Merck Hot on the Trails of Dynamic PolyConjugates by Arrowhead Research

Not only was I impressed by the Dynamic PolyConjugate delivery data presented at the late 2012 OTS meeting, many others in this peer group were, too.  This included favorable comments and keen questioning by a Merck scientist in the following Q&A session.  Not entirely surprising therefore, the presentation at OTS by Merck at the meeting revealed that it has recently shifted its delivery focus onto DPCs.  This week then, published evidence of that activity emerged in the form of a publication in Bioconjugate Chemistry (Parmar etal. 2013).  The DPC work described therein is consistent with a strategy in which the company aims at internally replicating the industry’s most promising/advanced delivery technologies, possibly hoping that not only can they overcome the scientific and manufacturing challenges, but also will find holes in the originator company’s intellectual property.  

Learning the DPC ABCs

The paper is essentially a replication of the basic DPC studies published in 2007 by Rozema et al. in PNAS.  Accordingly, they encountered much of the same challenges that the scientists at Arrowhead Research (formerly Mirus Bio, then Roche) had encountered in building the DPC delivery platform and includes issues with manufacturing yield and solubility.  The major difference is that Merck utilized a polymer backbone incorporating  disulfide bonds that one might hypothesize to be degraded in the reductive cytoplasm of cells. The fact that the first published Arrowhead DPC was not biodegradable was cited as a key toxicity issue.  All this is consistent with what Arrowhead started to report last year in explaining which challenges had to be overcome before they were able to clinically mature the technology.  Overall, the consistency of the findings with those first reported by Arrowhead gives me a good feeling about the theoretical basis for and robustness of the technology.

Lavishly Screening for Improvements

In order to discover suitable disulfide-containing polymers, Merck generated a small library of amphiphilic polymers by reacting together three types of chemical groups: an amine, an imidazole, and hydrophobic tails.  Conjugation of the targeting ligand and other masking groups that define DPCs was via the same CDM chemistry pioneered and still utilized by Mirus/Arrowhead.

The library was winnowed down via a series of tests, starting with membrane lysis assays down to tissue culture and rodent knockdown activity tests.  

Curiously, the paper lacked an assessment of toxicity in animals which was stated to be the entire point of the library and the study.  Whatever the motivation for this early publication of DPC research, this illustrates the early stage of Merck’s DPC development efforts.  The absence of published toxicity results may also mask a basic flaw with the disulfide concept: a) in order for these DPCs to fully degrade in the body, they would all have to be taken up into the cytoplasm; or b) the source of the toxicity is exclusively due to the intracellular accumulation of polymers.  Neither a) nor b), however, are not plausible in my humble opinion.

In any case, Merck likes to perform screening when it comes to optimizing RNAi technologies.  The most amazing example of this is probably their RNAi trigger modification screen involving over a hundred different types of nucleic acid modifications.   Regardless of what one might think of the wisdom of such brute-force and logically possibly flawed efforts, the size of these investments illustrate that Merck likely outspends all other companies in RNAi Therapeutics development, including Alnylam.

Merck Strategy

I am struggling to understand Merck’s strategy with regard to RNAi delivery.  It is obvious that all they are doing is to try and replicate the industry’s most promising technologies.  First it was SNALP (which they are still pursuing according to the OTS 2012 presentation), now it is DPC that they have set their eyes on.  I can only come up with two mutually non-exclusive strategies behind the approach. 

According to the first strategy, Merck wants confirm the validity of the promising reports.  If the technologies perform well in their hands they go out and license in the IP.  Extensive internal technology validation would be insurance against spending millions on technologies that turn out to be duds in an industry in which most technologies have not lived up to promises made.  Importantly, the decision to License technologies from the inventors and therefore presumably real experts would accelerate their pipeline development by years.  Of note, Merck still has not brought an RNAi candidate into the clinic since their $1.1B acquisition of Sirna Therapeutics and the pressure to achieve that milestone should be building.  According to the second strategy, Merck hopes to recreate or even exceed the originators’ achievements, and with luck can use the technologies without concern of infringing IP.  

Given Merck's significant investments which would seem to exceed those necessary for simple due diligence, Merck seems to be pursuing strategy No. 2.  It seems to be a risky strategy though because of IP uncertainty in general.  I therefore personally favor a more flexible implementation of strategy No. 2, namely one that envisions licenses and R&D collaborations if the IP situation or insurmountable technical hurdles eventually demand them. 

