Tackling skin cancer in organ transplant patients

Last year, the World Transplant Congress in Boston heard a number of interesting discussions, most concerning immunosuppression, infectious diseases and donor shortages, as one would imagine. However, a major topic for discussion was one the general public would know very little about -- the problem of rampant skin cancer in solid organ transplant recipients.

Approximations vary on prevalence, but conservative estimates put the numbers at between 35 and 70 per cent of all transplant recipients developing some form of skin cancer -- most commonly squamous and basal cell carcinomas but sometimes melanoma as well -- within 20 years of transplantation.

Of interest is the predominance of these cancers in fair-skinned organ transplant recipients. In cardiac transplant recipients in particular but also in renal patients, mortality can be as high as one in four due to skin cancer.

Protecting transplant recipients from skin cancer is the subject of many studies, but Melbourne biopharmaceutical company Clinuvel may have a headstart on the competition. It already has a compound approved to start Phase III trials in polymorphous light eruption (PLE) in Europe and other UV-related skin disorders in Phase II and has now filed patents in a new application of CUV1647, an analogue of alpha-melanocyte stimulating hormone, for skin cancer in organ transplant patients.

According to Clinuvel's CEO, Dr Philippe Wolgen, CUV1647 acts by stimulating the levels of eumelanin in the skin. First developed by scientists at the University of Arizona, it was licensed to EpiTan (the former name of now Clinuvel), in the late 1990s and is delivered from a subcutaneous implant.

"Initially the company looked at using CUV1647 in the cosmetic area, but the peptide is systemically applied so it is a real pharmaceutical agent that needs to go through human trials," Wolgen says. "The question posed was, can you find something for which this drug benefits patients? Is there a group of patients that really benefits from and needs melanin increase?"

It turns out there might be quite a few. CUV1647 is being developed as a prophylactic photo-protective agent for five indications, two in oncology and three UV-related. One is PLE, commonly known as sun poisoning, which results in a severe skin rash marked by red blisters. While not overly dangerous, it does have a significant effect on the quality of life of sufferers, who must avoid sunlight in spring and summer. In January this year, Clinuvel received approval from the UK's MHRA to commence Phase III trials in up to 200 patients with PLE. Preliminary data is expected at the end of this year or early 2008.

In April, Clinuvel received approval from the Swiss regulatory agency, Swissmedic, to commence a Phase III trial of CUV1647 in a second indication, erythropoietic protoporphyria (EPP), a rare and debilitating disorder in which sufferers are to all intents and purposes allergic to the sun. An inherited porphyrin metabolism disorder, it causes the chemical protoporphyrin IX to accumulate in the skin. Exposure to the sun causes excruciating pain, swelling and scarring.

Approval has also been granted by the medical ethics committee of a Zurich hospital, one of the sites where this multicentre trial will be conducted. The primary objective of the randomised, placebo-controlled trial is to determine whether CUV1647 reduces the number and severity of phototoxic skin reactions in patients with EPP. It is anticipated that between 50 and 70 patients will participate in the trial across a number of centres in Europe and Australia.

The third indication is solar urticaria, a rare form of hives. Sufferers have an anaphylactic reaction to the sun and often develop red wheals on their skin after exposure. Treatment is normally with antihistamines but the condition can be severe and debilitating. Clinuvel is preparing clinical trials for this indication at the moment.

The fourth is in the prevention of phototoxicity associated with photodynamic therapy (PDT) in cancer patients. The company has filed patent applications for the use of CUV1647 and any related compounds that serve as photoprotective agents for patients who have undergone PDT treatment.

PDT is uses laser or other light sources combined with a photosensitising agent to destroy cancer cells. This treatment is used in many cases where surgery is neither possible nor preferred. It is most frequently used in gastro-intestinal, esophageal, bladder, neurosurgical, prostate disorders and in wet age-related macular degeneration of the eyes.

One of the limiting factors and key side effects of PDT therapy is debilitating photosensitivity of skin and eyes to light, sunlight as well as artificial light. Patients suffer intense pain associated with this photosensitivity and are forced to avoid both the sun and artificial light for up to 90 days following treatment.

Immune suppression and UV

But it is the fifth indication -actinic keratosis (AK), or pre-cancerous skin lesions - that is getting Wolgen excited. A surgeon by training, Wolgen was working in financial research in pharma and biotech in Europe when he was asked to conduct due diligence on this interesting small cap Australian company.

"I did a year of research on the company before I joined," he says. "I had mixed feelings because it was old technology that hadn't made it in the market, but that piqued my curiosity. The compound seemingly worked and proved safe but wasn't commercialised.

"As a surgeon I have seen many cancers but I didn't realise the interaction between immune suppression and UV, because your focus is on preserving the organs. But it became very obvious that the most prevalent group of patients are those how have received a heart or a kidney or a lung transplant.

"They have a window of two to five years post-transplant where they break out in skin cancer, that is for fair skinned individuals with skin types 1 and 2 (Fitzpatrick classification). So a drug that is a effective and is a prophylactic makes sense."

Since taking over as CEO, Wolgen has sold off the EpiPharm side of the business, which licensed several prescription drugs for common skin complaints. His focus is on developing CUV1647 for the five indications, with particular emphasis on transplant recipients. Phase II trials in immune-suppressed patients should begin in Melbourne and Europe this year.

The market seems to like his direction, with the company raising over $35 million in new equity last year, the highest single raising of any biotech in Australia for 2006. Clinuvel has also opened an office in San Francisco to be closer to the FDA, with a view to applying for an IND in the near future.

Eventually, Wolgen hopes to have the drug approved as a first line of treatment for PLE, EPP and solar urticaria, but it is the organ transplant market that gets him talking. "There is a real demand for treating these patients and few people know about the clinical problem," he says.

There is also the potential for it to be offered to any person with Fitzpatrick skin types 1 and 2 as a preventative measure.

"It should be a preventative photo-protective drug for those who need it most," he says.

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