Thursday, March 20, 2014

Potency Concerns and Tekmira Could Be Spurring Extension of Arrowhead HBV Study

As picked up by sooner_or_later55 on the InvestorVillage mssage board on Arrowhead Research, there have been changes to the entry for the phase I study of ARC520.  These indicate that the study has not been concluded as I and probably most others had assumed following the release of top-line data in October 2013 and the more detailed results presented at HepDART 2013 last December.

At that point, 36 subjects had been treated in the single-dose dose-escalating study up to 2mg/kg.  In this healthy volunteer dose-finding safety study, the most significant event possibly related to ARC520 was a case of urticarial rash of moderate intensity.  In general, the safety profile was quite encouraging for the first test of DPC delivery technology in humans.

According to the entry, the target enrollment was upped to 48 subjects in February 2014.  The company has more or less confirmed the renewed activity in this email to an investor ('Linda').

So why is there still activity in a trial we thought had been wrapped up?  

After all, the 2mg/kg upper dose informed the dose selection for the single-dose study in HBV-infected patients in Hong Kong which is about to commence dosing any day.

My favorite hypothesis is that it has to do with concerns around efficacy.
As I had discussed in my companion HBV blog before, 2mg/kg may not be enough for the type of 1log+ knockdown activity that may be necessary for the Hepatitis B surface antigen (HBsAg) knockdown-immune reactivation hypothesis to really kick in.   3, 4, and especially 6mg/kg could make a big difference according to the preclinical studies by Arrowhead Research in achieving much greater HBsAg knockdowns (it is important to focus on the dose of the melittin-like peptide when reading these papers). 

And for this indication, the deeper and the more rapid the knockdown, the more patients to benefit from such a treatment.  Say with an 80% HBsAg knockdown (my prediction for the outcome of the single-dose Hong Kong study for 2mg/kg which is the approved top dose in the study), an HBV RNAi therapeutic can achieve a cure rate of 10%.  Similar to the interferons, the best we have right now for curing HBV, but with presumably much improved tolerability.  However, with 90% knockdown (half the HBsAg left to immune suppress compared to 80%), this could jump to 30% cure rates, with 95% knockdowns to 50% etc etc.

I already hear you cringe that all this is speculation.  To this, I respond that not only all of life and particularly drug development and the stock markets are a speculation, but that it is informed by biological intuition.  You either sufficiently lift your foot off the (immune) brake or not (--> threshold).  Throw in the fact that the set point where the brakes have been released will vary due to the variability in how much individuals’ immune systems have been repressed and damaged by HBsAg, you probably end up with a sigmoidal knockdown-response curve. 

Tekmira competition

As we consider the importance of knockdown efficacy in absolute terms, it will also not have been lost on Arrowhead Research that other companies, most notably Tekmira, has been gearing up with their own HBV RNAi and antisense knockdown drug candidates.
I call out Tekmira because I not only own the stock, but because of the value of knockdown potency in this indication and the fact that SNALP LNP delivery is and will remain the most potent gene knockdown technology for the foreseeable future.  SNALP LNP potency has been validated in humans with over 90% target gene knockdowns in the ALN-TTR02 study using 2nd generation technology and it is reasonable to expect that Tekmira’s most recent 3rd generation formulations will exceed that.

Although genes vary by the ease of knocking them down, I expect HBV to be an easier target than TTR given that its genes are expressed from an episomal template, i.e. not from copies integrated into the genome.   

Add to this potency advantage the decade-long experience of Tekmira working on HBV and other viral applications (e.g. HCV, Ebola, Marburg) of SNALP RNAi (see Nature Biotech publication from 2005 using 1st generation technology), which includes the design of escape-resistant and pan-genotypic RNAi triggers and should also manifest in a more thoughtful/thorough trial design, it is not a stretch to imagine that it was partly the Tekmira competition that is spurring Arrowhead Research to presumably be testing the feasibility of higher doses now.  

Moreover, the first-mover advantage of Arrowhead may not be as big as widely assumed since Tekmira could be moving directly into single-/multi-dose ascending studies in HBV infected patients in early 2015, just months behind, if at all, the Arrowhead multi-dose phase IIb study.  

The prospect of higher cure rates will not only inform the RNAi drugs a patient will be taking in the future, it may also divert investments today in an area that is rapidly gaining in investor and pharmaceutical interest.  After all, even just 10 million of the ~300 million HBV patients that would require treatment for medical reasons and could afford it would make for a ~10 million*$20k = $200B market, and that could well be an underestimate...  


Anonymous said...

Hope patients are better off because of the building competition.

