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)

ABSTRACT

Background

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.

Objectives

Evaluate the short‐ and long‐term safety and clinical effectiveness of afamelanotide 16 mg in EPP patients enrolled in the PASS in Germany.

Methods

The PASS (EUPAS13004) is an ongoing observational study collecting safety and effectiveness variables from treated and untreated EPP patients in the European EPP Disease Registry. Patients (n = 200, none untreated) received afamelanotide according to the summary of product characteristics. Treatment‐emergent adverse events were collected as safety variables. Clinical effectiveness was assessed with the EPP‐QoL tool and through treatment continuity.

Results

The short‐ and long‐term safety and benefit–risk profile of afamelanotide under real‐world conditions is consistent with the positive safety profile seen in clinical trials. EPP patients reported a significant increase in QoL compared with baseline values (p < 0.0001) and 91.0% of patients who started treatment continue being treated. The safety profile of afamelanotide in patients over 70 years of age is consistent with the overall patient population.

Conclusions

Afamelanotide treatment was highly effective and associated with a higher QoL in EPP patients. The study shows a positive safety profile of afamelanotide, with the treatment providing an ongoing clinical benefit.

1. Introduction

Erythropoietic protoporphyria (EPP) is a rare autosomal recessive inherited disorder of the haem biosynthesis pathway [1, 2, 3]. Patients experience severe and debilitating acute phototoxicity—anaphylactoid reactions and pain—resulting from endothelial cell photodamage due to an accumulation and activation of protoporphyrin IX (PPIX) [4, 5, 6, 7]. The reactions are unresponsive to analgesics, lasting for several days to weeks [2, 4, 8]. EPP typically manifests in childhood, leading to conditioned light‐avoidance behaviour and a severely impaired quality of life (QoL) [9].

The prevalence of EPP is estimated to be at least one in 140,000 of the European population, affecting males and females equally [10, 11]. EPP is an orphan indication and, until recently, there was no effective treatment. Afamelanotide [12] has been approved as a photoprotective treatment for adult EPP patients in Europe, the USA and Australia. The drug is a potent analogue of the natural α‐melanocyte‐stimulating hormone (α‐MSH), binding to the melanocortin 1 receptor in cutaneous cells [13, 14, 15]. The treatment increases the production of photoprotective eumelanin [16], which affects skin pigmentation and has anti‐oxidative and anti‐inflammatory properties [7, 17, 18, 19].

Clinical trials and observational studies of the 16 mg afamelanotide implant show patients can expose themselves to light and sun for a significantly longer period of time following afamelanotide treatment in comparison with before treatment, with no or less severe, phototoxic reactions and that treatment improves patient QoL [7, 17, 19, 20, 21, 22].

As conditions of the European Medicines Agency (EMA) marketing authorisation, a disease Registry and postauthorisation safety study (PASS) had to be established to collect and analyse safety data and outcome endpoints in EPP patients receiving, not receiving or having discontinued treatment with, afamelanotide. This study reports the first analyses of safety and outcomes data from four German EPP reference centres, collected from 2016 to 2021.

2. Patients and Methods

2.1. Design

The PASS (EUPAS13004) is an ongoing multicentre, noninterventional study. All adult patients (aged 18 years or above) presenting at four German EPP Expert Centres (EECs) between 14 November 2016 and 22 June 2021 with a confirmed diagnosis of EPP were eligible to enrol, pending written consent. Patients who received treatment with afamelanotide did so in accordance with the approved Summary of Product Characteristics (SmPC) [12]. The study was approved by the Medical Ethics Review Board of each participating centre. Data were entered into a bespoke registry within a validated open‐source clinical management software. Safety information was also entered into a separate safety database. Data were extracted from both databases. Patients remained enrolled until withdrawing consent.

2.2. Safety Variables

Treatment‐emergent adverse events (TEAEs) were assessed at every visit by the EECs. Characterisation of the overall short‐ and long‐term safety profile regarding all adverse events was collected. Short‐term usage is defined as patients who have received five or fewer implants. Long‐term treatment with afamelanotide is defined as 15 or more implants (range 15–27 implants). The safety profile of patients over 70 years old, for whom limited data are available as noted in the SmPC [12], was also evaluated.

