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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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November 17, 2010

Roche Has Problems - But RNA Interference Has More

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Posted by Derek

So Roche is (as long rumored) going through with a 6% headcount reduction, worldwide. That's bad news, but not unexpected bad news, and it certainly doesn't make them stand out from the rest of big pharma. This sort of headline has been relentlessly applicable for several years now.

What surprised me was their announcement that they're giving up on RNA interference as a drug mechanism. That's the biggest vote of no-confidence yet for RNAi, which has been a subject of great interest (and a lot of breathless hype) for some years now. (There's been a lot of discussion around here about the balance between those two).

That's not the sort of news that the smaller companies in this space needed. Alnylam, considered the leader in the field, already had over $300 million from Roche (back in 2007), but so much for anything more. The company is already putting on a brave face. It has not been a good fall season: they were already having to cut back after Novartis recently thanked them for their five-year deal, shook their hand, and left. To be sure, Novartis said that they're going to continue to develop the targets from the collaboration, and would pay milestones to Alnylam as any of them progress - but they apparently didn't feel as if they needed Alnylam around while they did so.

Then there's Tekmira, who had a deal with Roche for nanoparticle RNAi delivery. They're out with a statement this morning, too, saying (correctly) that they have other deals which are still alive. But there's no way around the fact that this is bad news.

What we don't know is what's going on in the other large companies (the Mercks, Pfizers, and so on) who have been helping to fund a lot of this work. Are they wondering what in the world Roche is up to? Looking at it as a market opportunity, and glad to see less competition? Or wishing that they could do the same thing?

Comments (23) + TrackBacks (0) | Category: Biological News | Business and Markets


COMMENTS

1. anchor on November 17, 2010 12:34 PM writes...

Companies such as Merck, Pfizer (with a plenty of $$ invested or wasted) should come out in open and confess that gene silencing (siRNA, RNAi or whatever) are helpful tools that accelerate the drug discovery (proof of concept etc.) process and by in itself will not be a drug. This will put to an end all the hype around this field.

Permalink to Comment

2. CR on November 17, 2010 12:48 PM writes...

@#1:
"...(siRNA, RNAi or whatever) are helpful tools that accelerate the drug discovery (proof of concept etc.)"

Do they really accelerate drug discovery? Or are they just helpful tools?

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3. anchor on November 17, 2010 12:57 PM writes...

#2 I would like to think a bit of both. Say for e.g. a critical protein is involved in a key disease can be "gene silenced" (complementary to gene KO studies) that gives you a very quick "proof of concept" studies. From that point on it just opens up lot of opportunities! Really, to think about it.

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4. LF on November 17, 2010 2:05 PM writes...

RNAi is a useful tool in any academic or industry lab. I do not think anyone can be sure about its prospective as drug at this moment. However I think its time will come!

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5. Chris on November 17, 2010 2:50 PM writes...

One of the leaders in this field Calando Pharmaceuticals has a phase 1 siRNA study going on that has shown promising results. Their RNA IT-101, that is outlicensed to Cerulean, has also shown positive results. So what Roche does doesnt have to mean anything for the other players in the field.

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6. Mark on November 17, 2010 3:13 PM writes...

Roche is selling off their Florence, SC API production facility, the one that makes Tamiflu.

Big changes are a comin'!!

Mark

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7. drug_hunter on November 17, 2010 4:25 PM writes...

siRNA was so 2000s. On to Micro-RNA !

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8. non-pharma chemist on November 17, 2010 5:10 PM writes...

I'm not in pharma so I haven't been keeping myself abreast of developments in this that or the other nucleic acids. However, one friend of mine formerly worked at one of the companies with the siRNA technology. Another friend formerly worked at the company that bought that same technology. What did I hear from the purchasing company friend? "It doesn't work". Well, that's how it goes with the billions of $$ spent to "insource" drug candidates.

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9. anony on November 17, 2010 5:39 PM writes...

"I got 99 problems but RNAi ain't one" - Roche 2011

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10. wait on November 17, 2010 6:06 PM writes...

Wait a minute, didn't some group reported a ultra-stable siRNA last year on Nature and showed it worked in apes upon injection? And I think Weinberg has a Nature Biotech paper this year using the same technology on a mouse cancer model. I was really excited when I read those two papers.

#2:According to those two papers I mentioned, seems like they are ready-to-use drugs.

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11. g on November 18, 2010 12:28 AM writes...

I've heard that siRNA is going to be difficult to develop into drugs, if at all, but I am not sure what the major limitations are. I can speculate about it (off-target side effects, targeting, etc), but I'd like to hear from someone who specifically is aware of the issues with siRNA drug development. Does anyone know about them?

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12. Resveratrol Receptor on November 18, 2010 1:54 AM writes...

