Antibody-RNAi Trigger Conjugates Show Signs of Life

Despite jettisoning RNAi Therapeutics 4 years ago, the more innovative arm of Roche, Genentech, has continued to dabble in the technology.  In particular, it has been interested in applying its monoclonal antibody know-how, including antibody-drug conjugates (ADCs) to the delivery of RNAi Therapeutics.  A recent publication by Cuellar and colleagues provides insights into these efforts.

THIOMABs for the creation of drug-like conjugates

While antibodies have a relatively long history in the delivery of RNAi Therapeutics, some of the early findings were generally quite difficult to replicate.  Part of the problem may have been the fact the early efforts involved structurally ill-defined non-covalent protein-nucleic acid complexes held together by charge-charge interactions.

To get around this issue, Genentech applied their THIOMAB platform which allows for the covalent addition of therapeutic payloads at defined cysteine residues.  This process yielded THIOMAB-siRNA conjugates with one, or more often two RNAi triggers per monoclonal antibody.  To help visualize them, also for pharmacokinetic considerations, think of the monoclonal antibody part being ~13x bigger/heavier than each RNAi trigger.

Of note, the RNAi triggers were partially (~50% of residues) modified with 2’-O-methyls and 2’-F for stability (siSTABLE from Dharmacon).

Not all receptors are created equal

One of the reasons why I am picking out this paper for discussion is the thoroughness of the research presented.  For example, the Genentech researchers selected not just one, but seven distinct cell surface receptors for which various THIOMAB-siRNA were created which in turn were be tested in a number of settings.  The receptors were partly chosen to capture a range of cellular trafficking behaviors such as rapid lysosomal uptake, recycling receptors, and slow-turnover receptors.

Importantly, the research validated a critical rationale for the use of antibody-RNAi trigger conjugates namely uptake of the RNAi triggers that is dependent on the presence of the cognate receptor and covalent linkage to the antibody.

For all the conjugates (ARCs), the bulk was shown to accumulate in lysosomes regardless of presumed uptake kinetics.  Interestingly, despite the seemingly shared uptake pathway, if not dynamics, only two of the seven receptors were associated with gene silencing (TENB2 and NaPi2b, but not e.g. Her2). 

The degree of silencing was much weaker compared to when the same conjugates were lipofected with ~50% silencing starting to be seen at 10nM.  This was followed by a shallow dose-response plateauing at 70-80% silencing around 500nM.  Based on the data presented, it seems that limiting amounts of receptors were responsible for this. 

Selective accumulation in mouse tumor model

A highlight of the publication to me was the investigation of THIOMAB-siRNAs in a mouse tumor model.  Although you may consider a ~30% silencing (i.e. 70% expression of normal remaining) when you cherrypick tumor areas of most efficient delivery a somewhat disappointing outcome as was reported in this case, important lessons can be learned from that.

Firstly, THIOMAB-siRNAs only accumulated in the tumor when the tumor expressed the cognate receptor.  This is unlike nanoparticulate RNAi delivery to tumors which relies on a passive process of accumulation (the EPR effect).  This opens up the prospect of RNAi drugs with ‘cleaner’ delivery profiles with an increased margin of safety.

Selective accumulation for these conjugates also suggests that the ~180kDa macromolecules were able to relatively rapidly exchange between tumor interstitium and blood circulation despite their size.  Consequently, other conjugates in a similar size range or below, including Arrowhead’s DPCs, should be amenable to such ‘active targeting’ as well.

Nevertheless, despite this apparent agility, imaging techniques showed that tumor delivery was largely restricted to areas next to the vasculature.  This limitation in fact is what is also seen with nanoparticles which rely on the EPR effect.  So while the active targeting capability is an important step forward, tumor penetration issues remain to be solved.

Path forward

Despite the arguably underwhelming in vitro and in vivo knockdown results if you just look at the numbers, I am optimistic that the studies have further supported that systemic RNAi delivery can be applied beyond the liver, vascular endothelial cells, certain cells in the kidney and phagocytes.

What is missing in that particular piece of research making the conjugates that make it into the cells count.  Given the lysosomal accumulation, an obvious strategy to unlocking the true potential of ARCs would be to apply endosomal escape chemistries, especially masked chemistries such as in the DPCs by Arrowhead Research (actually specifically referenced by the authors).

