Alnylam Now Sued by University of Utah Over 3’ Overhang Inventorship

Not a day goes by without a lawsuit involving Alnylam. This time it would seem unjustly so.

The company disclosed in a regulatory filing today that the University of Utah (‘Utah’) is suing the owners of the valuable Tuschl II (T-II) patent estate (Max Planck, the Whitehead Institute, MIT, and UMass) along with licensee Alnylam (but not Merck) for wrongfully omitting Utah scientist Brenda Bass as the inventor of the 3’ overhang feature central to that patent family. While the demands of the plaintiff, i.e. naming Dr. Bass as the sole or at least joint inventor plus damages, are unlikely to be met, it is a reminder that the validity of the T-II invention has yet to be confirmed in the US and that Alnylam’s aggressive bid to control the world of RNAi Therapeutics may have triggered a backlash gathering steam.

In the Complaint, Utah basically asserts that Dr. Bass first conceived of the 3’ overhang feature of the small RNA gene silencing mediators that Tuschl and colleagues saw in their elegant Drosophila lysate experiments. The plaintiffs cite as evidence a review on the Tuschl work that she began writing on March 21, 2000 and which incorporates a highly speculative model featuring small 3’ overhang siRNAs as the intermediates and likely mediators of RNAi. On April 11, 2000 she then presented her ideas at a conference at which Zamore, a co-inventor of T-I and claimed by some to be a co-inventor of T-II also, was present. More such presentations and communications as is normal in academia took place and which allegedly involved other inventors named on T-II.

The Complaint further alleges that the named T-II inventors improperly used that information to file on December 1, 2000, the first T-II priority document with the European patent office- but without naming her and therefore depriving the University of Utah of the economic benefit of T-II, arguably Alnylam’s crown jewels.

I find it very hard to believe that Utah’s request of Max Planck naming Dr. Bass as an inventor on the T-II patent application will go anywhere. First, she speculated that 3’ overhangs might be involved in the pathway, but it was only the presently named T-II inventors that actually demonstrated the utility of such overhangs. More importantly, however, if Dr. Bass and Utah really believed the 3’ overhang feature had economic value, they should have filed for their own patent application before publishing the review. Since this has not happened, the review became a public disclosure and a free-for-all. According to the description in the Complaint, there never existed a ‘real’ collaboration between Dr. Bass and the Tuschl inventors so that including her as an inventor would be wrong in my opinion.

But then again, because of her disclosure, whether she were to be included or not, it would be an invalid patent due to her own prior art if the review held up as such.

I would have expected the Bass issue to come up as part of the US T-II examination back-and-forth anyway, but not to the extent that it would have real threatening power. It is, however, highly unusual that Utah would challenge the inventorship of T-II already at this stage, in the same court that heard the Tuschl litigation, as inventorship questions are normally dealt with during patent prosecution or after a potential grant. The timing is even more so unfortunate for Alnylam, as they have to now deal with two lawsuits simultaneously, lawsuits that are challenging the two most important elements of Alnylam’s RNAi world domination strategy: SNALP delivery and T-II.

My humble advice: Deal with the Tekmira issue first, i.e. acquire Tekmira as Alnylam should have done all along, then focus on clinical progress. The Utah issue will then feel less of a nuisance and distraction.

Quark RNAi Therapeutics Drug Candidate for Diabetic Macular Edema Effective, but Changing Competitive Landscape Weighs

A lot has changed in the treatment of diabetic macular edema (DME) since Quark sub-licensed its AtuRNAi compound to Pfizer in 2006. Most notably, the monoclonal antibodies against VEGF, Lucentis and the cheaper derivative Avastin, are replacing laser photocoagulation as the standard of care in this condition that adversely impacts the vision of up to 10% of those living with diabetes.

Quark last week reported 12-month data from the phase II study of PF-04523655 run by Pfizer (DEGAS) enrolling 184 patients with DME. The data suggest that the drug was on track of meeting its primary end-point which would have been superior improvements in mean visual acuity at 24 months compared to laser treatment: a 5.8 letter improvement for ‘655 at the highest dose (3mg) compared to 2.4 for laser (p= 0.08). Pfizer, the company that ran the trial, however, decided to terminate the study at this midway point as it deemed that the study objectives could no longer be met.

