Clinical Experience with RNAi Therapeutics Suggests Class to be Remarkably Safe

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

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

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

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

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

RNAi Therapeutics is Dead, Long Live RNAi Therapeutics

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

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

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

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

Clinical Trial Update for Solid Cancer Candidate Atu-027 Highly Encouraging

After I tried to focus attention on the Silence Therapeutics presentation this afternoon at the BIO CEO & Investor Conference, as soon as I had published my earlier blog I half regretted my decision to do so because more often than not positive news does not materialize when you expect it. This blog in particular is littered with such speculations. Fortunately, this time was different as Silence Therapeutics was able to present some really neat data from the ongoing phase I study with Atu-027 in the treatment of advanced solid cancer.

To date, at least 20 patients have received at least one Atu027 siRNA-lipoplex infusion. While the dose escalation is being conducted in a very cautious manner, i.e. slowly, dosages are now approaching levels of around 0.1mg/kg where therapeutic efficacy may be expected based on pre-clinical non-human primate data. Importantly, after 157 infusions administered, the drug seems to be very well tolerated. The only notable safety concern may be the complement activation likely related to the positive charge of Silence’s lipoplex formulation and that the Company characterized to be ‘limited’ and ‘transient’ in nature. This would be consistent with the fact that no dose limiting toxicity was reported,

There was also anecdotal evidence for anti-tumor efficacy of Atu-027. 5 out of 20 patients experienced stable disease during the 3 month study period with one patient in the sixth cohort (7^th dose cohort now dosing) said to exhibit ‘remarkable shrinkage of target and non-target lesions’. There was also a mention of a reduction in lung metastases which could be clinically very meaningful for certain cancers (slide 16). Unfortunately, since this presentation was not webcast live, it is currently difficult for me to figure out the context in which this comment was made.

In sum, from today on, Atu-027 has to be considered one of the foremost RNAi clinical candidates and I look forward to data from the higher dose groups at ASCO. Congrats to the company for having come this far.

Silence Therapeutics to Present Blitz-Update on Atu-027

2011 promises to be a year of rich clinical data flow for RNAi Therapeutics. Results from clinical trials of ALN-VSP02, ALN-TTR01 (both Alnylam), Atu-027 (Silence Therapeutics), and TKM-PLK1 (Tekmira) in particular will be important in shaping the perception of RNAi Therapeutics as an investable drug modality. Following disappointment that Silence Therapeutics was not able to receive an attractive offer following the 'approach', the Company’s announcement this morning that it will provide an update, today at the Annual BIO CEO & Investor Conference, on the phase I trial of Atu-027 for solid cancers, fosters speculation that Silence Therapeutics rejected any bid as undervaluing it because of impending positive trial data and that the better game plan may be to raise capital at elevated prices following positive market reception of the trial data. Clearly, at this point Silence’s future depends to a large degree on Atu027 and the stakes are high.

This is an opportunity for me to urge the pure-play companies to treat retail investors fairly in upcoming financings. Believe it or not, with perhaps the exception of Alnylam, it is retail investors that keep these micro-cap companies alive. Financings of the type that Marina Biotech transacted last week are simply not acceptable: the underwriter and solicited large investors get hefty fees, discounts, and warrants which means that shares will be flipped for a quick profit and dumped onto retail investors which do not get the opportunity to participate on equal terms. In the end, these companies will have squandered the goodwill of their most important constituency as the deals will be perceived as a mutual back-scratching exercise to keep the biotech gravy train going while non-privileged investors lose their investments.

Despite its wide-spread practice, this does not have to be so. For example, in a recent financing by gene therapy company Oxford Biomedica, existing shareholders were given the opportunity to participate in the follow-on offering at the same (very steep) discount as the institutions. To be clear, this deal is still to be considered unfair in that the option to participate still did not allow retail investors to avoid substantial dilution while larger shareholders were given this opportunity and even could increase their stakes at the much reduced prices, on top of the obvious insider trading the week before the financing (but that’s a more general problem, I guess). So to the Tekmira’s, RXi’s and Rosetta’s of the world: if you have to issue shares, please consider your most loyal constituency and treat them fairly.

