Thursday, May 29, 2008
MiR-122 has been shown to facilitate HCV replication as well as to have a role in cholesterol synthesis. Because of these potential applications and its expression in the liver, the tissue that can be best addressed with today’s systemic delivery technologies for nucleic acid-based therapeutics, miR-122 has become the favorite target for first generation microRNA-based development programs.
Santaris has made rapid progress and appears to be leading anti-miR-122 efforts, at least based on the published literature, with most prominently a recent Nature study demonstrating miR-122 antagonism in non-human primates, but also a nice transcriptomic study looking at changes in gene expression following miR-122 inhibition in mice. Santaris is using so-called LNA-“mixmers” which consist of a combination of interspersed DNA and LNA nucleotides and a phosphorothioate backbone and appear to act by sequestering the microRNA in the cytoplasm.
In mice, this LNA-antimiR-122 was quite a bit more potent than a competing technology developed originally by Alnylam and now owned by Regulus Therapeutics (‘antagomirs’) which were thought to induce the degradation of miR-122, possibly by RNase H. While these differences may also relate to the tissue concentrations and tightness of hybridization achieved by the various chemistries, my impression is that sequestration rather than RNaseH is the more promising approach to antagonizing microRNAs while for mRNA inhibition by antisense the opposite may be the case (e.g. morpholino versus gapmers). Moreover, the exact mechanism of action of the antagomir is still somewhat controversial, and I am curious to learn about the potency of antagomirs in vivo when formulated into SNALP-like particles.
A remarkable aspect of the LNA-antimiR-122 studies in non-human primates was the long duration of activity, up to 100 days after 3 loading doses of the antisense as judged by the lowering of plasma cholesterol. However, at this time point, the shift in the Northern blots which was taken to directly reflect microRNA sequestration, was not observed at this point. This could either mean that the Northern blot shift may represent an experimental artifact due to hybridization of antisense to miR-122 following sample preparation, and/or that the cholesterol lowering had persisted after LNA-antimiR-122 has ceased to sequester miR-122.
Of course, while the speedy technological progress is encouraging, there are a number of risks associated with this program. One is that it is unclear whether successfully inhibiting miR-122 in a chronic hepatitis C infection in man will have a meaningful effecgt on HCV burden. Compared to targets in RNAi Therapeutics trials, little is known about the actual role of miR-122 in HCV replication. Unlike in tissue culture liver cell lines which generally express less miR-122, miR-122 is a very abundant microRNA in the liver and may not be as rate limiting for HCV repliation in vivo. The argument, however, that this drug candidate lacks in vivo validation could be applied to a range of other HCV therapeutic programs, some of which have proven to be successful. The development of more convenient animal models for HCV infection over the next 5 years should change this and benefit not only the development of miR-122-based HCV therapeutics, but particularly RNAi-based HCV antivirals.
The Nature studies have also shown that anti-miR-122 may have limited utility for the treatment of hypercholesterolemia as its inhibition downregulated the “good cholesterol” even more than it did the “bad cholesterol”. On the other hand, given its abundance in the liver, it is likely that other indications for miR-122 antagonism will emerge and for which the Santaris phase I trial could be leveraged.
As far as the business strategy is concerned, maybe Santaris ought to solve the IP issues surrounding miR-122 for HCV once they initiate HCV-specific studies, as related IP fundamental to such an application has been exclusively licensed to Regulus and may thus limit the partnership value of this promising program.
Tuesday, May 27, 2008
With the strong financial position thus secured, for future deals we should expect to see a gradual shift from upfront cash-loaded deals towards those with a focus on the long-term strategic goal of maximizing the upside from the actual sale of RNAi Therapeutics. Opt-in rights, including the option to wait until the rather late stage of phase III trial start and yet gain 50:50 US co-development rights for promising drug candidates, are an important component of that strategy. And while we haven’t heard about the royalty rates, they should be “significant”.
