New Antibody Data Indicate Tough Battle for RNAi Therapeutic PCSK9 Approach

The past week has been a busy one for the hypercholesterolemia field. New clinical data for PCSK9-targeting monoclonal antibodies from Amgen and Regeneron/Sanofi-Aventis were presented at the 2012 American College of Cardiology meeting, while ISIS/Sanofi-Aventis separately presented long-term efficacy, and especially safety data on the ApoB antisense compound mipomersen (aka KYNAMRO) for which marketing applications have now been submitted in Europe and the US. As hypercholesterolemia also represents a significant medical and commercial opportunity for RNAi Therapeutics due to the advances in knocking down genes in the liver, I will briefly summarize the new data and discuss some of the implications for RNAi approaches, including the phase I candidate ALN-PCS02 by Alnylam.

If there ever were doubts as to the commercial attractiveness of PCSK9 as a target for treating high cholesterol, last week dispelled them all. When it seems that all the thought leaders in the field, including famed cardiologist Steven Nissen, otherwise known for his ultra-critical views of certain medicines, and Wall Street (expected annual sales as a class of up to $20B thrown out) hail the data as proof that PCSK9 will be the final nail in the hypercholesterolemia coffin and thus throw their support behind the class, the commercial success of PCSK9-targeting therapeutics seems a foregone conclusion.

Although pretty much every large pharmaceutical company sports a PCSK9-targeting antibody, the excitement this time centered around the phase II data of Regeneron’s/Sanofi-Aventis’ REGN727 and phase I data of Amgen’s AMG145.

The REGN727 phase II 8-12 week multi-dose studies were conducted in close to 300 patients with elevated ‘bad’ LDL-cholesterol (LDLc) on statins. Depending on the amount and schedule of antibody administered, mean LDLc reductions (note: it is not entirely clear to me whether this refers to the LDLc reduction over time, or the peak LDLc reductions) of 40-73% were achieved. Interestingly, one press report said that ‘727 suffered from relatively short-lived activity such that subcutaneous administrations every 2 weeks would be required.

The phase I studies with ‘727, just published in NEJM (Stein et al.) indicated that the apparent rebound effect after 2 weeks may be due to the concomitant use of statins and that without statins, 50-55% persistent LDLc reductions can be achieved with close to 4-week dosing intervals. This is relevant for example for the statin-intolerant population. With statins, that type of persistent knockdown (more on the higher end of that range) would probably require every 2 week dosing.

AMG145 seemed to attract even more excitement than '727. In the 6 to 8-week phase I studies in around 100 patients taking statins, mean LDLc reductions of 63-75% were observed. These numbers indicate more potent, and likely more persistent LDLc lowering compared to REGN727, although without having seen the LDLc response curves over time, it is difficult to conclude that for sure.

Route of administration and dosing frequency are often cited as important competitive criteria for this class of drugs. In the case of ALN-PCS02 which is enabled by Tekmira’s SNALP technology, the current data indicate that a range of 40-55% persistent LDLc reductions with intravenous dosing every 4 weeks are conceivable. This, however, would require further improvements in potency over the 0.25mg/kg dose level which was the highest dose for which data was presented by Alnylam at their early January update. For this indication, it will also be important to wean the SNALP formulation off the transient immune suppression currently used. This would not only address criticisms that such immune suppressions carry risks, but it also would likely get rid of the observed PCSK9 rebound effect that was apparently linked to it and would thus contribute to prolonging the efficacy.

Of course, an important wildcard in the competition between MAbs and RNAi pertains to the safety of each drug candidate, especially when they are used long-term. The monoclonal antibodies seem to perform quite well in this regard in the short-term, albeit multi-dose studies. RNAi, however, has the theoretical advantage in that it does not involve the formation of antibody-PCSK9 complexes which could eventually have an impact on both long-term safety and efficacy/dosing frequency.

