Melanotan I

New and currently investigated pharmacotherapies for the erythropoietic protoporphyrias: spotlight on dersimelagon and bitopertin.

Jasmin Barman-Aksözen, Francesca Granata, Sebastian Wäscher +2 more

The erythropoietic protoporphyrias (EPP) are ultra-rare inborn errors of the heme biosynthesis characterized by painful and debilitating phototoxic reactions in the blood vessels upon exposure to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents pain and prolongs the time patients can spend in sunlight. However, afamelanotide does not address the underlying disease mechanism and is currently only approved for use in adult patients, leaving children and adolescents without a treatment option. The two investigational pharmacotherapies dersimelagon and bitopertin could offer benefits such as treatment options for children and prevention of some of the associated disease complications.

Afamelanotide improves quality of life and light tolerance in Austrian erythropoietic protoporphyria patients.

Magdalena Seidl-Philipp, Hanna Schratter, Johanna Auer +7 more

Erythropoietic protoporphyria (EPP) is a rare genetic disorder characterized by severe phototoxic reactions that occur within minutes of light exposure. In clinical studies, afamelanotide has been shown to prolong pain-free sun exposure, improve quality of life, and reduce the frequency and severity of phototoxic reactions.

Adjunctive use of Polypodium leucotomos extract in patients with erythropoietic protoporphyria: An exploratory study.

Nayha Shetty, Rebecca L Quiñonez, Marissa S Ceresnie +3 more

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) cause severe photosensitivity, resulting in significant quality of life (QoL) impairment. This study aims to evaluate the safety and efficacy of Polypodium leucotomos extract (PLE) as an adjunctive therapy in patients with persistent symptoms despite standard dosing of afamelanotide. In this prospective single-center cohort study, eight adults with confirmed EPP or XLP and ongoing symptoms despite regular afamelanotide implants every 2 months were enrolled. Participants received 480 mg oral PLE daily for 4 months. QoL and symptom severity were measured using questionnaires at baseline, Day 60, and Day 120. Six participants completed the study. Statistically significant improvements in QoL were observed on Day 60 (p = 0.014), but not at Day 120 (p = 0.152). Half of participants reported reduced reaction severity. No adverse events occurred. Adjunctive PLE improved short-term QoL in participants with incomplete symptom control on afamelanotide alone and was well tolerated. Larger studies are warranted.

Congenital Erythropoietic Porphyria with Persistent Severe Biochemical Abnormalities and a Non-Mutilating Clinical Course: A Case Report.

Supriya Peshin, Ehab Takrori, Kaneez S Khan +4 more

Background and Clinical Significance: Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by a deficiency of uroporphyrinogen III synthase, leading to the accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. Case Presentation: We report a 32-year-old woman diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade, yet who followed a relatively non-mutilating clinical course. Genetic testing identified a low-penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without the need for transfusion therapy or stem cell transplantation. Conclusions: This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.

Investigation of the stability profile of therapeutic α-MSH analogue: Insights from liquid chromatography-high resolution mass spectrometry analysis of afamelanotide.

