RARE DISEASE
Autosomal erythropoietic protoporphyria
Autosomal erythropoietic protoporphyria
Autosomal erythropoietic protoporphyria
Synonyms: EPP
Synonyms: EPP
Synonyms: EPP
Drug discovery
2
drugs
With orphan designations
Overview
Autosomal erythropoietic protoporphyria (EPP) is a rare genetic disorder caused by ferrochelatase (FECH) deficiency, leading to protoporphyrin accumulation in blood and tissues. It manifests as acute, painful photosensitivity typically beginning in early childhood after sunlight exposure (400–410 nm wavelengths) [1][3][5]. Chronic complications include hepatobiliary disease (e.g., protoporphyric liver failure) and gallstones [1][4][8]. Diagnosis involves elevated erythrocyte protoporphyrin levels, plasma fluorescence testing, and FECH genetic analysis [1][4][5]. Therapeutic goals focus on photoprotection and preventing liver damage [1][3][4].
Therapies
Photoprotection: Opaque sunscreens, protective clothing, and window filters to block Soret band light [1][3][8]
Pharmacologic: Afamelanotide (melanocortin analog) improves light tolerance; dersimelagon and bitopertin under clinical evaluation [1][4][6]
Liver management: Annual hepatic monitoring, cholestyramine for protoporphyrin excretion, and liver/bone marrow transplantation for advanced disease [1][3][8]
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare renal diseases, rare skin diseases
Research Papers
329 drug discovery papers about Autosomal erythropoietic protoporphyria, with 4 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
329 drug discovery papers about Autosomal erythropoietic protoporphyria, with 4 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-30 | An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.
2026-06-23 | Early-Onset Severe Liver Fibrosis in a Toddler with Erythropoietic Protoporphyria Associated with Rare Compound Heterozygous FECH Variants.
Erythropoietic Protoporphyria (EPP) is a rare inherited disorder of heme biosynthesis caused by pathogenic variants in FECH. Although most patients present with cutaneous photosensitivity in childhood, clinically significant liver disease is uncommon, and severe fibrosis in early childhood is rarely reported. A 2-year-old girl presented with recurrent photosensitivity and erythematous swelling after sun exposure. Laboratory evaluation revealed markedly elevated erythrocyte protoporphyrin (2406 µg/dL) and elevated plasma protoporphyrin. Genetic testing identified compound heterozygous FECH variants: c.901_902del (p.Trp301Alafs*23) and c.801G>A (p.Met267Ile). Liver enzymes were significantly elevated. Following liver biopsy demonstrated stage 3 bridging fibrosis with crystalline deposits in hepatocytes consistent with protoporphyric hepatopathy. The patient subsequently underwent hematopoietic stem cell transplantation with improvement of protoporphyrin levels and liver enzymes. However, the post-transplant course was complicated by severe infections, acute respiratory distress syndrome, and multiorgan failure, resulting in death. This case highlights rapidly progressive liver fibrosis in a toddler with EPP and emphasizes the importance of early hepatic monitoring in pediatric patients with markedly elevated protoporphyrin levels and rare FECH variants.
2026-05-11 | Heme arginate improves acute liver failure secondary to erythropoietic protoporphyria: a case report.
Erythropoietic protoporphyria (EPP) is a rare inherited disorder with limited therapeutic options. For EPP patients with advanced cholestasis or liver failure, liver transplantation has long been regarded as the definitive therapy to address the hepatic crisis but does not offer a cure. Previous studies have reported that intravenous hemin/hematin may benefit some EPP patients, while the efficacy of intravenous heme arginate in treating EPP remains unreported. We report a 24-year-old male with EPP and severe cholestasis. From 2017 to 2024, the patient was hospitalized eight times for recurrent episodes of jaundice and abdominal pain. These symptoms were effectively alleviated through a comprehensive treatment including artificial liver support (PE + DPMAS), hepatoprotective therapy, and high-glucose infusion. During his latest hospitalization in 2025, artificial liver support failed to improve the liver dysfunction, leading to progressive deterioration to liver failure. Notably, after two doses of intravenous heme arginate, the total bilirubin level gradually declined with significant improvement of ascites, coagulation dysfunction and neuropsychiatric symptoms. The patient was discharged with hepatoprotective therapy and light avoidance with no recurrence at 6-month follow-up. This case suggests that intravenous heme arginate may provide clinical benefit in patients with EPP-associated liver failure and contributes to the limited literature supporting heme-based therapy in treating EPP hepatic crisis.