In any case, Merck must be doing quite well given the generous time and money spent on such RNAi Therapeutics research.  Enviable.

Merck in Talks with Arrowhead?

There are some comments in the paper that leads me to believe that Merck is actually talking to Arrowhead Research directly.  Although there may be hints in the very recent patent literature and investor presentations that biodegradability had been an issue with first-generation DPCs (note: Arrowhead is now using biodegradable peptides as the polymer backbone), and/or some of that has emerged when Roche opened up their books during their RNAi sales process, I have not seen such comments in the still relatively sparse peer-reviewed DPC literature.  Yet strangely, Merck presents the rationale for the disulfide strategy as if it was common knowledge.

Merck is not entirely foreign to Arrowhead Research.  Just last year, they entered into a research alliance concerning Arrowhead’s new-fangled peptide drug conjugates (PDC).  So there are open lines of communication between the companies.  Whether it’s something to get excited about if you are an Arrowhead shareholder, I’m not sure: in this industry, lots of parties are talking to each other without it ever coming to a deal.  Having said this, the recent results with DPC technology have been tantalizing, and for RNAi Therapeutics at Merck to survive, I would think that they have to put something into the clinic over the next two years or so or face the cost-cutting axe of the new chief of Merck Research Labs, Roger Perlmutter.  DPCs would seem to be one of the few options they have to meet such timelines.

Arrowhead Research Lifts Veil on Recent Progress in DPC Delivery

Four years after Mirus scientists published their seminal paper in polymer-mediated siRNA delivery, and 3 years after the acquisition of the Dynamic Polyconjugate (DPC) technology by Roche, Arrowhead Research, the new owner of the technology, finally lifted the veil on recent progress in bringing DPC technology to the clinic.

The White Paper reveals, for the first time, that DPCs have been successfully delivered to the livers of non-human primates, and moreover that they may also have use for applications outside the liver, one of the theorized attractions of DPCs based on their small size. Reading between the lines, however, it is also possible to identify some of the factors that have delayed clinical translation, and despite the progress and substantial investments by Roche, it remains an open question when the first DPC-based RNAi Therapeutic will enter clinical development.

Short circulation times were one of the deficiencies of 1^st generation DPCs. In order to reach tissues besides the liver, it is critical to achieve circulation times that are long enough so that the drug gets a chance to find and accumulate in its target tissues. Although DPCs on paper seemed to incorporate the features necessary for achieving such long circulation times, it came somewhat as a surprise when a DPC imaging paper last year showed DPC circulation times to be quite poor (Mudd et al., 2010). Although the particles were still able to accumulate in the liver, the data also raised questions whether the causes of the unexpected pharmacokinetics could have other consequences besides impacting biodistribution, for example in terms of safety.

It turns out that the short circulation times were the result of the premature exposure of the chemical groups that were supposed to shield the membranolytic functionalities of the DPCs outside their target cells. This would also explain why there seem to have been toxicity issues not just due to the poor biodegradability of the polymers, but also because such premature exposure renders DPCs as troublesome as many of the positively charged first-generation polymer approaches.

The White Paper indicates that the instability (and biodegradability) issue has been remedied to some degree such that the longer-circulating DPCs now show first promise for delivery outside the liver. But DPCs may also be competitive for delivery to the liver considering the following performance in non-human primates (excerpt from the White Paper):

‘Latest generation DPCs are remarkably efficacious in rats and non-human primates with ED80 values of ~0.1 mg/kg siRNA after a single dose. Increasing the dose two-fold in non-human primates results in >99% knockdown with a duration of effect of nearly 7 weeks. This is a 10-fold increase in efficacy compared to first generation DPCs containing PBAVE polymer. Latest generation DPCs are also better tolerated and have therapeutic indices of >10 in non-human primates as calculated from ED80 and NOAEL values.’

A 99% knockdown with 0.2mg/kg for 7 weeks- I’m impressed! It will be important to publish these data so that it is possible to see which model system was used, whether the 99% knockdown was seen for pretty much the 7 weeks, what the tox/tolerability profile was, the route of administration, and finally an explanation why a simple 2-fold increase in dosage had such a dramatic effect on knockdown efficacy.

The White Paper is also a reminder that for RNAi delivery technologies to be viable, there needs to be efficient scale-up. Apparently, manufacturing was, and possibly still is, a major issue with DPCs. At least the initial formulations had to be purified so extensively such that the yield became unacceptable for clinical translation and commercialization. Besides general liposomal expertise, quality manufacturing, of course, is what has always differentiated RNAi delivery company Tekmira from its competition.

