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Drug Repurposing: How Often Does It Work?

Here’s an article that will not be popular among some constituencies. It’s in a special issue of the Journal of Chemical Information and Modeling, devoted to how these disciplines have responded to the coronavirus pandemic. And in it, Aled Edwards of the Structural Genomics Consortium surveys past attempts at drug repurposing and arrives at a conclusion that others in the field have as well: it rarely works the way you’d hope.

Indeed this paper says that it has been “unable to document a single instance of a drug approved for clinical use where the idea for the clinical trial derived first from a virtual or lab-based screen of old drugs“. And the other linked paper above noted that despite all the press, there have been “impressively few data on success rates” for the approach (which it goes on to try to provide). And as is always the case, success depends on how you define it. I agree with Edwards that using the stringent definition given above, that the success rate is likely zero. Unfortunately, that definition is what popular press stories about drug repurposing tend to play up.

The successes that have come along are more modest. Look at remdesivir, for example. Although its real utility in the pandemic is still being defined, I’m willing to stipulate that it’s a useful drug (although, sadly, not the “game changer” that everyone has been looking for). But trying it against the coronavirus did not require a random screen – remdesivir is expected to have some level of activity against basically every RNA virus that comes up, due to its mechanism targeting viral-RNA-dependent RNA polymerase. The same goes for the Emory/Ridgeback/Merck compound (MK-4482) that’s going into trials now – it’s shown strong activity against a whole range of RNA viruses, because it causes an “error catastrophe” in the same viral RNA replication step.

Compounds like this are great to have on the shelf, because of that broad-spectrum activity. At the same time, there’s a definite “jack of all trade, master of none” problem with broad-spectrum antiviral drugs. When you look at the field, the only time we’ve ever really been able to control or cure any viral infections with small molecules, it’s been with a cocktail of drugs that hit several mechanisms at once (HIV, HepC). Which makes perfect sense, given viral mutation rates. I don’t see how a single small molecule drug is ever going to be an effective antiviral by itself, at least not if it’s working by the mechanisms we know now. And in the case of remedesivir, or ribavirin, or AZT or any other broad-spectrum-ish antiviral you can name, the chances of a single agent hitting a knockout blow are basically zero. They’ll do some good, and they’ll do even more good if they can be combined with a drug with a completely different mechanism such as a viral protease inhibitor. (Note also that broad-spectrum viral protease inhibitors are a lot thinner on the ground, at least ones that aren’t cytotoxic at the same time!) All that is to say that calling remdesivir a “repurposed” drug isn’t quite accurate. It’s being used for its intended purpose: to mess up viral RNA replication. Next RNA virus that causes trouble, we’ll try it on that one, too.

And not just with antivirals – if we have some mechanistic understanding of a drug’s actions, it makes perfect sense to keep an eye out for similar applications that might turn out (you see this a lot in oncology, for example). Likewise, if a known drug has unexpected side effects and unusual activities when dosed in human patients, it makes perfect sense to try to figure out what’s causing these and add that information to the mechanistic understanding pile. That’s exactly what happened with thalidomide and led to its use as an anticancer drug – for that matter, intensive study of why thalidomide caused the disaster it did in human usage is what’s led to the modern field of targeted protein degradation, opening up a whole new area of medicinal chemistry and chemical biology. So one could call this repurposing as well, but it’s still very different from deliberately screening a collection of known drugs, hypothesis-free, and hoping for something interesting to happen. Because it rarely (if ever) does.

But mechanistic understanding is a sliding scale, too. All too often, we don’t understand the diseases understudy well enough to be sure about what we’re seeing. This example from today’s new paper is (sadly) very instructive:

In the early 2000s, the NIH’s Neurodegenerative Drug Screening Consortium launched what was among the first systematic repositioning initiatives.(9) Ahead of their time, they assembled approximately 1000 FDA-approved compounds, including many antibiotics, with the idea of identifying new uses for old drugs, and described the effort in a set of influential papers.(10)

The experiments were designed well; compounds were sent to many investigators blinded for testing in their various models. When the assay results were unblinded, several antibiotics, including minocycline, an antibiotic that had previously shown activity in other models of neurological diseases, and ceftriaxone, a cephalosporin antibiotic, showed great promise in a number of assays for amyotrophic lateral sclerosis (ALS). It was a brilliant concept, a beautiful experiment, and a beautiful result. . .

. . .Fast forward to 2014, when the results from the clinical testing of ceftriaxone in ALS patients were published,(11) and that story did not end well. Not only was ceftriaxone ineffective in ALS, but it actually caused serious adverse events. The clinical testing of minocycline in ALS also failed to show efficacy in patients.(12) However, this lesser known part of the story had little impact on the repositioning horse, which had long since left the stable.

Repurposing is hard because drug discovery is hard, because understanding human biology and human disease is hard. There are no shortcuts.

