RNAi Therapeutics Still Challenged with Re-Educating Pharmaceutical Industry

Judging from the body language of RNAi Therapeutics companies, it seems that they are still fighting a wide-spread perception, also in Big Pharma, that systemic siRNA delivery is limited to targeting genes in the liver and that as a result the current commercial opportunities are relatively small. To quote from Alnylam’s press release yesterday, on research presented at the 8^th International M. Judah Folkman Conference ‘The new research demonstrated effective silencing of target genes in distinct cell types and tissues beyond the liver with systemic delivery of RNAi therapeutics’ [emphasis mine]

To me this is frustrating as it should be obvious to any modern biologist that a strategy of selecting drug candidates starting with the characteristics of delivery systems that already show much promise for clinical development should yield a rich pipeline. Just think about 'only' the liver and how it affects a range of diseases in therapeutic areas ranging from metabolic, to cardiovascular, and even neurological diseases.

Or take systemic delivery to endothelial cells as another example. First pioneered in the commercial realm by Silence Therapeutics with their positively charged siRNA-lipoplexes (see Atu027 clinical candidate for solid cancers) which, as Alnylam rightly points out, has implications for diseases such as ‘atherosclerosis, diabetes, inflammation, and cancer’. Consequently, companies like Silence Therapeutics and Tekmira have made it a high priority to demonstrate the wider applicability of their delivery technologies.

This to me indicates that the established pharmaceutical industry may be even slower in adjusting their thinking than I originally imagined. One can only hope for both RNAi Therapeutics and Big Pharma that the transition from therapeutic franchise-driven to technology-driven drug development will be realized sooner rather than later. To put it bluntly, the franchise-driven strategy worked in an era where sales and profits were more a function of the number visits paid by large salesforces to primary care physicians and the number of drugs in a given franchise the salesperson was able to pitch in a single visit, rather driven by the data underlying an approved drug.

But with small molecule generics eroding Big Pharma's profit base, this has more and more become a losing proposition, and the focus has rightly shifted to advanced and highly targeted technology platforms having hopefully larger impacts on the diseases they address and akso being less easy to copy. Because such therapeutics can command high prices, this allows for a model in which only small, well trained and educated salesforces are needed to address very specialized markets.

A company that I consider to be torn between the franchise vs technology strategy is BiogenIdec. This is a company that much values their franchise in multiple sclerosis, and is rightly also proud of its capabilities in protein engineering. As a result of trying to marry both worlds, they seem to be paying the price of having to in-license drug candidates for the MS franchise which limits their profit growth. Proteins/antibodies alone seem to miss important opportunities in MS. However, considering all types of technologies for a given franchise appears to be too tall an order for a mid-sized company. And when that company has an opportunity in protein therapeutics, but outside its core franchises, no matter how exciting financially, it is faced with a real communication challenge (see BiogenIdec’s recent hemophilia roundtable).

It is my thesis that the use of the new platform technologies demands a re-thinking of what ought to be driving the selection of development candidates. It is for example clear that candidates based on RNAi Therapeutics depend heavily on having extensive RNAi expertise. Knowing the capabilities of the technologies, especially the tissues and cell types that they can address and pharmacology involved, one may then go out and consult with disease specialists in the various areas to discuss specific treatment strategies.

A model that is more likely to work for large companies is therefore to establish those Centers of Technology Excellence and have them interact with the more disease-oriented people in the rest of the company. Hardly a new concept and it is certainly also happening to some degree in the RNAi Therapeutics space, examples here being Roche Kulmbach, Merck Sirna Therapeutics, and Pfizer Coley/RTC. Nevertheless, despite these encouraging signs, even in those cases I’m still not sure whether the dynamics within those companies are conducive to RNAi technology-driven drug development.

Opko Health and its RNAi Therapeutics candidate (for wet AMD) is probably a good example of where an RNAi Therapeutics drug development project was run largely by disease specialists. Since I could never understand how a group without much of a track record in RNAi could possibly come up with the first RNAi Therapeutics candidates, it did not come as a surprise to me that that candidate eventually failed. I am also worried that when Pfizer and Novartis decided to license certain RNAi Therapeutics candidates from Quark, these were decisions largely made by the particular disease focus groups in those companies instead of being integral to those companies’ RNAi Therapeutics efforts.

Ironically, this situation can be partly attributed to the fact that RNAi has to a certain degree allowed for the democratization of drug development by facilitating translational research: I could teach any semi-bright 12-year-old in a day design an RNAi molecule that will knock down a gene. This, however, does not mean that it will make for a suitable development candidate.

So yes, it is worth reminding Big Pharma and investors that systemically delivered RNAi Therapeutics are on the horizon, not only for gene targets in the liver, but also beyond. The mere fact, however, that it is still necessary to emphasize this constantly tells me that a slow-moving pharmaceutical industry leaves a lot of RNAi Therapeutics value unlocked. Liver, cancer, endothelial cells, phagoctytic cells, sites of inflammation, the retina, neuronal cells…put a dozen RNAi scientists, another dozen geneticists and two dozen experts in the pathophysiology of important diseases in a room for a week, and you may end up with more interesting development projects based on currently available RNAi technologies than you have the manpower to pursue.

After this more general critique of the pharmaceutical industry, I will try and shed some light about the particular advances highlighted in the Alnylam press release in my next blog entry.