(AURORA) A Randomized, Double-blind, Placebo-Controlled Study of Bitopertin to Evaluate the Safety, Tolerability, Efficacy, and Protoporphyrin IX (PPIX) Concentrations in Participants With Erythropoietic Protoporphyria (EPP)
Phase: PHASE2
Conditions: Erythropoietic Protoporphyria
Sponsor: Disc Medicine, Inc

 
 
 
 
 
 
 
 
 
 
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CLINICAL STUDY PROTOCOL 
 
(AURORA) 
A Randomized, Double-blind, Placebo-Controlled Study of 
Bitopertin to Evaluate the Safety, Tolerability, Efficacy, and 
Protoporphyrin IX (PPIX) Concentrations in Participants 
with Erythropoietic Protoporphyria (EPP) 
 
 
Protocol Number: 
DISC-1459-201 
Investigational Medicinal 
Product: 
 
DISC-1459/bitopertin 
IND Number: 
157419 
Sponsor: 
Disc Medicine, Inc. 
 
321 Arsenal Street, Suite 101 
 
Watertown, MA  02472, USA 
Date of Protocol and Version: 
02 March 2022, v 1.0 
24 June 2022, v2.0 
11 August 2022, v3.0 
 
 
 
 
 
 
 
CONFIDENTIAL 
This protocol may not be reproduced or communicated to a third party without the written 
permission of Disc Medicine.  

 
 
 
 
 
 
 
 
 
 
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SIGNATURE PAGE 
Protocol Title: 
(AURORA) A Randomized, Double-blind, Placebo-
Controlled Study of Bitopertin to Evaluate the Safety, 
Tolerability, Efficacy, and Protoporphyrin IX (PPIX) 
Concentrations in Participants with Erythropoietic 
Protoporphyria (EPP) 
Protocol Number: 
DISC-1459-201 
Date of Protocol and Version: 
11 August 2022, v3.0 
Protocol DISC-1459-201, Version 3.0, was approved by: 
Sponsor Signatory: 
Signature: 
 
 
 
Date:   
 
 
 
 
 
 
12-Aug-2022
PPD

 
 
 
 
 
 
 
 
 
 
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INVESTIGATOR’S SIGNATURE 
Protocol Title: 
(AURORA) A Randomized, Double-blind, Placebo-
Controlled Study of Bitopertin to Evaluate the Safety, 
Tolerability, Efficacy, and Protoporphyrin IX (PPIX) 
Concentrations in Participants with Erythropoietic 
Protoporphyria (EPP) 
Protocol Number: 
DISC-1459-201 
Date of Protocol and Version: 
11 August 2022, v3.0 
I have read this clinical study protocol and agree to conduct this study in accordance with all 
stipulations of the protocol and in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, and that are consistent with International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 
(ICH), all applicable local Good Clinical Practice (GCP) guidelines, and the applicable 
regulatory requirement(s). 
Principal Investigator: 
Print/Type Name: 
 
Signature: 
 
Date: 
 
 

 
 
 
 
 
 
 
 
 
 
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Table of Contents 
 
Signature Page ................................................................................................................................ 2 
Investigator’s Signature .................................................................................................................. 3 
Table of Contents ............................................................................................................................ 4 
List of Tables .................................................................................................................................. 9 
List of Figures ................................................................................................................................. 9 
Summary of Changes .................................................................................................................... 10 
1. 
Synopsis .................................................................................................................. 13 
2. 
List of Abbreviations and Definitions of Terms ..................................................... 23 
3. 
Introduction: Background and Scientific Rationale ................................................ 26 
3.1. 
Background ..............................................................................................................26 
3.1.1. 
Bitopertin ................................................................................................................ 26 
3.1.2. 
Erythropoietic Protoporphyria (EPP) ...................................................................... 26 
3.2. 
Profile of Bitopertin and Previous Experience ........................................................27 
3.2.1. 
Non-clinical Pharmacology .................................................................................... 27 
3.2.2. 
Non-clinical Pharmacokinetics and Metabolism .................................................... 28 
3.2.3. 
Non-clinical Toxicology ......................................................................................... 28 
3.2.4. 
Clinical Experience with Bitopertin ....................................................................... 29 
3.3. 
Study Rationale ........................................................................................................30 
3.4. 
Rationale for Dose Selection ...................................................................................30 
3.5. 
Benefit-Risk Assessment .........................................................................................31 
3.5.1. 
Risk Monitoring and Mitigation ............................................................................. 31 
4. 
Study Objectives and Endpoints ............................................................................. 33 
4.1. 
Objectives ................................................................................................................33 
4.1.1. 
Primary Objective ................................................................................................... 33 
4.1.2. 
Secondary Objectives ............................................................................................. 33 
4.1.3. 
Exploratory Objectives ........................................................................................... 33 
4.2. 
Endpoints .................................................................................................................33 
4.2.1. 
Primary Endpoint .................................................................................................... 33 
4.2.2. 
Key Secondary Endpoint ........................................................................................ 33 

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4.2.3. 
Secondary Endpoints .............................................................................................. 33 
4.2.4. 
Pharmacokinetic Endpoints .................................................................................... 34 
4.2.5. 
Exploratory Endpoints ............................................................................................ 34 
5.
Investigational Plan ................................................................................................. 35 
5.1. 
Study Overview and Plan ........................................................................................35 
5.2. 
Independent Data Monitoring Committee ...............................................................36 
5.3. 
Overall Participant Study Duration and Follow-Up ................................................36 
6.
Selection of Participants ......................................................................................... 37 
6.1. 
Inclusion Criteria .....................................................................................................37 
6.2. 
Exclusion Criteria ....................................................................................................37 
6.3. 
Handling of Screen Failures ....................................................................................39 
7.
Treatment of Participants ........................................................................................ 40 
7.1. 
Enrollment ...............................................................................................................40 
7.1.1. 
Screening and Enrollment ....................................................................................... 40 
7.1.2. 
Randomization ........................................................................................................ 40 
7.2. 
Blinding ...................................................................................................................40 
7.3. 
Study Drug Administration ......................................................................................40 
7.4. 
Modification of Dose and/or Treatment Schedule ...................................................40 
7.5. 
Overdose ..................................................................................................................41 
7.6. 
Discontinuation of Study Drug ................................................................................41 
7.7. 
Withdrawal of Participants from Study ...................................................................41 
7.8. 
Study Stopping Rules ...............................................................................................42 
7.9. 
42 
7.10. 
 .......................................................................................43 
7.11. 
 ............................................................................................................43 
8.
Concomitant Therapy and Procedures .................................................................... 44 
8.1. 
Concomitant Therapy ..............................................................................................44 
8.2. 
Allowed Concomitant Therapy ................................................................................44 
8.3. 
Disallowed Concomitant Therapy ...........................................................................44 
8.4. 
Concomitant Procedures ..........................................................................................45 
Replacement of Participants ....................................................................................42 
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9. 
Description of Study Drug ...................................................................................... 46 
9.1. 
Study Drug Preparation and Dispensing ..................................................................46 
9.2. 
Study Drug Storage ..................................................................................................46 
9.3. 
Study Drug Labeling ................................................................................................46 
9.4. 
Study Drug Handling and Disposal .........................................................................46 
9.5. 
Study Drug Accountability, Control, and Return ....................................................47 
9.6. 
Control, Return, and Retention of Non-study-drug Supplies ..................................47 
10. 
Study Assessments and Schedules .......................................................................... 48 
10.1. 
Demographics ..........................................................................................................48 
10.2. 
Medical and Medication History, Concomitant Medications ..................................48 
10.3. 
Physical Examination ..............................................................................................48 
10.4. 
Targeted Neurological Examination ........................................................................49 
10.5. 
Body Weight and Height .........................................................................................49 
10.6. 
Vital Signs ................................................................................................................49 
10.7. 
Clinical Laboratory Tests .........................................................................................49 
10.8. 
Pregnancy Testing ....................................................................................................50 
10.9. 
Serology/Virology ...................................................................................................50 
10.10. 
Biomarker Assessments ...........................................................................................50 
10.10.1. 
Porphyrins ............................................................................................................... 50 
10.10.2. 
Iron Studies ............................................................................................................. 50 
10.11. 
Pharmacokinetic Assessments .................................................................................50 
10.12. 
 ........................50 
10.13. 
Sun Exposure Challenge Question (Time to Prodrome) .........................................51 
10.14. 
Patient Reported Outcomes .....................................................................................51 
10.14.1. 
 ................................................................................................................................ 51 
10.14.2. 
 
 ............................................................................... 51 
10.14.3. 
 