In retrospect, RNAi has picked a tough battle here. As a target that acts extracellularly, readily accessible from the blood, it seems an ideal target for monoclonal antibodies and thus falls outside the undruggable target space that currently still drives the interest of large pharmaceutical companies in RNAi Therapeutic development. On the other hand, the PCSK9 field is populated with antibody approaches, and should there be antibody-specific class adverse effects, RNAi could be the last one standing (note: the antisense candidates by ISIS and Santaris have already dropped out of the race, at least for now), something that one of the few Big Pharma/Biotech that has not yet invested in a PCSK9 candidate may value from a strategic point of view alone (RE partnering).

Meanwhile, the mipomersen extension study data presented this week suggest that the high drop-out rates and liver fat accumulations* (both possibly linked to some extent) at modest ~30% LDLc reductions make it a niche drug for the very small indication of homozygous familial hypercholesterolemia in the US and Europe, and possibly severe hypercholesterolemia in Europe. Although ISIS continues to claim that the liver fat accumulations normalize after reaching maximum median increases of +13% over baseline at week 52 (note: according to the mipo-related Visser et al. 2009 study, 5.6% absolute intrahepatic triglyceride contents are considered the upper-limit of normal), the absolute values would call for caution, especially when there are outliers in whom almost half the liver consists of fat. In the related conference call, ISIS further claimed that the apparent normalizations were not the result of the patients that discontinued mipomersen (possibly due to high liver fat contents). However, since ISIS has a history of erring on the side of optimism when it comes to mipomersen safety and tolerability, I’d like to see the liver fat-related sub-group analyses that take into account the discontinuations, dose reductions and interruptions.

The liver fat data may also mean that ApoB is unlikely to be a suitable stand-alone target for an RNAi Therapeutic, especially if even more pronounced ApoB knockdowns can be achieved than with mipomersen. Consequently, in order to exploit the therapeutic utility of ApoB as the critical protein of atherogenic lipoproteins, an ApoB-targeting RNAi Therapeutic should involve at least one other target gene which will also reduce liver fat content. It remains to be seen whether ApoC-III can be that target.

* Note: Despite the caution expressed in this article, I should add that there is general controversy about the relevance of simply elevated liver fat (NAFLD) in the absence of inflammation.

Fate of Quark Wet AMD Program in Limbo

PF-4523655 is arguably RNAi's most advanced clinical candidate. A naked, 19bp blunt-ended intravitreally injected AtuRNAi molecule, it had completed a phase II study in diabetic macular edema (DME) for which the results suggested a benefit over laser treatment; there was another phase II study of the same molecule in wet age-related macular degeneration (wet AMD) for which Quark, along with partner Pfizer had yet to report results.

These studies were also important for Silence Therapeutics, as an advance of any of these programs into phase III would have spelled the long-awaited non-dilutive funding (about $4M). Unfortunately, despite the suggestive DME efficacy data, Pfizer was not satisfied with the commercial competitiveness of the results in light of the newer VEGF pathway inhibitors. Therefore, Pfizer and Quark agreed that Quark would run a phase IIb study on its own dime testing higher doses of ‘655 in a head-to-head trial with VEGF MAb Lucentis. Pfizer would retain opt-in rights.

Still, the results from the wet AMD trial were outstanding. Expectations were relatively low though as in March 2011, as Quark attempted (yet again) to go public, the company disclosed that ‘655 was ‘not superior’ compared to Lucentis at the primary endpoint. Still, full results remained to be reported, probably in H2 2011. These results, however, never came. Since clinicaltrials.gov indicated that the study had been completed, it became obvious that there had been no positive surprises.

In its full-year results presentation, Silence Therapeutics today confirmed that while ‘[t]he trial demonstrated a dose-dependent increase in benefit of PF-04523655. Quark is now awaiting results from the Phase IIb trial in diabetic macular oedema before deciding on plans for the drug in age-related macular degeneration.’ In other words, not good for Quark and not good for Silence Therapeutics either: the fate of the wet AMD program now depends on the results from the phase IIb DME trial. It also seems that, like for DME, Pfizer has handed back the compound to Quark for wet AMD based on changes in the clinicaltrials.gov database in November 2011 that show ‘Pfizer’ being changed to ‘Quark’ in a number of entries relating to the sponsor of the trial. The silence (small letter) by Quark can be explained by the fact that it seems to have given up on going public for the time being.

