RNAi Therapeutics Now a Commercial Reality

Last Friday, Alnylam received notification from the US Food and Drug Administration (FDA) that ONPATTRO (aka Patisiran) has been approved for the treatment of hATTR-related polyneuropathy.  This marks the culmination of an almost picture-book translation of a brand-new biotechnology into therapeutic reality.  20 years from worms to patients is nothing.

ONPATTRO development path

Much has been made in the press about the great uncertainty, reflected in supposedly unusually long timelines, of whether RNAi can be a therapeutic modality at all.  Of course, the challenges of delivering RNAi triggers in WoMan, staving off unwanted innate immune responses, and the question of how the transcriptional noise stemming from slightly modulating dozens of unrelated targets will affect safety were all daunting at the beginning.

But looking back, with the exception of a 2-3 year delay due to having to change from an insufficiently potent LNP chemistry to the MC3 lipid-based LNP underlying ONPATTRO and having to institute steroid pretreatment to minimize ‘infusion reactions’, all these challenges more or less dissolved in the development path of ONPATTRO.

A special shout-out here to Ian MacLachlan and his team at formerly Tekmira for solving the critical delivery challenge first.

A best-case scenario would therefore have seen an approval in 2015-6.  2018 is therefore not that bad at all.  Here a quick run-down of the milestones leading up to the approval:

1998: discovery of double-strand RNAs (dsRNAs) being the trigger for RNAi in worms

2001: finding that RNAi can be triggered in WoMan by short dsRNAs

2002: first demonstration of RNAi in mice

2005: first therapeutically relevant demonstration of RNAi in monkeys

2009: initiation of first clinical trial of first-generation LNP-RNA (SNALP-ApoB, aka PRO-040201; ALN-VSP02)

2012: start of ONPATTRO clinical development

2012: first solid clinical proof-of-concept for RNAi in WoMan from ONPATTRO phase I study

2012: start of ONPATTRO phase II study

2013: start of ONPATTRO phase III study (APOLLO)

2017: positive data read-out from APOLLO

2018: EU and US marketing approvals for ONPATTRO  

ONPATTRO is just the beginning

Since ONPATTRO had been conceived starting about a decade ago, there has been, of course, considerable progress in RNAi trigger design (safety, efficacy) and (conjugate) delivery technologies.  As a result, a slew of other RNAi drug candidates by Alnylam, including Givosiran for Acute Intermittent Porphyria (likely 2019 approval), Inclisiran for cardiovascular disease (likely 2020 approval), and Lumasiran for primary hyperoxaluria (likely 2020 approval), are about to be approved.  Especially with the adoption of off-target-minimizing chemical modifications, I am confident that the success rate of RNAi drug candidates for tissue types for which delivery is robust will only increase.

After the liver, for which the current crop of marketing candidates is the target organ, the CNS should be the next huge opportunity as Alnylam gears up to bring a first candidate into that organ over the next year.  In addition, Arrowhead Pharmaceuticals and Alnylam have also started to talk about opportunities in the lung and cancer, although here I am still hesitant about whether these are near-term clinical opportunities or something that will have to wait another 3 years or so.

RNAi shatters antisense competition

As the world is abuzz about the first full-blown marketing approval of an RNAi Therapeutic (note: formal marketing authorization in the EU is still pending), I would be remiss not to display a key graph illustrating the power of RNAi gene silencing versus competing approaches such as gene silencing by mass action RNaseH antisense (TEGSEDI by Akcea Therapeutics) and trying to keep bad proteins from acting out with small molecules (generic tetramer stabilizer diflusinal):  

If you were diagnosed with TTR amyloidosis and had an average life-expectancy of 2-5 years, which treatment would you like to be on?

