INTRODUCTION
Erythropoietic protoporphyria (EPP) is a rare genetic disorder of the heme metabolic pathway, with prevalence estimates ranging from 1:75,000 to 1:200,000.1 This disorder is largely due to mutations in the ferrochelatase (FECH) gene that result in deficient activity of the enzyme ferrochelatase.1 When this enzyme does not function correctly, protoporphyrin IX accumulates in various tissues. Protoporphyrin accumulation is seen in the blood, skin, and the liver.1 The accumulation in dermal vasculature results in episodes of painful phototoxic reactions that are the characteristic clinical manifestation of EPP. This is due to the fact that the protoporphyrin molecule absorbs photons emitted along the 320 to 595 nm wavelengths.1
This disease often presents in early childhood. In one study of 223 patients, the median age of the cohort was 34 years and all were white-skinned apart from two Indo-Asians. The median age of onset of symptoms was 10 years (range: birth to 12 years). However, formal diagnosis tended to be delayed, with a median age at diagnosis of 12 years. In fact, for 75 patients, diagnosis was not made until the age of 20 years or more.3 When symptoms begin, patients start to experience painful, non-blistering phototoxicity after sun exposure.2 This pain can last for days and is sometimes even manifested with exposure to indoor lighting (LEDs, incandescent bulbs) depending on the wavelength of the source. The pain is often rated a 10 on the pain scale,2 and is not relieved by pain medications, including narcotic analgesics.5 The most affected areas include the hands and face. The severity of symptoms combined with the need to remain sheltered from the light and sun results in a reduction in quality of life and freedom of movement.6 Phototoxic episodes can last for hours to days, resulting in missed work or school. While phototoxicity varies between individuals, most EPP patients will develop cutaneous phototoxicity within 30 minutes of light and sun exposure.4 Multiple episodes of acute phototoxic reactions may lead to chronic alteration of skin appearance, such as skin thickening with a waxy/leathery appearance and areas of hyperkeratosis.1 Most EPP patients will develop phototoxicity within 30 minutes of exposure.4 EPP affects all members of the family, not just the patient. Jealousy of a sibling who can experience outdoor activities is just as pervasive as the guilt felt by the disease-free sibling.7
Diagnosis is established by presence of clinical symptoms with laboratory analysis showing increased plasma and red blood cell protoporphyrin levels and detection of plasma fluorescence peak at 634 nm.1,8 Genetic analysis for FECH mutations, family studies, and investigation for hepatic involvement is generally also undertaken.1
This disease often presents in early childhood. In one study of 223 patients, the median age of the cohort was 34 years and all were white-skinned apart from two Indo-Asians. The median age of onset of symptoms was 10 years (range: birth to 12 years). However, formal diagnosis tended to be delayed, with a median age at diagnosis of 12 years. In fact, for 75 patients, diagnosis was not made until the age of 20 years or more.3 When symptoms begin, patients start to experience painful, non-blistering phototoxicity after sun exposure.2 This pain can last for days and is sometimes even manifested with exposure to indoor lighting (LEDs, incandescent bulbs) depending on the wavelength of the source. The pain is often rated a 10 on the pain scale,2 and is not relieved by pain medications, including narcotic analgesics.5 The most affected areas include the hands and face. The severity of symptoms combined with the need to remain sheltered from the light and sun results in a reduction in quality of life and freedom of movement.6 Phototoxic episodes can last for hours to days, resulting in missed work or school. While phototoxicity varies between individuals, most EPP patients will develop cutaneous phototoxicity within 30 minutes of light and sun exposure.4 Multiple episodes of acute phototoxic reactions may lead to chronic alteration of skin appearance, such as skin thickening with a waxy/leathery appearance and areas of hyperkeratosis.1 Most EPP patients will develop phototoxicity within 30 minutes of exposure.4 EPP affects all members of the family, not just the patient. Jealousy of a sibling who can experience outdoor activities is just as pervasive as the guilt felt by the disease-free sibling.7
Diagnosis is established by presence of clinical symptoms with laboratory analysis showing increased plasma and red blood cell protoporphyrin levels and detection of plasma fluorescence peak at 634 nm.1,8 Genetic analysis for FECH mutations, family studies, and investigation for hepatic involvement is generally also undertaken.1
Sun avoidance, through use of protective clothing, shade, sunblock, and window-tinting,2 has been the mainstay of therapy for EPP.10 Other treatments, including beta carotene, cysteine, pyridoxine, vitamin C, antihistamines, and Puva hardening, have not been proven effective in clinical trials or clinical use.9-11
Afamelanotide (SCENESSE®, Clinuvel Pharmaceuticals) for the treatment of EPP was approved for use in the European Union (EU) in 2014 and in the United States (USA) in 2019. Afamelanotide is administered as an absorbable, controlled-release subcutaneous implant.12 Afamelanotide is an alpha melanocyte-stimulating hormone (α-MSH) analogue that binds the melanocortin receptors MC1R and MC4R.5,12,13 Activation of MC1R generates a photoprotective effect via increased melanogenesis and production of eumelanin within the epidermis.5,13,14 One study showed that subcutaneous injection of α-MSH significantly increased melanin density as measured by reflectance spectroscopy.15 Melanogenesis may offer antioxidant properties within melanocytes, assisting in neutralizing the harmful effects of the reactive oxygen species produced in the skin of EPP patients upon sun exposure.5,14
The first commercial afamelanotide implantation in the United States was performed at Resnik Skin Institute, Miami, Florida in April 2020. This study represents the first prospective post-authorization study of efficacy and safety in EPP patients treated with afamelanotide in the United States. We show that implantation of afamelanotide every second month continues to dramatically and positively impact the lives of EPP patients in the United States.
