Erythropoietic protoporphyria (EPP) is a rare inherited disease of heme biosynthesis characterized by dermal photosensitivity which occurs secondary to a partial deficiency of ferrochelatase. In a phenotypically similar X-linked protoporphyria (XLP), there is overactivity of the heme biosynthesis enzyme, erythropoietic aminolevulinate synthase (ALAS2). Both EPP and XLP result in the accumulation of the photosensitizer protoporphyrin IX (PPIX) in erythrocytes, plasma, skin and liver. The accumulated PPIX is activated by sun exposure generating free radicals which result in tissue damage and severe pain.
EPP is a devastating lifelong disorder with very few evidence-based clinical management tools and no approved treatments in the United States. The number of patients affected by EPP in the US is unknown. In Europe, it is estimated that about 1 in about 75,000 to 1 in 200,000 individuals are affected. Worldwide, EPP is the third most common porphyria, with an incidence of about 2 to 5 per 1,000,000 individuals. Diagnostic delay is not uncommon due to a lack of symptom awareness among pediatricians.
Clinically, EPP is characterized by both cutaneous and extracutaneous manifestation. Phototoxicity usually begins in infancy and manifests as intolerance to sunlight, including tingling, stinging, burning, itching and pain with an onset within minutes of exposure to sun or UV light. EPP can also be accompanied by lichenification, loss of lunulae, edema, erythema and petechiae. A phototoxic reaction typically lasts from hours to a few days, although reactions lasting 10 or more days have been reported, often accompanied by social isolation, excruciating pain, anxiety and sleep impairment.
Extracutaneous manifestations include PPIX-mediated bile duct obstruction, resulting in cholestatic liver injury in 20-30%, and eventually cholelithiasis, cholestatic hepatitis, fibrosis, cirrhosis and liver failure in 3-5% of patients. Progressive liver disease can require liver transplantation, although replacement of a diseased liver with the healthy liver can start the reaccumulation of PPIX. Thus, liver transplantation is not curative without a sequential liver and hematopoietic stem cell transplantation to correct the underlying enzymatic defect.
Absent effective treatments, photoprotection against UV-A and visible light, including sun avoidance are required to minimize cutaneous reactions and pain. Patients with EPP have to maintain a high level of vigilance about ambient and expected light conditions and undertake measures to minimize the risk of phototoxicity. Drastic lifestyle modification, including the use of protective clothing, skin foundation, shade, tinted windows and indoor living are essential to minimize the cutaneous sequelae of EPP. These symptoms, along with required behavioral modification markedly impact employment choices, socialization (sun avoidance), work or school attendance, productivity, activities of daily living and quality of life. Not surprisingly, one study reported that while most individuals with EPP were employed or attending school, almost half felt their choice of vocation had been influenced by their symptoms. Both lifestyle modification and sunlight avoidance can place a significant burden on families of individuals with EPP.
Although a number of treatments, including high dose β-Carotene, Vitamin C, N-Acetyl Cysteine and narrow band UVB therapy have been suggested in the literature, there is little evidence to support their use. The only evidence-based treatment for preventing phototoxicity in EPP is afamelanotide (Scenesse®), a controlled release subcutaneous implant (depot) from Clinuvel Pharmaceuticals, a Melbourne, Australia headquartered company. Afamelanotide, a structural analog of α-melanocyte stimulating hormone (α-MSH) was developed, patented and initially tested by Drs. Victor Hruby, Robert Dorr and (the late) Mac Hadley at the University of Arizona more than two decades ago. It was first envisaged developed as a sunless tanning agent. It is a melanocortin receptor agonist that binds predominantly to the melanocortin-1 receptor (MC1R), activating the synthesis of eumelanin which provides photoprotection through absorption of UV and visible light, scavenging of free radicals and increased superoxide dismutase availability.
Scenesse was approved by the EMA in December 2014 for prevention of phototoxicity in adult patients with EPP as a 16 mg subcutaneous implant administered every two months. The UK marketing authorization for Scenesse is under “exceptional circumstances” for ‘the prevention of phototoxicity in adult patients with EPP. Unfortunately, in 2017, the U.K. National Institute for Health and Care Excellence (NICE) concluded that Scenesse “is not recommended, within its marketing authorization, for preventing phototoxicity in adults with erythropoietic protoporphyria” and this ruling was upheld in 2018 on appeal. This means that the National Health Service (NHS) will not reimburse for Scenesse in England. In reaching its decision, NICE made several observations about data on Scenesse submitted by Clinuvel, including treatment allocation unmasking (unblinding), a modest albeit statistically significant benefit in daylight exposure without pain (approximately 10 minutes per day) and the choice, validation, and relevance of quality of life instruments used. In June 2018, Clinuvel submitted and NDA for which FDA has assigned a PDUFA date of July 8, 2019 and granted Scenesse a Priority Review.
There is a need for improved early diagnosis to reduce sun exposure and provide appropriate follow up, including monitoring for hepatic complications. This can be done through improved education and point of care protoporphyrin testing. There is also a need for improved treatments with robust efficacy in EPP, preferably by the oral route for both cutaneous and extracutaneous manifestations. There is also a need for improved study designs that leverage our increased understanding of adaptive clinical trials, quality of life and health economic outcomes, evaluating the role of photoprovocation in clinical trials, and understanding the role of geographic and seasonal differences in natural sunlight duration and time spent outdoors as potential variables in timing, site selection and data analysis of EPP clinical trials.
Dr. Najib Babul, PharmD, MBA, is an entrepreneur and experienced pharmaceutical scientist, drug developer, inventor, author and consultant with over two decades of experience in bringing new and repurposed drugs to market.