Stock market reaction

When Alnylam opens for trading today, it will likely be down due to disappointment that the FDA label, unlike the anticipated case in the EU, will only specify TTR-related polyneuropathy for which the APOLLO study had been designed, and not cardiomyopathy with none of the exploratory cardiomyopathy data from APOLLO included.  While this is somewhat disappointing in light of biomarker-based accelerated approvals of Eteplirsen in DMD where target modulation and therapeutic hypothesis were enough to win the day, this should only be a minor hiccup in the overall history of RNAi Therapeutic.  In light of the recent Pfizer small molecule Tafamidis cardiomyopathy data, it is very likely that RNAi trials will show a benefit for cardiomyopathy symptoms as well in a dedicated study (à ALN-TTRsc02). 

Until then, it is possible that the cardiomyopathy data are being withheld until Alnylam and the FDA can come up with a way to include those in an amendment, or as part of an accelerated approval submission.  It is also likely that TTR patients will now more readily be referred from cardiologists to neurologist for an intense neuro check-up such that primary cardiomyopathy patients can access ONPATTRO (and get paid for it) at the slightest signs of polyneuropathy.

Alnylam Reports Potential Advance in SNALP Safety

One concern with the use of any drug is that it ought to be eventually eliminated from the body.  This is a particular issue with nanoparticulate drugs for which efficacy have been the main design criterion.  To address biodegradability for Tekmira's SNALP delivery, a technology that routinely involves un-natural lipids which may not be easily biodegradable, Alnylam has just published on SNALP lipid-derivatives containing readily degradable ester bonds.   The results show that such SNALPs are rapidly eliminated from the body and indicate that their use can increase the therapeutic index.

In the paper, Maier and colleagues took the (once fiercely contested) MC3 lipid, which is part of the ALN-TTR02 formulation for which phase II results are imminent, and tested whether the incorporation of ester bonds at various positions in the lipid tail would retain knockdown efficacy.  The ester bond was chosen because it was predicted to maintain the MC3 lipid geometry and can be degraded by the ubiquitous esterases in the body.  Consistent with the idea that the apparent pKa of the head group is important for efficacy, positions were identified that left the pKa, and consequently knockdown activity in mice largely unchanged (ED50 of <0 .01mg="" kg="" o:p="">

To confirm the prediction that the resultant SNALP particles, economically formulated with microfluidics, were less stable than their parent particles, plasma and tissue elimination rates as well as the generation of turnover intermediates were tested.  Indeed, the new SNALP particles were much less stable.

What is more, at doses of more than 3mg/kg SNALP-siRNA there was a trend towards slight elevations with the MC3 SNALP, but not with a derivative.  The authors stopped short, however, to test concentrations at which much more toxicity can be seen.

The major downside of the study, however, was that in non-human primates, the new SNALPs had less activity than expected for MC3 SNALPs.  At 0.3mg/kg, the dose at which 80-90% knockdown was observed in the phase I study of ALN-TTR02, only a 70% TTR knockdown was achieved.  Nevertheless, it is likely that other biodegradable SNALPs optimized for primates will achieve MC3-type efficacy.    

I do not expect SNALP biodegradability to become an issue for the upcoming ALN-TTR02 phase II results.  The longer-term dosing experience with cancer RNAi Therapeutic ALN-VSP02, however, suggested that there could be spleen toxicity with extended dosing and at higher dose levels.  The last word from Alnylam on that issue had been that the spleen toxicity was due to on-target activity.   The paper by Maier et al., however, leads me to believe that both explanations are still on Alnylam’s table.   

Tekmira Regains Control over Leading Delivery Technology

When Tekmira filed its lawsuit against Alnylam in March 2011, it found itself in an impossible position: Alnylam’s apparent mis-use of SNALP-related trade secrets not only diminished their strategic value to Tekmira, including depriving it of potential pharmaceutical partnerships, Tekmira may even not have been able to use the technology it invented.  As a result, it might have been left to die in a little cage with ‘1^st generation’ technology as its technology was making rapid progress.    

