Great point about OnCore.
One has to ask exactly what is the value of the compounds that OnCore brought with them? As I understand it, most of it centered around cccDNA. So if ARWR's AD conclusions are valid, TKMR may have bought a few pigs in a poke. I tend to lean toward thinking that TKMR's old guard is kicking themselves for agreeing to the merger. (In addition, that merger, I believe, led TKMR's CTO, Dr. Ian MacLachlan, to leave. The internal dissension must have been fierce.)
As an investor, I am constantly asking myself am I better off waiting for more clarity before buying or does it make greater sense to step up to the plate right now (referring especially to ABUS but it applies to almost all my investments).
"I am a believer there can be several winners here."
The key, of course, is demonstrating FC. If RNAi kd is integral to FC then, based on what happened with Hep C, several players should do quite well with the big prize going to the one who shows first mover advantage. So far I see 3 players here: ARWR, ABUS & ALNY. I'll add ISIS even though they are not an RNAi play.
Would love to know which company is in the lead right now. I would have thought that ABUS would have issued some sort of release or indication about their compound successfully targeting integrated DNA. Seems to me that the more time that passes without confirmation from ABUS the better for ARWR. Would have loved to have been a fly on the wall inside ABUS hq when the topic of ARWR's AD was front and center.
Apropos of my concern over nucleosides, DH tweeted the following:
"$arwr or someone else should run a study looking at integrated HBV DNA before and after nuke treatment. $abus"
Good question, PT.
During their last presentation, the CEO said they will in license an HBV compound by the end of the year.
My original assumption going back to early 2015 was that CTRV would out license their HBV compound. I thought that coupling it with an RNAi compound would make a lot of sense. Now I don't see this happening in light of ARWR's AD and am wondering just how viable a next gen nucleoside is.
Curious what other people think and why.
Like you I sold my CTRV 2 days ago on the news release.
So you are buying back today on the sell off following the offering?
I'm on the fence. I have a concern about their nucleoside in light ARWR's AD. Am I being overly cautious?
Also, CTRV priced the secondary at $3 and further are giving warrants along with the common. The steep discount to yesterday's price coupled with the fact they are packaging the common with warrants tells me there is not much support. I expect purchasers of the secondary to immediately sell the common and sit on the warrants. Sort of like a free lottery ticket.
Would like to hear your candid thoughts on these issues.
I agree that ultimate proof awaits clinical results. Referencing those slides is certainly not meant to be dispositive. I am simply a non-scientist investor trying my best to get a grip on the implications of ARWR's AD presentation. So far it seems that TKM-HBV has a trigger that directly targets HBsAG (i.e., S-Antigen as used in Linda's post quoting Biochemist). As I understand it, both Dirk and Biochemist seem to think TKM-HBV will consequently kd the integrated DNA that ARC-520 doesn't target.
I think the point is that prior to AD, all things being equal, ARWR was a year or more ahead of ABUS in the clinic. If TKM-HBV successfully targets integrated DNA, seems to me they are now in the lead.
Oops. s/b slide 51--not slide 57. Apologies.
Slide 14 from ABUS' 9-10-2015 Baird Presentation states that TKN-HBV's "Primary viral target is HBsAg."
Slide 14 is a newer and slightly different version of slide 57 from TKMR's 11-20-2014 Analyst Day Presentation. This earlier slide stated that TKM-HBV's Trigger ‘payload’ "reduces viral protein production, especially HBsAg...." and "All three triggers target the 2.1/2.4 kb sAg encoding mRNAs and also cleave 3.5 kb and 0.7 kb mRNA and pgRNA with potential for additional therapeutic benefit by reducing eAg, HBx, and core Ag."
Much appreciated, Linda.
I read that post a few days ago but haven't really understood the precise mechanisms at work here such that I can see for myself the validity of the conclusions asserted by Biochemist.
Your analysis seems refreshingly candid and right based on the information in the public realm.
