Friday, January 10, 2014

Big Pharma Panic over Nucleic Acid Therapeutics

News this week of Roche licensing antisense technology from Santaris 3 years after having written down a related $500M+ investment in RNAi Therapeutics, is symptomatic for the apparent panic and resulting schizophrenic behavior that grips Big Pharma when it comes to Nucleic Acid Therapeutics (NATs).  Can NATs help rekindle their flagging discovery efforts or will NAT companies leave them in the dust as they advance to the top of the Pharma food chain?   

Meanwhile, Big Biotech in the form of BiogenIdec has also recognized that NATs are critical for their growth in the form of a partnership with Zinc Finger Nuclease specialist Sangamo Biosciences for the treatment of red blood cell disorders (sickle cell and beta-thalassemia).  This follows significant (~$150-200M) recent investments in ISIS’ antisense technology for diseases of the CNS and a deal with microRNA Rx company Regulus Therapeutics.

If you sit back and consider the clinical and preclinical developments in the space (look out for the upcoming RNAi Therapeutics Investment Guide 2014), there can be no doubt that nucleic acid therapeutics (including oligonucleotide therapeutics) are about to materialize as the 3rd major chemical class of drugs following small molecules and recombinant proteins.  In fact, their mechanistic versatility (gene up- and down-regulation, modulation of RNA processing etc) means that in a few decades, there will be many more NAT-based new molecular entities than small molecules and recombinant proteins combined, in many cases for genetically defined patient populations.  

Interestingly, in 2013, only 2 monoclonal antibody new molecular entities (NMEs) received marketing authorization by the FDA (see here).

Investors do not have to take such a very long view as a number of commercially attractive Oligonucleotide Therapeutics are gearing up to enter the market, including for TTR amyloidosis, Hepatitis B infection, spinal muscular atrophy, and hypertriglyceridemia.


For those interested in the more particular relevance of yesterday’s deals to RNAi Therapeutics stocks, the Roche-Santaris deal ($10M in upfront plus the usual biobucks and royalties) represents another blow to ISIS’ claim that it owns the IP in the space, especially in light of the ongoing litigations and patent battles between the companies and the fact that not long ago, Roche partnered with ISIS on Huntington’s Disease.  This should provide further comfort to those, including myself, speculating that Marina Biotech’s CRN chemistry is a valid equivalent, if not superior alternative to the ISIS and Santaris antisense chemistries.  Regarding the deal between Sangamo and BiogenIdec ($20M upfront plus the usual biobucks and royalties), it is a validation of the attractiveness of the hemoglobinopathy market that forms an important part of Alnylam’s pipeline options.


In additional RNAi Therapeutics developments...

Bad news for Benitec

In a recent paper by Lisowski et al. from Stanford (Kay lab) which appeared in Nature, very strong evidence was presented that the AAV8 serotype is far from ideal when it comes to transducing human hepatocytes.  This is in contrast to preclinical results mainly in mice that have shown highly efficient, almost 100% transduction of hepatocytes, the transduction level probably needed to achieve an RNAi cure of HepC.

Based on the preclinical work, the AAV8 serotype was readily embraced by gene therapists and adopted for various liver-related clinical studies. Surprisingly, however, the data so far in hemophilia did not support a significant advantage of AAV8 over the old AAV2 workhorse.

The study by Lisowski et al. shows that this is very likely the result of poor AAV8 transduction of human hepatocytes.  Among the multiple striking results, in mice with chimeric human/mouse livers, basically only the murine hepatocytes could be transduced whereas the adjacent human hepatocytes were not.

This is an unfortunate development that Benitec cannot be held responsible for.  It could be a double-whammy though for the company as in addition to the commercial concerns about the HepC indication for TT-034, results from the ongoing phase I study may not even support the delivery technology for other liver applications.  There is, however, light at the end of the tunnel as there are plenty new AAV serotype that appear to be as good in transducing human hepatocytes as AAV8 is in transducing murine hepatocytes.


36 comments:

Anonymous said...

I guess it won't be long before Benitec confirms whether the Stanford research is right or wrong. In fairness to Benitec, the non-human primate results for AAV8 were very similar to the murine model.