TEAEs were defined as adverse events that started on or after receiving the first dose of afamelanotide. TEAEs were categorised by System Organ Class (SOC) and Preferred Term (PT), according to the current version of the Medical Dictionary for Regulatory Activities (MedDRA). All TEAEs were assessed by the reporter and the Marketing Authorisation Holder to determine whether they were related to treatment.

2.3. Clinical Effectiveness Variables

Clinical effectiveness of afamelanotide was evaluated at regular intervals by longitudinal assessment of treatment continuity and QoL. Continuity on treatment was calculated by assessing the number of patients who were on treatment and who remained in the Registry at each 6‐month interval. The EPP specific QoL questionnaire (EPP‐QoL) [23] completed by patients was assessed at baseline prior to treatment in Year 1 and at each subsequent visit. A Total Score (0–100) was calculated, where a score of 0 represents the worst possible QoL and a score of 100 represents the best possible QoL.

2.4. Statistical Analysis

Analysis of all study data was conducted using SAS Version 9.4 (SAS Institute). The analysis of the study data presented is descriptive. Data are presented using summary statistics, by treatment subgroup (short‐term, long‐term and over 70 years of age) and for all patients. The total score for EPP‐QoL was compared at each 2‐month period postintervention versus the score recorded at baseline, using the Wilcoxon signed rank test at the two‐sided 5% significance level. The null hypothesis was that there is no change from baseline in total EPP‐QoL. The analysis was performed according to the treatment year on the Registry and according to calendar month and year. Only those patients with an assessment in the relevant post‐intervention period and in the baseline period were included in the analysis for comparison of the change. Statistical significance was accepted as a p value of ≤ 0.05. Patient characteristics are presented as mean, standard deviation (SD), minimum, median and maximum, unless specified otherwise. Tables present summary statistics for continuous variables and the number and percentage of patients in each category for categorical variables, for all enrolled patients with baseline assessments.

3. Results

3.1. Patient Characteristics

A total of 200 EPP patients treated with afamelanotide consented for their pseudonymised data to be entered into the EPP Disease Registry. Prior to the PASS, 159 patients (79.5%) had never received afamelanotide (treatment‐naïve), while 21 patients (10.5%) had previously been treated with afamelanotide through participation in interventional clinical trials, compassionate use and/or expanded access schemes. Ten patients (5.0%) were being treated with afamelanotide at the time of consent. Ten patients (5.0%) had previously been treated with afamelanotide and enrolled in the Disease Registry within another participating site. Table 1 summarises all demography and baseline patient data.

TABLE 1.

Summary of patient demography and baseline characteristics.

Characteristics	Statistic/category
Total number of patients	N	200
Sex	Male	93 (46.5%)
	Female	107 (53.5%)
Age (years)	Mean	39.8
	SD	14.9
	Median	39.0
	Minimum	18
	Maximum	81
Age group (years)	18–39	102 (51.0%)
	40–64	89 (44.5%)
	65–70	6 (3.0%)
	≥ 71	3 (1.5%)

3.2. Treatments

Figure 1 shows the mean number of doses for each treatment year. A mean number of 11.2 doses of afamelanotide were administered per patient between 14 November 2016 and 22 June 2021 (minimum 1, maximum 27). The maximum number of doses administered in any year were six and the minimum in any year was zero. Implant usage over time is consistent for individual patients with some patients requesting additional treatment to cover winter months. Year 1 includes all patients enrolled within the Disease Registry and treated with afamelanotide apart from one patient who elected not to receive treatment in their first year. Only partial year data are available for patients receiving their sixth year of treatment (up to the cut‐off date for this study). Due to differing enrolment dates of patients, there are fewer patients treated in Years 5 and 6.

FIGURE 1.

Frequency distribution of number of afamelanotide implants for patients by year.

3.3. Safety

Most patients (n = 174; 87.0%) reported one or more TEAE with 54.0% of patients (n = 108) reporting one or more TEAE assessed as related to treatment. Table 2 summarises the TEAEs experienced by patients during short‐ and long‐term usage throughout the study and those experienced by the subgroup of patients 71 years of age and above.

