RNAi and the Eye

One of the criticisms one encounters when evangelising about a hot new technology from the lab is that it hasn’t been proven yet ‘in the real world’. Given the glut of medical breakthrough announcements in the daily press, investors know all too well that much of those won’t ever have a clinical impact. Validation is the key, and while RNAi has seen many pre-clinical, and some clinical validations, a drug approved by the FDA has to be the gold standard. So when will we see the first RNAi drug on the “market”? Unless the government started stock-piling siRNAs against bioterrorism threats such as Ebola or a bird flu pandemic (note there is considerable effort ongoing in this area), my conservative guess would be 2010-2011 with the application being age-related macular degeneration (AMD). Currently, it is a race between 3 drugs in phases I to III for the glory of being first to have an RNAi-based drug approved.

That the eye and wet AMD should be the subject of so much early interest should not be surprising. AMD is considered to be a low-hanging fruit as the target cells are relatively easily accessible, the eye as an immune-privileged organ, and the existence of well validated targets. Notably, there are two other nucleic acid-based therapeutic classes of which the only approved drugs is one for a condition of the eye each: the antisense oligo Vitravene of ISIS Pharmaceuticals for CMV retinitis in people with AIDS, and the RNA aptamer Macugen of OSI Pharmaceuticals recently approved for wet AMD. Like Macugen, one of the siRNAs by Opko (formerly Acuity Pharmaceuticals) targets VEGF. However, more recently monoclonal antibodies by Genentech targeting VEGF have become a more popular and effective treatment option. This illustrates how fast the competitive landscape may change and the commercial risk from competing technologies. RNAi companies reacted in different ways to this situation. Realising that the market for AMD is becoming increasingly crowded, the Alnylam (www.alnylam.com) management made the brave and early decision to stop its VEGF-AMD development program and instead focus their precious early efforts on so called non-druggable targets. These targets are well validated in biology, but either because of their localisation or structure cannot be reached by non-RNAi drug classes. The next strategy is exemplified by Sirna Therapeutics. Instead of going after VEGF, they took the decision to go after another protein in the same pathway, namely the VEGF receptor 1. This target may have increased potency as it is thought to be required for the functioning of yet another signalling molecule implicated in AMD, the placental growth factor(PIGF). Also because it is a target different from VEGF itself, VEGF-R siRNAs may act synergistically with the now established VEGF therapies. In general, RNAi may be used synergistically with other drug modalities due to its unique mechanism of action. Sirna then went one step further and partnered with Allergan, a company with experience in treating eye-related diseases. In order to better position their drug, they put considerable effort into addressing one of the short-comings of existing therapies, namely the need for relative frequent needle injections into the eye. Each needle injection carries the risk of treatment-related complications, including blindness. Indeed, RNAi may be able to provide a solution for this as is indicated by early phase I pharmacokinetic data from Sirna and studies of RNAi knockdown in the liver by Protiva and Alnylam scientists that show long-lasting RNAi silencing effects following a single application of siRNAs. When combined with a slow-release formula, this property may eventually allow for once-every-6-months injection treatment regimens. The last strategy that I would like to highlight here is to go after completely new targets- really one of the great strengths of RNAi after all. Although carrying a higher development risk, Quark Biotech embraced this philosophy and is now targeting REDD1, a gene that they identified as playing a pivotal role in the progression of AMD.

Watching the drugs navigate through the complicated drug approval process will be fascinating. Let’s hope that these pioneers will be rewarded for the risk taken, but also caution them not to take any short-cuts in order to be the first to claim RNAi glory. For me meanwhile, there is little doubt about RNAi drugs in the future. Such a potent mechanism to regulate genes beckons to be used in the clinic, the only question therefore is therefore how many and how soon.

Tip: For those interested in investing in RNAi companies, the message board on Investor Village about Alnylam (symbol: Alny) is a great resource and discussion forum: http://www1.investorvillage.com/smbd.asp?mb=569&pt=m&clear=1