Afamelanotide for prevention of phototoxicity in erythropoietic protoporphyria

ABSTRACT

Introduction: In erythropoietic protoporphyria (EPP), an inherited disorder of heme biosynthesis, accumulation of protoporphyrin IX results in acute phototoxicity. EPP patients experience severe burning pain after light exposure, which results in a markedly reduced quality of life. Afamelanotide is the first effective approved medical treatment for EPP, acting on melanocortin-1 receptors. This article aims to review afamelanotide.

Areas covered: This review summarizes the chemical properties, pharmacokinetics, safety, preclinical and clinical data on afamelanotide in EPP, and post-marketing surveillance. PubMed search, manufacturers’ websites, and relevant articles used for approval by authorities were used for the literature search.

Expert opinion: Afamelanotide is an α-melanocyte-stimulating hormone analog. It can activate eumelanogenesis without exposure to UV radiation. Clinical studies in EPP showed that afamelanotide treatment significantly increased exposure to sunlight and QoL. In our clinical experience afamelanotide treatment is much more effective in clinical practice than demonstrated in clinical trials and should be made available for all EPP patients meeting inclusion criteria. The 60-day interval period was not based on effectiveness studies, and therefore for some of the patients the maximum of four implants per year with the 60-day interval is insufficient. Afamelanotide is well tolerated; common adverse events were headache, fatigue, and nausea.

KEYWORDS:

• Erythropoietic protoporphyria
• EPP
• afamelanotide
• phototoxicity
• inborn errors of metabolism
• melanocyte-stimulating hormone
• porphyria

1. Introduction

1.1. Erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) severely affects patient's quality of life [1–3] by causing severe phototoxicity. Patients develop severe pain after light exposure, sometimes after only a few minutes. The pain lasts for several days and is unresponsive to analgesics [4,5]. Pain is often followed by erythema, edema, petechiae, and erosions of the skin. Severe pain from early childhood onwards results in light-avoiding behavior, limiting daily and social activities [6]. Patients learn to recognize prodromal symptoms, the early warning signs to a phototoxic reaction, and immediately withdraw from light when they recognize these symptoms to prevent pain. Besides phototoxicity EPP can present with liver manifestations in 5–20% of patients, ranging from mild disease to fatal hepatic failure [7,8].

EPP (OMIM 177000) is a rare autosomal recessive inherited disorder of heme biosynthesis. Symptoms result from accumulation of protoporphyrin IX (PPIX), the photosensitizing precursor of heme, in erythroid cells [2,7]. PPIX can be activated by the blue spectrum (400–410 nm, the Soret Band) of visible light. As well as sunlight many artificial light sources can activate PPIX [9]. In most individuals (>90%) EPP is caused by mutations in the FECH gene resulting in decreased activity of ferrochelatase, the enzyme that converts PPIX to heme by incorporating ferrous iron into the tetrapyrrole ring. Rare causes of EPP are X-linked protoporphyria (XLP, OMIM 300752) [10] or mutations in the CLPX gene [11], presenting with identical phototoxic symptoms. PPIX in erythrocytes, plasma, and endothelial cells in the skin absorbs visible light (410 nm), resulting in formation of reactive oxygen species, which cause endothelial and dermal damage [12,13]. The prevalence of EPP ranges between 1:75,000 and 1:180,000 in Europe [2,14]. It is more frequent in Japan due to an increased prevalence of the milder variant with a loss of function mutation in the FECH-gene, c.315–48 T > C (present in 43% of Japanese people compared to approximately 10% in the Netherlands) [15]. This variant will only lead to EPP if the patient also has a severe pathogenic mutation in the FECH-gene.

Until recently there was no consistently effective medical therapy to prevent or treat the symptoms of EPP. Management of EPP mainly consisted of strict light avoidance. However, recently afamelanotide (‘Scenesse’, CLINUVEL Pharmaceuticals) has been approved for the treatment of patients with EPP. Afamelanotide is a symptomatic treatment for EPP, PPIX levels remain the same and it is unlikely to protect against PPIX-mediated liver damage. The European Medicines Agency (EMA) recommended approval of afamelanotide in the European Union in December 2014. This authorization of afamelanotide was granted under ‘exceptional circumstances’ to ensure that treatment can only to be given under strict conditions, monitoring both safety and effectiveness, through a post-authorization safety study (PASS) with effectiveness outcomes of all EPP patients [16]. In October 2019, the Food and Drug Administration (FDA) granted approval to afamelanotide treatment for EPP in the US, and the Australian TGA in October 2020. In this review, we discuss the chemical properties, pharmacokinetics and preclinical data of afamelanotide as well as the clinical trials evaluating the efficacy and safety of afamelanotide in patients with EPP. Literature used in this review was found through a PubMed search using the terms ‘afamelanotide’, ‘Scenesse’, ‘CUV-1647’, ‘Melanotan-1’, ‘NDP-MSH’, and ‘Erythropoietic protoporphyria’. Furthermore, manufacturers’ websites and relevant articles used for approval by authorities were used.

