Arrowhead Research Acquires Roche’s RNAi Therapeutics Assets

The long wait is finally over. Almost a year* after infamously announcing its retreat from developing RNAi Therapeutics in-house as part of a corporate restructuring, Roche has sold its related assets to Arrowhead Research. That announcement sent shockwaves through the RNAi Therapeutics World as investors and potential licensing partners alike took this to mean that something was very wrong with RNAi Therapeutics technology. This led to a freeze in business development activities and precipitously falling valuations. Today’s news brings some closure to Roche’s sorry RNAi adventures and also promises a number of interesting revelations and developments in the months to come.

Arrowhead Research, of course, is already a well known player in RNAi Therapeutics through its Calando subsidiary. Arrowhead in my mind has suffered, however, from not realizing that in order to be a credible platform company, you actually need real scientists, and not just collect abstract intellectual property. It has always baffled me how Calando attempted to license its RONDEL delivery technology without even having a laboratory to overcome some of the apparent challenges of this technology.

With about 40 scientists that will join the company from Roche’s Madison, Wisconsin, site ('Mirus') this has obviously changed. This, however, also means that one should expect Calando’s RONDEL technology to be de-emphasized as these scientists will be more motivated to develop the Dynamic PolyConjugate (DPC) delivery technology they invented. As a reminder, DPCs have shown promise in mouse models for delivering siRNAs to selected cell types in the liver. It remains to be seen, however, whether this translates into primates, and whether DPCs have use beyond the liver. A recent imaging paper on DPCs suggests that the latter may be more challenging than one had first hoped (Mudd et al., 2010). Manufacturing and scale-up question will likely also need to be resolved first before entering clinical development.

A key question will be whether Alnylam will bless this spin-out or whether it will it try to undermine Arrowhead Research which has now gained access to, amongst other assets, Tekmira’s SNALP delivery technology and Alnylam’s own RNAi triggers. This could make the New Arrowhead a direct competitor of Alnylam, similar to Tekmira. While I am not sure yet whether Arrowhead management shares my view, but given the advancements of SNALP technology in the clinic, whilst DPCs have been stuck in pre-clinical for some time now, it would be obvious for Arrowhead to create near-term value by taking advantage of the well trodden path of advancing SNALP programs into the clinic. Of course, access to some of the newer lipids would be desirable.

For Arrowhead shareholders, this is likely a good deal given the depressed asset valuations in RNAi Therapeutics and Roche’s apparent desire to get out of RNAi Therapeutics. However, Roche will not be out entirely as it obtained a minority stake in Arrowhead and apparently retained licensing options and milestone/royalty streams to future products which are likely to be somewhat punitive considering that Arrowhead Research did not have much cash to offer.

Equally interesting for Arrowhead shareholders is a financing agreement with Lincoln Park Capital (LPC) under which LPC will provide up to $15M in funding over the next 3 years. Sounds familiar? If so, then you have probably seen LPC reach an almost identical deal with Marina Biotech just last week. The benefit for Arrowhead and Marina is that this source of capital brings some much-needed financial stability to the companies, just as Benitec used a similar arrangement with La Jolla Cove Investors to finance its recent transformation. One can expect, however, that LPC does not view their investments as charitable donations, and based on Benitec’s experience, it will both likely serve to support Arrowhead’s share price, but also somewhat cap its upside.

* An earlier version incorrectly referred to the waiting period as two years.

Silence Therapeutics Finds another Cancer MicroRNA Therapeutics Partner

It’s actually very simple, and apparently it is small biotechnology companies that are first to realize and act on it: Develop a technology that can deliver small silencing RNAs to a given cell/tissue type, and only our exploding insights into the genetics of disease set the limit for the number of potential indications. This benefits both the delivery company that can re-coup some of their investments through licensing out its technology for a few of the many possible targets, and also the licensee which does not need to exhaust and risk its capital to develop its own delivery technology, but can focus on their targets and pick something already fairly de-risked off the shelf for what should be reasonable financial terms at this juncture.

This must have been the reason why Mirna Therapeutics, after apparently having given up on neutral lipid emulsion technology it had developed with BIOO Scientific (LANCEr), has now chosen to partner with Silence to evaluate that company’s endothelial cell-directed AtuPLEX delivery system, which has already shown some promising results in the clinic (see ASCO 2011 presentation), and Silence’s more novel DBTC delivery system for hepatic nucleic acid delivery, for use with its MicroRNA Therapeutic payloads (most likely mimics) to treat cancer. This follows similar deals last month with Dutch cancer MicroRNA Therapeutics company InteRNA, and a collaboration with a mysterious ‘Top Ten Pharma’ (most likely Takeda) concerning the AtuPLEX-related DACC delivery system for lung endothelial cell-directed siRNA delivery.

