Tekmira’s Amended Complaint Suggests that Alnylam’s Transgressions More Severe than Suspected

The Amended Complaint against Alnylam filed in early June by Tekmira revealed that the potential damages to the company as a result of Alnylam’s alleged transgressions may be much more severe than initially feared based on the original Complaint and their public relationship over the years.

In particular, Alnylam apparently used their insights into Tekmira’s technology, gained as a result of its collaborator status and by secretly hiring ex-Tekmira employees (in breach of non-compete agreements) to file for patents that may question Tekmira’s freedom-to-operate in the technology that it itself developed. One example concerns the MC class of lipids.

From the Amended Complaint:

‘35. After learning Tekmira’s MC Trade Secrets in the collaboration, Alnylam misused those trade secrets by, among other things, filing for patents in its own name, and without including any Tekmira inventors, on a lipid structure that was broad enough to include the MC class of cationic lipids developed by Tekmira. In so doing, Alnylam improperly claimed ownership over Tekmira’s MC Trade Secrets, including the MC class of cationic lipids, for itself.’

Even worse, Tekmira’s significant competitive advantage of being pretty much the only company that can make quality SNALP/LNP at commercial scale is threatened as regulatory demands allowed Alnylam to learn of Tekmira's LNP manufacturing know-how and trade secrets which it abused to not only make such information fair game apparently throughout the Alnylam organization, but even to disseminate it to 3rd parties such as Takeda- all despite of Tekmira's best efforts to limit such information to only a few Alnylam employees on a need-to-know basis, password protection, written agreements, and all:

From the Amended Complaint:

‘Tekmira provided the MBR for the Lead Formulation, which is one of Tekmira’s MBR Trade Secrets, to Mr. Konys and specific, identified employees within Alnylam pursuant to the terms of the September 2008 MBR Agreement. Tekmira tightly controlled access to this information, including by securing the MBR computer files with password protection in order to limit the universe of individuals within Alnylam who could gain access to the MBR Trade Secrets.’

…

‘Tekmira learned about Alnylam’s wrongful disclosure of Tekmira’s MBR [Master Batch Records] Trade Secrets to Takeda when Alnylam’s David Konys told Tekmira that Alnylam had received questions from Takeda about Tekmira’s delivery technology.

Mr. Konys forwarded Takeda’s questions and asked Tekmira to answer them. The questions included information taken directly from Tekmira’s MBR.’

In addition, Alnylam has been manufacturing LNPs for 3^rd parties, including at least Takeda and Novartis, in an alleged violation of the exclusive LNP manufacturing status of Tekmira which apparently included certain non-clinical LNP manufacturing. No wonder Tekmira investors have been waiting in vain for those sure-fire Novartis and Takeda deals and were instead diluted by about 15% in a capital raise this month. Meanwhile, Alnylam pocketed $50M in ‘technology transfer’ milestones from Takeda.

From the Amended Complaint:

‘83. On information and belief, Alnylam is manufacturing delivery formulations for at least Takeda and has also done so for another third party pharmaceutical company called Novartis. On further information and belief, the delivery technology that Alnylam is providing contains, is based upon, and derives in whole or in part from Tekmira technology, including its confidential information and trade secrets.

Alnylam’s use of Tekmira’s manufacturing and delivery technology to manufacture formulations for third parties is not authorized by the restrictions on use and disclosure in the Protiva Agreement, Tekmira Agreement, September 2008 MBR Agreement, and Manufacturing and Supply Agreement. Alnylam’s manufacturing activity also constitutes a breach of the Manufacturing Requirements provisions of the agreements, which require Alnylam to use Tekmira as its “exclusive manufacturer to Manufacture and supply its requirements” for toxicology and other non-clinical studies and clinical development, through the completion of all Phase II studies for each product licensed from Tekmira. §11.1.1, Manufacturing and Supply Agreement.’

In general, it is quite clear that Alnylam’s own, ‘independent’ LNP development efforts were in competition with that of Tekmira. This actually is nothing new as David Bumcrots lipidoid-vs-SNALP comments four years ago illustrate. However, by not only licensing Tekmira IP, but also seeking practical help in using the technology, Alnylam greatly restricted its ability to build a competing LNP technology platform as that would have been destined to collide with the collaboration agreement that protected Tekmira’s ownership over its technology during and after the collaboration. This includes that Alnylam could not develop and claim technology that would have been derived from Tekmira’s technology and benefited from Tekmira know-how and trade secrets. It won’t take much effort for an expert witness to demonstrate that ‘2^nd generation’, MC3, formulation ratios etc as claimed in patent applications by Alnylam, including its Canadian subsidiary Alnylam Canada, are all obviously derived from Tekmira technology and know-how.

