Friday, March 21, 2014

Further Possibilities for Arrowhead Phase I Dose Extension

Last night’s speculations on the reason for the phase I dose extension of the HBV RNAi phase I trial by Arrowhead Research was actually positive: they are tackling the potency issue presented by the 2mg/kg dose. 

In addition to further increase dose, it could also involve prolonging drug infusion times which we know, based on Alnylam’s GalNAc data, could optimize hepatocyte uptake by the GalNAc-targeted DPCs.

Regardless, you have got to question why extending beyond 2mg/kg had not been part of the original plan and why the study extension has not been publicly discussed, e.g. in the latest conference call.   

Extending the study to further potency is the most rose-colored scenario that one can draw.  The other scenario would have to do with safety concerns, possibly raised by regulators.  As I had discussed before, for DPC, especially the 2 molecule version, the tox-limiting element is the melittin-like peptide.  Melittin is derived from bee venom and although the MLP is not the identical sequence as melittin, there are theoretical concerns around allergic reactions.  In general, having peptides involved raises a new set of immune issues, especially when you require 2mg/kg of them.

Of note, one of the exclusion criteria for the phase IIa HongKong trial is excluding those with a history of allergy to bee venom, indicating that this has been an issue with regulators:
·         Has a history of allergy to bee venom or history of hypersensitivity reaction requiring an emergency visit to a physician or hospital and/or requirement for treatment with steroids and/or epinephrine.

So how about adding transient immune suppressant to the mix- e.g. an anti-histamine?  Nothing spectacular, a safety precaution, but once again highlighting the benefit of Arrowhead Research making advances with the single-molecule version, also for applications outside the liver (see today’s positive news around Endocyte and folate targeting for cancer as just one example of where such research could be directed at).


Potency matters, and wouldn’t it be ironic that as Tekmira is weaning itself off immune suppression (à dose-intensive TKM-EBOLA trial), on the back of developing more potent formulations, Arrowhead Research, not known as a public supporter of liposomal RNAi delivery, is adopting such?  

20 comments:

Anonymous said...

So did RBC and DB initiate their coverage on ARWR before or after the trial reopened to include the extra people. SHouldnt the COmpany release a PR about this ?
Thanks

Anonymous said...

I appreciate very much this blog and your posts.

It has been a while, I think, since you have posted a portfolio review. It would be great to know exactly where you stand currently with regard to ARWR, TKMR, etc.

Again, thanks.

Latebloomer said...

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."

Linda

Latebloomer said...

With the above in mind, and, in your words, for the sake of completeness, maybe you could write a post about other possibilities for extending the Phase I trial. For instance, might they use it to experiment with infusion rates, or something else similarly innocuous?

Linda

Anonymous said...

Dirk is probably too busy shorting Arrowhead to respond.
He has a record of reversing his opinions- too bad Arrowhead erased his glorious comments about CALA-01 back in 2010.
Too bad for all of us.

Dirk Haussecker said...

Linda,

Didn't I mention prolonging infusion times as one possible reason for the extension?

'In addition to further increase dose, it could also involve prolonging drug infusion times which we know, based on Alnylam’s GalNAc data, could optimize hepatocyte uptake by the GalNAc-targeted DPCs.'

Latebloomer said...

Why didn't you mention what that could mean, especially in your blog about potency? What do you expect your layperson readers to get from that statement?

Why did you, in your blog about potency, go on about how the preclinical trials point to 6mg use in mice, using that to infer that 2mg in humans might not be comparable? Why did you not mention anything about what the simple change in infusion rate could mean to help even out those differences?

Linda

Dirk Haussecker said...

Linda...you mean well and I hope you are still sitting on a hefty gain. Take some profits, pay off your debts and follow all this in a more relaxed manner.

I'm actually considering taking a trading long into the phase IIa results. An 80% rapid knockdown of HBsAg could receive a voracious market response as this has not been seen before and HBsAg is key.

Have a nice weekend.

Latebloomer said...

That's excellent advice, Dirk. I've certainly learned today to take you much less seriously.

As far as Tekmira and Arrowhead, I wish them both well.

Linda

Anonymous said...

Linda has trapped Dirk and exposed him completely. Thanks Linda.

Anonymous said...

Dirk

I love ya, man, but you have to be more careful in your posts and consider the potential financial effect of what you post has on others. Through your past hard work, research, and willingness to inform us (I'm a layperson) about the complexities of RNAi and associated biotech therapies, you've created quite a following. That includes laypersons who want to learn and invest in the tech, and now others much more well-versed in biotech in general and who also have a reader audience. In short, what you publish has both directly and indirectly a much larger, far reaching audience. That can dramatically affect the share price of a company or technological development that you may briefly or offhandedly mention. As one who sincerely appreciates all that you do and have done, I will continue to read your articles and hope to learn more. But I respectfully ask that you be more cautious, especially for the sake of accuracy or bias/ethics check, prior to hitting the Enter key when you publish an article or send a tweet. Not saying what you have done in the past has been unethical. To the contrary, you have fully disclosed your investment positions. But make sure your investment positions do not bias the quality and accuracy of what you publish.