Ashwini Chawathe, Nitish Sharma

Afamelanotide, also known as melanotan-1, is a synthetic 13-amino acid peptidomimetic of α-melanocyte stimulating hormone (α-MSH), and is a critical peptide orphan drug used for the management of erythropoietic protoporphyria. It contains norleucine and D-phenylalanine at positions 4 and 7, in place of methionine and L-phenylalanine, respectively as found in endogenous peptide. Therapeutic peptide stability profiling is crucial in drug development because chemical and physical degradation during storage alters structural properties, potentially reducing efficacy and compromising safety by preventing target engagement. Stability testing for synthetic peptides is performed by following the International Council for Harmonisation (ICH) guidelines Q1A(R2) and Q5C. The current work endeavours to explore afamelanotide's degradation pathways under various chemical and physical stress conditions: acidic, basic, neutral, and oxidative stress, UV light exposure, and increased temperature at 60⁰C. The study demonstrated that afamelanotide undergoes degradation under all applied stress conditions with the generation of fourteen different degradation products (DPs) which were separated by gradient reversed-phase HPLC on a Zorbax SB C18 column (300 Å, 4.6*150 mm, 3.5 µm) and the method was validated according to the ICH Q2(R1) guideline. To enable comprehensive characterization, the analysis was coupled with ultra-high-performance liquid chromatography-high resolution tandem mass spectrometry (UHPLC-HRMS/MS), where collision-induced dissociation yielded abundant and accurate fragmentation patterns, enabling the detailed structural elucidation of the products. While this work has identified several degradation pathways such as truncation, methylation, deacetylation, and oxidation, it also establishes complete stability profile of α-MSH analogue, thus offering key insights for the rational design of robust drug formulations.

From darkness to light: Case report on afamelanotide-treatment in a 9-year-old child with erythropoietic protoporphyria.

Anna-Elisabeth Minder, Jasmin Barman-Aksözen

New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective.

Cornelia Dechant, Sebastian Wäscher, Francesca Granata +6 more

The erythropoietic protoporphyrias (EPP) are a group of ultra-rare (1:100.000) inborn errors of the heme biosynthesis characterised by painful phototoxic reactions in tissue exposed to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents phototoxic reactions and improves the quality of life of the patients. In the past years, several new potential treatment options for EPP have been identified, some of which are currently under investigation in clinical trials. While these developments could improve patient care, it is important to know how safety and efficacy of drug candidates compare to the existing treatment, i.e. afamelanotide.

Letter to the Editor - Qualitative evidence submitted by patients to NICE: need for more quality or unrealistic and unfair requirements?

Rocco Falchetto, Jasmin Barman-Aksözen

Burden of illness and unmet needs in patients with erythropoietic protoporphyria and X-linked protoporphyria: A large US nationwide claims analysis.

Maral DerSarkissian, Chelsea Norregaard, Hela Romdhani +5 more

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare genetic disorders caused by the accumulation of the toxic metabolite protoporphyrin IX, which results in painful phototoxicity upon sunlight exposure. Despite their significant impact on quality of life and potential for serious complications, treatment options for EPP/XLP are limited and real-world burden of illness and unmet needs have been understudied in this population.

Afamelanotide in managing cutaneous phototoxicity in erythropoietic protoporphyria: a Scottish perspective.

Robert S Dawe, Alastair Kerr, Ewan Eadie +3 more

Afamelanotide for Treatment of the Protoporphyrias: Impact on Quality of Life and Laboratory Parameters in a US Cohort.

Rebecca K Leaf, Hetanshi Naik, Paul Y Jiang +11 more

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare disorders of heme biosynthesis characterized by severe cutaneous phototoxicity. Afamelanotide, an α-melanocyte-stimulating hormone analogue, is the only approved treatment for protoporphyria and leads to increased light tolerance and improved quality of life (QoL). However, published experience with afamelanotide in the US is limited.

Erythropoietic protoporphyria in childhood: clinical clues, missed diagnoses and emerging therapy.

Moritz Toenne, Tim Schaefer

Erythropoietic protoporphyria (EPP) is a rare photodermatosis presenting in early childhood with severe pain upon exposure to visible light, including sunlight and artificial sources, often without visible skin changes in the early phase. However, skin changes such as erythema, oedema or crusting may develop after prolonged exposure. This mini-review highlights key clinical features and proposes a structured diagnostic approach, illustrated by a representative paediatric case. Emerging therapies, including off-label afamelanotide and experimental visible light protection, are discussed alongside practical management in primary care. The review also addresses the psychosocial impact and systemic challenges in European care structures. The aim is to raise awareness among paediatricians and general practitioners, promote earlier diagnosis and support equitable care for affected children. What is Known: • EPP is the most common porphyria in childhood. It typically manifests with painful photosensitivity and no visible skin changes. Despite characteristic features, diagnosis is often delayed due to low awareness in paediatric care. What is New: • This mini-review proposes a practical diagnostic algorithm for paediatric primary care and highlights key clinical clues to sensitise general paediatricians to EPP. It also reviews emerging treatment options such as afamelanotide, already approved for adults, with promising adolescent data. These advances must now be widely communicated and translated into equitable access for children across Europe.