Still, this question about the number of triggers is confusing to me. I'm having trouble wrapping my head around the notion that more triggers are necessarily better than fewer triggers.
As I understand it, ABUS has 3 triggers, ARWR ARC-520 (and ARC-521) has 2, and ALNY has 1.
I have it in my head that the important question is what specific RNA sequences are targeted, not how many triggers are incorporated.
Am I thinking about this right? If so, what precisely do we know about the RNA sequences targeted by the various HBV compounds in development insofar as the integrated DNA is concerned? (I think we know the answer re ARWR and you have offered your best current sense about ABUS' compound, but what do we really know about ALNY's compound except that it has 1 trigger?)
Question: As a consequence of ARWR's AD findings, is NUC therapy obsolete?
-Beginning at about the 34.52 min mark of ARWR's AD Presentation, David Lewis of ARWR discusses the Chimp data:
“So this is the first data slide and shows and shows you kind of at the beginning of the study what the DNA levels were in the serum in the graph on the left and the HBs-Ag levels in the serum in the graph on the right. Now we've divided both of these data sets according to the HBeAg status of the chimps because, as Chris mentioned, we saw differential responses to ARC-520 in these 2 populations. So at the beginning of this study, we saw very high DNA levels in HBeAg positive chimps, about 108 to 109 copies per m/L. Much lower amounts in HBeAg negative chimps where the levels were around the Lower Limit Quantification or the LLQ as shown there. After 8-24 weeks of NUC therapy, we saw dramatic multi-log decrease in the viral DNA levels in the HBeAg positive chimps and also a drop to almost undetectable levels in the HBeAg negative chimps. So this data that shows only what happens in the NUC only lead in period is similar to what seen in humans taking this kind type of NUC therapy. On the right we have our HBsAg levels. Again at pre-study we saw increased ... HBeAg positive chimps compared to that in the HBsAg negative chimps although the difference wasn't quite as large as what we saw in the DNA titers. And then similar to what we saw in humans, under NUC therapy, these HBsAg levels didn't really change. You can see that in ARC-520 day one. So NUCs don't really, although they have a very large effect on lowering DNA levels in the serum, they really don't effect HBs-Ag levels at all.”
What are your current thoughts regarding the case for or against ABUS' current HBV compound being able to successfully and kd integrated DNA?
I agree, Linda. Slide 21 can't be used to support the view that ABUS' HBV compound will also fail to successfully target and kd the Integrated DNA.
Slide 21 corresponds with slide 45 found in TKMR's Analyst and Investor Day dated November 21, 2014 (I downloaded it at the time).
Notice that at the top of slide 21 it says "Validation of RNAi-LNP Approach in Chimpanzee." From the 11-21-2014 slide 45, it emphasizes near the top left the following: "Sirna Therapeutics" & "Merck (Alnylam)" indicating (to me) the original source of the slide. On slide 21, this info has been moved under "Sepp-Lorenzino et al." Otherwise the graphs and other info seem identical between those 2 slides.
It definitely appears to be the case that this slide was first offered by TKMR (now ABUS) to merely validate their RNAi HBV approach and has since been slightly modified to de-emphasize the fact that the original source was Sirna/Merck/Alnylam.
(I tried to post a version of the above last night but Yahoo gremlins got the better of it.)
First, I am no scientist so I am unsure whether I am on the right track with regard to the following:
With regard to the potential of ABUS's current HBV compound to "luckily" target the Integrated DNA that ARWR's new ARC-521 is supposed to target, the following is a quote from Arrowhead's AASLD poster dated 11-3-2013:
"The two siRNA molecules in ARC-520 were selected from a panel of 140 HBV siRNAs using an in vitro system. Both sequences are highly conserved across HBV genotypes and together cover 99.6% of known genome sequences. They target sequences that are common to all the HBV RNA transcripts."
