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

Anacor's eczema therapeutics: the Wankel rotary engines of dermatology

Anacor Pharmaceuticals, a company located near me in the Bay Area, has two interesting drug candidates in the pipeline to treat eczema. I've been meaning to review them for a while--at first I thought I needed to speak to someone at Anacor, but then I realized that a lot of the information is online and if I did manage to hear from an Anacor rep I'd probably only get a bland corporate response. (Ideally you want to hear criticism from a competitor to get the real dirt!)

The two compounds, AN2728 and AN2898, are also in clinical trials for treatment of psoriasis--the trials for psoriasis are a couple substages ahead of those for eczema. Look at the structures--you can see they are closely related compounds. They both inhibit the enzyme phosphodiesterase IV (PDE4). PDE4's job (it's primarily found in white blood cells) is to break a bond in a signaling molecule called cyclic AMP (cAMP).  Although cAMP participates in all kinds of processes in the body, in white blood cells it turns off inflammation. So if you inhibit the enzyme that breaks down cAMP, you inhibit inflammation.

So Anacor's compounds, which I believe are in trials as topical creams, could be an alternative to corticosteroids. Clinical trials in humans will show whether AN2728 and AN2898 have more or fewer side effects than steroids.

I find Anacor interesting because it's local, for me, and because boron compounds are chemically unusual in biology. Boron can form either three or four bonds with neighboring atoms, and while carbon can also do this (two single bonds and one double bond), Anacor says that using boron in their compounds lets them make molecules that can interact with enzymes in unusual ways that carbon compounds cannot.

A small contingent of medical chemists seems to be cheering Anacor on just because boron compounds are cool. It's like mechanics who love the Wankel rotary engine in the Mazda RX-7 because it works differently from engines in most other cars. But the ultimate test is whether these compounds work. It would be nice to have another topical option to reduce inflammation and itch.

Even if they do work, they'll only be treating the local symptom of the disease and not its cause or systemic origin. But, in their favor, that is how Protopic and Elidel work--when they DO work.

Here comes the asthma

So it happened, a few weeks ago: Voov showed the first signs of developing asthma. We were always aware that she might, because eczema runs in the family and my sister has eczema and asthma, and asthma is the final part of the famous Atopic Triad. Still, it is a bummer to see your two-year-old with a rubber mask over her face taking her twice-daily dose of an inhaler.

Voov had had a cold, and was in for a checkup, and the doctor noted that she had a slight wheeze; her blood oxygenation was at 95%. So, with her history, the doctor tentatively diagnosed asthma and sent her home with the inhaler and a special mask. Voov was initially pretty excited about the attention, but after a few days, applying the inhaler took two adults, one to straitjacket the kid and the other to handle the inhaler.

Then she got better or at least well enough that she didn't have a wheeze. For now, the inhaler's packed away. Voov is healthy and upbeat and I think she'll cruise right through childhood just fine even if she has to carry an inhaler with her.

* * * 

I thought I'd mention this great review I read recently titled "Epidermal Barrier Dysfunction in Atopic Dermatitis." It's from 2009 and provides an encyclopedic view of how known genetic factors are related to the breakdown of the skin barrier, and how many factors such as pH and enzymes and antimicrobial peptides are involved. It also has an interesting section toward the end featuring this graphic

with an accompanying explanation of how it is that many more kids than adults have eczema, and how the condition improves with age for the lucky majority. Basically, when we're newborn, our skin barrier is terrible, the worst it'll ever be. In the first few years of childhood, the quality of our skin improves. In those people who have minor genetic defects that affect the skin barrier, eczema develops early on but fades away as the skin improves past some threshold. People with serious genetic defects like major filaggrin mutations never see their skin improve past the threshold, so they never escape eczema.

