Repurposed drug could repair the skin barrier
Lisa Beck, a professor of dermatology at the University of Rochester Medical Center (URMC), will soon begin an NIH-funded clinical trial of Actos (pioglitazone), a drug often prescribed for diabetics, which may turn out to strengthen the skin barrier and reduce symptoms for eczema patients.
Actos, made by Takeda Pharmaceuticals and already approved by the FDA in pill form, could appear unofficially on the market for eczema therapy much sooner than a new drug discovered from scratch.
"Experts sometimes use off-label drugs to treat patients with moderate to severe eczema or atopic dermatitis,” Beck wrote in an email. “Such drugs include immunosuppressives such as cyclosporine, and many require close safety monitoring to prevent untoward effects.”
"The FDA goes through a lot of effort to certify new drugs in collaboration with drug companies, but once it's on the market, you can write for it off-label," said Alice Pentland, the James H. Sterner Professor of Dermatology and chair of the Department of Dermatology at URMC when I spoke to her on the phone recently.
There is not much in the pipeline when it comes to drugs for eczema. "I was at a planning meeting for the American Academy of Dermatology on the weekend," Pentland said. "They were sharing what the latest round of new therapies for atopic dermatitis might be. There just isn't much. It's the same old same old.” Companies are developing therapies, but for the most part nothing is past stage 2 clinical trials.
Actos has been shown in laboratory experiments to repair the skin barrier, and could block or slow or reduce the development of atopic dermatitis, Beck wrote, adding that this is a new tactic compared to the way steroids or calcineurin inhibitors work.
Actos was developed to treat type 2 diabetes. One of its effects is to increase the body's sensitivity to insulin. Pentland says that Actos should have little effect on the metabolism of non-diabetics, however.
Beck and her colleague, Anna De Benedetto, a research fellow at URMC, identified Actos in a survey looking for drug compounds that could affect “tight junctions,” which hold cells together in the upper layers of the skin. Tight junctions are “like carpet tacks—they go through from one cell to another and tighten up the attachments between them," Pentland said. Tight junctions are thought to be defective in eczema patients. This partly explains the dry skin, and may also explain why eczema patients are more susceptible to environmental allergens. Their skin isn’t tacked together.
Beck and De Benedetto believe that dysfunctional tight junctions may result in part from reduced levels of one protein component, claudin-1. In benchtop experiments on skin cells, De Benedetto found that Actos enhanced the production of a number of barrier genes, including claudin-1.
One known, potentially beneficial side effect is that Actos tilts the immune system from a T helper type 2 response to a type 1 response. In eczema patients the immune system has a strong—perhaps too-strong—Th2 response, so Actos could also help relieve the inflammatory component of the disease.
Beck writes that a number of research groups have shown that molecules involved in the Th2 response are also partly responsible for the weakened skin barrier, so Actos may improve barrier function by acting on both tight junctions and T cells.