This is likely at least partly due to the new competition from the Roche/Novartis drug Lucentis that showed 24-month improvements of 12.5 letters versus 2.6 letters for sham control in a pivotal phase III study (RISE). Nevertheless, the efficacy of ‘655 looks much better if one considers that taking into account the 12 month completers only, the improvement was a very promising 9.1 letters for ‘655 versus 3.2 letters for laser. Moreover, the ‘655 data were reported to be dose responsive whereas the Lucentis data were not. Importantly, no serious adverse events were reported, although additional details remain to be reported at an upcoming conference.

Based on this dataset, it seems to me that ‘655 was efficacious, but unlikely to match the Lucentis data with the doses studied even when allowing for more patients to complete the study. Given the encouraging data, Quark decided to run a phase IIb study on its own dime, hoping that with higher doses the efficacy of Lucentis can be matched or even surpassed. This would confirm that the safety profile in DEGAS was satisfactory. In return, Quark would receive increased milestones and royalties should the drug eventually be approved.

Overall, the data are good news for RNAi Therapeutics in ocular indications in general. 3mg siRNA translate into almost a whopping 100mg per kilogram of human eye that were apparently well tolerated in this study (note, however, that the cost of goods for monoclonal antibodies would still be higher even at the current 0.3-0.5mg/injection). This paves the way for improved RNAi Therapeutics candidates with larger therapeutic indexes due to enhanced uptake and at the minimum the same frequency of administration as Lucentis (monthly). Some RNAi approaches, such as attempted by RXi Pharmaceuticals and Eyegate, may even dispense of the need for needle injections altogether. This would be a major differentiating factor.

Moreover, even with comparable single-drug efficacy, safety, and route of administration, ‘655 may be a viable alternative or complement to Lucentis as its mechanism of action is anticipated to be anti-apoptotic (stabilizing the blood-retina-barrier) instead of anti-angiogenic (preventing abnormal blood vessel formation). However, as indicated in my somewhat less optimistic blog entry last week, this is yet to be convincingly proven given the possibility that ‘655 may have at least partly worked through a non-RNAi mechanism. Demonstrating synergistic action in some animal models would go a long way in showing this.

For investors of Silence Therapeutics, I consider this better-than-expected data as they keep the drug alive and demonstrate the safety of the AtuRNAi design. How the new terms between Quark and Pfizer will affect Silence’s financial stake in the program and whether the present result will trigger any immediate payments, remains to be seen.

Update from March 18 Quark registration statement: In the parallel study of '655 in wet AMD, an interim analysis has shown improvements in mean visual acuity over 3 month period, but at 4 months, the primary endpoint, no numerical benefit over Lucentis was seen in any of the doses. The trial will be continued with full data expected in the second half of 2011.

Tekmira Tells Alnylam ‘Enough is Enough’

The reason why I have been a strong supporter of Tekmira is because I give them the scientific credit for developing the most valuable systemic RNAi Therapeutics delivery technology without which the field would be in much worse shape. The gate-keeping position of Tekmira being the real enabler and innovator of LNP delivery, the result of having persisted through many years of dogged, high-class research, an effort older than Alnylam itself, however has been increasingly challenged by Alnylam’s apparent attempts to be seen as the go-to-guys for LNP delivery.

Tekmira now accuses Alnylam of having crossed the line by misusing critical trade secrets obtained during their LNP delivery partnership and otherwise undermining Tekmira's reputation and business relationships of the company. In its lawsuit filed with the Business Litigation Session of the Massachusetts Superior Court, Tekmira hopes to be awarded north of $1B in damages.

Since the alleged wrongdoings get to the core of Tekmira’s value as the leader in systemic RNAi Therapeutics delivery, a position which critically depends on its ability to protect ‘LNP’-related trade secrets and know-how, these are very serious allegations indeed. The latest developments, however, don’t surprise me in the slightest since from the outside it looked as if Tekmira was being treated quite unfairly, almost bullied in this relationship.

The $1B in damages most likely reflect the over half a billion in non-dilutive funding Alnylam was able to bring in as a result of its Tekmira/Protiva relationship. While the press releases highlighted that the deals were for RNAi trigger IP primarily, such trigger IP would have been worth much less without realistic delivery, and the four therapeutic areas covered in the Roche and Takeda deals, three of which are amenable to LNP delivery, strongly indicate that LNP, aka SNALP, was a driving force in reaching and valuing the deals.