Whether all these deals will pay off for Silence and their partners now depend on their progress in the lab. It is likely that the work with Mirna Therapeutics will involve miR-34 which is a well validated tumor suppressor microRNA, and has also been implicated in angiogenesis, making it an interesting microRNA mimic to be evaluated with Silence’s lipid-based delivery systems.

As I’m writing this, Arrowhead just announced that it has acquired Roche’s RNAi assets…deal activity in RNAi Therapeutics is clearly heating up again!

Liposomes Also Useful for Functional siRNA Delivery to Phagocytic Cells

The goal in developing a RNAi Therapeutics delivery technology is to achieve gene knockdown in a certain cell or tissue type. Once this is achieved, only our exploding genetic insights into disease limit the potential therapeutic applications. This is for example why we are seeing this SNALP-fuelled expansion in the clinical pipeline for indications in which gene knockdown is targeted in the liver.

In addition to the liver (SNALP), vascular endothelial cells (AtuPLEX, DACC), tumor cells (SNALP), skin (self-delivering rxRNAs), hematopoietic stem cells (lentivirus), and cells in the eye and CNS (lentivirus, AAV), RNAi Therapeutics delivery technologies have reached sufficient maturity to warrant their clinical development for knockdown in phagocytic cells of the immune system. In fact, there is already a clinical trial by Duke University that involves the ex vivo electroporation of siRNAs into dendritic cells for therapeutic cancer vaccine development (think Dendreon), and a first systemically administered example, Tekmira’s SNALP-EBOLA, is about to enter the clinic with an IND planned by year-end.

Probably fearing that the investing public has largely forgotten about such potential of Tekmira’s technology, Alnylam this week advertised two liposomal siRNA delivery studies, one published in Molecular Therapy (Basha et al.) and the other one in Nature Biotechnology (Leuschner et al.), which nicely characterized RNAi activity in phagocytic cells and provided a few tanatalizing examples of their potential therapeutic applications.

Leuschner et al: Interfering with Pathologic Phagocyte Recruitment by Knocking Down CCR2

The Leuschner at al. study, stemming from a collaboration between the Massachusetts General Hospital, MIT and Alnylam, used lipidoid lipid-formulated siRNAs to target chemokine receptor CCR2 in phagocytic cells. The lipid was the C12-200 cationic lipidoid that was shown in a paper last year to promote gene knockdown in the liver at much lower dosages compared to 1^st-generation lipidoids (Love at al. 2010).

After demonstrating that the systemically administered liposomes were taken up by various phagocytic cell populations in the bone marrow, spleen, and the circulation, the researchers then focused in, for the functional part of their study, on the Ly-6high subset of these cells from the spleen. These were chosen because of the particularly efficient liposomal uptake in this cell population and their role in the pathogenic, CCR2-dependent recruitment to sites of local inflammation.

As a reminder, while such inflammatory recruitment is a vital part of our first-line defense and response to foreign invaders and tissue damage, respectively, they often end up doing their job too enthusiastically leaving behind pathologic scars, unwittingly promote cancers, or interfere with medical interventions such as transplantation.

Leuschner and colleagues studied four settings where interfering with Ly-6high through CCR2 knockdown might be beneficial (all mouse studies): ischemia-reperfusion injury as would occur following a heart attack; inflammation at atherosclerotic lesions; pancreatic islet graft survival; and reducing the number of tumor-associated macrophages which are thought to promote cancer. In all four settings, it was found that a moderate ~50% knockdown of CCR2 was sufficient to effectively inhibit inflammatory cell recruitment to the sites of disease and was accompanied by the hoped-for outcome.

While this is certainly encouraging news and seems to open up many therapeutic avenues just based on CCR2 targeting, the degree of knockdown suggests that while it should be possible to achieve therapeutic outcomes with well-chosen target genes, further improvements in efficacy are necessary for the particular formulation to be broadly applicable to other target genes that may not be as dosage-sensitive as CCR2 appears to be.

