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Roche Has Problems – But RNA Interference Has More

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?

24 comments on “Roche Has Problems – But RNA Interference Has More”

  1. anchor says:

    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.

  2. CR says:

    @#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?

  3. anchor says:

    #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.

  4. LF says:

    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!

  5. Chris says:

    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.

  6. Mark says:

    Roche is selling off their Florence, SC API production facility, the one that makes Tamiflu.
    Big changes are a comin’!!
    Mark

  7. drug_hunter says:

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

  8. non-pharma chemist says:

    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.

  9. anony says:

    “I got 99 problems but RNAi ain’t one” – Roche 2011

  10. wait says:

    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.

  11. g says:

    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?

  12. Resveratrol Receptor says:

    @ 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.

  13. Just a VC says:

    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.

  14. anchor says:

    # 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!

  15. anana-mouse says:

    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

  16. pete says:

    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.

  17. Anonymous says:

    #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.”

  18. CR says:

    @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.

  19. goldilocks says:

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

  20. pete says:

    @ 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.

  21. Abhi says:

    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.

  22. Chris says:

    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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