Tuesday, May 21, 2013

Where to look for a surprise eczema cure to emerge

As I wrote in the previous post, the outlook is bleak for new eczema therapies that might qualify as a “cure.” On the fronts of barrier protection and repair and anti-inflammatories, nothing revolutionary is in the works apart from, perhaps, dupilumab, Regeneron’s antibody to IL-4. I can’t see anything emerging from research and entering and successfully exiting clinical trials for at least 25 years.

What might I have left out of this discussion? Where could a surprise come from?

Itch. Itch was the area that occurred to me. Imagine being able to break the itch-scratch cycle in eczema. You know what it’s like: your skin flares up and the itch becomes unbearable. You scratch to get relief. Sometimes you scratch in your sleep. Then your skin is torn up, which for a start can be embarrassing, but also often leads to infection. If there were no itch to begin with, eczema might never become anything more than a minor rash. Its impact on quality of life would be greatly minimized.

I believe we might see a convergence of two major trends that would result in a new anti-itch drug that patients could take in pill or cream form.

The first trend: In the past few years I have seen a number of papers describing newly identified neurons that transmit the sensation of itch, distinct from pain. The experiments were done on animals such as mice and cats; I don’t think these neurons have been found in people yet. But you can bet there are many scientists beavering away to be the first in the field.

Turning on or blocking neural receptors is what drugs do best. Think anesthetics. These itch neurons, if found in humans, are likely going to have receptors similar to those in other animals, and the search will be on to find drugs that block the receptors.

(You could also imagine a therapy using RNA interference to prevent neurons in the skin from making itch receptors in the first place.)

The second trend: scientists are developing powerful new techniques to speed the drug discovery process. While it does take around 15 years to take a new drug all the way through clinical trials to FDA approval, the path is shorter for “repurposed” drugs (such as Viagra, originally planned as a heart medication). The barrier is lower because the drug has already been proven nontoxic. Repurposed drugs have been approved as treatments for one condition but have side effects that, depending on your perspective, qualify as primary effects. There could well be an FDA-approved anti-itch drug out there already. It’s just being used to treat toenail fungus.

A company I am familiar with (I know the founders), SeaChange Pharmaceuticals, developed a rigorous way to search through databases of drugs and identify potential side effects or secondary uses, based on the chemistry of the protein targets for the drugs. (Wired magazine named SeaChange’s technology one of the top 10 breakthroughs of 2009.)

The idea would be that scientists would identify itch neurons in humans, and pin down the itch receptor; then somebody at Pfizer or Novartis or whatever would use a SeaChange-like technique to find FDA-approved drugs that block the receptor. Presto: no more itch. Conceivably this might happen within a decade.

Now, evidently these new drug discovery techniques could be applied in the areas of anti-inflammatories, or barrier repair. I think, though, that itch is a prime candidate for a surprise eczema “cure” because it’s likely that the itch sensation comes down to a single receptor. Blocking that receptor by a conventional drug will be a relatively simple task, compared to controlling inflammation without leaving the patient vulnerable to infection, or taking on the dubious task of compensating for a defective skin barrier in infants.

That’s my opinion.

19 comments:

  1. Hey, I just read some of your posts about having a cure in 25-40 years time and to be honest, it is discouraging to read that to be honest.

    I am a science illiterate so reading some of your post had me abit lost, haha. But about 1 or 2 days ago there are many articles popping out about a A discovery of a molecule in mice called Nppb that causes itch. Not sure what that means for the search for an eczema cure but it sounds promising for what in years to come.

    Linky to one of the articles : http://www.npr.org/blogs/health/2013/05/24/186294981/why-you-gotta-scratch-that-itch

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  2. Yes, you can imagine how psyched I was that that discovery was made public a few days after I wrote this post!

    My fault if my writing is hard to understand. I'm still searching for the right voice. And some of this science is really hard to understand and explain unless you have weeks to work on the best wording. Needed: a good editor.

    Thanks for reading!

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  3. Why would you say that the outlook for a cure is bleach, when filaggrin drugs currently are going through toxicology (one of the last stages in the pipeline before clinical trials), and other eczema genes, (such as the mattrin gene) are emerging as AD susceptibility genes?