77 comments on “Drug Repurposing: How Often Does It Work?”

  1. cynical1 says:

    “I don’t see how a single small molecule drug is ever going to be an effective antiviral by itself, at least not if it’s working by the mechanisms we know now. ”

    Acyclovir/Valacyclovir.

    1. Rasti says:

      yes, you can effectively suppress the viral replication with acyclovir (the same is true for tenofovir in HepB) but you will not get rid of it, it will still remain part of your genome and be the reason for recurencies

      1. cynical1 says:

        From the post – “When you look at the field, the only time we’ve ever really been able to control or cure any viral infections with small molecules, it’s been with a cocktail of drugs that hit several mechanisms at once (HIV, HepC). ”

        You do not need a cocktail of drugs to suppress HSV-1 and HSV-2.

  2. Matthew says:

    I’ve wondered why fringe people push drugs that don’t really seem to work (like HCQ or ivermectin) and it seems its mostly a psychological thing with them.

    1. Anthony Burnetti says:

      Ivermectin deserves careful study. It has shown antiviral activity before, is extremely safe, and the preliminary data is actually quite promising.

      1. Matthew says:

        It has been carefully studied, in Bangladesh and Egypt. Results were quite lukewarm.

        1. Cuibono says:

          Lukewarm? or underpowered? Studied in Iran and excellent results.

      2. Davo says:

        Very safe…as long as you’re not a Collie!

      3. Kevin C. Smith says:

        Ivermectin works well in vitro, but the in vitro MIC cannot be achieved systemically.
        Using 1% ivermectin cream [eg Soolantra, Rosiver], one can obtain local levels exceeding the MIC for SARS-CoV-2, so [reasoning that SARS-CoV-2 first infects nasal and upper airway tissues] I have been deeply swabbing out my nasal passages with this on a Q-tip twice a day for the past couple of months. Easy to do, doesn’t bother me, might help, unlikely to hurt.

    2. Driven says:

      They’re the same people who were banging on about UFOs, fluoride, and believed that “radiation” from Fukushima was going to cross the Pacific and poison our precious bodily fluids food.

      –> no edit, so lesee if it allows simple html tags

    3. Frank Dean says:

      “fringe people.” Nice one, indeed, very nice.

  3. John Wayne says:

    The choir is happy with what the preacher is saying.

    Drug repurposing a great idea that has yet to deliver much. This isn’t a failure, this is the job.

    1. Charles H. says:

      Drug re-purposing is a marvelous idea. But doing it blind isn’t. Someday we’ll understand things well enough to do it from first principles, but that’s not today, and likely not this decade. (Well, likely not the next decade, either.)

      What’s good right now it looking at drugs we know are safe and checking the ones whose mechanism of action looks appropriate. That’s a bit broader than Derek was listing in his examples, but it sure isn’t wide open. Consider when you might use aspirin as the drug of choice. I’m no medic, so I don’t have deep knowledge, but you might use it to calm inflamation, to ease pain, to prevent blood clots, etc. Each case you need to check carefully. I don’t use aspirin to calm inflamation, because I’m subject to nose-bleeds. So I prefer ibuprofen. Some people use acetaminophen to ease pain, but that doesn’t work for me in safe doses. No deep understanding required, but this affects re-purposing. If you understand things more deeply, you can see options that aren’t visible to a non-expert, and you can also see things that need to be avoided. If you understand things deeply enough, you can estimate good chances from chemical structure…but we generally aren’t there yet. Still, we see more deeply than we did a few decades ago.

  4. Peter Kenny says:

    Dose is one factor that drug repurposing advocates really do need to think about a bit more carefully and I think Paracelsus would have been more aware of the problems than the folk peddling Machine Learning as the solution to everything appear to be. I would invite anybody touting a 10 μM inhibitor of SARS-CoV-2 main protease as a cure for COVID-19 to consider both the difficulty and desirability of achieving the sustained free plasma levels required for meaningful engagement of the target (which is intracellular). I have linked “How not to repurpose a ‘drug’ ” as the URL for this comment which may provide some light relief those following this post (Lady Bracknell expresses an expert opinion on N-alkylpyridines).

    1. Antti says:

      Oh my goodness, that article made my day! We Finnish consume a fair bit of ammonium chloride in our salty licorice sweets (salmiakki, an acquired taste), so maybe someone should run the numbers on our COVID-19 infection & mortality rates vs. sweet tooth habits. I see good times ahead for Finnish confectionery producers… And if salmiakki alone doesn’t do the trick, why not take it with a chaser of mouthwash!

      The authors also manage to contradict themselves by referring to metabolic alkalosis in the text, and to acidosis in Table 1 re ammonium chloride. Quality authorship & review at work here, definitely.