The Amended Complaint further illustrates that Alnylam showed no respect for its partner. Is it because it believed that money entitled them to all of Tekmira property, to the degree that it confuses an exclusive license with actual ownership (e.g. Alnylam citing, in defense of allegations that it misappropriated MC technology, the Greene-Murray letter in which Tekmira's CEO acknowledged Alnylam's exclusive rights to MC3)? Is it because it considered Tekmira’s existence a potential weakness in its quest for RNAi Therapeutics world domination? Or is it because historic business development successes (which ironically are largely based on Tekmira's technology) made them lose touch with reality?

I’m not exactly sure, but what I do believe is that all this has been a concerted scheme to marginalize and, yes, destroy Tekmira. The fact that Alnylam has published and been claiming to have discovered that ApoE explains the preferred functional uptake of ionizable SNALPs in the liver, although this was based on confidential information provided to it by Tekmira, nicely captures that Alnylam knew no shame when it came to Tekmira. In the long-term, no matter how this litigation ends, a company that interprets Open Innovation to mean that first you evaluate, and if you like it then marginalize the inventor, will find it difficult to attract (small) biotech companies with real enabling RNAi technologies.

A word about myself and the Tekmira-Alnylam litigation

It is not surprising that there is speculation about my motives and strong language in supporting Tekmira in their litigation against Alnylam. Yes, I am a shareholder of Tekmira and have disclosed that a number of times- not that I would have to anyway. This, however, is not without reason and based on Tekmira’s critical contributions to siRNA delivery, a leadership that is continuing to this day (see e.g. nebulized LNPs or the manufacturing of quality antibody-targeted SNALPs). I have long taken exception with the way Alnylam has been treating Tekmira and have seen it getting worse. Tekmira’s Complaint therefore only confirms what I had feared some time ago, and I see no reason to mince my words and expect Tekmira to vigorously pursue this case until it regains rightful ownership over all of its technology- plus damages and more.

For discussion purposes, here the Amended Complaint.

Tekmira Reports Important Advances in Widening Applications of SNALP RNAi Therapeutics Delivery

‘We Make RNAi Work.’

Tekmira’s slogan may sound a bit cheesy as they all do, but when you consider that it is the only company that has managed to translate the theoretically very powerful unilamellar liposome technology into the clinic and ready for commercialization while essentially everybody else is being frustrated from following up on promising early-stage results with liposomal delivery, it is a very appropriate one.

This leadership position was underlined in a recent presentation by Tekmira Pharmaceuticals at the CC-CRS meeting on May 25 (see related press release here). There, the company presented the advances it has made in widening the applications of SNALP delivery for use in major additional medical and commercial opportunities. Some of these advances were made in collaboration with large pharmaceutical/biotech companies, illustrating that Tekmira views these collaborations not only as a way to simply monetize their assets, but also as a way to grow the potential of SNALP delivery to areas such as respiratory disease (after cancer arguably the highest priority area in drug development) and targeted RNAi delivery by leveraging the partners' capabilities.

However, before reporting on the company’s advances in nebulizing and tagging SNALPs with monoclonal antibodies, the presenter made the point that more potent lipids is not what is holding it, or the field back from applying SNALP technology. Using ApoB as a target in rodents (mouse and rats), the data show that many of Tekmira’s lipids developed without Alnylam, including Alnylam’s Canadian subsidiary Al-Cana, have equal or superior potency to the MC lipids that have become one point of contention in the Tekmira-Alnylam litigation as such lipids, in addition to manufacturing, have been one of the pillars of Tekmira's gate-keeping position in SNALP delivery. For example, in the case of ApoB and the 2111 lipid 10 microgram/kg SNALP-formulated siRNA triggered more than 50% target gene suppression.

The presentation then moved on to demonstrating the progress Tekmira has made in formulating SNALP for respiratory and actively targeted delivery applications. Actually, it is formulating SNALP at commercially relevant scales that is Tekmira’s most valuable competitive asset, and this is why the unbelievable disclosures in the Amended Complaint that Alnylam abused its insights into Tekmira’s technology to misappropriate and represent formulation technology as its own are so grave (I will give it a couple of more days rest before I comment on Tekmira's Amended Complaint).

