Clinuvel Pharmaceuticals Limited shared the first results of a phase II study (CUV156) evaluating afamelanotide in patients with xeroderma pigmentosum (XP), a genetic disease characterised by a defect in DNA skin repair (NER1 defect). Analyses showed a decrease in ultraviolet (UV) light-induced DNA skin damage following treatment. This study constitutes the first time globally that permission was granted to expose XPC patients to a novel systemic therapy.

Despite living in fully shielded and isolated conditions, this population suffers from frequent skin cancer(s), resulting in a median life expectancy of 30 years. INTERIM RESULTS CUV156: The CUV156 study is conducted over ten weeks, with a six month follow up. Patients are administered six doses of afamelanotide as well as controlled UVB radiation on unexposed areas of the skin (buttocks), with DNA markers evaluated.

UVB serves to evaluate tolerance (MED) to the point of inducing DNA skin lesions, cyclobutane pyrimidine dimers (CPDs), characteristic for photodamage. Skin biopsies are taken of UVB irradiated and non-irradiated anatomical sites before and after treatment and analysed through immunohistochemical staining (IHC; microscopic analyses). In the three patients, a reduction of CPDs was found, most specifically in the deeper layer of the skin (basal layer of epidermis).

In two patients, the skin specimens showed an increase in p53 expression, indicating activation of natural defence mechanisms. P53 serves as a biological marker in man for suppressing tumour formation. In three patients, H2AX (a DNA marker5) showed an increase, indicative of the activation of cellular repair mechanisms of the skin. All three patients showed reduced erythema when increasing UVB dosing, whereby two showed an increase in MED, indicating the ability to tolerate higher UV doses without incurring `skin burns'.

In all patients, an increase in melanin density (MD6) was seen, suggestive for the formation of skin pigmentation acting as a physical UV barrier. Overall, clinical assessment by the treating physicians was that afamelanotide provided effective systemic photoprotection in XPC patients. These first positive results justify further progression of the CUV156 study in XPC and the ongoing CUV152 study in XPV patients.

CLINICAL RELEVANCE OF THE FIRST RESULTS: Due to inherited defects in the DNA repair process, the XP population is globally known to experience the highest risk of skin cancer development. A therapy providing systemic photoprotection, reducing photodamage, and assisting DNA skin repair ­ nucleotide excision repair (NER) and base excision repair (BER) ­ would be of high value to these patients. This therapeutic approach bears relevance for a wider population at higher risk of skin cancers.

Melanocortin therapy would potentially benefit those affected by medical conditions, active in high-risk environments (reflective surfaces, high altitude, high UV intensity), or whose genetic make-up (those with non-pigmented skin, blue eyes, and fair hair colour) places them at higher risk of incurring solar damage. MODE OF ACTION AFAMELANOTIDE: Afamelanotide belongs to the family of proopiomelanocortins which exhibit a number of documented and published properties, such as the activation of melanin, the optimisation of cellular response (signalling) to UV skin damage, the assistance in DNA damage, the reduction of oxidative damage, reduction in oncosis (swelling), and decrease in inflammatory processes.