In almost the same vein, the sparse chemical modification used mean that potency improvements will be gained if heavier modification is applied even without adding endosomal escape chemistries.  This is also because some of the data are consistent with a model whereby the THIOMAB-siRNA conjugates get broken apart in late endolysosomal compartments and it is from that population of freed RNAi triggers that escape into the cytoplasm may occur (note: this does not exclude spontaneous endolysosomal rupture as an additional escape pathway).  If RNAi triggers were made metabolically more stable through more extensive modification, the amount of RNAi triggers available for such escape would obviously be larger.

All that is lacking then is the issue of tumor penetration.  I could imagine, however, that some self-delivering and/or lipophilic strategies could be quite useful here.  The Genentech researchers actually speculate that the RNAi trigger may have been the culprit in limiting the claimed natural ability of monoclonal antibodies to more deeply penetrate tumors.  This suggests that charge masking may overcome this limitation.  

I am open to this idea, but based on my understanding of the literature, tumor penetration is a challenging issue for basically all therapeutic modalities, monoclonal antibodies and 'even' small molecules, so let's not blame double-strandedness for all pharmacologic problems.

With interest in RNA Therapeutics growing by the day, expect lines of delivery research such as this one to be picked up and pushed to the next level.

PS: for antibody-mediated RNA delivery, Avidity NanoMedicines and the Roche-ISIS collaboration on CNS delivery should also be worth watching.

January RNA Therapeutics Deal Frenzy Kicked Off

As is now tradition for Januaries in RNA Therapeutics, expect this month to be filled with mouthwatering business development announcements.

Without a doubt, privately held messenger RNA Therapeutics company Moderna Therapeutics stole the show today by announcing a $450M financing involving 'Viking Global Investors LP, Invus, RA Capital Management, and Wellington Management Company, LLP, as well as existing investors AstraZeneca and Alexion Pharmaceuticals'.

Biggest private financing in biotech history EVER.

With $800M in cash, close to a billion USD raised since starting up 2 years ago or so, the biggest challenge will be how to efficiently put the capital to good use and move into the clinic in the not-too-distant future.  Before that happens, we should be seeing one of the hottest biotech IPOs in 2015.

Before Moderna announced their financing, ISIS Pharmaceuticals was the talk of the day with their GI-related autoimmune deal with Johnson&Johnson.  Not only does the early development deal provide ISIS with another nice junk of upfront cash, this time $35M, and a gazillion in potential biotech milestone payments and royalties, jn practical terms I expect the research to be particularly useful to ISIS as it develops oral delivery for systemic applications (think lipid franchise for which the new CEO will be officially enthroned tomorrow).  

I believe that the deal was primarily driven by JNJ's interest in the space following the whopping $710M upfront deal by Celgene last year when it acquired rights to an antisense compound developed by oligonucleotide therapeutics nobody Nogra Pharma for IBD applications.  The high upfront payment indicates that competitive bidding was involved and it is likely that JNJ lost out.

Remember, Big Pharma moves in herds.

The good news for JNJ is that if the first-generation phosphorothioate DNA is indeed working by an on-target mechanism (which I doubt), then a competing compound employing much more advanced chemistry and design by ISIS Pharmaceuticals will be infinitely more potent and beat Celgene in the market.  And for $35M and $800M in milestones if everything goes according to plan, it's a comparative steal.

For ISIS Pharmaceuticals it is just another step to broaden their expertise and applications of their platform.  Moreover, the upfront payment will help the company to remain cashflow neutral to slightly positive until 2017, at which time I expect drug sales to be finally taking off.

Genentech Research VP Predicts Industry Productivity to Increase

Besides the cloudy economic picture in the established pharmaceutical markets, much of the current cost-cutting in pharmaceutical R&D can be explained by a loss of confidence of the industry in their own ability to efficiently develop drugs. This assessment is largely made by MBAs without a biomedical background who will measure current industry productivity in terms of how many drugs get approved today, that is 10-15 years after most of the critical development decisions were made. Worse still, instead of considering the new biotechnologies and exponentially growing insights into human biology and disease as a solution, because the downturn in productivity seems to be correlated with the genomic revolution, of which RNAi has become an indispensable part, these very technologies are blamed for increasing the cost of drug development. If you thought Luddites were a phenomenon of the 19^th century, think again.

