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The NIH’s Drug Repurposing Initiative: Will It Be a Waste?

The NIH’s attempt to repurpose shelved development compounds and other older drugs is underway:

The National Institutes of Health (NIH) today announced a new plan for boosting drug development: It has reached a deal with three major pharmaceutical companies to share abandoned experimental drugs with academic researchers so they can look for new uses. NIH is putting up $20 million for grants to study the drugs.
“The goal is simple: to see whether we can teach old drugs new tricks,” said Health and Human Services Secretary Kathleen Sebelius at a press conference today that included officials from Pfizer, AstraZeneca, and Eli Lilly. These companies will give researchers access to two dozen compounds that passed through safety studies but didn’t make it beyond mid-stage clinical trials. They shelved the drugs either because they didn’t work well enough on the disease for which they were developed or because a business decision sidelined them.

There are plenty more where those came from, and I certainly wish people luck finding uses for them. But I’ve no idea what the chances for success might be. On the one hand, having a compound that’s passed all the preclinical stages of development and has then been into humans is no small thing. On that ever-present other hand, though, randomly throwing these compounds against unrelated diseases is unlikely to give you anything (there aren’t enough of them to do that). My best guess is that they have a shot in closely related disease fields – but then again, testing widely might show us that there are diseases that we didn’t realized were related to each other.
John LaMattina is skeptical:

Well, the NIH has recently expanded the remit of NCATS. NCATS will now be testing drugs that have been shelved by the pharmaceutical industry for other potential uses. The motivation for this is simple. They believe that these once promising but failed compounds could have other uses that the inventor companies haven’t yet identified. I’d like to reiterate the view of Dr. Vagelos – it’s fairy time again.
My views on this sort of initiative, which goes by a variety of names – “drug repurposing,” “drug repositioning,” “reusable drugs” – have been previously discussed in my blog. I do hope that people can have success in this type of work. But I believe successes are going to be rare.

The big question is, rare enough to count the money and time as wasted, or not? I guess we’ll find out. Overall, I’d rather start with a compound that I know does what I want it to do, and then try to turn it into a drug (phenotypic screening). Starting with a compound that you know is a drug, but doesn’t necessarily do what you want it to, is going to be tricky.

33 comments on “The NIH’s Drug Repurposing Initiative: Will It Be a Waste?”

  1. PPedroso says:

    I think that the Auranofin post a while ago is a perfectly good example of how this will work.
    The question is what kind of work was undertaken on the molecules by the companies that owned them. Is this information being passed on to the NIH?

  2. Rick Wobbe says:

    Everyone should also read Bernatd Munos’ comments following the article, which you will need to expand because John hasn’t called them out. (John, if you’re reading this, I’d like to respectfully suggest you do this) They offer a cogent and, IMHO, persuasive counterpoint to the argument against funding NCATS.

  3. Hap says:

    People seem to know a lot about how to find something that binds to or otherwise affects a target (although failures due to efficacy in P3 studies indicate that there a holes in such knowledge), but I didn’t think they knew as much about how to get something that behaves correctly in the body. Given that, choosing compounds that have known druglike properties but unknown secondary targets doesn’t seem like a bad idea. It certainly doesn’t sound like fairy time.
    I don’t know whether NIH will find enough to be worth the money it costs or worth what the money could have been spent on in more fundamental research. It does sound like something that might have been done with alternative plant-derived profit generators…urr, supplements.

  4. CMCguy says:

    This reminds me of the NCI efforts in 60s and 70s (War on Cancer?) that took compounds from “all comers” be it academic labs and even industry sources in order to discover new potential anti-tumor drugs. NCI had a few good assays, which they continued to expand, and believe lead to much understanding if only a few legitimate drugs.
    For this new venture Pharma collections may have a leg up on (possibly) being more drug like so if indeed NIH has good screening tools available that are not widely accessible there could be benefit even though seems to be a drift from the critical mission of supporting basic research activity.