........................................................................... 51 
10.14.4. 
 ................................................................................................ 51 
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10.14.5. 
 .................................................................................................. 51 
10.14.6. 
Exit Interview ......................................................................................................... 51 
10.15. 
Unscheduled Visits ..................................................................................................52 
10.16. 
Open-Label Visits ....................................................................................................52 
10.17. 
Pregnancy Testing and Reporting and Contraception Recommendations ...............52 
10.17.1. 
Pregnancy Testing Guidelines ................................................................................ 52 
10.17.2. 
Contraception Recommendations for Female Participants of Childbearing Potential
 ................................................................................................................................ 52 
10.17.3. 
Contraceptive Recommendations for Male Participants ........................................ 52 
10.17.4. 
Pregnancy Reporting ............................................................................................... 53 
10.18. 
Adverse Events ........................................................................................................53 
10.18.1. 
Definition of Adverse Events ................................................................................. 53 
10.18.2. 
Definition of an Adverse Event of Special Interest ................................................ 54 
10.18.3. 
Definition of an Unexpected Adverse Event .......................................................... 54 
10.18.4. 
Definition of Serious Adverse Events .................................................................... 54 
10.18.5. 
Reporting of Adverse Events, Adverse Events of Special Interest, and Serious 
Adverse Events ....................................................................................................... 55 
10.18.6. 
Severity of Adverse Events ..................................................................................... 56 
10.18.7. 
Relationship of Adverse Events to Study Drug ...................................................... 57 
10.18.8. 
Clinical Laboratory Adverse Events ....................................................................... 58 
10.19. 
Regulatory Aspects of Adverse Event Reporting ....................................................58 
11. 
Statistical Methods .................................................................................................. 59 
11.1. 
General Considerations ............................................................................................59 
11.2. 
Determination of Sample Size .................................................................................59 
11.3. 
Analysis Sets ............................................................................................................59 
11.3.1. 
Intent-to-Treat Analysis Set .................................................................................... 59 
11.3.2. 
Full Analysis Set ..................................................................................................... 60 
11.3.3. 
Per Protocol Analysis Set ....................................................................................... 60 
11.3.4. 
Safety Analysis Set ................................................................................................. 60 
11.4. 
Demographics and Baseline Characteristics ............................................................60 
11.5. 
Participant Disposition .............................................................................................60 
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11.6. 
Study Treatment Compliance ..................................................................................61 
11.7. 
Efficacy Analysis .....................................................................................................61 
11.7.1. 
Primary Efficacy Analysis ...................................................................................... 61 
11.7.1.1. 
Primary Efficacy Endpoint: Percent Change from Baseline Metal-Free PPIX .......61 
11.7.2. 
Key Secondary Efficacy Analysis .......................................................................... 62 
11.7.3. 
Secondary Efficacy Analyses ................................................................................. 62 
11.8. 
Safety Analyses ........................................................................................................63 
11.8.1. 
Clinical Laboratory Tests ........................................................................................ 63 
11.8.2. 
Adverse Events ....................................................................................................... 63 
11.8.3. 
Physical Examination and Vital Signs .................................................................... 63 
11.8.4. 
Prior Medications, Concomitant Medications and Procedures ............................... 64 
11.8.5. 
Pharmacokinetics .................................................................................................... 64 
11.9. 
Other Statistical Issues .............................................................................................64 
11.9.1. 
Significance Levels ................................................................................................. 64 
11.9.2. 
Multiple Comparisons/Multiplicity ........................................................................ 64 
11.9.3. 
Missing Data ........................................................................................................... 64 
12. 
Supporting Documentation and Operational Considerations ................................. 66 
12.1. 
Regulatory and Ethical Considerations ....................................................................66 
12.2. 
Financial Disclosure ................................................................................................66 
12.3. 
Informed Consent Process .......................................................................................67 
12.4. 
Participant Data Protection ......................................................................................67 
12.5. 
Dissemination of Clinical Study Data .....................................................................67 
12.6. 
Data Quality Assurance ...........................................................................................67 
12.7. 
Source Documents ...................................................................................................68 
12.8. 
Study and Site Opening and Closure .......................................................................69 
12.9. 
COVID-19 Mitigation Plan .....................................................................................69 
12.10. 
Future Use of Stored Specimens and Data ..............................................................70 
13. 
Publication Policy ................................................................................................... 71 
14. 
Appendices .............................................................................................................. 72 
APPENDIX 1. 
Strong CYP3A4 Inhibitors and Inducers .......................................................... 72 

 
 
 
 
 
 
 
 
 
 
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APPENDIX 2. 
Schedule of Assessments .................................................................................. 73 
APPENDIX 3. 
 ........................................................................ 76 
APPENDIX 4. 
 77 
APPENDIX 5. 
.................................................................... 81 
APPENDIX 6. 
 ............................................................................................ 82 
15. 
References ............................................................................................................... 83 
 
List of Tables 
Table 1: 
Risk Mitigation and Monitoring ................................................................................. 32 
Table 2: 
SAE Reporting Information........................................................................................ 56 
Table 3: 
CTCAE (Version 5.0) AE Grading ............................................................................ 57 
 
List of Figures 
Figure 1: Study Schematic ......................................................................................................... 36 
  
 
 
 
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SUMMARY OF CHANGES 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
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1. 
SYNOPSIS 
 
Protocol Number: DISC-1459-201 
Title: 
(AURORA) A Randomized, Double-blind, Placebo-Controlled Study of Bitopertin to 
Evaluate the Safety, Tolerability, Efficacy, and Protoporphyrin IX (PPIX) Concentrations in 
Participants with Erythropoietic Protoporphyria (EPP)  
Investigational Product Name: DISC-1459 (Bitopertin) 
Sponsor: Disc Medicine 
Study Centers: Approximately 10 in the United States (US) 
Development Phase: 2 
Study Objectives: 
Primary Objective: 
• To assess changes in PPIX concentrations in response to bitopertin treatment 
Secondary Objectives: 
• To characterize the effect of bitopertin on daily daylight tolerance 
• To assess the safety and tolerability of bitopertin at two dose levels 
• To characterize the relationship between bitopertin dose level and key biological 
indicators of mechanism engagement 
• To evaluate bitopertin pharmacokinetics (PK) 
Exploratory Objectives: 
• 
 
 
 
 
 
 
 
 
 
 
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Protocol Number: DISC-1459-201 
Study Endpoints: 
Primary: 
• Percent change from baseline in whole blood metal-free PPIX levels 
Key Secondary: 
• Total hours of sunlight exposure to skin on days with no pain from 1000 to 1800 hours 
(10:00 AM to 6:00 PM) 
Secondary: 
• A two-week average daily sunlight exposure time (minutes) to first prodromal 
symptom (e.g., burning, tingling, itching, or stinging) associated with sunlight 
exposure between 1 hour post -sunrise and 1 hour pre-sunset. 
• Pain intensity of phototoxic reactions according to a Likert scale (0-10) 
• Safety and tolerability of bitopertin, as assessed by the incidence of treatment-
emergent adverse events (TEAEs) 
• Erythrocyte metal-free PPIX concentrations 
• Plasma and whole blood total PPIX concentrations 
• Plasma bitopertin concentrations 
Pharmacokinetic: 
The following parameters will be determined from plasma PK sampling (if data permits): 
• Maximum observed drug concentration (Cmax) 
• Observed time of the maximum drug concentration (Tmax) 
• Area under the concentration-time curve from time 0 to 24 hours post-dose on Day 1 
(AUC0-24) 
Exploratory: 
• 
 
 
 
 
 
 
 
 
 
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Protocol Number: DISC-1459-201 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design: 
This is a Phase 2, multi-center, double-blind, placebo-controlled, parallel group study of 
bitopertin to evaluate the safety, tolerability, efficacy, and PPIX concentration change in 
participants with EPP. Participants will be screened for study eligibility within 
 days before 
Baseline (Day 1). All participants will undergo light tolerance assessment during Screening 
that includes a diary assessment and wearing a light dosimeter. 
Up to 75 participants aged 18 and older are planned to be enrolled. Participants who are 
determined to be eligible based on Screening assessments will be randomized upon 
confirmation of eligibility or on Day 1 in a 1:1:1 equal allocation ratio amongst the following 
three treatment groups: 
• 
Placebo (N=25) administered 
 
• 
Bitopertin 20 mg (N=25) administered 
 
• 
Bitopertin 60 mg (N=25) administered 
 
Randomization will be stratified by sunlight exposure time to prodromal symptom 
(<30 minutes or ≥30 minutes), as assessed during a 2-week run-in period.  
On Day 1, participants will begin study drug according to their random assignment and will be 
evaluated during a 120-day treatment period thereafter. Participants will be required to wear 
light dosimeters daily and maintain a daily sun exposure diary throughout the study. 
After completion of the 120-day treatment period, including assessment of light tolerance, and 
End-of-Study (EOS) visit,
 
 The study 
schema follows. 
 
 
 
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Protocol Number: DISC-1459-201 
 
 
Study Schematic: 
 
 
Study Treatments: 
Investigational Product, Dose, and Route of Administration: 
Bitopertin (chemical name: (S)-[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-
[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone) is presented in 
2
 
 
. 
 
Participants randomized to receive bitopertin will receive: 
• 
 once daily (QD) for 120 days (17 weeks) OR 
• 
 QD for 120 days (17 weeks). 
Reference Therapy, Dose, and Route of Administration: 
Placebo consists of the inactive ingredients, formed into tablets matching the size and 
appearance of the 
.  
 
Participants randomized to receive placebo will receive: 
• 
Two placebo tablets QD for 120 days (17 weeks) 
Duration of Individual Study Participation: 
Individual participation will be up to 5 months, consisting of: 
• 
Screening Period: up to 
 days 
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Protocol Number: DISC-1459-201 
• 
Treatment Period: up to 
 days (
) 
After completion of treatment phase, participants may continue on open-label bitopertin 
(20 mg QD). 
Independent Data Monitoring Committee: 
An Independent Data Monitoring Committee (IDMC) will aid in the monitoring of unblinded, 
accumulating study data to ensure the ongoing safety of trial participants. The IDMC 
membership will be composed of external medical experts with relevant clinical experience. 
The IDMC will have the right to recommend stopping the study at any time due to the 
concerns for the safety of the participants. 
Number of Participants: 
Planned: Approximately 75 adults (≥18 years) will be enrolled for an anticipated 69 adults 
completing 4 months of treatment. 
Inclusion criteria: 
Participants must meet all of the following criteria to be eligible for enrollment in the study: 
1. Aged 18 years or older at the time of signing the informed consent form (ICF).  
2. Diagnosis of EPP, based on medical history by ferrochelatase (FECH) genotyping or by 
biochemical porphyrin analysis. 
3. Body weight ≥50 kg. 
4. Washout of at least 2 months prior to Screening of afamelanotide and dersimelagon, if 
applicable. 
5. Aspartate aminotransferase (AST) and alanine transaminase (ALT) <2´ upper limit of 
normal (ULN) and total bilirubin <ULN (unless documented Gilbert syndrome) at 
Screening. Albumin >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: 
o abstinence 
o stable hormonal contraceptive 
o barrier method (e.g., condom [male or female] or diaphragm) 
o intrauterine device, in place for at least 3 months 
o surgically sterile by hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation 
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Protocol Number: DISC-1459-201 
7. If female of childbearing potential, defined as prior menarche, no hysterectomy, no 
bilateral oophorectomy, not postmenopausal (at least 12 months natural, spontaneous 
amenorrhea), must commit to one of the following methods of acceptable birth control 
during the study and for 30 days after the last study drug dose: 
o abstinence 
o stable hormonal contraceptive in conjunction with a barrier method (e.g., 
condom [male or female] or diaphragm) 
o intrauterine device, in place for at least 3 months 
8. Negative pregnancy test (females of childbearing potential) at Screening (Days 
 
AND Baseline (Day 1), prior to dosing. 
9. Able to understand the study aims, procedures, and requirements, and provide written 
informed consent. 
10. Able to comply with all study procedures. 
 