In this context, I found it quite refreshing to listen to a presentation by the Vice President of Research & Early Development at Genentech at the Stanford ‘DFJ Entrepreneurial Thought Leaders’ seminar series (highly recommended, podcast available on iTunes) in which Richard Scheller predicted that industry productivity is going to improve significantly (note: while Roche owns all of Genentech, Genentech’s R&D remains separate). In his opinion, one of the main reasons for the industry’s poor record these days of getting drugs past the regulatory agencies was a spending glut when biology wasn't ripe for it. In the 90's, right along with the internet bubble, there was a strong belief that the pharmaceutical industry was invincible. When the harvests from the small molecule revolution were aplenty, companies offered their R&D heads quite a bit of the profits for re-investment. Needless to say, these VPs did not hesitate one moment, accepted and spent it. Unfortunately, 'pre-genome era', there were not that many well validated targets and projects to spend that money on and that’s how we end up with the $1-1.5B figure popularly cited for what it takes to get a new drug approved- on average.

This, however, has changed dramatically according to Dr Scheller due to the information explosion brought about by the new biotechnologies (high throughput sequencing, RNAi, proteomics etc). As a result, we have now many more validated targets to choose from. This, he predicts, will be a major force in re-invigorating industry productivity.

It is the ability of RNAi Therapeutics to pretty much go after any drug target, and often not just one but a few in parallel (see Alnylam’s VSP or Tekmira’s Ebola programs), that should make it so valuable to the industry (my thoughts).

Richard Scheller then added that not all Big Pharma companies will participate in reaping the benefits of these advances. Without naming names, he said that some companies have 'lost their way' and will pay for neglecting R&D. Cutting internal R&D and out-sourcing the rest will cause these companies to lack the expertise to make the right technical go/no-go decisions. While commercialization is clearly important at the end of the process, he warned that commercial considerations are often brought into play too early in the process and he cited some examples in which products with mediocre sales forecasts became Genentech’s biggest sellers and vice versa.

I guess John Maraganore referred to this as ‘hyperanalytical insanity’ in a 2009 interview with Xconomy. It also reminds me of comments by Art Krieg, then head of Pfizer’s RNAi Therapeutics efforts, which doubted the commercial potential of drugs that are intravenously administered. If a translational medicine person credited as a father of TLR therapeutics starts to think along these lines, you get an impression of the brain-washing powers of sitting in the boardrooms of Big Pharma.

Intravenously administered RNAi Therapeutics for the treatment of hypercholesterolemia is probably a good example of such mis-placed early criticism. Critics say that with such a mode of administration alone, this can never be a big seller in the lipoprotein-modulating market. This, of course, entirely neglects the high unmet need of the millions of patients not well served by currently available medications alone. It also is not open to the possibility that the eventual clinical profile will be so differentiated and/or superior/complementary to existing approaches that patients and doctors are quite happy to accept infusions every month or two. Without testing it at least in phase II studies, nobody really knows what the commercial profile will be.

To most of the readers here, Richard Scheller probably stated the obvious. Nevertheless, it is good to hear somebody influential in the industry still apply logic to drug development at a time that RNAi Therapeutics has become such a popular punching ball. These pockets of reason within Big Pharma/Biotech will be critical in keeping RNAi Therapeutics move forward for everybody’s benefit.

Speaking of the Devil: Genentech Receives Full Takeover Offer from Roche; Stands to Become Alnylam’s Partner

Just as I was speculating that Genentech may become Alnylam’s next major RNAi Therapeutics partner, Roche makes an offer to buy the rest of Genentech’s shares that it does not own already. I’m sure the pundits will be all over what this event will mean for drug development, so just a few notes on its relevance for RNAi Therapeutics.

From the press release and based on historical comments against the notion of mega-mergers with fellow Big Pharma and against entering generics, it is clear that Roche is very keen on leading the development of innovative medicines, particularly personalized medicine. What better candidate than Genentech with all its know-how in this arena as well as size to sufficiently impact Roche's top and bottom lines? Just to demonstrate that personalized medicine is more and more becoming a reality, Roche appropriately also announced today European approval for an interferon-ribavirin treatment regimen for hepatitis C based on individual viral titers and rapid viral response. Interestingly, Alnylam disclosed really for the first time in the Pharmaceutical Executive report its interest in hepatitis C which might be best addressed by SNALP delivery. And how much more personalized can hepatitis C treatment get than to sequence the virus in a given patient and then deliver the appropriate siRNA combination?

Reassuringly, the press release prominently mentions RNAi Therapeutics as a central component of the innovation engine of the combined company:

“The structure of the combined company will allow for a diversity of approaches in research and early development, while also strengthening cross fertilization between the companies, leading to enhanced overall innovation within the Group. Roche's recently adopted Disease Biology Area approach, which allows five diverse groups to manage their innovative portfolios, will be maintained and strengthened. This, together with recent moves into RNAi (Ribonucleic Acid interference) and delivery technologies, as well as licensing activities, continues to provide a stimulating
environment for the creation of medically differentiated medicines.”

