RARE DISEASE
X-linked erythropoietic protoporphyria
X-linked erythropoietic protoporphyria
X-linked erythropoietic protoporphyria
Synonyms: X-linked dominant erythropoietic protoporphyria, X-linked dominant protoporphyria, XLDPP, XLPP
Synonyms: X-linked dominant erythropoietic protoporphyria, X-linked dominant protoporphyria, XLDPP, XLPP
Synonyms: X-linked dominant erythropoietic protoporphyria, X-linked dominant protoporphyria, XLDPP, XLPP
Drug discovery
1
drug
With orphan designation
Overview
X-linked erythropoietic protoporphyria (XLPP) is a rare X-linked dominant disorder of heme biosynthesis caused by gain-of-function mutations in ALAS2, leading to protoporphyrin IX accumulation. Patients experience acute, painful phototoxicity within minutes of sunlight exposure due to protoporphyrin activation in skin vasculature. Liver involvement (2%-5% of cases) ranges from cholestasis to failure, necessitating transplantation [1][5][13]. Diagnosis relies on elevated metal-free/zinc-bound protoporphyrin ratios, plasma fluorescence (635 nm peak), and ALAS2 genetic testing [5][13].
Burden
Morbidity: Debilitating phototoxic pain limits daily activities; 27%-47% develop anemia/liver enzyme abnormalities [1][7].
Hepatobiliary risks: Protoporphyrin deposition causes cholestasis, gallstones, and progressive liver disease (up to 5% require transplantation) [1][5].
Psychosocial impact: Chronic pain, sun avoidance, and need for lifestyle modifications impair quality of life [4][7].
Therapies
Sun protection: Opaque sunscreens (zinc oxide/titanium dioxide), protective clothing [5][12].
Pharmacologic: Afamelanotide (subcutaneous implant) increases melanin; oral dersimelagon under investigation [5][7].
Iron supplementation: Reduces protoporphyrin levels in XLPP (contrary to EPP); avoid IV iron in liver dysfunction [5][11].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare renal diseases, rare skin diseases
Research Papers
62 drug discovery papers about X-linked erythropoietic protoporphyria, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
62 drug discovery papers about X-linked erythropoietic protoporphyria, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-03-02 | Adjunctive use of Polypodium leucotomos extract in patients with erythropoietic protoporphyria: An exploratory study.
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) cause severe photosensitivity, resulting in significant quality of life (QoL) impairment. This study aims to evaluate the safety and efficacy of Polypodium leucotomos extract (PLE) as an adjunctive therapy in patients with persistent symptoms despite standard dosing of afamelanotide. In this prospective single-center cohort study, eight adults with confirmed EPP or XLP and ongoing symptoms despite regular afamelanotide implants every 2 months were enrolled. Participants received 480 mg oral PLE daily for 4 months. QoL and symptom severity were measured using questionnaires at baseline, Day 60, and Day 120. Six participants completed the study. Statistically significant improvements in QoL were observed on Day 60 (p = 0.014), but not at Day 120 (p = 0.152). Half of participants reported reduced reaction severity. No adverse events occurred. Adjunctive PLE improved short-term QoL in participants with incomplete symptom control on afamelanotide alone and was well tolerated. Larger studies are warranted.
2026-01-13 | An open-label phase II study of bitopertin in adults and adolescents with erythropoietic protoporphyria or X-linked protoporphyria.
