February 10th, 2014
Clinuvel Pharmaceuticals Limited today announced that a physician-led Phase II study of SCENESSE® (afamelanotide 16mg implant) in patients with the rare Hailey-Hailey Disease (HHD) has commenced in Italy. This study will enrol ten HHD patients to be treated with twelve doses of SCENESSE® during one year, with a three month clinical follow up period. Recruitment of all patients is expected to complete by March 2014.
In 2012, the first proof of concept open-label pilot study of afamelanotide in HHD was carried out in two female patients (age 53 and 61). At the time of the start of the study, the patients both had existing skin lesions and ulcerations which had been present since their adolescent years.
Following afamelanotide treatment, the lesions began to visibly decrease in size and totally disappeared by day 60. The clinical remission was also reflected by an improved QOL measured by the Medical Outcome Survey Short-Form 36 (SF-36). No adverse reactions were reported. Both patients experienced moderate skin tanning, as expected on the basis of the secondary pharmacology of SCENESSE®. Disease recurrence was only seen in the patients eight months after completion of the treatment (Biolcati et al., 2013). By comparison, only few complete or partial remissions are reported in the literature.
Afamelanotide, the active ingredient in SCENESSE®, is an analogue of alpha-melanocyte stimulating hormone (a-MSH) and has been shown to be an effective photoprotective agent in a range of skin disorders other than HHD. Several preclinical studies have provided evidence that natural a-MSH has potent protective and anti-oxidative effects in cutaneous cells. a-MSH affects various pathways implicated in the regulation of inflammation and cytoprotection. In particular, a-MSH has been shown to increase expression of nuclear respiratory factor 2 (Nrf2), a key transcription factor involved in the expression of anti-oxidative enzymes in keratinocytes. It is therefore plausible that SCENESSE®, as a potent a-MSH analogue, could mimic its physiological antioxidant properties.
Hailey-Hailey Disease (HHD, also known as familial benign chronic pemphigus) is a rare, lifelong, inherited disorder where epidermal skin cells (keratinocytes) cannot properly adhere. This causes periodic eruption of plaque-like lesions, blisters and ulcerations on areas where skin folds (flexural), often on the neck, armpits or groin. Most patients have permanent lesions. HHD usually appears in the third or fourth decade of life.
HHD is passed on as a dominant trait (autosomal dominant). In approximately 70% of all patients a positive family history can be traced. Mutations in the ATP2C1 gene (localised on chromosome 3q21-q24), encoding the Golgi secretory pathway calcium pump (Ca2+-dependent ATPase), impair epidermal keratinocyte adhesion.
Current ineffective treatments include topical corticosteroids, antibiotics, and mTor inhibitors which attempt to manage minor outbreaks. There is no professional consensus on a first-line therapy as no remission has been achieved in patients. Several literature reports indicate that HHD patients being predisposed to skin cancer.
The worldwide prevalence of HHD is 1:50,000. Orphanet lists Familial Benign Chronic Pemphigus under ORPHA number 2841 (Orphanet, 2006).