Cash and Control

Based on the disclosed terms of last night’s settlement with Alnylam (Tekmira's version here, Alnylam's version here), Tekmira got essentially all that it needed: control over its leading systemic RNAi Therapeutics delivery technology, including the contested MC3 lipids of which the IP was assigned to Tekmira, and a $65-75M payment (~$16-18M of which will go to pay outstanding legal fees).  The payment, of course, will finally allow the otherwise financially conservative company to push forward their development pipeline with interesting therapeutic candidates such as TKM-PLK1.  Notably, as part of the settlement, Tekmira obtained full ownership over this candidate which I believe addresses one of the most exciting RNAi targets in oncology. According to the Q3 financial results, also released today, TKM-PLK1 has been making good progress, including showing signs of drug activity and will advance into phase II studies next year.

Beyond the cash, the new IP licensing arrangement between the companies is at least as valuable.  Importantly, Tekmira has regained exclusive sub-licensing rights to ‘LNP intellectual property’, an incredibly important part of the settlement as before that Alnylam enjoyed such control, mainly via its rights to the Semple-Wheeler IP covering important aspects of ionizable SNALP technology.  This should open the door for Tekmira to enter into the long-expected pharmaceutical partnerships. Novartis and Takeda are here the most obvious near-term candidates for platform-type relationships.

Assuming that the new relationship is not restricted to RNAi Therapeutics, an added bonus is that the settlement could similarly pave the way for relationships in the microRNA Therapeutics space, particularly for the delivery of microRNA mimics.  Only recently, privately-held Mirna Therapeutics made headlines by raising $34.5M to fund the development of a microRNA mimic into the clinic, indicating the significant interest in this area of drug development.

Value of the Trade Secrets

Less clear is the damage to the trade secrets that were at the center of the dispute and on which much of Tekmira’s strategic advantage rested.  Numerous groups and companies have attempted home-brew liposomal RNAi trigger delivery, but only Tekmira’s technology has made it into the clinic.  Especially the ability to formulate and manufacture the particles is what set Tekmira apart from the competition.  In their press release, however, Alnylam stated their intention to use its own LNP manufacturing capabilities.  Apparently, it has already established such GMP manufacturing capability over the last year (in a separate building apparently for added suspense).  Assuming that Tekmira did not assist them in establishing such manufacturing, this indicates that the number of people with critical knowledge to the trade secrets has grown.  This can be particularly a problem in the wake of lay-offs in a place like biotech world capital Cambridge, Mass. 

Still, I assume there to be significant hurdles for other companies to replicate Tekmira’s processes, and with its liposomal experts, Tekmira should continue to lead in advancing SNALP delivery, making it the liposomal delivery partner of choice.

With cash of around $50M (excluding the $10M which are contingent on likely 2013 development milestones for ALN-VSP02 and ALN-TTR02), partnerships likely to come in due to the clarified IP situation, the $141M DoD Ebola biodefense contract (a new more potent and safer formulation will be used) and the income stream from Talon Therapeutics, Tekmira has thus emerged as the vibrant RNAi Therapeutics company it should have become 3 years ago.  Nevertheless, today's terms underline the value of Tekmira and RNAi delivery in general.  Exciting times ahead.

MC3 Authorship Discrepancies Increase Suspicions of Cover-Up

Last week was a tumultuous one in RNAi Therapeutics and in the relationship between Alnylam and Tekmira.  

On the positive side, results from the ALN-TTR02 phase I study revealed that highly potent knockdowns for liver-expressed genes are possible in Man.  Although solid knockdowns had been demonstrated before using the same delivery formulation for the hypercholesterolemia-related PCSK9 (ALN-PCS), the latest results demonstrate the most potent and prolonged knockdowns in RNAi Therapeutics history.  Thus, this should be reproducible for most liver-expressed genes as long as highly efficient RNAi triggers are selected, further substantiating the claim that RNAi trigger potency matters.