      1. Peter Kenny says:

        Hello Antti, I’ve enjoyed salty licorice sweets in Sweden (I used to visit occasionally when I worked at AstraZeneca) and I acquired the taste very quickly. I don’t know how similar what I had there is to your salmiakki but, knowing my tastes, I’m guessing that I’d like it (especially now that I know it’ll save me from COVID-19). Of course, I also know that it is uncouth to assume similarities between Swedes and Finns. I used to joke about my Swedish friends gorging themselves with rotted herring in their summer houses and thrashing each other with birch twigs in the sauna. With respect to the sauna, they would say “that’s the Finns” and I have come to the conclusion that Finland (which I have never visited) is way more fun than Sweden.

        1. Some idiot says:

          As a non-Dane, who lives and works in Denmark (and has a Danish wife), I get the feeling that most Danes believe that _anywhere_ is more fun than Sweden! I must admit that I do not agree, and that it sounds more to me like squabbling between siblings…!
          🙂

      2. Some idiot says:

        Wonderful article! And as a non-Nordic married to a Dane, I can certainly comment on the salted liquorice, but from the other side of the table, as it were… I can still distinctly remember the sensation when enthusiastically chewing on a piece of liquorice my then-fiancée had given me, thinking it was “normal”, ie “sweet liquorice”, and the conflicting signals that were wizzing through my brain, from “spit the damn stuff out!!!” to “be polite; you still want to marry her, don’t you???”

        I think I ended up with the cautious comment along the lines of “this is normal liquorice here, is it?”, to which she replied “yes, lovely salt liquorice”, to which I added a mental note, underlined thrice, to enquire more specifically on the type of liquorice in the future before chomping enthusiastically on it…!

        🙂

        1. DutchUK says:

          This reminds me of being a new arrival in the UK and being offered coffee. Which turned out to be Nescafe. That was 1999, it’s better now (the coffee that is). BTW salmiak is a treat in the Netherlands too, and yes I have been guilty feeding it to unsuspecting foreigners.

      3. Red Fiona says:

        A Mexican living in Finland introduced me to chili salted liquorice. It was an experience!

    2. Marc says:

      >> The main challenge to a proposal that cetylpyridinium chloride be repurposed for treatment of COVID-19 is that the compound does not appear to have actually been conventionally approved (i.e. shown to be efficacious and safe) as a drug for dosing as a nasal spray, mouth wash or gargle.

      This puzzles me; perhaps I’m missing something. Cetylpyridinium chloride (0.05%) is the active ingredient in Cepacol mouthwash, which has been on the market for decades and is recommended by many dentists. Is the quoted statement an oversight, or was the author saying that millions of bottles of the stuff have been sold and used without approval? (Either could be true; I’m genuinely curious.)

      1. Peter Kenny says:

        Hi Marc, cetylpyridinium chloride is generally considered to be safe but I’m not aware of any clinical trials in which it has been demonstrated to be efficacious (and the authors didn’t cite any such studies). I’ve linked Pottel et al (2020) The activities of drug inactive ingredients on biological targets. Science 369:403-413 as the URL for my comment.

      1. István Ujváry says:

        Here is an actual study in vitro:
        “Several formulations with significant SARS-CoV-2 inactivating properties in vitro support the idea that oral rinsing might reduce the viral load of saliva and could thus lower the transmission of SARS-CoV-2.”
        https://academic.oup.com/jid/article/222/8/1289/5878067
        I have stocked several mouthwashes available with these AIs in Hungary. I have been using them before and after visiting crowded places.

  5. Bryon says:

    I think that Apilimod, which came from library screenings, is in phase 2 trials. Hopefully we’ll see the pattern broken.

  6. Barry says:

    Depends on how you define “repurposing”, of course. Sildenafil was developed as a treatment for angina, but found a blockbuster market as “Viagra”. The Minoxidil/”Rogaine” story is similar.
    There was a time when people seriously advocated screening massive small molecule collections for drugs. Most have realized that what we’re looking for are not drugs, but leads from which we may then get to drugs. And that has changed our criteria for the compounds in those screening collections.

    1. Peter Ellis says:

      Well indeed, what counts as “repurposing”? Is dexamethasone repurposing? Or is it simply being used for the same purpose as ever – modulating inflammation? It strikes me that if a given drug works by the same mechanism in this disease as it does in others, then that’s purposing rather than repurposing.

      In other words, we only call it “repurposing” if we think it probably won’t work, and surprise surprise it usually doesn’t.

      1. WST says:

        Repurposing would be probably the following news story

        Avastin (cancer drug) to replace costly Lucentis (ophthalmo drug),
        http://www.reuters.com/article/us-novartis-roche-lucentis/france-fines-roche-novartis-444-million-euros-in-ongoing-eye-drug-clash-idUSKBN2601SD

        1. eub says:

          Not really. That was an anti-generic move that fell flat. Avastin always worked against wet MD and was used off-label, but because it faced generic (biosimilar) competition, the manufacturer put a twist on it and got that approved for MD instead.