  5. partial agonist says:

    Derek, the way this COULD work puts a twist on your last two statements “I’d rather start with a compound that I know does what I want it to do, and then try to turn it into a drug (phenotypic screening). Starting with a compound that you know is a drug, but doesn’t necessarily do what you want it to, is going to be tricky.”
    Why not start with a whole collection of compounds, pre-vetted for favorable PK at least for certain uses, and then use the collection in phenotypic screens. Then perhaps you have a hit that was at one point close to being a drug, that to at least a certain extent does what you want it to do. Eliminate toxic compounds from the collection, of course.
    People do this now with smaller collections of marketed drugs. With a much-extended collection it would work much better. Provided, of course, it wasn’t managed by the NIH… but that may be another discussion.

  6. Virgil says:

    IMHO this is a silly amount of money for such a small # of compounds. I suspect a lot of this has to do with drug companies milking the “collaboration with academia” angle, making it look like they’re cooperative, all the while keeping the “good stuff” out of the public eye. We in academia have absolutely no chance of ever accessing the big libraries under wraps inside big pharma. They’re all too protective of their pre-clinical candidates, and who can blame them? Nobody likes a shock during phase III because someone out there discovers an off target effect.
    One only has to look at Sirtris for a classic example of how this plays out…
    1) Can we have some SRT1720?
    2) The prep’ is published, just make some
    3) We made it and it doesn’t work. Can we have some of yours?
    4) No, the prep’ is published, just make some
    5) Can we have some of yours to compare, just to be sure we didn’t screw up the synthesis?
    6) Silence… then… actually we’re not interested in SRT1720 any more. Srt2104 is our new lead.
    7) Can we have some of that? The prep’ isn’t published.
    8) No.
    Contrast the above with this quote from GSK (Sirtris’ parent company) in a recent BBC piece entitled “The end of Drug Discovery” (http://www.bbc.co.uk/news/health-18095669)… “One of the things we have done is to be very public about when things go into the clinic. And we publish our results – we make our protocols available to reviewers when papers are submitted. Those sorts of things help to start better visibility of what is in the pipeline.”
    Anyone else see the contradiction here?

  7. Mike Pollastri says:

    Aurofin is indeed a good example! In that vein, I’m interested to see if anything could work for infectious diseases or parasitic diseases.
    A “failed” drug for cancer might be a really good drug for one of these neglected diseases. I would argue that NCATS is looking for rare/neglected disease treatments, among other things…and looking at endpoints other than what the original pharma clinical trials looked for might be fruitful…in the scheme of things, $20 million is not a lot of money to spend on a potentially large up-side.

  8. Rick Wobbe says:

    Derek, I’m not sure I understand what you mean by your last two sentences and how you liken or differentiate that from what NCATS is doing. If “do what you want it to do” means hitting a molecular target validated for your therapeutic area, the I supposenit’s fair to say that the NCATS’ “repurposing” initiatives are not doing that. However, I’d also suggest that there are many other useful things that one should want a drug to do (e.g. have decent PK, not be toxic, be orally available, be synthetically tractable and scalable, etc.) that NCATS would know about the compounds. Furthermore, the recent Swinney and Anthony NRDD paper suggests that knowing the target (to the extent that one can know it, which opens a whole other can of worms) hasn’t been the key to success we’d expected.

  9. David P says:

    The one part of this which I can see that might work is where a compound was dropped for business rather than scientific reasons. But how many of those are there, realistically?

  10. David P says:

    @Rick: Thanks for pointing out Bernard Munos’ comments to the article, interesting reading.
    Is there any kind of estimate of how many compounds they expect to look at?

  11. Former MedChemist says:

    The best way to discover a new drug is to start with an existing drug.
    Sir James Black

  12. newnickname says:

    I have heard from “retired” high level Big Pharma scientific leaders that there are many excellent projects that just can’t be funded and get shelved. One former VP of Research wanted to start a biotech for the purpose of licensing those projects and developing them within the biotech company, not that different from what is proposed here (academic v biotech; gov money v VC money; original purpose or repurpose wouldn’t matter). If you have ALL the data and can cherry pick, it doesn’t seem like a bad idea.

  13. Rick Wobbe says:

    An even larger issue LaMattina raised in the Forbes blog that Derek linked to is whether the ~$600 M budget proposed for NCATS, which would be used to essentially build and run a drug discovery unit at NIH, covering a lot more than just the drug repurposing grants, would be better invested elsewhere. Although I do not agree with it, he makes a cogent case, articulated by other influential people like Roy Vagelos, that says, essentially, it’s a waste of money. Issues worth thinking about.

