rythropoietic protoporphyria (EPP) (OMIM 177000) is a rare inherited disorder of heme biosynthesis, causing painful photosensitivity. 1 Erythropoietic protoporphyria is caused by FECH or ALAS2 gene mutations, leading to protoporphyrin IX accumulation in erythroid cells. 2,3 It severely affects patients' quality of life (QoL) 4 by causing severe pain after light exposure, which lasts several days and is unresponsive to analgesics. 2,5 This results in sunlightavoiding behavior, limiting daily and social activities. 4 Until recently, there was no effective therapy for EPP 6,7 ; management consisted of strict avoidance of sunlight and wearing protective clothing. In 2016, afamelanotide became available after the European Medicines Agency recommended approval in the European Union with an obligatory postauthorization safety and efficacy study. Afamelanotide is a potent α-melanocyte-stimulating hormone analogue, which increases eumelanin and stimulates anti-inflammatory and antioxidative pathways. 8 Placebo-controlled trials demonstrated statistically significant effects but a relatively small reduction in EPP symptoms. 9,10 We report on the association of afamelanotide treatment with outcomes in EPP in regular practice during longer-term follow-up. MethodsIn this single-center, prospective postauthorization safety and efficacy cohort study of afamelanotide, all adult patients with a confirmed diagnosis of EPP attending the outpatient clinic of the Erasmus University Medical Center in Rotterdam, the Netherlands, were eligible for inclusion (eFigure in the Supplement). Afamelanotide was offered as a controlled-release 16-mg IMPORTANCE The effectiveness of afamelanotide treatment in patients with erythropoietic protoporphyria (EPP) in clinical practice who experience pain after light exposure that substantially impairs quality of life is unknown.OBJECTIVE To evaluate the association of afamelanotide treatment with outcomes in patients with EPP in regular practice during longer-term follow-up. DESIGN, SETTING, AND PARTICIPANTSThis single-center, prospective postauthorization safety and efficacy cohort study was directed and approved by the European Medicines Agency. Data were collected from patients with EPP treated with afamelanotide at Erasmus MC between June 2016 and September 2018. Analysis began October 2018.MAIN OUTCOMES AND MEASURES Time spent outside during treatment, number of phototoxic reactions, disease-specific quality of life, usage of protective clothing, and adverse events.RESULTS A total of 117 patients with EPP (59 women [50.4%]; mean [SD] age, 43.0 [15.5] years) were treated with afamelanotide. Nearly all patients continued treatment (115 [98%]) with a median (interquartile range) follow-up of 2.0 (1.3-2.1) years. Compared with baseline, mean time spent outside during treatment increased significantly by an added 6.1 hours per week (95% CI, 3.62-8.67; P < .001). Mean quality of life score improved significantly by 14.01% (95% CI, 4.53%-23.50%; P < .001). Phototoxic reactions were less painful (β, −0.85;...

Introduction: In erythropoietic protoporphyria (EPP), an inherited disorder of heme biosynthesis, accumulation of protoporphyrin IX results in acute phototoxicity. EPP patients experience severe burning pain after light exposure, which results in a markedly reduced quality of life. Afamelanotide is the first effective approved medical treatment for EPP, acting on melanocortin-1 receptors. This article aims to review afamelanotide. Areas covered: This review summarizes the chemical properties, pharmacokinetics, safety, preclinical and clinical data on afamelanotide in EPP, and post-marketing surveillance. PubMed search, manufacturers' websites, and relevant articles used for approval by authorities were used for the literature search. Expert opinion: Afamelanotide is an α-melanocyte-stimulating hormone analog. It can activate eumelanogenesis without exposure to UV radiation. Clinical studies in EPP showed that afamelanotide treatment significantly increased exposure to sunlight and QoL. In our clinical experience afamelanotide treatment is much more effective in clinical practice than demonstrated in clinical trials and should be made available for all EPP patients meeting inclusion criteria. The 60-day interval period was not based on effectiveness studies, and therefore for some of the patients the maximum of four implants per year with the 60-day interval is insufficient. Afamelanotide is well tolerated; common adverse events were headache, fatigue, and nausea.

Background: In erythropoietic protoporphyria (EPP), which presents with severe painful phototoxicity, progressive deposition of protoporphyrins in hepatocytes and bile canaliculi may result in liver disease. Clinically EPP related liver disease ranges from mildly elevated liver enzymes to cirrhosis and acute cholestatic hepatic failure. The prevalence of liver disease in EPP, and factors predicting the risk of developing liver disease, have not been defined in a large series of unselected EPP patients. Aim: To determine the prevalence of liver disease in EPP-patients. Methods: A single-center prospective unselected cohort study of 114 adult EPP patients, who underwent routine laboratory testing, abdominal ultrasonography and transient elastography to assess the presence of steatosis (controlled attenuation parameter,dB/m) and liver stiffness (kPa). Results: 114 adult EPP patients were included. Elevated liver enzymes were found in 6.2% of the patients. Liver steatosis was detected in 29.0%, and significant fibrosis as assessed with liver stiffness measurements was present in 9.6% of patients. BMI positively predicted CAP-values ( p = 0.026); and protoporphyrin IX levels ( p = 0.043) positively predicted liver stiffness. Conclusions: This study demonstrates a prevalence of hepatic steatosis and fibrosis in adult EPP-patients comparable to that found in the general population. Protoporphyrin IX levels correlate with increased liver stiffness in EPP.

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