          Avastin (bevacizumab) is an antibody against VEGF (vascular endothelial growth factor), so Avastin makes mechanistic sense against wet MD, and off-label showed effectiveness. Lucentis (ranibizumab) is a fragment of the same antibody from the same manufacturer, on the premise that it would have better tissue penetration. It works fine, but it doesn’t seem to be any better except in patent term.

    2. johnnyboy says:

      Sildenafil was never actually approved for hypertension, and wasn’t even close to it, when that other effect manifested itself. Minoxidil did get approved for hypertension, but the hair growth effect was observed in treated patients, so it wasn’t a great scientific stretch to re-use it for that purpose. I think how the authors here are defining ‘re-purposing’ is taking a drug approved for one purpose, and based on mechanism of action, hypothesizing and testing whether it would work for a different purpose. That’s a bit higher bar than just getting it approved it for a side effect that is already apparent.

      1. Barry says:

        If I understand them correctly, the authors are not talking about taking an existing drug and extending it to a new indication based on mechanism of action. Rather, they’re talking about virtual screening of the structures–blind to mechanism of action–for (calculated) binding affinity to new targets.
        Sildenafil doesn’t fit this notion of “repurposing”. It just got a new market because its target (PDE4) was found to be relevant to another disease.

      2. Another Kevin says:

        Sildenafil is pretty routinely used (off-label?) for pulmonary artery hypertension. I believe that a wilderness EMT’s high-altitude kit includes acetazolamine (carbonic anhydrase inhibitor – the change to carbon dioxide metabolism promotes the breathing reflex); sildenafil (or tadalafil, similar mechanism of action) + furosemide (a loop diuretic) for pulmonary edema/pulmonary artery hypertension; and dexamethasone (for cerebral edema). I know, though that at least some of these uses are off label.

        Another off-label use that’s been successful is adding an H2 blocker to the cocktail for treating anaphylaxis, either because it potentiates the H1 blocker you’re already giving, or because of its off-target effect on atypical histamine receptors. Moreover, glucagon is routinely administered in that setting because of its off-target inotropic and chronotropic effect on the heart. So there are a whole bunch of drugs being administered to anaphylactic patients that were originally developed for other indications (diphenhydramine as a sedative, ranitidine as an antacid, dopamine for Parkinson’s, …)

        epinephrine, 200-500 microgram, possibly repeated at 10-15 minute intervals
        supplemental oxygen as needed
        fluid resuscitation to maintain a normotension, possibly augmented by pressors such as dopamine
        albuterol for airway management, or possibly aminophylline 5-6 mg/kg IV over 20 min, plus augment with glucagon 1 mg IV in patients taking beta-blockers
        simulaneous H1 + H2 blockade (diphenhydramine 1-2 mg/kg up to 50 mg + ranitidine 1 mg/kg or a dose equivalent of another H2 blocker)
        corticosteroid, such as hydrocortisone 5 mg/kg IV

    3. Daren Austin says:

      I think repurpose is defined in the absence of clinical data. Observation of an unintended AE (sildenafil) isn’t the same as a preclinical screen. Plenty of examples of clinical data leading to new hypotheses which may go on to be validated. But pure preclinical screening is not promising.

  7. Good to see the repurposing debate getting some oxygen; critical all the more welcome, it advances the discussion in a rational way. Also good to see the counterexamples in the comments.

  8. Christophe L Verlinde says:

    There may be no cases of drug repurposing after a drug was approved for a particular condition but the real champion of repurposing was the late Dr Paul Janssen (for the younger generations here is the link to his wikipedia entry https://en.wikipedia.org/wiki/Paul_Janssen) who decided that EVERY compound synthesized in his company had to be tested in ALL of the screens of the company, not only the screen of the program it was synthesized for. This is how he and his scientists created 80 new medicines, four of which are on the WHO list of essential medicines, an absolute world record.

    1. Barry says:

      But what we’ve learned from millions compounds screened over the last 20 years is that the valuable hits are lead-like rather than drug-like. Rather than finding a drug (that might come with documented PK and tox), we find a lead from which we may get a drug through a lot of modification and work.

  9. Blaine White, M.D. says:

    I agree there are no shortcuts. However, the situation physicians face in doing our best to care for patients in the middle of a killing pandemic is a different perspective from the purest science. For example, in the 17th century Peter Abelard reported restarting pigeon hearts with electric shocks. I’m sure there was never a RCT for clinical defibrillation. Do you want to be randomized if you are on the emergency gurney in V-fib?
    What we do is use the best knowledge we have on a scale that runs from x-ray crystalography to molecular biology to observational studies to RCT to try to save lives – one at a time. In that situation there is no “gold standard,” and drug repurposing is part of that continuous scale. In that regard, here is a living review of Covid-19 I use to teach. (https://drive.google.com/file/d/159rh2onLuW2fAQwac8fMQ5BDFQeAZmtj/view). Its about 35 pages single-spaced with 110 refs and will take at least an hour to read; the newest additions are in red. Perhaps it can also expand our knowledge and perspective here. Of course it contains some errors that we will discover, but that is how we grow knowledge and provide care.

