Effect of Bitopertin on the Liver and on Levels of Protoporphyrin IX in Bile, Blood, Liver, and Stool in Patients With Erythropoietic Protoporphyria/X-linked Protoporphyria and Increased Liver Stiffness and/or Liver Enzymes at Baseline

The primary goal of this study is to assess safety and tolerability of bitopertin in subjects with Erythropoietic Protoporphyria (EPP) or X-linked Protoporphyria (XLP) and evidence of compensated liver disease.

Study Overview

• Status: Withdrawn
• Conditions: Protoporphyria
• Intervention / Treatment: Drug: bitopertin

Detailed Description

This in an open-label, investigator-initiated study of bitopertin (60 mg/day) in selected and carefully monitored participants with Erythropoietic Protoporphyria (EPP) or X-linked Protoporphyria (XLP) who have increased liver stiffness and/or elevated liver enzymes at baseline.This study is designed to evaluate whether bitopertin is effective in reducing hepatic and biliary levels of protoporphyrin IX (PP), which over time, with chronic and ongoing bitopertin treatment, will ameliorate and forestall progression of PP hepatopathy, providing an additional major benefit and reason for its chronic use in patients with EPP/XLP.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of EEP or XLP that has been biochemically and genetically verified prior diagnosis of EPP or XLP
• Age 18-75 years
• Increased liver stiffness at baseline, defined as stiffness measurement [E value] by: Fibroscan >7 kPa; MRE that is >3.0 kPa; Velacur/Sonicincyte that is >6.0 kPa; and/or elevated liver enzymes: serum ALT > 2 X upper limit of normal (ULN), but not greater than 5 X ULN and/or serum AP > 2 X ULN, but not greater than 5 X ULN
• INR < 1.4
• Compensated liver disease at baseline, defined as lack of clinically evident ascites, encephalopathy, hepatocellular carcinoma, clinically evident icterus or jaundice, peripheral edema.
• Willingness and ability to volunteer and provide informed consent for a long-term study that will include liver biopsies and collection of bile from the second portion of the duodenum, at baseline and at the end of study. In addition, follow-up visits will be planned every 26 weeks throughout the study, with plans for repeat routine/safety labs at each visit and for measures of liver stiffness and markers of hepatic status and fibrosis (Fib-4, APRI, ELF, Fibrotest) performed once every 6 months.

Exclusion Criteria:

• Chronic hepatitis B, C, D, or E;
• Human immunodeficiency (HIV) infection;
• Alcohol use > 14 units/week for men or > 7 units/week for women;
• Pregnancy or breast feeding among women;
• Any known active malignancy other than small and localized squamous or basal cell carcinoma of the skin;
• Advanced or decompensated heart, lung, kidney, liver, or neuro-psychiatric disease;
• History of diagnosed depression or suicidality;
• History of diagnosed substance abuse or poor impulse control;
• Any other conditions that, in the opinion of the Investigator, renders the individual unfit to participate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: bitopertin; bitopertin 60 mg per day	Drug: bitopertin; bitopertin 60 mg will be taken once daily by mouth; Other Names: DISC-1459

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of treatment emergent adverse events (TEAE)	Number of treatment emergent adverse events (TEAE). Adverse events that begin after the first administration of study drug, or existing adverse events that worsen after the first dose of study drug will be considered TEAEs.	Week 104

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Protoporphyrin IX (PP) Serum Levels	To assess effects of bitopertin on levels of protoporphyrin IX (PP) and other porphyrins in the whole blood, plasma, and red blood cells	baseline to month 12, month 12 to month 24
Number of Participants with Change in Histopathology	To assess effects of bitopertin on hepatic histopathology the number of participants with change in histopathologic evidence will be tracked. Histopathology consists of histopathologic evidence of hepatic fibrosis, necroinflammation, fat, cholestasis, bile plugs, birefringent brown deposits in the liver, or other histopathology, as estimated by an experienced hepato-pathologist.	baseline to month 24
Percent Change in Protoporphyrin IX (PP) Bile Levels	the percent change of Protoporphyrin IX (PP) in bile will be used to assess effects of bitopertin on PP levels	baseline to month 24
Percent Change in Protoporphyrin IX (PP) Liver Levels	the percent change in Protoporphyrin IX (PP) in the liver will be measured by change in liver stiffness measured by vibration controlled elastography with use of dedicated instruments designed for this purpose (Fibroscan, Velocur)	baseline to month 12, baseline to month 24
Percent Change in Protoporphyrin IX (PP) Stool Levels	the percent change in Protoporphyrin IX (PP) in stool will be used to assess effects of bitopertin on PP levels	baseline to month 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Global Impression of Severity	Three items with total score range 3-15. Higher score indicates higher level of erythropoietic protoporphyria severity	baseline, week 26, week 52, week 78, week 104
Patient Global Impression of Change	Five items with total score range 5-25. Higher score indicates erythropoietic protoporphyria have gotten worse since start of the study.	baseline, week 26, week 52, week 78, week 104
Patient-Reported Outcomes Measurement Information System - Social Isolation	Seven items with total score range 3-15. Higher score indicates poor quality of life.	baseline, week 26, week 52, week 78, week 104
Serum of Level of Bitopertin	Trough concentrations of bitopertin will measured by using HPLC-mass spectroscopic procedures	baseline, week 26, week 52, week 78, week 104

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Investigators: Principal Investigator: Herbert Bonkovsky, MD, Atrium Health Wake Forest Baptist

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): December 1, 2035
• Study Completion (Estimated): December 1, 2035

Study Registration Dates

• First Submitted: August 7, 2025
• First Submitted That Met QC Criteria: August 7, 2025
• First Posted (Actual): August 14, 2025

Study Record Updates

• Last Update Posted (Actual): January 29, 2026
• Last Update Submitted That Met QC Criteria: January 26, 2026
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Erythropoietic Protoporphyria; X-linked Protoporphyria; Bitopertin
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Metabolic Diseases; Digestive System Diseases; Liver Diseases; Skin Diseases; Skin Diseases, Genetic; Porphyrias, Hepatic; Porphyrias; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Protoporphyria, Erythropoietic; Protoporphyria, Erythropoietic, X-Linked Dominant; (4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone
• Other Study ID Numbers: IRB00118441

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No