The Impact of Minimal Sunlight Exposure on Bone Health: Insights From a Cohort Study in Erythropoietic Protoporphyria.

Louisa G Kluijver, Margreet A E M Wagenmakers, J H Paul Wilson +1 more

Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disease, causing lifelong painful phototoxic reactions, minimal sunlight exposure, and vitamin D deficiency. Previous studies reported a high osteoporosis prevalence in EPP patients.

Treatment Advances in Vitiligo: An Updated Review.

Ishrat Binti Ismail, Yasmeen Jabeen Bhat, Mohd Shurjeel Ul Islam

Vitiligo is a common disorder of depigmentation caused by the progressive destruction of melanocytes that affects the skin, hair, and mucous membranes, clinically presenting as depigmented macules and leukotrichia. This condition, affecting millions of people worldwide, has a significant psychosocial burden on patients' quality of life, particularly in relation to skin colour. The etiopathogenesis of this disorder is obscure, but multiple factors contribute to the loss of melanocytes in the skin, like oxidative stress, inflammation, genetics, and autoimmunity. The treatment of vitiligo has been challenging over the past years, but recent developments in understanding the etiopathogenesis of the disease have paved the way for the development of more effective and promising therapeutic treatment options.

German Cohort Observational Study to Investigate the Short- and Long-Term Safety and Clinical Effectiveness of Afamelanotide 16 mg (SCENESSE) in Patients With Erythropoietic Protoporphyria (EPP).

Bernhard Homey, Kathrin Schelonke, Carla Marie Schlegel +10 more

Afamelanotide 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.

Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management.

Anna-Elisabeth Minder, Louisa G Kluijver, Jasmin Barman-Aksözen +2 more

The erythropoietic protoporphyrias consist of three ultra-rare genetic disorders of the erythroid heme biosynthesis, including erythropoietic protoporphyria (EPP1), X-linked protoporphyria (XLEPP) and CLPX-protoporphyria (EPP2), which all lead to the accumulation of protoporphyrin IX (PPIX) in erythrocytes. Affected patients usually present from early childhood with episodes of severe phototoxic pain in the skin exposed to visible light. The quantification of PPIX in erythrocytes with a metal-free PPIX ≥3 times the upper limit of normal confirms the diagnosis. Protoporphyria-related complications include liver failure, gallstones, mild anaemia and vitamin D deficiency with reduced bone mineral density. The management is focused on preventing phototoxic reactions and treating the complications. Vitamin D should be supplemented, and DEXA scans in adults should be considered. In EPP1, even in cases of biochemically determined iron deficiency, supplementation of iron may stimulate PPIX production, resulting in an increase in photosensitivity and the risk of cholestatic liver disease. However, for patients with XLEPP, iron supplementation can reduce PPIX levels, phototoxicity and liver damage. Because of its rarity, there is little data on the management of EPP-related liver disease. As a first measure, any hepatotoxins should be eliminated. Depending on the severity of the liver disease, phlebotomies, exchange transfusions and ultimately liver transplantation with subsequent haematopoietic stem cell transplantation (HSCT) are therapeutic options, whereby multidisciplinary management including porphyria experts is mandatory. Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, is currently the only approved specific treatment that increases pain-free sunlight exposure and quality of life.

Vitamin D status in patients with erythropoietic protoporphyria taking the systemic photoprotective agent afamelanotide.

Lesley E Rhodes

The effects of cholecalciferol and afamelanotide on vitamin D levels in erythropoietic protoporphyria: a multicentre cohort study.