    1. Irene says:

      Do you mean William Harvey? The only Peter Abelard I know of was an 11th century theologian, poet, musician, etc., but not much of a scientist that I ever heard.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232561/
      1600

      William Harvey restarted an arrested pigeon’s heart by a simple flick of the finger. In 1628 he described the circulation (Fig. 5).

      Or perhaps this (18th century):
      1775

      The Danish physicist Nickolev Abildgaard conducted the first studies on the effects of electrical energy when applied to the body. He placed electrodes on the sides of a hen’s head and applied an electric discharge which caused it to fall dead. Application of electrodes over various parts of the hen’s body failed to reanimate the bird, until they were placed across the chest. In this position they presumably defibrillated the heart after which the hen staggered onto its feet and walked away (Fig. 7).

      1. Blaine White, M.D. says:

        You are right, and I errored. I generally try to avoid producing BS by putting references in my notes, but for Peter Abelard and defibrillation I did not look back, and so I’m well and truly caught. I had manufactured that as a old man’s memory from Negovskii’s 1962 book “Resuscitation.” The actual V-fib citation from that book (that remains in my library!) was to an 1850 publication by Ludwig and Hoffa in Ztschr. rat. Med 1850; 9:107-144, and I didn’t know about your citation of Nickolev Abildgaard. I apologize. Hopefully I’ve given better support for the molecular biology, immunology, clinical experience, and approaches to CoV treatment in the 35-page 110-ref manuscript for our residents that I shared. But be careful – it’s sure to have mistakes too. And to you I say, “Well done.” Continuing correction is essential to growth of our models of understanding.

    2. There have been many RCTs of clinical defibrillation, comparing different doses of energy, different wave forms of the discharge, and so on. There may never have been placebo-controlled RCTs of defibrillation itself, which is probably what you meant.
      It’s important to speak carefully here, because one often hears that RCTs couldn’t be done when randomized dose-controlled trials, randomized placebo-controlled add-on trials, and randomized withdrawal trials are all ethically possible. The differences between today’s Advanced Cardiac Life Support and that of 25 years ago are all the results of randomized controlled trials.

      1. Blaine White, M.D. says:

        Because I looked it up for our residents ~1 year ago, I think you might be surprised if you try to find a US RCT for amiodarone, which is now ACLS dogma to facilitate difficult defibrillation. In fact there are now some comparative studies of lidocaine (used already 40 years ago) versus amiodarone suggesting lidocaine may produce better outcomes. I don’t know of a proper RCT of either against placebo to help with V-fib. And if we exclude the effect of AEDs and don’t include post-arrest hypothermia (which also has some variable evidence), I’m not convinced intact neurological outcome has been greatly improved for out-of-hospital cardiac arrest over the past 40 years. My intention was to point out that we often use repurposed interventions for desperate situations like cardiac arrest or SICK Covid because it’s the best we can imagine at the time. And there are some survivors; it’s just difficult to figure out why.

  10. Eugene says:

    The impression I have that repurposing efforts are more of a mechanism repurposing effort. A particular drug provides the framework for the effort to create a “new” drug. My undrstanding is that no drug hits one intended target (side-effects) and enhancing some of these other targets and blocking (to any extent possible) the original target creates a new drug.

    1. Stanislav Radl says:

      Your example is not a repurpusing, but SOSA (selective Optimization of Side Activities) approach, which was successful in many cases (sulfonylurea antidiabetics, sulfonamide diuretics, …). Unlike repurposing, SOSA approach requires full toxicity studies and also more extensive PK.

  11. A grad student says:

    My thesis research involves using machine learning for drug re-purposing. This is pretty much the hypothesis-free style of drug discovery that is criticized for being less productive than one might hope. That’s true of all drug discovery, so I don’t think it’s necessarily fair to single out re-purposing as somehow less productive than other paradigms. The biggest issue that I see is that there’s also a pretty strong financial disincentive to run clinical trial already approved drugs.

    1. Tommysdad says:

      A 0% success rate is clearly less productive.

  12. DTX says:

    The statement was “unable to document a single instance of a drug approved for clinical use where the idea for the clinical trial derived first from a virtual or lab-based screen of old drugs.” Both Viagra & Rogaine didn’t result from “virtual or lab-based screens”, but rather because a noted “side-effect” in clinical trials.

    Dexamethasone has countless clinical effects and its proposed use in Covid-19 was based on an understanding of these effects (i.e., not from “virtual or lab-based screens”.)

