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For patients with erythropoietic protoporphyria the tide has come in


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By Warren Heymann, MD
May 12, 2021
Vol. 3, No. 19

Oct. 8, 2019, was an eventful day for patients with erythopoietic protoporphyria (EPP) in the United States, when the FDA announced its approval of afamelanotide (Scenesse). (1) The drug was first approved in Italy in 2010. (2)

Patients with EPP and X-linked protoporphyria (XLP) present with acute, severe, non-blistering phototoxicity within minutes of sun-exposure. Anemia is seen in about half of patients and approximately a quarter will develop abnormal serum transaminases. (3) Gallstones are common; liver failure is rare. (4) EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. The diagnosis of EPP and XLP is made by detection of markedly increased erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin. Genetic testing by sequencing the FECH or ALAS2 gene confirms the diagnosis. (3) EPP has a profound effect on a patient’s quality of life, causing physical and psychologic distress, social isolation, and a sense of feeling misunderstood. (5). Other than sun avoidance, sunscreen and the questionable use of beta-carotene, the only established beneficial treatment for EPP is afamelanotide.

Afamelanotide is an α-melanocyte-stimulating hormone (MSH) analogue with greater activity and stability than the natural hormone. Afamelanotide binds to the melanocortin-1 receptor (MC1R) that increases melanin synthesis, induces antioxidant activities, enhances DNA repair processes, and modulates inflammation. (6)

Illustration for DWII on erythropoietic protoporphyria
Illustration for DWII on erythropoietic protoporphyria
Image from DermNetNZ

For patients with EPP, afamelanotide is administered every two months as a 16 mg subcutaneous implant. According to the FDA: “Scenesse’s most common side effects are implant site reaction, nausea, oropharyngeal...pain, cough, fatigue, skin hyperpigmentation, dizziness, melanocytic nevus (moles), respiratory tract infection, somnolence…, non-acute porphyria…and skin irritation. Scenesse should be administered by a health care professional who is proficient in the subcutaneous implantation procedure and has completed the applicant-provided training. Scenesse may induce skin darkening, and a full body skin examination is recommended for patients twice a year. In addition, patients are encouraged to maintain sun protection measures during treatment with Scenesse to prevent phototoxic reactions related to erythropoietic protoporphyria.” (1)

Wensink et al studied 117 patients with EPP (50.4% women; mean age 43.0 years) who were treated with afamelanotide. Nearly all patients continued treatment (98%) with a median follow-up of 2.0 years. Compared with baseline, mean time spent outside during treatment increased by an added 6.1 hours per week, which was highly statistically significant. Mean quality of life score improved significantly. Phototoxic reactions were statistically less painful, but there was no significant difference in number or duration of reactions. Minor self-limiting adverse events occurred, such as nausea, fatigue, and headache. The authors concluded that afamelanotide has clinically significant, sustained positive associations with quality of life, is associated with increased duration of sun exposure, and is associated with less severe phototoxic reactions. They remind us that although there has been no previous effective therapy for EPP, the disease is not cured by afamelanotide — despite improvement, sunlight avoidance and wearing protective clothing remains essential. (7)

What makes afamelanotide so intriguing is its potential use in other dermatologic diseases, based on its manifold biological effects. This literature has been reviewed by McNeil et al who cite references where afamelanotide has shown benefit: photoaggravated dermatoses (solar urticaria, polymorphous light reaction), vitiligo, Hailey-Hailey disease, and acne vulgaris. (8) For example, Toh et al demonstrated that combination afamelanotide-narrow-band UVB was superior to placebo-narrow band UVB for nonsegmental vitiligo in Asian patients. (9)

My enthusiasm for the hypothetical indications of afamelanotide is tempered by the reality of cost. Scenesse has been available in Europe since 2014, where its price ranges between 70,000 euros ($76,811.00) and 100,000 euros ($109,730.00) per patient per year. “We are not going to price the drug above levels that we price it in Europe,” Clinuvel Chief Executive Officer Philippe Wolgen told Reuters. (10) At this point, I just hope worthy EPP patients get approved for the drug.

Point to remember: Afamelanotide has now been approved in the United States for patients with erythropoietic protoporphyria and may improve their quality of life. Afamelanotide may also prove to be valuable in other photodermatoses, vitiligo, and additional cutaneous diseases.

Our expert’s viewpoint

Preston W. Chadwick, MD

I can vividly recall my first EPP patient encounter as a newly graduated resident. He sat in the room, tucked away from the window, dressed in long sleeves, long pants, gloves, sunglasses, a hat, and a scarf in the middle of summer. The delay in diagnosis, physical scarring, and the social isolation he described were truly heart-breaking. With great anticipation, we were thrilled with the approval of afamelanotide last October.

I have since been able to work with 15 other patients who relate similar experiences. On a “bad sun day” (which can be cloudy or sunny), it takes just one to five minutes for many patients to experience the burning akin to hot oil on the skin. Severe exposures create pain that can last several days and even weeks. In addition to avoiding daytime outdoor activities and protective clothing, many patients move to climates with reduced sunlight. As Dr. Heymann notes, afamelanotide is not a cure. However, the significant improvement of outside exposure has an exponentially greater impact on quality of life.

It is exciting and invigorating to practice in a time with novel treatments emerging for some of the more rare, but serious conditions. The battle for insurance approval is quite difficult, but without any other significant alternatives, we are slowly able to deliver afamelanotide to our patients.

  1. FDA approves first treatment to increase pain-free light exposure in patients with a rare disorder. FDA News Release October 8, 2019.

  2. Fabrikant J, Touloei K, Brown SM. A review and update on melanocyte stimulating hormone therapy. J Drug Dermatol 2013 12: 775-779.

  3. Balwani M. Erythropoietic protoporphyria and X-linked protoporphyria: Pathophysiology, genetics, clinical manifestations and management. Mol Genet Metab 2019;128(3):298-303.

  4. Dawe R. An overview of the cutaneous porphyrias. F1000 Res 2017; 6: 1906.

  5. Dickey A. Pitfalls and proposed solutions for patient communication about erythropoietic protoporphyria: A survey of parents and adult patients. J Am Acad Dermatol 2019; 81: 1204-1207.

  6. Minder EI, Barman-Aksoezen J, Schneider-Yin X. Pharmacokinetics and pharmacodynamics of afamelanotide and its clinical use in treating clinical disorders. Clin Phamacokinet 2017; 56: 815-823.

  7. Wensink D, Wagenmakers MAEM, Barman-Aksözen, Friesema ECH, et al. Association of afamelanotide with erythropoietic protoporphyria in clinical practice. JAMA Dermatol 2020 156 (5): 570-575.

  8. McNeil MM, Nahhas AF, Branberger TL, Hamzavi IH. Afamelanotide in the treatment of dermatologic disease. Skin Therapy Lett. 2018; 23(6):6-10.

  9. Toh JJH, Chuah SY, Jhingan A, Chong WS, Thng STG. Afamelanotide implants and narrow-band ultraviolet B phototherapy for the treatment of nonsegmental vitiligo in Asians. J Am Acad Dermatol 2020; 82: 1517-1519.

  10. Mishra M. Clinuvel says U.S. pricing of rare disorder drug will not top European levels. Reuters. Oct 9, 2019.


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