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to do what I just described, to increase the POS [probability of success] of our pipeline.
X: Do you have a lead drug candidate that’s been identified and ready for the clinic, or anything demonstrating safety and efficacy in the clinic?
AS: Again, our Phase Ib, IIa clinical trials [of RNAi molecules] biomarker driven studies are for target validation and de-risking. We wouldn’t disclose those, because those are targets that are quickly followed by a small-molecule or biologic. Because the indication might not be consistent with an RNAi therapeutic delivered through intravenous means. No diabetic in the general population, if you’re a Type 2 diabetic on [multiple oral drugs], then IV therapy isn’t going to work.
X: I understand that. But I’m talking about your RNAi therapeutics that are being developed for commercialization.
AS: We broadly state that we anticipate RNAi-based therapeutics, targeting the liver will be used for hepatocellular carcinoma (HCC) and likely hepatitis, whether it’s hepatitis B or hepatitis C. Things that are for acute treatment, represent an unmet need, or for people who are really suffering. [Unlike] companies developing [RNA-based] ApoB or PCSK9 therapies, for familial hypercholesterolemics, we’d stop our studies at Phase I to show that LDL is lowered or HDL is raised and follow with a small molecule.
X: I don’t know if you saw, but I just did an interview with Alnylam CEO John Maraganore in which he’s calling this the ‘RNA decade.’ By that he means this will be the decade that RNAi demonstrates efficacy. Do you agree?
AS: I have no doubt that RNAi, if it hasn’t already, will absolutely demonstrate efficacy. It’s an incredible drug. What’s interesting about what we do is that the drug isn’t the problem. It’s the delivery of it. It’s almost an inversion of the standard problems in this industry. Chemists struggle with PK [pharmacokinetics] and they struggle with oral bioavailability, but they really struggle with target selectivity. In this field, the RNA is a natural mechanism. It’s incredibly potent. And we’re maturing it to make it even better with RNA chemistry. But the challenge is in pharmaceutical chemistry, the delivery of the molecule.
John’s absolutely correct, this is a time in which RNA will bear fruit. It will be limited only by how easily, and how safely, it can be delivered.
X: Do you worry about things getting a little too frothy RNAi? Because history with other new therapies, like monoclonal antibodies, there was tons of hype in the 1980s, followed by a long bust in the 1990s, before a few products got across the finish line.
AS: My background in molecular profiling was around when the Human Genome Project sequence came out in 2000 and 2001, and living through that bubble. What you realize is that the essence of the excitement is correct, and the reduction to practice may make it less-than-anticipated, but it’s still real. The same thing will be true of the RNA therapeutics space. There is a lot of expectation and anticipation. The reality will be somewhere between that and zero. We’d like to think because of the experience we have in our company that we have a clear line of sight on what’s practical within a certain time frame.
This will settle down. The acquisition of Sirna by Merck really set this thing off. We’re three years past that. I think in two more years, you’ll see this settle down, much like in the genomics space. In genomics, many of the opportunities consolidated into a few big players. The same thing will happen here. But the big companies like Merck, Roche, Novartis and Pfizer, that have committed to do this, ultimately will be there. Because of the long-term potential of the modality, not the immediate potential, but the long-term potential. It’s huge.
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