Exclusion Criteria: 
Participants meeting any of the following criteria are not eligible for study enrollment: 
Medical History: 
1. Major surgery within 8 weeks before Screening or incomplete recovery from any previous 
surgery. 
2. Other than EPP, an inherited or acquired red cell disease associated with anemia. 
3. A history or known allergic reaction to any investigational product excipients or history of 
anaphylaxis to any food or drug. 
4. History of liver transplantation. 
5. History of alcohol dependence or excessive alcohol consumption, as assessed by the 
Investigator. 
6. Human immunodeficiency virus (HIV), active Hepatitis B, or C. A positive hepatitis 
result should be discussed between the Investigator and Sponsor prior to enrollment. 
7. 
 
8. Other medical or psychiatric condition or laboratory finding not specifically noted above 
that, in the judgment of the Investigator or Sponsor, would put the participant at 
unacceptable risk or otherwise preclude the participant from participating in the study 
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Protocol Number: DISC-1459-201 
9. Condition or concomitant medication that would confound the ability to interpret clinical, 
clinical laboratory, or participant diary data, including a major psychiatric condition that 
has had an exacerbation or required hospitalization in the last 6 months. 
Treatment History: 
10. Concurrent or planned treatment with afamelanotide or dersimelagon during the study 
period. 
11. Treatment with opioids for any period >7 days in the 2 months prior to screening or 
anticipated to require opioid use for >7 days at any point during the study. 
12. New treatment for anemia, including initiation of iron supplementation, in the 2 months 
prior to Screening. 
13. Current or planned use of any drugs or herbal remedies known to be strong inhibitors or 
inducers of CYP3A4 enzymes for 
 days prior to the first dose and throughout the study. 
14. Current or planned treatment with anti-psychotic medication. 
Laboratory Exclusions: 
15. 
. 
Miscellaneous: 
16. If female, pregnant or breastfeeding. 
17. Participation in any other clinical protocol or investigational trial that involves 
administration of experimental therapy and/or therapeutic devices within 30 days of 
Screening. 
18. Grapefruit/Seville orange and products containing them for 14 days prior to first dose and 
throughout the study. 
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Statistical Methods: 
Sample Size: 
Approximately 75 participants will be randomized and allocated in a 1:1:1 ratio to receive 
bitopertin 20 mg QD, bitopertin 60 mg QD, or placebo.  
The primary efficacy endpoint is percent change from baseline in whole blood metal-free 
PPIX level at Day 
 Means of percent change from baseline values will be compared for 
each bitopertin dose group and placebo. Assuming the difference in mean percent change in 
PPIX between bitopertin and placebo is 30% with a corresponding pooled SD of 35%, a 
sample size of 23 participants per group provides 80% power to detect a difference between 
each bitopertin dose group and placebo using a two-sample t-test with a 2-sided alpha=0.05. 
Assuming an 8% dropout rate, a total of 75 participants will be randomized. 
The key secondary efficacy endpoint is total hours of sunlight exposure to skin on days with 
no pain from 1000 to 1800 hours (10:00 AM to 6:00 PM) over 120 days. Means of total hours 
of sunlight exposure on days with no pain will be compared for each bitopertin dose group and 
placebo.  Assuming the difference in means between bitopertin and placebo is 55 hours with a 
corresponding pooled SD of 67 hours, a sample size of 25 participants per group provides 80% 
power to detect a difference between each bitopertin dose group and placebo using a two-
sample t-test with a 2-sided alpha=0.05.  
Analysis Sets: 
• Intent-to-Treat Analysis Set: To be included in the Intent-to-Treat (ITT) analysis set, 
participants must be randomized to study drug. 
All analyses of the ITT analysis set will be based on each participant’s randomized 
treatment. If a participant is randomized according to the incorrect stratification, the 
participant will be analyzed under the randomized treatment for the stratum recorded in 
the randomization system. All efficacy analyses will be based on the ITT analysis set. 
• Full Analysis Set: To be included in the Full Analysis Set (FAS), participants must be 
randomized and take at least one dose of double-blind study drug, and have a baseline 
measurement and at least one postbaseline measurement of the primary efficacy variable 
or key secondary efficacy variable. 
All analyses of the FAS will be based on each participant’s randomized treatment. If a 
participant is randomized according to the incorrect stratification, the participant will be 
analyzed under the randomized treatment for the stratum recorded in the randomization 
system. The FAS will be used for a sensitivity analysis of the primary and key secondary 
efficacy endpoints. 
• Per Protocol Analysis Set: The Per Protocol (PP) Analysis Set will include all 
participants in the FAS who meet the study eligibility requirements and have no major 
protocol deviations that affect the validity of the efficacy measurements. The PP 
Analysis Set will be used for a sensitivity analysis of the primary and key secondary 
efficacy endpoints. The criteria for inclusion in the PP Analysis Set will be finalized 
prior to study unblinding and detailed in the Statistical Analysis Plan (SAP). 
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• Safety Analysis Set: All participants who are randomized and take at least one dose of 
double-blind study drug will be included in the Safety Analysis Set. Safety analyses will 
be based on the study drug that was dispensed to each participant.  
Primary Efficacy Endpoint Analysis: 
For the primary endpoint of percent change from baseline in whole blood metal-free PPIX 
level, a mixed model repeated measures (MMRM) analysis of covariance (ANCOVA) model 
will be fitted using all data as observed. The dependent variable is the percent change from 
baseline whole blood metal-free PPIX level for all post-baseline assessments for each 
participant. The model will include fixed effects for treatment, sunlight exposure time to 
prodromal symptom randomization stratification factor , baseline metal-free PPIX level, visit 
(Days 
), and visit-by-treatment interaction and a random effect for the 
participant. 
The primary efficacy analysis will be based on comparisons of bitopertin and placebo at the 
Day 
 visit. From the MMRM model, the Day 
 pairwise differences between least 
square (LS) means of bitopertin treatment groups and placebo will be presented along with the 
corresponding 95% CIs and 2-sided p-values. This analysis will be repeated for the FAS and 
PP Analysis Set. 
Key Secondary Endpoint Analysis: 
The key secondary endpoint for this study is total hours of sunlight exposure on days with no 
pain summed over the entire treatment period from randomization to Day 
 An ANOVA 
model will be used for the ITT analysis set with effects for randomized treatment group and 
sunlight exposure time to prodromal symptom randomization stratification factor. Pairwise 
differences between LS means of bitopertin treatment groups and placebo will be presented 
along with the corresponding 95% CIs and 2-sided p-values. 
Since a highly skewed distribution for this endpoint is expected, a Kruskal-Wallis test will be 
used to test the treatment effect as a sensitivity analysis. The 2-sided p-values will be 
presented. The Hodges–Lehmann estimates of the median differences between the bitopertin 
treatment groups and placebo, and their 95% CIs will also be presented. 
Safety Analysis: 
All safety analyses will be based on the Safety Analysis Set. 
Safety data will include AEs, physical examination results, vital signs, 
, and 
clinical laboratory measurements. Observed data will be listed by participant and summarized 
using descriptive statistics by treatment group. 
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. The number and percentage of 
participants reporting TEAEs will be summarized for each treatment group by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term, by 
severity, and by relationship to study drug (drug-related TEAEs versus TEAEs not related to 
study drug). Drug-related TEAEs will be considered those to be at least possibly related to 
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Protocol Number: DISC-1459-201 
study drug based on the Investigator’s assessment. The number and percentage of participants 
reporting SAEs, and the number and percentage of participants reporting AEs leading to study 
drug discontinuation will also be summarized for each treatment group by MedDRA system 
organ class and preferred term. 
Clinical laboratory parameters and vital signs will be measured at baseline and post-baseline 
visits. Each continuous variable will be summarized as changes from baseline by treatment 
group. 
Laboratory and vital signs data will also be classified as low, normal, or high relative to the 
parameter’s reference range. Laboratory and vital signs abnormalities for each treatment group 
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2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Special Term 
Definition or Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-τ 
area under the curve over a dosing interval 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CHr 
reticulocyte hemoglobin 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CO2 
carbon dioxide 
Cmax 
maximum concentration 
CNS 
central nervous system 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DLT 
dose-limiting toxicity 
EC50 
half-maximal effective concentration 
 
 
eCRF 
electronic case report form 
EOS 
end of study 
EPP 
erythropoietic protoporphyria 
FAS 
full analysis set 
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Abbreviation or 
Special Term 
Definition or Explanation 
FDA 
US Food and Drug Administration 
FECH 
ferrochelatase 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
GlyT1 
glycine neurotransmitter transporter 1 
GMP 
good manufacturing practice 
Hb 
hemoglobin 
HBC 
hepatitis C virus 
HBV 
hepatitis B surface antigen 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
LLN 
lower limit of normal 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
OCD 
Obsessive Compulsive Disorder 
PD 
pharmacodynamic 

 
 
 
 
 
 
 
 
 
 
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Abbreviation or 
Special Term 
Definition or Explanation 
 
 
 
 
 
 
PK 
pharmacokinetics 
PP 
per protocol 
PPIX 
protoporphyrin IX 
PRO 
patient reported outcome 
 
 
QD 
once daily 
QOL 
quality of life 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum drug concentration 
ULN 
upper limit of normal 
WHO-DD 
World Health Organization Drug Dictionary 
XLP 
X-linked protoporphyria 
 
