RNAi Therapeutics and Whole-Genome Sequencing

It is my expectation that in 15-20 years, every newborn and newly diagnosed cancer patient with good healthcare coverage will have their genomes sequenced. Personally, I cannot wait for consumer genomics companies like 23andMe to provide services that would allow me, a non-bioinformaticist, to readily analyze the sequences of friends and family. All this is made possible by the technical advances in bringing down the cost of sequencing so that for the price of a semi-luxurious holiday (~$4000) you can get your genome sequenced these days. Roche’s bid for the 800 pound gorilla of DNA sequencing, Illumina, illustrates that with its other molecular Dx costing not that much less, next-gen sequencing, especially that of whole genomes, has reached a stage where it has become relevant for diagnostic applications.

15-20 years is also about the time-frame when we should see a healthy flow of RNAi Therapeutics getting approved, many of those as personalized medicines, e.g. for the treatment of dominant-negative diseases such as TTR amyloidosis, Huntington’s Disease, or, of course, cancer. With many people knowing their genome sequence from birth, it will be possible to monitor and then start treating many of these gene carriers before they manifest symptoms and progress to more debilitating states. Others will benefit from an improved ability to correctly diagnose a disease in genetic terms, thus allowing the physician to prescribe the appropriate medicine. As a genetic medicine (aka gene therapy), RNAi Therapeutics is ideally suited to address many of these diseases. Sequencing technologies will also help unearth which gene targets such RNAi Therapeutics ought to go after and thus reduce target risk.

There is considerable discussion in biotech what would be the best business model for sequencing companies. The buzz around PacBio has fizzled a bit as there is a sense that their machines are too expensive and not best suited for the mainstream sequencing applications. Illumina meanwhile has a dual model: It caters to those that don’t want to mess with the sequencing themselves but would rather hand over the job to somebody with experience; it also does well in selling sequencing machines to those that prefer doing it themselves. This model, however, is agnostic to the type of sequence (human or not; whole genome or exome).

Complete Genomics, on the other hand, has specialized on just human whole genome sequencing. I like this model a lot from a commercial perspective as this is the area where the future diagnostic sequencing volume will be, and specialization not only allows the company to optimize its technology for this single application but also to put relatively more resources into developing the requisite, value-adding bioinformatic analysis tools. The company is struggling with convincing the market that the currently more widely used/pushed exome sequencing is not more than a blip in the history of sequencing, a history which will inevitably culminate in routine whole genome sequencing. Claiming that exomes, which cost almost as much as whole genomes to sequence, have staying power feels kind of like arguing that Alnylam has 'proprietary' SNALP technology, just because Alnylam has a larger advertising budget. Maybe not the best analogy, I admit, but if you are still reading this, then chances are that you don't mind and even agree with me.

Ultimately, what I find exciting and scary at the same time about this business model is that at one point a company like Complete Genomics will have assembled a treasure trove of sequence information. It will e.g. have a very good idea where to find the families with severe hypercholesterolemia, information that I imagine a Genzyme or healthcare insurance providers would love to know about.

Vertex Pharmaceuticals today received approval for a genetically personalized Cystic Fibrosis drug, Kalydeco (probably named by the same consultants that gave Kynamro its name), for which it has plans to charge around…three hundred thousand US dollars per annum (note: an earlier version mistakenly referred to Genzyme as the CF drug maker). It’s difficult for me to understand what a 10% improvement in lung function means to a CF patient (probably a lot), but even if it’s a great relieve who does not wonder whether such costs are sustainable: have 10-15 adults work for nothing else but to pay for the treatment of an unfortunate CF patient. I’m sure we’ll witness similar debates raging once the first RNAi Therapeutics get approved. Hopefully, a winning combination like RNAi and whole genome sequencing can contribute to keeping the financial cost of personalized medicines low by increasing drug development success rates through better targets and RNAi platform efficiencies and keeping waste to a minimum by only treating people genetically predicted to respond to the therapeutic.

Disclosure: I do not hold GNOM (Complete Genomics), and unless it drops by 30% for no good reason, do not have plans to buy over the next week.

Silence Therapeutics About to Be Issued Broad Blunt RNAi Trigger Patent? An Update.

Note from 28 January, 2012:

On January 3, 2012, the EPO issued an 'Intention to grant'. Unlike suggested in the following blog entry, the claims in the accompanying 'Druckexemplar' are not blocking any more for blunt-ended RNAi triggers. The coverage, however, does include 19bp blunt end RNAi triggers which is certainly a useful structure.