At least that's how the authors put it. It's a pretty hand-waving theory. For one thing, many scientists think that a poor skin barrier lets in pathogens and allergens that trigger a heavy immune response early on, and that this response imprints a permanent memory in the body (in the form of antibodies) that powers reactions to certain foods. So if this "memory" is made early on in the 20% of kids who have eczema, why does it go away for most of them after the skin barrier improves?

* * *

One final item: Anacor Pharmaceuticals has begun phase 2 clinical trials of two novel anti-inflammatory ointments for treatment of eczema. The two compounds are boron-based (this is unusual) and have shown promise for treating psoriasis in more advanced clinical trials. For a thorough comparison of psoriasis and eczema, see the most recent JACI Journal Club, which discusses a two-part review paper on the topic.

The holiday challenge begins

Tomorrow in America, the first wave of the great tide of holiday craziness will wash over us-- beginning with the inevitable turkey dinner. I'm not a native-born American, so although I have come to love Thanksgiving, I'm still not used to the idea of the entire month of December being given over to overeating and indulgence. At work, the holiday parties start the Monday after next. It's almost impossible to avoid eating or drinking all kinds of things that trigger eczema: chocolates, booze, spices. More booze. And eggnog. I used to like eggnog--in fact, I still do--but a few years ago, after having had a skin prick test that showed I reacted to raw egg white, I suddenly realized that eggnog has RAW EGGS in it, and that's why I was always scratching like a monkey after a glass or three. (Sometimes the eggnog has booze in it, too.)

* * *

I'm always interested when there's a story in the news about someone with eczema. Here's a recent one from Scotland, about a five-year-old girl in Linlithgow (outside Edinburgh).

Despite being so young, Gaelle, a primary one pupil, has used her experiences of atopic dermatitis to educate her classmates and teachers, who have to help her apply her skin cream and bandages every day at school.

She even used her birthday party to fundraise for the cause.

At five years old, she can't have come up with these ideas on her own. She's got some parents who are taking the offensive. It's a good idea. When the kids in Gaelle's class are older and start to cast about for others to tease, they'll at least have had some hands-on experience with eczema and some understanding of what it means to someone who lives with it, and they may not be so quick to treat her as an alien.

* * *

Another news item: UAS Labs, a probiotics company in Minnesota has won an award for "Probiotic Customer Value Enhancement." Thrilling stuff, you will agree. What caught my attention was that UAS makes five "formulations" of live bacteria for specific conditions, and one of them is atopic dermatitis. What's in the AD formulation? A mix of Lactobacillus acidophilus (the yogurt bacterium) and Bifidobacterium lactis. Both are common gut bacteria, but also common probiotics. UAS worked with a scientist in Ukraine on a study to explore how their formulation might improve AD in kids aged one to three. It's not clear whether UAS funded the study; I expect they did, because otherwise there'd be no need for someone in Ukraine to obtain UAS's formulation. Still, the results of the study--presented at a symposium, not published in a journal--showed that eczema symptoms were reduced by 34% on a standard scale for kids taking the probiotics, versus being reduced 19% for kids taking placebo.

If these results are real, which is not at all certain, then it's interesting to think how intestinal bacteria could help reduce eczema. Are they helping the body digest milk proteins or sugars that would otherwise cause an inflammatory response that, in susceptible people, manifests in the skin? Lactose intolerance is widespread. Perhaps it's linked to milk reactions in eczema. I don't know at this point.

* * * 

And a novel topical anti-inflammatory cream/ointment is entering phase 2 trials in eczema patients. Anacor is a San Francisco Bay Area company that makes drugs based on its trade secret, a "boron chemistry" platform. Phase 2 is VERY early in drug discovery, but it's interesting to watch this sort of thing emerge. They seem to have a good idea of what their drug is doing to reduce inflammation.

I'll be off tomorrow. We may be lucky and hear from Dr. Sib. She's Canadian and had her Thanksgiving about a month and a half ago. Unless she's working the midnight-to-8 am ER shift, what possible excuse could she have for not writing?