Data on the Ebola biodefense program show that the US government contract has been successfully commenced and is working just as the program was intended to work: not only is the company on track to developing a treatment for Ebola infection with the goal of filing an IND in the second half of this year, but the process has proven very valuable in maturing and bringing SNALP delivery to the next level, especially in terms of one of the most critical steps in SNALP delivery: high-quality manufacturing at commercial scale. Being able to formulate 1 kilo-gram siRNA instead of just 10 grams at a time without changing critical SNALP parameters such as size, encapsulation efficiency and poly-dispersity is enormous and means that SNALP can not only be used for running clinical trials, but can also be readily commercialized.

Data on targeted SNALP delivery showed that it is possible to decorate SNALPs with antibodies using Genentech’s defined THIOMAB antibody conjugation technology, again without compromising on critical SNALP parameters. Tissue culture data show that highly specific, targeted uptake and gene silencing can be achieved using these antibody-decorated particles. Such liposomes will have particular utility for applications outside the liver where delivery does not rely on ApoE (apparently initially an insight of Tekmira, not Alnylam as that company claims- more on this in that other blog post). I look forward to learning more about the performance of these particles in animal models, especially for cancer applications.

Another area where antibody-targeting could have utility is in the delivery of siRNA to the respiratory epithelium following nebulization. As we know, Alnylam’s ALN-RSV01 has been overshadowed by concerns that some, or even most of the antiviral activity of the nebulized naked and unmodified siRNAs may be due to innate immune stimulation. More generally, while I am convinced by now that high concentrations of naked siRNAs on the epithelial lining of the respiratory tract can achieve some target gene knockdown, to my knowledge, there has been no convincing report of RNAi knockdown through inhaled siRNA delivery robust enough to warrant clinical development.

Tekmira’s success in nebulizing SNALP particles therefore is the first critical step in opening up the respiratory space for inhaled RNAi Therapeutics (there are some strategies such as cationic lipoplexes or PEIs that can deliver to parts of the lung following systemic administration). Again, the key to success will likely come from proper formulation/manufacturing.

Using traditional LNPs, nebulization leads to gross changes in morphology, uniformity, size, and dramatic loss of encapsulation efficiency (from mid 90%s to 10%s). However, with undisclosed changes to Tekmira’s SNALP formulation, it is now possible to nebulize SNALP without changing these parameters. Tissue culture data confirm that these particles retain unchanged knockdown activity.

Altogether the presentation emphasizes that not only has Tekmira/Protiva been leading SNALP technology in the past but is continuing to do so…by a distance. It seems that in order for it and shareholders to capitalize on this leadership, more than getting the technology right, it is preventing Alnylam from using partnership status, money and PR from misappropriating the technology and representing it as its own.

Comment on referring to Tekmira’s delivery technology as SNALP versus LNP

Stable nucleic acid lipid particles (SNALPs) are a form of liposomal nanoparticle (LNP). The reason why I prefer to keep using the narrower term ‘SNALP’ when referring to Tekmira’s liposomal delivery technology instead of adopting the broader term ‘LNP’ as both Tekmira and Alnylam have done, is that the liposomes in clinical development by Tekmira and Alnylam currently and in the foreseeable future are still based on the original formulation (cationic/ionizable lipid+neutral helper lipid+PEG-lipid+siRNA), whether the cationic/ionizable lipid is a different one or whether a ligand is added or not. The term ‘SNALP’ is therefore a reminder of the innovator behind the technology, Protiva (now part of Tekmira), as they coined the term.

In a way, you would think that such terms that lack precise scientific definition anyway should not matter that much. However, in Alnylam’s efforts to marginalize Tekmira’s role in liposomal delivery, first changing from ‘SNALP’ to ‘LNP’, and then calling the newer formulations ‘second-gen LNPs’ has been an effective way of hiding ownership of the technology with the goal of eventually not only denying Tekmira contractually owed milestones and royalties, but by-passing Tekmira altogether (incl. manufacturing) also to appease partners such as Novartis and Takeda. ALN-PCS01 looks set to be the first battleground.