"Thus, a delivery method must be used that efficiently transduces nearly all hepatocytes, hence our choice of AAV8. Biodistribution analysis of over 30 different tissues from the cynomolgus monkeys dosed with TT-033 demonstrates that nearly 90% of AAV8 vector administered localizes to the hepatic tissues (data not shown, additional manuscript in preparation). Furthermore, transduction must be accomplished from a single administration of the therapeutic, as repeat dosing is untenable because of the humoral immune response which is generated by the memory B cells in response to the large infusion of viral capsids. Figures 3 and ​4a4a and demonstrate that transduction of TT-033 is near homogeneous across hepatic tissues from a single administration of the drug."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437581/

Dirk Haussecker said...

I agree, non-human primates were not much discussed in the Stanford paper, although I expect new investigations in light of the Lisowski paper looking at this issue in more detail. Nobody wants a Benitec failure, but you have to acknowledge that the report is quite troubling and believe me, the researchers were not looking for such an outcome at the outset of their studies.

Anonymous said...

Dirk, didn't you work at Stanford under Kay? If so your interest in BLT and its delivery must be more than passing. Possibly even constituting an undeclared conflict of interest. Especially, when we look at the Avocell days and how certain people there ended up at Tacere, only to end up back at Benitec holding equity.

Anonymous said...

Is it just pure coincidence that the timing for underscoring this study is days before FDA green light due on the TT-034 clinical trial start?



Anonymous said...

Wasn't Kay the guy who also killed all the lab rats using a massive overdose of ddRNAi, and discovered nothing John Rossi hadn't already predicted.

Pfizer and Tacer moved past murine models to non human primates and cured 80 or so of them of HCV using TT-034.

"When it comes to liver-directed RNAi, non-human primates have been accepted to be a highly predictive surrogate for performance in humans"
- Dirk.H, Nov 2013.

Anonymous said...

"Surprisingly, however, the data so far in hemophilia did not support a significant advantage of AAV8 over the old AAV2 workhorse"

Which preliminary data would this be?

Anonymous said...

If a chimpanzee's liver is not a good proxy for the human's, then even Arrowhead's future is questionable.

Anonymous said...

Fortunately for benitec, there has been much more good news over the past 6 months, on many fronts. Eg: their lung cancer programme has leapt forward with the pre-clinical work, and they are meeting FDA in Feb to discuss clinical trial.

If Kay's paper worth highlighting as bad news for Benitec, then the lung cancer programme's pre-clinical success would also warrant highlighting.

In any case we'll shortly get to read about TT-034 work to date in a peer reviewed journal publication, and if that doesn't answer questions, the clinical trial sure will.

Dirk Haussecker said...

Benitec should be proud of their supportive shareholders. Being afraid to discuss risks in a balanced manner, however, does not bode well for investment success.

Anonymous said...

As a small non-scientific ‘investor’- my hope is something of real scientific and medical usefulness comes out of the discussions and exploratory research associated w/ RNA. New discoveries ought be incorporated w/ older work for the advancement of the story.

http://lgo.mit.edu/news/articles/lo-cancer-megafund/lo-cancer-megafund.html

Anonymous said...

Murine models are often very helpful when it comes to proof of concept, but can often fall down when attempts are made to replicate positive findings in mice/rats/guinea pigs/rabbits etc in non human primate models. Tacere has done the hard yards in NHP and claim very favourable results with AAV8, so why believe a rehash of the previous work done in mice in preference to those NHP studies?

And like some of the others here, I'm curious to know just why you whipped up some negative vibes at this particular time, if you know what I mean.

Anonymous said...

Yet Dirk buys at least 1.5% of Marina Biotech and stands on the back of the wagon and trumpets it to the throngs. Now he accuses you investors of imprudent investment behavior. Now would any of you have purchased Marina an almost bankrupt company with what proven tech? Talk about the pot calling the kettle black. Also Dirk do you have any connection with the Marina team past or present? Your Marina stock seems to be doing extremely well just after your call.

I've read this blog from it's beginning and it seems Dirk is now a trader willing to judge and pick the winners and losers. Sad to see you go from promising scientist to bio stock maven/pumper and basher.
The dark side of money has won.

Dirk Haussecker said...