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  5. Thanks for commenting. One of the reasons I created this blog was to learn everything I could about eczema and prospective therapies. Your question prompted me to look up Irwin McLean's website http://www.lifesci.dundee.ac.uk/people/irwin-mclean and a 2011 summary of the idea behind his work http://www.nature.com/nature/journal/v479/n7374_supp/box/479S12a_BX1.html --which is that
    1) in 50% of patients with severe eczema, at least one of the two copies of filaggrin is mutated
    2) I think that the most common mutations are "nonsense" mutations in which a confused ribosome just stops making protein
    3) McLean, together with GlaxoSmithKline, is developing "small molecule" drugs that might allow the body to skip over nonsense mutations and make filaggrin

    I am somewhat familiar with drug discovery, since I work with startup companies and industry scientists in pharmaceutical chemistry. Drug discovery is just a very long and expensive process in which virtually every compound fails. Hence my skepticism--though I admit I had not heard that McLean was actually developing drugs with GSK. (If their candidate compound hasn't even entered clinical trials, the chances of success are even smaller.)

    Here are a few questions that I think are relevant, to which I do not have answers:

    How many of those mutations in patients with severe eczema are nonsense mutations?
    Is filaggrin the major contributor to disease in these patients? It seems likely, but biology is complicated.
    Will fixing filaggrin improve the skin barrier?
    If it does improve the skin barrier, what about the allergic component of the disease, which appears to be a ratchet that cannot be turned back?
    Say McLean's new drug(s) DO fix eczema in a certain fraction of patients; will that be a large fraction? (I am motivated by my own experience with Protopic, which does diddly-squat for me)
    What will the side effects be?

    Mattrin I know even less about than filaggrin. I might get excited about it, but I did a preliminary web search and found little. "Emerging...AD susceptibility genes" are not drug targets until some mechanism has been established and it is clear that the gene or pathway is actually druggable.

    All that said, McLean's a pioneer and I think his work is invaluable--he has made by far the greatest contribution to our genetic understanding of AD. I'm saving my cheers for FDA approval though. Thanks again for your question! I learn more all the time.

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  6. BTW one of the joys and embarrassments of writing a blog is that you get to have your say--which means you put your opinion out in public. Then, of course, it often gets proved completely wrong.

    I was not aware that McLean had an actual compound close to clinical trial. So I'm glad to learn about it. It looks like a good idea for me to research McLean's compound and write about it. Don't expect me to rewrite THIS post, though. That's not the way a blog works! The mistakes get buried by later posts.

    One issue with McLean's compound is that at the moment, to my knowledge, the FDA has not approved any drugs that act by the same mechanism--making the ribosome ignore nonsense mutations. Ataluren, for cystic fibrosis and other conditions, is such a drug, and it's in phase III trials http://en.wikipedia.org/wiki/PTC124 but that does not guarantee success. The FDA is notoriously wary of approving drugs that are "first-in-class," or the first drug to act in a particular way.

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  7. 1)Correct, based on the number I have seen. 2)I don´t know the exact numbers, but filaggrin mutation are either nonsense or frameshift mutations, both giving rise to premature stop codons. Some say that the stop codon overriding drugs are aimed only at the nonsense mutations (like this article from John McGrath, an authority in the field of experimental dermatology: http://www.medicine.org.hk/hksdv/journal/2011v19n03-03.pdf)
    Others say that these drugs are able to override PTC´s from both frameshift and nonsense mutations, like this genetecist meeting abstract (page 16) from Peter Hull, (Who has published some papers with McLean over the years):
    http://www.ccmg-ccgm.org/documents/Annual_Meeting/2012/2012%20Book%20of%20Abstracts_Draft.pdf
    3) I don´t know if this is partnered with GSK or not,(where did you get that from?) but they are developing this type of drugs for filaggrin. Toxicology studies are not cheap, so I assume that they have partnered with some big pharma company, maybe GSK, as you say. They patented the use of this class of drugs back in 2007, right after their initial discovery, and probably knew some of the the path forward already back then.
    http://www.faqs.org/patents/app/20100210578#b
    The side effect will be evident when the drug reaches clinical trials, but I have seen some reports, and they seem to be non toxic in mice, and the pharmacokinetic properties are apparently good. As far as I know, these results are important in the process of getting the green light for trials in humans.
    They are also developing drugs aimed at the one functioning copy of carriers of one WT allele. (Mind you, there are way more carriers of on wild type and one mutated copy than two mutations, so this might be pretty useful in almost 50% of eczema, based on my math.). This is something that I don´t know all that much about, but dioxin, found in coal tar, somehow stimulates the aryl hydrocarbon receptor, which makes the gene produce more protein, and maybe the new drug works in a similar way, but without being toxic.