God bless ya, Sir, and please do good.

liqun wang said...

Dirk,
Thank you so much for your contributions to RNAI, especially educate us from a science persoective. And I appreciate your frankness and honesty. That is normal that people are not happy when they lost money or not earned enough. That is also normal sometimes you made minor mistakes. We just like the way you are now! You are human being and not God who can make everyone happy. Whoever not happy here are basically not mature enough. Be yourself, do not be affected by those non-sense. Please keep up the fabulous work you have done to the whole world!

Anonymous said...

Today Dirk tweeted:

1. "Strange 2 get all this criticism over $ARWR. Still think has huge potential,but near-ter risk/rewrd changed. Started to talk abt it Dec '13."
2. "Problem is not me bringing up trial extension, but Co doing it w/out explaining to market pro-actively. Hence we need to speculate."
3. "+if u think that $TKMR will not come up w/ more potent HBV candidate,you are living in denial."

The criticism is not that you brought up the trial extension or the relative potency of ARWR versus TKMR. The problem is the appearance that you inadvertently (or intentionally) engaged in stock manipulation. And appearances do matter.

I start with the premise that you are honest and not intentionally seeking to manipulate any stocks for trading gains. That said, the last couple of days blog entries do give the appearance of stock manipulation.

I fully appreciate that putting forth one's opinion in the manner you do is often a thankless task. One gets attacked from all sides for every real and imagined wrong or mistake. At a certain point, defending oneself against all comers is both impractical and almost never going to win any points with your attackers. Nevertheless, there is a time when one should take heed of criticism. I think this is one such time.

If your intention was to goose TKMR at the expense of ARWR, then job well done. If you were simply posting your honest opinions and thoughts, with no intent to manipulate share prices, then you need to think twice before posting and consider the timing of your posts and the likely effect on the market. A little more circumspection and a little less heat is needed if one wants to be a responsible blogger. Like it or not, you are an influential player and your posts move markets. You get to decide how you will respond to this reality but the reality is you are not posting in a vacuum. So the question is do you adjust the manner, style and timing of your posts to minimize or magnify the impact on markets? An unscrupulous person would try to use this power for short term gain. An honest but still careless person ignores his effects and posts whenever the spirit moves him. But a fully responsible poster takes into account (or tries to) the effect his posts have and, to the extent reasonable, minimize that effect.

One might be tempted to dismiss the above as unnecessary nit-picking, as Monday morning quarterbacking, or some other kind of sniping that merits no reflection or changes in behavior. But consider the fact that Linda feels aggrieved and deceived by recent events. I submit that she is no typical sniper or fault finder. Dirk, only you know whether you intentionally tried to manipulate share prices. But if you didn't intentionally try to manipulate share prices, then the events of the past few days might indicate you are not sufficiently sensitive to and unaware of the effects your posts have on the market. If you care about your reputation, the fact that Linda feels so aggrieved should be reason for pause and reflection.

Respectfully, I submit that you need to be much more sensitive and alert to the appearance of things, less recklessly speculating especially during volatile market periods (options expirations,) and more transparent in your stock holdings. Full and transparent disclosure of positions is an important and necessary tool in avoiding the appearance of impropriety. As I suggested in a comment yesterday, a portfolio review is in order. And changes to one's investment holdings should not be hinted at in off-hand tweets.

Dirk Haussecker said...

I admit that in retrospect the timing of the Thursday/Friday posts was unfortunate. Only Bill Ackman may have known about the congressional Gilead HCV letter.

In addition, I was only expanding on something that the markets were already discussing RE ARWR: the possible reasons behind the trial extension.

I also have got to say that I feel vindicated by the trial extension, because clearly the company feels the dosing is not optimal...as I had noted before. Apologies for taking credit for it and I wished that the company had been more forthcoming about what it was doing (NO hint that the phase I was still alive, a lesson for IR).

Financially, I have every reason to hope that the share price of Arrowhead Research stays elevated and pull Tekmira up (since I am pretty confident that their HBV candidate will be a more potent one- in addition to all the other stuff they have brewing). In my opinion, it is TKMR that should have twice the market cap of ARWR and not the other way round. Much better if that meant ARWR at $30 and TKMR at $120.

Anonymous said...

I'm going to move past the current debate about whether or not Dirk is evil (he is not) to ask a simple question. Why do you think Arrowhead paid a license to Alnylam (in the form of a DPC license) when they had other, free RNAi trigger options (including UNA like Tekmira) available to them? Potency is not the answer you should be looking for.

Don't be surprised if the next candidate from Arrowhead also use a RNAi trigger from Alnylam.