Basha et al.: Tekmira SNALPs Promote Gene Knockdown in Antigen-Presenting Cells

Unlike the Leuschner et al. study which focused on the potential therapeutic applications of gene knockdown in phagocytic cells, the Basha et al. studied the mechanism, efficacy, and safety of SNALP delivery to antigen-presenting cells (APCs). This paper was largely conducted in the laboratory of Alnylam's new friends from Vancouver.

Evaluating four SNALP formulations differing only in the nature of their ‘critical’ lipid- DlinDAP, DLinDMA, DLinK-DMA, or DLinKC2-DMA- it was found that three of them (DMA, K-DMA, KC2-DMA) were capable of promoting gene knockdown in antigen-presenting macrophages and dendritic cells- both in vitro and in vivo following systemic administration. Taking into account safety, the authors favored the formulation with the KC2-DMA lipid, the lipid of the Tekmira line-of-research that was shown last year in the Nature Biotechnology paper to be highly efficient also for gene knockdown in the liver (Semple et al. 2010).

Importantly, the present data showed that increased efficacy did not come at the cost of safety. Safety is all the more important here since, similar to the lipidoid formulations described above, the delivery efficacy is still much less compared to their use in functional SNALP delivery to the liver, meaning that higher dosages would have to be administered. Since hepatotoxicity could be a dose-limiting toxicity for these formulations, the demonstration that by increasing particle size, gene knockdown in the liver could be abolished without compromising gene silencing in APCs, suggests a strategy to increase the safety of APC-targeted SNALP applications.

The Basha et al. Study Employed Tekmira-Owned Lipids and Formulations and was Partly Funded by Tekmira

While the specific results were not really surprising in light of what has already been known about liposomal delivery, what really confused me was the fact that it was Alnylam that did all the advertising of the Basha et al. study with no word whatsoever from Tekmira. After all, the paper acknowledged Tekmira as a funder of the study and based on the Responses by Alnylam, including their Canadian subsidiary Alnylam-Canada (aka AlCana), to Tekmira’s allegations, neither Alnylam nor AlCana contest that all four lipids are owned by Tekmira. In fact, KC2 is the latest in the series and, as we know, the Nature Biotech paper in early 2010 was advertised by both companies (see here and here).

The acknowledgement:

‘The authors would like to acknowledge support from the Canadian Institutes for Health Research (CIHR) under U0P grant FRN 59836, as well as support from Tekmira Pharmaceuticals and Alnylam Pharmaceuticals. P.R.C. has a financial interest in Tekmira and receives grant support from Alnylam.’

Sure, Alnylam has acted a bit irrational and confused when it came to Tekmira and its general understanding of what constitutes ownership. However, advertising a lipid for which there has been little controversy that it belongs to Tekmira and a study that was in part paid for by Tekmira, without so much as an acknowledgement of Tekmira sets a new standard. Perhaps as perplexing is the fact that Tekmira has not responded at all to these developments.

I entertain two explanations for this, explanations that I consider equally likely. The first one is that things have gotten so much out of control that Alnylam does not care any more about the liabilities of such press releases. If Tekmira needed to find an example of where Alnylam falsely advertised Tekmira’s technology as its own, one of Tekmira’s allegations, Alnylam just provided it with the most striking one.

The other explanation is that maybe things are pointing towards a settlement or merger of the two companies. This would explain why Tekmira seems to co-operate with Alnylam by not protesting about last week’s press release. It is also of note that Alnylam, as of October 8, is now represented by a new lead counsel in the ALN-VSP02 patent Interference case. Initially represented by Rothwell, Figg, Ernest & Manbeck, it is now the attorneys from Wilmer, Cutler, Pickering, Hale, and Dorr that have taken charge of the Interference for Alnylam…you guessed correctly, the same law firm representing Alnylam in the Big One with Tekmira. An alignment of these two cases would have always made sense. At this advanced stage of the Interference, however, the change seems somewhat surprising, but would make sense if it is now critical to have the two cases strongly aligned so as not to jeopardize a mutual understanding that may have been reached.

Big Pharma RNAi Therapeutics Backlash Shows Signs in Literature

There has been some unhappiness among certain Big Pharma companies about their adventures in RNAi Therapeutics. Roche, Pfizer, and Abbott Labs were among the publicized companies that discontinued RNAi Therapeutics platform development efforts not too long ago. Unsurprisingly, you could hear criticism from these companies about alleged immaturity of the technology and having been misled by the RNAi Therapeutics industry. Some of that backlash can now be felt in the peer-reviewed literature. Two recent papers by Abbott and Pfizer allow us to gain further insight into the causes of this unhappiness based on their actual practical experiences with the technology.