Alnylam’s achievement of pioneering such a wide-reaching platform licensing strategy is both envied but at the same time also respected and admired by its peers, and unprecedented for biotech, including competing nucleic acid platform technologies, and points towards an important part of the future of drug development. In the words of John Maraganore, RNAi has become the big thirst quencher for innovation by the pharmaceutical industry, and Alnylam’s know-how and IP are the beer and tap for that.
Novartis looks to be the next to order a drink from Alnylam’s bar as it is now likely that it will exercise its right to more recent IP and enablement to put it on par with Roche and Takeda. Although the conversion of Novartis’ relationship with Alnylam is on pre-negotiated terms and will not necessarily follow the current $50M price tag per non-exclusive therapeutic area, John Maraganore assured analysts and investors that they were unlikely to be disappointed, especially since double-digit million dollar platform deals do not justify any more Alnylam’s deal efforts. After Novartis, the question then begs as to which US pharmaceutical is keen to gain first access to Alnylam-enabled near-term RNAi Therapeutics opportunities.
For those interested in following further developments in this story including the mechanics of Alnylam’s platform alliances, tomorrow’s special Annual Shareholder Meeting by Tekmira which will seal its reunification with Protiva and whose delivery technology is driving many of these first generation RNAi Therapeutics platform deals, is the place to turn your attention to.
Clarification: In my earlier post, I suggested that the $50M “near-term technology transfer payments” may be due if not as early as tomorrow on the close of Tekmira and Protiva, when Tekmira and Takeda will finalize their relationship. While much of the $50M may still relate to SNALP-RNAi, the company has now guided that the amount will be paid out, largely under the control of Alnylam, within 36 months and I guess could also be partly for tax efficiency purposes.
Alnylam Grants Takeda RNAi Therapeutics License for Cancer and Metabolic Disease and Anoints Asian Partner of Choice
The agreement is also another validation as to how important SNALP RNAi has become for the current valuation of RNAi Therapeutics, as both metabolic disease and cancer are the two major near-term opportunities for SNALP RNAi. Remember, Roche’s therapeutic areas also included metabolic disease and cancer, as well as certain liver diseases and respiratory disease.
That this deal was announced one day before the close of the Tekmira-Protiva reunion should also be no coincidence and the exact timing may relate to the interests of various Tekmira and Protiva shareholders. Furthermore, my expectation is that the announced $50M in near-term technology transfer payments refers to the final closing of Tekmira-Protiva as well as finalization of an R&D collaboration agreement for SNALP similar to the ones that Tekmira currently has with Alnylam and probably soon with Roche as well. It also reminds us that there are at least another 3 Big Pharma and biotechs that are currently evaluating SNALP RNAi with Protiva-Tekmira. So plenty of more news to come and auction dynamics to set in.
Takeda’s move once more emphasizes the thirst of Big Pharma for innovation. Takeda itself has just propped up its sales numbers and cancer franchise with a headline-grabbing $8.8billion purchase of Millennium Pharmaceuticals and adding to that another $150M for planning more long-term may not be bad for balance. And on the same business trip at that. This is because Millennium is also Alnylam’s Cambridge, MA, neighbor and former employer of Alnylam’s CEO John Maraganore. In fact, it is rather curious that John Maraganore was chosen by the Boston Globe to voice his views on the Millennium deal, to which he responded that “the deal could potentially free Millennium from worries about making every quarter's profit figures, allowing it to invest more money in drug development.” Well, with the $150M in added cash, and ~$400 already stashed in the bank, he has just gotten one step closer to that dream.
Takeda has just had a high-profile failure for an cholesterol-lowering drug candidate, and may now be keen more than ever on exercising its right to partner Alnylam’s PCSK9 program for Asia. ALN-RSV01 interestingly is the only program that Takeda does not have first right of refusal, and may indicate yet another deal in the Alnylam pipeline.
Takeda is also strong in the diabetes area, and it will be interesting as to whether Takeda will pursue such programs with RNAi soon and for which liver-expressed genes may be targeted. This may particularly benefit Alnylam since, unlike in the Roche deal, it now has also the opportunity to opt into Takeda’s RNAi Therapeutics programs in a 50:50 relationship.