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3. 
INTRODUCTION: BACKGROUND AND SCIENTIFIC 
RATIONALE 
3.1. 
Background 
3.1.1. 
Bitopertin 
Bitopertin selectively inhibits glycine neurotransmitter transporter 1 (GlyT1), a transporter that 
influences the intracellular and extracellular levels of glycine. Glycine plays a critical role in 
several biological functions with one of these functions being heme biosynthesis in the 
erythroblast. Inhibition of GlyT1 leads to reduced intracellular glycine levels affecting the 
biosynthesis of heme. Since GlyT1 is also expressed in other tissues, for example in the central 
nervous system (CNS), GlyT1 inhibition affects the extracellular (synaptic) levels of glycine that 
acts as a neurotransmitter. 
The initial hypothesis for developing bitopertin for a CNS indication was that this mode of action 
might have a positive effect in patients with schizophrenia and obsessive-compulsive disorder 
(OCD). However, after extensive development the clinical programs in these indications were 
terminated due to lack of efficacy. 
One of the consistent side effects observed in all clinical studies was the reversible, dose-
dependent reduction in hemoglobin (Hb) levels in healthy volunteers as well as in psychiatric 
patients treated with bitopertin. The GlyT1 protein is also expressed by the erythroid lineage, in 
all precursors of red blood cells (RBCs), including reticulocytes. Glycine is an important amino 
acid for the first biochemical step in heme synthesis. Inhibiting glycine transport into developing 
RBCs, erythroid cells produce less heme, leading to Hb level reduction in healthy participants. 
In a study of 69 healthy volunteers treated for 4 months with 0, 10, 30, or 60 mg bitopertin daily, 
the reduction in Hb was dose-dependent and mild, with maximal decreases of ~2 g/dL with 
chronic dosing at 60 mg once daily (QD). Decreases in reticulocyte mean corpuscular volume 
(MCV) and reticulocyte hemoglobin (CHr) at 2 weeks were predictive of whole blood Hb 
decreases that stabilized at approximately 4 months into chronic dosing. The effect of Hb 
reduction with bitopertin is anticipated to be attenuated in people with erythropoietic 
protoporphyria (EPP) because excess (protoporphyrin IX) PPIX substrate should always be 
available to ferrochelatase (FECH), even in the context of reduced flux in the heme synthesis 
pathway due to GlyT1 inhibition. 
3.1.2. 
Erythropoietic Protoporphyria (EPP) 
In most cases, EPP is caused by a mutation of FECH, which is the final enzyme in the heme 
biosynthesis cycle, adding Fe+2 with PPIX to make heme. Approximately 5-10% of cases are 
caused by a gain of function mutation in ALAS2, the first enzyme in the heme biosynthesis 
cycle. The ALAS2 mutation subtype of EPP is also known as X-linked protoporphyria (XLP). In 
patients with EPP, PPIX significantly accumulates and causes elevated PPIX concentration in 
RBCs, plasma, liver, and skin.(1) (2) Insufficient FECH enzyme activity results in increased 
accumulation of protoporphyrin that lacks Fe+2 or other metals, particularly zinc (i.e., metal-free 

 
 
 
 
 
 
 
 
 
 
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protoporphyrin). In EPP, the main source of production of increased red cell and plasma 
protoporphyrin is bone marrow reticulocytes, as red cells are major sources of heme production 
in the body. Conditions that increase erythropoiesis may result in increased formation of 
protoporphyrins by the bone marrow.(3) PPIX can be actively transported out of RBCs into 
plasma or enter plasma after RBC membrane damage. PPIX absorbs visible light and releases its 
energy to oxygen, which may create free radicals that result in skin damages when the patients 
with EPP are exposed to light.(2) This reactivity is the basis for the acute, painful, non-blistering 
photosensitivity and liver disease.(4) (5) 
EPP typically presents in early childhood with immediate pain and crying upon exposure to 
bright sunlight. It is seasonal in nature with symptoms principally occurring in the spring and 
summer season. EPP is a lifelong disease, and repeated phototoxic reactions eventually lead to 
thickening of the skin and wax-like scarring on the face. In a small number of patients, the 
accumulation of PPIX in the liver leads to cirrhosis and liver failure. Onset in adulthood is rare, 
but an acquired form has been identified, in which clones of cells with mutated FECH expand in 
the setting of the myelodysplastic or myeloproliferative syndrome.(6) 
There are several lines of evidence that link PPIX concentrations with the degree of 
phototoxicity in people with EPP. First, there is epidemiologic evidence that lower sunlight 
tolerance is associated with higher blood PPIX concentrations.(2) Second, women with EPP who 
become pregnant have a reduction in PPIX of 40-50% (for unknown reasons), and this reduction 
is associated with a remission of phototoxicity in many cases.(7) Third, in an interventional study 
of extracorporeal photoinactivation, a procedure that temporarily reduced blood PPIX by 
approximately 30%, light tolerance increased 14-fold.(6) Thus, a treatment that causes reduction 
in PPIX is anticipated to lead to increased sunlight tolerance. 
3.2. 
Profile of Bitopertin and Previous Experience 
3.2.1. 
Non-clinical Pharmacology 
A functional assay using a recombinant human transporter demonstrated that bitopertin potently 
inhibited GlyT1b mediated glycine uptake with a half-maximal effective concentration (EC50) of 
0.025 µM and selectivity was greater than 1000-fold selectivity compared to human recombinant 
GlyT2 mediated glycine uptake. Ex vivo glycine uptake study has demonstrated that bitopertin 
can reduce glycine uptake into RBCs from rat, non-human primate, and humans in a dose-
dependent manner.  
In vitro studies using K562-EPP and human CD34+-EPP cellular models demonstrated bitopertin 
can reduce the PPIX accumulation in erythroid cells in a dose-dependent manner and without 
affecting heme formation. The PPIX-lowering EC50 for bitopertin in K562-EPP cellular models 
ranges from 3 to 10 nM. The PPIX-lowering EC50 for bitopertin in CD34+-EPP cellular models 
ranges from 23 to 33 nM. 
The efficacy of bitopertin to treat EPP was further evaluated in female Fechm1Pas EPP and male 
Alas2Q548X/Y XLP mouse models. At 8 weeks, PPIX levels had decreased in the 

 
 
 
 
 
 
 
 
 
 
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Fechm1Pas/Fechm1Pas and Alas2Q548X/Y animals receiving bitopertin with a mean reduction of 45% 
and 73%, respectively, compared to the control group. Importantly, no changes in hemoglobin 
levels were observed, indicating bitopertin can reduce PPIX accumulation without significant 
impact on erythropoiesis at the current dosing regimen. 
3.2.2. 
Non-clinical Pharmacokinetics and Metabolism 
In mice, rats, and cynomolgus monkeys, bitopertin showed 78% (rats) absolute oral 
bioavailability and a high plasma protein binding (free fraction 2-3%). The in vitro hepatic 
metabolism of bitopertin in hepatocytes and microsomal incubations was qualitatively similar 
across species (rat, cynomolgus monkey and human), with the two primary metabolites being 
formed via CYP3A4. 
In rat, drug-related material was rapidly distributed into nearly all tissues, with the highest 
concentration found in the liver. Excretion of bitopertin and its metabolites in rat and 
cynomolgus was rapid and complete, and occurred mainly via bile into feces (~92% of dose). 
The parent molecule bitopertin accounted for less than 5% of the drug related material excreted 
into rat bile and was detected only in trace amounts in urine. 
In human liver microsomes, bitopertin showed little inhibition of cytochrome P450s (CYPs) 
1A2, 2C8, 2C9, 2C19, 2D6 or 3A4/5 activities at concentrations up to 9 μM. Drug-drug 
interactions due to inhibition of CYP-based metabolism of a co-medication are therefore not 
expected. Bitopertin showed no potential to induce the activity of CYP450 isoenzymes CYP3A4, 
CYP2C9 and CYP1A2 in human hepatocytes and no signs of reduced exposure after multiple 
dosing in rats and cynomolgus have been detected. Metabolism mediated by CYP3A4 is the 
major elimination pathway for bitopertin. Co-medications, which are CYP3A4 inhibitors or 
inducers, will have an influence on the elimination of bitopertin since CYP3A4 is the major 
metabolizing enzyme. 
3.2.3. 
Non-clinical Toxicology 
In repeat-dose studies, the main targets for bitopertin-related systemic toxicity were identified as 
the CNS and the RBC system. Incidence, severity and onset of the CNS-related effects were 
dose-dependent (hypersalivation; hypoactivity and tremor; posture anomalies; reduced body 
temperature) and they were generally transient overnight or reversible upon cessation of 
treatment. Effects on the RBC system (mainly increased reticulocyte and RBC counts and 
decreased hemoglobin concentration, mean corpuscular volume and mean corpuscular 
hemoglobin) were generally reversible and not accompanied by any relevant bone marrow 
toxicity. The hematological effects noted following 44 days (rat) and 79 days (monkey) of 
dosing did not show further significant worsening until the end of the entire 26-week dosing 
period (plateau). There were also no indications for hemolysis and no relevant changes in white 
blood cells (WBC) or lymphoid tissues. The side effects (on the CNS and the RBC system) 
identified in non-clinical safety studies are related to the pharmacological target (i.e., GLYT1). 
In safety pharmacology studies, bitopertin did not induce pro-convulsant effects or catalepsy and 
no pro-arrhythmic potential was determined in vitro (hERG channel and isolated heart tests) or in 

 
 
 
 
 
 
 
 
 
 
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vivo (single-dose telemetry and repeat-dose monkey toxicity studies). The telemetry study 
indicated a mild hypertensive effect at high doses. 
Following repeated dosing in toxicological studies, comparatively low heart rate was seen. In the 
6-week toxicology study this was also coupled with long QTcF in male monkeys at dose levels 
also associated with behavioral changes. In single dose studies in rats, high doses decreased the 
respiratory rate associated with compensatory increases of expiration time and tidal volume, 
delayed gastric emptying and decreased intestinal motility. 
No signs of a genotoxic potential were identified and bitopertin was not classified as an irritant 
or skin sensitizer. 
Bitopertin had no effect on reproductive performance and fertility and showed no effects on 
sperm motility or head count in the rat and no effect on sexual organ weights and testicular size, 
and no histopathological findings in sexual organs in the rat and the monkey. 
Potential effects of bitopertin on embryo-fetal development were investigated in the rat and 
rabbit. Bitopertin did not prove to be teratogenic (i.e., dysmorphogenic) in any species. 
3.2.4. 
Clinical Experience with Bitopertin 
Bitopertin has been investigated by F. Hoffmann La-Roche in 26 clinical pharmacology studies 
in healthy volunteers, in two Phase II studies in schizophrenia, and one long-term treatment 
study in Japanese patients and in five global Phase III studies in schizophrenia. One Phase 3 
study, plus one long-term extension treatment study, were carried out in Japanese patients and 
one Phase II study in OCD. 
The clinical safety of bitopertin has been assessed in adult healthy volunteers, patients with renal 
or hepatic impairment, and patients with psychiatric disorders. Cumulatively, 4334 participants 
have received bitopertin in clinical trials where the product was the investigational drug. 
Single dose studies escalated to 240 mg bitopertin, and the maximum tolerated dose (MTD) was 
240 mg. In multiple dose studies that escalated up to 180 mg, the MTD was considered to be 
120 mg. The most common dose-dependent adverse event (AE) in healthy volunteers was 
dizziness. Headache and somnolence were the other identified AEs. In the Phase 2 programs in 
schizophrenia, obsessive-compulsive disorder and β-thalassemia, daily doses up to 90 mg 
bitopertin were well tolerated. In healthy volunteer studies, reversible blurred vision was 
observed in some participants, especially at doses of 60 mg and above. 
 