From a medical point of view, the DME and wet AMD developments are a pity. If it is indeed the commercial profile vis-à-vis the protein-based VEGF pathway inhibitors that is keeping ‘655 from going into phase III, and not lack of efficacy, it may indicate some unjustified bias against RNAi Therapeutics. Both classes are intravitreally injected and there are many patients that are dissatisfied with the efficacy of these proteins. As a result, patients seek help from (expensive) treatments (such as acupuncture) that have not passed, or even undertaken formal clinical studies. What would be attractive with a molecule such as ‘655 is that it is not supposed to work as a VEGF pathway inhibitor and would thus offer a complementary mechanism of action (anti-apoptotic). On the other hand, since Quark has been so coy with the data, I suspect that bias alone may not explain Pfizer’s decision. Maybe with a sounder basis of delivery, next-generation RNAi Therapeutics candidates can address that void.

Alnylam Launches Pair of Pre-emptive PR Strikes to Cover Patent Losses

When the therapeutic relevance of a patent (Tuschl-I) that once had the potential to be broadly applicable to RNAi Therapeutics has been lost forever in Europe, and when in another US patent proceeding an important claim covering a cancer drug candidate that has just completed a phase I study has been declared invalid due to lack of written description support and may actually belong to your worst nightmare, it seems hardly a time to declare victories. Nevertheless, the PR department at Alnylam has risen to the challenge and done just that: two press releases (here and here) by the company shortly following these patent outcomes announced with great fanfare that Alnylam’s IP position had been bolstered. The reward for the skilled use of small qualifiers such as ‘requested’ and ‘key’ and obedience? Not just keeping your job, but actually being promoted to Vice President of Investor Relations.

Alnylam vs Silence Therapeutics et al.: Tuschl I in Europe

As Silence Therapeutics can attest, the Tuschl I patent estate, licensed by Alnylam and Merck, was once an effective deterrent against competing RNAi triggers of 21-23 nucleotides and/or base-pairs. While certainly an important contribution to the eventual discovery of RNAi triggers for use in human cells, its main vulnerability in IP terms derived from the fact that its research was mainly conducted in Drosophila fly lysates and tissue culture cells.

Consequently, in both the US and Europe its importance for RNAi Therapeutics has been waning to the point of being essentially relegated to the use of RNAi triggers isolated from Dicer processing reactions in the test tube (my bet is that we will never see such a product candidate). Nevertheless, some passages in the written description and claim language in the European T-I patent EP 1309726 was sufficiently ambiguous that it must have worried companies like Silence Therapeutics, BASF, and Sanofi-Aventis that it might be exploited by a legally aggressive company such as Alnylam as a convenient casus belli, causing them to oppose the patent. Specifically (former) independent claim 10 may have raised such concerns:

‘10. A method of producing knockdown cells, comprising introducing into cells in which a gene is to be knocked down isolated double-stranded RNA of from 21 to 23 nucleotides in length and corresponding to a sequence of the gene, that targets the mRNA corresponding to the gene and maintaining the resulting cells under conditions under which RNAi occurs, resulting in degradation of the mRNA of the gene, thereby producing knockdown cells.’

On February 29 and March 1 there was an unusually lengthy, and therefore probably highly contested Oral Hearing on the case, the outcome of which was quickly claimed by Alnylam (and patent co-owner UMass) as a victory. Particularly, it claimed that the ‘requested claims of the ‘726 patent were upheld without modification’ [emphasis mine]. Turns out that a comment poster on this blog last week got it right in that he/she pointed to the qualifier ‘requested’. To back up, essentially what happens in such an Oral Proceeding is that the Defending Party (here: Alnylam/Umass) submits alternative claim sets in case that the original claim language is rejected by the EPO based on the principle that a weaker patent is better than no patent at all (e.g. for the purposes of appearance).

