CLARK COUNTY, NV / ACCESSWIRE / January 7, 2021 / Erythropoietic protoporphyria (EPP) is a devastating lifelong disorder characterized by dermal photosensitivity with only one recently approved treatment and very few evidence-based clinical management tools. Dr. Najib Babul, an experienced drug development and regulatory affairs consultant discusses this serious debilitating condition.
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.
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 for use 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. In reaching its decision, NICE made several observations about the clinical trial design and data submitted by Clinuvel, including (i) inadvertent 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 a remarkable recent paper, Dr. Jasmin Barman-Aksözen a molecular biologist with a PhD in EPP research shared her journey as an EPP patient, advocate and subject matter expert during the regulatory review of Scenesse in Europe.
On October 8, 2019, FDA approved Scenesse "to increase pain free light exposure in adult patients with a history of phototoxic reactions from erythropoietic protoporphyria". Importantly, FDA did not refer Scenesse to an advisory committee because "the application did not raise significant safety or efficacy issues in the intended population".
There are a limited number of other investigational therapeutics for EPP. Mitsubishi Tanabe Pharma has initiated a Phase-3 clinical trial in the U.S. of MT-7117 (dersimelagon), an Orphan and Fast Track Designated selective oral MC1R agonist in adolescent and adult patients with EPP or XLP. If safe and effective, it would represent a potential game changer for patients with EPP.
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 occupational and recreational time spent outdoors as potential variables in EPP clinical trials.
Dr. Najib Babul, PharmD, MBA, a drug development and regulatory affairs consultant is a graduate of the University of British Columbia, the State University of New York, and the California Institute of Advanced Management. He has over two decades of experience in bringing new and repurposed drugs to market. Dr. Babul is the author of over 180 abstracts and manuscripts published in leading medical journals and scientific proceedings, including the Lancet, the Journal of Clinical Pharmacology, the Journal of Clinical Oncology, Cancer, Anesthesiology, Clinical Pharmacology & Therapeutics, and Anesthesia & Analgesia.