MATERIALS AND METHODS
In this single-center, prospective efficacy study of afamelanotide (SCENESSE®, Clinuvel Pharmaceuticals), patients with a confirmed diagnosis of EPP seen at the Resnik Skin Institute in Miami, FL were included. Every patient was required to have positive genetic testing showing mutation in the FECH gene, and a blood fluorescence test positive for EPP. Eligibility criteria included confirmed diagnosis of EPP and age greater than 18 years. Ineligibility criteria included current pregnancy, current lactation, liver and/or kidney pathology, and age younger than 18 years. Afamelanotide was offered as a controlled-release 16-mg implant that was placed subcutaneously at an interval of at least 60 days. Implants were placed initially in the right flank and then placement was alternated between the left and right flanks for each subsequent visit. Data were collected between April 2020 and May 2021. All patients provided written informed consent to participate in the study. The study protocol was submitted to the Advarra Internal Review Board, which approved the Full Waiver of HIPAA Authorization after determining the waiver of authorization satisfied the waiver criteria outlined in the HIPAA Privacy Rule (45 CFR 164.512(i)(2)).
Data collection occurred at each office visit for drug implantation. The data collected included demographic information, full-body skin examination, and Daily Activity Inventory (DAI) questionnaires entitled:
Only DAI responses up to and including those completed prior to the 5th implant were included in the analysis. This represents the First Visit or Baseline DAI questionnaire plus 4 subsequent DAI questionnaires per patient. Three patients provided DAI data prior to their 5th implant and 1 patient who provided DAI data prior to their 6th implant; however, these were not included as these patient numbers were deemed too small to draw any meaningful conclusions.
Data collection occurred at each office visit for drug implantation. The data collected included demographic information, full-body skin examination, and Daily Activity Inventory (DAI) questionnaires entitled:
1) DAI-First Visit: completed prior to first implantation
2) DAI-Subsequent Visit: completed prior to second and each subsequent implantation.
The DAI are multi-item questionnaires, where responses are collected from an ordered list of categories. At the start of each visit, the patient would answer the survey questions based on their experience in the prior two months. Given the rarity of EPP and the resultant small patient population, the DAI questionnaires have not yet been validated. Full questionnaires available upon request.
Outcome measures included time spent in outdoor activities, use of protective clothing, experience of phototoxic reactions, effect of EPP on patient confidence, effect of EPP on patient’s family, and patient willingness to go outside.
The demographic characteristics included in the evaluation are presented using descriptive statistics. Results are presented in tabular format and as a bar chart.
All raw data were imported from Excel into SAS version 9.4 for analysis. Descriptive statistics were used to evaluate changes in responses to the DAI from prior to receiving afamelanotide (Baseline) and after receiving each subsequent implant. For each question on the DAI, the number and percentage of patients responding in each category were presented. For the calculation of percentages, the denominator was the number of patients completing the questionnaire at each assessment.
Only DAI responses up to and including those completed prior to the 5th implant were included in the analysis. This represents the First Visit or Baseline DAI questionnaire plus 4 subsequent DAI questionnaires per patient. Three patients provided DAI data prior to their 5th implant and 1 patient who provided DAI data prior to their 6th implant; however, these were not included as these patient numbers were deemed too small to draw any meaningful conclusions.
RESULTS
The mean age of the study population was 41 years (+15.81), with ages ranging from 19 to 71 years. The total number of patients was 26, with 13 female patients and 13 male patients. Regarding ethnicity, 25 (96.2%) patients identified as Caucasian, and 1 (3.8%) identified as Caucasian/Hispanic. Data are presented according to the number of implants received at the analysis cut-off date. This means that at the cut-off date, the subjects had received differing numbers of implants. At the time
