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Androgen Receptors for COVID-19

There’s a report of an interesting small-molecule drug effort against the coronavirus that seems to have produced rather significant results. The idea goes back to effects that were noticed last year – for example, in this population-based study from Italy. It’s been known since the early days of the pandemic that males were overall more susceptible to severe disease than females, and there have been a number of hypotheses put forward to try to explain this. But an answer might lie back in the virus’s mechanism of infection. As the world knows, the current coronavirus uses the ACE2 protein as a cellular entry point, followed by a key protein cleavage effected by the nearby TMPRSS2 transmembrane serine protease. That one’s involved in more than one viral infection route, and the idea of using serine protease inhibitors as antivirals had already been tried against type A influenza  – but, it has to be said, without any dramatic success. Favipiravir is one such molecule, but it hasn’t made much of a dent in the pandemic, either.

But there are other ways to target this mechanism. It turns out that TMPRSS2 expression is linked to the transcriptional-activating activity of the androgen receptor. The Italian work linked above found that men who were taking androgen receptor antagonists (generally as a treatment for prostate cancer) seemed to be at significantly lower COVID-19 risk, which result is especially striking considering that pre-existing cancer in general is a risk factor for severe coronavirus outcomes. Instead of trying to inhibit TMPRSS2 activity at its active site, AR antagonists keep it from being expressed in the cell membrane in the first place.

This line of thought has led to several followups. Here’s a proposal from last June that androgen antagonists be tried out in this fashion, and here’s a later study from Michigan that established that specific cell types in the airway do indeed co-express androgen receptors and TMPRSS2, which is then regulated in the lung by AR activity. In July, a Chinese company (Kintor Pharmaceutical) announced that it was providing an investigational androgen receptor antagonist (proxalutamide) for a clinical trial to be run in Brazil. And that trial (involving 588 patients) has now read out. The press release says that there were very significant reductions in disease severity, in overall mortality, and in the length of hospitalization. These look like strong results, and I’m glad to see them. Anti-androgen therapy is pretty strong stuff, so it’s good that the course of treatment is reasonably short. This is indeed the receptor through which testosterone exerts most of its effects, so the effects of long-term treatment in men can be quite noticeable (women have fewer side effects, but non-zero). But blockade of the androgen receptor in this way is generally a cleaner route than (say) blocking the synthesis of testosterone itself, because there are quite a few other pathways involved with testosterone metabolites, etc.

Now, one thing to note is that proxalutamide itself is still an investigational drug – to the best of my knowledge, it hasn’t been approved anywhere. Here’s a trial in Florida looking at a much more common AR antagonist (bicalutamide), but unfortunately it’s only 100 patients. And here’s one looking at the combination of bicalutamide and the serine protease inhibitor camostat at Johns Hopkins, but it’s only 60 patients. I think we might be in a more useful place if the Brazil trial had been run with an already-approved AR antagonist, but this is one of those situations when interests and feasibility don’t overlap as well as they should. We have in general had far too many small, underpowered trials of possible therapies during this pandemic (a topic that will get a blog post all its own!) I hope that if the effect size of this treatment is as large as it appeared in the proxalutamide trial that these others will show something as well, but we’ll see.

Back on the biological level, you may be wondering how the expression of some transmembrane serine protease gene ended up being tied to the testosterone receptor in the first place. Well, that’s gene expression, for better or for worse. It’s a tangle – all sorts of things are wired crossways to all sorts of other things, in patterns that sometimes seem reasonable and sometimes seem random. Remember, there are far more genes out there than there are transcription factors, so everything at that level is doing multiple duty and affecting the expression of a long list of things. As always, evolution’s one question is “Did you survive to produce offspring” and its one rule is “Whatever works”. It’s important to remember that the AR isn’t just a male thing: women have androgen receptors as well, and those pathways are most certainly not silent. For a recent example, here’s evidence that for estrogen-receptor-positive breast cancer, you might also want to activate the androgen receptors as well in therapy. This hypothesis has been argued about for some time, but evidence for it has been increasing, and clinical trials around it are underway.

Let’s hope that the AR blockade idea can have a positive impact in the current pandemic, then. And we can also hold this idea if we face another virus that uses the ACE2 receptor for cell entry. That was the case with SARS in 2003, and we might see it again!