At the same time, the results once again brought into focus the hard-fought battle for this most valuable RNAi Therapeutics delivery asset: SNALP.  On the celebratory conference call, Alnylam’s management was more aggressive than ever in claiming that this ‘second-generation LNP’ technology was entirely theirs: ‘Proprietary!’  Of course, this makes little sense for the reason alone that the composition and formulation method of these particles clearly identify them as SNALPs which belong to Tekmira.  Just as a reminder, there is an important distinction between an exclusive license and owning something.

Not only does it reveal that Alnylam management is apparently unable to grasp this very basic concept of property rights, well captured by John Maraganore's statement 'you pay for it, you own it', Tekmira alleges that what enabled this improvement in liver gene knockdown potency over the ‘first-generation’ liposomal formulations and which is the basis for Alnylam’s ‘proprietary’ statement, namely the MC3 ionizable lipid, was stolen from them in a covert operation.  This operation apparently happened at the end of a series of actions to not only appropriate valuable SNALP technology on which Alnylam has come to essentially wholly rely upon (despite its recent attempts to claim that it employs four different delivery approaches), but also marginalize, and ultimately destroy Tekmira.

The reason why I strongly believe that Tekmira is not making up these shocking allegations, is not just based on the fact that Alnylam’s PR strategy has been so obviously aimed at wrestling away from Tekmira its reputation as THE liposomal RNAi delivery company (see the promotion of the clinically unfit lipidoids to a point where many observers believe that the clinically employed liposomal technology originated at MIT; Alnylam oligonucleotide chemists prominently listed on liposomal patents; or back-handed compliments in the context of ‘1^st-generation’ technology).  No, it is also because all of the evidence and accounts that I have gathered in my investigations were consistent with Alnylam having had little respect for Tekmira and thought their financial might and influence can be used to take full possession of SNALP technology and leave Tekmira in the dust. 

MC3 Origins

Probably the most telling of these acts concerns the origin of the MC3 lipid.  This lipid is an important component in ALN-PCS and ALN-TTR02 which have attracted so much attention recently, and which forms the basis for Alnylam’s ‘proprietary’ claim.  Briefly, Tekmira alleges that former employees of the company were hired by Alnylam (first as consultants, and then as employees at pseudo-independent Alnylam Canada, pardon me, AlCana) and were supposedly struck by genius essentially the moment they had left the company's premises (and apparently finished downloading the files) to come up with MC3, ownerhip of which was duly transferred to Alnylam.

Alnylam claims that MC3 was an ‘independent’ lipid and thus would fall under the scope of the Supplemental Agreement.  Based the above timelines alone, it seems that Alnylam management must have very low expectations for the IQ of the jury that they will be facing in late October.  Moreover, it is obvious that MC3 was part of a series of lipids that these employees had started work on as full Tekmira employees.  Note: although they may have been the rightful inventors of the MC series of lipids and may even hate their former employer for personal reasons, the fact remains that they did so when employed by Tekmira.  Consequently, the lipids and related trade secrets are not theirs.  Moreover, the key insight in the 2010KC2 Nature Biotechnology paper by the same authors (when employed by Tekmira) was that changing the length of the linker between the lipid headgroup and tails had a profound impact on performance.  Hence, developing new lipid scaffolds and then start testing series thereof with variable linker lengths was Tekmira's trade secret until then.  And that, of course, is what got them to discover MC3 (from the recent Jayaraman et al): 'In the second group, the dimethylamino moiety is maintained but the distance between the ester and the amine is varied from one to five methylene units to generate lipids with pKa values ranging from 4.17 to 7.16.'

Too bad for Alnylam that ‘rational’ appears in the title of that key Nature Biotechnology paper (Rational design of cationic lipids for siRNA delivery) as it will be Alnylam’s strategy at the trial to convince the jurors that successful lipid discovery is an extremely unlikely chance event, further hoping that the jurors won’t be able to make the distinction between unpredictability in terms of how many carbon atoms exactly would yield the most useful lipid and unpredictability in terms of which search strategy (Tekmira know-how) would likely yield such a lipid.