Based on statements such as "We believe this alliance will accelerate our initiatives to establish the foundation for RNAi drug discovery" in the presss release by president of Takeda, Yasuchika Hasegawa, it also appears that Takeda has been quite a bit active in RNAi Therapeutics already. Moreover, the deal provides for a cross-licensing of delivery technologies, and it will be exciting to learn what these are.
Novartis, Roche, and now the Takeda deal by yet another major foreign company may illustrate two points. One is that the US currency has fallen so low that foreign companies cannot resist the opportunity to secure their rights to US innovation, in this case to RNAi Therapeutics at bargain exchange rates. The other is that Alnylam may want to keep US rights to itself for the time being.
Finally, the deal is yet another validation that if you have money and are serious about developing RNAi Therapeutics, Alnylam is the company to partner with for access to fundamental IP and, thus far, enablement, too.
Sunday, May 25, 2008
While the share price decline in companies such as Nastech is to a large degree to be blamed on company-specific issues, the difficulty of raising capital at reasonable terms has only accentuated the downfall of companies in need of near-term funding and has taken on dynamics that make me think twice about whether the time to do some bottom-fishing has come.
When it comes to bottom-fishing in RNAi Therapeutics, the issue is whether the markets have only accelerated the inevitable process of separating the good from the bad, or whether some the of the affected companies could be turned around with good management if they were afforded the necessary funding.
Separation based on scientific and financial track records probably accounts for the difference between Alnylam’s +1.6% increase versus -46.4%, -48.9%, and -67.9% declines, respectively, for Alnylam’s main synthetic RNAi competitors Silence Therapeutics, RXi Pharmaceuticals, and Nastech. Among those three, RXi with its motley patent portfolio (access to Hannon and Tuschl I) and preferential treatment by the State of Massachusetts may be the most interesting, but is hurt by development programs that do not appear to have sufficient maturity.
Nastech may be better off not to compete on the RNAi trigger side (“mdRNAs”) and instead concentrate on peptide-mediated RNAi delivery. As by far the best performer in the portfolio, Tekmira, demonstrates, innovative and clinically credible RNAi delivery capabilities are more likely to be rewarded by the market than companies built on yet another, not-so-innovative RNAi trigger designs.
Next to siRNA delivery companies that have gone down with the overall markets, but of which the science is promising, it is DNA-directed RNAi companies that may offer some of the most attractive investment opportunities right now. Admittedly, gene therapy investments historically have been a huge disappointment with an even much greater failure rate than for normal drug development already and a handful of overly publicized safety incidents. This means that even a phase II rheumatoid arthritis program by Targeted Genetics is valued essentially at zero. However, an increasing number of exciting gene therapy proof-of-concept studies, such as the two recent publications on the vision improvement by AAV gene therapy for Leber’s Congenital Amaurosis, indicates that gene therapy is finally starting to realize its therapeutic potential after years of trial and error.
While (synthetic) siRNA Therapeutics may be preferable for the majority of RNAi Therapeutics applications, DNA-directed RNAi, especially in conjunction with AAV and lentivirus, due to its often more advanced delivery efficiencies, potencies, and long-term expression may have a number of applications for serious and difficult-to-treat conditions such as neurological disorders or together with stem cell therapy (e.g. HIV trials by COH/Benitec). With the right IP, therapeutic portfolio selection and resource allocation strategy, an investment in DNA-directed RNAi at this point may both give the companies' R&D efforts the much needed financial boost as well as reward the investor once the biotech market has returned to more normal valuations. Of course, if the overall market conditions don’t change, there is nothing to stop investors to remain on the sidelines and just wait for even cheaper prices while, unless of course Big Pharma's thirst for innovation causes it to pull the trigger first.