Early January update on ALN-VSP02

Since I would like to shift the focus of this blog towards the clinical developments in RNAi Therapeutics, a quick re-cap of the data presented by Alnylam a month ago which showed that the LNP-delivered ALN-VP02 achieved therapeutically relevant tissue levels and promoted RNAi-mediated target cleavage in the liver of cancer patients. This is similar to data published in Nature a year ago by Calando with their RNAi compound for solid cancer.

Certainly, the 5’ RACE assay used to determine the RNAi-mediated mechanism is (still) a non-quantitative technology and as such can only tell whether RNAi has occurred or not. However, in practice, this assay is not without its challenges even under standardized tissue culture conditions, so the fact that cleavage could be detected in a clinical setting where sampling issues were especially challenging is an important finding.

The other important piece of new data presented was on the drug accumulation in the liver where about half of the reported values well exceeded the 1ng/mg threshold that Alnylam reported to have 50% Factor VII knockdown efficacy by a log or so (Landesman et al. 2010). Although the dose responsiveness of siRNA accumulation in the liver was a bit shaky, possibly due to sampling challenges, the data also suggests that LNP delivery efficiency to rat and human liver may not differ by too much. It has to be said, however, that ALN-VSP02 is a first gen LNP formulation whereas the 1ng/mg threshold was established with a 2^nd gen formulation. Moreover, the 50% threshold is always target gene specific and will differ between Factor VII and the ALN-VSP02-related VEGF.

In sum, the data supports that ALN-VSP02 may have a therapeutically meaningful impact in a subset of patients should maximally tolerated dosages of 1.25mg/kg or above be achieved and the genetics play out as hoped. We should not have to wait much longer for more clarity on the efficacy of ALN-VSP02 given that Alnylam has collected many more biopsies and should have conducted additional types of assays (e.g. RNA knockdown; mitotic spreads for spindle abnormalities expected from KSP knockdown etc) than were reported on.

Big Pharma and RNAi Therapeutics: In-house Platform Development is ‘Out’, External Product-specific Deals are ‘In’

As if to add insult to injury, a few month after Roche exiting RNAi Therapeutics, plans emerged that Pfizer is about to shut down internal oligonucleotide therapeutics development efforts. This is depressing news for sure to me, and I would assume the wider RNAi Therapeutics community. But then again maybe not that surprising, and it would shock me no more to see Last-Man-Standing Merck shut down as well if the Tuschl trial goes against them.

Just as Big Pharma jumped onto the RNAi Therapeutics bandwagon 3-5 years ago, seemingly believing that all you need to do is to inject an siRNA into the blood and all those multi-billion dollar patent expiration woes will go away, the Big Pharma herd is now running for the exits. If you study this quarter’s financial results by Pfizer and Merck, you’ll know that there is little or no room for developing a new technology platform. Rather, it is about rescuing the top-line through Mega-Mergers with the few stilll growing large pharmaceutical companies, phase III, launch, and emerging markets, and managing the bottom-line by cutting in-house R&D. We’ve all heard it, again and again.

In essence, it is an acknowledgment that Big Pharma has failed as an innovation engine and R&D is no more a place to hide from responsibility in Big Pharma. The industry has decided that internal efforts that just serve as evaluation units of external technologies (e.g. delivery) without spearheading cutting-edge R&D themselves are not an efficient use of capital. Instead, if a therapeutic business unit was interested in a specific RNAi Therapeutics candidate, they can deal with the external company directly without the need for an in-house middleman. In fact, Pfizer has already pursued this alternative pathway as they have partnered the ddRNAi program for HCV with Tacere and a synthetic siRNA candidate from Quark for wet AMD. In both cases, there seemed to have been little involvement by Pfizer’s in-house oligonucleotide therapeutics unit.

