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Review
. 2016 Dec 12:9:179-189.
doi: 10.2147/TACG.S122030. eCollection 2016.

Advances in the management of erythropoietic protoporphyria - role of afamelanotide

Ashley M Lane  1 , Jerome T McKay  2 , Herbert L Bonkovsky  1
Affiliations
Review

Advances in the management of erythropoietic protoporphyria - role of afamelanotide

Ashley M Lane et al. Appl Clin Genet. .

Abstract

Erythropoietic protoporphyria (EPP) and the phenotypically similar disease X-linked protoporphyria (XLPP) are inherited cutaneous porphyrias characterized clinically by acute non-blistering photosensitivity, intolerance to sunlight, and significantly reduced quality of life. They are due to marked overproduction of protoporphyrin (PP) chiefly by erythroblasts and reticulocytes. In EPP, the underlying genetic defect is in the ferrochelatase gene, which encodes the final enzyme in the heme synthetic pathway. In XLPP, the genetic defect is a gain-of-function mutation, usually a four-base deletion, in the gene that encodes the enzyme 5-aminolevulinic acid synthase-2, the first and rate-controlling enzyme of heme synthesis in developing red blood cells. The excess PP causes acute and painful photosensitivity, being activated by light in the long ultraviolet to blue spectrum (380-420 nm, the Soret band). Although several treatments have been proposed, presently no very effective treatment exists for EPP or XLPP. Afamelanotide (Scenesse®) is a first-in-class synthetic analog of α-melanocyte stimulating hormone. Afamelanotide mimics the naturally occurring hormone to increase skin pigmentation by increasing melanin production in melanocytes, resulting in increased sunlight tolerance in those with EPP/XLPP. Afamelanotide is currently approved for use in the European Union and Switzerland, and it is under review in the United States by the Food and Drug Administration for use in patients with EPP/XLPP. This paper provides a review of the clinical characteristics and current therapies for EPP/XLPP. We discuss the pharmacology, clinical efficacy, safety, and tolerability of afamelanotide and summarize the results of several key Phase II and III clinical trials. These data indicate that afamelanotide is a promising therapy for those with these debilitating diseases.

Keywords: afamelanotide; eumelanin; heme; melanocyte stimulating hormone; photosensitivity; porphyria.

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Conflict of interest statement

Within the past 3 years, Dr Bonkovsky has received research funding from Alnylam Pharma. He has served as a consultant to Alnylam Pharma, Clinuvel, Recordati Rare Chemicals, and Mitsubishi-Tanabe. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Summary of the heme synthetic pathway, highlighting enzymatic defects associated with the porphyrias. Notes: The heme synthetic pathway involves eight enzymes, four of which are active in the mitochondria, and four of which are active in the cytoplasm., The pathway is initiated and completed in the mitochondria. Intermediate steps in the cytoplasm begin with the activity of ALA dehydratase. Open arrows indicate progression through the pathway. Deficiency (indicated by blocked red arrows) in any of the eight enzymes involved in the pathway may contribute to development of acute or chronic hepatic porphyrias or erythropoietic porphyrias, as shown in red. Abbreviations: Ac, acetate; AIP, acute intermittent porphyria; ALA, 5-aminolevulinic acid; ALADP, ALA dehydratase deficiency porphyria; CEP, congenital erythropoietic porphyria; copro’gen, coproporphyrinogen; EPP, erythropoietic protoporphyria; HCP, hereditary coproporphyria; HEP, hepatoreythropoietic porphyria; PBG, porphobilinogen; PCT, porphyria cutanea tarda; Pr, propionate; proto’gen, protoporphyrinogen; Uro’gen, uroporphyrinogen; Vi, vinyl; VP, variegate porphyria; XLPP, X-linked protoporphyria.
Figure 2
Figure 2
Different regulation of the housekeeping (ALAS1) and erythroid (ALAS2) forms of 5-aminolevulinate synthase. Notes: The two isozymes for ALAS are encoded by separate genes (ALAS1 on chromosome 3 and ALAS2 on the X chromosome), and provide ALA for eventual heme for hemoproteins and other cellular needs. The genes are uniquely induced and repressed in varying tissues., (A) The C terminal polypeptide sequence of human ALAS2 with mutation sites (red) known to contribute to XLPP. (B) bp sequence of human ALAS2 spanning known deletion (red) polymorphisms resulting in gain of function. The truncated bp sequences of the XLPP mutants are also displayed with amino acid substitutions. (C) Differential location and regulation of ALAS1 vs ALAS2 are reflected in the potential resulting porphyrias manifested when there is uncontrolled upregulation of the respective genes. Heme markedly downregulates (red) ALAS1, acting at several different levels. In contrast, heme has little if any down-regulatory effect on ALAS2, but this gene is upregulated by iron acting through iron regulatory proteins to increase translation and downregulated by lack of iron in developing red blood cells, such that a balance is normally retained between PP synthesis and availability of iron for heme and hemoglobin formation., Upregulation (green) of either ALAS1 (chemicals) or ALAS2 (gain-of-function mutations) leads to different forms of porphyria (acute porphyrias or XLPP). Abbreviations: XLPP, X-linked protoporphyria; bp, base pair; ALAS, 5-aminolevulinate synthase; PP, protoporphyrin; WT, wild type.
Figure 3
Figure 3
Cardinal features and characteristics of skin lesions of EPP/XLPP. Notes: (A) The common signs and symptoms found in both erythropoietic protoporphyria and X-linked protoporphyria. (B, C) Common cutaneous lesions in protoporphyria. (B) The image shows an acute photosensitivity reaction resulting in edema of the face and erythema on the bridge of the nose following sun exposure. (C) The image demonstrates the chronic skin changes on the hand of a patient with protoporphyric liver disease. There are thickening and lichenification of the dorsum of the hand in areas that had experienced repeated sun exposure. (Photos kindly provided by JR Bloomer, MD). Abbreviations: EPP, erythropoietic protoporphyria; XLPP, X-linked protoporphyria.
Figure 4
Figure 4
Liver findings in protoporphyric hepatopathy. Notes: (A) Gross appearance of the liver showing pigmentary cirrhosis. (B–D) Representative microscopic images of the liver, including (B) the pigmented deposits of PP crystals (arrow) under light microscopy, (C) characteristic pink fluorescence indicative of differential excretion of PP in the liver under fluorescence microscopy (arrow), and (D) polarization microscopy. (E) Birefringence on polarization microscopy reveals visible Maltese cross patterns (arrow; D and E) within hepatocytes due to crystals of PP. (F) Electron microscopy demonstrating crystals of PP within hepatocytes (arrow). (Photos kindly provided by JR Bloomer, MD). Abbreviation: PP, protoporphyrin.
Figure 5
Figure 5
Structural differences between afamelanotide and α-melanocyte stimulating hormone. Notes: Afamelanotide differs from human α-MSH at the fourth and seventh amino acids, where norleucine replaces methionine (red) and d-phenylalanine replaces l-phenylalanine (red), respectively. These substitutions in the polypeptide confer unique biological properties, including resistance to enzymatic degradation, prolonged plasma half-life, and increased duration of action., Abbreviations: CID, PubChem compound identifier number; α-MSH, α-melanocyte-stimulating hormone.
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