This is the main claim that is likely to be issued. As you can see there have been some last-minute modifications.

The original blog entry from November 26, 2011, follows:

Silence Therapeutics (rightly or wrongly) was once considered by Big Pharma as an attractive RNAi trigger alternative to Alnylam. This was because its early RNAi trigger work (e.g. Czauderna et al. [2003] Nucleic Acids Res. 31: 2705) gave it a shot at broad patent coverage. In particular, if patent oppositions in Europe had not caused the AtuRNAi design to be limited to very narrow modification patterns (blunt dsRNAs with alternating 2’-o-methyl-unmodified residues, with a modified residue facing an unmodified one on the other strand), things may not have turned out as ugly as they did for its shareholders and some of its employees.

The problem with the AtuRNAi design is that it makes it difficult to find potent RNAi triggers. If Silence had succeeded in its goal of obtaining a patent covering a broad range of modification patterns instead of just the one, the increased design flexibility would have made it more likely to find potent RNAi triggers within the constraints of the patent claims and, of course, licensees.

I had noted about a year ago that Silence was pursuing another patent prosecution based on the same subject matter that the AtuRNAi patent was derived from (patent application EP 02017601.2). At first, I interpreted it as a Hail Marry, possibly sign of slight desperation trying to take a second bite from the same apple despite all the odds being that it will go the same way as before. When I looked, however, into the last claim set that Silence submitted during an oral hearing on the patent at the EPO earlier this year, I realized that Silence had actually been pursuing not claims to broaden the modification patterns of the AtuRNAi design, but claims covering essentially any blunt-ended RNAi trigger per se:

"1. A ribonucleic acid mediating RNA interference consisting of a double stranded structure whereby the double-stranded structure comprises a first stretch of contiguous nucleotides and whereby said first stretch is at least partially complementary to a target nucleic acid, the second strand comprises a second stretch of contiguous nucleotides whereby said second stretch is at least partially identical to the target nucleic acid and whereby the first stretch and the second stretch for a cuplex, characterized in that the double-stranded structure is blunt ended on both sides of the double strand and the length of said first strand and the length of said second strand is from about 15 to about 23 bases, 17 to 21 bases or 18 or 19 bases, for use in a method for the treatment of a disease."

Although I once considered such a claim plausible as in the early days when Silence (then Atugen) published its blunt-ended RNAi triggers (e.g. Czauderna et al. [2003] Nucleic Acids Res. 31: 2705) such non-3’overhang RNAi triggers were considered a bit heretical so soon after Tuschl’s work. Heretical means that, if the AtuRNAi triggers were effective, they would fulfill at least the patentability criteria of novelty and non-obviousness. As such claims never seem to materialize, I had thought that the moment for that had passed. Apparently not.

It now seems that such a patent is about to be granted. What the exact claims will be remain an open question as the response of the patent office to the latest claim set is not public. The fact, however, that Silence did not protest and the fact that the title for the patent application was just recently changed from ‘Novel forms of interfering RNA molecules’ to ‘Blunt-ended interfering RNA molecules’, makes me think that an important patent grant is coming down the chimney for Silence this Christmas.

The importance of a broad blunt-end RNAi trigger patent

As I will discuss in more detail in a report titled ‘The Business of RNAi Therapeutics 2012’ that I hope will be published soon, the absence of RNAi trigger IP with gate-keeping potential has greatly reduced the attraction of simple workaround solutions, and I believe that Silence with its AtuRNAi workaround has somewhat suffered from this as well (on the other hand, the threat of Kreutzer-Limmer to its freedom-to-operate has subsided). Not surprisingly, Silence is now advertising itself as a delivery company. With a broad blunt-end RNAi trigger patent in a market such as Europe, however, Silence's RNAi trigger offerings would become more competitive again, not as a workaround, but based on scientific potential. It would thus own a good part of the blunt-ended half of the RNAi triggers there. Together with the Zamore patents, Silence therefore could be considered to have a stronger issued RNAi trigger IP position than you know who.

As the current RNAi Therapeutics clinical dataflow should be re-igniting interest in RNAi Therapeutics in general, such a patent could be worth something again.

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The Keystone Nucleic Acid Therapeutics Meeting Report

This offer expired. For the record, the comments section of this blog entry is posted.

Anonymous said...

any thoughts on the Silence annoucnement with AZ.Just a bit of smoke?