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare genetic disorders characterized by accumulation of protoporphyrin IX (PPIX), painful phototoxic reactions and hepatobiliary disease. No disease-modifying therapies are approved for these conditions. To evaluate the safety and efficacy of bitopertin in adults and adolescents with EPP or XLP. BEACON (ACTRN12622000799752) was a phase II, randomized, open-label, parallel-arm study in adult and adolescent participants with EPP or XLP. Participants received an oral, once-daily administration of bitopertin 20 mg or 60 mg for 24 weeks. Twenty-six participants were randomized to 20 mg (n = 14) or 60 mg (n = 12) of bitopertin. The study met its primary efficacy endpoint. Treatment with bitopertin resulted in significant, dose-dependent reductions in PPIX levels compared with baseline at both the 20-mg and 60-mg dose levels (mean -31.7%, SE 7.0; P < 0.001 vs. baseline and mean -57.7%, SE 7.4; P < 0.001 vs. baseline, respectively). Similar efficacy was observed across the adult and adolescent populations. No serious adverse events were reported. Dizziness was the most common adverse event reported with bitopertin, in 9 (64%) and 8 (67%) participants completing the study in the 20-mg and 60-mg dose groups, respectively. By reducing whole-blood PPIX levels, bitopertin targets the underlying pathophysiology of EPP, resulting in consistent improvements in multiple measures of light tolerance and quality of life. Bitopertin was well tolerated, and most adverse events were mild or moderate in severity.
2025-12-17 | Complementary and alternative medicines and cannabis use among individuals with erythropoietic protoporphyria.
Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP) are rare, inherited disorders that present with severe cutaneous phototoxicity. Pain from phototoxic reactions does not respond to analgesics, and there is a need to identify therapies to address EPP-pain. Anecdotal reports from individuals with EPP indicate that cannabis may alleviate symptoms during phototoxic reactions. These reports warrant further systematic investigation. Therefore, this study aimed to explore how patients with EPP utilize cannabis and complementary and alternative medicines (CAM). A cross-sectional survey assessing the use of CAMs and cannabis in individuals with EPP and XLP was conducted. The survey included demographics, EPP/XLP symptoms, CAM use (the International CAM Questionnaire and Daily Session (I-CAM-Q)), and cannabis use (the Frequency, Age of Onset and Quantity of Cannabis Use Inventory (DFAQ-CU)). A total of 149 participants completed the survey. More than half of participants (62.9 %, 78/124) reported having used cannabis, either currently or in the past. Among the cannabis users, 12.9 % (9/70) reported using it only for EPP symptoms, 34.2 % (24/70) only recreationally, and 47.4 % (37/70) for both reasons. Individuals reported that cannabis mitigated anxieties around symptoms, though it was not perceived to directly reduce EPP-pain. Participants with more severe symptoms reported higher cannabis use. Few participants reported seeing a CAM provider for symptoms related to EPP, with most seeing providers to improve general well-being or for other reasons not related to EPP. Additionally, 76.0 % (89/117) of participants used self-help practices, though generally not for their EPP symptoms. Overall, findings from this study suggest that cannabis may be impactful on secondary effects of EPP symptoms. Also, that individuals with EPP primarily used other CAMs to improve general well-being rather than as treatment for EPP-related symptoms or pain. Given the limited treatment options for EPP-pain and the findings here, additional research is needed to determine the effectiveness of cannabis on EPP symptoms.
2025-10-21 | Burden of illness and unmet needs in patients with erythropoietic protoporphyria and X-linked protoporphyria: A large US nationwide claims analysis.