 
 
Hb levels gradually decreased from baseline in a dose-dependent manner in participants 
receiving bitopertin in line with the mechanism of action of the study drug. This decline was 
small in magnitude and had a gradual onset. Few participants (<1%) met the protocol withdrawal 
criteria for decreased hemoglobin and were discontinued from study drug. As observed in the 
cellular and mouse models of EPP discussed earlier, such an effect is not expected in participants 
with EPP; even though bitopertin is anticipated to reduce PPIX concentrations, there is still 
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expected to be a significant excess of PPIX available to serve as substrate to make adequate 
heme. 
No effects on vital signs, visual function assessments including electroretinogram parameters and 
electrocardiogram parameters were seen. 
In the drug-drug interaction study, 400 mg ketoconazole QD for 17 days increased the maximum 
concentration (Cmax) of single doses of 10 mg bitopertin by approximately 20% (exposure ratio: 
1.21, 90% confidence interval (CI) 1.12-1.32) from 77.0 ± 20.2 ng/mL to 94.7 ± 20.7 ng/mL and 
the area under the curve (AUC)0-312 increased by a factor of approximately 4.2 (90% CI 3.5-5.0) 
from 2450 ± 1050 ng×h/mL to 9770 ± 1520 ng×h/mL. The half-life increased from 
approximately 2.5 days to approximately 20 days. Therefore, strong CYP3A4 inhibitors and 
inducers will be excluded from use in all clinical studies. 
In a prior randomized, double blind safety and PK study in 67 healthy volunteers in which 
patients were randomized to 120 days of treatment with placebo or bitopertin (10, 30 or 60 mg 
daily) 3 participants in the 60 mg group discontinued within the first month of the study with a 
constellation of depression plus at least one of the following: dizziness, visual impairment, 
headache, malaise. Two participants also withdrew each from the placebo, 10 mg, and 30 mg 
arms. 
3.3. 
Study Rationale 
Bitopertin is a GlyT1 inhibitor, and erythroid precursors utilize GlyT1 as a glycine source for the 
first step in heme synthesis. By reducing the availability of glycine via inhibition of GlyT1, it is 
hypothesized that a decrease in the flux of heme synthesis intermediates will decrease the 
formation of PPIX. Because PPIX is the photoreactive compound that leads to phototoxicity, the 
reduction of PPIX is anticipated to translate into an improved sunlight tolerance. 
3.4. 
Rationale for Dose Selection 
The rationale for dose selection considers the extensive clinical safety profile demonstrated in 
the bitopertin development program, clinical pharmacokinetic (PK) information, 
PK/pharmacodynamic (PD) relationship, and indicators of bitopertin concentration predictive of 
PD effects in heme synthesis, which aim to at maximize the prospect of benefit in people with 
EPP. 
Generally, bitopertin PK in patient populations were similar to healthy volunteers. Single oral 
doses up to 240 mg showed a slightly less than proportional increase in AUC and Cmax with dose, 
whereas multiple doses up to 180 mg showed a linear and dose proportional increase in the 
respective parameters (AUC0-t,ss and Cmax,ss respectively). Overall, the half-life estimate of 
bitopertin is around 2 days, supporting once daily dosing regimen. There was relevant 
accumulation after daily repeat dosing. Area under the curve over a dosing interval (AUC0-τ) 
increased from Day 1 to Day 10 about 2.7 to 3.8-fold with a tendency for greater accumulation 
with higher doses. Attainment of steady state was estimated to be between 6 and 8 days. The PK 

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characteristics indicate that 20 mg and 60 mg doses of bitopertin will be in the linear PK range 
and result in meaningfully different exposures of approximately 3-fold. 
The pharmacological effect of bitopertin was observed in an ex-vivo assay in circulating blood. 
The relationship between total bitopertin plasma concentrations and inhibition of the GlyT1 in 
RBCs showed that a near maximal effect would be achieved at a 60 mg dose exposure and 83% 
inhibition is achieved at a 20 mg dose exposure. 
3.5. 
Benefit-Risk Assessment 
3.5.1. 
Risk Monitoring and Mitigation 
The monitoring requirements were designed to protect the safety of individual participants. 
To evaluate and mitigate the potential risks of bitopertin, the following safety measures 
and monitoring requirements have been implemented (Table 1). 

 
 
 
 
 
 
 
 
 
 
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Table 1: 
Risk Mitigation and Monitoring 
Organ 
Potential Risk 
Proposed Mitigation and Monitoring 
Liver 
Bitopertin did not cause liver 
toxicity in prior clinical 
studies, but EPP is associated 
with hepatic impairment and 
participants with EPP may be 
an at-risk population. 
Serial monitoring of AST, ALT, bilirubin, 
albumin, and alkaline phosphatase. DLT for 
Grade 3 clinical lab elevations, considered by 
the Investigator to be treatment-related with 
at least possible imputability. 
Blood 
Bitopertin causes a mild 
anemia in people with 
normal heme synthesis 
pathway enzymes, although 
anemia is not expected based 
on cell and animal model 
data of EPP. 
Serial monitoring of reticulocyte and 
complete blood counts. DLT for Hb drop of 2 
g/dL from lowest pre-dose Hb value. Hold 
and/or reduce dose for developing anemia. 
 
 
• 
 
 
 
 
• 
 
 
 
• 
 
 
 
 
 
 
 
 
 
AST=aspartate aminotransferase; ALT=alanine aminotransferase; DLT=dose-limiting toxicity 
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4. 
STUDY OBJECTIVES AND ENDPOINTS 
4.1. 
Objectives 
4.1.1. 
Primary Objective 
• To assess changes in PPIX concentration in response to bitopertin treatment 
4.1.2. 
Secondary Objectives 
• To characterize the effect of bitopertin on daily daylight tolerance 
• To assess the safety and tolerability of bitopertin at two dose levels 
• To characterize the relationship between bitopertin dose level and key biological 
indicators of mechanism engagement 
• To evaluate bitopertin PK 
4.1.3. 
Exploratory Objectives 
• 
 
 
 
 
 
 
 
 
 
 
4.2. 
Endpoints 
4.2.1. 
Primary Endpoint 
• Percent change from baseline in whole blood metal-free PPIX levels 
4.2.2. 
Key Secondary Endpoint 
• Total hours of sunlight exposure to skin on days with no pain from 1000 to 1800 
hours (10:00 AM to 6:00 PM) 
4.2.3. 
Secondary Endpoints 
• 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. 
• Pain intensity of phototoxic reactions according to a Likert scale (0-10) 
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• Safety and tolerability of bitopertin, as assessed by the incidence of treatment-
emergent adverse events (TEAEs) 
• Erythrocyte metal-free PPIX concentrations 
• Plasma and whole blood total PPIX concentrations 
• Plasma bitopertin concentrations 
4.2.4. 
Pharmacokinetic Endpoints 
• Cmax 
• Observed time of the maximum drug concentration (Tmax) 
• AUC from time 0 to 24 hours post-dose on Day 1 (AUC0-24) 
4.2.5. 
Exploratory Endpoints 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5. 
INVESTIGATIONAL PLAN 
5.1. 
Study Overview and Plan 
This is a Phase 2, multi-center, double-blind, placebo-controlled, parallel group study of 
bitopertin to evaluate the safety, tolerability, efficacy, and PPIX concentration change in 
participants with EPP.  
Participants will be screened for study eligibility within 
 days before Baseline (Day 1). All 
participants will undergo light tolerance assessment during Screening that includes a diary 
assessment of historical light tolerance as well as maximal sunlight tolerance time until 
phototoxic prodrome during one day per week over a 2-week run-in period. Patient reported 
recall of maximal average sunlight tolerance time until phototoxic prodrome may be used in the 
event that sufficient sun exposure to elicit prodrome cannot be achieved.  Participants will also 
wear a light dosimeter during this Screening light tolerance assessment. 
Up to 75 participants aged 18 and older are planned to be enrolled. Participants who are 
determined to be eligible based on Screening assessments will be randomized on Day 1 in a 1:1:1 
equal allocation ratio amongst the following three treatment groups: 
Placebo (N=25) administered as 
 
Bitopertin 20 mg (N=25) administered as 
 
Bitopertin 60 mg (N=25) administered as 
. 
Randomization will be stratified by sunlight exposure time to prodromal symptom (<30 minutes 
or ≥30 minutes), as assessed during a 2-week screening period.  
On Day 1, participants will begin study drug according to their random assignment and will be 
evaluated during a 120-day treatment period thereafter. Participants will be 
 
 
.  
An Independent Data Monitoring Committee (IDMC) will aid in the monitoring of unblinded, 
accumulating study data to ensure the ongoing safety of trial participants. The IDMC will have 
the right to recommend stopping the study at any time due to the concerns for the safety of the 
participants. 
After completion of the 120-day treatment period, including assessment of light tolerance, and 
End-of-Study (EOS) visit, participants may 
 
. Study visits will be scheduled every  weeks. 
Figure 1 depicts the study schema.  
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Figure 1: 
Study Schematic
 