1.2. Overview of treatment options

It is extremely challenging to investigate the efficacy of a potentially beneficial treatment in EPP because, as Corbett et al. stated in 1977, it is difficult to assess the efficacy of treatment in a disease where signs and symptoms are provoked by sunlight. Light exposure is unpredictable in many climates [17] and symptoms can be prevented by avoiding light. Moreover, results of artificial irradiation tests are unreliable, because the intolerance of individual patients to light varies from one occasion to another, even in the absence of treatment, and some patients show consistently negative tests when artificial light is used [18].

In the past, numerous therapies to prevent or treat EPP symptoms have been tried and studied. As sunscreen only blocks UVA and UVB and does not block light in the visible spectrum such as blue light (>400 nm), conventional topical sunscreens are not effective in EPP [19]. Pain medication and stronger analgesics like morphine are notoriously ineffective to give pain relief during a phototoxic reaction [7].

Many potential treatments for EPP have aimed at increasing skin pigmentation, in order to prevent blue light from penetrating the skin and activating PPIX. Beta-carotene, which causes an orange skin pigmentation, was thought to be an effective treatment and has been studied frequently in small open-label studies. However, only one randomized double-blind placebo-controlled crossover trial was performed, which did not show a beneficial effect of beta-carotene on hours spent outdoors. Even though this study was meant to be double blinded, it was deblinded due to the orange coloration of the skin during treatment with beta-carotene [18]. Two later published population-based studies observed modest perceived efficacy of beta-carotene and low continuation rates [1,2]. Besides, due to toxicity beta-carotene should not even be given in high dosages (≥20 mg/day) [20]. A more successful therapy to improve light tolerance by inducing skin pigmentation in EPP was narrowband ultraviolet Bphototherapy [21,22]. However, it was only partially effective in asubset of patients and prolonged use was linked to DNA damage raising concerns on increased risk of skin cancer [23], limiting its usefulness. Areview on therapies for EPP [24] reported no proven effect of free radical scavenging therapies using N-acetyl cysteine [25,26], cysteine [27,28], vitamin C[29] and dihydroxyacetone [30–32]. Another treatment option is to reduce protoporphyrin levels by giving blood transfusions or even exchange transfusions. Both can reduce erythropoiesis [33–35]. Van Wijk etal. demonstrated that the PPIX pool can be reduced and heme (and PPIX) synthesis can be suppressed, by treating patients with blood exchange transfusions in which the hemoglobin level was raised and kept above 9 mmol/liter [36]. Blood transfusions and/or exchange transfusions are indeed indicated and proven effective to treat patients with EPP-related acute cholestatic hepatitis, which is alife-threatening complication of EPP. Since (exchange) transfusions are only effective for ashort period of time, ongoing transfusions cannot be considered as astandard and long-term treatment considering the potential side effects [37]. The only currently available curative option for EPP is an allogeneic bone marrow transplantation. However, due to the high mortality risks of bone marrow transplantation, this is generally only performed in patients with severe EPP-associated liver disease (which is apotentially lethal condition), and is mostly combined with aliver transplantation [38,39]. Since there is an inherent risk of bone marrow transplantation, and there are doubts if EPP related acute cholestatic hepatitis is strictly erythropoietic [40], this will rule out the bone marrow transplantation as astandard treatment option. Due to the limitations of all treatment options strict avoidance of (sun) light, wearing protective clothing, and applying yellow films to windows to block blue light (<460 nm) was the only option patients had to prevent symptoms. Since the most serious reactions to artificial light have been to exposure to operating theater light [41,42], yellow filters can be used as preventive measures [43]. Avoidance of light has major implications for the daily life of patients with EPP, affecting family life (e.g. parents with EPP cannot bring their children to school), social life, and their ability to work. Furthermore, since the symptomatology of the disease is most apparent from early spring to late fall wearing protective clothing is agreat burden, and staying indoors when others go outside severely limits social interaction [44]. EPP therefore has agreat negative impact on quality of life and their ability to participate in daily and social activities [4]. Afamelanotide is the first treatment option that can actually change this and fulfill this unmet need for EPP patients. Furthermore, anew molecule and possible alternative treatment, MT-7117 (dersimelagon), is currently tested in aphase III trial [45,46].The chemical properties, pharmacokinetics, and preclinical data of afamelanotide as well as the clinical trials evaluating the efficacy and safety of afamelanotide in patients with EPP will be discussed in the remainder of this review.