This is not a criticism of the individuals themselves that have been part of those platform development units, but more one of an organizational nature. The more I learn about Big Pharma, the more I am struck by how little co-ordination there is within these sprawling organizations. For example, a group in one part of the world may utilize RNAi for target discovery and validation, but may not be fully aware of the technologies available from units elsewhere which work on the therapeutic aspects of RNAi.

It is, however, also a criticism of the arrogance of some organizations that innovation will happen if only you throw money at it. More than $500M by Roche, more than $200M by Pfizer, and more than $1.5B by Merck, and little to show in terms of delivery progress compared to a company like Tekmira with much more limited means. What is frustrating is that often money is spent on trying to replicate what already exists, such as LNP delivery, instead of admitting that innovation can’t be manufactured and if you really want to bring it in-house, then it is by buying it where it emerges, wherever in the world.

Almost on cue, the same day that Pfizer’s plans emerged, Marina Biotech announced a product-specific development deal with Swiss drug licensing and development company Debiopharm. This deal covers a pre-clinical stage RNAi Therapeutics program for bladder cancer (via topical LNP-siRNA administration) where much of the early development work will stay with Marina, but which will all be funded by Debiopharm, with potential downstream development milestones and royalties for Marina Biotech. Given the circumstances, severe cash crunch I would think, it is a good deal for Marina given the early stage of the program (pre-clinical). And who knows, maybe some of the work by Marina Biotech and Tekmira with Pfizer will similarly result in product-specific development deals with Pfizer therapeutic area units if results obtained thus far have been promising.

The Pfizer news is definitely not good for building investor confidence in RNAi Therapeutics, but long term it may just mean that companies with already viable clinical technologies will succeed as it will allow them to efficiently churn out and monetize high-quality development candidates, somewhat akin to what Quark’s and ISIS’ business models have been until now. That’s not to say that this is ideal for RNAi therapeutic technology development, but with maybe the exception of Alnylam, most companies won’t have many other choices.

Note: I am currently planning to resume more regular blogging as clinical results come in. Only these will be able to turn around sentiment for RNAi Therapeutics in a lasting manner.

A Lean RNAi Therapeutics Will Do Just Fine

The media coverage on Roche’s decision to ‘abandon’ all things RNAi Therapeutics almost makes one believe that we have just witnessed the demise of RNAi as a therapeutic modality. The naysayers of the technology had their heyday, apparently delighted by the that Roche's decision is absolute proof that RNAi has failed in its quest to improve human health. Nevermind that the Roche news has to be seen in the context of Big Pharma’s crisis of confidence in its own ability to innovate and investor pressure to cut almost everything that does not immediately produce positive cash flow. Even Roche has to admit that in the 3 years since it took the $300M+ license from Alnylam and the 2 years since it bought Mirus Bio for $125M, nothing fundamental has changed with the science, except for maybe that the potency of LNP delivery has improved by 100-fold for some applications.

On the other hand, it is also the time to acknowledge the significant financial support that Big Pharma, including Roche, has provided to RNAi R&D at times in the capital markets that were otherwise quite hostile for companies based on novel biotechnologies. I’m quite hopeful that measured investments in RNAi Therapeutics by larger pharmaceutical companies will continue, and even increase again in the not-so-distant future as results confirming gene-specific knockdown in Man emerge from a number of the ongoing clinical studies.

Unfortunately, the Roche news has done much damage to investor confidence. As valuations of RNAi companies have dropped to levels that may sicken some investors, companies in the space will have to change how they conduct business.

If done smartly, there is an amazing amount of progress to take advantage of, not only as described in the literally thousands and thousands of RNAi-related papers coming out at ever increasing speed, but also progress in disciplines as varied as human genetics, ‘omic’ technologies and bioinformatics, nucleic acid chemistry, and IT and how it has allowed for business models with increased capital efficiency. By judiciously combining the growing knowledge of human biology with technologies that lower the barriers of entry by the day, biotechnology in general is poised to become one of the major pillars in many of the world’s economies, similar to how the eroding cost of computing power has changed the way we lead our lives.