January 7, 2012 4:10 AM

Dirk Haussecker said...

A little bit of smoke, but not all. It seems that AZ is still in the RNAi game. Also, the AZ guy on the PR is going to attend the Keystone conference. Seems to have a background in vascular endothelial biology (see AtuPLEX, DACC).

January 7, 2012 7:23 AM

Anonymous said...

Dirk... you've been pretty quite on the latest Tekmira/Talon and Alnylam developments...

-Value your thoughts?

January 13, 2012 2:17 PM

Dirk Haussecker said...

I'll be back. Just trying to get as much as possible out of the Keystone meeting.

RE Talon: I have not delved yet into Talon's chances of getting approval for Marqibo. Still, it seems a tall order since the submission appears to be based on open-label, uncontrolled phase II results. I'm therefore hopeful that Talon, and their re-newed investors, know what they are doing. An approval though would be a nice upside surprise to Tekmira.

January 14, 2012 2:51 PM

Anonymous said...

"I'll be back"
The Hausse is coming to silence the Terminator for good.

January 14, 2012 7:34 PM

Anonymous said...

" It is clear that from a scientific perspective, oligonucleotide, including RNAi Therapeutics are feasible."

Wow, that does not sound very optimistic about RNAi, and differs considerably in tone from your numerous bullish articles about the future of RNAi. What the hell happened at the meeting to make you gear down your outlook?

January 16, 2012 8:31 PM

Anonymous said...

Dirk,

Can you comment on the basis for the ALNY patent infrigement suit?

January 17, 2012 9:17 AM

Dirk Haussecker said...

Over 3 years after Tekmira and BMS have openly been collaborating on SNALP delivery, Alnylam now interprets Tekmira's target validation deal with BMS as an infringing activity under the exclusive license of certain SNALP IP to Alnylam (you can forget about the cited ISIS patent as that one is of little relevance to RNAi, so it was thrown into the fray anyway). Of course, if you want to find a reason to sue somebody, you find them, and this looks like one of these gray areas. Tekmira may now cite the Research Exemption, that it was free to conduct such work under its target picks, and/or that the actual formulations used in that deal (to which Alnylam will not be privvy) did not have much to do with the cited patents.

But whatever, I believe Alnylam's motivation in this suit is quite obvious and that's what today was about.

January 17, 2012 3:28 PM

Giles said...

Any thoughts on the RaNa Atlas investment?Is it presaging new monies into RNAi?

January 18, 2012 11:10 AM

Anonymous said...

Dirk

Read the report. Very informative, even to a lay person like me. Thanks much.

Have some questions, and let me know if they're something you prefer to answer by email rather than on your blog site.

Questions regarding the discussion in your report about Tekmira/Alnylam's reference to 1st gen, 2d gen (MC3), and Tekmira's 3d gen LNP. Regarding the latter, were there any more specifics on how it differs, other than dose concentration for efficacy, from MC3? Were there any reactions, questions, or response from Alnylam or other participants on this "3d generation" LNP from Tekmira? Did Ian indicate that further clinical testing of TKM-PLK1 would use either MC3 or the 3d generation lipid?

Shame Madden had to "depart" prematurely due to some news from British Columbia (ha! timing of the court order was great).

Thanks for any information you can share on those issues.

January 21, 2012 12:58 PM

Dirk Haussecker said...

The PLK1 question is one that I was asking myself. I really like PLK1 as a target, and also the PLK1 SNALP formulation should be superior to ALN-VSP02 due to its longer predicted circulatory half-life. On the other hand, it does seem that just like 1st, 2nd, 3rd gen for SNALP liver delivery, Tekmira has made progress in solid tumor delivery that may be significant enough to follow up on the first PLK1 candidate. It would be a tough decision though, and possibly should be done with a larger partner. Ironically, it might be easier to sell such a decision to investor if they get positive TKM-PLK1 data first. The next few weeks could be interesting in that regard.

January 22, 2012 1:22 PM

Anonymous said...

What is your view on the Roche bid for illumina?

January 26, 2012 6:47 PM

Dirk Haussecker said...

I see the Roche bid for ILMN very positive for RNAi Therapeutics. After all, RNAi is ideally suited for personalized medicine as it works on the genetic level (ILMN sequences genomes). Furthermore, as in 15-20 years essentially everybody will have their genomes sequenced (and cancer patients their cancers, too), it will be quite easy for example for Alnylam find the people which are about to develop TTR amyloidosis, Huntingtons's Disease, and Tekmira those cancer patients which are expected to respond to PLK1 treatment best.