Louisa G Kluijver, Mitra Nekouei Shahraki, Margreet A E M Wagenmakers +5 more

Patients with erythropoietic protoporphyria experience lifelong painful photosensitivity resulting in a lack of sunlight exposure. Previous studies have shown that 47-63% of patients with EPP suffer from vitamin D deficiency and a high prevalence of osteoporosis. An effective treatment for EPP has been available since 2016: the α-melanocyte stimulating hormone analogue afamelanotide. So far, studies on vitamin D levels in EPP have only investigated patients who have not been treated with afamelanotide.

Quality of life in children with erythropoietic protoporphyria: a case-control study.

Louisa G Kluijver, Debby Wensink, Margreet A E M Wagenmakers +4 more

Erythropoietic protoporphyria (EPP) is an inherited metabolic disease that causes painful phototoxic reactions, starting in childhood. Studies have shown a reduced quality of life (QoL) in adults with EPP, however, data on children with the disease are lacking. Since treatment for EPP is currently not registered for children, knowledge about their QoL is of crucial importance. In this prospective, case-control study, we included children from the Netherlands and Belgium diagnosed with EPP and matched to healthy controls. Previously collected EPP quality of life (EPP-QoL) data from matched adults with EPP were used. QoL scores, utilizing the Pediatric Quality of Life Inventory (PedsQL) and the disease-specific EPP-QoL, were collected. Scores range from 0 to 100, with higher scores indicating a higher QoL. Non-parametric tests were used to compare groups. A total of 15 cases, 13 matched healthy control children, and 15 matched adults with EPP were included. Children with EPP exhibited lower median scores in the PedsQL in both physical (cases: 87.5 (interquartile range [IQR] 77.7-96.1), controls: 99.2 [IQR 94.9-100.0], p = 0.03) and social (cases: 77.5 [IQR 69.4-86.3], controls: 97.5 [IQR 78.8-100.0], p = 0.04) domains compared to healthy children, although these differences were not statistically significant after correcting for multiple testing. The overall median EPP-QoL score for children was similar to adults with EPP (children: 44.4 [IQR 25.0-54.2], adults: 45.8 [IQR 25.7-68.1], p = 0.68). However, within the EPP-QoL subdomain on QoL, children were found to have significantly lower median scores (children: 16.7 [IQR 0.0-33.3], adults: 33.3 [IQR 33.3-62.5], p < 0.01). In conclusion, children with EPP experience a reduced QoL compared to both healthy children and adults with EPP. Ensuring treatment availability for this patient group is crucial for improving their QoL. We advocate the inclusion of children in safety and efficacy studies, to ensure availability of treatment in the future.

When the diagnosis is written in the DNA: a case of erythropoietic protoporphyria in a patient with a chromosome-18 deletion.

Sara Rovaris, Giuseppe La Rosa, Sara Mezzana +6 more

In this case study, we describe a 21-year-old man with erythropoietic protoporphyria who sought medical attention in April 2022 for diffuse edema and erythema of the hands. These symptoms had been present since childhood and usually occurred soon after sun exposure. The patient's medical history showed that chromosome 18's long arm had partially deleted. We performed a number of tests, including measuring total erythrocyte protoporphyrin levels and utilizing a spectrofluorometer to assess the fluorometric emission peak of plasma porphyrins, based on the patient's medical history and clinical symptoms. Furthermore, a genetic analysis identified an intronic variant on one allele, c.315-48T>C (IVS3-48T>C), which is categorized as a susceptibility polymorphism, and a complete deletion of the ferrochelatase gene on the other allele. The patient's clinical condition improved following the June 2022 afamelanotide implant procedure.

Bridging Molecular Mechanism and Clinical Practice in Vitiligo Treatment: An Updated Review.

Hyun Jeong Ju, Jung Min Bae

Treatment of vitiligo seeks to achieve three goals: cessation of disease progression, regeneration of pigmentation, and prevention of recurrence.