Not all companies, of course, will adapt equally well. Humble Tekmira, as the re-incarnation of Protiva, may serve as a great example in how it is possible to make speedy technology progress without having to throw millions at the wall and hope that something will stick, and without building corporate structures to rival that of Big Pharma. It is also my hope, and expectation, that chastised Alnylam will find back to its roots and put technology and clinical results front and center without letting empire building take primacy as I believe it did when Alnylam let go of its Kulmbach operations. A market cap of less than $400M for a company with a financial profile that is the envy of the biotech industry, and with a pipeline poised to yield critical proof-of-concept data for a potentially transformative technology…I would not have dreamt to see such bargain prices for ALNY again.

I will now take a little writing break. After a good year of re-commencing this blog, I am at the risk of repeating myself. As the RNAi research engine powers ahead just as swiftly without my commentary, I will dive into the literature and take a more detailed look at some of the technologies. It is truly amazing how far we have come in understanding human biology and rationally interfere with it, also for therapeutic purposes.

Merck: “Tekmira are Truly Experts [When It Comes to Formulating SiRNA-Liposomes]”

Roche’s decision this week to terminate in-house RNAi Therapeutics development is widely reported to be a vote of no confidence in the platform. The alternative interpretation, however, namely that it might reflect a vote of no confidence in the ability of Big Pharma to innovate from within receives little or no consideration in an online media world that, at best, gets compensated according to click number. Even more so in an environment that demands immediate financial results, they may prefer to play it ‘safe’ by buying innovation in later for hundreds of millions in the form of drug candidates that have already proven themselves in phase III studies or have even received regulatory approval.

In addition, it is widely understood that since Roche intended to use liposomal delivery for its first RNAi-based product candidates, Roche must have been disappointed with the performance of Tekmira’s LNP delivery technology. Again, I strongly disagree that this is necessarily the right conclusion, because for Roche the development of LNP-delivered siRNA therapeutics did not really require a large in-house RNAi Therapeutics development organization. One could even hypothesize that the collaboration with Tekmira and Alnylam opened Roche’s eyes just how difficult it is to develop cutting-edge technologies such as RNAi Therapeutics with the same efficiencies as pure-play companies can, at least within current organizational structures.

In this light, I found the presentation by Alan Sachs, Head of Merck's RNAi Therapeutics efforts, at the recent RNAi Asia meeting particularly telling as he went out of his way to complement Alnylam and particularly Tekmira for their pioneering work in RNAi Therapeutics. It almost appeared like Merck considered them less as competition and that Merck would stand to benefit from their success in developing the breakthrough technologies necessary for RNAi a therapeutic reality.

The number one example of how Merck, and Big Pharma in general is dependent on biotech innovation in the field of RNAi Therapeutics is siRNA delivery, in LNP-mediated delivery. The statement thus emphasizes that all liposomal siRNA formulations are not created equal. Failures that others see and report with their home-brew liposomal delivery methods cannot necessarily be applied to Tekmira’s LNP technology.

If the RNAi Asia meeting is any guide, then Tekmira’s LNP technology is the de-facto gold standard in systemic siRNA delivery, widely acknowledged by industry and academia. As the gold standard, of course, it is also exposed to a lot of criticism. An interesting dynamic that emerged in this meeting is that not only does liposomal siRNA delivery receive heaps of criticisms by those companies that develop competing delivery technologies, but that liposomal researchers themselves start criticizing it. Unfortunately, these are also the scientists that get approached by the investment community and pharmaceutical industry for their views on liposomal delivery.

As Alan Sachs put it: there are dozens of variables in formulating a liposomal siRNA nanoparticle. Slight variations can have large effects on shape, stability, and reproducibility of the process, all with important implications for the toxicity, potency, and commercialization of such therapeutics. It is formulation that Alan Sachs considers Tekmira to be ‘truly experts’ in. He goes on to say that the question of IP exclusivity is not really that relevant, what matters at the end of the day is really the know-how behind reproducibly formulating safe and efficacious LNPs, at commercial scale at that.