TABLE 2.

Summary of percentage of patients with TEAEs and subgroups.

	Treatment
	Overall (n = 200)	Short term (n = 200)	Long term (n = 53)	> 70 years (n = 7)
TEAEs	87.0%	77.5%	45.3%	71.4%
Related TEAES	54.0%	45.5%	11.3%	14.3%
Serious TEAEs	18.0%	10.5%	3.8%	42.9%
Serious‐related TEAEs	2.0%	1.0%	0.0%	0.0%
	Patients experiencing the most frequent TEAEs by MedDRA PT total % (assessed as related to treatment %) a
Vitamin D deficiency b	29.0% (0.0%)	6.0% (0.0%)	13.2% (0.0%)
Nausea	18.5% (16.5%)	14.5% (13.0%)	3.8% (3.8%)
Nasopharyngitis	18.0% (1.0%)	11.0% (0.5%)	7.5% (1.9%)
Headache	16.0% (12.5%)	13.5% (10.0%)	5.7% (1.9%)
Fatigue	10.5% (9.5%)	9.0% (8.0%)	0.0%

^a No single MedDRA PT was reported by more than one patient in the > 70 years group.

^b Consequence of lack of exposure to sunlight due to the lifestyle and conditioned behaviour of EPP patients.

The most frequent TEAEs reported were vitamin D deficiency 58 TEAEs, n = 58 (29.0%), nausea 62 TEAEs, n = 37 (18.5%), nasopharyngitis 54 TEAEs, n = 36, (18.0%), headache 52 TEAEs, n = 32 (16.0%) and fatigue 34 TEAEs, n = 21 (10.5%). None of the cases of vitamin D deficiency were related to treatment.

18.0% of all patients treated with afamelanotide (n = 36) reported a serious TEAE. Only four patients (2.0%) reported serious TEAE(s) assessed as related to treatment with afamelanotide. Due to the activation of eumelanin and expected increase in light and UV exposure for patients, the SmPC encourage 6‐monthly skin monitoring. 30.5% patients (n = 61) reported a total of 71 TEAEs categorised as pigmentary expressions. No pigmentary lesions or expressions of concern were identified. Nine (n = 7, 3.5%) TEAEs reported biopsy of a naevus, with histopathology results reporting all were benign. Afamelanotide may have a role in preventing skin cancers and is currently being evaluated as a photoprotective and reparative therapy in xeroderma pigmentosum [24, 25]. The drug was previously evaluated by the manufacturer as a preventative for actinic keratoses and squamous cell carcinomas in immunosuppressed transplant recipient patients [26].

3.3.1. Short‐ and Long‐Term Use

Safety variables indicated the safety profile of the drug in both short‐ and long‐term use were consistent with the SmPC. The most frequently reported TEAEs are summarised in Table 2. TEAEs assessed as related to treatment were transient in nature and less frequent in the long‐term patient cohort.

A total of 520 TEAEs were reported by 77.5% of patients (n = 155) during short‐term treatment with afamelanotide, with 45.5% (n = 91) of patients treated reporting one or more TEAEs related to treatment. The most frequently reported TEAEs in this group were nausea (14.5% of patients, n = 29) and headache (13.5%, n = 27).

Forty‐seven TEAEs were reported by 45.3% of patients (n = 24) receiving long‐term treatment with afamelanotide, with 11.3% of patients (6 out of 53) reporting one or more TEAEs related to treatment. The most frequently reported TEAEs during long‐term treatment were vitamin D deficiency (13.2% of patients, n = 7, none related to treatment) and nasopharyngitis (7.5% of patients, n = 4).

3.3.2. Patients Aged Over 70 Years

The safety profile in patients over 70 years old (n = 7) was consistent with the general patient cohort. These patients were either aged over 70 years at entry into the Disease Registry (n = 3, 42.9%) or turned 71 years old after enrolment. A total of 17 TEAEs were reported in this subgroup, (n = 5, 71.4%). Of the seven patients aged over 70 treated with afamelanotide, one patient (14.3%) experienced one TEAE (vomiting) assessed as related to treatment. Three serious TEAEs were reported by 42.9% of patients (n = 3), none of which were assessed as related to treatment.