 

35 comments on “Androgen Receptors for COVID-19”

  1. gippgig says:

    Off topic, but may be of interest:
    The Japan public TV network NHK (In Maryland it airs on channel 22.4 (secondary channel of WMPT) in Annapolis; it can be picked up in the Washington, D.C. region with a good antenna) is scheduled to air an episode of The Signs titled mRNA: Medical Messenger of Hope on March 12 at 10:40PM EST, rerun March 13 at 4:40AM, 9:40AM, & 3:40PM. (Also recommended: Medical Frontiers, every Monday at 10:30AM, rerun at 4:30PM, 10:30PM, & 4:30AM the following day but add 1 hour when DST starts.)

  2. mkn says:

    I think that’s nafamostat and camostat, favipiravir is nucleoside analogue

  3. Mark says:

    Could it be that people who know they have cancer may have been more diligent in their protective actions they may have taken to avoid catching Corona virus?

    1. luysii says:

      Mark: Exactly. It’s the same logic as arguing you should buy a yacht if you want a long life. The yacht is a marker for wealth which is an important variable for longevity, just as cancer is a marker for cautious behavior which is a very important variable for COVID19 attack rates

      1. eyesoars says:

        Holy F-word, Batman! That’s pretty significant… that’s an “I’d kill for that kind of significance in a clinical trial” level of improvement.

        1. Brian says:

          It would seem that in countries with large public health databases (Norway?), it might be possible to do a retrospective study on folks who have been hospitalized with COVID and are also being treated with androgen receptor antagonists. It might be difficult to interpret given the possibility that if the effect is real, fewer prostate cancer patients on this kind of therapy might end up in the hospital. However, if the effect is really as large as 3.7% Vs 47.6%, it should be possible to find some evidence to support or refute the idea.

  4. cynical1 says:

    I’ve seen so much work done with Vero cells and SARS-CoV-2. Proxalutamide was tested in lung cell lines. From a quick search, it appears as if Vero cells do not express much TMPRSS2 but they have engineered Vero cells which express TMPRSS2 which show enhanced infection of SARS-CoV-2 (surprise, surprise). So it would appear that TMPRSS2 isn’t a prerequisite for infection in vitro for SARS-CoV-2. If I had to guess, I’d bet that the lung cell lines are probably a more relevant cell line for small molecule antiviral research. You can infect HeLa cells with HIV which only requires one round of infection but an HIV protease inhibitor will be inactive in that cell line at any concentration. There’s a reason why most researchers working on HIV antivirals typically use lymphocyte cell lines with the gold standard being freshly isolated PBLs. I wonder how many red herrings are/were out there with SARS-CoV-2 based on Vero cell data. I’d love to see a group test all the small molecule anti-SARS-CoV-2 “antivirals” side-by-side in multiple cell lines just so we can compare apples to apples and then put them in the animal models with some PK data to compare plasma levels. I also wonder how well proxalutamide would compare to molnupiravir and favipiravir in that ferret infection model that Merck was using. (I wouldn’t be surprised if Merck knows.). I also suspect that when it comes to SARS-CoV-2, humans are a lot more like a ferret than a green monkey’s kidney. We might as well be ready when SARS-CoV-3 comes along in a few years. Thank you for your post on this.

    1. Some idiot says:

      I think your suggestion for a side-by-side screen sounds extremely sensible… Btw, novice question (I’m in a different area), but would there be many labs that regularly use all the cell lines you mention?

      “ humans are a lot more like a ferret than a green monkey’s kidney” is going to stay with me for a while…! 😊

      1. cynical1 says:

        One caveat to what I wrote above is that I have no idea what the sequence homology between the ferret androgen receptor and the human androgen receptor. So, if AR antagonist X,Y or Z doesn’t hit the ferret AR receptor, that in vivo model will show squat.

  5. Fraud Guy says:

    Have you seen this story on the effects some anti-depressants seem to have on severity of COVID?

    https://inverse.com/mind-body/best-covid-treatment-discovery

  6. Julien Potet says:

    In addition to the trial of bicalutamide mentioned by Derek, there is also a trial of enzalutamide for COVID-19 in Sweden. Here is the link to the preprint : https://www.researchsquare.com/article/rs-229140/v1

  7. John Waybe says:

    This looks promising. I don’t see any data that splits the results into male and female cohorts. One might expect the results to be nonidentical, and vary a bit with age (especially with men.) Has anybody seen that information?