    1. Barry says:

      Hmmmm
      Why didn’t anyone else think of those?

  13. David Eugene Young says:

    I know that I have mentioned this before, several times, but I would really like to see invitro and then clinical trials of combinations of antivirals. At this time, I believe that Remdesivir and MK 4481 (aka EIDD-2801) could have good additive and perhaps synergistic effects together and still be tolerable. At least, please, test that in-vitro. And then there is Favipiravir, which is the “Rodney Dangerfield” drug for this epidemic… “it gets no respect.” Although studied all over the world (and approved in 5 countries based upon little data) it is barely getting any attention in the US. Might a combination of Remdesivir and Favipiravir have good activity and remain well tolerated? Maybe, but if no one studies it, we will never know. Even Roger Permutter, head of clinical research at Merck gave an interview with Financial Times where he mentioned that he though the antiviral treatment of Covid19 would involve a drug combination. Please, folks, consider a combination. At least test combinations in-vitro first.

  14. David Eugene Young says:

    And, in another news-story, you’ve now read that Artemisinin and analogues are being repurposed for Covid19. Step aside Hydroxychloroquine and Ivermectin, there is a new kid on the block.

    1. Lane Simonian says:

      Artemisia annua may have a better chance of success than artemisinin itself.

      https://lavierebelle.org/action-de-l-artemisia-annua-sur-l-200?lang=en

  15. David says:

    “unable to document a single instance of a drug approved for clinical use where the idea for the clinical trial derived first from a virtual or lab-based screen of old drugs“

    Phenytoin was repurposed. A derivative of barbiturates, it was originally designed as a sedative, but was only mildly sedating and so was shelved by Parke-Davis. It was later discovered to be anticonvulsant in a systematic screening program (using electroshock testing in cats) by Merritt & Putnam, and became one of the most important drugs of the 20th century (now largely supplanted by safer alternatives).

    1. Al says:

      Cool. Out of interest, was phenytoin already an approved drug? Interesting that it took 15 years from the cat experiment til the phenytoin was approved by the FDA (according to wikipedia!)

      What is being advertised today as re-purposing in academia, and being funded by patient organizations (and COVID funds), is the testing of already approved drugs in lab assays (virtual, biochemical or phenotypic), with the idea that it would cut out 5 years of early discovery if there was a hit. For patients and their families, desperate for a disease treatment quickly, this is hypnotically enticing. And they do not get any dose of reality from many inexperienced profs, all of whom are “sure” it will work. What this piece argues is that time and time again over 20 years, despite the allure, it has not led to a new hypothesis that has resulted in an approved drug. The counter argument is that there are now repurposed drugs making their way through the clinic, and one might eventually work. Of course this is possible and we all hope it does, though Vladimir and Estragon are still waiting. And why is this important? Funding for these screens is at the expense of doing science to find underlying disease mechanisms.

      1. David says:

        Not so sure about Wikipedia. Merritt & Putnam conducted their first animal experiments using phenytoin in 1937, almost immediately ran a small human open-label study, and gained FDA approval in 1938.

      2. Stanislav Radl says:

        Hypoglycemic activity of metformin was first described in 1929. It was approved as antiinfluenza medication in Philippines in 1949. In GB, metformin was approved as antidiabetic in 1958. And finally in 1994 it was approved by FDA as Glucophage. It took 63 years from the activity discovery to the US market approval…

      3. Anon says:

        “For patients and their families, desperate for a disease treatment quickly, this is hypnotically enticing”

        You’re absolutely correct! Another example is the issue of Clemastine Fumarate and its purported role in alleviating MS. Just read the volumes of uncontrolled OTC self-conducted trials on the internet, and how big evil pharma is trying to keep this cheap cure from the masses…

  16. JonB says:

    Tamoxifen at high doses works well for bipolar disorder selected by untargeted screening of cell libraries (PKC inhibition >> estrogen receptor blockade). Confirmed by multiple human RDBPCT studies conducted by highly reputable groups, consistent with my clinical experience in the last 10 years.

  17. Dr. Wood says:

    While not quite on point I would like to modify your last statement slightly:

    Good Science is hard. There are no shortcuts.

    Far too many people (myself included) want to take shortcuts, and bypass the hard work part. We at some point have to go collect data in well run experiments, analyze it carefully, and be careful not to draw conclusions that data does not support (Thank you to a certain professor who rightly took umbrage with a conclusion in my dissertation for the reminder of this).

  18. a says:

    That’s exactly what happened with thalidomide and led to its use as an anticancer drug – for that matter, intensive study of why thalidomide caused the disaster it did in human usage is what’s led to the modern field of targeted protein degradation,

    Does anyone have a review or history describing this story?