And on the “enhanced ability to innovate”, the press release goes:

“The transaction will over time significantly enhance cooperation and cross fertilization among all research hubs inside and outside of the combined company. Sharing of technologies (e.g. RNAi, novel protein architectures), assets (e.g. chemical libraries), intellectual property(e.g. antibody production), unique capabilities (e.g. exploratory development, modeling and simulation) and know-how of the combined research organization will strengthen the Group's ability to innovate.”

I wonder how much Genentech will be surprised by the offer. In this regard, it is also interesting to speculate whether Alnylam had been in negotiations with Genentech or not. If so, would an unsolicited takeover of Genentech by Roche mean that Alnylam has to forego platform license fees that it would have otherwise received if Genentech remained independent? On the other hand, could it be that Genentech’s moves into RNAi Therapeutics had long been co-ordinated with Roche’s efforts, relying on being able to access RNAi know-how and IP through Roche? I guess the answer will come whether the $89 a share offer will be recommended by Genentech management to shareholders or not. Given the close ties between the companies a Ventana-like takeover battle is difficult to imagine. The weak dollar may also aid Roche in increasing the price a little bit to satisfy all Genentech shareholders.

Today’s development promises to be a defining moment in the history of drug development. With the recent acquisitions of diagnostics company Ventana and now Genentech, Roche has now fully committed to embracing the future of personalized medicine. Based on comments by the new CEO Severin Schwan who has now more than amply demonstrated that he really means what he says, RNAi Therapeutics is to play a key part in this.

Genentech and RNAi Therapeutics- Part 1

A very enjoyable, yet detailed feature article by Walter Armstrong on the state and prospects of RNAi Therapeutics in the Pharmaceutical Executive this month, concludes with a somewhat bold prediction of mine: Genentech will partner with Alnylam to develop RNAi Therapeutics. I would like to use the next two blogs to expand on this speculation, explaining why such an alliance would not just make Alnylam shareholders happy (Part 1), but also the ways that Genentech’s participation in RNAi Therapeutics should benefit the entire sector (Part 2).

First off, all of this is conjecture and not based on inside information. I think it is fair to say that Alnylam is the bellwether of the RNAi sector. At the same time, however, Alnylam has made it no secret that it in turn is following the example of another biotech company- the iconic Genentech. For example, when Alnylam won the prestigious biotechnology James D. Watson Helix award for the mid-cap category in 2006, it was particularly proud to join Genentech as that year’s winner of the large cap category. References to Genentech’s business development strategy can also be heard at regular intervals in its conference calls and interviews like the one by Nature Biotech with Alnylam CEO John Maraganore in 2007 from which this excerpt is taken:

“JM: By that, I mean good old-fashioned, peer-reviewed, published research, appearing in top journals like Nature, Science and Cell. In this, we have a prominent role model: Genentech (S. San Francisco, CA, USA).When I was starting my career in biotech in the 1980s, Genentech wowed both academic and industrial scientists by blazing a trail in genetic engineering. Every week, it seemed, there
was a paper in one of those top journals describing an exciting new advance—Axel Ullrich making fusion receptors with cytoplasmic tails that helped us understand cell signaling, the cloning of tissue plasminogen activator—all of which were amazing feats at the time. Just as importantly,Genentech captured the imagination first of academic scientists, then of public-market investors and then of Hoffmann-
La Roche (Basel, Switzerland), all of whom profited handsomely on their decisions to place their trust and their capital in the hands of that company’s leaders.”

Also note the reference to Roche and Alnylam's deal with Roche announced 3 months thereafter. It was then also a statement by Roche made in the wake of Roche-Alnylam expressing their hopes that Alnylam may be their second Genentech (Roche is the majority owner of Genentech), that then confirmed that there may be more to Alnylam-Genentech than just the respect and admiration of an emerging company for the industry powerhouse. I’d like to think that at the time the statement was made, it was not merely hopes of making lots of money that where on Severin Schwan’s mind, now the CEO of Roche.

When as part of the Tekmira-Protiva reunion it was mentioned that out of the four technology evaluations by unnamed companies there was a Big Biotech, it was possible to start seeing the scientific dimensions take shape. Appropriately, in addition to Alnylam upping their stake, Roche joined by buying 4% of New Tekmira. As a reminder, one of the most promising therapeutic areas for SNALP RNAi delivery technology is oncology, and when it comes to Roche and cancer, we really mean Genentech and cancer.

Genentech not only pioneered recombinant protein therapeutics, but is also leading the pack in developing personalized cancer medicines. As I mentioned in an earlier blog, Genentech is now looking at small molecules as monoclonal antibodies cannot address the numerous targets it has discovered and accumulated considerable know-how in as part of their oncology efforts. These targets are downstream of the much more limited upstream components of cancer signaling pathways (downstream in general also means more specific/safer). This is particularly problematic when resistance mutations occur that render targeting the upstream ones futile. While RNAi Therapeutics had not been officially mentioned, I have to admit that I would be very surprised and quite frankly disappointed if Genentech did not resort to RNAi to harness its oncology target know-how by non-monoclonal means.

RNAi-related microRNAs should also be of great interest to Genentech as they could be developed as companion diagnostics for personalized cancer drug treatment, and possibly as therapeutic targets themselves to which Alnylam could provide access via Regulus.

Building on publicly disclosed RNAi screening know-how, the following job advertisement by Genentech earlier this year suggests that its RNAi Therapeutics plans are rapidly materializing:

“Responsibilities: We are seeking a highly motivated Research Associate or Senior Research Associate to conduct a range of research activities to enable delivery of an exciting new class of therapeutics based on RNA interference (RNAi). As a key member of our research team, this scientist will use a variety of methods (molecular biology, cell biology and biochemistry) to: (a) develop technologies to effectively deliver RNA-based drugs for a variety of therapeutic indications and (b) discover and elucidate the mechanisms of delivery and gene silencing.”

Whether an alliance is announced this year or not, the above circumstantial evidence and the secretive Genentech conference participants suggest to me that srtl RNAi Therapeutics will not only be validated as the innovation outlet for Big Pharma, but even biotech.

To be continued…

RNAi Therapeutics: RNA Research Blossoms in Economically Challenging Times

As the war in Iraq continues to cannibalize investments into the US health-care system and particularly funding for basic research, and spiraling commodity prices and the bursting of the credit bubble conspire to create risk-averse capital markets in which small biotech companies are struggling to fund R&D, RNA research is blossoming while RNAi Therapeutics appears to be one of the very few areas in biotech financing where money is still readily available.

This view is not only supported by the exploding number of RNA-related research publications, not to a small degree triggered by interest in RNAi and microRNAs, but also anecdotally by the exponentially increasing numbers of official registrants of the Bay Area RNA Club meetings. An impromptu meeting for RNA researchers to gather and schmooze over RNA science every half a year or so, it drew more than 250 RNA enthusiasts this past week to the UCSF Mission Bay Campus across the street from the expanding Merck subsidiary Sirna Therapeutics in San Francisco, also the place that had just hosted the Qiagen HT RNAi user meeting the week before. At the same time, the corporate RNAi world was assembled for the Beyond Genome conference at the lofty Fairmont Hotel.

Of course, the big meeting taking place concurrently in San Francisco was the enormous ADA conference. Although RNAi was not really represented there, this should change in the coming years as metabolic disease together with other liver disease and cancer is emerging as one of the hot areas for first-generation systemic RNAi Therapeutics. RNAi Therapeutics appears to be the logical answer as the genome revolution is yielding serious therapeutic targets for metabolic disease and cancer on an almost daily basis. Recent papers studying non-alcoholic steatohepatitis with AAV RNAi (a very potent technology for persistently knocking down genes in the liver, at least in mice) or the surprising identification of transcription factor XBP1 in regulating lipogenesis in the liver are just two examples. The latter is also particularly interesting as targeting XBP1 may require tissue-specific delivery, and the availability of RNAi delivery technologies such as SNALP RNAi which can carry up to 95% of the injected dose to the liver.

Given the potential for innovation, rational drug development, and more efficient and shortened development time-lines, it is therefore not surprising that one of the very few areas in Big Pharma R&D not affected by big cutbacks is RNAi Therapeutics. Think Merck, GSK, Pfizer, Abbott, Takeda, Novartis… a list of those Big Pharma companies not participating in RNAi Therapeutics research would probably be more informative at this point.