2. Afamelanotide

2.1. Chemistry

First, we start with a short introduction on the physiological mechanism of action of α-melanocyte-stimulating hormone (α-MSH), to clarify the working mechanism of afamelanotide thereafter. Natural α-MSH is a 13 amino acid peptide that is only produced in small amounts by the pars distalis of the pituitary gland and by extra pituitary cells including keratinocytes, this is in contrast to most mammalian species where it is only synthesized by the anterior pituitary gland. Alpha-MSH is an endogenous peptide hormone and neuropeptide of the melanocortin family, it stimulates melanogenesis via the melanocortin-1 receptor (MC1R) and tyrosinase activation, the rate-limiting enzyme in this pathway. This results in eumelanin production, which accounts for the skin-darkening effect of α-MSH [47]. In the human skin, melanogenesis is initiated by exposure to UV radiation, also causing the skin to darken. α-MSH has besides this skin-darkening effect due to activation of eumelanogeneisis, also an anti-inflammatory effect [48]. There are three basic types of melanin: eumelanin, pheomelanin, and neuromelanin. Eumelanin is photoprotective, while pheomelanin may contribute to UV-induced skin damage, this is related to its potential to generate free radicals in response to UV [49]. Individuals with a predominance of pheomelanin, a less protective yellow-red pigment, in their skin and/or a reduced ability to produce eumelanin, will hardly tan and are at risk from UV-related damage, like skin cancer. Previous studies have shown that eumelanin is preferentially produced when α-MSH stimulates melanogenesis in human melanocytes [50]. Besides the increase in total synthesis, MC1R activation also results in a switch from pheomelanin, to eumelanin production, a more protective brown-black pigment [51]. The MC1R gene has a lot of polymorphisms, some of them associated with variation in pigmentation phenotypes within human populations [52]. MC1R activity is related to different genotypes, a homozygous low-activity genotype will result in a phenotype featuring fair skin, red hair, freckling, and an inability to tan [53].

Afamelanotide is a synthetic α-MSH analog. Afamelanotide chemically differs from α-MSH by substitution of the amino acids methionine and L-phenylalanine at positions 4 and 7 with norleucine and D-phenylalanine [Nle⁴-D-Phe⁷]-α-MSH. This manipulation of the stereo-chemical structure of α-MSH was performed in order to make afamelanotide more potent and prolong biological activity [54]. Afamelanotide works as an agonist on the MC1R, a G protein-coupled receptor that plays a key role in the biosynthesis of melanin. Binding of afamelanotide to MC1R activates eumelanogenesis, by increasing intracellular content of cyclic AMP (cAMP) and increasing tyrosinase activity, the rate-limiting step in melanogenesis [55]. Afamelanotide acts in the same way as endogenous MSH on MC1R, but independent of UV stimulation. Eumelanin exhibits numerous effects, including photo protection against ultraviolet (UV) light (by absorbing the UV light) and scavenging of free radicals [56].

In previous studies afamelanotide was also named NDP-MSH, CUV1647, or Melanotan-I. In this review we will use afamelanotide in all these cases. However, afamelanotide should not be confused with Melanotan-II (Ac-Nle-c[Asp, HisDPhe, Arg, Trp, Lys]-NH2) which is a smaller molecule than afamelanotide. Melanotan II is just as potent for skin pigmentation as afamelanotide and cheaper to manufacture, but can also cross the blood brain barrier and has more side effects including nausea and penile erections [57,58]. Both Melanotan-I and Melanotan-II are commercially available, not registered nor approved as medical drugs, and without regulatory oversight. However, there has been illegal supply of unlicensed and unregulated products claiming to be Melanotan-I or Melanotan-II that are possibly harmful, due to potential impurity of chemicals and transmission of bloodborne diseases from needle sharing [59].

2.2. Pharmacodynamics, pharmacokinetics and metabolism

Data on afamelanotide’s clearance and half-life, distribution, and metabolism are limited. The available data are mostly confined to healthy individuals. Sawyer et al. first synthesized afamelanotide in the 1980s [54]. Animal studies showed a higher (10–1000 times) physiological activity and stability of afamelanotide than α-MSH, and the capacity to stimulate tyrosinase activity for longer than the endogenous compound [54,60]. Ugwu et al. performed an initial pharmacokinetic study with afamelanotide in healthy humans in 1997. To do so, they administered afamelanotide intravenously (IV, 0.16 mg/kg), orally (0.16 mg/kg) and subcutaneously (s.c., 0.08–0.21 mg/kg). No levels of afamelanotide were detectable in plasma following oral administration. However, subcutaneous administration resulted in full bioavailability compared to the equivalent IV dose. With both subcutaneous and IV administration the absorption was very quick, and a plasma β-phase elimination half-life of 1.3 ± 0.46 h for s.c. injections and 1.07 ± 0.46 h for IV dosing were reported. Although this is much longer than the half-life of the native hormone α-MSH (20.8 min) it is still relatively short. The results of Ugwu et al. also suggested greater skin pigmentation if the s.c. route was used compared to the IV route and therefore concluded that the s.c. route is the preferred method of administration for afamelanotide [61]. These findings eventually lead to the development of the biodegradable subcutaneous injectable implant that has now been approved for treatment of EPP.