    1. Barry says:

      here’s part of the thalidomide/ligase/ubiquitinylation story
      https://pubmed.ncbi.nlm.nih.gov/26231201/

  19. Philip says:

    Until we have better testing, antivirals are not going to be an effective therapy. We will not even know which antivirals work until we have enough testing to catch the infected very early in their infection in order to make a trial meaningful.

    Just because SARS-CoV-2 antiviral trials are hard to do is not an excuse not to do them and do the correctly.

  20. SB says:

    not only the Viagra and Thalidomide stories but also:
    Dimethyl-fumarate: psoriasis to MS
    Aspirin: pain to platelet coagulation
    Doxocycline: antibacterial to antimalarial
    Clomiphene: breast cancer to ovulation induction to hypogonadism
    Carbamazepine: anticonvulsant to neuropathic pain
    Flutamide: antibacterial to prostate cancer
    Aminoglutethimide: anticonvulsant to breast cancer
    Tamoxifen: contraception to breast cancer
    Beta-blockers: hypertension to migraine prophylaxis
    Everolimus: imunnosuppressant to neuroendocrine tumors
    Methylphenidate: narcolepsy/depression/memory deficits to ADHD
    Tretinoin: from acne to promyelocytic leukemia
    Ofatumumab: from CLL to MS
    Etc.

    1. Charles H. says:

      But those examples aren’t from analytical projection, they’re from noticed side effects.

      This is what Derek meant when he quoted “unable to document a single instance of a drug approved for clinical use where the idea for the clinical trial derived first from a virtual or lab-based screen of old drugs“.

      Yes, they fit my idea of “re-purposed drugs”, but they don’t fit that limited definition. Some day we’ll be able to do it from first principles, but probably not until we have “strong AI”. (It wouldn’t need to be a general AI for this purpose, as one specialized to understanding biological principles should work. But it would need to be a lot more than what we’ve got so far.)

      1. Kamil says:

        What I find odd about this strict definition of repurposing. Let’s stipulate you are right, all these drugs only fit the more relaxed definition of repurposing based on known effects or side-effects. However, *had* you run these in high throughput preclinical assays, would they’ve hit or not? If they would have hit, doesn’t this prove that the concept is valid? I don’t know. But assuming they worked, adding 2000 approved compounds to your screening library should be cheap in the grand scheme of things (although perhaps undesirable since most of these are off patent or already patented by the competition?)

        It is also interesting to think about repurposing of human drugs to test them in animal models (as we do in the aging field). For example, rapamycin and acarbose were repurposed to extend mouse lifespan based on “known” (or likely) mechanisms. In contrast, dasatinib and quercetin were discovered as senolytics in a small screen, but this was still based on their predicted targets matching the expected targets in senescent cells (e.g. EFNB3 signalling). If that does not count as repurposing I am really at a loss.

        1. Marko says:

          “….dasatinib and quercetin were discovered as senolytics in a small screen”

          If the repurposing goal was to find a drug , the mere mention of the name of which would be enough to drive Derek completely over the edge , then “quercetin” would be the winner , hands down.

          It would also be the ultimate proof-of-principle example that repurposing screens can indeed be useful exercises.

        2. Tommysdad says:

          The point here is that everyone DOES screen these molecules. And, yet; no documented successes to date ( using the definition provided).

          This may say more about how we currently look for drugs, rather than the concept.

    2. Anon says:

      Dimethyl-fumarate: psoriasis to MS

      Little trivia about Biogen’s “tour de force” (Tecfidera/Dimethyl Fumarate $1Billion drug). The drug in question was used as an antifungal to preserve (of all things) leather recliners, sofas, furniture, during shipment from China to retail markets in the west. Lots of people got “sofa dermatitis” from the leftover white powder pouches stapled into the insides of the furniture. Biogen turned it into a blockbuster. Talk about the ultimate in “repurposing”.

  21. drsnowboard says:

    To be cynical, the first wave of enthusiasm for re-purposing was a pharma exec desire to get something from the drugs that failed efficacy trials in man for their predicted indication but had at least some safety data. Why not get something for that maybe 5 million that somebody had spent on getting into P1/P2? It has always been a hail mary play, but it scores big if somehow someone comes down with the ball

  22. Toby Gibson says:

    A couple of candidates for repurposing with COVID-19

    Ibrutinib, an inhibitor of Bruton’s Tyrosine Kinase (BTK), a key signalling protein in the white blood cell lineage appears to be protective for chronic lymphocytic leukaemia (CLL) and Waldenstrom macroglobulinaemia (WM) patients.

    https://pubmed.ncbi.nlm.nih.gov/32302379/
    https://pubmed.ncbi.nlm.nih.gov/32433778/
    https://pubmed.ncbi.nlm.nih.gov/32647324/

    Acalabrutinib, another BTK inhibitor, was also found to modulate severity in a small off-label study of COVID-19 patients.