2026-03-26 | New and currently investigated pharmacotherapies for the erythropoietic protoporphyrias: spotlight on dersimelagon and bitopertin.
The erythropoietic protoporphyrias (EPP) are ultra-rare inborn errors of the heme biosynthesis characterized by painful and debilitating phototoxic reactions in the blood vessels upon exposure to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents pain and prolongs the time patients can spend in sunlight. However, afamelanotide does not address the underlying disease mechanism and is currently only approved for use in adult patients, leaving children and adolescents without a treatment option. The two investigational pharmacotherapies, dersimelagon and bitopertin, could offer benefits such as treatment options for children and prevention of some of the associated disease complications. This narrative review (using Pubmed and trial databases) aims to provide an overview of the status of development of dersimelagon and bitopertin, with a focus on the prevention of phototoxicity. The currently available trial data on dersimelagon and bitopertin suggests treatment effects in EPP as compared to placebo control groups. However, safety and efficacy of dersimelagon and bitopertin need to be further characterized. Moreover, to ensure benefit for patients and access to therapy after regulatory approval, it also would be important to generate data on the relative safety and efficacy as compared to afamelanotide.
2026-03-12 | Hematopoietic stem cell transplantation for erythropoietic porphyria-induced acute liver failure: a case report and literature review.
Protoporphyrias are rare genetic disorders in heme biosynthesis, causing protoporphyrin IX accumulation with progressive liver injury. Liver transplantation has traditionally treated protoporphyria-induced liver injury but does not correct the underlying hematopoietic defect. We present a 16-year-old male with painful cutaneous photosensitivity who developed cholestatic liver dysfunction and severe abdominal pain. After plasmapheresis, red blood cell (RBC) transfusions, and intravenous hemin, he had transient improvement and subsequently underwent hematopoietic stem cell transplantation (HSCT) without liver transplantation, which normalized his protoporphyrin levels, liver function, and symptoms. This case underscores HSCT as a disease-modifying therapy that may prevent liver transplantation when performed before irreversible hepatic damage.
2026-07-30 | An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.
2026-06-23 | Early-Onset Severe Liver Fibrosis in a Toddler with Erythropoietic Protoporphyria Associated with Rare Compound Heterozygous FECH Variants.
Erythropoietic Protoporphyria (EPP) is a rare inherited disorder of heme biosynthesis caused by pathogenic variants in FECH. Although most patients present with cutaneous photosensitivity in childhood, clinically significant liver disease is uncommon, and severe fibrosis in early childhood is rarely reported. A 2-year-old girl presented with recurrent photosensitivity and erythematous swelling after sun exposure. Laboratory evaluation revealed markedly elevated erythrocyte protoporphyrin (2406 µg/dL) and elevated plasma protoporphyrin. Genetic testing identified compound heterozygous FECH variants: c.901_902del (p.Trp301Alafs*23) and c.801G>A (p.Met267Ile). Liver enzymes were significantly elevated. Following liver biopsy demonstrated stage 3 bridging fibrosis with crystalline deposits in hepatocytes consistent with protoporphyric hepatopathy. The patient subsequently underwent hematopoietic stem cell transplantation with improvement of protoporphyrin levels and liver enzymes. However, the post-transplant course was complicated by severe infections, acute respiratory distress syndrome, and multiorgan failure, resulting in death. This case highlights rapidly progressive liver fibrosis in a toddler with EPP and emphasizes the importance of early hepatic monitoring in pediatric patients with markedly elevated protoporphyrin levels and rare FECH variants.