 
5.2. 
Independent Data Monitoring Committee 
The IDMC will aid in the monitoring of unblinded, accumulating study data to ensure the 
ongoing safety of trial participants. The IDMC membership will be composed of external 
medical experts with relevant clinical experience. The IDMC will have the right to recommend 
stopping the study or discontinuing a treatment arm at any time due to the concerns for the safety 
of the participants. 
The IDMC will evaluate for study stopping in any instance when 2 participants need study 
treatment interruption due to CTCAE Grade 3 or above psychiatric, neurological or eye AEs.    
5.3. 
Overall Participant Study Duration and Follow-Up 
The overall study duration for participants is up to 7 months as described below: 
Screening: up to
days 
Treatment Period: 
 days  
• The EOS visit (
) occurs the day after the final double-blind dose (
). 
Additional, open-label treatment may occur on study after the EOS visit, for up to 
. 
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6. 
SELECTION OF PARTICIPANTS  
6.1. 
Inclusion Criteria 
Participants are eligible for the study if all of the following criteria apply: 
1. Aged 18 years or older at the time of signing the informed consent form (ICF).  
2. Diagnosis of EPP, based on medical history by FECH genotyping or by biochemical 
porphyrin analysis. 
3. Body weight ≥50 kg. 
4. Washout of at least 2 months prior to Screening of afamelanotide and dersimelagon, if 
applicable. 
5. Aspartate aminotransferase (AST) and alanine transaminase (ALT) <2× upper limit of 
normal (ULN) and total bilirubin <ULN (unless documented Gilbert syndrome) at 
Screening. Albumin >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: 
o abstinence 
o stable hormonal contraceptive 
o barrier method (e.g., condom [male or female] or diaphragm) 
o intrauterine device, in place for at least 3 months 
o surgically sterile by hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation 
7. If female of childbearing potential, defined as prior menarche, no hysterectomy, no 
bilateral oophorectomy, not postmenopausal (at least 12 months natural, spontaneous 
amenorrhea), must commit to one of the following methods of acceptable birth control 
during the study and for 30 days after the last study drug dose: 
o abstinence 
o stable hormonal contraceptive in conjunction with a barrier method (e.g., 
condom [male or female] or diaphragm) 
o intrauterine device, in place for at least 3 months 
8. Negative pregnancy test (females of childbearing potential) at Screening (Days 
to 
) 
AND Baseline (Day 1), prior to dosing. 
9. Able to understand the study aims, procedures, and requirements, and provide written 
informed consent. 
10. Able to comply with all study procedures. 
6.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical History: 
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1.
Major surgery within 8 weeks before Screening or incomplete recovery from any
previous surgery.
2.
Other than EPP, an inherited or acquired red cell disease associated with anemia.
3.
A history or known allergic reaction to any investigational product excipients or history
of anaphylaxis to any food or drug.
4.
History of liver transplantation.
5.
History of alcohol dependence or excessive alcohol consumption, as assessed by the
Investigator.
6.
Human immunodeficiency virus (HIV), active Hepatitis B, or C. A positive hepatitis
result,  should be discussed between the Investigator and Sponsor prior to enrollment.
7.
8.
Other medical or psychiatric condition or laboratory finding not specifically noted above
that, in the judgment of the Investigator or Sponsor, would put the participant at
unacceptable risk or otherwise preclude the participant from participating in the study
9.
Condition or concomitant medication that would confound the ability to interpret clinical,
clinical laboratory, or participant diary data, including a major psychiatric condition that
has had an exacerbation or required hospitalization in the last 6 months.
Treatment History: 
10.
Concurrent or planned treatment with afamelanotide or dersimelagon during the study
period.
11.
Treatment with opioids for any period >7 days in the 2 months prior to screening or
anticipated to require opioid use for >7 days at any point during the study.
12.
New treatment for anemia, including initiation of iron supplementation, in the 2 months
prior to Screening.
13.
Current or planned use of any drugs or herbal remedies known to be strong inhibitors or
inducers of CYP3A4 enzymes for 
 days prior to the first dose and throughout the study
(see Appendix 1).
14.
Current or planned treatment with anti-psychotic medication.
Laboratory Exclusions: 
15.
.
Miscellaneous:
16.
If female, pregnant or breastfeeding.
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17. 
Participation in any other clinical protocol or investigational trial that involves 
administration of experimental therapy and/or therapeutic devices within 30 days of 
Screening. 
18. 
Grapefruit/Seville orange and products containing them for 14 days prior to first dose and 
throughout the study. 
6.3. 
Handling of Screen Failures 
A screen failure is defined as a candidate who consents to study participation but does not get 
randomized to study drug. Candidates determined to be screen failures must be captured in the 
clinical database by completion of the appropriate electronic case report form (eCRF) pages. 
Please refer to the eCRF guidelines for additional instructions. 
The following information should be collected in the candidate’s source documents and eCRF 
page(s): the date the ICF was signed, demographics, the reason(s) for ineligibility, and the 
Investigator’s signature for the eCRF pages. Serious adverse events (SAEs) experienced by 
screen failure candidates will be collected from the date of signing consent to the day the 
candidate is confirmed as a screen failure (see Section 10.18.5 for information on SAE 
reporting). Relevant information will also be recorded on the Screening Log.  
Screen failures will be allowed to rescreen once, ≥weeks after the initial screen failure. Partial 
re-screening for Hb, AST, ALT, and bilirubin entry criteria will be allowed once within the 
screening period. 
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7. 
TREATMENT OF PARTICIPANTS 
7.1. 
Enrollment 
7.1.1. 
Screening and Enrollment 
75 adult (≥18 years) participants will be enrolled. All participants will be screened for study 
eligibility within 
 days of randomization (Day 1).  
7.1.2. 
Randomization 
Adult participants will be randomized on Day 1 in a 1:1:1 allocation ratio to one of the following 
three treatment groups: 
• 
Placebo (N=25) administered as 
 
• 
Bitopertin 20 mg once daily (N=25) administered as 
 
• 
Bitopertin 60 mg once daily (N=25) administered as 
 
Randomization will be stratified by average sunlight exposure time to prodromal symptom 
(<30 minutes or ≥30 minutes), as assessed during a 2-week run-in period. 
7.2. 
Blinding 
Study drug and dose group allocation will be blinded to all participants and study personnel. 
7.3. 
Study Drug Administration 
Study drug dosing will begin on Day 1 and continue over a 
-day treatment period. Tablets 
will be taken orally, once daily, in the morning on an empty stomach, at least 30 minutes prior to 
food. If a participant inadvertently eats before taking study drug, it is acceptable to take study 
drug 2 hours after the food ingestion. 
7.4. 
Modification of Dose and/or Treatment Schedule 
If a participant becomes intolerant of study drug, as assessed by the Investigator, study drug may 
be withheld and subsequently restarted following consultation between the Investigator and 
Sponsor. 
 
 
 
f symptoms resolve, treatment may be re-introduced 
 
). Then, if after 2 weeks symptoms have not recurred, the full dose will be 
resumed. If the symptoms recur and are not tolerated, then subject may have the dose reduced 
again or be withdrawn from the study at the discretion of the investigator. 
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 Then, if after 2 
weeks symptoms have not recurred, the full dose will be resumed. If the symptoms recur to any 
degree severity after reintroduction of drug, then subject may have the dose reduced again or be 
withdrawn from the study at the discretion of the investigator. 
 
7.5. 
Overdose 
An overdose is defined as any dose of study drug greater than the intended dose. 
A known or suspected overdose must be reported to the study team immediately, and medical 
monitoring is recommended. There is no known antidote for bitopertin overdose. Based on the 
available clinical and non-clinical data for bitopertin, all reported TEAEs have been reversible. 
7.6. 
Discontinuation of Study Drug 
Study drug administration must be discontinued if any of the following events occur: 
• Hypersensitivity or suspected allergic reaction to the study drug. 
• Withdrawal of consent. 
• At the discretion of the Investigator or Sponsor for situations including, but not limited 
to, a clinically significant event, non-compliance with treatments or procedures to the 
extent that study integrity is compromised, or prohibited medication exposure. 
• A medical emergency that requires permanent discontinuation of study drug. 
• 
 
• Participant becomes pregnant. 
• 
. 
• Return of signs or symptoms of an AE after reintroduction of study drug, as described in 
Section 7.4 
Participants should remain in the study and follow the schedule of assessments, even if they meet 
study drug discontinuation criteria.  
The reason for discontinuation of study drug must be recorded in the participant’s eCRF.  
Participants who prematurely discontinue study drug should be encouraged to continue in the 
study and continue protocol-required clinic visits, tests, and assessments.  
7.7. 
Withdrawal of Participants from Study 
Participants must be withdrawn from the study for any of the following reasons:  
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• As determined by the Investigator in conjunction with the Sponsor, participant does not 
sufficiently adhere to study drug or protocol requirements. 
• Participant withdraws consent. 
• Participant is unwilling or unable to comply with the protocol to an extent that 
undermines the integrity of the study. 
• At the discretion of the Investigator or Sponsor for medical reasons. 
• Participant is lost to follow-up. 
• Return of signs or symptoms of an AE after reintroduction of study drug, as described in 
Section 7.4 
The reason for study withdrawal is to be documented in the participant’s eCRF. 
Participants who prematurely withdraw from the study during the treatment period should be 
encouraged to complete the study assessments for the EOS visit at the time of withdrawal. 
Participants who prematurely withdraw from the follow-up period should be encouraged to 
complete the appropriate follow-up assessments at the time of withdrawal. 
A participant will be declared lost to follow-up if reasonable attempts by the site have been made 
to contact the participant at least three times using any of the following methods: telephone calls, 
e-mails, text messages. At least one time should be an attempt to contact by telephone. 
7.8. 
Study Stopping Rules 
Enrollment or treatment in this study may be paused at any time for safety reasons. This study 
may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause.  
 
    
Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the Investigator and regulatory authorities. 
If the study is prematurely terminated or suspended, the Investigator will promptly inform the 
institutional review board (IRB)/independent ethics committee (IEC) and will provide the 
reason(s) for the termination or suspension. 
Circumstances that may warrant study termination or suspension include, but are not limited to: 
• Determination of unexpected, clinically significant, or unacceptable risk to participants 
• Sponsor decision 
7.9. 
Replacement of Participants 
Participants who withdraw or are withdrawn will not be replaced. 
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7.10. 
 
After completion of the 120-day treatment period, including assessment of light tolerance, and 
EOS visit 
 
7.11. 
End of Study 
The end of the study is defined as completion of the last participant’s last procedure shown in the 
randomized, double-blind, placebo-controlled phase of the study as detailed in the Schedule of 
Assessments (Appendix 2).
 
