Coming out of the Shadows: EMA approves first treatment for EPP

Perseverance and adaptability are requisite qualities in drug development.

Afamelanotide receives EMA approval for Rare Skin Disease Erythropoietic Protoporphyria (EPP).  On October 24th, 2014, the European Medicines Agency (EMA) approved the first treatment for this disease, a new drug originally discovered and tested at the University of Arizona.


Melanotropin Team circa 1990

 The Melanotropin Team circa 1990 left to right:
Mac Hadley, Robert Dorr, Norman Levine MD (dermatologist), Victor Hruby

Approximately 20,000 people worldwide have a rare skin disorder that causes intense pain and blistering upon exposure to sunlight. These patients live a life in the shadows and if they must come out in the sunlight, they are covered near-completely to avoid the pain and blistering if they have direct contact with sunlight. Some historians even think that these people and their strict avoidance of sunlight, were one of the models Bram Stoker used for his Dracula novel on vampires. In reality, this disease is caused by the formation of an abnormal blood protein called porphyrin that reacts violently when sunlight hits any unprotected skin. Up to now, there was no treatment for this disease and sufferers could only avoid direct sunlight with great disruption to a normal life and normal leisure or sports activities.

On October 24th, 2014, the European Medicines Agency (EMA) approved the first treatment for this disease, a new drug originally discovered and tested at the University of Arizona. The drug called afamelanotide (trade name ScenesseR),is a peptide which made up of 13 amino acids in a string. The drug binds to receptors in the skin cells that produce the dark pigment melanin. This stimulates the production of melanin in the skin. Afamelanotide is based on the natural hormone alpha-MSH, which is the molecule that signals for tanning in humans exposed to the sun. Scenesse is formulated as a dissolvable implant, about the size of a grain of rice that is placed under the skin to release drug over several weeks. It is expected to be commercially available in Europe in a few months and a filing for approval by the US FDA is expected early next year.

The history of this agent is unique since all of the early development was done at the University of Arizona. Working in the chemistry laboratory of Victor Hruby at the University of Arizona, graduate student Tomi Sawyer (now a major pharmaceutical executive) created afamelanotide. Although based on the native a-MSH structure, two amino acids were changed to produce much greater potency compared the natural a-MSH hormone. It was originally tested in frogs by the late UA biologist Mac Hadley and it showed striking potency for inducing skin darkening. But the real question was whether humans could respond to the drug?


Throughout his career, David Alberts, MD, has focused on translational cancer prevention and treatment research. The emphasis of his laboratory-based and clinical research has been on the chemoprevention and treatment of such pervasive and potentially deadly diseases as cancers of the breast, colon, ovary, and skin. He became the UA Cancer Center’s director in 2005 and retired from the position in June 2013. Dr. Alberts was honored in 2012 by the Arizona Bioindustry Association (AZBio) with the AZBio Pioneer Awards for Lifetime Achievement.

This was the question posed to a scientific review panel for a National Cancer Institute grant on Skin Cancer Prevention at the Arizona Cancer Center in the late 1980’s. That grant was headed by David Alberts MD and the tanning project was led by pharmacologist Robert Dorr. The panel recommended funding for the project and over the next several years Dr. Dorr and the team developed the pre-clinical information needed to perform an FDA-approved, first-in-human clinical trial of the compound in normal volunteers. The drug was made at an FDA-approved facility using the chemical synthesis methods worked out in the Hruby lab. For the clinical trial, the drug was administered as a subcutaneous injection once daily for 12 days. The results of that trial, headed by UA dermatologist Norman Levine MD, were published in 1991. The results were stunning: all of the volunteers exhibited clearly-visible tanning from the drug. This was remarkable in that all subjects practiced strict avoidance of any sunlight exposure. Areas of the greatest darkening were the face and the upper body. Even subjects who normally tanned poorly in sunlight, experienced skin darkening from the drug, although the best effects were observed in those who normally tanned well with sunlight. Side effects were minimal consisting mainly of an immediate flushing of the face and neck after injection.

With some venture capital investment by Valley Ventures in Phoenix the group in Tucson worked further to show that the drug did not cause skin cancer, and if anything, was a potent inhibitor of melanoma growth in experimental settings. This answered an important question about whether the drug could be developed for a therapeutic application in humans. Other studies performed at the UA College of Pharmacy by Jim Blanchard, Ph.D, showed that the drug was much more potent when formulated into a slowly-dissolving subcutaneous implant, compared to a simple SQ injection in saline. Based on all this information, in 1995 the UA licensed the drug to a start-up biotechnology company based in Melbourne, Australia. Epi-Tan Ltd. went public on the Australian stock exchange in 2001 and started work on developing afamelanotide as a tanning agent or more-specifically as an injectable sunscreen. However, this plan was not favored by the regulatory agencies and Epi-Tan had to change course and try to find an ethical indication for the drug.

In 2005 with new management and a new name, Clinuvel Ltd. chose to develop the drug as a treatment for the rare skin condition called EPP, which is a type of porphyria, or blood disorder. This rare genetic disorder allowed the granting of an Orphan Drug Designation for Scenesse since so few patients were effected by EPP.  Over the course of the next 9 years, and with over $100million (Australian $) invested, Clinuvel had conducted three phase III randomized clinical trials of Scenesse in patients with EPP. Two studies were conducted in Europe and one in the US. The results were similar in all three trials: EPP patients could tolerate substantial time in sunlight without pain and scarring. This constituted a life-changing event for these patients and in February of 2012, Clinuvel filed a Marketing Authorization Application with the European Medicine Agency. After a lengthy review and input from the EPP patients, the EMA approved the drug on October 24, 2015. Commercial availability in the US is anticipated for late 2015.

In the meantime several other uses for the drug have been evaluated. It appears that Scenesse is also active in treating vitiligo, a skin condition characterized by areas of de-pigmented skin. Possibly the best known vitiligo sufferer was the late pop singer Michael Jackson. When combined with UV light, Scenesse appears to re-pigment the vitiligo areas, as described in two published phase II trials. A randomized phase III trial in vitiligo is currently underway in Singapore. In addition, Scenesse has shown activity in another skin disease called Hailey-Hailey Disease (formerly known as benign familial pemphigus). A phase II trial is currently underway for this indication in Italy.

Overall, the Scenesse story demonstrates how long it can take to actually translate laboratory discoveries into bedside treatments for patients. Consider that this molecule was first created in the mid 1980’s. And it is also of interest that a drug originally tested for skin cancer prevention, eventually ended up treating other rare skin disorders. The good news is that there is now an effective treatment for patients who used to reside in the shadows of everyday life. Imagine avoiding all sunlight exposure for your entire life and then changing that with a new drug given three times over the course of a summer. The main message then has to be that perseverance and adaptability are requisite qualities in drug development.

About the Author: 

DorrRobert T. Dorr

Professor of Pharmacology and Director, Pharmacology Research Program, Arizona Cancer Center, PhD., University of Arizona, 1984

Arizona Cancer Center 4963C
(520) 626-7892

Posted in AZ Pipeline.