RXi Pharmaceuticals Invites Biotech Speculators

Times have never been tougher if you are a preclinical-stage biotechnology company with a high demand for cash to support operations. At least this must be the conclusion that RXi Pharmaceuticals drew after it struggled to attract investor interest in their self-delivering RNAi trigger technology, but a technology that has yet to enter the clinic. As a result, it announced today that it will acquire late-stage cancer immunotherapy company Apthera.

Biotech investment these days is largely placing bets on the next drug approval candidate. There is little patient money that allows public companies to see through their technology development which especially hits those platform companies hard which cannot find alternative sources of non-dilutive capital. Talk about RNAi Therapeutics.

Actually, I liked the way that RXi has recently developed their fairly differentiated rxRNAs. These should have utility for a number of localized RNAi approaches. But it seems that RXi’s raison d’etre has never been the science anyway. So as we say good-bye to short-time CEO Noah Beerman, I wish everybody more of the Happy Trading that RXII has become known for.

Alnylam and Big Pharma: Tekmira Caught in a Tangled Web of Interests

(Notice: The following account is a largely hypothetical explanation of what is underlying Alnylam's current troubles)

The last time Alnylam expressed surprise and regret was in September 2010 when Novartis declined to exercise an option for wide, non-exclusive rights to Alnylam’s RNAi Therapeutics IP estate ('Adoption License'). Since then Alnylam has been hit with a string of other partnership setbacks and other not-so-positive news pieces. The official party line, of course, is that these are all isolated events and Big Pharma does what it does because it has to cut down on R&D that won’t generate significant revenues in the next 3-5 years. Meanwhile, the popular story line is that Big Pharma has given up on RNAi Therapeutics because of the delivery challenge.

I believe that neither of these views are correct, and instead like to propose that while it is true that delivery is a challenge, there are technologies that show great potential, and it is the fight for ownership over and access to these technologies that is at the root of the recent developments. As you’ve heard me preach over the last 3 years or so, Tekmira’s SNALP delivery technology is at the forefront of systemic delivery and has consequently become the major bone of contention as Alnylam, its partners, and Merck struggle to protect their investments in RNAi Therapeutics.

Novartis Poses Target Threat to Alnylam and Partners, but needs SNALP

In retrospect it is clear why Novartis has acted the way it did. Initially, I had thought that Novartis' target selection strategy might be uncoupled from delivery considerations and instead would focus on the industry’s hottest GPCRs and kinases. Instead, Novartis appears to have done the scientifically sensible (Big Pharma and scientifically sensible in the same sentence...must be a first in this blog) and held off with their decisions until there was more clarity which targets and indications could be addressed based on the most advanced delivery technologies. As such, I believe that Novartis has mainly picked a bunch of targets in the liver, solid cancers, and maybe a few ocular and CNS indications, too.

In the Novartis post-mortem conference call, I was surprised to learn that as part of selecting their targets, Novartis and Alnylam had conducted quite a few pre-clinical in vivo studies in anticipation of IND filings, meaning that SNALP delivery was most likely employed, and that along with the targets came rights to some of Alnylam's current, and future (!) delivery capabilities!!! This to me was a bombshell because I had believed that delivery was Alnylam’s biggest negotiating advantage in making sure that Novartis will pay the $100M exercise fee. Well, the reason for my belief was that since Alnylam liked to emphasize that the Adoption License excluded delivery, similar restrictions applied to Novartis target picks.

Note that Novartis, which only recently appears to have ramped up their RNAi-related staff to around 100 (not really what you consider a sign of their losing interest in RNAi Therapeutics), was named in the Complaint by Tekmira as a company that Alnylam might have improperly shared SNALP delivery with. It may also be of interest that the first author of a high-profile Nature Biotech paper in 2005, David Morrissey, describing the use of SNALP delivery in a mouse model of hepatitis B is now heading RNAi Therapeutics efforts at Novartis.

31 targets, exclusive, heavily focused on the liver and solid cancers…what does that leave for Alnylam and its other Big Pharma partners? Is ‘5x15’, Alnylam’s strategy launched in January, i.e. after Novartis, a reflection of Novartis having picked higher-profile targets such as hepatitis C?

So 2 months after Novartis, Roche announces that it does not view RNAi Therapeutics a sufficiently broad commercial opportunity to justify the significant operations they had going. Since Roche, like Alnylam and Novartis, were likely to have focused their efforts on liver and cancer targets as they were looking at the same delivery technologies, this comment can also be interpreted as ‘After Novartis has taken many of the targets that we were interested in, what we are left with isn't attractive enough to make our large-scale effort worthwhile. Moreover, we are contrite that Novartis got so much paying so little'. And when they licensed the liver, metabolic, and cancer fields from Alnylam for $50M each, they must have done so in view of SNALP delivery.