In 1997 Levine et al. published a randomized placebo-controlled trial (RCT) in which afamelanotide was administered via subcutaneous injection in healthy volunteers with skin type I–IV (Fitzpatrick Scale). The treatment schedule was 10 injections of 0.08 mg/kg during 12 consecutive days. This resulted in darkening of the skin even though participants avoided ultraviolet radiation exposure. The changes in pigmentation, which became apparent during the second week after the volunteers started with the injections, were maximal during week 3 to 5, and clearly faded by week nine [62]. Thereafter, a dose finding study was performed in eight male volunteers with skin types III–IV (Fitzpatrick scale). Treatment schedule was daily afamelanotide subcutaneous injections for 10 days, with three different doses: 0.16 mg/kg per dose, 0.26 mg/kg per dose, and 0.4 mg/kg per dose. Although all subjects tanned during the study, and there was no improved tanning beyond that obtained at the 0.16 mg/kg dose, setting it as the optimal dosage. Besides, the 0.16 mg/kg dose did not show toxicities over grade 2 grading based on World Health Organization (WHO) criteria [63]. Another study using this 0.16 mg/kg dose in skin type III–IV volunteers (six males and one female) containing 10 daily subcutaneous injections over two weeks, confirmed increased tanning by particularly eumelanin expression, while overall there was no increase in pheomelanin expression (except in one subject who experienced a substantial increase in eumelanin and pheomelanin) [50]. Additionally, afamelanotide resulted in a greater increase of melanin density in fair-skinned subjects, skin type I/II according to Fitzpatrick scale, compared to darker skin subjects, providing much needed photoprotection in patients with a lighter skin type [64]. In the EMA EPAR assessment report for afamelanotide, results of unpublished studies performed by the producing company of the biodegradable implant (CLINUVEL) were submitted. This report is publicly available and used for this review. CLINUVEL developed a biodegradable and biocompatible subcutaneous implant, with polylactide (PLA) and poly lactide-co-glycolide (PLG) as excipients, capable to modulate the release of afamelanotide over a defined number of days. In the performed dose-escalation study (EP004) in 30 volunteers using other formulations as subcutaneous implants with dosage between 5 mg and 40 mg, as expected based on earlier studies with subcutaneous injections, all dosages resulted in increased melanin densities in skin, but pigmentation was most increased with the implants of 20 mg and 40 mg. The currently available formulation with 16 mg per implant was tested in two pharmacokinetic studies. The first study (CUV028) consisted of 24 healthy adults, who were assigned to receive either a 16 mg afamelanotide implant from the earlier manufacturing process (Group 1) or from the optimized final manufacturing process (Group 2). Both implants appeared to be comparable to those implants manufactured using the previous process. The second study contained twelve healthy volunteers (CUV038) with collection of blood samples at days 0, 1, 2, 3, 4, 7, 10, and day 14. These studies demonstrated that 2 weeks post dose there were no measurable afamelanotide levels in plasma in any subjects [65].

No extensive studies have been published on the metabolism of afamelanotide. The natural hormone α-MSH is rapidly degraded by unspecific proteases in animals, or in vitro by trypsin or chymotrypsin, whereas afamelanotide is resistant to all these enzymes [66].

Distribution studies have been performed in mice (CD1, BALB/c albino, and pigmented mice) and rats (albino SD) using radiolabelled afamelanotide. These studies found high levels of afamelanotide in urine, small intestine, liver, and kidney 1 to 4 hours after s.c. injection, with highest levels in kidney and urine suggesting that afamelanotide is mainly excreted via the kidneys [65]. For the biodegradable implant after injection in the body PLG degrades by hydrolysis into the monomers glycolic and lactic acid, which are metabolized mostly to carbon dioxide and water and to a lesser extent excreted by the kidney [65].

