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.
Showing posts with label cure. Show all posts
Showing posts with label cure. Show all posts
Tuesday, May 21, 2013
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
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
Wednesday, May 15, 2013
What would count as a "cure" for eczema?
A commenter on my most recent post took me to task for being too pessimistic about the possibility of a cure for eczema appearing in my lifetime. (For the record, I’m 41, so that means within the next 40 years.)
This raises a good question: what qualifies as a "cure"? And who cares?
You know if you care. You're an adult who lives with severe eczema, or the parent of a severely affected child.
I propose that a cure be defined as a therapy that doesn’t take that long to apply and relieves the symptoms to less than a quarter of what they were to begin with. (Take your pick of how to measure it; how about SCORAD?)
A cure would take less than 10 minutes out of your day, and you could wear a swimsuit to the beach.
Most likely a cure would take the form of a drug or biotherapy (e.g. antibody) administered as a pill, cream, or injection. It would be OK if the cure took a whole day to administer, as long as you only had to do it once a year. That would work out to about 10 minutes per day.
Intense, complicated therapy like the National Jewish Health regimen—moisturizing, wet wraps, special diet, and a team dedicated to your personal health, may work for a small number of people for a limited time, but is too expensive and impractical to count as a cure.
What about "partial" cures? Eczema is a complex disease with many aspects that affect each other: skin barrier, allergies, itch, psychology. What if we discover an agent that relieves allergies or turns off itch? Would that count as a cure?
I think it would—if it took a patient less than 10 minutes a day to apply, and they could wear a swimsuit to the beach.
In following posts, I will explore why such a cure will likely NOT happen within the next 40 years—and then I will explain why it COULD happen in the next 40 years.
This raises a good question: what qualifies as a "cure"? And who cares?
You know if you care. You're an adult who lives with severe eczema, or the parent of a severely affected child.
I propose that a cure be defined as a therapy that doesn’t take that long to apply and relieves the symptoms to less than a quarter of what they were to begin with. (Take your pick of how to measure it; how about SCORAD?)
A cure would take less than 10 minutes out of your day, and you could wear a swimsuit to the beach.
Most likely a cure would take the form of a drug or biotherapy (e.g. antibody) administered as a pill, cream, or injection. It would be OK if the cure took a whole day to administer, as long as you only had to do it once a year. That would work out to about 10 minutes per day.
Intense, complicated therapy like the National Jewish Health regimen—moisturizing, wet wraps, special diet, and a team dedicated to your personal health, may work for a small number of people for a limited time, but is too expensive and impractical to count as a cure.
What about "partial" cures? Eczema is a complex disease with many aspects that affect each other: skin barrier, allergies, itch, psychology. What if we discover an agent that relieves allergies or turns off itch? Would that count as a cure?
I think it would—if it took a patient less than 10 minutes a day to apply, and they could wear a swimsuit to the beach.
In following posts, I will explore why such a cure will likely NOT happen within the next 40 years—and then I will explain why it COULD happen in the next 40 years.
Tuesday, October 26, 2010
Antibodies, parasitic worms, and cures
Funny vignette: home from work today--I have to bike up a steep hill to get home, and then I'm always hot and sweaty, which triggers the itch. I'm sitting on the floor leaning against the couch scratching the backs of my knees. Voov toddles over and helps me scratch. Shmoop joins in too-- all three of us scratching away at my legs.
Thanks, kids. Though scratching is a department I usually don't need much help with.
I've been reading up on the genetics of eczema. When I've managed to get my head around the subject I'll try to write about it. Suffice it to say that filaggrin is only part of the whole picture, which is complex enough that this picture doesn't do it justice.
In the academic literature, eczema is referred to as "atopic dermatitis" (AD). I always thought this was disingenuous on the part of doctors, to use fancy words that mean the same thing as plain words, in order to maintain the illusion of expertise. "Dermatitis" obviously means "skin inflammation," and I assumed "atopic" meant "we don't know what the hell causes it." (Now I know that would be "idiopathic.") A Google definition search reveals that "atopy" actually has a specific meaning: "allergic hypersensitivity affecting parts of the body not directly in contact with the allergen." Who knew?
Anyway-- eczema, or AD, covers a whole spectrum of disorders. I would like to be as clear on this blog as possible about what I mean by eczema and how it might be cured. You might be interested to know, for example, that two major types of eczema have been identified: "extrinsic" and "intrinsic." Extrinsic AD affects 70-80% of adult patients and involves high levels of circulating IgE antibodies and reactions to environmental allergens. The remainder of adult patients have intrinsic AD, which is defined as the kind that DOESN'T involve high IgE levels or allergies.
IgE is one of five antibody types. IgE is the kind involved in allergies-- when mast cells and basophils bind IgE, they release histamine, which triggers inflammation. IgE is also, somehow, protective against parasitic worms. It could be that those of us with eczema are descended from a population that was under severe evolutionary pressure from parasitic worms. These worms are no frickin' joke-- look up "elephantiasis" or "river blindness" if you can stomach the photos. I don't know about you, but I'd rather have eczema.
I'm guessing that I and my family have extrinsic AD. Naturally, that's the kind I'm interested in!-- but, knowing all too well what it's like to live with eczema, I'd like to see all of us cured.
I'm not naive, either-- I know eczema is fiendishly complex and there's no cure at the moment. It may turn out that we won't see a cure for hundreds of years. It may turn out that the only way to prevent eczema is gene therapy in embryos. It may turn out that you can reduce symptoms dramatically by rubbing your baby with a certain type of protective cream to prevent allergen entry through the skin, and that if you do this during a certain time window, the protection will extend to adulthood. It may turn out that we can't fix anything fundamental, but that we can turn off itching and scratching by using some miracle drug that gets discovered completely by accident. (And, likely, the drug will only work for a certain fraction of people-- but maybe we can identify them by genomic screening.)
Anyway-- eczema, or AD, covers a whole spectrum of disorders. I would like to be as clear on this blog as possible about what I mean by eczema and how it might be cured. You might be interested to know, for example, that two major types of eczema have been identified: "extrinsic" and "intrinsic." Extrinsic AD affects 70-80% of adult patients and involves high levels of circulating IgE antibodies and reactions to environmental allergens. The remainder of adult patients have intrinsic AD, which is defined as the kind that DOESN'T involve high IgE levels or allergies.
IgE is one of five antibody types. IgE is the kind involved in allergies-- when mast cells and basophils bind IgE, they release histamine, which triggers inflammation. IgE is also, somehow, protective against parasitic worms. It could be that those of us with eczema are descended from a population that was under severe evolutionary pressure from parasitic worms. These worms are no frickin' joke-- look up "elephantiasis" or "river blindness" if you can stomach the photos. I don't know about you, but I'd rather have eczema.
I'm guessing that I and my family have extrinsic AD. Naturally, that's the kind I'm interested in!-- but, knowing all too well what it's like to live with eczema, I'd like to see all of us cured.
I'm not naive, either-- I know eczema is fiendishly complex and there's no cure at the moment. It may turn out that we won't see a cure for hundreds of years. It may turn out that the only way to prevent eczema is gene therapy in embryos. It may turn out that you can reduce symptoms dramatically by rubbing your baby with a certain type of protective cream to prevent allergen entry through the skin, and that if you do this during a certain time window, the protection will extend to adulthood. It may turn out that we can't fix anything fundamental, but that we can turn off itching and scratching by using some miracle drug that gets discovered completely by accident. (And, likely, the drug will only work for a certain fraction of people-- but maybe we can identify them by genomic screening.)
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