Anonymous said...

You're simply wrong on this one Dirk. Your use of "could" is the giveaway. And it implies wishful thinking instead of well-researched analysis. Maybe you should have talked to ARWR before jumping to these conclusions. Since his money is back in TKMR, Dirk COULD be thinking with his wallet instead of his head on this one.

tufulipo said...

>>To this, I respond that not only all of life and particularly drug development and the stock markets are a speculation, but that it is informed by biological intuition.>>
Are you aware how many scientists caught fudging their research justified it based on "intuition"?

Anonymous said...

"Dirk COULD be thinking with his wallet instead of his head on this one"

Thats never been a measure of Dirk's comments on his blog. Blatant and utter bias is what I call it.

Anonymous said...

If you have an opinion on the science share it. If you don't trust his intuition don't buy on it, short it. If you don't care for his comments don't read it. For the rest of us whom are following RNAi Dirk is Sheppard were all just sheep.. Unless another pied piper comes along with a better tune I'd side his intuition over your useless comments.

Anonymous said...

Dirk's blog is essential reading, if only to judge where the herd is stampeding toward. The previous comment epitomizes Dirk's influence on the trading crowd.

Dirk Haussecker said...

I like to think that my trading decisions are informed by the science first, not the other way round. If you want to shoot holes of why 2-molecule DPC ARC520 should be equal to or superior to 3rd or even 2nd gen SNALP, please feel free. It's an easy one for me to conclude which one is superior. From that point of view it surprises that Tekmira has not pushed into the clinic itself before, but believe that one is explained by the litigation with Alnylam and Tekmira's choice of usiRNAs over Tuschl-siRNAs for this indication.

Anonymous said...

How soon do people forget that Dirk H. himself blogged questioning why higher doses weren't explored?:

Monday, December 9, 2013

"ARC520 Phase I Safety Data Raise Question of Why Higher Doses Not Explored"

And now that Arrowhead is exploring higher doses at people's suggestions, likely the HK authority's as well, and because 2mg/kg has gone so well, suddenly Mr. RNAi Analyst claims that it's because of his trade du jour, TKMR's more potent brew?

Perhaps this is why Dirk is no longer a research scientist and blogs for a living.

This kind of leap is an example of bad logic chain that invariably leads to bad "scientific" proposition and prediction, aka, failed theory.

While we don't know the outcome prior to experimental verification, it is already clear that the logical basis is poor. So good luck with that theory, you'll need it.

The same can be said about Dirk H.'s constant pumping of his investment in TKMR, in particular the unknown HBV candidate, that has not seen the light of day!

It's one thing if TKMR had it out for peer review with supporting data. It's quite another to go on and on about what is currently "vaporware."

No scientist in his right mind would with a straight face compare a known quantity with mountain of supporting data, Arrowhead's ARC-520, with an unknown quantity, X, prescribing to the latter miracle qualities. Science has never accepted such a leap over an abysmal void of data. We are no longer dealing with science but stock market shenanigan.

For comparison, we can also talk all day about the single molecule DPC / ARC-520 and how it will be superior but we don't because it is not yet a fact.

Mr. RNAi Analyst would do well to observe some minimal standard of scientific practices if he wants serious people to pay attention to his blog, other than members of the peanut gallery who are essentially herded sheep.

Anonymous said...

Dirk had little credibility from beginning. I feel sorry for those who listened to him. And even sorrier who bought his "reports".

Anonymous said...

He is right about TKMR and ARWR as I am short both. Dirk, when do you plan to go short on TKMR?

Latebloomer said...

(I've also posted this under the most recent blog about safety.)

Dirk, you had posted the following in response to a question I asked following your blogpost about the 2mg dosing, which still seems to be pertinent, at least in regard to potency (might it also help with reaction in the arm - a slower infusion rate?):

"In any case, I don't want to make too much of an issue with the top dose at this point and first await the phase IIa knockdown results. We can always revisit. There is also a problem with extrapolating dosing from mice to humans as in the mouse experiments the drug was given over a relatively short period of time whereas in the clinical trial the infusion time can easily be extended to take full advantage of the fast ASGPR-receptor turnover that is responsible for the uptake of the melittin-like endosomolytic peptide in ARC520. This could more than make up for 2mg/kg in humans vs 6mg/kg in mice.

Another example are the Silence Therapeutics Atuplex formulations which are given as a push in the 2-3mg/kg range in mice, but at 10-fold less in humans given as a slow infusion with comparable efficacy results."


Anonymous said...