This, I guess, also addresses the claims by other company, valid or not, that they do not require Tekmira’s IP for their own liposomal siRNA delivery purposes. It is true that many groups can efficiently knock down genes in the liver, and some also in tumors in rodents. Some now also at quite low microgram per kg potencies. Transitioning from rodents to non-human primates, however, has proven to be a big hurdle for almost all of these groups.

And listening to the talks and reading the literature, it is not difficult to see why performances differ so widely. Often, lipid formulations are cooked up to superficially approximate what has been reported by Tekmira and their collaborators. However, because the formulation processes are typically not comparable and little effort is put into characterizing what particles have actually been generated, these particles will behave very differently to a Tekmira LNP, no matter how similar the lipid chemistries and molar ratios applied. In more extreme examples certain lipid components have been dropped out, or the particles are highly positively charged and unshielded and therefore prone to aggregate. Still, implications are directly drawn towards the safety of Tekmira’s LNP technology. Sometimes it appears that some research groups have only recently entered the field and are trying to re-invent the wheel by reporting what should have already be well known.

My cynical view is that pointing out such supposed safety issues, is what gets you research grants these days. Since Tekmira’s LNP technology is the gold standard, funding agencies are more likely to fund research into the safety of LNP technologies than on the safety of some obscure delivery technology.

I do not want to suggest that there are no safety concerns with LNP delivery, also as practiced by Tekmira. But from my perspective, I am more than encouraged by the clinical record so far: the Tekmira ApoB study went up to 0.6mg/kg and experienced (only) one case of apparent immune stimulation, and Alnylam’s ALN-VSP02 is still dose-escalating, having reached 1.5mg/kg. Before these programs went into the clinic, my biggest concern for Tekmira’s LNP technology had been immune stimulation at much lower dosages based on Protiva’s experience with the liposomal delivery of plasmids almost a decade ago.

With regard to safety, Alan Sachs complemented Tekmira on putting patient safety first and making Tekmira’s whole-blood immune assay immediately available to the industry. Like Alnylam, Merck also quickly adopted/tested it. He added, however, that in Merck’s limited experience with the assay, results could vary quite a bit when using blood from different patients and that, as a result, the test cannot be considered to be reliable yet. My tendency, however, is to interpret the data to mean that the test is in fact very sensitive and reliable and that there may be some natural variability in how patients respond to LNPs. If a test like this can pick up some of these differences, then it should only contribute to the safety of LNP delivery. I’m sure Alnylam, and soon again Tekmira with TKM-PLK1, are busy collecting patient blood in an effort to determine the basis, maybe genetic, of such variability.

As an investor in Tekmira Pharmaceuticals, I must say that I do not really mind LNP formulation to be such a complex process. After all, one reason why the pharmaceutical industry is abandoning small molecules and flocking into biologics is that small molecules sales are easily canabilized by generic competition. A ‘naked’ antisense or siRNA that can be generated by straightforward chemical synthesis may face similar generic issues as small molecules. The story, however, would be quite different for an LNP-delivered RNAi Therapeutics with high technical barriers of entry.

In summary, in contrast to what seemed to be the message of an interview with Alan Sachs by Xconomy earlier this year, Merck appears to be as enthusiastic as ever about the potential of RNAi Therapeutics. Liposomal delivery won’t cure all diseases, but ‘even’ Merck considers it promising enough to focus most of their delivery efforts on this technology. As supported by Alan Sachs’ talk at RNAi Asia and the robust publication record by Merck RNAi scientists this year (at least 7 papers by my count), RNAi to Merck is not just about target discovery and validation. It’s much more, but since even with such an effort a Big Pharma like Merck expects to be dependent on sourcing RNAi innovation from the outside, it is best to lower, or ‘manage’ in the words of a Merck spokesperson, overall expectations and enjoy bargain prices.