    1. Eduardo Gauze says:

      Hello, this study mentioned above is from the same group of researchers who studied proxalutamide. The results are “a breath of hope”. Here in Brazil any type of treatment / drug that can benefit critically ill patients is contextualized by the country’s scientific community and also by the mainstream media, in order to denigrate researchers. A feather. We will wait for the publication of Proxalutamide and its review by the scientific community, as the results presented may change the course of the pandemic (treating the most serious side by side with corticosteroids, anticoagulants, colchicine, oxygen therapy). A big hug!

  8. David E. Young, MD says:

    The one thing about biclutamide…. its’s quite inexpensive.

  9. Mr. Lomez says:

    What a population study with men taking finsteride for alopecia?

  10. Wilson says:

    Great write up, and fantastic results from that Chinese study.

    I have a question though. Im just a layman, but really interested in getting some actual scientists opinions here

    There’s not a week that has gone by where I don’t wonder why are compounds like Pyrvinium pamoaote are not considered for trials like RECOVERY.

    PP is an antihelmic just like the much hyped damn squib ivermectin– yet the doses and toxicity of PP are less of an issue. Its cheap, FDA approved, available OTC many places. Crucially in recent years PP has been identified as a potent noncompetitive androgen receptor inhibitor with novel mode of action & it’s shown great promise against aggressive forms of prostate cancer that are resistant to standard drug regimen

    in addition to the AR inhibitory aspect, it’s been shown as active as broad spectrum antiviral against covs in vitro and most interestingly to me– to my non expert eyes — it seems like in bright neon lights there is also a plausible basis for it aiding the uncloaking of SC2 immune evasion; which is arguably a driver of pathogenecitiy.

    in short, studies have shown PP has a unique trick, it activates RIPA independently without affecting the transcriptional activity of IRF3. Based on our current understanding of how SC2 suppresses, inhibits immune response it seems that therefore may be able to help override SC2 evasion tricks

    The paper:
    Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway

    Doesn’t specifically cover PP or covid but basically gives a nice blueprint of the rationale. I would post a bunch of links here but not sure if allowed. Would be happy to go into more detail if requested

    However I’m very interested in anyone’s thoughts here. I’ve been posting links to the anti-androgenic affects of PP and how it could maybe be used against SC2 for more than a year now- but I’ve not seen any actual scientists pick up on this. There’s no trials, no nothing.

    Is there a reason absolutely nobody is talking about or trialing this cheap, approved compound as a prophalyxis, meanwhile compounds like HCQ or remdesevir were seemingly everywhere? It seems like there’s a rational basis behind exploring it. Am I missing something?

    1. wilson says:

      Further info on PP because I didn’t really expand much on the original comment: it has been shown that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), it’s the only identified AR inhibitor that functions via this domain. It was also among the first small molecules shown to directly inhibit the activity of AR splice variants (Proxalutamide has a similar USP) PP also inhibits androgen-independent AR activation by HER2 kinase.

      From the limited data I was able to ascertain
      About Proxalutamide, it’s mode of action and it’s performance relative to bicalutamide, enzalutamide etc, it seems intuitive from the anti-androgen angle alone (and the results we’ve seen from past ADT studies on covid outcome) we might expect not too wildly dissimilar positive results from this generic, widely available approved OTC compound PP – and that’s before we even touch on the aforementioned possible broad antiviral activity and hypothesized role in combatting SC2 immune evasion. It seems hard for my –admittedly highly unscientific — eyes to imagine a net negative outcome or no difference in outcome to the point it warrants not bothering investigating

      Every month for past 10 months I search the term up on clinical trial registry, expecting *surely* some scientists have thought there may be a small chance of promise in studying PP against covid, but there’s nothing. Seems destined to be never brought up , nevermind getting trialed anywhere. I just don’t understand, it’s sitting there on shelves, it’s not expensive, not in short supply, not patented, has decent safety profile, bioavailability etc.

      I guess we won’t/dont need it if the results from this Brazil study translate to the wider world, and that compound could be mass produced because that’s an absolutely fantastic reduction in mortality but still, just a little baffled. Why does nobody talk about it? Is it a money thing? Is it that the generic ‘covid miracle drug’ idea was tainted by hcq, ivermectin etc. Or am I missing something obvious about why it’s not being trialed?

  11. exGlaxoid says:

    There is a strong profit motive to study a branded drug against new targets. There is not much of one for generics, and the government research funded labs operate at the speed of US funding, which is glacial. So while lots of labs can do simple tests with monkey cells, few groups other than big pharma and the government can afford to do real drug clinical trials. I would be all for the NIH to fund them quickly and efficiently, but that rarely happens at the pace of covid research speed. Hopefully some groups like Gates or other private researcher funds can fund some of these, but I doubt that generic manufacturers will do it.