January 27, 2012 1:20 AM

Dirk Haussecker said...

Madden was not only missing at his poster, but apparently also on the MC3 US patent that is about to issue.

January 30, 2012 5:24 AM

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Alnylam Shocks with a further 33% Reduction of Its Workforce

When I saw the announcement a few minutes ago, I had to gasp for air: A little more than a year after laying off 25-30% of its workforce after Novartis failed to exercise the $100M IP option, Alnylam announced this evening that it will further reduce its workforce by another 33%. Even the PR person seemed shocked, as the same PR went out twice.

Following recent guidance that the company would only advance two clinical candidates for orphan diseases, ALN-TTR and ALN-APC, on its own dime and was planning to give everything else away in their pipeline at what could likely be at firesale prices, it already looked like something was deeply wrong. Today’s news and Alnylam’s lawsuit this week against Tekmira in an apparent desperate attempt to make anything stick against that company, only add to that suspicion. After all, Alnylam still enjoys a fairly lavish cash balance of $260M, and its share price, especially in light of the very positive clinical results recently, would put it again into a position to raise a bit of capital on the public markets.

The cost-saving measures and the new mantra of having transformed from a platform into a product-focused company is also at odds with the notion that Alnylam wants to remain at the forefront of RNAi Therapeutics innovation.

Moreover, when the Novartis lay-offs were announced, it was naturally felt that it would be a good thing to make one deep cut and be done with it instead of depressing employee moral by a series of gradual workforce reductions. I’m therefore convinced that today’s news had not been anticipated back then.

So what’s wrong?

The only reasonable explanation that I can come up with is that they are putting contingency plans into place for a potentially hefty settlement with Tekmira. A capital raise may be difficult to do if they had good reasons to expect that the Tekmira litigation could end up being costly, in which case they would probably have to disclose that in a prospectus.

I know- these are a lot of speculations, and definitely don’t buy Tekmira shares based on those. I invite you though to share your suspicions of what’s going on inside (survey on top right hand corner): a) the company has lost all belief that the science will mature in time; b) they expect the Tekmira litigation to end up being very costly and are starting to save up for it (settlement or buy-out); or c) none of the above.

My eyes are now peeled on that financial guidance in February, and I'm truly sorry for all those that now see their lives turned upside down after having pursued the dream of turning RNAi Therapeutics into a reality.

Issued Baulcombe Patents Fundamental to Mainstream RNAi Therapeutics in USA

Yesterday, UK-based Plant Biosciences Limited (PBL) announced that it was awarded a fundamental RNAi patent in the US. The patents can be considered necessary for commercializing RNAi in the US as long as both strands of the RNAi trigger are between 20-24 nucleotides in length.

Claim 1 of US patent 8,097,710:

1. A method of silencing a gene in cells by post-transcriptional gene silencing (PTGS) which method comprises introducing into said cells a composition that contains short RNA molecules (SRMs),

which SRMs are isolated short sense RNA molecules (SSRMs) and isolated short antisense RNA molecules (SARMs) at the same abundance;

wherein said SARMs are complementary to a region of a target RNA transcribed from a gene which is silenced when said short RNA molecules are present in cells containing said gene and said SSRMs correspond to said target RNA; and

wherein the SSRMs and SARMs consist of 20, 21, 22, 23 or 24 nucleotides,

whereby said gene is silenced.

The patent issuance is a testament to the seminal contributions the plant RNAi community have made to the field. In fact, there was considerable unhappiness that the Nobel Prize committee did not recognize this when it awarded the RNAi-related Prize to Fire and Mello. Baulcombe, it was felt, should have been added as a 3^rd recipient.

The issued patent is based on work by Hamilton and Baulcombe from the Sainsbury Laboratory in Norwich, UK, who found that small RNAs were generated during post-transcriptional gene silencing (PTGS), that is RNAi in plants (Hamilton and Baulcombe SCIENCE 1999). It was then instantly realized, also in light of the fact that a previously discovered microRNA (in C. elegans) was in that size range, that small silencing RNAs are likely the universal (i.e. plants and animals) mediators of RNAi.