    https://pubmed.ncbi.nlm.nih.gov/32503877/

    Of course these BTK inhibitors are not anti-virals but are treating a symptom by calming the macrophages and reducing the severity of inflammation in the lungs. Acalabrutinib is listed as one of the drugs being tested in the UK ACCORD trials.

    https://pubmed.ncbi.nlm.nih.gov/32736596/

    The chemical cosh and archetypal dirty drug Chlorpromazine (CPM) is an endocytosis inhibitor (as are its other tricyclic antipsychotic relatives). It binds to and blocks the activity of the dynamin motor protein, which closes off the endocytic vesicle.

    https://pubmed.ncbi.nlm.nih.gov/25693808/

    Virologists routinely use Chlorpromazine in infectious tissue culture to establish whether a virus enters the cell by endocytosis uptake, as SARS-CoV-2 does, or by some other mechanism. The hospital in Paris where Chlorpromazine was discovered reports that, anecdotally, coronavirus-infected patients suffer serious disease rather less frequently than medical staff. A clinical trial is planned.

    https://pubmed.ncbi.nlm.nih.gov/32425222/

  23. Kaleberg says:

    Repurposing isn’t that uncommon. Some years back, a friend of mine told me that his ten year old daughter was on viagra, obviously not for erectile disfunction. She had a serious lung problem and has since had a transplant.

    My girlfriend borrows my latanoprost to thicken and grow her eyelashes. I got the Rx for high eyeball pressure, but now my lashes are long, longer, longest too.

    1. Toby Gibson says:

      Apilimod was also mentioned by Bryon above. It’s action is at the late endosomes, so later in the endocytosis pathway than Chlorpromazine. It failed in trials for some autoimmune conditions but appears to have a good safety profile.

  24. Marko says:

    This suggests that we may be unknowingly repurposing heparin and its derivatives as direct antivirals when we use them for anticoagulation in COVID patients :

    “SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2”

    https://www.cell.com/cell/fulltext/S0092-8674(20)31230-7?rss=yes

  25. JasonP says:

    >>>>When you look at the field, the only time we’ve ever really been able to control or cure any viral infections with small molecules, it’s been with a cocktail of drugs that hit several mechanisms at once (HIV, HepC). Which makes perfect sense, given viral mutation rates. I don’t see how a single small molecule drug is ever going to be an effective antiviral by itself, at least not if it’s working by the mechanisms we know now. And in the case of remedesivir, or ribavirin, or AZT or any other broad-spectrum-ish antiviral you can name, the chances of a single agent hitting a knockout blow are basically zero. They’ll do some good, and they’ll do even more good if they can be combined with a drug with a completely different mechanism such as a viral protease inhibitor. (Note also that broad-spectrum viral protease inhibitors are a lot thinner on the ground, at least ones that aren’t cytotoxic at the same time!) <<<<

    The irony of this paragraph is astounding as it boarders on blasphemy in regards to the authors profession! Isn't the whole purpose of pharmaceutical companies to find that ONE silver bullet compound that solves Clinical Issue A – Z as a blockbuster to reap billions in revenue to keep the drug discovery process going? Cocktail of drugs? By the time we get our thinking to drug combinations and do studies, patents have expired along with economic incentives.

    I can't help but think that Alzheimer's Disease (along with numerous other conditions) could be substituted for "viral infections" in essence, in that paragraph. Seems like in medicine we need to address the root cause but also manage resultant inflammation and other mechanisms.

    But if I understand the clinical progress of COVID-19 treatment, management of the cytokine storm, von Willebrand factor, etc are the approaches taken. While no anti-viral exists, it sure looks like, from the death graph in my state that such approaches have been wildly successful.

  26. JP Leonard says:

    The last laugh could be for zinc after all.
    It’s a key ingredient in the ICAM protocol that is showing a 95% cure rate on Covid.
    Just as claimed by Zinky Zelenko et al. Zinc works by supporting the immune system in prevention and early onset stages.
    Immunity is the letter I in ICAM.
    The other three elements are treatments for later stage complications.
    None of it is new. However you define repurposed.
    https://bgr.com/2020/09/26/coronavirus-cure-icam-protocol-florida/
    “The ICAM protocol has the potential to trigger the reopening of the country,” Director of Pharmacy at AdventHealth Ocala Dr. Carlette Norwood-Williams told Fox 35…
    ICAM isn’t a new drug, it’s an acronym for a combination of existing medications used simultaneously on patients. It uses Immunosupport drugs (Vitamin C and Zinc), Corticosteroids against inflammation, Anticoagulants against blood clots, and Macrolides to help fight infection.”
    Azithromycin is a macrolide antibiotic.
    “The last shall be first, and the first shall be last.”

  27. JP Leonard says:

    https://medicalxpress.com/news/2020-07-drugs-covid-.html
    New study identifies 21 existing drugs that could treat COVID-19

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