 
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8. 
CONCOMITANT THERAPY AND PROCEDURES 
8.1. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant reports from 
 days before signing the ICF up to 
the end-of-study visit must be recorded on the eCRF along with: 
Reason for use 
Dates of administration including start and end dates 
Dosage information including dose and frequency 
Prior medications are those received up to 
 days before signing of the ICF to the first dose of 
study drug and concomitant medications are those received after the first dose. 
If the use of any concomitant treatment becomes necessary (e.g., for treatment of an AE), the 
treatment and administration details must be recorded in the source documents and the eCRF. 
The Medical Monitor must be notified of all prohibited medications administered to any 
participant, in order to assess the participant’s eligibility to continue in the study. 
8.2. 
Allowed Concomitant Therapy 
Participants are allowed to continue taking any stable dose of prescription or over-the-counter 
medications during the study other than those listed in Section 8.3 at the discretion of the 
Investigator. 
8.3. 
Disallowed Concomitant Therapy 
Prohibited medications during the study are listed in the exclusion criteria for enrollment 
(Section 6.2). The following concomitant medications are specifically excluded during the 
course of the study: 
Any known strong inhibitor of CYP3A4 (see Appendix 1) taken within 
 days prior to the first 
dose of study drug (Day 1) 
Any known strong inducer of CYP3A4 (see Appendix 1) taken within 
 days prior to the first 
dose of study drug (Day 1) 
Products containing grapefruit or Seville orange, or grapefruit/Seville orange juice are not to be 
consumed from 14 days prior to the first dose of study drug and throughout the study 
Afamelanotide 
Dersimelagon 
New or discontinued iron replacement therapy (oral or intravenous). Stable or chronic 
replacement acceptable. 
Chronic opioids (>7 days) 
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Another investigational drug or device 
8.4. 
Concomitant Procedures 
Any procedure, including transfusion, that the participant reports from 
 days before signing the 
ICF up to the end-of-study visit must be recorded on the eCRF along with: 
• Reason for procedure(s) 
• Dates of procedure(s) 
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9. 
DESCRIPTION OF STUDY DRUG 
Bitopertin (chemical name: (S)-[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-
[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone) is presented in 
 
Further details are presented in the 
Investigator’s Brochure. 
9.1. 
Study Drug Preparation and Dispensing 
Film-coated tablets at the dosage strength of 
 mg and 
 mg of bitopertin will be used. No 
special drug preparation is required. 
Dispensing of bitopertin will be carefully recorded on appropriate study drug accountability 
forms and will be verified by the study monitor at each monitoring visit. 
More detailed information is located in the Pharmacy Manual for the study. 
9.2. 
Study Drug Storage 
The Sponsor reserves the right to inspect the study drug storage area before and during the study. 
A written record will be made of the storage condition of the study materials and retained 
according to institutional operating procedures 
Bitopertin will be stored by the site study personnel or pharmacist according to the Pharmacy 
Manual. Bitopertin should be stored in a locked area with access limited to designated personnel. 
The recommended storage condition for bitopertin drug product is at 15-30˚C. Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained within 
an established temperature range. The Investigator or site designee is responsible for ensuring 
that the temperature is monitored throughout the duration of the study and that records are 
maintained. Please refer to the study Pharmacy Manual for additional storage instructions. 
9.3. 
Study Drug Labeling 
Bitopertin will be labeled in accordance with text that is in full regulatory compliance. Study 
drug labels will not bear any statement that is false or misleading in any manner or represents 
that the study drug is safe or effective for the purposes for which it is being investigated. 
The Pharmacy Manual for the study will have more detailed information. 
9.4. 
Study Drug Handling and Disposal 
Bitopertin accountability and traceability are ultimately the responsibility of the Investigator and 
Sponsor. However, this responsibility may be delegated to suitably qualified personnel who have 
had appropriate study-specific training and whose names have been appropriately listed on the 
Delegation of Responsibility Log for this task. 
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Following completion and verification of accountability logs, all unused and used study drug 
must be destroyed. Study drug may be destroyed on site according to good clinical practice 
(GCP) and site practice. Alternatively, the Sponsor may arrange for destruction with a third-party 
vendor operating in accordance with GCP and/or good manufacturing practice (GMP), as 
applicable. See the Study Procedures Manual for complete instructions on how to dispose of 
study drugs. 
Detailed records will be maintained to allow for accurate accountability of bitopertin as per 
applicable Sponsor and clinical site procedures. All material containing bitopertin will be treated 
and disposed of as hazardous waste in accordance with governing regulations and clinical site 
procedures. 
9.5. 
Study Drug Accountability, Control, and Return 
The Investigator is responsible for bitopertin accountability, reconciliation, and record 
maintenance at the investigational site. In accordance with all applicable regulatory 
requirements, the Investigator or designated site staff must maintain accountability records 
throughout the course of the study. The amount of bitopertin received from the Sponsor, and the 
amount supplied and/or administered to participants will be documented. 
The accountability logs should include dates, quantities, batch numbers, expiration dates (if 
applicable), and any unique pack numbers assigned to the study drug and/or participant. The 
accountability logs will also include general details related to the study including the 
protocol/amendment number, Sponsor, indication, and the Investigator. 
The Investigator must maintain accurate records demonstrating dates and amount of study drug 
received and dispensed, and accounts of any study drug accidentally or deliberately destroyed. It 
will be the responsibility of the Sponsor to ensure that adequate samples of all study drug doses 
are retained in accordance with the relevant regulatory guidelines. 
The study monitor will review bitopertin accountability logs and check returns (unused and used) 
prior to authorizing the destruction of used study drug by the study site. 
Further details for study drug dispensing and accountability are included in the Pharmacy 
Manual. 
9.6. 
Control, Return, and Retention of Non-study-drug Supplies 
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10. 
STUDY ASSESSMENTS AND SCHEDULES 
Refer to the Schedule of Assessments in Appendix 2 for the timing of all study assessments. All 
assessments on Day 1 and subsequent study visits will precede dosing. 
 
visits are recommended to be performed at the study site. 
 visits, as noted 
on the Schedule of Assessments, may be conducted remotely with laboratory assessments 
obtained by a home-health study team member.  
In the event of multiple procedures scheduled at the same time, the order, where possible, will 
be: PROs, vital signs, PK sampling, porphyrins, and then clinical laboratory sampling. Urinalysis 
may occur whenever is most convenient for the participant.   
On Day 1, participants will receive instructions for study drug storage and administration and 
completion of paper and/or electronic PROs and other assessments/diaries. Repeat instruction 
will be provided as necessary throughout study. 
No study assessments or procedures will occur until after the ICF is signed. 
10.1. 
Demographics 
Date of birth, sex, ethnicity, and race will be collected during Screening. 
10.2. 
Medical and Medication History, Concomitant Medications 
Complete medical history collected at Screening will include evaluation for past or present 
cardiovascular, respiratory, GI, renal, hepatic, neurological, endocrine, metabolic, lymphatic, 
hematologic, immunologic, dermatologic, psychiatric, and genitourinary disorders, medication 
and surgical history, and review of any other diseases or disorders.  
A history of EPP will be recorded during Screening, including therapies and treatments 
previously received. If the participant’s EPP genotype is not documented in the medical history, 
genotyping will occur during Screening, but medical history of EPP is sufficient for eligibility. 
A review of prior and concomitant medications will be completed. Prior medications are those 
received from 
 days before informed consent up to first dose of study drug. Concomitant 
medications are those being taken at the time of informed consent and continuing through first 
dose of study drug and beyond, and those begun during the study (beginning Day 1 or later). 
10.3. 
Physical Examination 
At Screening, a full physical examination will be performed and will include assessment of the 
following: general appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, 
cardiovascular system, respiratory system, GI system, musculoskeletal system, lymph nodes, and 
nervous system. Any findings made during the physical examination must be noted even if they 
are part of the participant’s medical history. 
A complete physical examination will be repeated at the Day 
(EOS) visit. 
 
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10.4. 
Targeted Neurological Examination 
At 
, a targeted neurologic exam that includes mental status, optical 
and eye movement cranial nerves (CNII, CNIII, CNIV, CNVI), motor function, gait, stance, and 
coordination will be performed. Any findings made during the physical examination must be 
noted even if they are part of the participant’s medical history. 
10.5. 
Body Weight and Height 
Body weight (wearing light clothes, no shoes) and height will be measured at Screening. Body 
weight only will be assessed at EOS. 
10.6. 
Vital Signs 
Vital signs measurements will include resting systolic and diastolic blood pressure, body 
temperature (oral), respiratory rate, and pulse. Blood pressure must be taken before study drug 
administration and after the participant has rested comfortably in a supine position for at least 
5 minutes. Vital signs will be recorded using consistent methods between participants. Vital 
signs will be collected at Screening, and at each visit. Abnormal vital signs may be repeated 
twice at Screening and once at subsequent visits. 
10.7. 
Clinical Laboratory Tests 
Participants will fast overnight (minimum 6 hours) prior to blood draws. Water is allowed. Blood 
draws should occur pre-dose and at the same time of day at each scheduled assessment (except 
for post-dose PK sampling). Scheduled assessment times for blood chemistry and hematology 
will be at all study visits except for Day 2. For urinalysis, collection will occur at Baseline 
(Day 1) and on Days 
(EOS), prior to dosing. 
The blood samples will be assessed for: 
• Blood Chemistry: blood glucose, sodium, potassium, blood urea nitrogen (BUN), 
creatinine, AST, ALT, alkaline phosphatase, total bilirubin, direct bilirubin, 
gamma-glutamyl transferase (GGT), albumin, calcium, phosphorus, carbon dioxide 
(CO2), and chloride 
• Hematology: hemoglobin, hematocrit, RBC count, red cell distribution width, WBC 
count with differential, platelet count, MCV, MCH, and MCHC 
• Special Hematology: reticulocyte (absolute), reticulocyte %, and CHr 
• Urinalysis: color, pH, specific gravity, protein, blood, glucose, nitrites, and ketones. 
Urine sediment microscopy will be conducted in the instance of abnormal findings for 
blood. 
A list of all laboratory parameters is provided in Appendix 3. 
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In the event of an unexplained, clinically significant abnormal laboratory test result, the test 
should be repeated once and followed until it has returned to the normal range and/or an 
adequate explanation of the abnormality is found. 
During the study, all out of range (abnormal) laboratory values must be evaluated and 
commented on by the Investigator for clinical significance. 
Clinical laboratory samples will be analyzed at a central laboratory. Please refer to the 
Laboratory Manual for sample collection and processing procedures. 
10.8. 
Pregnancy Testing 
Urine pregnancy test will be given to participants of females of childbearing potential at 
Screening and Baseline. If a urine test is positive, serum pregnancy test is required. 
10.9. 
Serology/Virology 
Testing for hepatitis B surface antigen (HBV), hepatitis C virus (HBC), and HIV will occur at 
Screening. Results must be available before the first dose. A positive result, indicating active 
disease status, should be discussed between the Investigator and Sponsor prior to enrollment. 
10.10. 
Biomarker Assessments 
10.10.1. 
Porphyrins 
Porphyrins (metal-free whole blood PPIX, metal-free erythrocyte PPIX, whole blood total PPIX, 
plasma total PPIX) will be measured at Screening and all visits except Day 2. 
10.10.2. 
 Iron Studies 
Blood for iron studies will be collected in the fasted state (≥ 6 hours), between 6:00 AM and 
noon. Collection will occur at Baseline (Day 1) and on 
 (EOS). 
The iron parameters to be assessed are: TIBC, serum iron, TSAT, and ferritin. 
10.11. 
Pharmacokinetic Assessments 
Blood sampling for PK analyses will occur on Day
 
. The Day 
 dose 
will be administered by the study site 24 hours (+/-1 hour) after the previous day’s dose, and the 
subject’s study drug supply may be used. 
10.12. 
 