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare genetic disorders caused by the accumulation of the toxic metabolite protoporphyrin IX, which results in painful phototoxicity upon sunlight exposure. Despite their significant impact on quality of life and potential for serious complications, treatment options for EPP/XLP are limited and real-world burden of illness and unmet needs have been understudied in this population. To retrospectively evaluate real-world health care resource utilization (HRU) and costs among patients with EPP/XLP compared with matched comparators and to characterize the current EPP/XLP management in the United States using a large, nationwide claims database. Data were obtained from the Komodo Research Database (2016-2023). Patients with EPP/XLP (≥2 EPP/XLP diagnosis codes, first diagnosis defined index date) and comparator patients without an EPP/XLP diagnosis were identified and matched at a 1:4 ratio on index date and key characteristics. Patients were required to have at least 6 months of continuous enrollment pre-index (baseline period). HRU and costs were assessed post-index on a per patient per year (PPPY) basis. Comparison between cohorts were conducted using rate ratios (RRs) estimated from negative binomial regressions and cost ratios estimated from 2-part linear models, respectively. The use of treatments for EPP/XLP and concomitant medications commonly prescribed for associated comorbidities was also assessed during the follow-up period. In total, 696 patients with EPP/XLP and 2,784 matched comparator patients were included. In both cohorts, mean age was approximately 45.5 years; 55% were female and 55% were White. Over a mean follow-up of 30 months, patients with EPP/XLP had significantly higher all-cause HRU compared with comparators, with a mean PPPY number of inpatient stays of 0.8 vs 0.2 (RR = 3.4; P < 0.001), emergency department visits of 1.5 vs 0.9 (RR = 1.7; P = 0.002), and outpatient visits of 35.2 vs 17.5 (RR = 2.0; P < 0.001). All-cause costs were also significantly higher among patients with EPP/XLP compared with comparators with a mean PPPY total cost of $71,714 vs $18,646 (ratio = 3.9; P < 0.001), driven by inpatient costs (mean = $30,909 vs $6,318; ratio = 4.9; P < 0.001) and outpatient costs (mean = $33,416 vs $7,573; ratio = 4.4; P < 0.001). Although only 7.6% of patients with EPP/XLP received treatment for EPP/XLP, most commonly afamelanotide (3.9%), most (68.4%) used medication related to EPP/XLP-associated comorbidities, including narcotics (46.3%), nonsteroidal anti-inflammatory drugs (38.2%), and antidepressants (35.1%). Patients with EPP/XLP experienced substantially higher HRU and costs compared with matched comparators, yet few received EPP/XLP-specific treatment. This highlights the need for new effective and accessible treatments that could improve patient outcomes and alleviate the broader disease burden.
2025-07-15 | The GLYT1 inhibitor bitopertin mitigates erythroid PPIX production and liver disease in erythroid protoporphyria.
Erythropoietic protoporphyria (EPP) is a genetic disorder typically resulting from decreased ferrochelatase (FECH) activity, the last enzyme in heme biosynthesis. Patients with X-linked protoporphyria (XLPP) have an overlapping phenotype caused by increased activity of 5-aminolevulinic acid synthase 2 (ALAS2), the first enzyme in erythroid heme synthesis. In both cases, protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in plasma and tissues. Patients develop acute phototoxicity reactions upon brief exposure to sunlight. Some also experience chronic liver disease, and a small fraction develop acute cholestatic liver failure. Therapeutic options are limited, and none, save hematopoietic stem cell transplantation, directly targets erythroid PPIX accumulation. Bitopertin is an investigational orally available small-molecule inhibitor of the erythroid cell-surface glycine transporter GLYT1. We established the bitopertin PPIX inhibitory half-maximal effective concentration in a human erythroblast EPP model and confirmed a marked reduction of PPIX in erythroblasts derived from patients with EPP. We demonstrate that bitopertin also reduced erythrocyte and plasma PPIX accumulation in vivo in both EPP and XLPP mouse models. Finally, the reduction in erythroid PPIX ameliorated liver disease in the EPP mouse model. Altogether, these data support the development of bitopertin to treat patients with EPP or XLPP.
2026-03-02 | Adjunctive use of Polypodium leucotomos extract in patients with erythropoietic protoporphyria: An exploratory study.
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) cause severe photosensitivity, resulting in significant quality of life (QoL) impairment. This study aims to evaluate the safety and efficacy of Polypodium leucotomos extract (PLE) as an adjunctive therapy in patients with persistent symptoms despite standard dosing of afamelanotide. In this prospective single-center cohort study, eight adults with confirmed EPP or XLP and ongoing symptoms despite regular afamelanotide implants every 2 months were enrolled. Participants received 480 mg oral PLE daily for 4 months. QoL and symptom severity were measured using questionnaires at baseline, Day 60, and Day 120. Six participants completed the study. Statistically significant improvements in QoL were observed on Day 60 (p = 0.014), but not at Day 120 (p = 0.152). Half of participants reported reduced reaction severity. No adverse events occurred. Adjunctive PLE improved short-term QoL in participants with incomplete symptom control on afamelanotide alone and was well tolerated. Larger studies are warranted.