3. Clinical efficacy of afamelanotide

3.1. Phase I/II studies

The first phase II open-label study with the biodegradable implant of afamelanotide for EPP dates back to 2006. At that time there were no previous studies using standardized or validated endpoints to measure efficacy on phototoxicity in EPP patients, and there was and still is much to learn on this exceptionally complex disease and its symptoms. During the studies a major clinical challenge appeared in estimating the treatment effect of afamelanotide, as patients need to be willing to expose themselves to sunlight in order to be able to measure an effect. This means that patients need to overcome their fear and memory of phototoxic episodes and must accept the risk of developing very painful phototoxic reactions. This has proved to be very difficult for patients and resulted in the adaptation of older endpoints, and because of progressive insight in the clinical consequences of the disease, the continuous development of new suitable endpoints during the clinical trials. This progressive insight is clearly demonstrated by the different endpoints used during different studies (Table 1), starting with the endpoint time to response after photoprovocation in the first study, leading to time spent outside (hours per week) as an endpoint currently used in the EMA directed PASS. At this moment new endpoints, for example time-to-prodrome, are being studied to increase relevance and using more patient reported outcome (PRO) endpoints, since patients are more likely to test time-to-prodrome and prevent the occurrence of a phototoxic reaction [67]. The use of afamelanotide is contraindicated for EPP patients in the presence of severe hepatic disease, hepatic impairment, renal impairment, pregnancy, or age below 18 years [65].

Table 1. Clinical studies on afamelanotide for erythropoietic protoporphyria

Study	Location	Design	Duration	Dosage	n	Outcome parameter	Results	Reference
Phase II
Harms et al.	Switzerland	Phase II, open label	4 months	20mg	5	Time to response after photo provocation (minutes) Melanin density units	Tolerance to artificial light increased significantly to 11 times (p = 0.004) Melanin density increased significantly by 1.3 times (p = 0.007)	[68]
CUV 030	USA	Phase III study, randomized controlled trial	6 months	16mg	77	Severity of phototoxic reactions (post hoc changed to direct sunlight exposure between 10 a.m. en 3 p.m.) Number of severe phototoxic reactions	Significant three-fold increase in time in direct sunlight between 10 AM and 3 PM (p = 0.036) No differences in overall time spent outside and number of severe phototoxic reactions	[65,69]
Phase III
CUV 017	Europe/Australia	Phase III, randomized placebo-controlled crossover study	12 months	16mg	100	Number of days on which patients experienced pain Pain severity (11-point Likert scale)	Distribution of frequency of days with pain of different severity differed between active and placebo (p = 0.0042)	[65]
Langendonk et al.	Europe/USA	Phase III, double-blind randomized controlled trial	9/6 months	16mg	74/ 94	Duration of direct exposure to sunlight without pain between 10AM and 3PM (EU trial) and between10AM and 6PM (US trial) Number of phototoxic reactions Quality of life (EPP QoL in %)	Longer pain-free time after 6 month of treatment (69.4 vs. 40.8 hours, p = 0.04) Less phototoxic reactions on treatment (77 vs 146, p = 0.04) Improved QoL (78.8 vs. 63.6%, p = 0.005)	[70]
Observational
Biolcati et al.	Italy/Switzerland	Longitudinal observation study	Up to 8 years	16mg	115	Quality of life (EPP QoL in %)	QoL scores increased from 31% till 74% during afamelanotide treatment	[71]
Wensink et al. Barman-Aksözen et al.	The Netherlands Switzerland	Longitudinal observation study Longitudinal observation study	24 months 3 years	16mg 16mg	117 39	Time spent outside (hours per week) Quality of life (EPP QoL in %) Number and severity of phototoxic reactions (Likert-scale) Phototoxic burn tolerance time (PBTT, in minutes) Severity of phototoxic reactions (Likert-scale) Quality of life (EPP QoL in %)	Time spent outside increased significantly by 6.1 hours per week (p < 0.001) QoL improved significantly by 14.01% (p < 0.001) Phototoxic reactions were less painful (p < 0.001), no differences in number of phototoxic reactions. PBTT significantly increased from median 10 to 180 minutes (p < 0.0001), Pain intensity decreased significantly from median 10 to 6 (p < 0.0001) QoL in continuously treated patients stayed the same (p = 0.24) QoL after an interrupted treatment was significantly lower compared to that who were treatment-naíve (p = 0.00473).	[72] [73]

Abbreviations: n number of patients. USA United States of America. EU European. EPP erythropoietic protoporphyria. QoL Quality of life. PBTT phototoxic burn tolerance time.