I can say the above pretty confidently from my own experience as my exposure to RNAi began in 2000 (before the Tuschl II publication) in- you guessed it- a plant laboratory in the UK (Edinburgh University). There I was an undergrad designing plant RNAi expression vectors and it was pretty obvious then that small RNAs are involved in microRNA and RNAi silencing, two phenomena which had been linked genetically through work in a diverse set of organisms: slime mold, C. elegans, Arabidopsis, fruit flies and the likes. The only remaining uncertainty at that time was whether RNAi would also exist in humans, although I can well remember a speculation in my ‘RNA World’ elective class by David Tollervey that he more or less was certain that RNAi would be shown to exist in humans (not sure whether this was based on scientific intuition or rumors in the scientific community).

(My other claim to getting close to RNAi fame is that David Baulcombe, now Sir David Baulcombe, was my D.Phil. examiner regarding my graduate work on Dicer biology in humans)

I can well imagine that this uncertainty was an issue as PBL argued its case for an all-organism-encompassing patent, but it now seems that it prevailed.

Note on Alnylam patent infringement suit

The timing of the patent issuance, of course, is a bit ironic since the biggest violator of this patent as of January 17 is Alnylam which, as you will know, has just sued Tekmira for patent infringement. It is also of note that since Alnylam has cited an RNAi-unrelated patent by ISIS (US 7,695,902) in the suit, Alnylam has officially revealed itself as a patent troll. Benitec may want to take note since Alnylam acquired the Nucleonics patents which I suspect was done to provide similar cannon fodder for the courts in future litigations.

Also, since Alnylam only threw patents licensed from other companies into the fray, it is a lesson to any company about the perils of licensing IP to Alnylam: Alnylam is more likely than not to first expose such licensed patents before it will expose their own (note: a patent infringement suit such as this one predicts that the patents will be challenged by the alleged infringer and thus stands to be revoked or cut back in scope).

My Keystone meeting was great, and I also learned of interesting work by Alnylam. But I can tell you that coming home from a long trip and the first thing I see is that Alnylam is looking hard to come up with reasons to bury Tekmira under legal costs has quickly eroded any of that goodwill. Somebody needs to stop the insanity, and it's not going to be Alnylam's legal advisers which are making a fortune out of this.

ISIS TTR Results Show 1st Gen SNALP Already on Par with RNase H Antisense

ISIS today reported knockdown results from a phase I trial with its RNase H antisense compound ISIS-TTRRx against the transthyretin gene for the treatment of TTR amyloidosis. The results show that while high 81% knockdowns can be achieved, very large amounts of oligonucleotides (400mg weekly for 4 weeks) had to be given. When clinically more relevant doses were given (200mg as in mipomersen and the next lower dose from 400mg), a mean knockdown of 44% was achieved.

As you will remember (SNALP Works!), the RNAi Therapeutics candidate ALN-TTR01 last November showed a mean reduction of 41% of serum TTR from baseline following a single 1.0mg/kg infusion. In light of yesterday’s results with ALN-PCS02 where a supposedly less potent RNAi trigger was employed and a ~60% knockdown was achieved with 0.25mg/kg, it seems likely that the Tekmira SNALP-enabled ALN-TTR02 which is about to enter clinical development and which employs a formulation similar to PCS02 will show the type of 70-80% knockdown at 0.25mg/kg.

We have yet to learn more about the safety profile of ISIS-TTRRx which is being developed under an option agreement with GSK. ISIS stated in their press release that they were planning to enter pivotal studies with this compound soon. If it is with the 400mg dosage, they may be tempting fate. It might be interesting to try 300mg.

As you know, these days I’m strongly advocating RNAi Therapeutics as the technology is currently being sold at much below the worth of the science which has progressed steadily over the years despite the up and downs in public perceptions. Today’s results by ISIS show that the new darling in nucleic acid therapeutics can certainly knock down genes in the liver (and some other tissues). They also show, however, that even the initial SNALP formulations are already on par with it in terms of efficacy at the higher end of tolerability (not talking about other aspects such as absolute differences in dosage or route of administration).

