Saturday, May 18, 2013

Why there will be no cure for eczema for at least 25 years

In a previous post, I made the Eeyore-like prediction that we are unlikely to see a cure for eczema during my lifetime, which means the next 40 years.

Upon reflection, I have become more optimistic: now I only think we might have 25 years to wait.

Several factors combine to make this so: our incomplete understanding of eczema; the ratchet-like course of the disease; its allergic component; and the expense and inertia of drug development.

As currently understood, eczema is initially a defective skin barrier that lets in allergens. In the first few years of life, children develop antibodies that protect them from disease over their lifetime. The defective barrier overstimulates this part of the immune system, and children build the capacity for allergic reactions to common things in the environment that most people don’t react to—pollen and foods for example.

The allergies get locked in. What may originally have been a leaky skin barrier now gets connected to allergies and inflammation.

In recent years scientists have discovered a number of genetic defects in various components of the skin barrier—the super-protein filaggrin, in particular. I can understand that the average patient must have the impression that with this genetic data is coming in, all that scientists have to do is develop targeted drugs to solve the defects. Or gene therapy to replace the bad genes. Surely these are on the horizon?

Here’s why they aren’t. Let’s start with gene therapy. Only one gene therapeutic has been approved anywhere in the world. The European Commission gave permission for Glybera to be used to treat a rare metabolic disease. Gene therapy is most famous in the US for the 1999 death of a teenager who signed up for a risky clinical trial. It is unlikely that over the next few decades we’ll see gene therapies emerge for anything but rare, fatal, incurable diseases. Eczema doesn’t qualify—and even if you could fix the skin barrier by gene therapy, you’d have to act within the first few months of life. What parent would let doctors give their newborn a potentially lethal treatment based only on the likelihood that the kid might grow up to have eczema?

Another possibility is RNA interference, a technique that blocks the conversion of genetic information into protein. RNAi was discovered sometime in the past two decades and recently the FDA approved the very first RNAi therapeutic, for a rare metabolic disease. To treat eczema, RNAi might be used to cut down on the amount of inflammatory molecules produced in the body or in the skin. A number of academic laboratories--I am aware of a couple in Japan--are looking at RNAi for eczema. However, there are no therapies anywhere near a clinical trial, and new "drugs" in this field would face even steeper regulatory hurdles than conventional drugs. Conversely, the reason to get excited about RNAi is that in theory it could allow us to choose which inflammatory molecules to turn off (rather than shutting down most of the immune system, as steroids do).

Now, let's consider traditional drug discovery. Research does show that filaggrin defects are found in up to 50% of patients with severe eczema. (Naturally, there are apparently unaffected people who have filaggrin defects, as well as eczema patients who do not.)

So you’re going to develop some drug to target filaggrin? Irwin McLean, the filaggrin expert, says that targeting filaggrin could have a big payoff. But he admits that little is known about how the filaggrin gene is turned on or off. Eventually we will know, and perhaps that knowledge will suggest what drug might work.

The question is how a drug might fix or compensate for the defect. [See the comments for a couple possibilities.] And if we eventually find a drug that can correct for a single or double filaggrin mutation, there is still the question of how much benefit that will provide if a patient has already developed allergies.

Drugs are just not custom-designed—that is currently a pipe dream. Drug discovery is time-consuming and costly. It takes $1 billion and 15 years of trials to get a drug approved by the FDA. Scientists start with the protein of interest. Then they screen gigantic libraries of drugs to see if any of them affect the protein in useful ways. They tweak those initial “lead” compounds to make them better.

Then they file an application for a new drug. Then they proceed to animal trials: mice, rats, dogs, pigs, chimps. Then human trials—phase 1, 2, 3, 4. At any stage, and if you’re lucky it’s the early going, it can become apparent that your drug is ineffective or toxic.

And here’s another factor: many proteins are just not “druggable” for various reasons. Because of the shape of the molecule or the way it interacts with something else, tiny drug molecules can’t get to the active site; or they get in but can’t get out. Etc.