Pfizer: If it’s not ‘naked’ or involves invasive routes of administrations, we aren't interested

Pfizer, famous for its track-record of turning life-style drugs into blockbusters, apparently made the decision to pursue phosphorothioate LNA antisense over RNAi Therapeutics. As could be deduced from comments by then Pfizer oligonucleotide therapeutics chief Art Krieg that the need for intravenous administration makes a number of RNAi delivery technologies much less attractive, this was partly driven by concerns about patient convenience. Somewhat related and as could be seen from Pfizer’s conference abstracts, Pfizer also abhorred the complexity of some RNAi formulations. Consequently, instead of having therapeutic efficacy drive their research, Pfizer tried to make RNAi conform to their commercial principles (convenience and simplicity) meaning that they asked RNAi do what it is not suited to.

This type of scientifically conflicted approach was also exhibited in a paper by Pfizer published this month in Molecular Therapy (Moschos et al.: Uptake, Efficacy, and Systemic Distribution of Naked, Inhaled Short Interfering RNA (siRNA) and Locked Nucleic Acid (LNA) Antisense). The researchers set out to test the utility of unformulated siRNAs or LNA antisense for knocking down genes in the lung following intratracheal administration. To their disappointment, they were not able to observe target gene knockdown in the lung by either RNAi or LNA phosphorothioate antisense. This, of course, is in contrast to Alnylam’s studies that claimed that unformulated, unmodified siRNAs were an effective way to knock down genes in the respiratory epithelium and therefore fight respiratory syncytial viral (RSV) infection via RNAi gene knockdown.

Another surprising (this time for real) observation from these studies was that quite a bit of the unformulated oligonucleotides apparently made it into the systemic circulation following intratracheal administration, and as would be expected from the pharmacology of unformulated siRNAs and phophorothiote antisense, they were then either rapidly excreted into urine (siRNAs) or in the case of phosphorothioate antisense accumulated in various tissues, essentially identical to their biodistributions following intravenous or subcutaneous administrations.

For antisense therapeutics, inhalation may therefore be an interesting new route of administration for systemic therapy (e.g. knocking down ApoB in the liver). No more needles and injection site reactions.

In summary, Pfizer came out disappointed on RNAi Therapeutics as it approached it in one of the worst possible ways. Whether this ‘naked’ oligonucleotide thinking is really a choice or also reflects lack of know-how and technology access, only Pfizer really knows. As could be seen from the author affiliations in the paper, a number of scientists lost their jobs over this strange approach towards developing RNAi Therapeutics.

Abbott: Even the much-touted ‘SNALP’ cannot satisfy our cancer needs

The next technology to receive a scolding from Big Pharma, in this case the siRNA Therapeutics group from Abbott Labs, was…SNALP. The Li et al. paper published online in Gene Therapy at the end of September investigated the use of SNALP for knocking down genes in solid tumors. For this, they used their mouse cancer model where either a beta-gal or luciferase reporter gene in cancer cells was suppressed by the tetracycline repressor, tetR. Knockdown of tetR causes the derepression of the reporter genes which can be used as a marker of RNAi activity. They used SNALP because they had, in their own hands, previously identified it to be the most effective delivery system using this model system (Lin et al. 2011).

To summarize the results, Abbott found that SNALP-mediated gene knockdown was most effective in cells close to the vasculature. Cells in areas further removed did not exhibit knockdown sufficiently potent to cause the de-repression of the reporter gene. This in fact is in line with what is known from the pharmacology of similar liposomal particles and is relevant for the development of ALN-VSP02 and TKM-PLK1, two SNALP-delivered RNAi Therapeutics in clinical development for solid cancer: higher vascularized tumors will likely respond better, and the target gene should allow for strategies where a tumor can be killed from the vasculature outside in. It’s also not like all small molecules or antibodies would homogenously distribute within a tumor.

Overall, the Abbott scientists did not seem all too pleased as the following concluding remarks of that paper show: ‘Although, in a general sense, the impact of tumor vasculature on nanoparticle-mediated delivery is not surprising, it is enlightening that the delivery efficiency of SNALP, the perceived current state of art in siRNA delivery, is still severely limited by tumor vascularity.’

