A Phase 2, Randomized, Open Label Study of Bitopertin administered orally to Evaluate the Safety, Tolerability, Efficacy, and Protoporphyrin IX (PPIX) Concentrations in Participants with Erythropoietic Protoporphyria (EPP)

INTERVENTION: This study is an open label study of bitopertin to evaluate the safety, tolerability, efficacy, and Protoporphyrin I X(PPIX) concentration change in participants with Erythropoietic Protoporphyria (EPP). Participants will be screened for study eligibility within 28 days before Baseline (Day 1). All participants will undergo light tolerance assessment during Screening that includes a diary assessment. Up to 22 participants aged 18 and older are planned to be enrolled and completing 24 weeks of treatment in each group as follows: • Bitopertin 20 mg administered as 2 X10 mg tablets • Bitopertin 60 mg administered as 2 X30 mg tablets Study drug dosing will begin on Day 1 and continue over a 24‐week treatment period. Tablets will be taken orally, once daily, in the morning on an empty stomach after at least a 2 hour fast. Participants will remain fasted for at least 30 minutes following study drug administration. Water intake is not restricted during the fasting period. Participants will be required to maintain a daily sun exposure diary throughout the study. After completion of the 24‐week (168 days) treatment period, including assessment of light tolerance and End‐of‐Study (EOS) visit (Day 169), participants may continue on bitopertin (60 mg every day) for an additional 24 weeks or up to 1‐year total treatment period from Day 1. During the extension period, study visits will be scheduled every 8 weeks, the last of which is to be conducted at the end of study after 1‐year total treatment period. At each extension treatment period visit the following assessments will be conducted: vital signs, urine or serum pregnancy test for female participants of childbearing potential, blood chemistry and hematology, porphyrins and iron stu CONDITION: Erythropoietic Protoporphyria (EPP); ; Erythropoietic Protoporphyria (EPP) Metabolic and Endocrine ‐ Metabolic disorders PRIMARY OUTCOME: To assess changes in Protoporphyrin IX (PPIX) concentrations in response to bitopertin treatment. ; ; Measured by Percent change from baseline in erythrocyte metal‐free PPIX levels. Blood samples will be collected to analyse markers relevant to the mechanism of action to bitopertin.[Day 15 (after starting treatment) to Day 169 (End of Study) at all visits during treatment and Extension (every 8 weeks up to 1 year from Day 1); ; ] SECONDARY OUTCOME: To assess the safety and tolerability of bitopertin at two dose levels. ; ; Measured by the incidence of treatment‐emergent adverse events (TEAEs), vital signs, physical examinations, and clinical laboratory parameters.[• Incidence, severity, and relationship of AEs/TEAEs graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE) (Version 5). AEs that begin after the first administration of study drug, or existing AEs that worsen after the first dose of study drug will be considered TEAEs. Timepoint: Daily from Screening to Day 169 (End of Study) and Extension (every 8 weeks). After Day 1, AEs may be assessed by phone. ; ; • Clinical laboratory parameters: Blood sample for safety haematology and blood chemistry, Screening, Baseline (Day 1), pre‐dose from Day 15 to Day 169 (End of Study) and Extension (every 8 weeks). Urine sample for Urinalysis.: Baseline (Day 1), Day 29, Day 71, Day 169 (End of Study) ; ; • Vital signs: Blood pressure and heart rate is assessed using a sphygmomanometer and temperature by thermometer. Timepoint: Daily from Screening to Day 169 (End of Study) and Extension (every 8 weeks). ; ; • Physical Examination: Screening only ; ] To characterize the effect of bitopertin on daily daylight tolerance. ; ; Measured as a composite outcome by: ; 1. a two‐week average daily sunlight exposure time (minutes) to first prodromal symptom (burning, tingling, itching, or stinging) associated with sunlight exposure between 1 hour post‐sunrise and 1 hour pre‐sunset. ; 2. Pain intensity of phototoxic reactions according to a Likert scale (0‐10)[Total hours of direct sunlight exposure to skin on days with no pain from 1000 to 1800 hours (10:00 AM to 6:00 PM) ; ; Diaries are to be completed daily for 2 weeks during Screening and daily during the bitopertin dosing period (Day 1 and Day 15 to Day 169 (End of Study). Once a week participants will measure and record in the diary the time (minutes) it takes to experience first prodromal symptom (burning, tingling, itching, or stinging) associated with sunlight exposure.] To characterize the relationship between bitopertin dose level and key biological indicators of mechanism engagement ; ; Measured by assessment of Erythrocyte total PPI Xconcentrations, Plasma and blood total PPI Xconcentrations and Plasma bitopertin concentrations[Screening, Day 15 (after starting treatment) to Day 169 (End of Study) and Extension (every 8 weeks up to 1 year from Day 1)] To evaluate bitopertin pharmacokinetics (PK): ; ; Measured by blood/plasma (if data permits) as follows: ; • Cma X; • Observed time of the maximum drug concentration (Tmax) ; • AUC from time 0 to 24 hours post‐dose on Day 1 (AUC0‐24)[Assess PK parameters Day 1 (first treatment day): pre‐dose, 2, 4 and 6 hours post‐dose, Day 2: 24 hours post‐dose and Day 29: pre‐dose and 4 hours post‐dose] INCLUSION CRITERIA: 1. Aged 18 years or older 2. Diagnosis of EPP or XLP, based on medical history of FECH or ALAS2 genotyping or by biochemical porphyrin analysis. 3. Body weight greater than or equal to 50 kg. 4. Washout of at least 2 months prior to Screening of afamelanotide or dersimelagon, if applicable. 5. Aspartate aminotransferase (AST) and alanine transaminase (ALT) less than 2×upper limit of normal (ULN) and total bilirubin less than ULN (unless documented Gilbert syndrome) at Screening. Albumin greater than lower limit of normal (LLN). 6. If male with female sexual partner(s) of childbearing potential, agrees he and partner will use one of the following acceptable methods of birth control during the study and for 30 days after the last study drug dose: a. abstinence b. stable hormonal contraceptive or a barrier method (e.g., condom [male or female] or diaphragm) c. intrauterine device, in place for at least 3 months d. surgically sterile