It is extremely difficult to develop new drugs.

Also, in the past few years the pharmaceutical industry has been in a slow-motion crash. Big companies are laying off scientists because a lot of the original big moneymaking drugs are coming off-patent and not generating enough income for R&D anymore.

Add to this the fact that there’s hardly anything in the pipeline for atopic dermatitis. I know Anacor has two candidates in Phase II trials—new topical anti-inflammatories. Great,  but hardly revolutionary. Regeneron has something interesting going: dupilumab, a monoclonal anti-IL4 antibody. It’s in Phase I.

Venture capital won’t even invest in startup companies unless their technology has passed Phase II.

You can understand my pessimism.

Next: why I might be wrong

13 comments:

  1. Interesting reading. Allthough, there are some things I would like to point out: First, filaggrin mutations is not found in about 10% of eczema -patients, it's found in 10% of the general population in Europe.(that is also what your link tells us). It is estimated that nearly 50% of servere AD cases are caused by flg mutations. (I could have shown you some sources, but this written on my iPad, my Mac crashed the other day)
    Secondly, there are considerable efforts to develop therapies aimed at FLG. There are two approaches. Haploinsuffiency may be compensated for by the use of a molecule that makes the functional copy work harder, and complete defiency (two mutated copies) due to one or two nonsense mutations may be fixed by using a drug that makes the cell ignore the PTC. The last approach is in clinical trials for CF and DMD. (ptc124/ataluren). The team in Dundee have discovered lead molecules in both classes. (Again; I could have shown you some links, but I need my Mac back from service!!). I think a clearer understanding of filaggrin pathways is needed before any trials will be conducted,the recent findings about how coal tar induces flg expression in a heterozygous carrier may provide some clues.
    Thirdly, I can't see the relevance of siRNA in an eczema discussion. The reason I brought it up some days ago, was to point out recent advances in drug discovery in general. siRNA is used when too much protein, such as keratin in PC is produced. This is not the case in flg related AD. (of course, other genes may evolve, but this is too early to say. IMO, it is more relevant to discuss potential treatments aimed at genes that has been discovered already).

    I am looking forward to your post on why a cure COULD be a reality within the next 25 or 40 years. In the mean time, take care.

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  2. And sorry for typos and bad english :)

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  3. Thank you for the constructive criticism! (Might you be able to avoid technical acronyms though? I don't know what some of them mean, and I'm sure other readers are also puzzled.)

    Indeed, I read that abstract wrong, for which I apologize. You are right, filaggrin mutations appear to be found in 9% of the general population, and I can believe that a double mutation would be found in many patients with severe eczema. There is no doubt that filaggrin is a prime suspect and a valuable lead.

    You have some good points about how a filaggrin drug might work. I agree that a drug to stimulate a single copy of the gene sounds feasible (mind you--what else would such a drug be stimulating? It'd have to be pretty specific).

    Re: a drug to make the ribosome ignore premature stop codons--hoo boy! Had not heard of such a thing. My question--what OTHER premature stop codons would the drug make the ribosome ignore? You could imagine all sorts of side effects. The proof will be in whether, first of all, "ptc124/ataluren" works, and secondly, whether such an approach could be engineered for filaggrin genes with premature stop codons.

    This is all very exciting, but science fiction at the moment.

    Plus, in many scientific papers I see scientists justifying their work by saying their results could help us find drug leads. I work around a number of pharmaceutical scientists whose business it is to find drug leads, and they make it abundantly clear that it's no simple matter. (UC San Francisco, with a strong pharmaceutical chemistry program, has in its entire history of looking for drug leads for parasitic diseases found only one, which has not yet made it to clinical trials.) So I maintain a healthy skepticism about "drug leads" and will believe it when I see it!

    About RNA interference--I thank you for bringing my attention to the subject in your previous comments. I looked into it and found that there are several labs considering RNAi to reduce the expression of inflammatory molecules in AD, and also exploring ways to make RNAi work as a skin therapeutic. This approach actually seems kind of practical to me.