Not surprising, but enlightening...Apparently, Abbott people have also lost their jobs over RNAi Therapeutics, so some of the bitterness is understandable. On the other hand, when I look at the Big Pharma RNAi literature and conference abstracts, perhaps with the exception of Merck, I see little problem solving or innovation. Instead, it is dominated by passive technology evaluations, often using home-made brews rather than the original stuff, or pretty mundane process development studies which, in the absence of viable delivery technologies, seems like putting the cart before the horse. It is even possible that having these internal RNAi groups has been harmful for allowing the technology to get a fair evaluation in Big Pharma as such groups may cause the companies to become too much inward-looking, protective of one’s own people, instead of tapping into what is already out there. Without owning a leading delivery technology themselves, the best strategy may be for Big Pharma to just license product candidates instead of trying to build their own RNAi Therapeutics platforms in-house.

Santaris Terminates PCSK9 Hypercholesterolemia Trial

Antisense company Santaris seems hardly able to catch its breath these days. After being sued by ISIS Pharmaceuticals for patent infringement, reporting first clinical proof-of-concept for a MicroRNA Therapeutic, it has now been revealed that the company prematurely terminated a phase I trial of its PCSK9 phosphorothioate LNA RNase H antisense inhibitor SPC5001 for the treatment of hypercholesterolemia. This study had been initiated in May of this year with an estimated enrollment of 40 healthy and familial hypercholesterolemia subjects.

Reasons for the trial termination were not revealed. However, since this was a phase I safety trial, it is likely that the trial termination was due to some safety issue. Supporting this is that, coinciding with the PCSK9 trial termination, enrollment has been halted in another phase I hypercholesterolemia trial sponsored by Santaris, this time targeting ApoB (SPC4955).

Consequently, after the premature trial termination last year of BMS/ISIS’ phosphorothioate 2’ MOE RNase H PCSK9 antisense inhibitor (BMS-844421), Alnylam’s SNALP-delivered ALN-PCS has suddenly taken the lead in the race to develop a PCSK9-targeting RNA Therapeutic, pitting it against the monoclonal antibodies by the likes of Regeneron and Amgen.

Without explanations for the trial terminations, it is difficult to pin down the exact cause(s) of the presumed toxicities. What the compounds by Santaris and BMS/ISIS Pharmaceuticals obviously share is that they both use phosphorothioate chemistries and work via an RNaseH mechanism. Phosphorothioates are widely used in antisense development because they bind to proteins in the plasma and various tissues, thereby allowing one to achieve tissue concentrations high enough such that mass action will allow for cell penetration and target gene knockdown. In my opinion, phosphorothioate oligonucleotides are promising for a number of local applications. The problem with systemic applications, however, is that the high concentrations reached in tissues such as liver, spleen, and kidney, ultimately limit their therapeutic window. Some industry experts have referred to this issue as the ‘hazardous waste’ problem of systemic phosphorothioate oligonucleotides.

ISIS supporters will point out that Santaris’ specific LNA chemistry is the most likely culprit, whereas ISIS’ chemistries are relatively safe as supported by ISIS’ comparative studies. Of course, these studies were published to make Santaris look bad, just as the recent lawsuit was aimed at blunting Santaris’ competitive threat. Conspiracy theorists may even suspect that the sudden turmoil around Santaris is no coincidence and was orchestrated to inflict maximum damage at a time that Santaris seemed to be on a roll with a number of trial initiations, positive HCV data, and depriving RNAi Therapeutics of a deal with Pfizer (Pfizer apparently being attracted to ‘naked’ oligonucleotide approaches over RNAi nanoparticle ones). However, if Santaris intended to go public to satisfy its increasing cash needs (maybe less so with the trial terminations), it can probably scratch that now.

RNA Therapeutics is intensely competitive as they compete for pretty much the same investment dollars. Investors, including Big Pharma, are easily influenced by public opinions and fashion trends. 4 years ago it was all about the fear of being left behind in RNAi Therapeutics, with little attention being paid to true enablement and expertise in a noisy field. This made antisense look like the ugly cousin. In the last 2 years, however, antisense has regained favor as the RNAi delivery ‘problem’ became widely publicized which made antisense look deceptively simple. Santaris especially made a living of that by advertising, e.g. at conferences and press releases, the delivery problem of RNAi Therapeutics and getting a few laughs by stating their motto of 'staying naked’ and ‘staying short’.