    1. Rob says:

      It’s a dilemma. No one is well positioned to run these trials, especially if they focus early in the disease progression, targeting outpatients. It’s too late to fix this time, and it’s hard to be optimistic about next time.

  12. cb says:

    It is now well recognized that antiviral therapy is only effective when started 1-2 days hours after infection. I doubt that delivery of an anti-androgen in this time-frame reduces TMPRSS2 density at the lung-cell membrane fast enough.

  13. Paolo Zanotto says:

    Derek, you should be aware that the results were presented by the researchers involved in the DB RCT. Unfortunately, it looks like you wrote this nice text based on a press release, else you would be informed that women were included as well in the trial run on several different localities in Brazil at the same time. Keep the great work. BTW, several other AR antagonists have been used by the same researchers, but they say that proxa appears to be more effective. Time and further DB RCT with different compounds will tell, however. A good point is that proxa works well on patients at advanced stages of the disease and in combination with several other drugs and as an effective early treatment option.

  14. Johns Hopkins Faculty says:

    We are proud that we have fired hundreds of pathogen biologists and chemists during the pandemic to save $$$$ and enforce the no contact order.

  15. Colin Brown says:

    May I make 2 comments on AR agents?
    1. oestrogen is anti-androgenic – but is that at a later stage than TMPRSS2 activation? I see there is some early research into its use. Has anyone looked at female morbidity association with prior oestrogen use, either as contraception, or HRT?
    2. Spironolactone is both anti-androgen, and anti-Mineralocorticoid Receptor, which is part of the RAAS dysregulation of Covid19. It has shown good results in combination with bromhexine, for dual entry inhibition, in a study from Moscow reported at https://pubmed.ncbi.nlm.nih.gov/33487145/
    From this:
    “Its additional anti-androgen effects, which have always
    been considered to be drawbacks of spironolactone,
    are also important … in COVID-19, since activation
    of both the ACE2 receptor and the transmembrane
    serine protease is directly related to male sex hormones
    and hyperactivation of androgen receptors”
    Should this Observational Study with Propensity scoring be upgraded to full RCT?

    1. Doug H MD says:

      anecdotally, yes. 2 patients of mine with end stage heart failure got covid and did fine , both on spironolactone.

    2. Diego says:

      On clinicaltrials.gov, this russian study was initially registered as a randomized trial (open-label). It seems that the staff stopped randomizing the patients during the trial because the efficacy was obvious to them.

    3. Irene says:

      I was also wondering about estrogen or testosterone use by trans patients.

  16. Hólmsteinn Jónasson says:

    This hypothesis will soon be tested: two clinical trials investigating the potential protective role of the antiandrogens dutasteride and bicalutamide in SARS-CoV-2 infection are about to start [Anti-Androgen Treatment for COVID-19, NCT04446429, registered on June 24, 2020; Trial to Promote Recovery From COVID-19 With Ivermectin or Endocrine Therapy (RECOVER), NCT04374279, registered on May 5, 2020). See also STAT3 pathway https://www.nature.com/articles/s41418-020-00633-7

    1. Smut Clyde says:

      “About to start”? NCT04446429 is long over.

      Before putting much trust in the results, check the history of changes, which are bizarre.
      https://clinicaltrials.gov/ct2/history/NCT04446429

  17. Covidiot19 says:

    But have they tried dosing these with Zinc?

  18. I’m sorry, but that Cadegiani & Zimmermann trial in Brazil with proxalutamide is so badly rigged one can only hope they made it all up and didn’t really treat same patients with all possible drugs simultaneously. They also all are pay-rolled by the company selling that drug while declaring no COI whatsoever.
    Read this, and also the comments by Smut Clyde below:
    http://forbetterscience.com/2021/03/16/why-not-chemical-castration-to-escape-covid-19/

    Remember the guy who claimed 5G mobile phone signal induces the creation of coronavirus in the skin? He is part of the team.
    https://forbetterscience.com/2020/09/02/torello-lottis-arousal-disorder/

  19. Hólmsteinn Jónasson says:

    “Ivermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions. Ivermectin potentiated activity of anti–androgen receptor and anti-EGFR drugs in prostate and EGFR/HER2-driven tumor models, respectively, identifying a repurposing approach for cotargeting stress-adaptive responses to overcome resistance to inhibitors of oncogenic pathway signaling.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994194/

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