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

Will we see gene therapy for eczema?

The European Commission is close to approving the first gene therapy in the Western world, according to the New York Times.

The treatment, called Glybera and developed by the Dutch company uniQure, treats a rare condition in which people are unable to break down fat-carrying molecules.

Gene therapy is one way that I imagine patients of the future might be cured of eczema. Glybera gives us a peek into how that might happen.

In gene therapy, doctors replace a patient’s faulty gene with a good one. The large protein filaggrin is currently the best candidate for eczema gene therapy. Several studies have linked filaggrin mutations to a higher risk of developing eczema.

Filaggrin gene therapy would have to be applied early in life. This is because in our current understanding, eczema is caused by a skin barrier defect that allows allergies to develop after a critical time window. Filaggrin mutations cause a faulty skin barrier. So you’d have to fix filaggrin early, because waiting too long would allow allergies to develop, after which fixing filaggrin solves only half the problem.

Glybera is a biotherapeutic, a gene (length of DNA) that is attached to a well-characterized and benign virus. Doctors will inject Glybera into leg muscles, where the virus infects cells and incorporates itself and the therapeutic gene into the patient's DNA—but only in leg muscle cells, presumably because Glybera gets absorbed locally. Then the patients will be able to break down the fat-carrying molecules, and their blood will no longer be overloaded with fat.

A biotherapeutic for eczema would likely be an intact filaggrin gene incorporated into a similar virus.

Gene therapy for the skin would have to be restricted to skin cells. You could accomplish this with a topical cream or ointment applied in the clinic. I'm guessing you would want to treat your whole skin, not just spots that were flaring up at the time.

How long will it last? The effects of Glybera apparently last for years, probably because muscle cells live a long time. Skin cells are a different matter—they are turning over continually. This could turn out to make gene therapy for skin conditions near-impossible.

But perhaps you could take regular doses—pills or injections—of a gene therapy that includes a genetic switch that turns on only in skin cells.

The critical early window for developing allergies in eczema patients could turn out to be a bonus in disguise. Maybe filaggrin gene therapy would only be required during a window of a few years, after which it could be discontinued and allergies would never develop.

Obviously extensive clinical trials for safety would be necessary. I could imagine this type of therapy becoming available within two decades. My grandchildren could be among the first to benefit.