In return, Tekmira got very little by comparison. A few millions as a result of their IP deal that gave Alnylam access to some of Tekmira's LNP delivery IP and some co-development and especially manufacturing income. Nevertheless, Alnylam seemed unsatisfied with this situation since Roche and Takeda highlighted the fact that it was still necessary to consult with Tekmira if Alnylam wanted to fully use and sub-license Tekmira's LNP technology. As a result, it seems that Alnylam engaged in tactics to downplay Tekmira’s importance which became first apparent in the summer of 2007 when Alnylam went out on a limb and claimed that it would be able use Alnylam-made LNPs with ‘lipidoids’ for its liver cancer program instead of those made by Tekmira (see blog 'Alnylam Chooses Lipidoids over Cationic Liposomes for their First Systemic RNAi Clinical Studies'). Of course, we now know that ALN-VSP01 became ALN-VSP02, a formulation comprising Tekmira technology and lipids.

A patent application by Roche for Factor VII knockdown in the liver (WO 2010/055041) may also be indicative of the dynamics of the Tekmira-Alnylam relationship. Almost throughout the application, LNP01 'lipidoid' formulations were used, but then without much discussion Tekmira formulations were used for the non-human primate part of the study. When I read that application for the first time, it immediately raised questions in my head whether Alnylam led on Roche to believe that it could do without Tekmira's help. Instead, Roche ended up partnering with Tekmira for developing its first RNAi Therapeutics candidates to the IND stage.

The campaign of marginalizing Tekmira reached a point where LNP newcomer Alnylam, still by far the more visible company in RNAi Therapeutics due to its widely admired deal record, started to shape the vocabulary of LNP delivery. Examples of this are terms that were introduced such as ‘lipidoids’ suggesting non-violating IP and superior technology (in fact, these cationic liposomes have shown little promise for clinical development), ‘first-generation’ versus ‘second-generation’ to suggest that Alnylam has by-passed Tekmira in LNP prowess and does not need it any more, and the very term ‘LNP’ itself which replaced ‘SNALP’ that Tekmira, the true liposomal delivery innovator, had once coined. Such simple language created, and still causes significant uncertainty among Tekmira investors consequently damaging Tekmira’s ability to finance.

Alnylam caused further confusion by setting up shop right in Tekmira's very own backyard in Vancouver by helping to form and fully fund Alcana, a company made up largely of former Tekmira scientists that got laid off in the wake of the Tekmira-Protiva merger. Since Tekmira’s value is heavily dependent on its ability to protect its trade secrets around LNP formulation and Vancouver is not that big a place, this move by Alnylam seemed rather brazen. On top of that, Alnylam teamed up with Pieter Cullis, a well known LNP delivery expert from UBC in Vancouver and formerly closely associated with Tekmira. Quite degrading of a business partner, I would say.

Alnylam crossed the line

While one might shelve much of the above under the category 'bullying behavior', Tekmira’s Complaint alleges that Alnylam clearly crossed the lines of legal propriety and caused substantial harm to the Company by improperly disclosing trade secrets to third parties, in an apparent effort to marginalize Tekmira in business development discussions, by filing for patent protection for inventions based on such trade secrets, and maybe worst, by documenting some of them in patent applications.

Followers of this blog may not be surprised to learn that I believe Tekmira to have a good chance at proving their case in front of a jury as this latest development has been a trainwreck a long time in the making. For what it’s worth, I had written both companies that theirs seemed to be a very unhealthy relationship and that they should take action to remedy it. The most logical option, of course, would have been for Alnylam to acquire Tekmira. It would have given Alnylam not only full ownership of Tekmira technology and, equally important, filled up Alnylam’s pipeline with three promising development programs. In fact, acquiring Tekmira may still be Alnylam’s best hope to come out of this unscathed. Counter-suing Tekmira into bankruptcy would only mean that it is destroying the manufacturing base for almost all of its pipeline candidates. Unfortunately, based on the allegations and actions it may require some reminding that Alnylam does not actually already own Tekmira.

I have no good explanation as to why Alnylam treated Tekmira the way it apparently did. Alnylam has been much more generous to partners such as ISIS and to MIT (see lipidoid deal). Is it because it deemed Tekmira’s financial and political clout to be much more limited? Has it put politics over fairly compensating for scientific value?

Merck lurking again?

This week, of course, has also seen the settlement of the Tuschl litigation (best documented in the RNAi Litigation blog by John Leavitt and colleagues) where Alnylam and Max Planck regained control over the valuable Tuschl II patent estate, but not without granting UMass the right to sublicense some of it to Merck. As I was walking the streets of Paris this week just as the Tuschl settlement was coming down the pike, I was reminded by the above poster of the possibility that without access to Tuschl II and leading RNAi delivery, Merck employees working on RNAi Therapeutics may soon be looking for new job opportunities.