It is also curious that the research organizations of Tekmira and Protiva had been kept separate until in late 2008.  Supposedly, Alnylam demanded this as a precondition to blessing the Protiva-Tekmira merger so as to keep Merck from getting their hand on certain Old Tekmira’s technology.  Whether true or not, it likely also had the effect that not only Merck, but also Old Protiva were left in the dark on these trade secrets (although they belonged to the combined company).   This darkness was then allegedly exploited to get MC3 ownerhip transferred to Alnylam and to obtain a broad covenant not to sue from Tekmira that according to Alnylam’s interpretation would also absolve it from IP and trade secret theft.

MC3 Authorship Discrepancies

Over a year ago, when the lawsuit broke, it bothered me that in the MC3 patent application (now issued patent US8158601), the key ex-Tekmira employees which should have been the real inventors behind MC3 according to my logic described above, i.e. Madden, Hope, and Semple, were missing as listed inventors.  M. Hope, importantly, was the senior author of the KC2 Nature Biotech paper, which served as the blueprint for the MC series.  Instead, a slew of Alnylam oligonucleotide chemists are listed as if the synthesis of an extra carbon in the linker group here and there was an inventive contribution. Surely not.

This to me strongly smelled like part of the cover-up.  Read for yourself my speculations at the time:

'But looking at the (published) patent application, all these key people are actually missing as named inventors. I would identify these key scientists as Thomas Madden, Sean Semple, and Michael Hope and it would have been natural for Tekmira to have non-compete arrangements in place for these individuals. Importantly, these are also the senior authors on the KC2 Nature Biotech paper from January 2010, a lipid from which MC3 is derived (see also e.g. slide 28 in August 4, 2010, presentation by Alnylam at the International Liposome Research Days held in…Vancouver).

However, despite of Alnylam’s assertions that it was the fired Tekmira employees now working, for apparently legal purposes, at AlCana (but practically for Alnylam) that invented MC3, the published patent application only lists Alnylam employees (and maybe some consultants) as inventors and Alnylam as the applicant: Akinc, Dorkin, Qin, Cantley, Manoharan,Kallanthottathil, Narayanannair, Jayaraman; and (for US purposes only) Chen, Ansell. (the latter two being the two ex-Tekmira employees, but no mention of AlCana).

You would think that, as the inventors of KC2, the inventive contributions by Madden, Semple, and Hope would have played an important role in MC3, much more so than the number of trained oligonucleotide chemists from Alnylam listed as inventors on the application. Given that the Response admits that Alnylam hired the ex-Tekmira employees that would eventually form AlCana as consultants, it seems highly unlikely that Madden, Semple, and Hope played no role in the MC3 patent application.'

12 days ago then finally appeared the peer-reviewed publication concerning the discovery of MC3 (actually a long time after the 2009 patent application).  I could not believe my eyes when the list of authors indeed revealed Michael Hope as the senior author on the paper (highlighted in red along with Thomas Madden):

Muthusamy Jayaraman,* Steven M. Ansell, Barbara L. Mui, Ying K. Tam, Jianxin Chen, Xinyao Du, David Butler, Laxman Eltepu, Shigeo Matsuda, Jayaprakash K. Narayanannair, Kallanthottathil G. Rajeev, Ismail M. Hafez, Akin Akinc, Martin A. Maier, Mark A. Tracy, Pieter R. Cullis, Thomas D. Madden, Muthiah Manoharan, and Michael J. Hope*

For those unfamiliar with how authors are listed on papers in the biomedical sciences, the last author is the senior author with responsibility for the overall study.