My sense is that DPCs still have the potential to become an important delivery alternative. However, it is also clear that the path of DPCs was a tough one and, in the absence of guidance from Arrowhead Research, I expect additional delays (2-3 years?) before we will see the first DPC-based RNAi Therapeutic candidate in the clinic. This view is possibly shared by Alnylam as $10M in upfront and an increase of about $10M in annual operating costs would have been a small price to pay for Alnylam if DPCs were as advanced as Alnylam’s current systemic delivery workhorse, Tekmira’s SNALPs.

Until then, Arrowhead Resesarch needs to hit the ground running on the business development front given the increase in expenses that come with the 40+ research team in Wisconsin. The $15M facility with Lincoln Park Capital at least provides Arrowhead with increased financial flexibility. Ironically, it is positive clinical data from the RNAi Therapeutics candidates that are based on Tekmira’s SNALPs, DPCs most direct competitor that would greatly aid in that goal by re-igniting interest in the RNAi Therapeutics platform.

Roche Nabs Mirus Bio’s RNAi Therapeutics Delivery Technology

Roche again...before this week will have come to an end, Roche has drastically changed the RNAi Therapeutics playing field leaving many heads in the RNAi space spinning.

You may think it is because I live in an RNAi Therapeutics bubble, but the Roche-Genentech press release and conference call to me clearly shows that a major motivation for the proposed taking private of Genentech was to broaden their RNAi Therapeutics efforts by bringing in a company with deep immunology and personalized cancer know-how, as well as being able to leverage Genentech’s monoclonal antibody capabilities for targeted RNAi Therapeutics delivery.

To this they now add for $125M, a sum that makes related companies look very cheap in comparison, the privately held Madison, Wisconsin, nucleic acid delivery company Mirus Bio. The jewel of Mirus Bio is their Dynamic PolyConjugates (DPCs), small, flexible designer particles for the targeted systemic delivery of siRNAs. Although the technology is relatively young and data scarce, from the PNAS publication last year (reviewed here in the RNAi Therapeutics blog) and conference presentations, DPCs are very competitive with liposomal technologies for delivery to the liver. Also very attractive from a safety and efficacy point-of-view is their apparent ability to selectively target silencing either to hepatocytes or Kupffer cells in the liver, depending on whether glucose or galactose-derivatives were attached. Although I haven’t seen data beyond the liver, the small size and modularity suggests that with the appropriate pharmacology it could well have applications for a number of other tissue types and organs and nicely complement larger nanoparticle delivery technologies.

It’s unlikely to be a coincidence that Roche is making all these moves in such short order. What has started with an IP license from Alnylam for basic access to RNAi mechanism of action, within 2 days they have now added to that one of the most coveted delivery technologies and scientific depth. The rapid moves by Roche means that fellow Big Pharmas like Pfizer, which had a non-exclusive license to DPCs, and Merck which had probably also been very interested in DPCs, now risk falling behind on delivery while their core RNAi IP has either not been secured yet (Pfizer) or is at best uncertain (Sirna Therapeutics/Merck). From a strategic perspective, it will be interesting whether due to their close relationships there will be any sharing/coordination of DPC technology with Alnylam and Tekmira, and for which indications Roche will employ the two leading delivery technologies (DPCs and SNALPs) both of which it has now immediate access to.

Today's acquisition is yet another piece of evidence that Roche is building their future on RNAi Therapeutics in a big and bold way. It's also encouraging that this comes a year after the Alnylam platform licensing agreement and suggests that they must have been pleased with what they have seen since.

Final Day of Keystone RNAi Conference

There were quite a number of RNAi Therapeutics related talks on the last day of the conference. Muthiah Manoharan from Alnylam Pharmaceuticals gave an overview of some of the important chemistries and formulations the company is developing.

The liposomal delivery section of his presentation, Alnylam develops liposomes both for dsRNA as well as single-stranded antagomir delivery, proved a bit hard to follow (or maybe it was just me having difficulties concentrating towards the end of the conference) since some data related to Protiva SNALP technology, then Tekmira developed novel cationic liposome formulations, and then the next moment to lipid-like particles. It is befitting that given the overlap and complementarity in terms of biodistribution and pharmacokinetics of these technologies much of this has now been consolidated into the new Tekmira. If I have it right, the previously shown successful repeat-administration data for sustained gene knockdown in the liver made use of MIT’s lipidoid technology, while the impressive mouse liver cancer data were the result of a Protiva collaboration.