The first study was performed in five patients (CUV010), receiving a subcutaneous implant at a dose of 20 mg, given twice at an interval of 60 days [68]. The dosage interval was chosen based on very limited data, and understanding of clinical behavior of patients with the expectation that elevated melanin levels would stay above baseline after 60 days, and the implant would be fully resorbed. This was not studied in an evidence-based manner since no dose ranging studies have been performed. The primary endpoint of photoprovocation was time until intolerable pain on the dorsum of the hand following exposure to a standardized white light source, a xenon arc lamp with UV filters. There was an 11 times increase in time to response after photoprovocation at day 120 compared to baseline, this increase did not correlate with increased melanin density. Reported adverse events were short-term nausea and headache. A second phase II study (CUV030) was a randomized controlled trial (n = 77) using 16 mg subcutaneous implants every 60 days, 3 doses in total. No peer-reviewed publication was found for this trial. The sponsor reported to the EMA: following treatment, more direct sunlight exposure between 10:00 and 15:00 hours on days when no pain was experienced, though no difference between groups for overall time spent outdoors or number of severe phototoxic reactions was observed [65,69].

3.2. Phase III studies

The pharmaceutical company performed a phase III, randomized placebo-controlled crossover study (CUV017) in 100 EPP patients, of whom 93 completed the study. The intervention group was treated with a 16 mg subcutaneous implant every 120 days, three doses in total. A placebo implant was administered on days 60, 180, and 300. The placebo group had the same treatment sequence. Patients who had not exposed themselves sufficiently to sunlight were excluded post hoc from efficacy analysis. This study reported more sun exposure in patients receiving afamelanotide, and that distribution of frequency of days with pain of different severities significantly differed between treatment with afamelanotide and placebo. However, melanin density results showed that by the time patients were treated with placebo there was a potential carryover effect from the earlier given afamelanotide implant. This led to parallel treatment groups in future studies [65]. No peer-reviewed publication was found for this trial.

In Europe and the USA two phase III, double blind randomized controlled trials in 74 and 94 patients were performed [70]. These trials have been peer-reviewed and published. Patients were randomly assigned, in a 1:1 ratio, to receive afamelanotide 16 mg or placebo every 60 days (5 implants in Europe and 3 in the USA). The primary endpoint was the duration of time spent in direct sunlight between 10 a.m. and 3 p.m. in Europe, and between 10 a.m. and 6 p.m. in the USA. The secondary endpoints were number, severity, and duration of phototoxic reactions, quality of life (EPP QoL) and safety (clinical chemistry and physical examination changes). Both studies demonstrated a significantly increased duration of pain-free time: in Europe, after 9 months median 6.0 hours vs. 0.8 hours in the placebo group, and in the USA study after 6 months, median 69.4 hours, vs. 40.8 hours in the placebo group. Furthermore, there was a decreased number of phototoxic reactions, and an ongoing improvement in quality of life with afamelanotide treatment. The EMA considered this trial to provide pivotal data for the assessment of efficacy of afamelanotide to support marketing authorization.

3.3. Observational studies

Although the previous trial was considered pivotal there were still questions regarding the efficacy, leading to disappointing reimbursement discussions, which will be addressed later in this article. Two observational studies (Table 1) were published reporting on efficacy and safety of 16 mg afamelanotide implants. The first observational study included 115 patients, covering 314 patient years of treatment. Patients were treated for up to eight years. This observational study demonstrated increased quality of life over the entire observation period. Besides, this study has shown that more than four implants per year are safe, and do not result in increased adverse events [71]. The second observational study was performed in 117 patients in the Netherlands during clinical practice. Patients were also treated with 16 mg afamelanotide implants with a minimum interval of 60 days, max four implants per year. This observational study, based on the EMA requested PASS protocol, demonstrated clinically significant, and sustained, positive effects on quality of life (an improvement of 14% on the EPP QoL), increased reported duration of light exposure with an added 6.1 hours per week and less painful phototoxic reactions [72]. Recently, a study was published introducing the new endpoint phototoxic burn protection factor (PBTT) for assessing treatment effect in EPP. The study investigated 39 patients being treated with afamelanotide 16 mg, during three years. PBTT was defined as the reported maximum time the patients are able to expose themselves to sunlight without experiencing a phototoxic reaction. Afamelanotide treatment showed an increase in PBTT, there was a decrease in pain severity and an increase in quality of life [73]. This new endpoint is in line with the presented Time-to-Prodrome endpoint, using more patient reported outcome (PRO) efficacy endpoints for future EPP treatments [67]. No peer-reviewed publication was found for this study yet.

