Finally! Long overdue
(because so obvious and compelling), with the founding of Voyager Therapeutics, the
foundations have now been laid for a strong AAV (adeno-associated virus) platform gene therapy company, including DNA-directed RNAi Therapeutics. Taking advantage of new AAV shuffling approaches to
identify novel serotypes (Gao and Kay labs) to more efficiently and specifically
target cell types of interest and the world-class expertise in RNAi trigger design of two of its scientific co-founders (Kay and Zamore labs), the new company will make use of the best available
science to realize the potential of AAV and ddRNAi technology for the many diseases of
high unmet medical need in the CNS (e.g. Huntington's disease).
With $45M in start-up funding from Third Rock Ventures (the VC that has started the comparable lentiviral-based gene therapy company which recently went public, bluebird bio), they will deepen that expertise
through in-house research and
thereby sail by Benitec which sadly has refused to face the fact that in order
to be a platform company and stay relevant you need to have such efforts. If not at a time like this when interest is
high, then when?? The latest publication by Benitec and Pfizer (Denise et al. 2014) was ironically the best illustration of that omission by showing that the first-generation ddRNAi expression
technology of Benitec generates a plethora of small RNAs which obviously is less than
ideal. By contrast, work in the Kay lab
in particular (e.g. Gu et al. 2012) has shown how to generate much cleaner expression cassettes.
Voyager strutting its RNAi expertise and related therapeutic development plans is further
confirmation of the dramatic decrease in the value of Benitec's once-prominent IP position in ddRNAi (Graham patent). With an expiration of ~2018-2020 and Baulcombe the real gate-keeper (although the clock on that one is also rapidly running down),
I don’t see why there should be a need to take a license except for maybe the
likes of Calimmune which may have something close to commercialization by then
should things proceed without a hitch.
The start of a company like Voyager is always very exciting and I trust that the
scientific founders have the expertise and wisdom to guide it along the way. It is also a good time to acknowledge the
likes of Dirk Grimm (Heidelberg), Shuo Gu (NCI), and most recently Leszek Lisowski (Salk) which I had the privilege of
working next to in the Kay lab when they were critically contributing to the
technology underlying Voyager. The
pharmaceutical industry and indeed the investor community is wasting a lot of
potential by not tapping into the skills of such driven scientists just because they may not labor in one of the biotech hotbeds.
You are pro Tekmira and anti-Benitec. Do not twist stories Dirk
ReplyDeleteDirk - If you are hoping Benitec to fail, that will remain as a hope. May God bless you for all your good intentions
ReplyDeleteDirk, HCV phase 1 trial will prove you wrong. Good luck with your assessment on Benitec!
ReplyDeleteDirk: you must have a Mick Graham voodoo doll that you jab pins into these days.
ReplyDeleteRight now there is one, and but one, study raising a question about Benitec's AAV8 approach. That is the recent Kay paper using mice with mouse/human chimera livers. I think you should read sometime about how those mice are made hepatically chimerical. Nothing about their resultant liver histology is normal, including access to lymphocytes and macrophages and adjacency to endothelial cells. To posit that such human hepatocytes should behave as normal when it comes to transfectability by AAV8 in a mouse system, well that is preposterous really. It is one study, and hardly a definitive venue for assessing AAV8s vis a vis human hepatocytes.
You diss Benitec's IP portfolio, but Voyager has no IP portfolio to diss.
I agree with anonymous, Dirk. You are distorting narratives. You seek to have but one song to sing, and it is wearying.
obviously less than ideal?
ReplyDelete"The capacity to tolerate mismatches is important for an antiviral RNAi-based agent, particularly against a pathogen exquisitely equipped for resistance development through mutational escape. This is a well-described problem in HCV therapy on account of it’s error-prone RNA-dependent RNA polymerase.45 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,12 especially if one takes into account the mismatches in the replicon system and the inherent positive selection bias towards viral escape for cell propagation under G418 antibiotic selection."
..and a contradiction of a result from an earlier kay paper...
ReplyDeleteInterestingly, RNAi susceptibility studies on HCV using reporter constructs have indicated that the (−) strand RNA intermediate of the HCV genome may not be accessible to RNAi pathways.46 Our RACE-Seq results, however, suggest otherwise for TT-034 at least for shRNA6, introducing additional therapeutic advantages by extending the number of loci targeted to four, and involving both versions of the HCV genome.