After reading the now published documents from the Oral Hearing (if you have problems accessing them, you can request them by email from me), what happened is that Alnylam has indeed had the boldness to represent that after having been forced to modify the claims, the new claims were upheld in unmodified form. If you are an Alnylam investor/supporter, you may want to ask the new VP whether you are justified in feeling cheated by such an insincere conclusion and may want to re-think the general credibility of that company.

The upshot in terms of the patent: by clarifying the written description with expressions such as ‘isolating from combination’ and ‘in vitro’ and completely re-writing the claims, T-I is confirmed to be without relevance for RNAi Therapeutics. It remains important, however, for the commercialization of in vitro RNAi-based target discovery/validation services such as offered by companies like Cenix, although only for dsRNAs of 21-23nucleotides in length.

Alnylam vs Tekmira: Alnylam about to lose ‘key’ ALN-VSP patent

Similar to the T-I patent confrontation, Alnylam was quick to claim victory in yet another of its patent fights: ‘Alnylam retains key claims for Kinesin Spindle Protein (KSP) RNAi Patent in Interference Proceedings’. Briefly, last year the USPTO had called an Interference between an issued patent by Alnylam (US 7718629) covering an siRNA sequence in ALN-VSP02 (phase I studies completed) and a patent application by Tekmira which may in fact cover the same sequence.

As the UTPTO cannot grant identical claims in two different patents, the Interference proceeding will decide on the validity and priority of these claims. As Tekmira pointed out, this Interference has no relevance to that company’s pipeline. It could, however, mean that a patent covering a ‘key’ feature of ALN-VSP02 (an siRNA sequence) may not only turn out to be invalid, but actually belong to Alnylam’s worst nightmare: Tekmira.

By now, we all know the drill: look for the little qualifiers. ‘Key claims’ would be the obvious candidate here to home in on. But in this case, not even twisted logic can explain Alnylam’s conclusion, as in fact no claim (at least those contested and related to synthetic RNAi triggers) was ‘upheld’. Quite the opposite, the Appeals Board (BPAI) granted Protiva’s/Tekmira’s Motion 2 which requested that Alnylam’s KSP sequence claim be ruled unpatentable. The explanation was that while the claim covered dsRNAs between 15 and 30 nucleotides, only 19bp siRNAs with 2 nucleotide overhangs were presented in the application (--> lack of written description support). Since all the other claims relating to synthetic RNAi triggers are dependent on claim 1, I’m puzzled as to how Alnylam could ever claim that ‘key claims’ had been upheld, when in fact it looks like all the relevant claims will be revoked.

Claim 1 of US patent 7718629:

‘1. A double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a human kinesin family member 11 (Eg5) gene in a cell, wherein said dsRNA comprises a sense strand comprising a first sequence and an antisense strand comprising a second sequence complementary to SEQ ID NO:1311, wherein said first sequence is complementary to said second sequence and wherein said dsRNA is between 15 and 30 base pairs in length.’

Protiva’s Motion 1 that Alnylam’s provisional applications be declared invalid as priority documents was denied. The importance of this ruling is that it may affect the outcome of the second stage of the Intererence proceeding which will be about determining priority. Because the provisional applications by Tekmira and Alnylam were filed only two months apart, with Alnylam having the earlier date, chances are that Alnylam would enjoy priority IF Alnylam’s ‘key’ claims were held valid. However, with the above ruling and a recent rejection of claim 32 in a pending patent application by Alnylam (serial number 13/165568), this seems highly unlikely (note: I am unable to see the pending patent application, but claim 32 should be directed at the KSP sequence). By contrast, the Appeals Board decided that, unlike Alnylam’s patent, the KSP sequence claims are supported in the written description in Tekmira's competing patent.

The upshot: Tekmira prevailed on all Motions (filed by Alnylam and Protiva), except for on the validity of Alnylam’s provisional applications for priority purposes and the Appeals Board deferring decision on including claim 32 from the pending patent application which, based on the March 6 rejection does not seem to help Alnylam much anyway. This means that not only are the ‘key’ sequence claims about to be rejected, but Alnylam’s worst nightmare may actually end up owning it.