Mark Kay asked me to post this in response to some of the comments made here:

I would like to make a few statements in response to some of the comments about the paper we published in Nature. I was one of the senior investigators on the first clinical trial in which AAV was administered systemically in a human. This was AAV-2 vector expressing human factor IX. Although there was limited human data, the initial dose response was similar to what was predicted from the mouse and non-human primate preclinical data. The trial was stopped due to an unforeseen late T cell response that eliminated transgene expression. All of the investigators agreed the trial should not continue but there were mixed opinions about whether moving forward with AAV-8 should be the next approach.
I was a strong supporter of this idea but the company that made the AAV2 clinical grade vector was not willing (for many valid reasons) to make the AAV8 vector. I participated in the St. Judes/London AAV8-human factor IX trial. The first set of results have now been published in the NEJM (end of 2011). Prior to the trial and during the trial, I continued to support the idea of using AAV-8-shRNAs for treating hepatic viral infections. However, after the clinical trial was initiated, there was a result that was not anticipated. The AAV-8 dose response in humans was about 10 to 20 times less than that predicted from mouse and non-human primate preclinical studies. There are lots of possible reasons for this and I for one did not think the most likely explanation was a difference between human, monkey and mouse hepatocytes. We know there are lots of discrepancies between in vivo and in vitro transduction – even when the studies are limited to primary cells. Therefore, one of the goals of the Nature study was to use the chimeric murine human liver model to see if there were innate differences in AAV vector transduction between species in an anatomically intact organ. Realizing that all animal models have potential strengths and weaknesses, short of injecting people—this was the best way we could think of to make a comparison.

The second goal was to use the chimeric murine human liver and a process known as DNA molecular shuffling to select for AAVs with improved transduction properties. This is also described in the paper.

In terms of timing, the paper was published on Dec 25th. Nonetheless, we presented our data at multiple international meetings for more than a year and Benitec was aware of the results. For the person who commented on the shRNA induced toxicity in mice---many other labs have reproduced similar results in different tissues and animal models. Benitec scientists observed toxicity in both large and small animal models, which resulted in the need to use an altered promoter.

For the sake of disclosure, I was the scientific founder of Avocel. Even after I elected not to continue with Tacerebio, I was still in favor of an AAV8-shRNA trial for HCV infection. Of note, I would have used a very different expression cassette. However, my opinion on using AAV8 as a vector for an HCV trial has changed over the last couple of years.
The data is the data --- my opinions are shaped based on the data.

bio said...

I'm sometimes thrown by the seemingly random bouts of emotion that run through the gamut of responses/accusations in the comment sections of Dirk's articles.


"Yet Dirk buys at least 1.5% of Marina Biotech and stands on the back of the wagon and trumpets it to the throngs. Now he accuses you investors of imprudent investment behavior. Now would any of you have purchased Marina an almost bankrupt company with what proven tech? Talk about the pot calling the kettle black. Also Dirk do you have any connection with the Marina team past or present? Your Marina stock seems to be doing extremely well just after your call."

On the above statements, really? Dirk writes a free (scientifically accurate) blog that has zero competition as second, third, or fourth place contenders, publicly states his investment strategy AND HIS TRADES, and you can't help but be pissy about it? Are you more upset you didn't buy on Dirk's recommendation, or that he has been right on so many calls in the RNAi field?

I would agree that Dirk's blog is popular enough, because he has been correct much of the time on investments, that there is a 'Dirk Effect' where the mention of purchasing causes an influx of long investment and concomitant rise in stock price. How is this wrong? He stated he purchased the stock, you buy or not and either way take your chances.

Anonymous said...

The FDA has just approved an HCV RNAi gene therapy clinical trial.

http://uk.reuters.com/business/quotes/BLT.AX/key-developments/article/2902773

Anonymous said...

This paper newly published in Nature by Tacere / Pfizer researchers of interest to those invested in, or considering investment in, Benitec. Importantly, it's very material to the TT-034 clinical trial itself.

Knockers will knock but this is an absolute game changer if the trial results come out solid.

http://www.nature.com/mtna/journal/v3/n2/full/mtna201373a.html

Dirk Haussecker said...

The paper is the best support for what I've been saying for the last several years regarding Benitec: the company has failed to further develop its technology. This is because the paper shows that their expression cassettes generate a lot of 'garbage' RNAs as researchers in the field (including work by the Kay lab and Shuo Gu) have shown how to design more cleanly processed ddRNA expression cassettes. But hey, this is all free advice, so please don't take it seriously.

And I think it's funny that you are touting the paper although it actually represents a (unsurprising) setback.

Anonymous said...