Friday, May 23, 2008
Since the discussion will be, by necessity, quite technical and probably cannot easily be followed by every reader of this blog, here the take-home messages upfront:
1) Dicer may enhance gene silencing by short, less than 23 base-pair siRNAs without, as expected, actually cleaving them and, in the broad sense, such siRNAs could be therefore regarded Dicer-substrates, too;
2) Long >23bp dsRNAs may function in gene silencing without having been cleaved first, similar to how classical short siRNAs are thought to function; since typically the majority of synthetic Dicer-substrate RNAs recovered from cells following delivery remain unprocessed, the question arises what fraction of the silencing effect in “Dicer-substrate” gene silencing experiments is actually caused by products of endonucleolytic Dicer processing;
3) The 2 nucleotide 3’ overhangs structure is the consequence of Dicer processing and may not be a required feature of RNAi triggers;
4) A large-scale comparative study comparing the effect of length, Dicer endonucleolytic processing, and 3’ overhang on RNAi activity, is warranted;
5) Lawyers are certain to profit where biological boundaries blur.
To understand the fundamental importance of size in RNAi Therapeutics, one has to appreciate that while in 1998 Fire and Mello made the seminal discovery that double-stranded RNA (dsRNAs) was the inducer of RNAi, it was Tuschl and colleagues three years later that discovered that it was 19-23 base-pair dsRNAs with 2 nucleotide 3’ overhangs, the products of Dicer processing of long dsRNAs, that were the more immediate mediators of mRNA targeting during endogenous RNAi in Drosophila. Importantly, these siRNAs allowed RNAi for the first time to be used in mammalian cells since, unlike long dsRNAs which had been used until then in lower eukaryotes, were not efficient triggers of the non-specific and cytotoxic interferon response. And it was only then that the adoption of RNAi as a tool for human gene function analysis and its development as a therapeutic really took of (see page 8 of RNAi IP study).
By adding to cells the structural mimics of long dsRNA processing by Dicer, the use of siRNAs of less than 23 base-pairs was therefore thought to circumvent the need for Dicer processing and that the RNAi trigger would be directly incorporated into RiSC (RiSC is the effector enzyme complex containing the endonucleolyic Argonaute protein at its center that uses the guide single-stranded RNA of the siRNA for seeking out and destroying mRNAs with base pair complementarity).
However, the way most biological pathways work efficiently is by connecting the individual steps, and so it probably didn’t come as a great surprise that more and more data emerged showing that the dsRNA processing and downstream gene silencing stages in RNAi would be both physically and functionally coupled.
The very first dsRNA processing studies by Tuschl himself (2001) provided “evidence that the direction of dsRNA processing determines whether sense or antisense target RNA can be cleaved by the siRNA-protein complex”, meaning that although in isolation two Dicer products may be chemically identical, their activity may differ depending on how they were generated by Dicer, thereby indicating coupling.
In 2003 then, Doi and colleagues demonstrated that when Dicer activity was suppressed, the efficacy of gene silencing by <23 base-pair siRNAs was also suppressed as a consequence, similarly indicating coupling between Dicer and RiSC, but this time separable from actual Dicer cleavage. It therefore challenges the notion that only longer dsRNAs would benefit from biological coupling since only they would function as endonucleolytic substrates of Dicer. This notion has partly been based on results from work in ES cells in which Dicer had been completely eliminated and short siRNAs were still functional. I would argue that while this may well be the case, it in no way excludes a contributory role for Dicer in RiSC loading of the siRNA.
Another interesting study in 2002, again by the Tuschl group, showed that single-stranded RNAs could also induce RNAi, albeit at a much reduced efficacy compared to siRNAs. With the benefit of hindsight, maybe this was not too surprising as well since the double-stranded RNA at one point had to become single-stranded to guide target mRNA cleavage. What I, however, found a particularly interesting observation in that study and in a related patent application was that single-stranded RNAs of various lengths, from 19 to at least 29 nucleotides if not longer, could function as guides in RNA silencing. This for the first time suggested that while classical siRNAs and related microRNAs of similar length and structure may well be the natural inducers of RNA silencing in humans and their processing was functionally coupled to the RiSC effector stage, RiSC may actually also be able to use RNAs of different size and structure.