Fair Funding Decisions: Consistency of the Time Horizons Used in the Calculation of Quality-Adjusted Life Years for Therapies for Very Rare Diseases by the National Institute for Health and Care Excellence in England.

Jasmin Barman-Aksözen, Nicole Hentschel, Mårten Pettersson +5 more

The National Institute for Health and Care Excellence (NICE) in England uses quality-adjusted life years (QALYs) to assess the cost-effectiveness of treatments. A QALY is a measure that combines the size of the clinical benefit of a treatment with the time the patient benefits from it, i.e., the time horizon. We wanted to know how consistently QALY gains are calculated at NICE. Therefore, we have analysed information on the time horizons used for the QALY calculations of the concluded evaluations conducted under the Highly Specialised Technologies programme for treatments of very rare diseases at NICE. For treatments with final guidance published by December 2023 (n = 29), a time horizon of median 97.5 years (range: 35 to 125 years) was used to calculate the QALY gains. For most QALY calculations, the accepted time horizon was longer than either the expected treatment duration or the estimated life expectancy. In contrast, for the only technology with a final negative funding decision, i.e., afamelanotide for treating the lifelong chronic disease erythropoietic protoporphyria, a time horizon that was shorter than the expected treatment duration was used. The fairness and consistency of the evaluation process of treatments for very rare diseases at NICE should be reviewed.

Afamelanotide in protoporphyria and other skin diseases: a review.

Adriana Polańska, Joanna Wegner, Paula Nutbohm +4 more

Afamelanotide is a synthetic alpha melanocyte stimulating hormone presenting a higher activity than natural hormones. Its main properties are related to the enhanced production of eumelanin by agonistically binding to the melanocortin-1 receptor. Since 2016 afamelanotide has been especially applied to treat cases of erythropoietic porphyria (EPP), where painful photosensitivity has been observed since early childhood. The positive effect of afamelanotide in EPP administered subcutaneously improved tolerance to artificial white light and increased pain-free time spent in direct sunlight. In this review we summarize the possible use of afamelanotide in dermatology, with special emphasis on EPP and encourage including afamelanotide as a treatment option in patient care.

A systematic review of case series and clinical trials investigating systemic oral or injectable therapies for the treatment of vitiligo.

Alireza Jafarzadeh, Arash Pour Mohammad, Mina Khosravi +4 more

The purpose of this study is to investigate the effectiveness and safety of oral and injectable systemic treatments, such as methotrexate, azathioprine, cyclosporine, tofacitinib, baricitinib, corticosteroids, statins, zinc, apremilast, etc., for treating vitiligo lesions.

Erythropoietic protoporphyria and afamelanotide: a patient's perspective.

Marese O'Reilly, Vicky A McGuire, Robert S Dawe

Vitiligo: Pathogenesis and New and Emerging Treatments.

Javier Perez-Bootello, Ruth Cova-Martin, Jorge Naharro-Rodriguez +1 more

Vitiligo is a complex disease with a multifactorial nature and a high impact on the quality of life of patients. Although there are multiple therapeutic alternatives, there is currently no fully effective treatment for this disease. In the current era, multiple drugs are being developed for the treatment of autoimmune diseases. This review assesses the available evidence on the pathogenesis of vitiligo, and a comprehensive review of treatments available for vitiligo now and in the near future is provided. This qualitative analysis spans 116 articles. We reviewed the mechanism of action, efficacy and safety data of phototherapy, afamelanotide, cyclosporine, phosphodiesterase 4 inhibitors, trichloroacetic acid, basic fibroblast growth factor, tumor necrosis factor (TNF) inhibitors, secukinumab, pseudocatalase and janus kinase (JAK) inhibitors. At the moment, there is no clearly outstanding option or fully satisfactory treatment for vitiligo, so it is necessary to keep up the development of new drugs as well as the publication of long-term effectiveness and safety data for existing treatments.