3.4. Effectiveness

3.4.1. Enrolment and Continuation

As of June 2021, 182 patients (91.0%) were still receiving treatment with afamelanotide and participating in the Disease Registry. Eighteen patients (9.0%) withdrew from both treatment and participation in the Disease Registry. Figure 2 illustrates the patient enrolment in the Disease Registry and start of treatment with afamelanotide cumulative over time (grey line) and those still taking part in the Disease Registry (dotted black line).

FIGURE 2.

Enrolment and patient status over time. Solid line represents cumulative number of patients enrolled; dotted line connotes number of patients continuing to receive treatment in Germany.

3.4.2. Quality of Life

A significant increase was observed in EPP‐QoL scores following afamelanotide treatment when compared to a matched baseline. Patients who had assessments during each 2‐month period were identified and their EPP‐QoL Total Scores were included in the analysis for that period. The baseline EPP‐QoL Total Scores (for questionnaires completed at the first visit in Year 1) for these patients were then included in the matched baseline for that same time period for comparison. This means that the matched baseline data can come from any 2‐month period in the year and is pooled to provide an indication of change in scores for the patient subgroup. For instance, 114 patients had treatment visits in May–June 2019 and the mean EPP‐QoL Total Score has been compared with the mean baseline Total Scores for the same 114 patients (matched baseline). Significance (p < 0.05) was found at most time points when comparing time points to matched baseline. Table 3 depicts the time point, number of patients, percentage increases and p values; a higher score equates to a better quality of life. The patients' mean Total Score increases varied from 25.2 (range: −39 to 94; reported in May–June 2018) to 60.2 (range: 25–86; November–December 2017).

TABLE 3.

Summary of mean percentage change and p values for EPP‐QoL total score for treated patients in Germany after treatment compared with matched baseline.

Month of reporting during treatment	n patients	% Increase change	p
Jan–Feb 2017	3	105	0.5000
Mar–Apr 2017	8	70	0.0469
May–Jun 2017	27	63	< 0.0001*
Jul–Aug 2017	41	101	< 0.0001*
Sep–Oct 2017	39	150	< 0.0001*
Nov–Dec 2017	17	245	< 0.0001*
Jan–Feb 2018	45	139	< 0.0001*
Mar–Apr 2018	75	81	< 0.0001*
May–Jun 2018	110	55	< 0.0001*
Jul–Aug 2018	110	65	< 0.0001*
Sep–Oct 2018	51	85	< 0.0001*
Nov–Dec 2018	5	180	0.0625
Jan–Feb 2019	61	74	< 0.0001*
Mar–Apr 2019	108	71	< 0.0001*
May–Jun 2019	114	71	< 0.0001*
Jul–Aug 2019	108	71	< 0.0001*
Sep–Oct 2019	71	120	< 0.0001*
Nov–Dec 2019	17	217	< 0.0001*
Jan–Feb 2020	68	86	< 0.0001*
Mar–Apr 2020	124	78	< 0.0001*
May–Jun 2020	134	70	< 0.0001*
Jul–Aug 2020	144	75	< 0.0001*
Sep–Oct 2020	53	92	< 0.0001*
Nov–Dec 2020	9	113	0.0078
Jan–Feb 2021	48	81	< 0.0001*
Mar–Apr 2021	139	79	< 0.0001*
May–Jun 2021	114	63	< 0.0001*

^*Represents a statistically significant difference (p < 0.005).

A summary of actual values and within‐patient changes from matched baseline in the EPP‐QoL Total Score by calendar month and year is presented in Figure 3 where, for each time interval (month of completing the EPP‐QoL questionnaire, x‐axis), the mean EPP‐QoL Total Score is displayed (y‐axis) for patients during their treatment with afamelanotide against their baseline Total Score. The matched baseline assessment may have been carried out at any 2‐month period (i.e., the baseline is not represented by the month on the x‐axis). The mean EPP‐QoL Total Score reported by the patients during treatment with afamelanotide was higher than their Total Score reported prior to any treatment, for each time interval up to 22 June 2021. Significant time points are connoted with an asterisk.