Needless to say, my favored technology is RNAi Therapeutics: ‘natural’ and ‘potent’ is my motto. The hypercholesterolemia arena will be a particularly good battleground for antisense and RNAi Therapeutics to test their metals: same targets, easy biomarkers, chronic applications. The next chapter will be top-line data from Alnylam’s ALN-PCS phase I trial which are expected by year-end.

Santaris Reports Clinical Efficacy of Anti-miR122 Treatment for HCV

Santaris reported yesterday intriguing antiviral HCV efficacy results from an ongoing phase IIa study of miravirsen, Santaris’ LNA-based antisense inhibitor of microRNA-122 (miR-122), miravirsen, an important host factor in HCV replication. Full interim results will be presented in a late-breaking oral session at the upcoming AASLD, The Liver Meeting.

The phase IIa study investigates 3, 5, and 7mg/kg of miravirsen, given weekly to treatment-naïve HCV patients subcutaneously for 29 days. According to the abstract, with the study now in the 3^rd and last dose cohort, patients in the second, 5mg/kg cohort showed very encouraging mean reductions in viral plasma RNA levels from baseline of up to 2.5logs when miravirsen was given as a single agent compared to placebo control. 5 of the 9 miravirsen subjects had reductions of more than 2 logs (>100-fold) with viral RNA in one patient becoming undetectable 10 weeks after the dose. Although the cohorts were relatively small, 9:3 drug:placebo, almost all efficacy measurements reached statistical significance.

What was interesting is that the decline in viral titers was quite prolonged, with the biggest viral reductions being observed after treatment had finished. While having prolonged drug activity per se is positive, the gradual decline is not optimal as it increases the chance of selecting for escape mutants, a major issue in HCV treatment in general and reason why the industry is busy developing new HCV treatment options to be added to the arsenal. In fact, a recent study out of Denmark showed that it is possible to select for HCVs that do not require miR-122 for replication, at least in tissue culture systems. On the other hand, given that miravirsen is targeted at a host factor and since the miR-122-viral interaction occurs at conserved sites, it may be relatively more difficult for the virus to develop such resistance as compared to for example direct antivirals. I would expect the company to report sequencing data at the conference next month.

Irrespective of the viral escape issue, slow clinical responses may also make it somewhat more difficult to integrate miravirsen into the newly emerging treatment paradigms, one aim of which is the reduction of treatment times. Here, RNAi Therapeutics would have an obvious advantage over miravirsen by acting much more rapidly than phosphorothioate antisense oligos which rely on tissue enrichment over time. This is also supported by the data that were recently reported by SomaGenics in collaboration with Tekmira and Roche.

On the safety front, the abstract noted the absence of drug-related serious adverse events. It did, however, note that among the supposed biomarker signals for anti-122 efficacy was an elevation of alkaline phosphatase (ALP) levels. ALP elevations are normally considered a marker of liver injury similar to ALT/AST, so I am not really sure how why this is not considered a safety signal. We will therefore have to for the conference presentation to learn more about the safety profile of miravirsen.

Overall, with the demonstration of antiviral activity and reductions in cholesterol levels which further support functional inhibition of miR-122, the abstract marks an important milestone in the development of microRNA Therapeutics: The first unambiguous demonstration of MicroRNA Therapeutic activity in Man.

Roche AASLD RNAi Therapeutics abstracts: HCV and LNP

Roche will present at the AASLD meeting on two RNAi Therapeutics studies. Both studies involve LNP01, which I assume involves ‘lipidoid’ LNP delivery chemistry. In one study, Roche and their academic collaborators targeted a host factor believed to be involved in the development of HCV drug resistance, especially to the interferons which are at the risk of becoming replaced and, unsurprisingly, Roche would like to revive that franchise. The abstract, together with the recent SomaGenics/Tekmira revelations, further demonstrates that Roche had been quite interested in RNAi Therapeutics for HCV. It also makes me think that maybe Novartis has not picked HCV as a target under Alnylam IP which would e.g. allow Tekmira to step into the void- well, if it saw any reason to do so, maybe out of strategic considerations.

The other abstract concerned potential innate immune stimulation elicited by LNPs. Consistent with what had already been known or suspected, TLR7/8 are the major innate immune receptors and cause of LNP hepatotoxicity, and this can be alleviated by simple 2’-O-methylation as demonstrated before by Tekmira before. What was particularly nice though in this particular study was that with the use of TLR3 knockout mice, TLR3 can now essentially be excluded as a significant tox factor for LNP delivery.

Read also: Miravirsen shows efficacy in HCV chimpanzee models.