ALN-PCS02 Results Provide Glimpse of First RNAi Therapeutics Blockbuster

If the experts at Roche and other Big Pharma companies got you convinced that RNAi Therapeutics was about to disappear from the scene by pulling the plug on the technology…think again. Alnylam this morning reported tantalizing insights into the safety and efficacy of ALN-PCS02, a SNALP-formulated RNAi Therapeutic targeting PCSK9 for the treatment of hypercholesterolemia. Given that PCSK9 is viewed as potentially the next biggest thing in cardiovascular drug development after statins have come off patent, and considering the results so far from the monoclonal antibody and antisense competition, this RNAi Therapeutic has the potential to become the field’s first blockbuster. As we know, a field does not need too many blockbusters to become more widely accepted, and it is acceptance, not so much lack of scientific progress, which has been lacking over the last 2-3 years. Together with the ALN-TTR01 results reported in November, I expect these results to dramatically change perceptions about RNAi Therapeutics in the pharmaceutical industry. And if I had to write the script, Alnylam will announce a share offering tomorrow or Friday afternoon in order to go hostile on Tekmira to remove the uncertainties arising from their use of Tekmira’s SNALP technology which critically enabled these results and on which most of Alnylam's $400M market cap depends on.

ALN-PCS02 Phase I Data

This trial was a simple single-dose escalation trial in subjects with slightly elevated levels of bad LDL cholesterol. Dosing in the 5 dose cohorts commenced at 0.015mg/kg and went up to 0.250mg/kg with each cohort consisting of 3 subjects receiving an intravenous infusion of ALN-PCS02 and 1 receiving placebo. As could have been expected with this particular rationally designed '2nd gen' SNALP formulation, robust target protein knockdown was observed at the highest dose tested with a mean 60% reduction in plasma PCSK9 levels presumably 3-5 days after administration. In line with PCSK9 genetics, this type of knockdown entailed a mean 39% reduction in bad LDL cholesterol. Importantly, and again consistent with the wealth of non-human primate data, this knockdown was sustained for days and weeks. Given that ALN-PCS02 apparently was well tolerated, with the only noted adverse event being a rash that was likely to be related to the mode of administration and not the drug itself, Alnylam now plans further dose escalation to a) increase knockdown potency, but b) also extend the duration of PCSK9/LDLc suppression. This is particularly desirable in light of the competitive situation.

The PCSK9 Competition

Needless to say, having now two examples in short order where RNAi Therapeutics unambiguously hit their targets, proof-of-concept of technical success can be claimed and one can now focus on the medical and commercial potential of these therapies. In this regard, the competition in the PCSK9 space is fierce. Big Pharma and Big Biotech have fielded their A-teams to develop monoclonal antibodies against PCSK9. Since much of the LDL-related effect is due to PCSK9 in the serum, this target is a particularly amenable to MAb technology.

Sanofi-Aventis/Regeneron are most advanced with REGN727 which is in the middle of a number of phase II studies. Amgen also reported recently phase I results with their PCSK9 MAb. Studies with both compounds have shown more potent LDLc reductions of around 65% compared to the 39% with ALN-PCS02 so far. This, of course, is a good reason for Alnylam to go ahead with its plans and continue dose escalation. However, once you achieve the type of 60-70% reductions in LDLc, the next major focus becomes safety, and so far the RNAi Therapeutic looks quite competitive in that regard.

As discussed in October, the PCSK9 antisense compounds by Santaris and ISIS have fallen a bit behind due to probably both safety (Santaris) and efficacy (ISIS) issues, although I expect ISIS to reciprocate tomorrow by presenting TTR knockdowns at their Investor Day tomorrow that are more pronounced than Alnylam’s first attempt with ALN-TTR01.

[Update 5Jan12: ISIS reported 44% mean TTR reductions at 200mg per week, very similar to ALN-TTR01 at 1mg/kg; and 81% reductions at 400mg per week, a dose that I consider too high for tolerability and commercialization; ISIS also disclosed that the BMS-partnered PCSK9 candidate was dropped citing a slow partner and regulatory concerns about PCSK9 as a drug target].

Overall, we can now conclude that the ALN-TTR01 results were no fluke (I never expected that to be the case anyway) and that in theory all targets in the liver are fair game now for RNAi Therapeutics. Moreover, the data show that the preclinical data with SNALPs translate very well into humans, removing a considerable uncertainty and opening up the prospect of further improvements in SNALP delivery based on what Tekmira and Alnylam have presented over the last few months.

A biotech company does not need many these PCSK9-type products to rise into the ranks of Big Biotech. While there is still a long clinical way to go, I believe that sometimes you are allowed to cheat and look at hard preclinical data, and in doing so I believe that today we may have seen the first glimpse of an RNAi Therapeutics blockbuster. I’m wondering how the Roches and Pfizers will be feeling over the coming months and years as the field of RNAi Therapeutics matures at this rate. It is also an opportunity for new entrants to build strong positions in the space with relatively small investments (still). Am I a bit vindictive today? Yes, definitely.