So with Tuschl II in the bag, Merck may now want access to LNP delivery. One scenario envisages that as part of the settlement Alnylam provides Merck with access to LNP delivery. In that case, it would be easy to understand Tekmira’s frustrations. However, given the historical rivalry between Alnylam and Merck, this is difficult for me to imagine.

The other scenario would be that should the current lawsuit lead to Alnylam forfeiting their rights to Tekmira’s LNP technology, it would open up Tekmira for a sale to Merck. Yes, Protiva/Tekmira once sued Merck for similarly misappropriating LNP-related trade secrets and got a nice $45M plus potential $12M from Merck as part of a settlement, but that lawsuit was filed for events that happened before Merck acquired Sirna Therapeutics and most of the people involved in that affair are likely to have left Merck by now. Supporting the view that Merck is somewhat Tekmira-friendly and, more importantly, thinks highly of their technology and scientific team are comments made by Alan Sachs, the Head of RNAi Therapeutics at Merck, at the RNAiAsia conference: ‘[Tekmira] are truly LNP experts’.

Update: Alnylam just responded to the lawsuit, calling it 'surprising and extremely unfortunate'. Read more 'here'. Furthermore, Alnylam believes that its investments in Tekmira, approx. $50M including an equity investment, entitle it to broad use of its technology.

Are Quark Pharmaceuticals’ Ocular Programs About to Meet Expected Fate?

Recent entries to the ocular clinical trials by Pfizer listed in ClinicalTrials.gov (see here and here) suggest that its first-generation RNAi Therapeutics candidate for wet age-related macular degeneration and diabetic macular edema, PF-04523655, is about to meet the same fate as did those for similar indications by Opko and Sirna Therapeutics (Merck)/Allergan before. The phase II study in diabetic macular edema (DEGAS) has already been terminated in December 2010 as ‘the objectives of the study could no longer be achieved’; a study run in parallel with the same candidate for wet AMD (MONET) meanwhile is still ongoing, but without recruiting new patients and after having been intermittently terminated in January as a result of the DEGAS trial.

Although making no mention of the clinical trials interruptions, Quark revealed in its Preliminary Prospectus filed this February that results from the DEGAS study are about to be unveiled this month. Quark is the company from which Pfizer had sub-licensed the AtuRNAi trigger candidate developed originally by Silence Therapeutics and is now making renewed attempts to go public. The Company would likely need such capital quite urgently in case those programs were indeed terminated as most of the recent funding had come from the Pfizer partnership in the form of $52.5M in milestones and cost reimbursements according to the registration statement; about $6M of which went to Silence Therapeutics.

The recent revelations also make it apparent just how much Pfizer had already invested in RNAi Therapeutics. Given that Pfizer announced plans to close its in-house RNAi Therapeutics effort in February, it is no stretch to imagine that the ocular program troubles were the final trigger for Pfizer's decision.

Approach not on sound scientific footing

Just like the previous discontinuations of the ocular RNAi programs by Opko and Allergan/Merck (Sirna Therapeutics), Pfizer’s approach involved the intravitreal needle injection of naked siRNA oligonucleotides and yielded phase I/II results suggestive of efficacy. I was personally never able to make sense of those candidates as they lacked a sound scientific basis for how they would enter target cells in the back of the eye. A study in 2008 by Ambati from the University of Kentucky likely shed light on these results by showing that TLR3 responses triggered by some siRNA structures may ultimately cause the inhibition of blood vessel growth that is a critical factor in those diseases. With the Quark/Pfizer drug likely to meet its unavoidable fate, the door is open for second-generation ocular RNAi Therapeutics approaches that get around TLR3 and into the cytosol of cells. Such efforts include those by RXi Pharmaceuticals and Korean company BioMolecular Therapeutics.

Shares of Silence Therapeutics trade at historic lows following revelations

At this point, it is important to emphasize that the ‘study was not terminated for safety’ according to the clinicaltrials.gov site and have little to no direct bearing on the other clinical and pre-clinical AtuRNAi programs.

Nevertheless, the stock of Silence Therapeutics traded down quite sharply as the revelations made the rounds among Silence investors, giving that company a ridiculous market cap of down to 10M UK pounds. What likely triggered the meltdown is investor worry that Silence had unduly relied on milestone payments from Quark’s programs in their financial planning. I therefore contacted the company on this topic and was informed that the Company does in fact not rely on such milestones in its cash guidance as these are out of their control. The Company added that data from the DEGAS study are yet to be unveiled and that it is not aware of any discontinuation of these programs.