Silence Therapeutics Reports at ASCO 2011 that Atu027 has Achieved Important Pharmacokinetic and Safety Endpoints

On Monday at ASCO 2011, Silence Therapeutics provided an extensive update on its ongoing phase I trial of Atu027 for the treatment of advanced solid tumors (additional background on Atu027 and the current study provided here and here). While there are a few signs already that the drug candidate may have some anti-tumor activity, the even more important message was that Atu027 has been remarkably safe and well tolerated, while reaching drug exposures in the ongoing dose escalation at which, based on the pre-clinical experience, bona fide RNAi knockdown of the targeted gene can be expected.

In cancer drug development in particular, the name of the game in phase I trials is to test how much drug can be given without causing severe, dose-limiting toxicities. Often, in studies like this one, patients of highly varied, late-stage cancers are enrolled and too few of them are treated at the high dose levels. In that regard, the trial progress can be called quite satisfactory in that no dose-limiting toxicities were reported and the SAEs judged as unrelated to study drug. The most commonly reported side-effect was minor grade 1 fatigue. It is possible that this is drug-related, although many cancer patients suffer from fatigue for many reasons. Also of note, and as indicated in the abstract, the observed complement activations were transient and not clinically significant.

Making the safety findings even more meaningful, the measured pharmacokinetic data indicate that the drug was safe at concentrations in the blood where RNAi knockdown can be expected based on the preclinical studies in rodents and monkeys and the known knockdown potency of the RNAi trigger in tissue culture cells.

There were also preliminary signs of anti-tumor efficacy. 9 of the 24 patients had stable disease one week after receiving the last of 9 doses 2 months after study initiation, 6 of which remained stable until the end of the study (3 months after initiation). Moreover, there were two cases where tumor masses were notably reduced. Particularly notable was the case of the individual with the neuroendocrine cancer where a 2-3cm tumor mass disappeared following the re-peat administration of Atu027 (see also my earlier blog on the abstract). However, none of these apparent responses could be scored as responses by stringent RECIST criteria. It is possible that this is because other masses present in those patients did not respond. Also, stable disease did not appear to be dose-related, which may not be surprising given that most of the 24 patients enrolled so far were not given pharmacologically relevant dosages.

Outlook

Considering the safety profile so far, i.e. the absence of dose-limiting and other dose-proportional toxicities, I am hopeful that even higher dosages will be tolerated. Silence Therapeutics may even want to seek an extension of the study should the remaining 3 dose cohorts remain uneventful in terms of safety. As for Alnylam’s ALN-VSP02, the future development plan, especially a narrower patient selection and combination treatments, remain unclear and will be best explored in collaboration with a larger partner so that Atu027 can test and reach its full potential in a timely manner. Further investments seem more than justified and the main risk may be in the drug target.

Alnylam Presents ALN-VSP02 Liver Cancer Data at ASCO 2011

Widely expected, Alnylam presented over the weekend detailed safety and preliminary efficacy data from its multi-dose, dose-escalation phase I trial of ALN-VSP02 in 41 patients of advanced solid tumors with liver involvement. ALN-VSP02 is a SNALP formulation containing 2 siRNAs, one targeting VEGF (anti-angiogenic mechanism), the other kinesin spindle protein (KSP; anti-proliferative).

The data suggest that ALN-VSP02 has an adequate safety profile for such a cancer application at dosages where gene knockdown can be expected with such formulations in normal liver cells. While not geared towards showing efficacy, there are preliminary signs of efficacy with one case of clear tumor response and a dose-dependent increase in the number of stable patients.

Safety profile bodes well for SNALP delivery platform

Probably as, or even more important than studying the safety of ALN-VSP02, this study was the most rigorous test yet for the SNALP delivery platform. The detailed safety data show that while there were some minor toxicities at the lower dosages, innate immune-related toxicities such as chills and rigor become an issue at doses of 1mg/kg and higher, although none of these events were of high severity (grade 3) where they would be considered dose-limiting. There were also two cases of dose-limiting grade 3 thrombocytopenias at the 1.25mg/kg. Overall, this profile justified a recommended dose of 1mg/kg every 2 weeks for future studies.

Importantly, this study strongly suggests that SNALP delivery is amenable to repeat-administration with no apparent changes in the pharmacology upon re-administration. The ability to repeat-administer had been one of the question marks when SNALP delivery was in its infancy and this was the first such clinical experience.