Dirk, if you are no longer working in academia, then who are you working for. Perhaps full disclosure is warranted here?
ReplyDelete1) In regards to the differences in the negative strand HCV targeting claims---- Please compare the types of analyses that were performed in the two studies and then form your own opinion.
ReplyDelete2) The point Dirk makes about the various siRNA derived species made from the shRNA sequences in TT-034 has been taken out of context in terms of enhancing its ability to target HCV quasi species.
3) If you do not believe the results from the chimeric mouse studies--- how do you explain the 10-20-fold discrepancy in animal vs human AAV8 clinical trials?
What a biased load of rubbish Dirk... You constantly skew your content away from Benitec without genuine scientific validation and consideration of the fact that the majority of work in this field is currently covered by their patents!
ReplyDeleteFull disclosure: I'm a freelance RNAi Therapeutics analyst and consultant. I only tout/diss stocks when it is my own conviction. If you don't believe me, just ignore me.
ReplyDeleteDisk... your disclaimer says "This blog expresses only my opinions, they may be flawed and are for entertainment purposes only"... what value is there to purchasing your RNAi Guide is if is provided for entertainment purposes only!
ReplyDeleteBenitec have begun the first RNAi one shot cure clinical trial in humans, yet they are being left behind..I'm definitely missing something here.
ReplyDeleteWell, we know now how many are on staff at Benitec, if you include janitor.
ReplyDeleteThis is the problem with Australians.Is Ross still involved?
ReplyDeleteThe Baulcombe reference as being the real gatekeeper is plain wrong.
ReplyDeleteIts IP claim acknowledges the prior art included Graham, and their invention only applies after Graham.
Slightly important because it would not have been allowed otherwise, had it claimed Graham invention.
Calimmune already have a licence with Benitec, and their HIV trial is already dosing patients. Uniqure also have a licence with Benitec, for Huntington's disease.
ReplyDeleteSplitting hairs I know.
Can we can assume Voyager don't plan on commercialising anything until the next decade,
seeing as they figure a licence from Benitec won't be required?
Are they comfortable with the risk that the USPTO might be told by a higher court to extend Graham, if they don't decide to extend it themselves, due to the flawed re-exam which delayed re-award by 5 years.
Do they realise who actually owns Graham IP and defends it, and how bloody impossible they are to beat in an IP battle regardless of how long it takes?
Seems like a lot of people have seen right through this crappy blog post Dirk- I for one am not surprised as your affiliations (stock investments?) have been obvious for years. Are you selling your RNAi investment guide at AsiaTIDEs? I would be careful about what I say on the podium there, that ex-Pfizer author will be presenting this paper in Tokyo too and I hear he takes no prisoners with people touting hype. I sure hope he hasn't read what you have to say about his work and sure wish they invite him to TIDEs too.
ReplyDeleteIf you look at the author list, you will notice that these are the guys that made Alnylam tuck their tails between their legs about RSV01 (remember 15 by 15 folks?), washed out Santaris's claim on how their LNA antisense supposedly engages miR-122, and now they show Stanford how mode of action should be done - with the drug target as close as it gets to the real deal rather than some freak animal experiment or a reporter system artefact. I bet Kay is fuming he didnt think of using deep sequencing.
You can claim whatever you want Dirk. Benitec have done all the ground work more diligently than anyone else in the RNAi world- who goes so far out of their way to show how their candidate works, or even that the drug works in the first place?
You dont need a PhD to get it; they received earlier than deadline approval to start trials for a gene therapy for a disease that is not orphan/cancer/neglected/low hanging fruit. Its unheard of. Show respect where it's due and acknowledge the service to the field these guys are making, especially those nursing redundancy checks from Pfizer despite this quality work.
Er, folks? Nice argument about who's got the longest schlong and all, but am I the only one to be popping my eyeballs on the results that a 5 bp mismatch on the seed can still give on-target RNAi with an siRNA? Is it me or are these data putting into question how we think RNAi mediators pick their targets?
ReplyDeleteTHIS IS NOT FULL DISCLOSURE!
ReplyDeleteFull disclosure: I'm a freelance RNAi Therapeutics analyst and consultant.
Dirk was to lazy to more then cut and paste from the blog.
Freelance and consultant means hired hand to anyone who wants to pay his price.
