BACKGROUND: Erythropoietic protoporphyria is a severe photodermatosis that is 
associated with acute phototoxicity. Patients with this condition have 
excruciating pain and a markedly reduced quality of life. We evaluated the 
safety and efficacy of an α-melanocyte-stimulating hormone analogue, 
afamelanotide, to decrease pain and improve quality of life.
METHODS: We conducted two multicenter, randomized, double-blind, 
placebo-controlled trials of subcutaneous implants containing 16 mg of 
afamelanotide. Patients in the European Union (74 patients) and the United 
States (94 patients) were randomly assigned, in a 1:1 ratio, to receive a 
subcutaneous implant containing either afamelanotide or placebo every 60 days (a 
total of five implants in the European Union study and three in the U.S study). 
The type and duration of sun exposure, number and severity of phototoxic 
reactions, and adverse events were recorded over the respective 180-day and 
270-day study periods. Quality of life was assessed with the use of validated 
questionnaires. A subgroup of U.S. patients underwent photoprovocation testing. 
The primary efficacy end point was the number of hours of direct exposure to 
sunlight without pain.
RESULTS: In the U.S. study, the duration of pain-free time after 6 months was 
longer in the afamelanotide group (median, 69.4 hours, vs. 40.8 hours in the 
placebo group; P=0.04). In the European Union study, the duration of pain-free 
time after 9 months was also longer in the afamelanotide group than in the 
placebo group (median, 6.0 hours vs. 0.8 hours; P=0.005), and the number of 
phototoxic reactions was lower in the the afamelanotide group (77 vs. 146, 
P=0.04). In both trials, quality of life improved with afamelanotide therapy. 
Adverse events were mostly mild; serious adverse events were not thought to be 
related to the study drug.
CONCLUSIONS: Afamelanotide had an acceptable side-effect and adverse-event 
profile and was associated with an increased duration of sun exposure without 
pain and improved quality of life in patients with erythropoietic 
protoporphyria. (Funded by Clinuvel Pharmaceuticals and others; 
ClinicalTrials.gov numbers, NCT01605136 and NCT00979745.).