The somewhat blurred distinction between classical Tuschl siRNAs and longer dsRNAs should also have implications for the interpretation of RNAi-related IP. For example, would a company like Dicerna have to proof that the majority of the observed silencing effect is mediated by siRNAs that had been processed from longer precursor dsRNAs? And does the definition of Dicer substrates include Dicer-mediated RiSC loading in the absence of cleavage? There is also, not surprisingly, some discrepancy in the literature. Whereas some groups report that only longer dsRNAs benefit from the presence of Dicer (e.g. Gregory et al.), other reports (e.g. Doi et al.) suggest that Dicer promotes the activity of short siRNAs as well. Also, the observation that so-called “rxRNAs”, RXi Pharmaceuticals’ quite heavily modified blunt-end 25mers that are not cleaved by Dicer (Keystone poster, 2008), can still function in RNAi, further supports that differences in RNAi activity dependent on the dsRNA length may not necessarily be a consequence of Dicer processing.
Regardless of the practicalities and relative safety of using dsRNAs of various lengths and end structures for RNAi Therapeutics, it would be interesting to conduct a detailed, large-scale comparison of RNAi functionality of the various RNAi triggers, including an investigation of the contribution to silencing activity by Dicer, both in RiSC loading and endonucleolytic processing, through the use of Dicer knockout cells.
Saturday, May 17, 2008
Certainly, progress in both areas in the last 3-5 years has mutually benefitted the investment climate for both technologies as it has heightened interest and increased confidence in RNA therapeutics in general. However, the two technologies also compete for investment dollars with many of the same investors, which are typically upbeat about the future of gene-based medicines but unsure where to place their bets, allocating their investments based on where they see most promise. One issue that often comes up in making this decision is the observation that while for systemic applications antisense, as practiced in the most advanced programs today, is typically administered without a particular delivery formulation, the development of specialized delivery technology is frequently cited as the key challenge for RNAi to realize its ultimate therapeutic potential.
Antisense for gene knockdown works largely by two mechanisms: interfering with translational initiation (e.g. AVI Biopharma's morpholinos) or through an RNase H-type mechanism (e.g. Santaris and ISIS Pharmaceuticals). For this, the key factor is to achieve efficient hybridization of a single-stranded oligonucleotide antisense with its target mRNA which either prevents productive ribosome association to the mRNA (inhibition of translation initiation) or may be recognized as a substrate for the RNase H enzyme which may degrade the RNA portion of the mRNA-DNA duplex, but normally functions in the degradation of the RNA primer during DNA replication.
Various oligonucleotide chemistries have been developed to optimize these processes for in vivo applications. Essentially all of these are single-stranded oligos of which the sugar phosphate backbone is heavily modified to a) increase their in vivo stability; b) improve their pharmacokinetics and avoid rapid renal excretion by promoting their association with components of the blood; c) similarly allows them to be retained in tissues; d) facilitate crossing of cell membranes; and finally e) increase their target mRNA binding. By contrast siRNAs, because of their charge and more rigid double-stranded nature and with apparently some exceptions that include mucosal epithelia, do not cross cell membranes efficiently on their own and therefore need to be specially formulated for most applications.
The use of unformulated antisense is consistent with their mechanism of action. Since antisense does not harness a naturally existing endogenous gene silencing pathway, it relies on achieving concentrations of oligonucleotides in the target tissue over a prolonged period of time that are high enough such that, as a result of the rules of thermodynamics, a sufficient fraction of target mRNA will be recognized. Similarly, unlike RNAi, the specificity of antisense is largely governed by biophysics and benefits only relatively little from biological proof-reading.
