Thursday, July 18, 2013

Eczema patients not protected by intradermal flu vaccine

When I talked to Donald Leung earlier this week (he's head of pediatric allergy & immunology at National Jewish Health, and leads the Atopic Dermatitis Research Network) he mentioned one interesting result that has already emerged from a small-scale ADRN trial. Leung and others showed that patients with atopic dermatitis were not adequately protected, by FDA standards, by the new influenza vaccine Fluzone.

Fluzone is administered using a super-short needle--the technique is called "intradermal" injection in which the vaccine gets squirted into the upper skin layers rather than muscle tissue.

Presumably the super-short needle is less scary than a regular needle, and more people will get their flu vaccinations this way; it could be a public health issue in the event of a flu pandemic.

Scientists know that the immune system functions differently in the skin of patients with eczema. Leung and colleagues looked at how 20 eczema patients fared with Fluzone, compared to 20 non-atopic patients. Twenty-eight days after vaccination, they measured the levels of flu antibodies in the patients' blood. The non-atopic patients met the FDA standard; the eczema patients did not.

The scientists published their results in a preliminary form as an abstract at the meeting earlier this year of the American Academy of Allergy, Asthma and Immunology.

Wednesday, July 17, 2013

New NEA post: Atopic Dermatitis Research Network needs trial participants

This week you'll find me blogging over at the National Eczema Association website. I interviewed Donald Leung of National Jewish Health about the Atopic Dermatitis Research Network. Three years in to a $42M program to investigate the links between genetics and our susceptibility to skin infections, the ADRN is registering patients with the NIH before proceeding with clinical trials.

They still need black and Hispanic patients to sign up--eczema, genetics, and skin pathogens are different for different ethnic groups. The better your demographic is represented in the trials, the more that scientists will learn that applies to you.

The ADRN has centers in Boston, Chicago, Denver, Los Angeles, Portland OR, and Rochester NY.

If you're interested in participating, email Judy Lairsmith at National Jewish or call 1-888-413-5852.

Wednesday, July 10, 2013

Irwin McLean's filaggrin readthrough drug could be revolutionary

Recently I predicted that nothing resembling a cure for eczema would appear for at least 25 years. I followed that up with a prediction that if a surprise cure were to emerge, it would be an anti-itch therapy.

At least one reader disagreed, and pointed me to a strategy now being developed at the University of Dundee in Scotland: drugs to stimulate or enable filaggrin expression in patients with one or two defective copies of the corresponding gene, FLG. At least one such drug is in the very earliest stages of drug development, toxicology studies in animals. If the drug succeeds in human clinical trials, we might see it in clinics in about 15 years. Potentially, such a drug could help some of the patients most severely affected by eczema.

The best review on filaggrin I’ve seen was co-written by three authors, two of whose names I am familiar with as among the biggest in the field of eczema research: Irwin McLean, who led the team that linked mutations in FLG to increased risk of developing ichthyosis vulgaris and eczema, and Donald Leung, principal investigator of the Atopic Dermatitis Research Network. (The first author is Alan Irvine, a colleague of McLean’s who works in Ireland.)

FLG is a giant, and unusual, gene, one of the last to be sequenced by the Human Genome Project. It encodes an enormous protein, profilaggrin, which contains from 10 to 12 repeats that are cleaved off into individual filaggrin units. Filaggrin itself has several important roles in the upper layers of the skin: it flattens skin cells into their characteristic final shape; it helps bind these cells together into a barrier; and it breaks down into the acidic “natural moisturizing factor.”

Many mutations have been found in FLG. Interestingly, if you take any particular ethnic group (say Japanese), there will be a characteristic profile of mutations for this group that is likely to be different than the profile for another group (say Scottish).
FLG (read from left to right; red hexagons are filaggrin units.) Common mutations in Asian and European populations. Look how early the nonsense mutation R501X appears. Figure 3A from Irvine, McLean, and Leung's NEJM review

All filaggrin variants are either “nonsense” or “frameshift” mutations in DNA that encodes protein (as opposed to so-called “junk DNA”). In a nonsense mutation, the correct DNA base has been replaced with a wrong one, and the upshot is that the protein-making machinery, known as the ribosome, runs into a code that it doesn’t recognize; it can’t add an amino acid to the growing protein, and it stops decoding profilaggrin at that point.

If the nonsense mutation occurs early enough, before the first filaggrin unit in FLG, no filaggrin gets made at all.

I believe that with a frameshift mutation (in which one or more DNA bases are missing or added) the protein is very likely to be terminated soon afterward. The end result is the same: little or no filaggrin.