Fair enough, and maybe, amid the confusion and insanely low valuations of some RNAi Therapeutics companies, a buyer will see an opportunity in acquiring a promising cancer candidate and some equally promising delivery technologies to endothelial cells and the lung for…maybe $30M?

Marina Biotech Finds Success with Local Bladder Cancer Approach

Marina Biotech this week reported pre-clinical data supporting the use of local, intravesicular siRNA delivery for the treatment of nonmuscle invasive bladder cancer. The publication in Molecular Therapy comes weeks after this early-stage program was partnered with Swiss pharmaceutical Debiopharm which will be responsible for funding the rest of the development.

According to the National Cancer Institute, there are about 70,000 new cases of bladder cancer in the US alone, most of them related to smoking. Because bladder cancer typically starts at the epithelium lining exposed to the urine, simple surgical resection is often sufficient to stop the disease in its tracks. Unfortunately, in some cases the cancer recurs and progresses into a more aggressive, muscle-invasive form of cancer contributing to the 14,700 deaths from bladder cancer annually (US number). Current strategies to prevent recurrence include the instillation of immuno- and chemotherapeutics into the bladder. When this fails, the bladder often has to be removed. Clearly, more treatment options are needed to limit the progression of bladder cancer into the more aggressive forms and maybe also to provide an alternative for bladder removal once more aggressive cancers have developed.

In the present study, Seth and colleagues first screened a range of RNAi triggers against the cancer-related genes polo-like kinase 1 (PLK1) and survivin and were able to demonstrate that Marina’s usiRNA chemistry platform allows for very satisfactory knockdown efficacies with IC50 values in the 10 to 30pM range (bladder cancer cell lines in tissue culture). This triggered widespread apoptosis and, in the case of PLK1, a strong reduction in cell viability. The data therefore add to the notion that PLK1, incidentally also the target in Tekmira’s phase I clinical program TKM-PLK1, may be the single-most promising RNAi cancer target, a view apparently shared by Marina scientists as evidenced in the Discussion part of the paper. Nevertheless, survivin may still be a highly desirable drug target for sensitizing cancer to chemo- and radiation therapies.

The selected siRNAs were then formulated into positively charged multilamellar liposomes of around 100nm. Due to the negatively charged proteoglycan-rich urothelium, a formulation with a lipid containing a guanidinium group was deemed particularly promising in being able to penetrate the 6-7 cell-layered urothelium. Accordingly, these formulations, when instilled into the bladder, were able to very efficiently suppress the growth of nonmuscle invasive bladder cancers in mouse models of the disease. Although equally highly efficient in vivo knockdowns were reported, 90-95% with 1mg/kg (relative to body weight), in my mind there are still some unanswered questions as to how much of that merely reflected the reduction in the size of the tumor.

In terms of safety, no untoward reactions to the formulations were reported. One important reason for this should be the lack of systemic exposure from such treatment. The authors also stated that they were not able to find evidence of innate immune stimulation despite careful investigation. Ideally this analysis would have included a positive control, but then again, also taking into account the 5’ RACE analysis for sequence-specific target cleavage, the overall evidence strongly supports that RNAi knockdown was a main contributor to the in vivo efficacy. Actually, in the case of bladder cancer, having a bit of local immune stimulation may very well be a good thing as I was surprised to learn that bathing the bladder with a solution containing the Calmette-Guerin bacterium (BCG), the famous vaccine against tuberculosis, is part of the current standard of care for superficial bladder cancer and is thought to work by stimulating the immune system. Who knows, Marina may even want to adapt BCG to trans-kingdom RNAi for bladder cancer to combine the RNAi and BCG mechanisms of action into a single agent.

Study Adds yet Another Indication Suitable for Current RNAi technologies

Marina Biotech has made it into an art to select development programs amenable to their current technologies. Given the challenges of systemic RNAi delivery, in a relatively short period of time, the company has already identified and progressed three cancer applications where local approaches can probably be used: familial adenomatous polyposis (FAP; ingested trans-kingdom RNAi), bladder cancer (intravesicular LNP), and most recently malignant ascites (intraperitoneal LNP). Together with developments elsewhere in the field, this clearly shows that the time for RNAi Therapeutics is Now: a range of solid cancers (e.g. liver, lung, FAP, bladder, melanoma), hypercholesterolemia, hemorrhagic fever viruses (Ebola, Marburg), TTR amyloidosis, PHN, AMD, Huntington’s disease etc etc.