As it's been proven safe and effective in mice and NHP's, and the FDA has agreed for the trial start, maybe Benitec are actually pretty smart on getting on with this therapeutic in the clinic. They will soon have more learnings than all the mice and NHP studies will ever give them.
And if they can improve their ddRNA expression cassette design even more then great, a potentially better therapuetic. If that is required.

This new paper shows they have done their due diligence on TT-034,and taking this deeper understanding of the candidate into the clinic is better than not knowing until later.

As for a set back, this from the paper argues otherwise:

"This is a well-described problem in HCV therapy on account of it’s error-prone RNA-dependent RNA polymerase. Herein, perhaps, might lie the biggest advantage of TT-034, in its capacity to generate a diverse panel of putative guide strands. Thus, mutations arising within the shRNA-targeted region might be tolerated by TT-034, allowing it to continue to suppress the virus effectively. Our in vitro observations so far suggest this might be the case,..."

So, sure, their expression cassettes may not be as elegant as Kay's, but maybe it's also a don't care to the bigger picture.

Good also to see this paper's support of TT-034's action against both the (+) & (-) strands of HCV RNA genome.

Anonymous said...

There will always be a 2.0 version, 2.1, 2.2 . . . Ok. While that ddrnai 2025 10.0 version is being developed on paper or in a lab, the real life story is live and in person, treating patients, right now. . .

Anonymous said...

Also, what you call "garbage", I call the lasting and beneficial production of an intracellular "vaccine" that has the ability to stop reinfection. . . Now, today. . . Will insurance companies pay for a second or third "cure". . .

Anonymous said...

I expect more of you, Dirk. . Too All: Please read benitec's ceo update from Jan 2014. While Kay researches how to make a better mousetrap, let's cure some human patients sooner. . . . .and with Kay's improved science, cure some more later. . . AAV8 today . . . Version LK03. . . tomorrow. . . Free advice would be harmless. . . Unfortunately your monologue is not helping patients get cured of a chronic disease . . .the patients of the world await . . . Seriously, Dirk, get back on board...

Anonymous said...

Man! What is it with these anonymous Benitec supporters who blame Dirk for all its failings?

I guess the leadership from shareholders and executive have got nothing to do with it. It's all Dirk's fault.

First rule of investing: don't fall in love with a stock.

Anonymous said...

Anyone see the BLT tweets from Dirk?

Most unusual for the vigilantes to still be in their holes.

Anonymous said...

Benitec announcement of confirmed shRNA transduction actually very encouraging! Dirk's tweets on the other hand say, well, nothing really from what I can tell.

Righto, back in my hole.

Robert Zack said...

I'm not anonymous. . . after Dirk's tweets and Micheal Murphys report, the stock goes up. No blame or complaints, here. Whatever these guys are saying, keep it up.

Robert Zack said...

Next article should be:

TRANSDUCTION PROVEN WITH 1 PERCENT OF THERAPEUTIC DOSE

again, not anonymous.

Robert Zack said...

Are you working with Benitec to make use of Lk03?

Robert Zack said...
This comment has been removed by the author.
Robert Zack said...

Note:

Not a random bout of emotion.

Robert Zack said...

Ladies and gentlemen: your attention please. Dirk, has finally decided to stop downsiding benitec. . . and . . . the anonymous accuser continues to be annonymous.

Anonymous said...

Benitec is using old technology. Wonder how much screwing with the promoter to circumvent toxicity contributed to the heterogeneity of transcription initiation that they observed? Garbage was indeed produced at the end of the day, not something to tout or be proud of, beyond them doing due diligence.

Anonymous said...

You may have a point there. RA Capital's Kolchinsky is selling down their holding with another million gone. Why would he be doing that just ahead of an IPO?

Maybe the IPO will never see the light of day. CEO will have to dream of big houses on the waterfront.

Anonymous said...

would suggest anyone thinking ra reducing holdings on the surface is a bad sign for the future of benitec to stop investing. if you had been watching the stock movements closely for some time now you would clearly see this is an attempt to draw more shares from previous holders. give it a couple of months, you will see what i mean.

Robert Zack said...

Fiscal year tax sale

Robert Zack said...

Dirk quit writing just when things are getting bright. . . I wonder how much he is buying before the ipo.

Robert Zack said...

Radiation is a "treatment". All medicine has garbage, side effects, toxicity. . . even vitamins. Everyone knows treatment is about dosing. . . and we got it.

By Dirk Haussecker. All rights reserved.

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