In practice, to achieve the necessary tissue concentrations, patients are typically dosed frequently at the initiation of therapy so that the tissue concentrations reach steady-state therapeutic levels. Targeted delivery of antisense into cells of interest may allow one to achieve a knockdown earlier, but any benefit would only be short-lived as antisense is not retained in specific gene silencing complexes but will soon redistribute according to their partition coefficient throughout the entire tissue so that ultimately similar amounts have to be administered and a formulation would only be a nuisance with little benefit.
By contrast, RNAi harnesses an endogenous and catalytic gene silencing mechanism, which means that once it has been delivered, either by conjugation or in nanoparticles into the cytosol, they are efficiently recognized and stably incorporated into the RiSC silencing complex to achieve prolonged gene silencing. In fact, measurable RNAi-mediated gene silencing can be observed at siRNA concentrations so low that it becomes difficult to detect them (e.g. fluorescently-tagged siRNAs by microscopy). This means that as the majority of siRNAs that do not reach the cytoplasm may disappear quite rapidly, the total exposure of the body to the nucleic acid can be much lower compared to antisense which should be beneficial both in terms of safety and pharmacodynamics (activity profile of drug over time).
This is not to say that chemical modification is not practiced in RNAi. However, unlike in antisense, the purpose of modification in RNAi is mainly to avoid triggering innate immune responses, making the siRNA sufficiently stable so that they survive their journey into their target cells, and also to stabilize them as part of RiSC (Merck has been talking about that concept on several occasions); and as we learn more about the biochemistry of endogenous RNA silencing pathways, modification is also increasingly used to increase the inherent biological specificity of RNAi. Unfortunately, it is surprising to me that compared to RNAi only very little, if at all, is reported about the specificity of antisense and I would be grateful if somebody here could point out pertinent studies that I should be aware of.
Targeted delivery may also avoid unnecessary drug exposure of non-target tissues. For unformulated antisense, no matter what the indication and target tissue, the biodistribution is essentially the same, and toxicities of the liver and kidney due to extended exposure to large amounts of the heavily modified antisense compounds is well known.
Certainly, improving the therapeutic index is an important issue for RNAi Therapeutics, too, but as the many transgenic mouse models which express ample and highly efficient RNAi throughout their life without causing overt toxicity attest, ultimately the improvement in the therapeutic index of RNAi is not limited by its very mechanism of action.
While it is a certainty that antisense companies will come out with 4th and 5th generation antisense technology, advances after decades of antisense research aiming to improve target mRNA recognition will only be marginal and based on trying out yet more nucleic acid modifications, although it appears to be a challenge to improve upon the efficacy of probably the most potent antisense modification that have now been known for a while, namely LNAs and their derivatives.
While RNAi efficacy in animals has already surpassed that of antisense for applications of the liver and lung as well as other tissues, I am confident that future advancements in RNAi will be more than marginal. For example, even as recent liposomal formulations achieve 90% gene knockdown in the liver at 1mg/kg, this still means that only about 1 in 10,000 siRNAs that have reached the liver makes it into the cytoplasm (assuming it takes about 1000 cytosolic siRNAs to achieve that level of knockdown according to a recent presentation by Phil Sharp). Alone a better understanding of the endosomal uptake of these nanoparticles, which is only in its infancy and starting to be explored, should allow for more than incremental improvements in the therapeutic index of RNAi Therapeutics.
And if you are still undecided on where the future is heading, numerous transfection studies in vitro where it can be assumed that equal amounts of antisense and siRNAs are present in cells, have shown that RNAi is quite a bit more potent on a mole-by-mole basis comnpared to antisense.
I am aware that some in the antisense community, including investors, may take offense with this blog, but since I am often asked about this issue, I think a more straightforward approach is better than to keep beating about the bush. And, of course, there is always the comment section.
Sunday, May 11, 2008
As discussed before, both bioinformatics and gene profiling technologies can be applied in the selection of candidate siRNAs with the least likely adverse off-targeting effects. Bioinformatics may avoid sequence elements that occur at high frequencies in mRNAs or in a particular unwanted genes, while microarray profiling may experimentally pick out those genes which are downregulated at least on the RNA level which, despite some caveats, is still a pretty good predictor of off-targeting (note that potentially even more predictive protein mass-spec techniques may also be applied soon for off-targeting). In that manner, it is possible for Merck, for example, to screen out those siRNAs which off-target numerous genes or those genes that you would rather leave untouched. Finally, chemical siRNA modifications may allow for the general reduction in the number off-target interactions.
