RNAi Therapeutics: Integrate, Collaborate, or Die

It was with a healthy dose of suspicion that I went today to a presentation by Mike Varney from Genentech on their small molecule operations which is a new addition to the Genentech and which he was spear-heading. Of course, as the pioneer of biotech the first question to be addressed was why Genentech would go into small molecules at all if that was part of the reason why Big Pharma was ailing anyway?

Hearing about the challenges of RNAi delivery ad nauseum, you’d think that relative ease of delivery such as by oral bioavailability would be a major motivation, but this was not the case. In the business of treating serious, life-threatening disease with large unmet medical needs, it becomes less relevant if you can go home and take a pill twice a day, or whether you get an intravenous infusion every other week. No, the main rationale provided was that as Genentech scientists dive deep into the biology of disease pathways, they often find themselves with promising drug targets, but which cannot be reached by antibodies. Antibodies are great for targeting cell surface proteins, but useless for intracellular targets whereas small molecules can more easily achieve that feat. Target space is the keyword here, and according to Dr. Varney target space is very limited, so limited so that as a biotech reaches the size of a Genentech or Amgen it has to think about other drug classes while at the same time Big Pharma is expanding into biologics.

You can imagine how my mind was racing wishing to tell Genentech that it was right in front of their eyes and RNAi is what they were really looking for, a technology that may address virtually any gene and also circumvent the painful lead optimization process for small molecules Mike Varney was going through (and yes, I cannot believe that they have not thought about small RNAs already even if much of the thinking was done for them by mother Roche).

But that’s not really my main point tonight. As he was describing the diverse skills it took to bring the clinic and pointing out that part of the reason that current productivity in drug development is so dismal (the latest number is $1.4B spent for every new drug developed) and Genentech was so successful is that many companies think they can get away with by just concentrating on a small part of the skill pie. And this may be very true for the current RNAi Therapeutics space as well.

While the entry barrier for target discovery using RNAi is relatively low, developing an actual RNAi Therapeutics is much more complicated than that. Just considering the scientific aspects, the development of an RNAi Therapeutic requires among other things, precise knowledge of the disease biology, basic RNAi and microRNA biology, know-how in siRNA design and chemistry, assessing off-target risk and the interplay of the RNAi trigger and/or delivery vehicle with the immune system, RNAi pharmacology, and being able to safely deliver the RNAi cargo.

I get the impression that there are a number of programs/companies out there that do not take into account e.g. the off-target profile in their design of an RNAi trigger and instead select a published sequence or one that they find can simply knock down a gene and eventually take that into the clinic, or lack the know-how required to adequately assess innate immune responses. This could be avoided if smaller companies weren’t so afraid in collaborating with each other or larger companies, partly for fear that it may negatively affect how the investment community perceives their competitive scientific prowess and IP position. Right now, I can only see very few companies that have the financial wherewithal and scientific know-how to establish an integrated RNAi Therapeutics development platform that alone could shepherd RNAi Therapeutic candidates into the clinic. Alnylam, Merck, maybe Novartis, and probably soon Roche and Pfizer may have such capabilities, and these examples may not even cover all the bases just as Genentech is collaborating with both small and large.

Smaller companies, particularly those with a focus on delivery should probably seek help in deciding which RNAi trigger to use with their particular technology. Of course, having something to offer in return will help their negotiation position. As you know, I think Tekmira/Protiva have done that quite well and obtained up to 7 InterfeRx picks from Alnylam in exchange for liposomal siRNA delivery technology. In other instances where the technological payback may not be that obvious for the established company, it may still be a good investment to help with siRNA design as part of granting a technology license, as it should also increase the odds of successful clinical development and therefore potential for royalty income further downstream. Big Pharma most likely would not be interested in such top-to-bottom technology transfer arrangements, but it may be a consideration for some of the more established pure play RNAi Therapeutics companies.