    Please keep your valuable comments coming! They make the blog better. (You know, you could always start your own blog...)

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  4. PS I could see RNAi as particularly valuable because it allows you to knock down the expression of only certain molecules. So you can choose one or more cytokines, for example, to reduce inflammation that has origins in eczema, while leaving the rest of the immune system intact to fight pathogens. Compare that with steroids, which just dial down the whole inflammatory response and leave you vulnerable to infection.

    RNAi is very interesting, but unfortunately over the horizon at the moment.

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  5. Well, thank you for being willing to discuss the subject with me.
    Of course, the drug targets have to be specific. In the case of the drug that upregulates the functional copy, I have no idea of the mechanism behind this.
    Then it comes to the read-through agents. It is important to distinguish between a premature termination codon (PTC) and a natural stop codon. The PTC is a result of a nonsense mutation, and the result is non functioning protein or no protein at all. You asked me what other premature stop codons the drug will "fix". That is, as far as I know, not the main challenge. The challenge is to make the drug "stay away" from the NATURAL codons. (maybe that is what you meant). But based on the assays I have seen on another drug in the same class, the drug can be tweaked into binding only to the ribosome of interest.

    I think the university of Dundee has a collaboration with GSK going on, which is about the use of read-through drugs in disease far more servere than AD, called dystrophic epidermolysis bullosa. And Ataluren has made I to and through at least some stages of trials. This tells me that read-through agents can be modified into both high safety and efficacy, as the team in Dundee has done with their molecule aimed at FLG. (http://gtr.rcuk.ac.uk:80/project/141DE7F5-ADFB-4B3F-AA22-02AA4794F8BC)

    My point here is not to convince anybody into having the same opinion as me, as i'm just a non-prfessional optimist. But this is the biggest breakthrough ever in the field of dermatology and eczema research. The potential cost savings for the millions suffering are enormous. (Glybera, for instance, is a treatment for people suffering "only" from an orphan disease). The high prevalence of FLG mutations will probably make it easier to conduct clinical trials (as opposed to the case of Glybera), ensuring a high safety profile and efficacy before launch of a final product. I believe that the only reason we currently don't have a cure for filaggrin defiency, is that it was such a hard task to crack the sequence, that it took decades. And of course, the link between AD and filaggrin makes this an even bigger potential gold mine for pharma companies, national health care systems, and the patients than IV alone. Based on this, I can't see why FLG related disorders shouldn't be among the most attractive to tackle appropiately. A recent paper (http://www.nature.com/milestones/skinbio5/full/skinbio20126a.html) also gives me hope that the treatment (for filaggrin related AD) may be closer than 25/40 years away) I won't believe until i see it, and things may go wrong before and during clinical trials, but objectively: I think so.

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  6. And Spanish Key: I'm sorry, i think I got you wrong regarding the use of siRNA in eczema. The way you presented it in your comment was easier to understand. Initially, I thought you meant that it could be used as some sort of barrier repair treatment, but I understand now what you were refering to. This is totally outside my intellectual capacity, so instead of talking about something I don't have an opinion about, I find it better to shut my mouth.

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  7. OMG so annoying...I was editing my post for clarity based on your points, and accidentally deleted the whole thing because of a Blogger glitch. What now appears above is a re-edited version of an earlier draft.

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  8. Blogging is not a walk in the park. I'm still looking forward to your next post. Will save my comments until then.

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  9. Thanks for Posting ! first time I have found a genuine post related to Eczema Treatment

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  11. http://www.cbsnews.com/news/breakthrough-therapy-could-help-millions-with-eczema/

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  12. Your blog is very informative. Thank you for sharing it, I say don't stop blogging. You're like my own personal thought processor!!! I have a question to you, Please answer me, If possible- What is the difference between eczema and psoriasis? Is it possible to have both at the same time? ? Read About atopic eczema .

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