Soon after, or even a little bit before the 2007 alliance, Roche together with Alnylam already got underway with validating targets and moving them into clinical development. But then another snag hit: Despite of what Alnylam might have promised Roche, Tekmira’s SNALP turned out to be more difficult to replicate than they thought. This is very apparent from Roche’s Factor VII patent application which started out with lipidoids up to the mouse stage, but then adopted Tekmira’s SNALPs for the non-human primate studies. If you are from Big Pharma and reading this, it is a lesson not to be blinded by company brands, but closely look at who actually has the know-how and partner with them instead.

These frustrations first came to the fore in comments by Alnylam’s David Bumcrot in the summer of 2007 in which he proclaimed that the MIT lipidoids that Alnylam helped fund are much superior to Tekmira’s SNALP technology and will be used for their upcoming clinical programs. To boot, he added that Tekmira’s ApoB was a terrible target. But, of course, despite of Alnylam’s efforts already in 2007 to marginalize Protiva/Tekmira, both Roche and Alnylam had to admit defeat and come back to Tekmira which allowed Alnylam to file their IND for liver cancer.

All this made it clear to Roche that it needed alternative delivery options. Roche went out to look for alternative delivery technologies and in 2008 bought Mirus Bio for the Dynamic Polyconjugates (DPCs) for $125M (almost 4x Tekmira’s current market cap). This number just illustrates the value of delivery in any of Alnylam’s deals, and if you consider that Alnylam most likely passed on DPCs and is betting the house on SNALP instead, the $1B figure that Tekmira demands is very well anchored in what actual money has changed hands.

In addition to Novartis crossing Roche’s RNAi plans, another reason for Roche unhappiness could therefore be that Alnylam over-promised them in terms of what Alnylam had to offer in delivery. As Roche interacted with Tekmira, it may also have noticed that Tekmira’s views on what SNALP know-how and IP access could be gotten from Alnylam and what Roche had to come to Tekmira for strongly differed with what Alnylam might have told them. As a result, on top of the ~$300M upfront they had given to Alnylam, they now had to close a separate deal with Tekmira to actually be able to do something with that RNAi trigger IP.

Obviously, as SNALP delivery solidified its position as the industry's leading systemic delivery technology with not that many other advanced options (maybe Silence's lipoplex comes closest, but for endothelial indications), it turned out to be a bad deal for Roche.

Coming back to Novartis and SNALP delivery. In early 2009, Novartis surprisingly bailed out Marina Biotech, under the name of mdRNA then, by giving them $7.25M for kicking the tires on their ‘DiLa2’ liposomal delivery technology. This came a bit surprising to me, because I had considered Tekmira to be leading in systemic liposomal delivery. This to me indicated that Alnylam indeed is trying to keep Novartis’ RNAi ambitions in check by restricting access to delivery and this is why Novartis, knowing of the potential of liposomal delivery, took a chance with Marina.

You can easily see what pressures Alnylam might be facing from its current and former partners. It has taken over half a billion in license fees, a lot of that presumably driven by Alnylam’s claims about the maturity of and, importantly, control over SNALP delivery. The question is: Do the partners want their money back or are they insisting on their promised access to SNALP delivery?

One of these partners not mentioned so far in this story is Takeda. In 2008, Takeda paid Alnylam $100M for non-exclusive access to the metabolic and cancer fields, plus $50M in technology transfer payments, the latter of which has apparently been completed just in the nick of time to meet the guidance provided by Alnylam. In other words, Takeda paid Alnylam $150M for SNALP technology. In previous conference calls, Tekmira noted that it was working together with Takeda to sort out SNALP delivery (as Takeda and Alnylam were working on the ‘tech transfer’). Despite of Takeda’s complementary comments in yesterday’s press release, I would not be surprised if Takeda, like Roche, is quite frustrated by now over the uncertainties over SNALP access and the Novartis exclusive target picks, and you’ve got to wonder what role Takeda will play in Tekmira’s case against Alnylam.

Merck

And lest we forget, there is, of course, Merck. Once spurned by Alnylam and having invested probably over $1.5B in RNAi Therapeutics development already with hundreds working on the technology, Merck has every reason to turn the table on Alnylam. Merck's publication record also makes it clear that they harbor strong ambitions in SNALP delivery. While the details of the Tuschl II settlement under which Merck gained access to Tuschl II IP are unknown to the public, it is quite possible that Merck is satisfied with that outcome and is now focusing their attention on gaining control over the most advanced systemic delivery technology. Should it view the Tekmira litigation against Alnylam an opportunity to gain leverage over Alnylam, I would bet that they will indeed grasp at it.

Considering this tangled web of interest and the central importance of Tekmira’s technology, it is no wonder that Alnylam is scrambling to stand on its own SNALP feet. Alnylam- setting aside personal issues for a moment, the decision can’t be that hard, can it? In fact, I don’t think there is even a choice.

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.