Don’t take my word for it, you can read the relevant documents yourself here (T-I) and here (Interference). If you are somewhat familiar with reading such documents, it will only take you 30-45min to read (and understand) them each. It seems that Alnylam is relying on the fact that most news organizations and analysts cannot be bothered to read the primary documents and conveniently adopt Alnylam’s version of events. If you do a Google search for news related to Alnylam, you will see that this happens more often than not. After all, Alnylam has more money to feed into the biotech machine: why antagonize a lucrative source of income?

Silence Strongly Disagrees with Alnylam’s Version of Tuschl I Hearing

On February 29, there was a hearing on the Tuschl I patent in Europe (EP 1309726; co-owners: UMass, MIT, Max-Planck, the Whitehead; licensees: Alnylam and Merck). Once with the potential to be a relatively broad patent covering the sweet-spot of most RNAi triggers (dsRNA lengths between 21-23nt/bp), the importance of this patent has been greatly watered down due to interpretations by the patent offices, and to some degree even by one of the licensees of the patent (Alnylam) during the Tuschl litigation, that the importance of this patent is largely limited to a mix of RNAi triggers produced in fly tissue lysates. Nevertheless, ambiguities in the wording of the Tuschl I claims gave rise to the concern that a legally aggressive company such as Alnylam would sue based on the tenuous interpretation that some of the claims would be relevant to mainstream therapeutic use in humans (note: precedence shows that Alnylam has filed lawsuits on much less substance).

To remove these ambiguities, Silence Therapeutics, along with Aventis and BASF, opposed and thereby sought to invalidate, or at least clarify T-I to their benefit. This attempt was the subject of the Oral Hearing.

The Hearing documents have not posted yet to the EPO site, so I will only comment on what has transpired from the two main antagonists: Alnylam and Silence.

On March 1, Alnylam (and patent holder UMass) proudly announced: ‘The requested claims of the ‘726 patent were upheld without any modification.’, and go on to strongly suggest that this is a strong, if not blocking patent for RNAi therapeutic development and commercialization: ‘The Tuschl I ‘726 patent consists of 14 claims broadly covering RNAi methods, including methods of reducing the expression of a gene, with double-stranded RNAs between 21 and 23 nucleotides in length of mammalian or viral origin.’

By contrast, Silence Therapeutics just issued a press release basically expressing that Alnylam’s representations of the T-I Oral Hearings are, to put it mildly, inaccurate. Titled ‘Silence and Other Opponents of Tuschl I Patent Succeed in Limiting Scope and Ambiguity in the Patent’, the PR further states that ‘the claims as originally granted were modified [emphasis mine] during the hearing…’

Clearly, between ‘modified’ and ‘unmodified’ there is little room for reconciliation, and if there were (‘as originally granted’), then it would be in meaningless semantics.

Personally, when the Hearing docs come out, I will look out for what was particularly said about independent claim 10 which states:

‘10. A method of producing knockdown cells, comprising introducing into cells in which a gene is to be knocked down isolated double-stranded RNA of from 21 to 23 nucleotides in length and corresponding to a sequence of the gene, that targets the mRNA corresponding to the gene and maintaining the resulting cells under conditions under which RNAi occurs, resulting in degradation of the mRNA of the gene, thereby producing knockdown cells.’

In the context of the patent prosecution and patent description, it seems pretty clear that this was also a ‘fly lysate claim’, but read in isolation, it is not obvious. Note also that even if not reflected in the wording of a patent, what is said during patent prosecution would matter in an infringement suit.

To be continued…here

Technology Trends: MicroRNA Inhibitors and Single-Strand RNAi

There have been developments in the areas of microRNA inhibition and single-strand RNA-mediated RNAi that might have strategic implications for delivery technologies and RNAi Therapeutics, respectively.

MicroRNA inhibition: naked antisense no more?

