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Existing therapies and therapeutic targets for erythropoietic protoporphyria

ABSTRACT Introduction: Erythropoietic protoporphyria (EPP) is a metabolic disorder of heme-biosynthesis that is caused by an accumulation of protoporphyrin (PPIX), which sensitizes the skin to light and leads to severely painful phototoxicity. Excess PPIX in the bile causes cholestatic liver insufficiency in 2–5% of patients. Area covered: The clinical trials of afamelanotide, an alpha-melanocyte-stimulating-hormone analogue aimed to prevent phototoxicity, are delineated. The challenges facing clinical trials in EPP and other rare diseases are discussed. Since no medical procedures have been evaluated, the patients themselves manage acute phototoxic reactions. The therapeutic modalities to reverse progressive liver disease are not comprehensive and are based on single case reports. Iron-restriction may decrease PPIX load of the liver in ferrochelatase-deficient EPP. Liver transplantation saves lives, but disease recurrence is high. Bone marrow transplantation with the potential to cure EPP should be considered in patients with liver failure only, because of the risks associated with this procedure. Gene replacement and splice site modulation are in pre-clinical testing. Expert opinion: Afamelanotide offers a major therapeutic advance for the prevention of phototoxicity in EPP as it enables the patients to lead a more normal life. The management of both acute phototoxic reactions and progressive liver disease are empirical and need systematic evaluation.