Turns out Protopic and Elidel carry no cancer risk

If you’ve ever considered using Protopic or Elidel as an alternative to steroids, you, like me, will have been taken aback by the FDA’s black-box warning that these drugs theoretically could increase your risk of getting cancer. (In the US, there's an actual black box on the packaging, somewhat more prominent than the warning on cigarette packs.)

A new, well-written report debunks this claim thoroughly.

Written by two researchers at Saint Louis University in Missouri and UT Medical School in Texas and a science writer in Chicago, and published in the American Journal of Clinical Dermatology, the paper points out that the FDA’s 2005 advisory was based on three justifications: extensive off-label use to treat children under two years old; a very small number of adverse drug reports (two for Elidel and five for Protopic); and a study done in monkeys in which the animals were given much larger doses than would be typical for human patients.

Now, eight years after the first FDA warnings appeared, the authors say that use of these creams has not been shown to increase a patient’s risk of developing any type of cancer.

Elidel (pimecrolimus) and Protopic (tacrolimus) are “calcineurin inhibitors” formulated as creams. They reduce the levels of pro-inflammatory molecules produced by T cells. With all immune-suppressant drugs there is always a possibility that the drug will prevent the body from destroying cells that have become malignant. But Elidel and Protopic do not raise the risk above the background level.

Unlike topical steroids, calcineurin inhibitors do not thin the skin, and patients who use them apparently do not experience a “rebound” effect in which the eczema returns after drug use stops, as is the case with steroids.

According to a graph in the report, Elidel sales are now much lower than they were in 2005, while Protopic sales have recovered to their original levels.

This matters because calcineurin inhibitors are a valuable alternative to steroids—for some, at least. When I tried Elidel, it did nothing for me, and Protopic gave me an intense burning sensation and a terrible headache.

So if you have been putting off using these drugs for fear they might cause cancer—now’s the time to give them a try!

"Itch molecule" discovery a big step forward

All over the media last week was the news that two scientists at the National Institutes of Health in Bethesda, MD had discovered “the molecule responsible for itch.”

This molecule, “Nppb,” relays signals from certain neurons that detect itch in the skin to other neurons that carry the signals up the spinal cord to the brain. The scientists, Santosh Mishra and Mark Hoon, engineered mice in which the gene for Nppb had been turned off. The mice could not, apparently, feel itch.

The media hype is evident. Nppb is not THE molecule responsible for itch. Several molecules are known to be involved in detecting itch in the first place, and we know many others must be involved in the signaling pathway.

What is remarkable, though, is that the scientists were able to define a model for how itch gets from the skin to the spinal cord.

Mishra and Hoon's model of how neurons carry the itch signal. (Fig 4G from their Science paper.)

We now know that there are at least two pinch points: the synapse across which Nppb carries the signal, and a second downstream synapse across which another molecule, GRP, sends the information to the next stage of neurons.

Blocking the receptors for Nppb or GRP would seem to be a prime candidate for an anti-itch therapy. 

But, of course, there are complications. Nppb was originally known because it is important in the heart, where it controls blood pressure. GRP controls digestion. The genetically engineered Nppb-free mice died early. (The scientists said so in their media interviews.) 

So you can’t just take a pill that blocks Nppb receptors everywhere. That would be a disaster.

But this kind of restriction on where a drug can act is well-known in pharmacology. That’s why, e.g., I can use the anti-pain Voltaren gel (diclofenac) safely by rubbing it into my joints, but diclofenac is known to be pretty toxic if you swallow it.

You can’t design an Nppb receptor-blocking topical cream, because the important synapses are in the spinal cord. A cream would only be effective on the surface.

But it might be possible to take a pill that blocks Nppb only in the spinal cord. I’m not sure how, but that’s what major pharma companies are paying their scientists the big bucks to find out. Maybe the receptors in the spinal cord are subtly different than those elsewhere in the body.

This is very exciting stuff. The massive question is whether the work applies to humans. I would expect it did. Mice and human immune systems are quite different, but our nervous systems are not. We most likely have an analog of Nppb that carries our itch signals.

Just to put this in context—the new work tells us substantially more about itch signaling than previous work in the field. I’d been aware of studies that had identified a class of itch neurons, or certain molecules important in detecting itch in the skin, but this research builds on those foundations in a big way.

TopMD conducts clinical trial of CLn Bodywash for marketing purposes

CLn Bodywash, the “bleach bath in a can,” sounds like a product that we all need—a quick and easy way to cleanse your skin of Staphylococcus aureus and other nasty bacteria associated with eczema. But the marketing campaign arranged by CLn’s maker, Dallas-based TopMD, could be better.

For a start, they could arrange a decent clinical trial.

CLn must be classified as a cosmetic and not a medical product, because the FDA didn’t require tests before CLn hit the stores.

You would think the usual way to proceed with a medical product would be:

1)    clinical trial to prove safe and effective
2)    manufacturing and marketing

But TopMD scientists recently published the results of a clinical trial for CLn in the journal Pediatric Dermatology, about nine months after I first heard the product was for sale.

Of course dilute bleach baths are a known household treatment to manage skin bacteria. CLn is a portable bleach bath and isn't going to be any more hazardous than what thousands of people are already doing in their bathtubs. But is it any better? Is it worth paying money for?

I think that some marketing analyst decided that doctors around the US were reluctant to buy or recommend CLn because it hadn’t undergone a clinical trial. Now it has—with the shiny label “peer-reviewed,” although the journal it was published in is low-impact, and the “peer” who deemed the study worthy of publication could well have been a single graduate student.

The study might possibly qualify as a “phase 0” trial. It’s conducted on 18 subjects all of whom are given the product. There’s no control group that receives a placebo.

This is a problem, because both the doctors conducting the trial and the patients both want the product to work. So the reported results are bound to look better than they really are. Scientifically, this study is far from the final word on whether CLn is truly effective.

The way to avoid this problem is to have a double-blind randomized control trial where, at the very least, half of the patients get CLn and half get something that looks like it but isn’t, and nobody knows which is which until the results have been recorded.

For an example of how this might be done, at least in a way that looks good from a marketing perspective, you can see that the makers of DermaSilk clothing appear to get it right in their studies, the most recent of which was published online this week.

That the recent CLn study was motivated by marketing is clear from one of its measures. Participants were asked “Would you recommend CLn to a friend?” This is not a data point you see in too many scientific papers.

The company’s press release quotes UC San Diego’s Dr. Larry Eichenfield, chief of pediatric and adolescent dermatology at Children's Hospital, San Diego—a world leader in the field. Eichenfield says “I am excited to read the study by Dr. Ryan et al showing the benefits of TopMD's sodium hypochlorite-based body wash.”

The release doesn’t mention that Eichenfield sits on TopMD’s medical board.

I like the idea of CLn, and I think it’s probably a valuable product. I’m happy they sent me a free bottle to review back in October, and I’m keeping it in case I need it. But I wish they could present some more convincing evidence that it works. Are they afraid that it doesn’t? If not, why not use a control group in the study?

Where to look for a surprise eczema cure to emerge

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.

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