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Merck’s Alan Sachs, on RNAi’s Big Challenge: Delivery, Delivery, Delivery

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of the things we are told are true are things we can confirm to be true enough to have value.

X: So I guess that means there’s a lot of hype here, right?

AS: There’s a lot of hype, and there’s a lot of ideas. But it’s not a straightforward problem. Injecting something in the bloodstream, leading to something appearing in the cytoplasm in the RNA-silencing complex, there are a lot of black boxes between those two steps. People who are entering the field start with a white paper. It’s much like people who started on targeted therapeutics years ago started with a white paper. If it were so easy, one would have to describe why so few examples exist. The same is true in the RNAi delivery process. You can write down the steps. You can write down what you think will happen. But then you have to put it in a 50-nanometer particle that’s safe and potent to deliver.

X: OK, so you have a graph that shows the 250 or so opportunities that you’ve evaluated. You’ve actually consummated a handful of collaborations? Have they been announced?

AS: No. But we’ve done a lot of evaluations in anticipation of collaborations. A few have proceeded to collaborations, and we don’t disclose those. We generally don’t unless it’s something unusual. There’s a lot of activity we’ve done that we can’t or choose not to disclose.

X: Why? Because of the competition?

AS: It’s a combination of the competition, and from our seat, a misunderstanding of the intent of the collaboration. That is, the field is so ready to put money in, we don’t want a Merck collaboration to be read as a sign of approval. The goals of our collaboration, after an initial period, are to develop something that is usable in the non-human primate.

Ian McConnell: It’s fundamentally about managing expectations.

X: On a different train of thought, what kind of delivery technologies do you like or think have promise at the moment?

AS: There are three main areas of delivery. First are lipid-based delivery systems. At the time of our acquisition of Sirna, they had successfully shown lipid-based delivery to the liver. Initially, it was through a collaboration with what is now called [Vancouver, BC-based] Tekmira. That was really the leading standard for the area. Several [applications to begin clinical trials] have been filed with the FDA. We spent a lot of internal research money and time on novel lipids. The liability of that platform is absolutely its safety. As you know from writing about the area, the biodistribution of lipid is focused toward the liver. Which has some indications that are useful for IV therapy, but it’s restrictive with respect to cancers and diseases of other organs.

We’ve also moved into two other delivery areas. One is polymer-based delivery. It’s exemplified by the Mirus delivery system that Roche fully acquired in 2008 for $125 million. That’s a really nice delivery system because it’s a targeted delivery system. But, it too, has liabilities as does every delivery system.

The last one is a conjugation to RNA system. You directly attach to the RNA molecule a targeting agent. It’s a defined complex, which for local delivery, works well. It can work well for systemic delivery as well. By local I mean something like injection into the joint.

X: What kind of data do you have in hand at this point to support your programs? What’s the best thing that happened in this department in 2009?

AS: There have been a lot of breakthroughs in the department. I think one thing I emphasize, and is good to capture, is that the value for this space is in the commercial product. That’s the long-term goal. The short to mid-term goal may be somewhat opaque to a biotech company, because they don’t have the same pipeline needs as someone like Merck or another large company. It’s about increasing … Next Page »

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  • Roger

    So Merck spends $1.1 billion for Sirna and Dr. Sachs talks mostly of target validation by RNAi. RNAi knockout of target genes can be done without spending $1.1 billion. He’s remarkably standoffish about RNAi pipeline therapeutics.

  • Nice article Luke thanks for putting it together. Alan is giving some great insights here after a drought of information on RNAi at Merck post siRNA. Very nice to see Alan devote so much time to the delivery aspects of this modality as being core to future success. His honesty throughout the article is refreshing. I hope Merck succeeds in their efforts surrounding RNAi therapeutics.

  • Roger–you raise a fair point. While I think this interview definitely shed some new light on Merck’s thinking about RNAi, I was hoping to pry loose some more specifics on how Merck is going to use this to create important new drugs.

    Eric–thanks for the comment. I’m curious if you have something more to add on Alan’s comments about the RNAi delivery challenge. Do you think biotech startups have been downplaying the delivery challenge too much?

  • Raj Bandaru

    Thanks for interviewing Alan. I heard Alan before in few conferences and he is absolutely right on money about delivery of RNAi. Unless we improve pharmaceutical properties and delivery of RNAi, it is extrmely difficult to think that these molecules will work in the clinic. I agree with Alan, we should not repeat same old mistakes by rushing the technology into clinic and downplay lessons learnt from similar technologies such as antisense and ribozyme. There is no rush and it is very important to prove new RNAi drug delivery technologies work first.

  • Eric Lynch

    Luke, in a word, yes. Anyone saying they can apply RNAi topically in a cream or just inject it IP or IV and bang it goes where it is needed and works well, needs to be questioned thoroughly.

  • RAM

    To me this looks like begining of the end for Merck’s siRNA efforts. When Merck brought in this technology, lot of people said “wow”. Many people who spent several years in medicinal chemistry had a serious doubts then and justifiably “cellular delivery” was a key issue. In fact I reckon that delivery is still a “achillis heel” for this technology. siRNA is a good tool and complementary to validate the target (other than gene KO) and that pretty much sums it up.