  14. cirby says:

    This reminds me of a presentation I saw about ten years ago. Some guy decided that a failed “antibiotic” compound that was researched and discarded back in the 1960s should be retested for a number of possible therapeutic uses.
    So he talked his (small) university out of some research cash, ran trials for a number of possible applications over a year or two, and found… nothing, actually. It wasn’t toxic, but it also wasn’t good for anything at all. It didn’t kill any bugs, it didn’t reduce blood pressure, didn’t make hair grow – nothing. If it wasn’t so expensive to make, it would have made a dandy placebo.
    By the time he got to the end of his hour-long presentation, the attendees were ready to kill him for wasting their time.

  15. anon says:

    Post office, take-two.

  16. patentgeek says:

    As noted by #11:
    ‘The most fruitful basis for the discovery of a new drug is to start with an old drug’, Sir James Black, Nobel Laureate 1988 in Physiology and Medicine’
    This was the opening quote to an article about this approach in J. Med. Chem. a few years back:
    J. Med. Chem. 2004, 47, 1303-1314.

  17. cookingwithsolvents says:

    Science consisting of “solutions looking for a problem” is rarely productive.

  18. Electrochemist says:

    Auranofin is not a good example, IMHO. It is a drug that has already received regulatory approval and is on the market. The regulatory hurdles (i.e., clinical studies) needed to add a new indication to an approved drug are much less significant than those that will be required to get one of these failed Phase II compounds registered.
    Also consider that the patent clock is well underway for these compounds, making the length of time a company who submits for marketing authorization will have to recoup Phase III costs limited.
    “Terminated for business reasons” can mean a lot of things: short projected patent life, unfavorable licensing issues with co-innovators, generally poor IP position, high cost of manufacturing due to synthetic complexity, etc.

  19. Electrochemist says:

    As for Bernard Munos’ comments, I would be interested in learning of drugs approved by the FDA on the basis of 2 (and only 2) pivotal trials. While that may be possible in theory, and while there may be examples where the NDA focused on a limited number of trials (10 or less), the agency is well aware of all of the other trials involved in development (e.g., from end-of-Phase II meetings), and expects a substantial body of clinical data to be available at submission.
    Drug development is an expensive, high-risk undertaking. If a sustainable business model were possible for repurposed drugs, major Pharma companies would have already pursued this line (given the thin pipelines they’ve had to contend with in recent years).

  20. Electrochemist says:

    As for Bernard Munos’ comments, I would be interested in learning of drugs approved by the FDA on the basis of 2 (and only 2) pivotal trials. While that may be possible in theory, and while there may be examples where the NDA focused on a limited number of trials (10 or less), the agency is well aware of all of the other trials involved in development (e.g., from end-of-Phase II meetings), and expects a substantial body of clinical data to be available at submission.
    Drug development is an expensive, high-risk undertaking. If a sustainable business model were possible for repurposed drugs, major Pharma companies would have already pursued this line (given the thin pipelines they’ve had to contend with in recent years).

  21. Neuropharm says:

    Everyone on here seems to negative about this idea.
    It seems to me like it might make sense to test these compounds on a battery of CNS indications. Doing the anxiety, depression, epilepsy, obesity, learning & memory ect behavioral batteries + perhaps a few disease models really wouldn’t be all that expensive. Since we really have no clue how most CNS disorders work or how what systems feed into them, all work in these areas is pretty much a fishing expedition anyways. Screening compounds with good PK and known biological activity really wouldn’t be a bad starting point for that sort of work.

  22. anonymous says:

    #6: GSK is full of contradictions and hypocracy which comes from the very top. Perfect example of “believe what I say, not what based on what i do” Sirtris is most extreme.

  23. watcher says:

    This NIH initiative will largely be a waste of time and money. The $20 million is just a drop in the bucket for what would be needed for any one or two compounds to be evaluated, let alone a greater number. It shows just how little those in NIH who conceive of these concepts actually know how Pharma works and under-appreciate the efforts typically expended in Pharma to rescue “failed” compounds. The quote from Dr. Vagelos is dead-on; what is most needed in Pharma are more leaders like him. On the other side, with concepts like this one, it increasinly looks as if much of NIH’s funding is absolutely wasted, and their allocation in the Federal budget should be drastically cut.

