Erythropoietic Protoporphyria: A Rare Inherited Disorder

In this post, I share a few thoughts about erythropoietic protoporphyria (EPP), a serious debilitating condition for which there are presently no approved treatments.

EPP is a rare inherited disorder of heme biosynthesis characterized by dermal photosensitivity 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, thus generating free radicals which damage tissue and cause 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 having an onset within minutes of exposure to sun or UV light. The phototoxicity 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 a replacement healthy liver can start the reaccumulating PPIX. Thus, liver transplantation is not curative without a sequential liver and hematopoietic stem cell or bone marrow transplantation to correct the underlying enzymatic defect.

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 changing 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 and school attendance, productivity, activities of daily living and quality of life. 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.

Although a number of treatments, including high dose β-Carotene, Vitamin C, N-Acetyl Cysteine and narrow band UVB have been suggested, 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 as a sunless tanning agent. Afamelanotide 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 the clinical trial design and data submitted by Clinuvel, including (i) inadvertant treatment allocation unmasking (unblinding); (ii) a "small" but statistically significant benefit in daylight exposure without pain (approximately 10 minutes per day); and (iii) the pharmaceutical sponsor's the choice, validation, and relevance for quality of life instruments. In June 2018, Clinuvel submitted an NDA for which FDA has granted a Priority Review and assigned a PDUFA date of July 8, 2019.

In summary, there is a need for improved early diagnosis of EPP to reduce sun exposure and provide appropriate follow up, including monitoring for hepatic complications. This can be done through improved education and orphan diseases awareness. There is a need for improved treatments with robust efficacy in EPP, preferably by the oral route. 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, and possible integration of photoprovocation in clinical trials. Finally, it is important to appreciate the potential role of geographic and seasonal differences in natural sunlight duration and occuptaionala nd recreational time spent outdoors as potential variables in EPP clinical trials. 

Dr. Najib Babul, PharmD, MBA

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