I love how the shorts are trying to drive down price through slander without merit's.. If you think he's wrong in his dissertation of the facts based on his opinions provide a compelling opinion on the subject yourself.. Why is ARWR doing what they are doing ? None of the naysayers have stated an opinion other then Dirk doesn't know.. well I guess that's an opinion..

Anonymous said...


If it's not already obvious, Dirk is stomping for his trade, TKMR, which has done poorly since the new offering.

You have to look at his current blog and comments from that perspective.

His original assessments which you smartly quoted are in fact more objective and true.

There is NOTHING to indicate that ARC-520 will not perform to the best extent possible as dosing hasn't even begun!!!

Dirk is wildly speculating in favor of his trading which is losing him all his credibility hence forward.

- investron

Anonymous said...

First ARWR had Dirk's blessing and now TKMR is back as the favored child. Maybe next month it will be someone else (maybe MRNA?). Beware RNAi investors: Dirk giveth, but he also taketh away.

Latebloomer said...

I definitely now think his wallet is leading him in the cases of these two latest posts.

He knows very well what a lot of his lay readers might not know (I didn't until he wrote about it in response to me) regarding the simple act of extending the infusion rate:

" the clinical trial the infusion time can easily be extended to take full advantage of the fast ASGPR-receptor turnover that is responsible for the uptake of the melittin-like endosomolytic peptide in ARC520. This could more than make up for 2mg/kg in humans vs 6mg/kg in mice."

Bad form, Mr. Haussecker... bad form...


Anonymous said...

To be fair.. Dirks commenting on whats information is available. In all cases he's commenting on the science not the stock ie fund raising from ARWR or TKMR. The comment today is based on the new info from ARWR. I there was negative news from TKMR he would comment on that too.. But for those of you hammering him on his bias truth is there hasn't been any bad news about TKMR.

Latebloomer said...

I was giving him the benefit of the doubt until I recalled his words to me.

Now, yes, I'm hammering him - on his blatent contradiction about the potential potency of using 2mg in humans (vs mice), something that he has stated the simple change in the rate of infusion could make a significant difference in (but conveniently failed to mention in his blog post today).

Why hasn't he speculated on anything innocuous that might be occurring in the extension trial, which may have nothing to do with raising the dose, but perhaps something as simple as experimenting to find the optimal safety rate of infusion (which could then go on to make a quite significant difference in potency, according to Dirk's earlier words, and maybe even in the mild adverse reactions seen in the earlier trial)?

He can be very proud of his influence today. It does look like (with an assist from options expiry) there has been a lot of movement away from Arrowhead and toward Tekmira today, and my guess is that, at least where layperson retailers are concerned, his posts may have had something to do with that.

I hope all those folks are prepared in the event that there really was something quite innocuous about the extension of the Phase I trial, and that the potency of ARC520 using 2mg in humans, as well as safety issues, might not be quite as questionable as Dirk has made it appear today and yesterday.


Anonymous said...

But his speculations turn positive or negative depending upon his own positions. Anybody can speculate anything. Credibility loss undoubtedly.

Anonymous said...

About now, we should also remember his put downs of Benitec as well.
That's the bitterness of being fired.
Wonder what this one is founded in.

Anonymous said...

People, it is not fair to say anything to Dirk or question his analysis. He is entitled to his medical opinions and you are yours. You dont have to be at this website. You dont have to be posting here. You dont need to read his blog. He never took on the role for as your financial advisor. He like any other person is speculating. You have no right to be upset at him or accuse him. Do your own DD and be responsible for you own decisions. Silly People.

Anonymous said...

TKMR will exceed 35% cure rates and be a multi-billion dollar company -- it's that simple. Arcturus will benefit too, as TKMR advances its HBV product and fills its pipeline with additional UNA medicines. Dirk: Any word on the street about an Arcturus IPO?

Joe said...

Linda - I do not see any contradictions in Dirks comments regarding the ARC520 trial change. The net effect is undoubtedly to achieve better knockdown, particularly in light of Tekmira's joining the race. Arrowhead will now need to have a superior formulation to the competition, which may only be achieved by higher dosing, irrespective of whether this is aided by receptor turnover rates. Potency in a competitive environment is the driver.

Joe said...

I would also add that this is nothing but positive for Arrowhead, as long as there is some upward room in the dosing regimen. Improvements in efficacy will throw down the gauntlet to Tekmira and make this a more evenly matched race where both companies may be eaually successful. Anyone who sold ARWR last week may very much regret doing so, though it's more likely due to options expiration (remember, not so easy to manipulate TKM which trades on the Toronto Exchange, in addition to the US).

Pendaftaran CPNS 2014 said...

i hope more better

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