While this safety profile is adequate for most cancer applications and other applications for severe diseases such as Ebola viral infections, the record suggests that for less severe indications, especially when chronic application is required, improvements in the potency and tolerability of SNALP delivery are necessary. Of course, based on Tekmira’s proprietary insights, considerable improvements in the therapeutic index have been achieved since ALN-VSP02 was locked down. In this light, the 1mg/kg mark determined here is very encouraging. Nevertheless, we still have to await clinical data with the newer formulations, starting with ALN-PCS later this year to fully justify such optimism.

Signs of preliminary efficacy

Although not the primary objective of such a study, Alnylam made significant efforts to study whether ALN-VSP02 works as designed and whether there are any signs of anti-tumor efficacy. In this regard, the highlight of the study is probably a patient with primary endometrial cancer and multiple liver metastases that showed a partial, but very considerable 70% tumor response and that has been on study drug for now more than a year. Moreover, among evaluable patients, only 1 in 13 given a dose up to 0.4mg/kg had stable disease for 2 months compared to 12 in 24 dosed with larger amounts of study drug (caveat: base-line criteria may not be fully comparable as the patient recruitment criteria were slightly adjusted during dose escalation).

In terms of mechanism of action, 5’ RACE RNAi cleavage results and a reduction in tumor blood flow and leakiness as measured by DCE-MRI support an anti-angiogenic mechanism of action due to VEGF knockdown, but overall the mechanism of action data fell slightly short of my expectations, although technical challenges in taking such biopsies and analyzing them may account for that. In particular, no data supporting a knockdown of KSP was reported. 5’ RACE cleavage assays apparently suffered from technical challenges, and the analysis of mitotic spreads was not mentioned at all.

Study validates SNALP siRNA delivery to liver

When I reviewed last year ALN-VSP02, I was a bit confused about Alnylam’s choice of a short-circulating C14-PEG-lipid instead of a longer-circulating C18-PEG-lipid. I even thought that there might be a mistake in Alnylam’s cartoons of the formulations, but my question remained unanswered. Having listened to the recent ThinkEquity presentation by Tekmira’s CEO Mark Murray, it is clear to me that this was not a typo: Tekmira’s solid cancer candidate TKM-PLK1 is a longer-circulating formulation, and as we know, Tekmira is getting more and more interested in competing with ALN-VSP02 in liver cancer.

Why does C14 vs C18 matter? In short, C14-PEG-lipids are most suited for gene knockdown in normal liver cells, not liver cancer cells. Normal hepatocytes largely derive their blood supply from the portal vein, whereas most liver cancers primarily tap into the arterial blood supply. For this reason, even when addressing tumors in the liver, a more stable formulation would have been desirable. This also applies to tumors outside the liver (note: the vast majority of patients in Alnylam’s phase I study had such turmors).

Therefore, when Alnylam reports siRNA concentrations in the liver biopsies that were often well above concentrations associated with potent knockdown of genes expressed in the liver in pre-clinical studies, it is mainly a validation that the DLinDMA C14 formulations successfully deliver siRNAs to the liver.

Why did Alnylam choose C14? This may be more of a rhetorical questions and if you follow the Tekmira litigation you will understand why. In other words, my suspicion is that if Alnylam were to develop another liver cancer candidate, it would indeed choose a longer-circulating formulation.

In conclusion, the ALN-VSP02 phase I study nicely adds to the accumulating evidence that up to 1mg/kg of SNALP-siRNA is readily feasible which predicts a comfortable therapeutic index for the liver-targeted SNALP pipeline. ALN-VSP02 will likely have to be studied in more targeted patient population and together with other therapeutic modalities before its real potential becomes clear. It won’t be an easy stroll, but the data show that there are a few reasons to be optimistic.

PS: Silence Therapeutics also presented today at ASCO an update on Atu027 for advanced solid cancers. The press release can be found here. I am currently traveling and will provide further commentary when I get a chance.

Big Pharma Support for RNAi Therapeutics Growing

In case you have not noticed: “Big Pharma” is slowly coming back to RNAi Therapeutics. This marks a fourth phase in the delicate relationship of the small pure-play RNAi Therapeutics companies with their larger counterparts.

The relationship in the first phase (2002-5) may be characterized as one of benign neglect and certain curiosity. Sure, RNAi was a hot emerging scientific area, but Big Pharma preferred to let the small companies kick the tires and take the risk while continuing to do what they were most comfortable with: small molecules along with some monoclonal antibody work. The patent cliff still seemed like a management generation away.