This can mean: Other Pharma that wants the Benitec technolgy to fail, or stock boiler rooms that want to short or pump a stock for gain, Dirks personal investments are threatened, a Biosciences VC wants to accumulate stock at a cheaper price undercover, or a bigger Pharma wants to accumulate a position before a deal is made or may want to attempt a takeover. He can work with any of these people.
There are many ways for a "freelance analyst and consultant" to prostitute themselves. Dirk a while back used to post his stock holdings but that stopped probably because he was losing his rear. You will never get him to post who he analyzes for, consults with, or his true holdings. His dishonesty has become truly epic.
That's a bit rich. Dirk should delete that one as its based on nothing but the authors own bias.
ReplyDeleteI prefer to think of Dirk n Kays enmity for BLT being rooted in a much more personal level.
Dirk because he was fired by them and La Jolla.
Kay because of the Avocell history and his failed relationship with the CEO. Who ended up in Tacere. Now holds equity in BLT. Kay wants his revenge.
It really is that personal.
Agree completely on the bad karma between the principals.
ReplyDeleteAnswer this: Dirk buys quietly, he says, with his own money 1.5% or more of Marina Biotech. He then gives them a big verbal pump on the blog without explaining, in depth, the underlying value and tech of Marina. It was a very cursory explantion for an investment that size.
Since Dirk purchased 1.5 % of all shares at around the 25 cent level and it since has moved to 90 cents right after his recommendation I call this self dealing. He has a, scientific and public, fiduciary duty to give his readers the truth. He currently is up approx. $185,000 dollars on that one pump if he liquidates his position today.
Now tell me again that he's only here to enlighten the masses. I have a bridge to sell anyone who believes that. Oh by the way none of this is hearsay. It's on his blog.
So you make some money trashing and you make some money pumping. I guess it's all good. Nice payday by the way.
Dirk please give us an explanation on the blog not in the comments why you would put out a pump for Marina Biotech without a significant amount of backup corroboration?
I think we will hear crickets.......
Sounds like a Cramer trick.
ReplyDeleteDepending on who he is contracted to the SEC might find some fertile ground here.
Which could provide a reason as to why he was fired.
So the whole future in cancer research and 'the new science' revolves about dirk/ kay?
ReplyDeleteHope both die broke of cancer.
Who cares where his bias is.. Im just grateful someone is summarizing this field for those of us whom wish to follow this but not through FDA filings.
ReplyDeleteAt the end of the day its up to each of us to decide how we wish to invest and with whom. The final tally will come when the science is proven..
If your pining for Benitec and Dirks bashing them you should be glad your getting a discount.. its only in your favour that he doesn't like em. Actually you should be thanking him..
As for Marina we all saw the post its up to each of us to either follow him into that trade or not.. as in his disclaimer "its highly speculative" if a whack of other morons followed good on them they made money.. for those of us whom didn't have the balls or didn't believe Dirk stop frigging complaining because you missed a trade..
There is no doubt that this post has stirred up a lot feeling about Voyager using ddRNAi and Benitec's position. However, Dirk is entitled to his opinion and, in fairness to him, he has retained all the comments which disagree with his position, so I don't think we could reasonably expect more than that.
ReplyDeleteOn the BLT positive side, IF Voyager do not intend to take a licence from Benitec, then clearly they are not expecting to be in the market before 2018. Meanwhile, Benitec will be clinically advanced or trading commercially in ddRNAi drugs for HCV and NSCLC and its partners will be in the same position with HIV and Retinitis Pigmentosa.
While Voyager technology MAY be more elegant than the current BLT technology the fact is that BLT, its partners and Gradalis are the only companies likely to make any money out of ddRNAi for the foreseeable future.
I retract the statement about dying of cancer as very foolish. Both men should be applauded for their work and contributions to a dignified and necessary art. Sorry.
ReplyDeleteDirk, are you aware of VLA and their coxsakie virus for delivery viz the AAV?
ReplyDeleteDoes this shift with Voyager mean you don't rate it if you are?
May be the University of Westminster knows more about Benitec's TT-034 than some of the the commentators on this blog.
ReplyDeletehttp://www.westminster.ac.uk/news-and-events/news/science-and-technology/2014/university-of-westminster-develops-groundbreaking-method-to-test-hepatitis-c-cure
After Calimmune getting more CIRM funding for their BLT licenced ddRNAi HIV moon shot, yet more money, smarter than the smartest individual biotech brain, is going into City of Hope's ddRNAi HIV moonshots (plural - 3 ways to deliver to the masses).
