The news this week that a young Southern Californian start-up has raised $18M in VC funding may not seem that much of an event in the
greater scheme of things. Considering,
however, that it concerns an RNAi Therapeutics platform technology, the
investment by VenBio and Aeris in Solstice Biologics deserves our full
attention. In fact, it suggests that the
RNAissance (Take 2) has finally worked its way through the biotech investment food
chain.
Investment suggests Big Pharma appetite for RNAi
Therapeutics
After Roche announced that I would leave the field a little more than two years ago, RNAi
Therapeutics platform plays were shunned by the VC community as untouchable
outcasts. More so than the knock it gave
on the confidence about the technology, the Roche exit, and following that related
moves by other Big Pharmas, was interpreted as if Big Pharma demand for the RNAi
Therapeutics platform was gone forever.
As Big Pharma interest is critical to platform plays because it provides
them with critical access to capital through technology licensing and perhaps
even an exit, the perceived lack thereof dried out VC funding for RNAi
Therapeutics.
Looking at the people behind VenBio, one would have to think
that they did their due diligence on this important matter such as by talking to Big
Pharma about RNAi Theraspeutics directly. Corey Goodman for example is a well
known, well-connected drug hunter and biotech entrepreneur who in 2007, as the
President of Pfizer’s Biotherapeutics and Bioinnovation Center
And yes, the renewed confidence may not come all that surprising given the clinical results that the field has produced over the last year, but it's very encouraging to see it come from VCs.
Technology behind Solstice
Unsurprisingly, the investment at issue is aimed at developing RNAi
delivery technology, currently the main driver of platform value. The idea here is to add to the RNAi trigger chemistries
that reversibly mask their negative charge so as to facilitate cell entry. Once in the cytosol of cells, enzymes chew off the
masking chemistries to reveal the RNAi trigger.
The idea is not entirely new. In the antisense field, morpholinos take a
similar approach to traversing the cell membranes in a neutral/slightly positive charge state. In RNAi Therapeutics, Merck according to their partnering website is actively soliciting for such technology solutions. If I may say so, the idea has
even crossed my mind and probably means that everybody else had
similar ideas even before that.
I would therefore have to believe that either the charm of
or the particular solution by the inventor Steve Dowdy (who also happens to be
the scientific founder of just-bankrupt Dicer dsRBD RNAi delivery company TaversaTherapeutics) has particular promise in the eyes of the investors. I’ve only had time to skim through the patent
applications, esp. WO 2010/141471, so I do not want to speculate too much about
the prospect of the technology by Solstice (shameless advertisement: I can
always be had for due diligence, of course).
Take the survey on the top right-hand side: Which Big Pharma company will make the first significant RNAi Therapeutics move in 2013? Merck, Novartis, Takeda, Pfizer, or Company X?
RNAissance!! It's so meant to be!
ReplyDeleteThis technology is not new. Isis tried this many years ago and is a spin off old Imbach oligo pro-drug chemistry using bio-cleavable phospate triester protecting groups. The literature shows that too many of these groups on an oligo led to insolubility, or they weren't cleaved in a reasonable therapeutic window. I guess Dowdy figured something out. Also, phosphate triesters are chiral, so in essence your drug would be a wicked mess of isomers that you'd think the FDA would not like. Verdine's brain child 'Ontorii' seems to address this. Any comment Dirk?
ReplyDelete$24m private funding ann last week to take Gradalis's Fang vaccine cancer clinical trials to late stage also significant for
ReplyDeleteRNAi, as this private funding party has had a good look
at this trial data.
Imbach/Ontorii...thanks for the pointers. What I would say off-hand about the issue that it has been tried before for antisense is that the window in which these groups would have to be taken off for RNAi applications would not be as exacting as it is for antisense applications. Actually, a slow-release may even increase RNAi potency.
ReplyDeleteGradalis...As I had alluded to before, Gradalis is an odd one to me. The press release about the $24M did not even mention the funding source...do you know? Maybe some crazy born-again Texas oil billionaire behind it? I'm not saying there is, but why the secrecy?
No i don't know who the Gradalis backer is, but i do think whoever he/she is they have undoubtedly had full access to the trial data to date, and they've decided to shell out copious amounts of cash.
ReplyDeleteThe beauty of having that trial data in the due diligence, which may well include actual face to face with patients, is even a big pharma exec from a soft drink company background, let alone a texas oil billionaire, can grasp whether it's worth getting behind or not.
and for dd on the science side of it, he would have paid someone super smart to do that, just from the loose change in his pockets.
Thankfully Gradalis certainly aren't the same type of outfit that Nucleonics were. In 2009 Gradalis delayed the start of their clinical trials, to better sort the delivery.
ReplyDeleteHere's an abstract due out that might shed more light on what Gradalis have done to date:
http://www.ncbi.nlm.nih.gov/pubmed/23027056
Regarding the chiral issue, the prodrug is chiral at the phosphates and composed of isomers, but the active drug converts to phosphodiesters and is not chiral at the phosphates. In comparison, every phosphorothioate ASO, including FDA approved ASOs, is chiral and remains as isomers in the active drug configuration. So the FDA does not appear to be concerned about phosphate chirality or multiple isomeric confirmations of oligonucleotide therapeutics (at least at this point in time).
