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.
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.
Monday, May 13, 2013
June 8 Itching for a Cure walk in New Jersey: it's not about you
The National Eczema Association recently announced the second annual Itching for a Cure walk, which will raise awareness and funds for eczema outreach and research. It will take place June 8 on the Monmouth University campus in New Jersey--essentially greater New York City. (Last year's walk was held in Asheville, North Carolina.)
The largest barrier for me, as an adult patient, to participating in such a walk--were one to be held in the area I live in--is embarrassment. Eczema is not a socially acceptable disease. It's there on your skin, sometimes your face, where people can see there's something wrong with you. And when it's not visible, that's a good thing. You want to hide it.
In this matter, there's a huge difference between a parent of a child with eczema and an adult patient with eczema. The mother or father of a child with eczema is not embarrassed. They are concerned and want to do everything they can to make their child better.
On top of the embarrassment factor, it seems a bit selfish, a bit like a panhandler, for an adult patient to take part in an eczema walk. Sponsor me, it seems to say, to raise money for a cure for me!
Mothers and fathers are ready to fight for their kids. They are not doing it for themselves. They will proudly take part in an eczema walk, and look you in the eye.
The absence of adult patients from Itching for a Cure is probably not a major factor. After all, eczema is predominantly a condition that children outgrow. But how might we convince adult patients, including me, to take part?
I think the key lies in altruism. It's not about you.
Let's face it--if you're raising money to increase awareness of the prevalence of eczema, or how it should be properly treated, or to fund research that might lead to a pharmaceutical cure--you are not doing it for yourself. There will be no cure for eczema in your lifetime. You are doing it for other people. Your grandkids, and millions of people you will never know.
It becomes a lot less embarrassing when you're doing it for somebody else.
And that is why if there is ever an Itching for a Cure walk in my area, I'll be signing up. I know exactly how shitty it is to live with this condition, and how important it is that other people be spared the torment and the embarrassment. It's not me I'll be doing it for--it's you!
The largest barrier for me, as an adult patient, to participating in such a walk--were one to be held in the area I live in--is embarrassment. Eczema is not a socially acceptable disease. It's there on your skin, sometimes your face, where people can see there's something wrong with you. And when it's not visible, that's a good thing. You want to hide it.
In this matter, there's a huge difference between a parent of a child with eczema and an adult patient with eczema. The mother or father of a child with eczema is not embarrassed. They are concerned and want to do everything they can to make their child better.
On top of the embarrassment factor, it seems a bit selfish, a bit like a panhandler, for an adult patient to take part in an eczema walk. Sponsor me, it seems to say, to raise money for a cure for me!
Mothers and fathers are ready to fight for their kids. They are not doing it for themselves. They will proudly take part in an eczema walk, and look you in the eye.
The absence of adult patients from Itching for a Cure is probably not a major factor. After all, eczema is predominantly a condition that children outgrow. But how might we convince adult patients, including me, to take part?
I think the key lies in altruism. It's not about you.
Let's face it--if you're raising money to increase awareness of the prevalence of eczema, or how it should be properly treated, or to fund research that might lead to a pharmaceutical cure--you are not doing it for yourself. There will be no cure for eczema in your lifetime. You are doing it for other people. Your grandkids, and millions of people you will never know.
It becomes a lot less embarrassing when you're doing it for somebody else.
And that is why if there is ever an Itching for a Cure walk in my area, I'll be signing up. I know exactly how shitty it is to live with this condition, and how important it is that other people be spared the torment and the embarrassment. It's not me I'll be doing it for--it's you!
Thursday, May 9, 2013
Thumbs up for shea butter as a scalp moisturizer
In my ongoing search for a scalp moisturizer, I have a new favorite: shea butter.
I had heard about shea butter about for years. I hadn't tried it because it cost a lot and seemed a kooky natural product of dubious merit and uncertain quality control. But dry skin and eczema on my scalp is now my primary problem. For several months I have been coating my head with Aveeno Daily Moisturizing lotion and feeling like I'm wearing a rubber bathing cap all day. It works OK but leaves something to be desired as a hair product. So I was up for trying new things.
Then, I found a jar of shea butter just sitting around on my four-year-old daughter's dresser. She has eczema and my wife must have bought the shea butter and tried it out without me knowing. (Cue the eye-rolling on my wife's part.) Anyway, the stuff was no longer in use, she informed me, so, having already paid for it, I was free to try it out.
The brand was True Blue Spa Too Shea, if you're interested. $17.50 for 3.5 oz.
It goes on like actual butter--it's hard at first, but you take a bit in your fingers and it warms up and melts a bit. Then you rub it on your scalp and once it's on, it stays melted.
It works for me because I buzz my head with a 1/2 inch clipper attachment. So I am not wasting too much of it on my actual hair.
The feeling is a little greasy but not terrible. Plus shea butter is actually used as a hair product. Would you believe I had a compliment on my hair earlier this week? The first in a very long time.
I looked into shea butter. It comes from the nuts of the shea tree in west and central Africa. It's a complex fat and apparently there is a wide range in quality. Someone named Samuel Hunter recently created the American Shea Butter Institute, which could well be a one-man operation for all I could determine, to certify various grades of shea butter depending on their oil content, melting profile, impurities and "rancidity values." Shea butter is edible, and therefore goes bad like real butter. (But no mention is made of refrigeration.)
I can't recommend one type or brand of shea butter to use, because it's not clear what would make one better than another. You just wouldn't want it to be rancid, evidently.
I don't search out natural products, because I don't think they're necessarily any better than manufactured moisturizers and so on, but shea butter is the best solution I've found so far for moisturizing my scalp.
I had heard about shea butter about for years. I hadn't tried it because it cost a lot and seemed a kooky natural product of dubious merit and uncertain quality control. But dry skin and eczema on my scalp is now my primary problem. For several months I have been coating my head with Aveeno Daily Moisturizing lotion and feeling like I'm wearing a rubber bathing cap all day. It works OK but leaves something to be desired as a hair product. So I was up for trying new things.
Then, I found a jar of shea butter just sitting around on my four-year-old daughter's dresser. She has eczema and my wife must have bought the shea butter and tried it out without me knowing. (Cue the eye-rolling on my wife's part.) Anyway, the stuff was no longer in use, she informed me, so, having already paid for it, I was free to try it out.
The brand was True Blue Spa Too Shea, if you're interested. $17.50 for 3.5 oz.
It goes on like actual butter--it's hard at first, but you take a bit in your fingers and it warms up and melts a bit. Then you rub it on your scalp and once it's on, it stays melted.
It works for me because I buzz my head with a 1/2 inch clipper attachment. So I am not wasting too much of it on my actual hair.
The feeling is a little greasy but not terrible. Plus shea butter is actually used as a hair product. Would you believe I had a compliment on my hair earlier this week? The first in a very long time.
I looked into shea butter. It comes from the nuts of the shea tree in west and central Africa. It's a complex fat and apparently there is a wide range in quality. Someone named Samuel Hunter recently created the American Shea Butter Institute, which could well be a one-man operation for all I could determine, to certify various grades of shea butter depending on their oil content, melting profile, impurities and "rancidity values." Shea butter is edible, and therefore goes bad like real butter. (But no mention is made of refrigeration.)
I can't recommend one type or brand of shea butter to use, because it's not clear what would make one better than another. You just wouldn't want it to be rancid, evidently.
I don't search out natural products, because I don't think they're necessarily any better than manufactured moisturizers and so on, but shea butter is the best solution I've found so far for moisturizing my scalp.
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