ReplyDeleteNice thing for Benitec, who can start looking to open a lab now they are also well funded, is they have licence options on this programs CoH HIV patents which go well into the 2020's.
http://breakthroughs.cityofhope.org/rossi-grant-hiv/12322/
So might be an idea to go easy on the Aussie science sledging Dirk, or you may be the recipient of that GM pineapple Mick Graham is holding.
" is they have licence options on this programs CoH HIV patents which go well into the 2020's"
ReplyDeleteActually, Benitec does not have the option to license these patents. The option has lapsed and CoH is now free to license to whoever else they like.
According to BLT puff videoes, they have a lab with beaker carrying eye candy for staff. No wonder they fired Monsoon and Rudi.
ReplyDeleteDirk is completely right. Australian biotech is a weeping wound devoid of any credibility. BLT being the most notable. At least other failures were able to get into trials. Of their HCV trial ever does start it will finish the way PRAN did overnight.
No independent validation by peers says it all. Instead the company has been handed to Wall St VC sharks.
A get rich quick scheme for CEO'es, directors and now VCs it seems. Some Tacere folk have come back for a second bite on the cherry it wad that sweet the first time.
Don't agree with a lot of what Dirk says but on this one he is right on the money.
I would say its the poster child for all that is wrong in Australian biotech. I think the fault lies with Ausbiotech and CSIRO. Along with appointed management.
How would you know the CoH patent options expired as the terms were undisclosed? Making it all up like the last poster's tangential prose I think.
ReplyDeleteCoH HIV Option Expired
ReplyDeleteIf you don't believe me, simply ring the company and ask them. Then you can post an apology on this thread.
CoH option expired. BLTO about to in a week. If their execs weren't so busy self promoting in the media they would've had time to comply with listing requirements and suspend trading in them.
ReplyDeleteJust another clumsy piece of non-management from management.
Is Voyager any closer to achieving the following? Would give it commercial credibility of they were. Noteworthy too, is CSL, $34bn worth of company, has initiated the same type of ADR with the same sponsor for themselves. They go live tomorrow. Perhaps there are others from Australia doing same.
ReplyDeleteOddly however, there are still no quotes for the said code.
SYDNEY, May 30, 2014 /PRNewswire/ -- Benitec Biopharma Limited (BLT.AX) (OTC:BTEBY) is pleased to announce the establishment of a sponsored, Level 1 American Depositary Receipt (ADR) program facility, trading in the Over-The-Counter (OTC) market in the United States. The ADR program was declared effective in the U.S. on Friday 30 May 2014. The ADR ticker symbol is BTEBY.
From today's NYTimes (features Voyager Therapeutics within the article):
ReplyDeletehttp://tinyurl.com/ofr79vp
Gene Strategy to Fight Alzheimer’s Clears a Hurdle
By PAM BELLUCK
August 11, 2014 5:19 pm
Excerpt:
Dr. Steven Paul, a professor of neuroscience at Weill Cornell Medical College, has found that by using gene therapy to implant mice with APOE2, “we reduced plaque quite effectively and quite quickly,” even in mice that also had APOE4, he said.
Dr. Paul, who is head of research and development at Voyager Therapeutics, said he is now studying the effect in monkeys. “If all goes well, in a year or so we could be thinking seriously about doing this in humans.”
[Having cared for a grandmother and mother w/ Alzheimer's, hard for me to imagine something more exciting/satisfying than any form of real breakthrough in treating AD.]
Linda
Sure hope you have FTO from Benitec to go ahead and make all these appointments. lol
ReplyDeleteBut more interesting is what it is you are using to get across the BBB.
Brave enough to post a piece on your blog about that?
From Voyager's website:
Voyager Therapeutics is developing life-changing gene therapies for fatal and debilitating diseases of the central nervous system. Our founders include scientific and clinical leaders in the fields of adeno-associated virus (AAV) gene therapy, expressed RNA interference and neuroscience
What do you make of Benitec's agreement with Touchlight? You have called for Benitec to have its own lab and now it has. Do you see the doggybone technology as being a useful tool in the development of ddRNAi in the way that you have advocated in this blog?
ReplyDelete