2026-01-13 | An open-label phase II study of bitopertin in adults and adolescents with erythropoietic protoporphyria or X-linked protoporphyria.
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare genetic disorders characterized by accumulation of protoporphyrin IX (PPIX), painful phototoxic reactions and hepatobiliary disease. No disease-modifying therapies are approved for these conditions. To evaluate the safety and efficacy of bitopertin in adults and adolescents with EPP or XLP. BEACON (ACTRN12622000799752) was a phase II, randomized, open-label, parallel-arm study in adult and adolescent participants with EPP or XLP. Participants received an oral, once-daily administration of bitopertin 20 mg or 60 mg for 24 weeks. Twenty-six participants were randomized to 20 mg (n = 14) or 60 mg (n = 12) of bitopertin. The study met its primary efficacy endpoint. Treatment with bitopertin resulted in significant, dose-dependent reductions in PPIX levels compared with baseline at both the 20-mg and 60-mg dose levels (mean -31.7%, SE 7.0; P < 0.001 vs. baseline and mean -57.7%, SE 7.4; P < 0.001 vs. baseline, respectively). Similar efficacy was observed across the adult and adolescent populations. No serious adverse events were reported. Dizziness was the most common adverse event reported with bitopertin, in 9 (64%) and 8 (67%) participants completing the study in the 20-mg and 60-mg dose groups, respectively. By reducing whole-blood PPIX levels, bitopertin targets the underlying pathophysiology of EPP, resulting in consistent improvements in multiple measures of light tolerance and quality of life. Bitopertin was well tolerated, and most adverse events were mild or moderate in severity.
2025-12-17 | Complementary and alternative medicines and cannabis use among individuals with erythropoietic protoporphyria.
Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP) are rare, inherited disorders that present with severe cutaneous phototoxicity. Pain from phototoxic reactions does not respond to analgesics, and there is a need to identify therapies to address EPP-pain. Anecdotal reports from individuals with EPP indicate that cannabis may alleviate symptoms during phototoxic reactions. These reports warrant further systematic investigation. Therefore, this study aimed to explore how patients with EPP utilize cannabis and complementary and alternative medicines (CAM). A cross-sectional survey assessing the use of CAMs and cannabis in individuals with EPP and XLP was conducted. The survey included demographics, EPP/XLP symptoms, CAM use (the International CAM Questionnaire and Daily Session (I-CAM-Q)), and cannabis use (the Frequency, Age of Onset and Quantity of Cannabis Use Inventory (DFAQ-CU)). A total of 149 participants completed the survey. More than half of participants (62.9 %, 78/124) reported having used cannabis, either currently or in the past. Among the cannabis users, 12.9 % (9/70) reported using it only for EPP symptoms, 34.2 % (24/70) only recreationally, and 47.4 % (37/70) for both reasons. Individuals reported that cannabis mitigated anxieties around symptoms, though it was not perceived to directly reduce EPP-pain. Participants with more severe symptoms reported higher cannabis use. Few participants reported seeing a CAM provider for symptoms related to EPP, with most seeing providers to improve general well-being or for other reasons not related to EPP. Additionally, 76.0 % (89/117) of participants used self-help practices, though generally not for their EPP symptoms. Overall, findings from this study suggest that cannabis may be impactful on secondary effects of EPP symptoms. Also, that individuals with EPP primarily used other CAMs to improve general well-being rather than as treatment for EPP-related symptoms or pain. Given the limited treatment options for EPP-pain and the findings here, additional research is needed to determine the effectiveness of cannabis on EPP symptoms.
2025-10-21 | Burden of illness and unmet needs in patients with erythropoietic protoporphyria and X-linked protoporphyria: A large US nationwide claims analysis.