Conjugation of siRNAs to cholesterol is well known for the systemic delivery to the liver and jejunum. Less well known in the context of siRNAs is the PEG-conjugation. Since according to Dr. Manoharan this conjugation facilitates equally efficient delivery to the jejunum as cholesterol does, but largely avoids the liver, PEGylation strategies may lessen the risk for liver toxities in targeted therapies of the jejunum.

With respect to modification technology, in contrast to Merck’s (notably absent from the speaker roster) emphasis on siRNA modification (‘siNAs’), Alnylam follows the natural trend and applies modifications as little as possible. It is interesting that they are still using the classical Tuschl dTdT 3’ overhang structure, albeit substituting a thioate for a phosphate in the last linkage. Their favorite modification, however, appears to be the 2’-fluoro modification, long a workhorse for many RNA technology platforms before RNAi, which has now also proven to be very promising for RNAi Therapeutics. This modification imparts not only stability on the siRNA, but also helps in avoiding immune recognition and favors a molecular conformation that may aid in target recognition. In addition to the associated higher lipophilicity, all of this appears to result in significantly improved knockdown efficiencies.

Next on the list was the session chair of the afternoon RNAi Therapeutics workshop, Frank Bennett from the antisense company ISIS Pharmaceuticals. ISIS is developing single-stranded RNAs for the induction of therapeutic RNAi. This may be due to their IP estate in single-stranded antisense as well as the notion that single-stranded molecules may have cost and delivery advantages. The flexibility of single-stranded molecules plus its amphipathic nature, particularly when extensive phosphortioate backbone modifications are applied, should make it easier for ssRNAs to cross the cell membrane (note, however, that naked antisense delivery may not always be sufficient as their own Regulus venture is looking at systemically formulated, conjugated or liposomal, antisense for the inhibition of microRNAs). Maybe not surprising, ISIS, too, has found 2’fluoro modifications to be “magic” as this has significantly improved single-strand RNAi potency, with the IC50s in a number of cases in the low or even subnanomolar range. But his own comparisons show that since 2’fluoro also improved the potency of dsRNAi, the fold-difference in potency between single-stranded vs dsRNA RNAi has not really changed, with ssRNAi being 10-fold less efficient at best (please correct me if I am wrong here, but numbers probably based on lipoplexed oligo delivery in tissue culture). For example, the most potent ssRNAi shown molecule had an IC50 of 0.43nM, while the corresponding 2’fluoro siRNA came in at 0.01nM.

Part in me believes that ISIS has a sincere interest in developing ssRNAi for their future pipeline, but another part makes me believe that ISIS’ work is supposed to widen their claim onto IP in RNAi. Accordingly, Bennett noted that in was in 1998 that ISIS evaluated the use of single-stranded RNAs to modulate gene regulation, and as it turns out, these RNAs worked via RNAi. In any case, this was a fact-based presentation and not meant as an advertisement of single-strand RNAi or antisense technology and it will be interesting to follow just how efficiently single-stranded RNAs can be designed so that they are recognized by RNAi.

David Lewis (Mirus Bio) then gave us an update on his company’s progress with Dynamic Polyconjugates (DPC), a non-liposomal technology for the systemic delivery of RNAi to the liver. As I had
noted here before , DPCs may be particularly promising in terms of safety, as depending on the attached sugar, Kupffer cells and hepatocytes can be selectively targeted. This was corroborated by the presentation of extensive safety data, a topic that unfortunately was not really addressed in the previous two speakers’ presentations. Knockdown was remarkably sustained, and particles repeat-administrable in mice for over 100 days without loss of silencing activity, at relatively low 1.25mg/kg doses. Moreover, sustained silencing was also demonstrated for non-human primates. It is notable that by targeting ApoB in monkeys, they, like many other groups, also observe the fatty liver phenotype. The small size of DPCs should make the technology also a candidate for more difficult-to-penetrate tissues.

Beverly Davidson (Iowa) summarized her group’s experience with AAV-shRNAs for the treatment of Huntington’s Disease. Like many other laboratories have observed, they also find toxicity following U6-driven shRNA expression. Albeit very potent, it is probably recommended to stay away from the U6 promoter for future development programs, especially when high copy-numbers of expression cassettes may get into individual cells, and there are more than enough alternative potent hairpin expression technologies that do not cause toxicity. According to Davidson, incorporating the RNAi trigger within a microRNA context for example was safe. AAV delivery to the striatum, the anatomical site that matters most in HD, was “phenomenal”, particularly with a viral preparation from their collaborators at Targeted Genetics (Seattle). Before RNAi gene therapy for HD can progress into the clinic though, it will be important to determine whether knocking down both the wild-type and mutant huntingtin alleles is safe or whether allele-specific knockdown is required. Studies that address this issue are now ongoing. Overall, I am quite optimistic about the future of AAV- and lentivirally mediated RNAi gene therapy.

