ABSTRACTBackgroundAfamelanotide 16 mg (SCENESSE) is the first approved treatment for erythropoietic protoporphyria (EPP). EPP is a rare autosomal recessive inherited disorder of the haem biosynthesis pathway, where patients experience severe and debilitating acute phototoxicity. It affects at least one in 140,000 of the European population. A postauthorisation safety study (PASS) and a disease registry were imposed as conditions of the European marketing authorisation.ObjectivesEvaluate the short‐ and long‐term safety and clinical effectiveness of afamelanotide 16 mg in EPP patients enrolled in the PASS in Germany.MethodsThe PASS (EUPAS13004) is an ongoing observational study collecting safety and effectiveness variables from treated and untreated EPP patients in the European EPP Disease Registry. Patients (n = 200, none untreated) received afamelanotide according to the summary of product characteristics. Treatment‐emergent adverse events were collected as safety variables. Clinical effectiveness was assessed with the EPP‐QoL tool and through treatment continuity.ResultsThe short‐ and long‐term safety and benefit–risk profile of afamelanotide under real‐world conditions is consistent with the positive safety profile seen in clinical trials. EPP patients reported a significant increase in QoL compared with baseline values (p < 0.0001) and 91.0% of patients who started treatment continue being treated. The safety profile of afamelanotide in patients over 70 years of age is consistent with the overall patient population.ConclusionsAfamelanotide treatment was highly effective and associated with a higher QoL in EPP patients. The study shows a positive safety profile of afamelanotide, with the treatment providing an ongoing clinical benefit.