful here.

Anonymous said...

Unfortunately ARWR's sRNA tech is like throwing bullets compared to ddRNAi's bullets being fired by a gun. At best this will be worth a yawn because it will not knock it out, after ddRNAi is effective in HCV (which is actually easier than HBV, and I wish HBV had been chosen as the testing ground for ddRNAi) then it will also be adapted for HBV with a one shot cure. Throwing bullets vs. shooting them.

Anonymous said...

Previous post is spot on.

Benitec will usurp this. And soon.

Anonymous said...

Did this dosing use transient immune suppression? In how far is it comparable to Tekmira Haertetest?

Dirk Haussecker said...

Arrowhead used oral anti-histamine pre-treatment which apparently successfully took care of the skin reactions observed before (urticarial rash). Seems benign.

Benitec...sure. ARC520 duration of activity already on order of 2 months and regenerating hepatocytes in HBV infection will kick out AAV vector. HBV not best ddRNAi application IMO. Maybe if they added some other functionality such as expression of a protein.

Anonymous said...

Benitec will dose one cohort per decade (exaggeration intentional). And then, when and if they do have success, they'll have regulators in their pants. Love the company and what they're attempting to do. But ddRNA is only a blip on distant horizon.

Anonymous said...

I have reservations regarding trial design and endpoints using HBsAg as an endpoint and using nucleoside tx concurrently. Traditional tx aims at HBV DNA suppression, sero-conversion from HBeAg + to - w/ appearance of eAB. I know ARWR is wanting a "cure," but it would still be nice to have back up data on the effects on other serology that isn't confounded by the use of a nucleoside inhibitor.

I also, like other posters would like to see liver biopsy with pathology reports and ALT data.

Too many questions unanswered so far IMO and questionable trial design.

Anonymous said...


You tweeted, "Since I'm invested in $ARWR again, can we pls focus on 1st-mover instead of most-potent or most-convenient again? #HBV $TKMR $ALNY"

I am not sure whether you stated the above tongue in cheek or with a straight face. If serious, the attitude behind such a statement is a bit disconcerting because it shows a willingness to skew your message based on your portfolio holdings.

Be that as it may, I value your contributions more than any other single source, and for your efforts I say, "thank you."

I have two questions:

1. ARWR has moved aggressively with regard to AAT. In terms of speed to the clinic, ARWR seems to have leap frogged ALNY with regard to this indication. In your view, does this show that ARWR is probably cutting corners in its race to the clinic or does ARWR's relative speed highlight the fact that ALNY is a slow and lethargic competitor (I am inclined to believe the latter)? What are the broader implications (if any) of the discrepancy in speed to the clinic by ARWR versus ALNY?

2. You are obviously quite well connected in the RNAi field. Do you have any insight into what occurred between ARWR and ALNY to turn that relationship sour? They reached an apparently amicable arrangement allowing ARWR to move into the HBV space. Then MRK sold its RNAi assets to ALNY, then ARWR moved into the AAT space that ALNY seemed to have to itself. Obviously, a lot occurred behind the scenes. Please tell us what you know about those machinations. Even (informed) speculation will be appreciated.

Thanks in advance.

Anonymous said...

The response of ALNY to this data will be interesting. All the might of Wall St behind them, all the money they could wish for and it seems they are moribund. Going nowhere fast.

Only response I can see is the patent suit threat.

Anonymous said...

ARWR moving ahead of ALNY in AAT doesn't mean anything. It only means ALNY was focusing more on many of its other programs and AAT was less of a priority. It may also mean that ALNY was being more cautious and wanted to try out its new ESC-GalNAc in humans in other programs before aggressively moving with the rest of its other programs. Also, ARWR has only about 6 months lead over ALNY in AAT. Is that much of a lead?

Anonymous said...

ARC-520 may turn out to be a better compound than TKMR-HBV. ARC-520 will need less frequent dosing and can also use immune stimulant agent which most likely Tekmira can not use with its LNP delivery.

Anonymous said...

"Going nowhere fast...."