4. Post-marketing surveillance

In the initial studies where afamelanotide was administered to healthy volunteers in an aqueous solution, the dosage was extremely high compared to the used dose in the phase II and III trials [61], which in contrast to the studies in healthy individuals did not report any long-term negative effects. The aqueous solution used solute in saline required high doses of afamelanotide leading to high peak plasma levels, resulting in more frequent reported adverse events. The final subcutaneous implant that is approved for the treatment of EPP, results in lower peak plasma levels, solving this problem. Generally, afamelanotide was well tolerated, although most patients treated with afamelanotide reported some mild self-limiting adverse events. In the performed phase III trial the most frequently reported adverse events were headache, nausea, nasopharyngitis, and back pain [70]. No deaths or related serious adverse events were reported in any of the discussed studies. In the observational study where 115 patients were followed for almost 8 years a total of 680 adverse events were recorded. Most frequently reported were nausea, headache, and fatigue [71]. The observational study using the EMA directed protocol during clinical practice reported that 89% of patients experienced adverse events; all events were self-limiting with an average duration of one to two days, occurring hours to one day after implantation. Most frequently reported were nausea, fatigue, flushing, and nausea with headache. No related serious adverse events occurred during the study [72]. Skin hyperpigmentation is the most prominent visible effect of afamelanotide; some patients reported increased skin pigmentation and darkening of preexisting nevi and ephelides. Since this is due to the pharmacologic effect of afamelanotide these effects were no longer considered and reported as adverse events. Overall, related adverse events are mild in severity. Additional studies demonstrated that afamelanotide is not immunogenic over time [74]. They measured anti-drug antibodies (ADA) with a new ELISA method testing both ADA against afamelanotide and against α-MSH. Some patients had preexisting immunoreactivity for afamelanotide, without any increase in reactivity during long-term treatment.

Some concerns were raised regarding possible carcinogenic effects of afamelanotide, especially the potential increased risk for the development of melanoma [75]. These concerns were raised due to the illegal commercial use of Melanotan, the so-called ‘Barbie drug’ which was associated with melanoma [76]. However, the increased risk of melanoma in Melanotan users, who use it for tanning and exhibit sun-seeking behavior, can probably be explained by more UV exposure. The primary risk factor for melanoma formation is genetic predisposition (MC1R gene) in combination with too much UV exposure, which can induce DNA damage [77]. In contrast, afamelanotide increases eumelanin production irrespective of UV exposure, inhibiting the production of pro-inflammatory cytokines and stimulating DNA repair [78,79]. Moreover eumelanin can protect against melanoma development by reducing UV penetration, and scavenge the UV-induced oxygen radicals [80]. Data on safety regarding carcinogenic effects of afamelanotide is still being collected in the EU following the EMA directed PASS, although until now after 5 years no melanoma was reported.

5. Regulatory affairs

The EMA recommended approval of afamelanotide for the treatment of adult EPP patients in the European Union in December 2014. Afamelanotide was granted approval due to an inability to prove efficacy in EPP, a lack of scientific tools or instruments available to measure treatment effect and the fact it would be unethical to subject EPP patients to further placebo-controlled trials with inevitable pain exposure. The authorization of afamelanotide was granted under ‘exceptional circumstances’ to ensure that treatment can only to be given under carefully monitored conditions. This resulted in the obligation to perform a PASS in the European Union in all EPP patients receiving treatment. Treatment can only be prescribed in accredited specialized porphyria centers. These centers are also urged to include patients off-treatment, as part of the risk management plan [16]. Despite the accumulating evidence that afamelanotide may be a life-changing treatment for patients with EPP, there is still doubt about its efficacy because measuring effect size remains difficult. Therefore, worldwide, it is currently only available and reimbursed for adult EPP patients in Switzerland, the Netherlands, Germany, and, based on case-by-case decisions for reimbursement, for some patients in Austria, Italy, and Belgium. Recently, in October 2019, the Food and Drug Administration (FDA) granted approval to afamelanotide treatment for EPP in the US, and the Australian TGA in October 2020.

Afamelanotide is also being investigated for the treatment of diseases other than EPP, like solar urticarial, polymorphic light eruption, vitiligo, and Hailey-Hailey disease. In the future afamelanotide will also be investigated in patients with variegate porphyria, xeroderma pigmentosum, and arterial ischemic stroke. A phase II trial of afamelanotide for solar urticaria showed promising results on reducing the solar urticarial response across a broad spectrum of wavelengths [81]. In studies on afamelanotide treatment, combined with ultraviolet therapy, for vitiligo it resulted in superior and faster regimentation [82]. Afamelanotide was also effective for the treatment of skin lesions in Hailey-Hailey disease, resulting in improved patient reported outcome (SF-36) and clearance of skin lesions, independently of the lesion location [83].

6. Conclusion

Afamelanotide is a synthetic α-MSH analog, which increases skin pigmentation by activation of eumelanin production. Performed studies on afamelanotide treatment for EPP have proven to be effective. Afamelanotide offers an important improvement in increasing light exposure and quality of life in patients with EPP. Besides, it has proven to be well tolerated with only mild adverse events, like nausea, headache, and fatigue, only occurring the first days after administration. Despite the study outcomes afamelanotide is still not available worldwide for the treatment of EPP.