ReplyDeleteIsis found the SATE/SPTE protecting group linkers to be unstable and that they spontaneously reversed before interpretable data could be accumulated. I have to wonder if this is another example of an under controlled and over-sold academic level project misleading the field.
ReplyDeleteThe 3000 lb fraud
ReplyDeletePlease, stop just providing hype for your stock investment and give al little more realistic evaluations of technologies. Forbes just coined Isis Pharmaceuticals as the Worst Biotech of 2012. In that article the author describes the Stanley Crooke in the following way “Crooke himself, who had a reputation for being too eager to hype experimental medicines and not willing enough to admit their flaws”. Steve Dowdy is mini version of Stanley Crooke: he too has no knowledge or understanding of the chemistry, biochemistry, or molecular biology of nucleic acids. Everything he has done at Transversa and now Solstice is a rehash or rebranding of work that has existed in the field for decades. The first time I saw him was when he embarrassed himself at the Nucleic Acids Therapeutics Society in Dana Point. When he presented absolute nonsense, Michael Gait asked how he was able to make, isolate, and use compounds that had been previously shown to be unstable in water, he answered that he had recently converted a cell biology graduate student to a chemist and that person had “magic hands” and could do things that no other chemist could do (like fudge data).
This is like watching the Chinese calendar that just cycles a set number of symbols but instead of asking if this the year of the rat or the year of the dog we just need to ask what lame attempt at reviving previously failed technology is Alnylam and its many disciples going to be using to get money this year?
1. Cholesterol conjugation
2. Lipids
3. Folic Acid conjugation
4. Peptide conjugation
5. Carbohydrate conjugation
6. Nano-particles
7. Two or more of the above combined
Companies like Isis, Alnylam, and now Solstice are the reason that no real progress has been made in nucleic acids therapeutics in years. They don’t invest in real research, they are the proverbial drunk who only looks for his keys under the street lamp because the light (or their patent position) is better there than up the street where he actually dropped them.
Is anyone interested in the SCIENCE behind siRNN?
ReplyDeleteI am the Chemist, UW-Madison trained not the “Converted Cell Biology Student” behind the proof of concept trials in the Dowdy lab and the Chemistry Founder of Traversa Therapeutics. I assembled the biolabile phosphotriester program within Dowdy’s lab and laid the foundation for all of his currently published work on the approach. The initial public UCSD data sets, at the time, were in fact compelling enough to fund further research through a round of financing. However, Traversa quickly re-discovered the SPTE platform stability issue and spent the next 3 years focusing on overcoming the premature reversal and potential genotoxicity issues associated with the first generation chemistry. Before its demise the company developed a working biolabile phosphotriester approach that was isolable and stable in aqueous systems. The modified siRNN constructs elicited a robust RNAi response and the modifications remained intact in boiling aqueous boiling buffer for up to 6m. I have since purchased full rights the technology US 13/120,409 with my own savings and I am happy to share the advances that we made with community in hopes that we can make some real progress towards the clinic with deliverable oligonucleotide therapeutics. I am available off-line at scott@triphosthera.com for continued discussions and through my LinkedIn account.
Hi Scott,
ReplyDeleteThanks for the comment. I am confused though...is the phosphotriester chemistry you refer to and have obtained rights to related patent application part of Solstice's technology?
Hi Scott,
ReplyDeleteThank you for the clarification, and for pointing us to US 13/120,409. I am not a chemist, so I was having a hard time picturing what a phosphotriester looks like - now I can see from Figure 1!
Correct me if I am wrong (your patent document had a lot of figures): At most, I count three positions that the phosphotriester can be incorporated into an siRNA: The 5' position of the 5' terminal nucleotide of passenger strand, the 3' position of the 3' terminal nucleotide of the passenger strand, and the 3' position of the 3' terminal nucleotide of the guide strand. I exclude the 5' position of the 5' terminal nucleotide of the guide strand because that position must be monophosphorylated in order to be loaded into Ago2's MID domain (unless, you already have some data as to how the Clp1 kinase can still use a 5' phosphotriester as a substrate?). So, how does the charge neutralization of three phosphates overcome the 39 other negative charges on the rest of the siRNA backbone, and allow cell internalization without a transfection reagent? Looking forward to these new chemistry developments.
Hello Dirk, the reversible phosphotriester approach works by modifying the amidite building blocks. These monomers are placed on an oligonucleotide synthesizer and can be added at any site within the miRNA, siRNA, hybrid or antisense oligo. In theory any phosphate can be modified with charge neutral protecting groups (RNN), groups that are modified to impart a positive charge (RNB) or a combination to achieve aqueous solubility. As already pointed out, a completely or even mostly neutral construct is not water soluble. By modulating the lipophilicity of the modified oligo the resulting pro-oligo is able to interact with the cell surface with the assistance of a cell localization moiety. Following an uncertain and highly debated entry mechanism the pro-oligo phosphotriester protecting groups are enzymatically cleaved inside the cell to reveal the therapeutic phosphodiester.
ReplyDeleteThanks, Scott. I'm still confused though about whether the technology you have acquired is the same one Solstice is based on. They do sound extremely similar.
ReplyDeleteDoes anyone know of the valuation of any of these investments? I am curious to know how siRNA therapeutics are doing compared to the rest of the field in terms of valuation.
ReplyDelete