I even wouldn’t be surprised to see Genentech, based on their increased presence at RNAi conferences, make themselves less reliant on protein-based therapeutics and throw their support behind RNAi Therapeutics relatively soon, probably before 2010. Genentech, the pioneer and poster child of personalized cancer therapeutics, would be the logical, unnamed Big Pharma that Tekmira mentioned has been evaluating their SNALP delivery technology. I should apologize for mentioning SNALP RNAi so often, but by following the Alnylam-Tekmira, I believe one can gain invaluable insights into current RNAi Therapeutics trends.

I am confident that the intense efforts in RNA research in academia and industry will provide a fertile soil on which RNAi Therapeutics will continue to thrive, and may not only survive the very real economic downturn, but given the pressures experienced by Big Pharma and the healthcare system even benefit from it. Merck, Roche, Takeda and others are not the result of clever business development removed from science, but a consequence of such efforts.

RNAi Therapeutics: Integrate, Collaborate, or Die

It was with a healthy dose of suspicion that I went today to a presentation by Mike Varney from Genentech on their small molecule operations which is a new addition to the Genentech and which he was spear-heading. Of course, as the pioneer of biotech the first question to be addressed was why Genentech would go into small molecules at all if that was part of the reason why Big Pharma was ailing anyway?

Hearing about the challenges of RNAi delivery ad nauseum, you’d think that relative ease of delivery such as by oral bioavailability would be a major motivation, but this was not the case. In the business of treating serious, life-threatening disease with large unmet medical needs, it becomes less relevant if you can go home and take a pill twice a day, or whether you get an intravenous infusion every other week. No, the main rationale provided was that as Genentech scientists dive deep into the biology of disease pathways, they often find themselves with promising drug targets, but which cannot be reached by antibodies. Antibodies are great for targeting cell surface proteins, but useless for intracellular targets whereas small molecules can more easily achieve that feat. Target space is the keyword here, and according to Dr. Varney target space is very limited, so limited so that as a biotech reaches the size of a Genentech or Amgen it has to think about other drug classes while at the same time Big Pharma is expanding into biologics.

You can imagine how my mind was racing wishing to tell Genentech that it was right in front of their eyes and RNAi is what they were really looking for, a technology that may address virtually any gene and also circumvent the painful lead optimization process for small molecules Mike Varney was going through (and yes, I cannot believe that they have not thought about small RNAs already even if much of the thinking was done for them by mother Roche).

But that’s not really my main point tonight. As he was describing the diverse skills it took to bring the clinic and pointing out that part of the reason that current productivity in drug development is so dismal (the latest number is $1.4B spent for every new drug developed) and Genentech was so successful is that many companies think they can get away with by just concentrating on a small part of the skill pie. And this may be very true for the current RNAi Therapeutics space as well.

While the entry barrier for target discovery using RNAi is relatively low, developing an actual RNAi Therapeutics is much more complicated than that. Just considering the scientific aspects, the development of an RNAi Therapeutic requires among other things, precise knowledge of the disease biology, basic RNAi and microRNA biology, know-how in siRNA design and chemistry, assessing off-target risk and the interplay of the RNAi trigger and/or delivery vehicle with the immune system, RNAi pharmacology, and being able to safely deliver the RNAi cargo.

I get the impression that there are a number of programs/companies out there that do not take into account e.g. the off-target profile in their design of an RNAi trigger and instead select a published sequence or one that they find can simply knock down a gene and eventually take that into the clinic, or lack the know-how required to adequately assess innate immune responses. This could be avoided if smaller companies weren’t so afraid in collaborating with each other or larger companies, partly for fear that it may negatively affect how the investment community perceives their competitive scientific prowess and IP position. Right now, I can only see very few companies that have the financial wherewithal and scientific know-how to establish an integrated RNAi Therapeutics development platform that alone could shepherd RNAi Therapeutic candidates into the clinic. Alnylam, Merck, maybe Novartis, and probably soon Roche and Pfizer may have such capabilities, and these examples may not even cover all the bases just as Genentech is collaborating with both small and large.

Smaller companies, particularly those with a focus on delivery should probably seek help in deciding which RNAi trigger to use with their particular technology. Of course, having something to offer in return will help their negotiation position. As you know, I think Tekmira/Protiva have done that quite well and obtained up to 7 InterfeRx picks from Alnylam in exchange for liposomal siRNA delivery technology. In other instances where the technological payback may not be that obvious for the established company, it may still be a good investment to help with siRNA design as part of granting a technology license, as it should also increase the odds of successful clinical development and therefore potential for royalty income further downstream. Big Pharma most likely would not be interested in such top-to-bottom technology transfer arrangements, but it may be a consideration for some of the more established pure play RNAi Therapeutics companies.