Still, with all of this in hand, off-target risk remains. Due to the redundancy of the genetic code, it should be generally easier to translate into humans off-target phenotypes from preclinical models for protein-targeting drugs than for RNA knockdown therapeutics. That means, a given drug is more likely to still interact with the same homologous protein in different species because the overall function and therefore usually shape of a protein is more conserved than the underlying mRNA sequence, while even a slight nucleic acid change at even a single position may decide whether an mRNA is an off-target for an siRNA or not at all. So what may be true for off-targeting even in a non-human primate may look quite different in man.
Off-targeting should be a concern particularly for chronic applications of RNAi Therapeutics. A 50% reduction in an important gene due to an siRNA for hypercholesterolemia for example may eventually manifest itself as an off-target toxicity following prolonged drug use. While this is true for essentially any class of drugs, RNAi Therapeutics may have an advantage. Because siRNAs as a class are quite homogenous in terms of pharmacological properties, how about entering two siRNAs targeting the same gene into the clinic, as a single drug development program, but whereby the siRNAs are given alternately?
This would be somewhat similar to how siRNA cocktails are considered for cancer and antiviral RNAi, but with a different rationale, or the idea behind Dharmacon’s smartpools. Just change the siRNA and leave the rest the same, including the delivery formulation. Similar to food where it’s better to consume a varied diet than constantly eat a single healthy dish, that way the siRNA would be changed before an off-target had the chance to manifest itself without having to take a drug holiday. That way, the fact that, unlike protein-targeting therapeutics, two siRNAs even for the same target have completely different off-target spectra, could be turned into an advantage.
I’m not sure how well this would go down with the increasingly defensive FDA, but maybe they could make a start and be more open-minded when it comes to new technologies.
PS: Another advantage of RNA knockdown therapeutics versus protein therapeutics is that it’s much easier to measure changes in RNA and protein abundance (RNA therapeutics) than determine drug-host interactions and their potential consequences, which in the case of RNA therapeutics, as a class, should be quite predictable while they should differ much more widely in the case of say small molecules.
Wednesday, May 7, 2008
It is no secret that Big Pharma, already in the midst of fighting a losing battle against loss of marketing exclusivity for many of their blockbuster drugs, is desperate for innovation. RNAi may have been one answer for Novartis in 2005 for the longer term, but it wasn’t really clear then what the time-lines would be, and Novartis certainly could not have viewed RNAi as a solution for the imminent bleeding. In terms of systemic delivery of synthetic siRNAs, the ability of which would significantly add to the value of the RNAi Therapeutics platform, a 2004 Nature paper on intravenously injected cholesterol-conjugated siRNAs in mice using non-therapeutic dosages was the best Alnylam had to offer. $10M upfront cash and the validation by a respected Big Pharma company seemed like a fair deal at the time in return for quite broad access to the leading IP estate in RNAi Therapeutics.
Novartis-Alnylam was a visionary deal. It does not matter so much if you label a deal a “$1 billion” deal or not, since more often than not, you’ll find that those are biotech dollars, not the kind of money you can actually use to buy something at the supermarket, with little hard, non-dilutive upfront cash. Blue-sky thinking, however, cannot command $M270+ upfront payments, or come even close to justifying Merck’s $1.1billion acquisition of Sirna Therapeutics in October 2006. To demand such numbers, RNAi Therapeutics companies must be able to present Big Pharma with good evidence at the deal table that tools exist that could make RNAi Therapeutics become a reality in the not-too-distant future.