Clinical Experience with RNAi Therapeutics Suggests Class to be Remarkably Safe

One of the biggest concerns in developing an entirely new class of drugs is whether they will be well tolerated. At the height of the TLR scare, it almost seemed that just looking at an siRNA would cause you anaphylactic shock. Nevertheless, after several hundreds of patients have been dosed with probably around 1000 siRNA administrations for diseases affecting the eye, lung, skin, blood cells, liver, solid tumors, and kidney, RNAi Therapeutics have shown a very promising safety profile.

When RNAi Therapeutics candidates have been abandoned, it was mostly not because of safety issues, but for factors such as lack of efficacy, doubts about the mechanism of action of observed therapeutic effects, or changes in the commercial attractiveness of compounds (e.g. wet AMD candidates by Allergan/Merck and Opko). In one case, Tekmira’s ApoB SNALP for hypercholesterolemia, the decision to voluntarily abandon this first-generation ApoB candidate after one patient experienced mild flu-like symptoms, may well have had to do with the fact that much more potent LNPs had already been developed by then and there was thus no point to tempt fate and further dose escalate.

It is not surprising that side-effects related to the innate immune stimulatory potential of nucleic acids were the most frequently cited safety issue in clinical trials. In the case of nanoparticles, complement activation seems to be another area where attention needs to be paid. However, even when formulated with lipids, the currently most potent systemic delivery agents but which are known for their potential to amplify immune responses, patient lives have not been needlessly put at risk and the potencies of both Silence’s cationic lipoplexes and Tekmira’s (neutral) LNPs, especially in light of the significantly improved potencies of 2^nd generation LNPs, may be well within the therapeutic windows for a number of indications.

The most demanding test for the safety of RNAi Therapeutics are the ongoing cancer trials where the ability to dose escalate is the name of the game. Here, all 4 nanoparticle-formulated candidates by Calando, Silence, and Alnylam, seem to be still dose-escalating after having reached dosages of between 0.1 and 1.25mg/kg, dosages where anti-cancer efficacies may be expected based on animal models.

With this type of record, RNAi Therapeutics does not have to hide behind the more established classes of drugs. Even protein-based therapeutics which are highly sought after by Big Pharma and investors these days (well, all is relative) have to deal with a number of immune-related issues, both direct responses of the immune system to their introduction (anaphylaxis, antibody formation) as well as target-based toxicities as most of these drugs work by suppressing the immune system. And similar to protein-based therapeutics, and maybe even more so because they are likely to resemble each other more than protein-based therapeutics resemble each other, with experience the rate of attrition of RNAi Therapeutics due to safety should only decrease over time.

RNAi Therapeutics is Dead, Long Live RNAi Therapeutics

You have all seen the obituaries on RNAi Therapeutics. Following the terminations of in-house RNAi Therapeutics efforts by Roche, Pfizer, and Novartis (oh wait, Novartis actually hasn’t stopped developing RNAi Therapeutics, but with 31 targets has more than enough on its plate- minor detail), major news outlets have finally pronounced: RNAi Therapeutics is Dead!

Meanwhile, in the 3-4 years since Roche made its famous commitment, the field has made major progress in reaching the market with Tekmira’s liposomal delivery technology rapidly generating a wealth of important clinical data and showing unprecedented efficacy in the most challenging of animal models for Ebola, Silence Therapeutics’ lipoplex delivery technology pleasantly surprising in terms of its safety and first signs of efficacy, a Chinese group reporting success with RNAi Cosmetics in Wo-Man, and Rosetta Genomics having brought to market a microRNA Diagnostic for Cancer of Unknown Primary that, under normal circumstances, that is proper quality control and marketing, should be a commercial success story. Not far behind, RXi Pharmaceuticals is reporting impressive data for their self-delivering rxRNAs in dermal applications.

By any rational standard of scientific progress, this is more than satisfactory, yet investors and the industry itself it seems have become infected by the Big Pharma RNAi Therapeutics mood swings. Actually, Big Pharma should be in the best position to sweep up RNAi assets as pure-play companies experience financial difficulties. However, it seems that it took less guts for Merck to buy Sirna Therapeutics for more than a Billion US dollars than for Big Pharma today to spend about 10 times less to acquire the two companies that have developed the clinically most advanced systemic RNAi delivery technologies: Tekmira and Silence.

Unfortunately, for RNAi Therapeutics to be able to maintain that pace of progress, it depends on (financial) supporters with deep pockets or, ironically, a spark that will ignite another round of RNAi Therapeutics exuberance. Steady scientific progress superimposed by stone-age fear and greed.