  24. Anonymous says:

    Anyone ever heard of thalidomide? 50 years on and it’s still being retooled.

  25. Chris D says:

    Even better than a few dozen new compounds from pharma shown to be safe in the clinic are the approx. 1000 FDA approved drugs that are widely available in various screening collections. These have been available for repurposing for years, and in fact researchers like Camille Wermuth have been using this strategy (e.g. his Selective Optimization of Side Activities) for years. Maybe someone can comment on the success of these ventures? Regardless, is this what the NIH considers a “signature initiative”? Am I missing something??? It would seem that Vagelos is right on the money.

  26. Morten G says:

    Where is the list of compounds?

  27. SP says:

    Isn’t Electrochemist @18-19 making the case for the NIH supporting this? Say you have something that might improve human health but can’t be supported by a for-profit model for the “business reasons” indicated. In that case, isn’t it worth a public investment to bring something to market that a company won’t touch because they can’t make money? That sounds like the very definition of the purpose of publicly funded research.
    As for this @ 23: “how little those in NIH who conceive of these concepts actually know how Pharma works”- maybe 20 years ago that was the case, but this argument went off patent long ago.
    Finally, none of the current $600M under NCATS is newly appropriated funding, just redirected from existing initiatives- the vast majority is rolling the CTSAs under the new center. If you want to argue against those previously existing programs, that’s fine, but it’s not like Congress opened the spigot to the tune of half a billion dollars.

  28. emjeff says:

    This kind of thing goes on all the time within industry. To me, the biggest sign that a compound has no value is when it is moved randomly from indication to indication. The compounds that the NIH gets have likely gone through this process already and come up empty.

  29. Jose says:

    I can’t help but wonder if thalidomide-era drug candidates are simply a different kettle of fish from modern hyper-optimized leads. I suspect today’s assays bias out most everything with really interesting, and potentially useful, off-target activity….

  30. Electrochemist says:

    @ #27 (SP) – My assumption is that NIH will (at best) only be able to organize small Phase II studies to examine efficacy for new indications. I do not believe that the NIH understands or is capable of meeting the current FDA requirements for registering a new molecular entity. If (by some miracle) a use for one of these molecules is found, it will require partnering with industry to get the molecule registered. I do not believe that there is any business model under which this scenario would be successful (even including tax incentives).

  31. SP says:

    There are mechanisms under the Orphan Drug Act for granting patent protection in exchange for conducting clinical trials of a generic or off-patent compound. (Perhaps not the example you want to follow, but see the case of Makena.)
    And anyway, even if composition of matter has expired, any new discovery resets the clock on use- not as strong as composition but still something.

  32. Chris D says:

    @Morten G: Prestwick Chemicals has sold a large collection of FDA-approved drugs for years, but I just remembered that the NIH itself has a large collecton that can be accessed:
    http://tripod.nih.gov/npc/
    What is the big advantage of a few dozen failed compounds over the 2750 approved compounds already accessible at NCGC? I’d love to know, Dr. Collins.

  33. SE says:

    I am pretty sure any of the groups trying to discover a hit/ lead/ drug for the 7000 or so rare diseases would love $20M to move their project along. So how to select which compounds to test versus which disease /target? Its seems so random to me.
    Even the use of FDA approved commercial screening libraries in academic hands over the past 5-6 yrs is kind of haphazard, while it leads to hits these are potentially artifacts of screening in vitro (http://www.ncbi.nlm.nih.gov/pubmed/21607776) and I am not aware of the in vitro hits following through in vivo.
    While its certainly worthwhile looking at failed compounds I think the screening should be prioritized by some computational or informatics effort (there, I will ignite another fire)..so that money and compounds can spread further.
    If I had the $20M I would contract the screening out and be very picky about which compounds were tested against which targets – using models etc.
    Run it like a virtual drug discovery company, like many of the little companies currently trying to find a cure for their rare disease at present.
    I think there is also a lesson in this for Bill and Melinda Gates, WHO, NIAID etc and others funding work on malaria and TB (as well other neglected diseases) in which for the $100M’s invested there is a wealth of screening hits but we are yet to see any drugs approved. Why not screen failed drugs?
    When will a vendor take this as a business opportunity and plate out failed drugs as a library, (Microsource, Selleckchem etc) so that we do not have to wait for the NIH.

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