Judy Lieberman (Harvard), together with Phil Sharp a co-organizer of the conference, presented more data on targeting cancer stem cells by RNAi, the underlying rationale being that in order to get rid of a tumour, you really need to get rid of the cancer stem cells from which the tumour mass derives. While previous work centered on antibody-protamine siRNAs targeted to stem cell-specific surface receptors, her latest work makes use of targeted liposomes, which can be potentially more consistently manufactured as well as have the added advantage that many siRNAs can be delivered with just one liposome. Using this to deliver let-7 mimics, a microRNA that is becoming more and more clear to serve as a key differentiation factor, her group showed that breast cancer stem cells dramatically lose their ability to self-renew as well as metastasize to the lung and liver.

Equally interesting was Markus Stoffel’s presentation (ETH, Zurich) on the mechanism of cholesterol-conjugated siRNA uptake. In a study previously published in Nature Biotech and discussed here , Stoffel and his collaborators at Alnylam found that the favorable pharmacokinetics and liver uptake of cholesterol-conjugates is due to their association into lipoprotein particles of the blood, and that it is cholesterol-siRNA bound by LDL that carries the RNAi to the LDL-receptor on the hepatocytes, thereby causing gene silencing in the liver. Moreover, cholesterol-siRNA pre-formulated with LDL in vitro and then administered into mice, proved useful in enhancing the hepatic delivery of RNAi.

Extending this work, his group has now found that cholesterol-conjugated siRNAs can also be consistently formulated with Intralipid , a clinically tested fat emulsion used for nutritional purposes as well as a drug carrier for certain anaesthetics, especially for indications of the heart. Quite excitingly, and in retrospect maybe not that surprising, it turns out that cholesterol-siRNAs are not delivered to the liver (a potential safety advantage when targeting other tissues), but instead go to the lung and even better, the muscle, including heart. At reasonable 10mg/kg, they observe an 80% ApoB knockdown in the lung, but this needs to be repeated now targeting genes more highly expressed in muscle/lung. Developments such as this are all the more important, since the ability to target new tissues opens up RNAi Therapeutics to a whole new spectrum of disease (note that this is an siRNA method and gene therapy methods such as AAV-mediated RNAi may also be useful for the systemic treatment of the heart).

Represented in the poster session was work by Nastech on meroduplexes. Maybe I don’t get it, but the suggested advantages of meroduplexes are so tenuous while creating all the additional challenges in developing tri-partite siRNAs. If Nastech was really making progress on delivery as has been suggested, it would make more sense focusing on those efforts which should be sufficient to create partnering interest and financing at favorable terms. I’m sure a company like Alnylam would be more than happy to then cross-license siRNA and delivery IP.

Finally, a poster by Takanori Yokota (Tokyo) reported on the delivery of alpha-tocopherol conjugated Dicer-substrate siRNAs to the liver. Effective silencing of ApoB in mice was achieved at low mg/kg dosages and was apparently well tolerated, except for the- you hear it once again- ApoB knockdown-specific fatty liver phenotype.

Overall, this year’s Keystone has proven a must-go for those that can only go to only a limited number of scientific meetings, giving them a chance to catch up on the important developments in the field over the past year and getting a glimpse into emerging trends. Next year, the RNAi community will be split between three RNAi-related Keystone meetings, one on the basic mechanisms of RNAi, another one centered on RNAi Therapeutics, and finally one on microRNAs and cancer just illustrating how much this field has grown and diversified.

2008: The Year of the Liver

It is true that next year could bring the first human proof-of-concept for an RNAi therapeutic. But since results from the experimental infection studies for ALN-RSV01 were originally expected in late 2007 and the results would be an overhang of work done in ’07, I find it more appropriate to pick a fresh candidate. It is also true that the lung may rival the liver in the number of programs moving into the clinic in ‘08 given recent data that suggest delivery of siRNAs to the lung by nebulizer to be fairly innocuous, and the fact that AstraZeneca and GSK should be busy working in that area following their agreements with Silence and Sirna Therapeutics, respectively.