I have only four possible explanations for this:

1)      Sheer stupidity/carelessness on the part of Alnylam and their lawyers- this would not be a first considering the VSP Interference history alone;

2)      This hypothesized cover-up had so many tracks to conceal that some of them would always make it through to the daylight;

3)      For scientists which see their future in the academic sciences, it is publish-or-perish and Michael Hope and Thomas Madden insisted being on the paper for this reason (note that also the academic Pieter Cullis from the University of British Columbia is on the paper, likewise absent on the patent);

4)      Alnylam knows that the evidence is such that the involvement of Hope and Madden will be revealed anyway, and trying to further conceal the fact would make it look even worse.  Now, they may claim that the omission of Madden and Hope was an honest mistake and they may file for a correction of inventorship on the patent (otherwise they risk the patent becoming invalid due to Inequitable Conduct).

Personally, I favor a combination of 1) and 2).  Alnylam and their lawyers have surprised me a number of times already with their carelessness, a carelessness that is possibly born out of arrogance.  This arrogance may very well be its downfall.  There are only three months to go until the trial and it looks like, despite of Alnylam's delay and cost-intensifying tactics, as if the jury will have it!

Next up: Judge in Tekmira-Alnylam case orders no more delays and why I believe Alnylam is a highly attractive short here...

Tekmira Partner to Initiate Phase I Study for the Treatment of Severe Hypercholesterolemia

Tekmira’s partner and licensee Alnylam Pharmaceuticals announced today the submission of files to a European regulatory agency in anticipation of a phase I study with a candidate targeting PCSK9 for the treatment of Severe Hypercholesterolemia. The primary aim of this early-stage study is naturally the safety and tolerability of ALN-PCS. An important secondary aim, not just for Alnylam but also for the entire field of RNAi Therapeutics, will be assessing drug activity as measured by target protein levels in serum. Initial data are expected by year end.

ALN-PCS represents Alnylam’s 4^th clinical candidate, three of which are based on Tekmira’s SNALP technology (VSP, TTR, PCS). It also represents the 2^nd candidate under its 5x15(TM)program which aims to advance five RNAi Therapeutics candidates into late-stage clinical development by 2015. All disclosed candidates under that program (TTR, PCS, HPN) are based on SNALP technology.

Despite the success of statin in lowering cholesterol, many patients are still considered to be in need of additional treatment options. PCSK9 has emerged as a very attractive target for such uses based on human genetics which suggest PCSK9 knockdown to reduce ‘bad’ LDL cholesterol in addition to being well tolerated. While ALN-PCS is the first RNAi Therapeutics candidate to target PCSK9, other companies have already started clinical development of PCSK9-targeting hypercholesterolemia candidates.

These competitive efforts are based on monoclonal antibodies and antisense approaches and include a recently initiated program by Santaris (LNA antisense) and monoclonal antibody programs by Amgen, Pfizer, and Regeneron amongst others (mostly phase I and II). ISIS with partner BMS together are also developing a PCSK9 antisense candidate. This candidate, however, still appears to be in late preclinical studies following some delays.

The pre-clinical data show that RNAi, antisense, and monoclonal antibodies can all potently down-regulate or bind and inhibit PCSK9. It seems, however, that one advantage of ALN-PCS could turn out to be that it does not simultaneously down-regulate ‘good’ HDL cholesterol as was observed e.g. in a rodent study by ISIS (antisense; significant 50% reductions; Graham et al 2007) or in a non-human primate monoclonal antibody study by Amgen (moderate 20% reductions; Chan et al 2009).

Obviously, it is still early days to speculate on the eventual competitive profile of the various candidates. With regard to safety and tolerability it is notable, however, that the anticipated highest dose with ALN-PCS in the study is 0.25mg/kg. This means that an average Caucasian may receive only about 10-20mg siRNA per week (assuming bi-weekly or monthly administration). While there is still some more uncertainty about the safety profile of non-DLinDMA SNALPs such as ALN-PCS (this candidate uses MC3 while all other SNALP candidates so far made use of DLinDMA), such low doses make me optimistic that the safety profile should be quite competitive.