In my opinion, such evidence was provided by two major publications on the systemic delivery of siRNAs using SNALP liposomal technology. One was published in late July 2005 and concerned the successful targeting of HBV in a mouse model using dosages of SNALP-siRNAs that started to look clinically realistic and sufficiently scalable for commercialisation (a Sirna Therapeutics-Protiva collaboration), the other one was the first demonstration of systemic RNAi in non-human primates in March 2006, also using SNALP-siRNA formulations (an Alnylam-Protiva collaboration). The value of this was not lost on Tekmira, Protiva, Sirna, and Alnylam, and soon a messy four-way battle for ownership and access to SNALP-RNAi ensued.
As the dust began to settle, it appeared that while Protiva was to be credited with much of the scientific work, Tekmira owned the IP. Sirna therefore cancelled the relationship they had with Protiva in February 2006 and pressed ahead with their own “proprietary” liposomal formulations, which a judge would later determine may have not been that proprietary after all. Alnylam, on the other hand, was more concerned about respecting both IP ownership and scientific collaborations and, as we know now, continued to work with both Tekmira and Protiva.
What evidence besides the legal wrangling is there for SNALP RNAi having considerably contributed to the $273M and $1.1billion price tags? Three events can be cited: the Merck-Protiva settlement in October 2007, the scope of the Roche-Alnylam alliance in July 2007, and the recent Protiva-Tekmira reunion. Whether or not Merck actually has a SNALP-RNAi candidate in clinical trials or not is open to speculation, but the fact that they were forced into a settlement with Protiva, essentially allowing Protiva to stay alive, after a California Court severely limited Sirna Therapeutics/Merck’s use of SNALP-related technology on issues of trade secret infringement, indicates the importance of this technology in Merck’s RNAi Therapeutics efforts. Similarly, when one carefully analyses the scope of the Roche-Alnylam licensing deal, three out of the four therapeutic areas that Roche obtained access to through this deal, non-exclusively, can be addressed, at least in part, by SNALP RNAi: liver disease, cancer, and metabolic disease. The fourth therapeutic area, respiratory disease, further illustrates that this deal was tightly linked to currently available enabling technologies (note that Alnylam’s lead product, ALN-RSV01 involves a respiratory target), SNALP RNAi most importantly. This could possibly also mean that as the time approaches for Novartis to decide whether to extend their relationship with Alnylam or not, that a new deal will be similarly based on such realities, making it in fact easier for both parties to arrive at fair values. Again, the Tekmira-Protiva reunion came just in time.
And finally, the Protiva-Tekmira reunion clearly signals that clarifying the legal situation around SNALP RNAi and streamlining its scientific development, was important for both Protiva-Tekmira and Alnylam in their future business development efforts. Since Alnylam enjoys exclusive rights to SNALP for RNAi Therapeutics uses, the reunion strengthens their ability to close the next major platform alliance deal by being able offer access not only to scientifically promising technology, but also the peace of mind to their partners that they would be using technology with sound IP to support it. Roche took a risk and took this step without the clarity, but has now been rewarded with being the first major pharma to get access to fundamental SNALP RNAi IP, and likely know-how relatively soon as well by way of an R&D collaboration with Tekmira. The $5M equity investment at a close to 200% premium by Roche in the new Tekmira only underlined the importance it places on SNALP for its RNAi Therapeutics activities.
According to Tekmira-Protiva, there are, however, four additional Big Pharma/biotech companies actively evaluating SNALP-RNAi (possibly SNALP for microRNA therapeutics as well). What this means is that access to SNALP will have to be through Alnylam, the gatekeeper of SNALP RNAi. I would not be surprised to see Alnylam announce the next platform alliance deal after Protiva-Tekmira closes at the end of this month. SNALP RNAi should account for a considerable fraction of the deal value. Novartis, and then somebody else? The plot thickens.
Disclosure: the author holds shares in both Alnylam and Tekmira. These are my interpretations and conjectures only of past events, and do not necessarily reflect actual events. SNALP technology has not been clinically proven yet, and it is a real possibility that trials fail to show therapeutic effects at acceptable doses.
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