Currently, all development-stage anti-miR programs to my knowledge envisage the use of unformulated phosphorothioated antisense molecules with various high-affinity modifications such as LNA/LNA-type conformationally restricted nucleotides or 2’F and 2’MOE. To some degree, antisense and certain microRNA companies are making a living out of advertising that, unlike (most) RNAi Therapeutics, no intravenous administration was required.

At the same time, it is becoming clear that more complex structures such as Dharmacon’s miRIDIAN hairpin microRNA inhibitors or the tough decoys (also the synthetic versions that were newly developed in collaboration with Japanese RNAi behemoth Kyowa Hakko: Haraguchi et al. 2012) are considerably more potent on a per molecule basis. Because of their structural complexity, however, they would require delivery formulations for therapeutic use. It remains to be seen how often such formulations would need to be applied, but the early research by Haraguchi in tissue culture shows that the anti-miR effect with these structures can be relatively long-lived. Nevertheless, the in vivo pharmacology of these structured anti-miRs remains to be better explored, but I could imagine that especially for antiviral or oncology applications, the more rapid onset of action and the potentially improved targeting due to the delivery technology could yield positive surprises.

Single-strand RNAi Therapeutics: Stable 5’ phosphate and 2'F

A little more than a year after ISIS and Alnylam ended their ssRNAi Therapeutics collaboration (for which I believe Alnylam had greatly overpaid), ISIS and Merck have made progress in the area.

It had been well known based on particularly protein structural work that the 5’ phosphate modification in the guide strand is important for incorporation in the RNAi effector complex RISC. There has also been corresponding early evidence in ssRNAi research (Martinez et al 2002) that ssRNAs with a 5’ phosphate are more efficient inducers of RNAi, albeit at much lower efficicay compared to dsRNAi triggers. Notably, in the case of double-strand RNA-induced RNAi, prior 5’ phosphorylation is not necessary as this is efficiently accomplished inside the cells.

Based on work by ISIS presented at the Keystone conference in January it now seems that lability of the 5’ phosphate is partly responsible for the reduced efficacy of ssRNAi. Using a new 5’ phosphate mimic (and some other lipophilic modification strategies) that is much more stable than the natural counterpart, it was now possible, following subcutaneous administration, to achieve solid knockdown in rodents. However, the cumulative dose required to get there is still very high, in the range of 2^nd generation RNaseH antisense.

ssRNAi work just published by Merck (Haringsma et al. 2012) confirmed that the 5’ phosphate modification was important, but more importantly worked out the beneficial role of the sticky 2’-fluoro (2’F) modification in ssRNAi. The impressive efficacy-enhancing activity of the 2’-F modification (for which, I believe, Alnylam holds rights to an important patent via a license from ISIS, but a modification that has also raised genotoxicity concerns) was found to apply to both tissue culture and animal settings [Note: an earlier version mistakenly stated that the IP belonged to Alnylam]. Unlike the ISIS work, however, Merck studied ssRNAi in mice using SNALP-like liposomal delivery. It therefore seems as if Merck would need to extra work on adding chemistries such as phosphorothioates or conjugates so that its ssRNAi technology can be used in the ‘naked’ form. This is because the prospect of using ssRNAi in the naked versus formulated form would really be the only motivation for pursuing ssRNAi.

RNAi Therapeutics Investors Are Getting More Selective

The recent share price performances of RNAi Therapeutics companies have confirmed that clinical data have become the critical new bar for investors. Even discounting the fact that biotech in general has performed well this year, it is clear that the SNALP-enabled clinical phase I results for ALN-TTR01 (transthyretin amyloidosis) and ALN-PCS02 (hypercholesterolemia) have had the desired impact on the share prices of Tekmira and Alnylam: +57.5% and +73.5% increases since the ALN-TTR01 results were announced in November ’11, respectively. Moreover, the recent $80M+ financing by Alnylam, and to a smaller degree the $4M private placement by Tekmira, underline that new money is flowing into these companies.