Hint: Listen to the first few minutes of C. Anzalone's recent presentation at the Barclays Conference. The answer to this question should help Arrowhead investors sleep better at night.

Dirk Haussecker said...

2'F modification that Arrowhead, but not Tekmira employs, could be a reason for the license. UNAs can bring advantages, but they are not essential.

Anonymous said...

"I admit that in retrospect the timing of the Thursday/Friday posts was unfortunate. Only Bill Ackman may have known about the congressional Gilead HCV letter." - Dirk H.


The gentleman referred to major options expiry, surely you are not that ignorant.


"In addition, I was only expanding on something that the markets were already discussing RE ARWR: the possible reasons behind the trial extension." - Dirk H.


That you did. With a heavy negative bias. That's people's complaint. Not that you had a mouth and could talk.


"I also have got to say that I feel vindicated by the trial extension, because clearly the company feels the dosing is not optimal...as I had noted before. Apologies for taking credit for it and I wished that the company had been more forthcoming about what it was doing (NO hint that the phase I was still alive, a lesson for IR)." - Dirk H.


Said who is the reason, "the company feels the dosing is not optimal..."? Did you have it from Arrowhead? Or is it your negative bias since taking profit in ARWR and rolling it into the TKMR laggard? Arrowhead had made it clear that they wanted to accelerate the program and release test results as soon as possible. And they did, to the great relief of many of their investors. Since the initially planned cohorts went so well why is further exploration a negative automatically? Isn't the more data, the better foundation with which to go forward? After all, this is Ph 1, safety and tolerability on healthy volunteers, not efficacy. Your negative twists to everything are blatantly explained in your following statements:


"Financially, I have every reason to hope that the share price of Arrowhead Research stays elevated and pull Tekmira up (since I am pretty confident that their HBV candidate will be a more potent one- in addition to all the other stuff they have brewing). In my opinion, it is TKMR that should have twice the market cap of ARWR and not the other way round. Much better if that meant ARWR at $30 and TKMR at $120." - Dirk H.


There you have it, people. Straight from the horse's mouth. Dirk H. is all about pushing the TKMR laggard where he's put his trading money. Seeing it falling so below the new share offering price was the reason for all this hoopla about nothing.

People who still think this is about the science and not trading profits are beyond gullible.

Linda did well in showing the stock manipulator his own previous comments which completely negate his current trade driven negative twists re: dosing potency.

Yes, I am an investor in ARWR. On the basis that DPC will go far beyond the liver. And where liver targets are concerned, starting with HBV and ARC-520, the efficacy will not disappoint.

It's important to remember that ARWR's ARC-520 is now starting Ph 2. And the results will be known to the world shortly, where Dirk H. himself plans to buy shares to profit from the expected stellar results.

In contrast, TKMR's candidate has not seen the light of day! And all this pumping and hyping of a vaporware while putting down the more timely competitor is simply Dirk H. stomping for his wallet.

Sadly, the price of this short term gain is Dirk Haussecker's credibility fast approaching zero.


- investron

Anonymous said...

As a person with nothing other than a mediocre undergraduate degree who still has to clock in and clock out week after week to feed and house myself and the family, I can definitely say, I am reviled by the likes of Dirk, of which there are many, who through one means or another have come to be in a position of leadership and have ended up selling their ass for pennies to the detriment of many.

It is greed pure and simple. One of the most basic failings of human character. A deadly sin soon to be followed by gluttony and other avarice no doubt.

In the end, you have to wonder what kind of hyprocisy it is that consumes a person to do what he does one day, yet on another he holds up his mentor in HBV as someone to emulate.

Somehow, I got a feeling, someones career in their chosen space is about to come to an abrupt end. But at least you will have made your millions Dirk.

Sheldon Robbins said...

A six month lead in development of a compound over a competitor does not translate into overwhelming market dominance. The preference for two competing therapeutics will depend on safety, efficacy, durability of therapeutic response, ease of administration, frequency of administration, and price. For those of us who look at peer valuations and pipelines, there is a clear disconnect in the valuations of ARWR, DRNA, and TKMR. In twelve months, it is more likely that the market will confer a higher value to TKMR and perhaps, lower values to the other two. If you still want to be in the HBV space but can't stand the drama, consider DVAX.

Anonymous said...

ARWR were using a technology they referred to as able to escape the endosome.

Yesterday, a company in Australia called Phylogica (PYC), made a statement to market saying their endosome escape technology is able to increase efficacy of existing drugs by between 25 and 50 times. Not percent. Magnitude.

Frankly, I don't think I can believe them. It seems preposterous when the underlying technology is peptide based.

But after seeing the gains being made by ARWR with the chimpanzee and their claim of having similar technology the flip side of the coin says, maybe.

Are you aware of such claims by this company Dirk? Do you have an opinion on them?

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