2026-05-11 | Heme arginate improves acute liver failure secondary to erythropoietic protoporphyria: a case report.
Erythropoietic protoporphyria (EPP) is a rare inherited disorder with limited therapeutic options. For EPP patients with advanced cholestasis or liver failure, liver transplantation has long been regarded as the definitive therapy to address the hepatic crisis but does not offer a cure. Previous studies have reported that intravenous hemin/hematin may benefit some EPP patients, while the efficacy of intravenous heme arginate in treating EPP remains unreported. We report a 24-year-old male with EPP and severe cholestasis. From 2017 to 2024, the patient was hospitalized eight times for recurrent episodes of jaundice and abdominal pain. These symptoms were effectively alleviated through a comprehensive treatment including artificial liver support (PE + DPMAS), hepatoprotective therapy, and high-glucose infusion. During his latest hospitalization in 2025, artificial liver support failed to improve the liver dysfunction, leading to progressive deterioration to liver failure. Notably, after two doses of intravenous heme arginate, the total bilirubin level gradually declined with significant improvement of ascites, coagulation dysfunction and neuropsychiatric symptoms. The patient was discharged with hepatoprotective therapy and light avoidance with no recurrence at 6-month follow-up. This case suggests that intravenous heme arginate may provide clinical benefit in patients with EPP-associated liver failure and contributes to the limited literature supporting heme-based therapy in treating EPP hepatic crisis.
2026-03-26 | New and currently investigated pharmacotherapies for the erythropoietic protoporphyrias: spotlight on dersimelagon and bitopertin.
The erythropoietic protoporphyrias (EPP) are ultra-rare inborn errors of the heme biosynthesis characterized by painful and debilitating phototoxic reactions in the blood vessels upon exposure to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents pain and prolongs the time patients can spend in sunlight. However, afamelanotide does not address the underlying disease mechanism and is currently only approved for use in adult patients, leaving children and adolescents without a treatment option. The two investigational pharmacotherapies, dersimelagon and bitopertin, could offer benefits such as treatment options for children and prevention of some of the associated disease complications. This narrative review (using Pubmed and trial databases) aims to provide an overview of the status of development of dersimelagon and bitopertin, with a focus on the prevention of phototoxicity. The currently available trial data on dersimelagon and bitopertin suggests treatment effects in EPP as compared to placebo control groups. However, safety and efficacy of dersimelagon and bitopertin need to be further characterized. Moreover, to ensure benefit for patients and access to therapy after regulatory approval, it also would be important to generate data on the relative safety and efficacy as compared to afamelanotide.
2026-03-12 | Hematopoietic stem cell transplantation for erythropoietic porphyria-induced acute liver failure: a case report and literature review.
Protoporphyrias are rare genetic disorders in heme biosynthesis, causing protoporphyrin IX accumulation with progressive liver injury. Liver transplantation has traditionally treated protoporphyria-induced liver injury but does not correct the underlying hematopoietic defect. We present a 16-year-old male with painful cutaneous photosensitivity who developed cholestatic liver dysfunction and severe abdominal pain. After plasmapheresis, red blood cell (RBC) transfusions, and intravenous hemin, he had transient improvement and subsequently underwent hematopoietic stem cell transplantation (HSCT) without liver transplantation, which normalized his protoporphyrin levels, liver function, and symptoms. This case underscores HSCT as a disease-modifying therapy that may prevent liver transplantation when performed before irreversible hepatic damage.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Autosomal erythropoietic protoporphyria.
2 orphan drug designations for Autosomal erythropoietic protoporphyria.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
2-((3S,6S,12aS)-9-chloro-6-isobutyl-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)-N,N-dimethylacetamide | small molecules | FDA | 2025-09-08 | — | Portal Therapeutics, Inc. |
L-cysteine | small molecules | FDA | 1994-05-16 | — | Brigham and Women's Hospital |
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