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    1. PS my comment below is in response. Still figuring out this blogging thing.

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  8. do really think that enhancing skin barrier will do A LOT for sufferers. I think of it as simply as this: If you have asthma, and walk through a room full of allergens, but without inhaling or breathing, you probably won't get inflamed lungs, because allergens won´t enter the lungs, and the immune system won't recognize it. I believe the same principle goes for eczema: If the immune system in the skin never sees the allergens due to the enhanced barrier, skin inflmmation wil not occur. Of course, we don´t know if it will work, but it´s all about keeping allergens away from the immune system.
    I agree with you on that it will be hard to turn around the whole atopic march, unless these treatments are administered early in life. I am allergic to dogs, and my immune system will probably assure that I always will be, even if my skin some day recovers. But eczema is IMO far more distressing. I believe that if my AD is "cured" one day, I won't care that much about allergies. Of course, it´s not fun, but it´s more "socially accepted", sort of speak. And a stronger barrier will at least close one route of entry for allergens to my body. The skin is the body´s largest organ, so I believe the befits from fixing it will be considerable.
    When it comes to the mattrin gene: I don't know much about it, but when they find new AD genes, I know that the main reason for the hunt, is that they will try to treat it. Especially when it comes from the Dundee team.
    And I do understand that the FDA is careful when reviewing drugs that act in new way. But keep in mind that a Phase 1 study is designed to determine the long term safety of a drug (often in healthy patients), phase 2 to determine both safety and efficacy, and phase 3 to determine both in the long run. This indicates, or at least may indicate that ataluren has proven safe and effective in phase 1 and 2. If not, I think the trials would have been terminated.

    Btw: Loved your comment on that "Don't scratch your itch. Ever"-tweet, that was hilarious!

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    1. I agree. An intact skin barrier would be awesome. Who cares about a runny nose or weepy eyes.

      Mind you, I don't think the allergens are getting in through the skin anymore. That's probably how they got in to begin with, and now we have allergic reactions to stuff that we eat and breathe.

      For a filaggrin drug to proactively cure eczema in young kids, it'll have to be tested in young kids. I'm guessing that that is one of the hardest trial groups because nobody wants their kids to volunteer for drug trials--especially if, with eczema, there's a good chance the kid will outgrow the condition. It could well be that the trials get done in some impoverished Eastern European country with slack regulation.

      Re: the tweet, that episode convinced me that getting in an argument on Twitter is a bad idea, especially if, like me, you only log in to Twitter once or twice a day. It's hard to sustain outrage without feeling silly!

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  9. Thanks for all the intelligent comments. This is exactly the sort of discussion I was hoping would happen.

    I did indeed misread McLean's webpage--the filaggrin-rescue drug is in development not with GSK but with Univ Dundee's Drug Discovery Unit. McLean is partnered with GSK on a different project.

    I definitely have to interview McLean to find out more.

    Here's a related link about the filaggin-null mouse model they are using.

    Where are you getting your info about McLean's filaggrin toxicology studies?

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  10. I got the info from the abstract in the link. Abstracts from scientific meetings are pretty neat, cause they give short summaries of the current research.

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  11. Check out the US patent. All kinds of interesting information. Seems to cover use of certain antibiotics or tRNAs to treat one specific mutation and only for treatment of icthyosis vulgaris--not eczema, explicitly.

    Amusing in the light of the recent meta-review that claims antibiotics increase the risk of children developing eczema,

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  12. Comment not truncated...mistyped period as comma.

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  13. If you read a bit more of this, you`ll see that the actual drug probably won`t be an aminoglycoside antibiotic like gentamcin, but a so called "designer aminoglycoside".

    http://www.skinandallergynews.com/index.php?id=1059&type=98&tx_ttnews%5Btt_news%5D=1400&cHash=da03e20e36

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    1. Hi Guys

      I have IV and eczema.
      Is there any update on the McLean research?

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  14. From everything I am seeing, Dupilumab could be a game-changer.

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