FIGURE 3.

Mean EPP‐QoL total score for treated patients in Germany after treatment and matched baseline (at least one administration: Plain black bar, matched baseline: Striped bar). *Represents a statistically significant difference (p < 0.05).

4. Discussion

This study is the largest reported cohort of EPP patients to have received interventional therapy. The TEAEs reported during the PASS in Germany reflects those observed during clinical trials. Except for vitamin D deficiency, all frequent TEAEs, seen in the patient entire cohort, are listed in the SmPC as common or very common adverse reactions. Vitamin D levels were not assessed during the clinical trials and are not routinely collected, but the largest German reference centre started routinely testing for vitamin D deficiency during this study, leading to an increase in TEAE reports. An in‐depth review by the Marketing Authorisation Holder following the reports did not confirm any causal relationship between afamelanotide and vitamin D deficiency but concluded that the deficiency was a consequence of a lack of exposure to sunlight due to the lifestyle and conditioned behaviour of EPP patients. We agree with this assessment as it is in line with other research reporting a high prevalence of low vitamin D levels in EPP patients [9, 27, 28].

During short‐ and long‐term treatment 45.5% and 11.3% of TEAEs, respectively, were assessed as related to treatment. It is possible that the overall number of TEAEs and the number of TEAEs related to treatment with afamelanotide decreases with longer time on treatment. However, it is also possible that patients (or their EECs) do not continue to report events that they associate and accept as part of their response to the treatment. This might be the case because of the reduction in the frequency of reporting by patients of very common and common (as per SmPC) [12] TEAEs such as nausea, headache and fatigue seen during long‐term treatment compared with short‐term treatment reporting.

All studies and publications to date on the interventional use of afamelanotide in EPP report an increase in QoL following afamelanotide treatment. In this present study, the mean EPP‐QoL Total Score was reported by patients during treatment with afamelanotide for up to 6 years. The EPP‐QoL Total Score during treatment was significantly higher than that reported by patients prior to any treatment (p ≤ 0.005), for each time interval up to 22 June 2021, apart from three time points. In the CUV029 clinical trial (NCT00979745), results showed that the EPP‐QoL improved with afamelanotide therapy, with a significant difference on days 120 (p = 0.005) and 270 (p = 0.011) [15]. A further clinical trial (CUV039, NCT01605136) indicated that EPP‐QoL improved with afamelanotide therapy, with a significant difference on Days 60 (p < 0.001), 120 (p < 0.001) and 180 (p = 0.02) [29]. An increase of QoL following afamelanotide treatment in the commercial setting has also been reported by authors using another EPP specific questionnaire [30], and other investigators using the EPP‐QoL [15, 20, 29, 31].

In this 6‐year study, a positive change was reported at all time points in patients' QoL as measured by the EPP‐QoL, with most time points being statistically significant (p < 0.05), indicating that treatment improved patients' QoL, compared to baseline, year‐round. The mean EPP‐QoL Total Score reported by the patients during treatment with afamelanotide was significantly higher than their Total Score reported prior to any treatment, for each time interval up to 22 June 2021 when matched to their baseline score (p < 0.05), with an average increase in 100%. Therefore, it can be concluded that afamelanotide significantly increases the QoL of patients in comparison with no treatment, with a range of 55% to 245%. However, the increase in QoL varies depending on the time of the year.

Although significant in each case, the lowest changes occurred in May–June months with an increase range of 55%–71% in 2017–2021. The highest percent EPP‐QoL increases occurred in November–December with increases of 113%–245% in 2017–2021 although only low numbers of patients (range 5–17 patients per year) opt to receive treatment during these months and these changes were not always significant. The spring and summer months represent the time of year when patients usually experience the most EPP symptoms due to the lengthening hours and increasing intensity of daylight and thus when EPP can have the greatest impact on quality of life. During treatment with afamelanotide, patients report a significant increase of at least 55% in EPP‐QoL Total Scores during these most challenging months, demonstrating a positive impact.