7. Expert opinion

Patients with rare diseases often have to wait years to get a diagnosis because it remains unrecognized. This is also the case for EPP patients. Until a couple of years ago EPP patients were only attending the clinic to present symptoms, without therapy being available. However, recognition and acknowledgment of their lifelong suffering are essential for patients. Rare diseases also present operational challenges in finding an effective treatment, and with small populations, conducting natural history studies and clinical trials is difficult. As described previously, this also applies to afamelanotide treatment for patients with EPP, and therefore there are still difficulties in acknowledging and approving reimbursement. Earlier placebo-controlled trials showed a significant improvement in endpoints on afamelanotide treatment, but the improvement in absolute terms had been interpreted as small. In contrast to the small improvement under controlled conditions during clinical trials, patients continue under conditions of use to report a great improvement in symptoms and quality of life during treatment with afamelanotide. In retrospect, the primary endpoint in the randomized trials, namely time spent outside in direct sunlight, may not have been a suitable endpoint to measure the clinical effectiveness of afamelanotide. Starting in childhood, at a very young age, EPP patients are conditioned to avoid direct sunlight due to the painful attacks inflicted by light exposure. It is likely that such conditioned behavior can only change gradually with ongoing positive reinforcements. The fact that finding a suitable endpoint for novel clinical trials is difficult for assessing treatment effects in patients with EPP is demonstrated by the variability of endpoints used during previous studies. Progressive insights on EPP resulted in the need to change endpoints, and the development of suitable endpoints for clinical trials is still ongoing. In our years of clinical experience, afamelanotide treatment is much more effective in clinical practice than demonstrated in clinical trials. Patients continue to tell us how life changing it has been. Recently we performed an unpublished qualitative quality of life study with in-depth interviews, where patients reported to ‘forget to have EPP during treatment’ and they mentioned that they ‘experience less stress’. However, the current dosing schedule of afamelanotide that has been approved by the EMA is a 16 mg implant, four times a year with at least 60 days between implants. This has proven insufficient in the majority of the EPP patients, before 60 days they relapse with again severe limitations to participate socially and professionally during the non-treated intervals during the year. The limitation in the number of implants has also a psychological impact, since patients can experience an improved life during treated periods, and have to return to their impaired life afterward. Many patients reported spontaneously return of symptoms and ‘normalized’ severe light intolerance within the 60 days between two implants, this is based on qualitative data, the patients fill this in open remarks of questionnaires of the PASS protocol. Furthermore, during untreated periods, with more than 60 days between to implants, most patients return to their previous limitations, which is very distressing. For an optimum effect in all EPP patients, more implant administrations per year are needed and in a selection of the patients with shorter intervals between implants (for example every 40–50 days).

In our clinical experience afamelanotide treatment is much more effective in clinical practice than demonstrated in clinical trials, and should be available for all EPP patients meeting inclusion criteria. However, although the treatment is very effective, EPP is not cured and some adaptive behavior to light exposure is needed in most patients, and there is a wide variability in response. Further studies on more effective and ideally curative treatment modalities are needed. Especially gene therapies could be an interesting target for a curative treatment option since they could cure the phototoxicity and prevent the PPIX-mediated hepatoxicity, but it is unlikely that this will be developed in the near future. In the coming five years we expect that there will be progression in developing treatment for children with EPP (which is much needed), with either additional afamelanotide dosage forms as well as new molecules like MT‑7117 (dersimelagon). Dersimelagon seems promising, and can be an oral alternative to afamelanotide, which would be easier to administer, maybe inducing a wider availability for EPP. Although, we have to await the results of the phase-III trial on effectiveness and adverse events to draw conclusions.

Article highlights

• Afamelanotide is an α-melanocyte-stimulating hormone analog and activates eumelanogenesis.

• Afamelanotide was approved by the EMA for the symptomatic treatment of erythropoietic protoporphyria in 2014, and was recently approved by the US FDA (October 2019) and the Australian TGA (October 2020) for this purpose.

• Multiple studies have shown that afamelanotide leads to increased light and sun exposure, less severe phototoxic reactions, and improvement of quality of life in patients with erythropoietic protoporphyria.

• The EMA recommended dosage is one 16 mg subcutaneous implant every 60 days, with a maximum of four implants per year, but at the discretion of the prescribing physician. The US and Australian dosage is one implant every 60 days (US) or two months (Australia).

• Common adverse reactions of afamelanotide were short-term nausea, fatigue, flushing, and headache.

Declaration of interest

JG Langendonk reports financial support from CLINUVEL to cover expenses incurred for data entry for the European Medicines Agency (EMA) directed afamelanotide registry. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have been a consultant of Clinuvel Pharmaceuticals Ltd. Clinuvel Pharmaceuticals Ltd provided a scientific accuracy review at the request of the journal editor. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.