Friday, November 19, 2010

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.


Anonymous said...

Thanks for the post.
I have a simple question,
why Alnylam start to do LNP delivery ? I mean, is there any problem of virus delivery?

Dirk Haussecker said...

The applications for LNP versus viral delivery are largely non-overlapping. Moreover, Alnylam is not in the business of ddRNAi Therapeutics.

Anonymous said...

I understand what you mean,
However, the question was virus is the oldest natural way to deliver RNA, why Alnylam didn't decide to use it instead of developing expensive man-made LNP ?

Dirk Haussecker said...

LNPs are cheaper compared to viruses, but I really believe that's not the point here. Different businesses have different objectives. Alnylam was built on synthetic RNAi trigger-related IP, not ddRNAi.

Anonymous said...


Read your "FEAR" post n the IV message board. ROch and NVS were not RNAi specific. Those companies are looking for revenue and cutting out distant programs is just common sense. ROche and NVS are not leaving the space. They will allow TKM et al to continuie and they will keep a few chips in the game. The decision was corporate not scientific.

Imagine what PFE is going to do next year when Lipitor goes generic. I see a multi billion dollar drop in in-house programs.

Dirk Haussecker said...

Definitely agree that the Roche Decision says a lot about the pressure that Roche suddenly finds itself under to maintain earnings per share in the face of eroding top-line revenues, and that longer-term technology development projects like RNAi Rx won't help them much in that regard.

Like you, I also expect that Roche will continue and play a part in RNAi Rx through external collaborations and/or part-ownership of a Roche RNAi Rx spin-out.

I would, however, not interpret the Novartis decision in the same light as Roche's decision. Novartis seems to be expanding RNAi Rx, not cutting it. Let's hope, however, that the report by Regeneron of promising wet AMD data won't change that. Roche/NVS now stand to lose a good chunk of their $3B wet AMD franchise.

The press reports on RNAi Rx in the wake of Roche? Didn't expect anything else to be frank. It is clicks that count, not an in-depth dissection of the science.

Anonymous said...

Hey, what are you , and i mean that in the most sinsaeire way. You look like a nerd who knows alot about nothing so yuo would agree.... Please dont worry about thanks giving has got the better of me. Being drunk does that change anything in the rnai space, cus im feeling the germans have invaded again. Rnai is the next frotire of scince , yet the guys with the money say.....we where wrong and stuiped...Hey you know Plastic set himm Straight i have become ammunie to panadol

Anonymous said...

"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 a cynic, I'd also keep in mind that Merck's ongoing support for the field could also have something to do with their $1B purchase of Sirna. After paying that price, 'even' Merck couldn't risk the backlash of abandoning the field too quickly.

Anonymous said...

It is obvious the swiss are coming down under with the germans BLT.asx

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