@ 11. i'm an academic but we've do collaborations with the big dawgs of siRNA/ASO pharm. in my hands the big problem with antisense is 1) they piss macrophages/other innate immune cells off (TLR3 receptor activation) and 2) basically can only be counted on to hit liver targets. for those unconcerned with drug development or proteins not in liver or fat they are very handy indeed. much faster than making KOs (1-2 months) per in vivo study.

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13. Chris on November 18, 2010 3:07 AM writes...

Have a look at www.calandopharma.com


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14. Just a VC on November 18, 2010 8:47 AM writes...

IT-101 isn't an RNAi product, it's a polymer-microparticle version of a known chemothereapeutic (a topoisomerase-1 inhibitor). So the success of IT-101 doesn't speak to the efficacy of RNAi as a therapeutic modality.

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15. anchor on November 18, 2010 8:52 AM writes...


# 14, agree with you and IT-101 is a delivery vehicle that involvs nanaotubes, another technological jargon that has been around for years and yet to deliver!

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16. anana-mouse on November 18, 2010 9:45 AM writes...

A colleague who works with siRNA for a major player told me that they did safety on rhesus and cyno's and all of them died, for reasons that they have yet to figure out

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17. pete on November 18, 2010 12:51 PM writes...

Although I'm not privvy to all the gory details of why wider therapeutic indications for interfering RNAs has apparently crashed, I find the news quite depressing. As a MolBio-type, I'm intrigued at the clinical possibilities of altering gene set expression via modulations in siRNA, microRNA, lincRNA abundance. Seems to me that individual targeting of RNAs from these classes could be a far more surgical approach to disease intervention than going after transcription factors, chromatin/DNA-modifying enzymes (acetylases, etc), TF folding/stability pathways and so on.

Clinically-speaking, if siRNAs have "issues", who's to say that microRNA or lincRNA approaches won't also suffer from a much-reduced horizon of possible uses. I sincerely hope I'm wrong about that.

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18. Anonymous on November 18, 2010 1:06 PM writes...

#17: "Seems to me that individual targeting of RNAs from these classes could be a far more surgical approach to disease intervention than going after transcription factors, chromatin/DNA-modifying enzymes (acetylases, etc), TF folding/stability pathways and so on. "

Not really - here is cut and paste from Nat Struct Mol Biol. 2010 Oct;17(10):1169-74.

"Each miRNA may regulate hundreds of genes to control the cell's response to developmental and other environmental cues. The best way to understand the function of a miRNA is to identify the genes that it regulates. Target gene identification is challenging because miRNAs bind to their target mRNAs by partial complementarity over a short sequence, suppression of an individual target gene is often small, and the rules of targeting are not completely understood."

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19. CR on November 18, 2010 1:16 PM writes...

@10: Wait...
"#2:According to those two papers I mentioned, seems like they are ready-to-use drugs."

So something that shows efficacy in apes and mice are now classified as "ready-to-use drugs". Show me they work and are well tolerated in humans, then make that claim...

The original claim was they "accelerate" the drug discovery process and I have yet to see that.

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20. goldilocks on November 18, 2010 2:33 PM writes...

Has any company that Christoph Westphal has been involved in produced a successful drug?

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21. pete on November 18, 2010 3:11 PM writes...

@ 18 Anonymous
Point taken - I probably shouldn't have said "far more surgical approach" as I realize there's evidence of partially redundant regulation of gene sets by different ncRNAs, as well as variability in the extent to which any given microRNA affects expression of different genes. Still, there's a lot of intriguing literature about the relatively selective (to my mind) consequences of manipulating specific microRNAs in various disease models -- take Bob Weinberg lab's pubs in cancer metastasis models, for example.

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22. Abhi on November 22, 2010 1:10 AM writes...

I happened to hear Mark Davis at Northwestern couple of days back. He is the key person behind Calando's systemic cyclodextrin based targeted siRNA nanoparticles (although he told that he is no longer associated with Calando). He was talking about the various aspects siRNA ddelivery and he really touched upon a variety of aspects.. Good talk.. However, the dose of their targeted siRNA nanoparticle that seemed to show cytostatic effect (not regression) in humans is 0.75 mg/kg. That really disappointed me. I understand that it depends on several things, but even then it was disheartening for me... Let's see what microRNAs get to us.

Permalink to Comment

23. Chris on December 5, 2010 2:35 PM writes...

Abhi- Im not an expert but I guess a relevant question before drawing a conclusion on Calandos sirna is what the max tolerated dose is. According to phase 1 study they have now tested max tolerated dose over a 2 month period ending November 2010.
Last time they gave an update on phase 1 no toxicity had appeared so far if I remember correct.

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