So ARC-520 uses 2 siRNA molecules while ALNY uses 1 and ABUS uses 3. Why suppose that ABUS' 3 molecules are anything but ever so slightly more likely to hit the Integrated DNA than either ARC-520 or ALNY's molecule? Is there something beside the number of triggers that makes ABUS more "lucky" than either ALNY's HBV compound or ARWR's ARC-520?
(Again, I readily admit I may be misunderstanding what is going on here so please forgive me if that is the case.)
I always enjoy reading your posts. I find them knowledgeable, insightful and refreshingly sincere.
Was your decision to buy some ABUS shares influenced by DH's recent tweet to the effect that ABUS may be "the lucky winner?"
I had been a defender of DH's integrity but no longer. In this regard, after rereading DH's 6-28-2015 HBV Knockdown blog entry entitled, "Aiming to Get Rid of cccDNA is Wasted, Potentially Harmful Effort" (hats off to Robawto for drawing attention to this blog post in light of ARWR's AD) I was struck by its uncanny prescience and came away wondering whether he had been privy to what ARWR had been doing perhaps as a consequence of his consulting work. He bills himself as an RNAi consultant after all.
Regardless, bottom line, I will not defend the man's ethics any longer--not because of that particular blog post but as a result of his manifestly self-serving and almost certainly disingenuous tweets. I think it is clear he is front running ahead of his tweets (not unexpected) but also issuing misleading posts about his trading positions and actions.
(That said, his knowledge of the science seems to this reader absolutely first rate and still a must read for all biotech investors.)
Given that ARC-521 uses the very same DPC already shown safe in the Ph1 ARC-520 trials, I believe that ARC-521 can skip Ph1 safety trials and go right into Ph2.
I think your question about the data is legitimate. However, there is always a balance that a biotech company must draw between releasing material data and holding back enough for peer reviewed publication. This balancing act is a long standing and very valid thing these companies need to do. If they release too much data, these peer review journal won publish their findings.
Does this sufficiently answer your question about the data details the 3 & 4 mg cohorts? I am not sure. Your suspicions may prove out in the end. This management has shown itself to be a bit cagey. For example they initiated their Ph1 study with just 1 & 2 mg data cohorts but then surreptitiously went to 3 & 4 mgs without public disclosure until the data was in and proved safe. Perhaps I should feel otherwise but this is the kind of what I want management to do since they must both promote and protect their company's franchise which at the time was riding completely on ARC-520's safety data. If that data wasn't shown to be safe, their entire DPC platform would have been crippled.
Also, wasn't a question asked about the data (perhaps more generally than the specific data points you want to know about) and Bruce Givens said that they had to choose the most relevant data to present because of time limitations, etc. I found this explanation satisfactory. I am satisfied that when the full data set is presented, we will likely be able to discern whether management failed to disclose this data because they wished to hide or obfuscate that data or whether a more innocent explanation is the case. Hopefully, at that point, other data will clearly point to a recipe for FC and the single digit share price will be a thing of the past.
All in all, yesterday was an exciting and emotionally draining day for longs (as I have been for a little more than 2 years now).
Nice post regarding Shkreli. (Always great to find someone who has been in a stock for the long haul as it provides for the possibility of learning from someone who has a lot of institutional memory about a stock as your Shkreli post shows.)
I am relatively new to NAVB. I came upon it when NAVB signed their Manocept deal with BIND and went long after deciding the risk/reward was very favorable in light of the potential upside of the Manocept platform while the downside was limited due to Lymphoseek being an approved product.
What is your take on the Manocept platform. Are you as excited about it as I am or should I temper my enthusiasm? Also, according to Nasdaq, short interest seems way too high. Numbers as of 8-31-2015 show 31 mil.+ shares short with 54 days to cover. I suspect short covering is the reason for NAVB's recent advance from $1.70 to $2.40. Still, it seems like there is more to go (i.e., more short covering) as the last reported numbers are so high. Do you agree? Any additional thoughts will be greatly appreciated.