ALNY will be filing 3 IND by the end of the year. From being completely dependent on Tekmira for delivery, it has developed the best delivery system in the RNAi space which many are yet in denial. And the race for HBV has just begun. Apart from having a great HBV drug, it will need financing, partnership and IP to succeed in this race. Alnylam has all these things in place. It will be few more years before we will know who is the leader in HBV race.

Anonymous said...

Such stellar results and such a limp response. What is the missing ingredient? The magic spice that gives the dish a bit of flair and finish.

Even TKMR got a bigger jolt on the Ebola mystery drug.

If there is a bigger game going on then it can only be ARWR are going to go straight to market with this and have made secret application to the FDA. Success will ensure a re-rating. Failing that, someone somewhere, with enough clout to control markets (AlNY and friends)has an alternative plan and wants the headlines.

Could that be in Alzheimers? Or some execution of strategy to achieve their 5x15 plan.

ARWR definitely not responding the way you would think.

Latebloomer said...

Any chance viral clearance has begun to happen? ...leaving less infected cells and, therefore, less s-antigen production than would have been the case just before the start of treatment?...even after RNAi activity to KD s-antigen production may have come to an end? (also noting infection of new cells is being well controlled for due to nucs keeping HBV-DNA well in check).

If they hadn't yet completed 8 weeks for the whole of the 2nd cohort (Bruce Givens mentioned that 5 of 8 patients in the cohort had had data collection for week 8 by the time of the CC, leaving 3 more to be checked), then they likely wouldn't have gotten reports on key ALT readings yet (from Day 43, 6 weeks, and Day 57, 8 weeks), which, when completed, may indicate an active immune response is in the works.

It would at least be one possible explanation for lowered s-antigen levels way past the time they would have been expected to recover (if RNAi activity had wound down after about a month, as has been the case in preclinical models).

Hey, a girl can dream, can't she?

Here's hoping we see similar very long duration of s-antigen KD across several patients in both the 2nd and 3rd cohorts...


Anonymous said...

The curious thing about the fans the anonymous blogger on that site about people who like to chew gum stuck on their shoe is that they believe everything he says without doing any DD. If they did they would know their vaunted Dr. K may very well be a hepatologist, but one who has been banned from both Texas and N.D. for his troubling behavior and combatant attitude. He knows all. Claims he has secret transcripts, emails and correspodences that prove the CEO is lying to shareholders and should be ousted via activists or even a palace coup. What a joker. The readers over at gum stuck on my shoe need to also realize said expert tried to get a job down in Oz and they said, thanks mate, we'll call you. Nothing like a KSS scorned...he then goes into scorched earth mode. What he has been saying about PF and mgmt is ridiculous.

Anonymous said...

Dude can't abide. Thinks he is the only one with knowledge of Benitec. Hates anyone else who dares to question his opinions disguised as facts. They follow him off the cliff time after time with his picks. An anonymous blogger who is a middle aged, single doctor. How sad is that. Let's rumble in the jungle. Ugh even adores Jethro Tull. MWS, I heard as well, tried to get a job with beni and they laughed at his record.

Anonymous said...

Everyone is in for a surprise because Arrowhead left out the key details with what happened to date with the Ph 2a trial. They felt pressure to give an interim update even though they did not want to. They played it masterfully too. The actual results are going to be significantly different, not to mention much more relevant and revealing, than what everyone has interpreted, including the analysts whose job it is to understand better than the common investor. Anyone who understands the science, specifically and including the dynamics of sAg in humans, knows exactly what happened (and what will be released in November).

Anonymous said...

- HBsAg shows a strong correlation with HBV replication only in the early phases of infection.
- HBsAg levels and correlations with HBV replication differ between patients infected with HBV-genotypes A and D
(Jaroszewicz et al., 210, J Hepatology 52:514-522)
Would viral DNA have been a better marker and was it included in the study (or why not)?
Should we expect a biphasic, or even triphasic (immune activation) response to treatment rather than simple knockdown?


Dirk Haussecker said...

Viral knockdown was not/could not be assessed because patients were on nukes and therefore with undetectable virus in serum.

Raju Khan said...

Vito Glazers beats Ryan Eagle in court.

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