Other companies have had a harder time. In fact, with the market capitalizations of Marina Biotech and microRNA Dx company Rosetta Genomics reaching a point where the companies become increasingly unsustainable, and Galena (formerly known as RXi Pharmaceuticals) ridding itself of its RNAi Therapeutics heritage, the shake-out in the field of the publicly traded RNAi Therapeutics-related companies has only intensified. Consequently, aside from Tekmira and Alnylam, the most significant remaining public RNAi Therapeutics companies are Silence Therapeutics, Arrowhead Research, and Benitec. To what degree they can be joined by the likes of Quark, re-surrected RXi Pharmaceuticals, or Calimmune remains to be seen as not too long ago, RNAi IPOs were all but unthinkable.

Here a quick run-down of the companies:

Tekmira: SNALP systemic delivery technology has emerged as the major value driver in the industry. Overly focused on technical progress rather than brand building, Tekmira is still fighting with a market perception that because it’s market cap is so small (<$40M), Alnylam must rightfully have full ownership of Tekmira’s technology. Especially the analyst community has largely been ignoring their position, but it looks like the courts are starting to see through Alnylam’s strategy (e.g. here). The recent financing will give Tekmira some breathing room albeit at the cost of further dilution. Besides the litigation, additional clinical results from the TKM-PLK1, TKM-EBOLA, ALN-TTR, and ALN-PCS02 programs expected this year will be critical to Tekmira shareholders.

Alnylam: Good clinical execution with its new crop of SNALP-enabled therapeutic candidates. One year after announcing 5x15^TM, the company has become much more narrowly focused on introducing only a select few products in the market itself. This, and the recent financing, could be interpreted as preparing for a potentially adverse outcome to the Tekmira litigation, but it is also a structure that will allow the company to sell itself more easily. This is in stark contrast to the strategy of antisense partner/competitor ISIS Pharmaceuticals which has stretched itself out onto so many different therapeutic areas and partnerships that it is difficult to see that company being acquired any time soon.

The successful offering has confirmed once again that Alnylam is well connected in the biotech financial machinery. After receiving upgrades and (re-)newed analyst attention from the likes of Leerink Swann (!- because of the infamous 2008 report on the company), MLV, and Rodman and Renshaw, the company reciprocated by letting them all participate in the offering. As a shareholder of Tekmira, this to me is frustrating as these analysts would never say a critical word about Alnylam’s position with regard to the Tekmira litigation. And, of course, the legal process is not exactly fair when a cash-rich company apparently does its best to delay the litigation so that it can financially outlast its ‘small’ opponent.

Continued positive clinical results will be important to extend the positive trend in ALNY, but all bets are off as we approach the late October 2012 trial date with Tekmira.

Arrowhead Research: The company arguably made a good deal with the acquisition of the Roche RNAi Therapeutics assets for a few pennies on the dollar originally paid by Roche. Critical to the success of that company will be how quickly DPC delivery technology is ready for clinical development. The absence of peer-reviewed non-human primate data and knowledge of how advanced DPC manufacturing is increases the risk that the DPC-enabled HBV program may take longer to enter clinical development than hoped for.

Silence Therapeutics: Following promising phase I data with Atu027 for solid cancer and positive developments on the IP front, recent developments were not so positive. Most discouragingly, Thomas Christely unexpectedly resigned after only a short stint as the CEO. In the absence of any cogent explanation besides the usual ‘personal reasons’, one may come to the conclusion that after the 6-month data delay with Atu027 and the apparent failure to extend the critical AstraZeneca and Dainippon Sumitomo collaborations, another painful round of dilution may be inevitable.

Benitec: The fortunes of that company are looking up as Gradalis and Calimmune are progressing their ddRNAi Therapeutics products. Just this morning, Benitec announced that Calimmune has taken a non-exclusive license to Benitec’s ddRNAi IP for HIV/AIDS. It is critical to Benitec’s strategy to make sure that the early ddRNAi candidates that are in or close to the clinic are licensed under their IP. As its fundamental Graham IP matures, however, it will have to wean itself off its focus on IP and instead execute on product development. Particularly the pain program looks promising here.