Nevertheless, I feel that most systematic progress has been made in delivering RNAi to the liver with more progress likely to follow. There have now been a fair number of publications that clearly show target-specific RNAi knockdown in the liver, unlike maybe some of the lung studies where there were occasional data interpretation issues. Of course, in declaring 2008 ‘The Year of the Liver’, I should disclose that I am somewhat biased due to the hepatotropic focus of the laboratory that I work in.

For siRNA-mediated RNAi in the liver, I currently see three front-runners, although it is possible that among the considerable work that is ongoing and not yet published, others have reached a similar stage of technological maturity. These are the in-famous SNALPs, Mirus Bio’s “Dynamic PolyConjugates”, and MIT’s lipidoids. SNALPs, being worked on by Protiva, Tekmira, Alnylam, and Sirna/Merck, are probably 12-18 months ahead of the game and best characterized, whereas the data on PolyConjugates and lipidoids are very promising, but still somewhat spotty.

SNALPs, stable nucleic acid lipid particles, are set to enter the clinic in 2008 with programs in hypercholesterolemia and liver cancer (both Alnylam) and possibly a clinical candidate chosen by Tekmira. The hypercholesterolemia program is also an opportunity to get an early measure of therapeutic efficacy, possibly in ‘08. Protiva’s and Sirna/Merck’s intentions are less clear and I believe that Big Pharma often chooses to keep phase I programs secret for competitive reasons, so that it is theoretically possible that Sirna has already entered the clinic or is about to do so with the long-anticipated SNALP RNAi for Hepatitis C.

It is obvious that there were some delays in bringing SNALP RNAi to the clinic, and I believe that this is largely due to dosing and safety issues. Both of these concerns may come down to the propensity of SNALP liposomes to be taken up by immune cells such as Kupffer cells in the liver and plasmacytoid dendritic cells which a) function like a sink for the liposomes when they enter the liver so that SNALPs become available for entering the desired hepatocytes only after the sink is saturated, something that complicates dosing; and b) increases the risk of triggering unwanted cytokine responses. I am optimistic, however, that by varying the composition of SNALPs, safe and efficacious formulations may be found, particularly if the liposome uptake mechanism by the professional immune surveillance system were to be different from that by the hepatocytes, which I think is quite reasonable to assume. I therefore hope that the fact that so many scientists are working on SNALP RNAi is a sign of its promise rather than desperation. As such, the number of R&D staff at Tekmira has more than doubled from 17 to 39 in the year ending September 2006 largely due to work on SNALPs.

As I have written before, I am much taken by Mirus’ PolyConjugate work, although this is based on only a single paper published in the middle of ‘07 (see 24 July 07 Blog: “Mirus Scientists Publish Elegant Paper on Targeted siRNA Delivery to Hepatocytes”). The neat aspect of that work was that it showed that it should be possible to avoid the Kupffer cells in the liver and specifically target hepatocytes for knockdown with the help of carbohydrate ligands (I am curious whether similar targeting ligands would also work in the context of other formulations). As we know, this work is partnered with Pfizer, and I wonder whether the upcoming loss of exclusive marketing rights for their wonder-drug Lipitor will spur them into action here.

I am still waiting for more data on lipidoid-mediated RNAi which hopefully will become available soon as was indicated in the footnotes of an October 2007 paper on the effect of siRNA delivery on microRNA function. From both a business and scientific perspective, it will be interesting to see whether Alnylam may choose lipidoids over SNALPs for its first liver RNAi programs and the overlap of SNALP and lipidoid both in IP and manufacturing terms.

The liver may get further attention from the targeting of microRNA-122 for the treatment of hypercholesterolemia and Hepatitis C, and other programs on targeting certain microRNAs for the treatment of hepatocellular carcinoma. There are various programs by Santaris, Regulus and others that have progressed into larger animals and we may even see a first IND being filed for one of these applications by the end of 2008. Development in the antisense field, particularly the partnering of ISIS’ mipomersen, should also generate heightened awareness for RNA-based therapeutics of liver disease.

Other predictions for 2008:

1) Unpredicted delivery technologies
2) Pfizer finally makes its move
3) News on RNAi for wet AMD- good and/or bad?
4) Protiva-Tekmira dispute resolved (wishful thinking)

For a nice presentation on the powers of SNALPs by Protiva chief scientist Ian MacLachlan, please visit: http://mms.technologynetworks.net/RNAi06Presentations/maclachlan/Player.html