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

Merck hasn’t said much in public about what it’s doing in the field of RNA-based therapies, since it paid the jaw-dropping sum of $1.1 billion to acquire Sirna Therapeutics back in October 2006. So when I had the chance last week to sit down for an exclusive interview in San Francisco with Merck’s RNA therapeutics leader, Alan Sachs, I jumped at it.

What’s the big idea? RNA-based therapies hold the promise of silencing specific disease-related genes in ways conventional drugs don’t. They can potentially reach targets inside cells that have previously been inaccessible for a whole array of diseases.

This promise of a new wave of pharmaceuticals has enticed a generation of RNA-based drug companies to exploit this emerging science, including Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY), Vancouver, BC-based Tekmira Pharmaceuticals, and microRNA drug startups like Carlsbad, CA-based Regulus Therapeutics. So whatever Merck does has a big impact not just on its shareholders, but ripples through an emerging technology sector.

“This is a big story as it relates to RNA therapeutics in general,” says Regulus CEO Kleanthis Xanthopoulos.

There was a lot of ground to cover during my 45-minute interview with Sachs. Before diving in, I should provide a little background on him. He’s a former professor of molecular and cell biology at the University of California Berkeley. He joined Merck in July 2001, and has been given a lot of managerial experience running a couple of leading edge operations inside Merck, including Sirna and Rosetta Inpharmatics.

Here are the highlights of the conversation, edited for length and clarity as always. Merck spokesman Ian McConnell was also there for the meeting.

Xconomy: How did you first get exposed to RNAi?

Alan Sachs: At Berkeley, I worked on RNA post-transcriptional control. I joined Merck in 2001 to help start a clinical genomics group. At that time, we had just acquired [Seattle-based] Rosetta Inpharmatics, and so that first year I worked with [Stephen Friend, Rosetta’s founder] to build up a molecular profiling unit which included gene expression genetics, proteomics, [and] informatics of course.

Alan Sachs

Alan Sachs

Molecular profiling at Merck was broad. It extended beyond Seattle to research sites in Boston, West Point, PA, just outside of Philadelphia, and Rahway, NJ. Then as part of the work in Seattle, we were developing siRNA as a tool for [drug] target discovery using cell-based screens. Thanks to Stephen, we really had more of a therapeutic push. We initiated a partnership with Alnylam, it must have been around 2005.

Somewhere around the middle of 2006, we realized that Alnylam did a big deal with Roche, and we realized the area was heating up. We needed to do more than a collaboration per se. It ultimately led to the decision to acquire Sirna Therapeutics, which closed at the end of 2006.

So I was asked at that time to lead a new department at Merck called RNA Therapeutics. The Sirna site which you’re sitting in now is a geographic identifier. The department at Merck is called RNA Therapeutics. Sirna San Francisco is responsible for lead discovery and optimization. On the East Coast, we have a very large effort in RNAi delivery in West Point, PA. In Rahway, NJ, all of our manufacturing of oligonucleotides and delivery vehicles occurs. So RNA Therapeutics is split over three research sites within the company.

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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.

  • http://www.soundpharma.com Eric Lynch

    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.

  • http://www.xconomy.com/author/ltimmerman/ Luke Timmerman

    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.

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