Marina Biotech and Rosetta Genomics: With their tiny market caps of $2.5-5.0M, it becomes increasingly difficult to further justify their coverage. It’s a pity because some of their technologies have some value. The erratic strategies of these companies, however, seem to have destroyed all investor confidence.

ISIS Pharmaceuticals: The topline data evidence is quite strong that ISIS RNaseH antisense can knock down genes in the liver, kidney, some cancer, and possibly other tissues in the clinic. Safety and tolerability issues and other delays, however, seem to still come up with regularity when it counts and only by presenting the full dataset can it be determined whether continuously high phosphorothioate concentrations, particularly following systemic administration, are sufficiently well tolerated for broad clinical use. In terms of technical progress therefore, the corresponding liver and kidney concentrations at which a knockdown is achieved is a key parameter to watch going forward.

If mipomersen does not get approved for anything beyond hoFH and/or does not sell well, the company’s strategy of giving away value early in development could start to hurt as it will be some time until another in-house development candidate can reach regulatory approval.

Tekmira’s Drug Candidate for Alcohol Dependence Turns Intravenous Delivery into Strength

Tekmira’s SNALP delivery platform which makes up the majority of the active systemic RNAi Therapeutics pipeline symbolizes the potential efficiency of the RNAi Therapeutics platform: Once a delivery technology is found to be suitable for knocking down genes in a given tissue/cell type, only the sky, aka our understanding of disease genetics, is the limit. A frequently cited criticism of the SNALP platform, however, has been that the intravenous mode of delivery that most of its current applications call for would restrict the market potential of SNALP drugs. This particularly applies to chronic primary care applications in slowly, and often silently progressing diseases such as atherosclerosis. While I disagree that a once-a-month one-to-two-hour procedure will be a major hurdle towards market adoption for most applications that matter, Tekmira’s latest SNALP development candidate, TKM-ALDH2 for the treatment of alcohol dependence (AD), actually turns the intravenous mode of administration into a competitive advantage.

TKM-ALDH2 targets aldehyde dehydrogenase 2 in the liver and, as a result, causes very unpleasant hypersensitivity symptoms (e.g. flushing and nausea) after drinking alcohol which is the result of the inefficient removal of acetaldehyde during ethanol metabolism. The target is greatly validated by human genetics which has shown that individuals with a slow metabolizing isoform of ALDH2, particularly prevalent in Asia, are at much reduced risk of becoming dependent on alcohol. In fact, a mainstay of treating alcohol dependence in the US, disulfiram (Antabuse), works by inhibiting ALDH2 and thus deterring from drinking alcohol.

But disulfiram is not without its controversies. In fact, it is a drug that many like to hate. Perhaps not surprising to find that adults with an alcohol problem don’t have the same lobby as kids with a rare genetic disorder, although the costs of AD figures in the hundreds of billions a year in the US alone. Fuel for the detractors of disufiram and medicating alcoholics in general is the observation that a number of clinical studies have failed to show a benefit of disulfiram.

If one looks closer, however, it is pretty clear that the problem is not with the mechanism of disulfiram per se, but rather with patient compliance. Even in well supervised settings it may be difficult to make sure that the patient is actually swallowing the pill. Consequently, the pharmaceutical industry has become interested in developing disulfiram versions that are administered parenterally, e.g. via an implant or intravenously. TKM-ALDH2 thus would be related to intravenously administered disulfiram, but with the pharmacologic advantage of requiring less frequent administration. Based on population genetics a frequency of administration ensuring a ~60% trough knockdown should be a good target and should be achievable with current SNALP technology with once-a-month dosing.

I believe that TKM-ALDH2 is only the most obvious application to date where the intravenous route of administration is a beneficial feature of an RNAi Therapeutic. I also wonder how comfortable insurance companies are with relying on their patients diligently taking their $100,000+/year rare-disease medications in the comfort of their homes. Patient compliance is not just a huge issue when treating addiction, but with all types of medications.