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare genetic disorders caused by the accumulation of the toxic metabolite protoporphyrin IX, which results in painful phototoxicity upon sunlight exposure. Despite their significant impact on quality of life and potential for serious complications, treatment options for EPP/XLP are limited and real-world burden of illness and unmet needs have been understudied in this population. To retrospectively evaluate real-world health care resource utilization (HRU) and costs among patients with EPP/XLP compared with matched comparators and to characterize the current EPP/XLP management in the United States using a large, nationwide claims database. Data were obtained from the Komodo Research Database (2016-2023). Patients with EPP/XLP (≥2 EPP/XLP diagnosis codes, first diagnosis defined index date) and comparator patients without an EPP/XLP diagnosis were identified and matched at a 1:4 ratio on index date and key characteristics. Patients were required to have at least 6 months of continuous enrollment pre-index (baseline period). HRU and costs were assessed post-index on a per patient per year (PPPY) basis. Comparison between cohorts were conducted using rate ratios (RRs) estimated from negative binomial regressions and cost ratios estimated from 2-part linear models, respectively. The use of treatments for EPP/XLP and concomitant medications commonly prescribed for associated comorbidities was also assessed during the follow-up period. In total, 696 patients with EPP/XLP and 2,784 matched comparator patients were included. In both cohorts, mean age was approximately 45.5 years; 55% were female and 55% were White. Over a mean follow-up of 30 months, patients with EPP/XLP had significantly higher all-cause HRU compared with comparators, with a mean PPPY number of inpatient stays of 0.8 vs 0.2 (RR = 3.4; P < 0.001), emergency department visits of 1.5 vs 0.9 (RR = 1.7; P = 0.002), and outpatient visits of 35.2 vs 17.5 (RR = 2.0; P < 0.001). All-cause costs were also significantly higher among patients with EPP/XLP compared with comparators with a mean PPPY total cost of $71,714 vs $18,646 (ratio = 3.9; P < 0.001), driven by inpatient costs (mean = $30,909 vs $6,318; ratio = 4.9; P < 0.001) and outpatient costs (mean = $33,416 vs $7,573; ratio = 4.4; P < 0.001). Although only 7.6% of patients with EPP/XLP received treatment for EPP/XLP, most commonly afamelanotide (3.9%), most (68.4%) used medication related to EPP/XLP-associated comorbidities, including narcotics (46.3%), nonsteroidal anti-inflammatory drugs (38.2%), and antidepressants (35.1%). Patients with EPP/XLP experienced substantially higher HRU and costs compared with matched comparators, yet few received EPP/XLP-specific treatment. This highlights the need for new effective and accessible treatments that could improve patient outcomes and alleviate the broader disease burden.
2025-07-15 | The GLYT1 inhibitor bitopertin mitigates erythroid PPIX production and liver disease in erythroid protoporphyria.
Erythropoietic protoporphyria (EPP) is a genetic disorder typically resulting from decreased ferrochelatase (FECH) activity, the last enzyme in heme biosynthesis. Patients with X-linked protoporphyria (XLPP) have an overlapping phenotype caused by increased activity of 5-aminolevulinic acid synthase 2 (ALAS2), the first enzyme in erythroid heme synthesis. In both cases, protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in plasma and tissues. Patients develop acute phototoxicity reactions upon brief exposure to sunlight. Some also experience chronic liver disease, and a small fraction develop acute cholestatic liver failure. Therapeutic options are limited, and none, save hematopoietic stem cell transplantation, directly targets erythroid PPIX accumulation. Bitopertin is an investigational orally available small-molecule inhibitor of the erythroid cell-surface glycine transporter GLYT1. We established the bitopertin PPIX inhibitory half-maximal effective concentration in a human erythroblast EPP model and confirmed a marked reduction of PPIX in erythroblasts derived from patients with EPP. We demonstrate that bitopertin also reduced erythrocyte and plasma PPIX accumulation in vivo in both EPP and XLPP mouse models. Finally, the reduction in erythroid PPIX ameliorated liver disease in the EPP mouse model. Altogether, these data support the development of bitopertin to treat patients with EPP or XLPP.
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
1 orphan drug designation for X-linked erythropoietic protoporphyria.
1 orphan drug designation for X-linked erythropoietic protoporphyria.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Bitopertin | small molecules | EMA | 2023-02-15 | — | Disc Medicine B.V. |
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