Adding Tekmira’s efforts, this program is the 5^th SNALP candidate in 3 years to enter clinical development. At least two more are anticipated this year. ALN-PCS therefore further illustrates one of the advantages of RNAi Therapeutics development, namely that once there is a suitable delivery technology for a given target organ, in this case SNALP for liver delivery, the indications can be rapidly expanded to multiple drug targets. This also means that the inventor behind and manufacturer of ALN-PCS, Tekmira, should receive a milestone from its partner and licensee upon initiation of dosing, adding to an increasing royalty stream.

Alnylam Green Shoots After Corporate Restructuring

The latest quarter must have been the best quarterly performance by Alnylam in the last 3 years. After going through a rough patch that culminated in Novartis not adopting a widely expected $100M platform license with the attendant lay-off of a third of its staff, the results and also tone of the conference call struck me as if the company had re-discovered its old enthusiasm for RNAi Therapeutics drug development and is intensely focused on creating value by providing additional clinical proof-of-concept data over the coming months.

There is reason to be cautiously optimistic about the upcoming clinical data. For one, dose escalation for the liver cancer candidate ALN-VSP02 seems to have progressed beyond the magic 1mg/kg mark and is still ongoing! First generation or not, the fact that patients have now received and tolerated this kind of dosage, and on a repeat basis, is major de-risking for all of Alnylam’s, but also Tekmira’s pipeline candidates which involve LNP delivery (almost all of them). Similarly encouraging, ALN-TTR01 dosing is also ongoing and with 3 centers in Europe recruiting now, results may not be that far off (28 patients anticipated in this phase I study).

Although the first generation LNPs appear to be well tolerated, Alnylam seems to be even more excited about a potential quantum leap in LNP delivery: LNPs containing the next-generation MC3 lipid which not only silence in the unprecedented single micro-gram per kg range for gene targets in the liver, but also appear to be very well tolerated in animals. The MC3 lipids are derived from the DLin-KC2-DMA ionizable lipids developed by Tekmira, results from which were published earlier this year in Nature Biotech.

Besides the science, financials seem to be in better-than-expected shape, and I believe is what underlies today’s jump in share price (you can assume that the stock market wouldn't pay much attention to MC3). With over $370M cash/equivalents on the balance sheet, Alnylam is poised to close the year with well over the previously guided $325M cash/equivalents. Having slashed the work force, albeit probably at considerable personal cost, thus buys the company strategically valuable breathing room. In addition, there were a number of positive one-offs this quarter, including $2M for the successful award of 8 federal grants, a Quark milestone, and increased activities related to Novartis finalizing its 31 target picks. And with Novartis' relationship with Alnylam settled now, it should become easier to talk to other companies about partnerships and further add to the strong financial position.

Alnylam and Medtronic also stand to receive very significant funding from the Huntington’s Disease Foundation (CHDI), likely totaling over $10M, some of which has already been earned (agreement is retro-active). Somewhat dampening the excitement around that program was news that ALN-HTT is now a 2012 goal for entering the clinic, while LNP-delivered ALN-TTR02 and PCSK9 (both probably MC3) are poised to be the Company’s 2011 new clinical candidates.

An interesting tidbit on PCSK9 is that, faced with numerous competition from mainly monoclonal antibody candidates against the same target, some of which have already entered the clinic, it appears to be now Alnylam’s strategy to emphasize the fact that with RNAi you down-regulate both intra- and extracellular PCSK9 levels, which therefore is closest to recapitulating human genetics which has been driving the adoption of PCSK9 as a drug target for hypercholesterolemia in the first place. A good argument indeed.

Overall, my most important take-home was that this seems to be a re-energized company, and with some of the right clinical news, there may soon be a second honeymoon between Alnylam and its shareholders (of whom I’m btw not one of…yet).