In his 2006 Nature Genetics paper, McLean and his group identified two mutations, R501X (nonsense) and 2282del4 (frameshift), which have turned out to be the most common in Caucasian populations. Both R501X and 2282del4 occur early in the first filaggrin repeat. That means that if you have one such mutation, you will have one good copy of FLG and one bad copy; and if you have mutations on both your copies of FLG, you won’t have any filaggrin at all, and there is a high chance that you have eczema.

Soon after their 2006 discovery, McLean and first author Frances Smith applied for a US patent,  “Prevention/treatment of ichthyosis vulgaris, atopy and other disorders.” The patent, number 8,338,386, was granted only recently, on December 25, 2012. It makes many claims, all relating to the ability of five antibiotic drugs, or potentially tRNA molecules, to force the ribosome to read through nonsense mutations.

McLean and Smith’s patent is aimed at the nonsense mutation R501X (they say so in the patent), because it occurs so early in the gene. Such a drug would also work for nonsense mutations later in the sequence.

The drug or agent would not work on frameshift mutations such as 2282del4, as I understand it.

One cool thing about a readthrough drug would be that it would have its strongest effect on people who had nonsense mutations on both copies of FLG. A readthrough drug would theoretically make both copies functional. People with only one mutated copy of FLG would still benefit from having that number increased to two.

In the patent,“atopy” is mentioned in the title and the background information, but neither “atopy” nor “atopic dermatitis” appear in any of the 14 explicit claims. I don’t know whether this matters. I'm not an IP lawyer. It seems curious that the inventors left it out though.

Another curious fact is that only five specific drugs are mentioned: gentamicin, paromomycin, neomycin, tobramycin and negamycin. There is no discussion of the drug discovery process—any tweaking of molecules for greater effect or less toxicity—that I can see. I don’t know whether this matters either.

From what I can tell, McLean’s group has at least one of these compounds, which has most likely been altered from its original structure, in “toxicology” (which means testing in mice, rats, etc.) (see page 16). If you look at this handy graphic provided by the FDA, you will see that toxicology studies are step 2 of 12 in the drug discovery-to-market process. So it is extremely early days and you have to keep in mind that, as I keep saying, almost all drug candidates fail at some stage of clinical testing.

A relevant factor is also that currently there is no FDA-approved drug that acts by this mechanism—by causing the ribosome to ignore nonsense mutations. Ataluren, a drug to cure Duchenne muscular dystrophy and cystic fibrosis, is a readthrough drug in phase III clinical trials. The FDA is apparently especially careful when approving drugs that are “first-in-class,” or the first of their general type. So it is worth following Ataluren’s progress closely; its success could mean that we might see an eczema readthrough drug sooner.

Hat tip to Anonymous (you know who you are)

Tuesday, July 2, 2013

NYC area clinical trial for eczema therapy recruiting participants

A research group at Rockefeller University in New York City seeks participants for a clinical trial of an experimental therapy for atopic dermatitis. See below for details.

Dr. Emma Guttman-Yassky, Dr. Saakshi Khattri and others are exploring whether Stelara (ustekinumab), currently approved in the US for treatment of psoriasis, might benefit patients with moderate to severe AD whose condition has not improved with conventional treatment.

Ustekinumab is a monoclonal antibody to the p40 subunit of the signaling proteins IL-12 and IL-23. It binds to these proteins and prevents them from working. Since IL-12 and IL-23 are involved in the development of certain kinds of T cells, ustekinumab will put a damper on a subset of the T cell arm of the immune system.

I started to speculate about exactly how ustekinumab might work for AD but then I wisely looked at the researchers' own explanation on I was only 25% right, so you'd do well to look at their writeup if you're interested.


Randomized Pilot Study of Ustekinumab for Subjects with Chronic Atopic Dermatitis Who Have Sub-optimal Response to Prior Therapy

This study is currently recruiting participants.
Verified March 2013 by Rockefeller University

Rockefeller University

Information provided by:
Rockefeller University Identifier: NCT01806662

We are carrying out a clinical trial with the drug Stelara (ustekinumab), which is already FDA approved for Psoriasis, in patients with moderate to severe eczema, ages 18 years - 75 years.  In order to be eligible, a patient must have failed at least topical steroids and either light therapy or oral steroids. Patients will have 15 visits over the course of a year at Rockefeller University, which is located on the Upper East Side of New York City. Patients are guaranteed to receive 3 doses of Stelara throughout the study. Patients will also be allowed to use Triamcinolone 0.025% during the course of the study.  If the medication is effective at clearing a patient’s eczema, they will be eligible to receive an extra dose at the completion of the study.  For full participation, patients are compensated $600.

Name/Title of the Principal Investigator: Dr. Emma Guttman, MD/PhD

Contact Information:
Saakshi Khattri, MD - Clinical Research Fellow
1230 York Avenue
New York, NY  10065
Business number: 212-327-8354/8333
Fax number: 212-327-8232
Recruitment Office 1-800-782-2737

For more information, please visit: