Morgan M. McNeil, DO1; Amanda F. Nahhas, DO2,3; Taylor L. Braunberger, MD2; Iltefat H. Hamzavi, MD2

1Michigan State University College of Osteopathic Medicine, East Lansing, MI, USA
2Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA
3Department of Dermatology, Beaumont-Farmington Hills, Farmington Hills, MI, USA

Conflict of interest:
Dr. Hamzavi is an investigator for Incyte Corporation, Bayer, Clinuvel, Estée Lauder, Unigen Inc., and Ferndale Laboratories with grants received by the institution. Dr. Nahhas and Dr. Braunberger are sub-investigators for Bayer, Estée Lauder, Unigen Inc., and Ferndale Laboratories with grants received by the institution. Morgan McNeil has no conflicts of interest to declare. Dr. Nahhas and Dr. Braunberger were former sub-investigators for Ferndale Laboratories, Bayer, Estée Lauder, and Unigen Inc., with grants paid to the institution.
Funding: This article has no funding source.

Afamelanotide, an α-melanocyte stimulating hormone analogue, has become an emerging therapeutic option for a variety of skin conditions previously refractory to other treatments. Its efficacy has been demonstrated in several dermatologic conditions, including erythropoietic protoporphyria (EPP), solar urticaria, polymorphic light eruption (PMLE), vitiligo, acne, and Hailey-Hailey disease. Its relatively low risk side effect profile makes it an attractive treatment option and also paves the way for innovative use in other disorders.

Key Words:
acne, afamelanotide, alpha-melanocyte stimulating hormone, erythropoietic protoporphyria, Hailey-Hailey disease, polymorphic light eruption, solar urticaria, vitiligo.


Afamelanotide (Scenesse®) is a subcutaneous, controlledrelease, injectable α-melanocyte stimulating hormone (α-MSH) analogue.1 Afamelanotide is composed of a linear peptide of thirteen amino acids, two of which differ from α-MSH. These two different amino acids increase the affinity of afamelanotide to the melanocortin 1 receptor (MC1R), which in turn increase the stability, potency, and half-life of afamelanotide.1 Afamelanotide, like α-MSH, binds to MC1R in dermal cells and in melanocytes, thereby stimulating melanocyte production of eumelanin as well as melanocyte proliferation.1 Eumelanin exhibits numerous roles, including photoprotection against ultraviolet (UV) light and scavenging of free radicals, while also filtering out longer wavelengths of visible light.1 Therefore, afamelanotide is photoprotective against visible light photosensitivity and, thus, it is an effective treatment option for disorders such as erythropoietic protoporphyria (EPP), solar urticaria, and polymorphic light eruption (PMLE). Melanin also has antioxidant effects that help protect the skin against free radicals. Since such oxidative stress is responsible for inducing the painful symptoms experienced by patients with EPP and certain other dermatologic disorders in which oxygen free radicals are created upon visible light exposure, melanin replacement can help alleviate the associated discomfort.1

Pharmacokinetics studies reveal that subcutaneous delivery of afamelanotide results in full bioavailability, whereas oral and transdermal routes of administration inhibit measurable plasma concentrations or a pigmentation response, thus establishing its development as a subcutaneous injectable implant.1 Although not recommended by the manufacturer for use as a sunscreen, afamelanotide has been shown to enhance DNA repair processes following UV damage in keratinocytes through MC1R signaling.1,2 The side effect profile is reported to be minimal and includes nausea, headache and pigmentation, the latter of which could be seen as either a desirable endpoint in conditions such as vitiligo if inducing new pigment formation in previously depigmented macules or patches, or as an adverse event if new pigment appears hyperpigmented relative to a patient’s baseline skin hue.1 Afamelanotide was first approved for the treatment of EPP in Europe and is currently under study in both the United States and Europe for its use in other dermatologic disorders.3 We present a discussion of the various conditions that have been treated by afamelanotide and the rationale supporting its use in each condition.


Erythropoietic Protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited disorder of metabolism characterized by painful photosensitivity leading to swelling and redness of exposed skin areas.4 Accumulation of protoporphyrin levels in the skin and dermal blood vessels of these patients at baseline predisposes them to form reactive oxygen species upon exposure to visible light. Formed reactive oxygen species are then capable of inducing tissue and blood vessel damage.5 In the setting of EPP, melanin production may provide defense against oxidative stress by neutralizing free radicals and the reactive oxygen species produced, thus helping decrease symptom severity.2

Afamelanotide has been shown to significantly reduce phototoxic reactions and the recovery time associated with visible light exposure in patients with EPP.2 In both the United States and in the European Union, multicenter, randomized, double-blinded, placebo-controlled phase III trials of afamelanotide have been performed.2 In both trials, there was increased tolerance to direct sunlight exposure in patients receiving afamelanotide compared to those receiving the placebo.2 In patients who received afamelanotide in the European arm of the study, phototoxic reactions were less severe (P = 0.04) and recovery time was faster with a median duration of phototoxicity of 1 day for patients receiving afamelanotide versus 3 days for those receiving placebo (P = 0.04).2 EPP quality of life questionnaires performed in this study also demonstrated improvements in patients treated with afamelanotide versus placebo.2 In summary, it was shown that afamelanotide was safe, effective and capable of improving quality of life.2

In an observational study conducted in Italy and Switzerland, which took place over a period of 8 years, the results showed that 97% of patients considered afamelanotide to be effective in decreasing the symptoms of EPP and, furthermore, 93% of patients were able to adhere to treatment for a prolonged time period.6 Since afamelanotide has been proven to be effective in decreasing photosensitivity in EPP, regulatory approval has been granted for use in the European Union and Switzerland.5 Its use in EPP has been established for more than 8 years in Italy and Switzerland.2

In addition to the significant dermatological benefits in EPP, afamelanotide also positively impacts patient quality of life. By shortening recovery time from photosensitive reactions, affected individuals are able to be more productive and experience fewer absences from school and work.2 The photoprotective nature of afamelanotide also offers patients a longer duration of time to experience activities from which they may have been precluded previously, due to the symptoms associated with their disease while exposed to visible light. Since the elevated protoporphyrin levels do not change with treatment, afamelanotide does not impact liver disease that may occur in some patients with EPP.2

Solar Urticaria

Solar urticaria is a chronic photosensitivity disorder characterized by an itch, wheal and flare reaction that occurs within minutes of sunlight exposure.7 Though the exact cause is unknown, it is proposed that mast cells play a major role and an immunoglobulin E-mediated response to photo-induced endogenous cutaneous antigens may also be involved.8 Since melanin decreases the amount of UV radiation penetration, it is thought to be photoprotective in solar urticaria.7 Afamelanotide’s ability to increase melanin pigment has led to decreased wheal formation across a broad spectrum of wavelengths.7 In an openlabel, phase II investigator-initiated study, 5 participants received a single 16 mg subcutaneous implant of afamelanotide. At 30 days, all subjects showed increases in minimum urticarial dose, defined as the lowest dose at which a visible wheal response occurs, for various wavelengths.7 A significant decrease in wheal area occurred between 300-600 nm at 60 days post-insertion of the afamelanotide implant, suggesting a photoprotective effect.7 Subjects in this study also experienced a significant increase in melanization at sites exposed to photoprovocation with a light source across wavelengths of 300-600 nm and at unexposed sites.7 It may also be true that the decreased urticarial response with afamelanotide use is partially due to its immunomodulatory effects; however, additional studies are needed to evaluate this further.7 Overall, afamelanotide has shown to be a promising treatment in solar urticaria with the added benefit of improving quality of life.

Polymorphic Light Eruption

Polymorphic light eruption (PMLE) is a photodermatologic, immune disorder characterized by the development of pruritic papules and vesicles on sun-exposed areas of skin.1 The cause is unknown, though PMLE is considered a delayed-type hypersensitivity response to undefined, endogenous cutaneous photo-induced antigens.8,9 UV radiation-induced alteration of skin antioxidative capacity is thought to contribute to onset of disease.10-12 Although self-limited, many patients experience a decrease in quality of life due to efforts to avoid sun exposure in order to prevent the subsequent discomfort associated with PMLE flares.13 Treatment generally consists of sun avoidance and photoprotective measures (e.g., sunscreen, clothing, and a wide brim hat). During an eruption and for prevention of flares, local or systemic corticosteroids may be prescribed.1 Phototherapy with either low-dose psoralen ultraviolet A (PUVA), broadband ultraviolet B (BB-UVB) or narrowband UVB (NB-UVB) radiation is considered a standard part of prophylactic therapy in patients who seek treatment due to its photo-hardening effect.13 Photohardening implies the induction of melanization, epidermal thickening, immunomodulatory, and anti-inflammatory effects, which are beneficial in protecting against PMLE.14 Thus, afamelanotide, by increasing the pigment in the skin, could be photoprotective for these patients and induce this same photoadaptation without the need for phototherapy.

In a pilot trial involving 36 subjects with PMLE who were treated with a 20 mg subcutaneous implant of slow-release afamelanotide, dermal symptoms were reduced in the treatment group compared to the placebo group.15 All subjects in this study were found to have an increase in melanin density at 120 days in sun-exposed areas, which may have contributed to the improvement of symptoms.15


Vitiligo is an acquired, autoimmune disorder involving the development of depigmented macules and patches secondary to epidermal melanocyte destruction.1 It has been postulated that an α-MSH defect could be present in vitiligo secondary to loss of melanocytes, since these are a major source of MSH.16 The melanogenic effect of afamelanotide requires MC1R to be present. This mechanism is thought to be the reason behind the efficacy of afamelanotide in vitiligo. Since melanocytes are destroyed within lesions of vitiligo, the presence of MC1R is also lacking. However, since melanoblasts in the hair bulbs are preserved, NB-UVB phototherapy can activate their differentiation, thereby upregulating MC1R and allowing afamelanotide to exert its effect on those receptors.1,17 Therefore, it may be reasonable to consider supplementing afamelanotide treatment with NB-UVB in vitiligo, however, clinical studies are needed to further evaluate the efficacy of this approach.17

Studies have shown faster and more complete repigmentation when using afamelanotide as adjuvant treatment in vitiligo.1 A double-blind, multicenter study involving 55 subjects with generalized vitiligo (skin phototypes III-VI) compared combinat ion therapy (afamelanot ide plus NB-UVB phototherapy) versus NB-UVB phototherapy alone. One patient from each group failed to fulfill the criteria of the intent to treat population, which included those participants who received at least 1 treatment and underwent an efficacy evaluation at day 28 of the trial, leaving the study with 53 participants that fulfilled this criterion. There was 1 drop out from each of the 2 groups. Onset of repigmentation was found to be significantly earlier when afamelanotide was combined with NB-UVB phototherapy beginning at day 56. By day 168, repigmentation was more pronounced in the combination group (48.6%) versus the NBUVB phototherapy alone group (33.26%).17 This was evidenced by a relative reduction in the vitiligo area scoring index of 48.64% at day 169 versus 33.26% in the NB-UVB monotherapy group. Median time to onset of repigmentation in the face and upper extremities was also reported to be 20 days sooner in the combination therapy group and responses were reported to be rapid in skin phototypes IV-VI.17 The most common adverse effects in the aforementioned study were erythema, hyperpigmentation, pruritus, and nausea.17

In a case series involving 4 subjects with generalized vitiligo, the results of combination therapy (NB-UVB plus afamelanotide) revealed that following a 1-month course of bi- to tri-weekly NB-UVB phototherapy, a 16 mg dose implant delivered every 4 weeks for 4 months led to faster and deeper repigmentation.16 Further studies are needed to define the optimal treatment regimen for the synergistic use of afamelanotide in combination with NB-UVB for vitiligo treatment and to determine the rate of recurrence upon treatment discontinuation.

Hailey-Hailey Disease

Hailey-Hailey disease is a benign, familial pemphigus condition characterized by the formation of blisters with predilection to the intertriginous areas.18 Increased oxidant stress occurs secondary to a reduced intracellular antioxidant response in the keratinocytes of affected areas.18 Treatment can be challenging, as traditional therapies often fail to produce long-term results in many patients.18 MSH has been shown to increase the expression of a transcription factor (nuclear factor [erythroid-derived 2]- like 2 [Nrf2]) that coordinates the expression of antioxidant enzymes in keratinocytes.19 Afamelanotide may restore the defective proliferative capability of intralesional keratinocytes and defend against the harmful effects of oxidative stress.18

During a phase II, open-label pilot study, 2 patients with longstanding lesions of Hailey-Hailey disease were treated with subcutaneous afamelanotide implants delivered at a dose of 16 mg on day 0 and on day 30.19 Lesions improved by 30 days following the first injection and both demonstrated complete clearance by day 60.18 The results showed that the impaired oxidative stress balance in Hailey-Hailey disease leads to defects associated with downregulated expression of Nrf2; in this study, subjects treated with afamelanotide showed improvement in Nrf2 expression.19 Moderate skin pigmentation was the only reported side effect and following drug discontinuation, there was no evidence of disease recurrence sooner than 8 months.19


Acne vulgaris is an inflammatory skin disorder that occurs due to a combination of events, including increased sebum production, inflammation, hyperkeratinization, and proliferation of Propionibacterium acnes within hair follicles.1 It is proposed that afamelanotide, through its anti-inflammatory effects, can decrease the amount of acne lesions.20 In a phase II, open-label pilot study, 3 subjects with mild-to-moderate facial acne were given a 16 mg implant of afamelanotide subcutaneously and the results revealed that the total number (including inflammatory lesions and non-inflammatory open and closed comedones) and number of inflammatory acne lesions (papules, pustules and nodes) decreased in all subjects 56 days following implantation.20 In all subjects, quality of life improved as measured by the Dermatology Life Quality Index.20 Optimal dosing of afamelanotide for acne treatment has not yet been established, though larger studies are needed to further evaluate this (Table 1).20

DiseaseReaction Leading to SymptomsTheory of Efficacy of Afamelanotide
Protoporphyrin accumulation leading to the formation of reactive oxygen species with exposure to UVR and subsequent vascular and tissue damage5Melanin production provides defense against oxidative stress by neutralizing free radicals and reactive oxygen species2
Solar urticariaExact cause unknown; mast cells likely play a major role; may involve an immunoglobulin E-mediated response against photoinduced, endogenous cutaneous antigens8Melanin production decreases the amount of UVR penetration leading to photoprotection; possible immunomodulatory effects7
Polymorphic light
Exact cause unknown; delayed-type hypersensitivity response to undefined, endogenous, cutaneous photo-induced antigens8,9; UVR-induced alteration of skin antioxidative capacity is thought to contribute to disease onset10-12Classic treatment involves photo-hardening to increase melanization and to decrease UVR penetration13; afamelanotide may increase melanin pigment without the need for phototherapy
VitiligoImmune mediated epidermal melanocyte destruction, with possible defect in α-MSH16NB-UVB used initially to stimulate melanocyte differentiation because melanin production via afamelanotide requires the presence of MCR117; bound MCR1 is then upregulated by afamelanotide leading to melanin production1
Hailey-Hailey diseaseIncreased oxidant stress secondary to reduced intracellular antioxidant response in the keratinocytes of affected areas18MSH has been shown to increase expression of a transcription factor that coordinates the expression of antioxidant enzymes in keratinocytes; afamelanotide may restore the defective proliferative capability and defend against oxidant stress18
AcneVarious contributing factors, including increased sebum production, hyperkeratinization, and proliferation of Propionibacterium acnes1Unclear, possibly through anti-inflammatory properties20
Table 1: Summary of the rationale of afamelanotide use in dermatologic disorders
MCR1 = melanocortin receptor 1; MSH = melanocyte stimulating hormone; NB-UVB = narrowband ultraviolet B; UVR = ultraviolet radiation


Afamelanotide has a promising future as a treatment for a variety of skin diseases including EPP, solar urticaria, PMLE, acne vulgaris, vitiligo and Hailey-Hailey disease. In consideration of the limited data available on afamelanotide use in children, elderly patients, pregnant or lactating women, and those with hepatic or renal impairment, more studies are needed to evaluate safety and efficacy in these populations.5 The anti-inflammatory, pigmenting and free radical scavenging effects produced by the stimulation of melanin production, coupled with a mild side effect profile, make afamelanotide an attractive and versatile compound that shows therapeutic potential in a variety of dermatologic conditions.


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