In the second phase (2005-8), some pharmaceutical companies like Novartis and Merck started to see the light. It became apparent to them that as small molecules alone won’t cut it any more that a technology like RNAi Therapeutics may ideally fit into the personalized medicine paradigm of the future. Following their initial investments in the space, other companies like Roche, Pfizer, and Takeda began to worry about being left behind and looked to catch up, in some cases frantically so. The Nobel Prize added fuel to the fire and a small bubble developed where investments were often not made based on the best science. Big Pharma companies wanted to be seen as being at the fore-front of this technology and were happy to advertise their association with the technology in public.

The US real estate-triggered global financial meltdown marked the beginning of the 3^rd phase (2008-2011). If that and subsequent widespread healthcare rationing did not inflict enough pain on the pharmaceutical industry, major blockbusters were falling off the patent cliff. Investors in Big Pharma demanded much reduced R&D spending and instead share buy-backs and dividends. Ironically based on the productivity with small molecules, it was often believed that R&D per se is a money-losing proposition. It’s therefore somewhat understandable that companies like Merck and Novartis that continued to put considerable resources into RNAi Therapeutics preferred to keep this quiet. In addition to pacifying shareholders, another objective for their secretiveness was, of course, to cool down market prices for the technology. The interview with Alan Sachs in Xconomy early last year about Merck’s view of RNAi technology as a target validation technology initially was a good example of this policy.

RNAi Therapeutics did not fare well in this climate. As larger companies realized that they made some bad investments in the technologies, some probably feeling that they have been deceived by some of the pure-play companies. I believe that the blame is to be shared between Big Pharma companies too lazy to undertake not only proper IP, but also scientific due diligence, and the bad actors in the RNAi Therapeutics industry of which there were without doubt quite a few (but definitely decreasing in numbers now).

It was then especially those Big Pharma companies that got into the game relatively late and consequently with often less conviction in the technology that were the first to curtail their RNAi Therapeutics spending. The most dramatic example of this is Roche spending north of half a billion US dollars and then calling it off already after only 3 years. It may also be that even if the scientific progress was considered acceptable, having agreed to paying hundreds of millions in milestones for RNAi triggers at the pre-clinical stage made RNAi drug development not economical considering that RNAi triggers are only one part of the equation.

Unfortunately, the backlash hit the entire industry hard, including those few companies that have done the real work underlying many of the promising drug candidates that have recently started to enter the clinic.

There are, however, increasingly signs that companies like Takeda, BMS, and Genentech are willing to show support for the technology (phase 4). It must have occurred to these companies that RNAi Therapeutics has been making some progress over the last couple of years in addressing issues such as delivery, immune stimulation, and building clinical experience, all the while prices for the technology were plummeting to what I consider highly attractive price points.

It has also become clear that in terms of RNAi trigger structure and IP, Alnylam is not the only game in town any more.

From a Big Pharma perspective, this is probably the best time to invest. Pipeline productivity problems remain the same. Many of Big Pharma’s current blockbusters based on small molecules turn out to bring little or no benefit to patients and if they are honest to themselves, the future of healthcare won’t support, i.e. reimburse, me-too drugs with only little if any incremental benefit even if you can take them only once a day in pill form. I believe this will be borne out in the multiple sclerosis field where oral pills are all the rage at the moment and some analysts believe this to be the end of the incumbent treatments that are administered parenterally. In the end, medicines that stall and reverse severe diseases will win out, and for scientific reasons, targeted technologies like RNAi Therapeutics should have an edge. There had been similar concerns about technologies like monoclonal antibodies, and now cell-based therapeutic cancer vaccines, but in the end social acceptance is greatly driven by how much the industry establishment and thought leaders endorse a technology.

It is therefore critical for Big Pharma to support pure-play RNAi Therapeutics companies. All the important innovations in the field have come from the smaller companies, and if those that have developed them disappear, everybody will be worse off. While I expect Big Pharma investment to increase from now onwards, especially in light of the clinical progress that should become particularly apparent over the next couple of months, this time should be different from the 2005-8 scramble to buy a piece of RNAi Therapeutics. The focus will be more than ever on quality, and companies that have shown hands-on ability to overcome the challenges in developing viable RNAi drug candidates should be well rewarded for their contributions to the space.