The low discontinuation rate of afamelanotide treatment seen throughout the years of treatment in the post‐authorisation setting suggests that the treatment is effective, as has been reported by various treating physicians in recent publications [8, 32, 33, 34]. Wensink, Wagenmakers, and Langendonk [8] stated that, in contrast to the small improvement under controlled conditions during clinical trials, patients continue to report an increased improvement in symptoms and QoL during treatment with afamelanotide. The authors also stipulate treatment is much more effective in clinical practice than demonstrated in clinical trials. This is supported by observations in the present study of the data collected during the 6 years of postauthorisation treatment.

4.1. Strengths and Limitations

There are limitations to this study. The Disease Registry was set up at each EEC at different points in time, leading to possible inconsistencies in enrolment. The noninterventional design of this study limits the quality of the data: patients are being managed and treated with afamelanotide by the treating physicians as per the EECs' standard of care and requirements of the SmPC [12]. The treatment patterns differ between patients in regard to the start of their participation in the Disease Registry, the start of the treatment with afamelanotide, and the number and frequency of afamelanotide implants administered during a calendar year.

No comparison between treated/untreated patients and analysis on the effectiveness outcome can be made because all patients entering the Disease Registry but one elected to receive treatment with afamelanotide. This means that there is no control data from patients without treatment and no way of identifying possible differences between the patient population that is seeking and opting for treatment and those that remain untreated.

The strengths of this study are the duration and the large number of treated EPP patients. The high continuation rate also ensures that bias from loss to follow‐up is minimal.

5. Conclusions

Afamelanotide is a highly effective and safe treatment for EPP patients. Data from the largest EPP Disease Registry in the world and largest patient cohort ever reported has also shown that afamelanotide provides a significantly higher QoL, with overall health benefits for patients over the long term. The effectiveness data collected in the postauthorisation setting surpasses reports from the clinical trials, as shown by the increase of QoL after treatment and the high rate of patients continuing on treatment. The safety and benefit–risk profile of afamelanotide is consistent with that seen in clinical trials with minimal differences between short‐ and long‐term treatment, with a similar safety profile for patients over the age of 70. The observations made for the effectiveness outcome data reported show a significant clinical benefit of afamelanotide both from prior to treatment (baseline) and over treatment years.

Author Contributions

All authors contributed to the study conception and design. Material preparation and data collection were performed by B.H., K.S., C.M.S., D.B.‐G., K.W., L.K., U.S., P.S.‐R., J.W. and R.K.‐M. M.B., P.B. and G.W. analysed the data. The first draft of the manuscript was written by M.B., G.W. and P.B. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics Statement

All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the ethics committee of University of Düsseldorf (08 Jul 2016, ref.: 5554), University of Berlin (09 Jan 2017, ref.: AZ 570/16), the Saxony State Medical Association (27 Jun 2016, ref.: EK‐BR‐51/16‐1) and the Rhineland‐Palatinate State Medical Association (08 Nov 2018, ref.: 2018‐13136‐NIS).

Consent

Informed consent was obtained from all participants included in this study.

Conflicts of Interest

B.H., K.S., C.M.S., D.B.‐G., K.W., L.K., U.S., P.S.‐R., J.W. and R.K.‐M. have received research support from CLINUVEL including reimbursement for data entry for the EMA directed disease registry. P.B. receives a salary from and owns stock in CLINUVEL. M.B. and G.W. receive a salary from CLINUVEL.

Declarations

Prof. Bernhard Homey, Kathrin Schelonke, Carla Marie Schlegel, Dr. Karsten Weller, Dr. Lea Kiefer, Prof. Ulrich Stölzel, Prof. Petra Staubach‐Renz, Dr. Joanna Wegner and Dr. Regine Keller‐Melchior have received research support and funding from CLINUVEL including reimbursement for data entry for the EMA directed disease registry. At the time of writing, Dr. Pilar Bilbao was an employee of, and owns stock in, CLINUVEL. Malgorzata Bochno and Gillian Walker are employees of CLINUVEL.

Data Availability Statement

The data underlying this article will be shared upon reasonable request to the corresponding author.