 
 
 
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10.13. 
Sun Exposure Challenge Question (Time to Prodrome) 
Participants will be required to expose their skin to sunlight once a week and measure the time it 
takes to experience a prodrome. The time (minutes) to first prodromal symptom (e.g., burning, 
tingling, itching, or stinging) associated with sunlight exposure will be recorded in a diary 
(Appendix 4, Appendix 5). 
10.14. 
Patient Reported Outcomes 
10.14.1. 
 
 
 
 
 
10.14.2. 
 
 
 
10.14.3. 
 
 
 
 
10.14.4. 
 
 
 
 
 
 
10.14.5. 
 
 
 
10.14.6. 
 Exit Interview 
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Subjects who complete the double-blind treatment period will be invited to participate in an 
optional exit interview. The exit interview will be conducted after the last dose of the double-
blind treatment period and within three days of the last dose. Information gathered from these 
interviews will support the interpretation of results of the patient reported outcome measures and 
diary. 
10.15. 
Unscheduled Visits 
If a study assessment (e.g., laboratory tests or vital signs) must be repeated, the results of the 
repeat assessment should be entered as an additional unscheduled visit in the eCRF. Complete 
instructions are found in the eCRF Completion Guidelines. 
10.16. 
Open-Label Visits 
Participants who continue on 
 will have 
study visits scheduled every  weeks. 
Any adjustment to the 
 mg dose must be pre-determined in consultation with the Sponsor. 
10.17. 
Pregnancy Testing and Reporting and Contraception 
Recommendations 
10.17.1. 
 Pregnancy Testing Guidelines 
For each female participant, the Investigator will document non-childbearing status or potential 
childbearing status during the screening period and record it in the eCRF. 
Female participants of childbearing potential will have a urine pregnancy test at 
 
 If a urine pregnancy test is positive, it will be confirmed by a serum pregnancy test. 
10.17.2. 
 Contraception Recommendations for Female Participants of Childbearing 
Potential 
Female participants of childbearing potential (prior menarche, no hysterectomy, no bilateral 
oophorectomy, not postmenopausal [at least 12 months natural, spontaneous amenorrhea]) who 
are sexually active with males must agree to use highly effective contraception (listed below) on 
Day 1 (or earlier) through at least 30 days after the last dose of study drug: 
• Abstinence 
• Stable hormonal contraceptive in conjunction with a barrier method (e.g., condom [male 
or female] or diaphragm) 
• Intrauterine device, in place for at least 3 months 
10.17.3. 
 Contraceptive Recommendations for Male Participants 
Male participants who are sexually active with females of childbearing potential (prior 
menarche, no hysterectomy, no bilateral oophorectomy, not postmenopausal [at least 12 months 
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natural, spontaneous amenorrhea]) must agree from Day 1 through at least 30 days after the last 
dose of study drug to have the female partner(s) use one of these contraceptive measures: 
• Abstinence 
• Stable (at least 3 months) hormonal contraceptive 
• Barrier method (e.g., condom [male or female] or diaphragm) 
• Intrauterine device, in place for at least 3 months 
• Surgically sterile by hysterectomy, bilateral oophorectomy, or bilateral tubal ligation 
10.17.4. 
 Pregnancy Reporting 
Pregnancy in a participant or the female partner of a male participant occurring up to 60 days 
after the participant’s last dose of study drug must be reported to the Sponsor contract research 
organization pharmacovigilance group within 24 hours of the Investigator’s knowledge of the 
pregnancy using a Pregnancy Report Form. 
Pregnancy per se is not considered an AE unless there is a cause to believe that the study 
interventions may have interfered with the effectiveness of a contraceptive medication or if the 
outcome of the pregnancy meets SAE criteria (miscarriage/fetal death or congenital 
anomaly/birth defect), in which case it should be reported in the same manner and timelines as 
an SAE (Table 2). In addition, any infant death or congenital anomaly occurring 30 days or more 
after birth that the Investigator suspects is related to the in-utero exposure to the study 
interventions should also be reported as an SAE. Hospitalization for normal delivery of a healthy 
newborn is not an SAE.  
If a female partner of a male participant becomes pregnant, the Investigator should request 
consent from the partner to collect relevant safety information. If a pregnancy occurs in a female 
participant, study interventions must be discontinued immediately. The pregnant woman should 
be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling. The Investigator must notify the Sponsor contract research 
organization pharmacovigilance group of the outcome within 24 hours of the Investigator’s 
knowledge of the pregnancy outcome using a Pregnancy Report Form. 
At Screening, all participants (male and female) must agree to use a highly effective method of 
contraception (Section 10.17.2 and Section 10.17.3) during the duration of the study and for 
30 days after the last dose of study drug. 
10.18. 
Adverse Events 
10.18.1. 
 Definition of Adverse Events 

 
 
 
 
 
 
 
 
 
 
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An AE is defined as any untoward medical occurrence in a clinical study participant 
administered a medicinal product, which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not it is related to the medicinal 
(investigational) product.  
Untoward events that are part of the EPP/XLP pathophysiology and captured as study endpoints 
are not to be recorded as adverse events: 
• Phototoxic reactions  
• Pain and skin changes associated with phototoxic reactions 
• PPIX concentrations 
An AE includes but is not limited to any clinically significant worsening of a participant’s 
preexisting condition. An abnormal laboratory finding that requires an action or intervention by 
the Investigator, should be reported as an AE. 
AEs may be treatment emergent (i.e., occurring after initial receipt of study drug) or 
nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, disease, or 
other untoward medical event that begins after written informed consent has been obtained but 
before the participant has received study drug. 
The term AE is used to include both serious and non-serious AEs. 
It is the responsibility of the Investigator to document all AEs that occur during the study. AEs 
should be reported on the appropriate page of the eCRF. 
10.18.2. 
 Definition of an Adverse Event of Special Interest 
AESIs based on clinical AEs observed during development include: 
• 
 
 
 
 
 
 
10.18.3. 
 Definition of an Unexpected Adverse Event 
An unexpected AE is any event for which the nature or severity is not consistent with the 
information in the current Investigator’s Brochure. 
10.18.4. 
 Definition of Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose (including those occurring after the ICF 
is signed and before dosing) that: 
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• Results in death 
• Is life-threatening (subject is at immediate risk of death from the event as it occurred) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, are not immediately life-threatening, or do 
not require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
For SAE reporting purposes, hospitalization is defined as inpatient hospital stay. Hospitalizations 
for elective surgery or other medical procedures that are not related to a TEAE are not 
considered SAEs.  
Death should not be reported as an SAE. The primary reason for a subject’s death should be 
reported as the SAE, with death reported as the outcome. 
10.18.5. 
 Reporting of Adverse Events, Adverse Events of Special Interest, and Serious 
Adverse Events 
In the event of a Grade 3 eye/visual AE, participants will be referred immediately to an 
ophthalmologist for a complete evaluation which includes visual acuity, color vision test, 
Humphrey visual field test, slit lamp biomicroscopy of the anterior and posterior segment to 
include evaluation of the macula, optic nerve , retinal vessels and peripheral retina, and 
intraocular pressure. For Grade 1 and Grade 2 eye/visual AEs that have symptoms persist for 1 
week, regardless of dose reduction or discontinuation, the participant will be referred to an 
ophthalmologist for an evaluation that includes a slit lamp examination. All ophthalmologic 
evaluation results will be recorded in AE follow up and made available to the investigator. The 
evaluation by an ophthalmologist for eye/visual AEs also applies to all phases of the study. 
Additionally, all participants with treatment-related visual AEs must be followed until resolution. 
The AE reporting period begins from the time the subject signs an ICF through End of Study 
visit. During the pre-screening period, only AEs resulting from study procedures will be 
reported. All participants with treatment-related AEs/AESIs/SAEs should be observed until 
resolution or stabilization of the event. Any SAE/AESI occurring after the reporting period must 
be promptly reported if a causal relationship to the study intervention(s) is suspected.  
Elective or previously scheduled hospitalizations for pre-existing conditions that have not 
worsened after initiation of treatment should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE. 

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All AEs should be recorded individually unless, in the opinion of the Investigator or designated 
physician, the AEs constitute components of a recognized condition, disease, or syndrome. In the 
latter case, the condition, disease, or syndrome should be reported rather than each individual 
sign or symptom. If a constellation of signs and/or symptoms cannot be medically characterized 
as a single diagnosis or syndrome at the time of reporting, each individual event should be 
recorded as an AE, AESI, or SAE, as appropriate, on the relevant form(s) (SAE/AESI Report 
Form and/or AE eCRF). If a diagnosis is subsequently established, it should be reported as 
follow-up information becomes available. If a diagnosis is determined after the reporting of the 
constellation of symptoms, the signs/symptoms should be updated to reflect the diagnosis. 
Each AE will be evaluated for duration, severity, seriousness, and causal relationship to each 
study intervention. The action taken with each study intervention and the outcome must also be 
recorded. 
All SAEs/AESIs, regardless of relationship to each study intervention, must be reported 
immediately (within 24 hours of awareness of event by Investigator) to the Sponsor contract 
research organization pharmacovigilance group. Initial SAE/AESI notification should be made 
according to the information provided in Table 2. 
Table 2: 
SAE Reporting Information 
SAEs should be reported in the eCRF 
Instructions found in the CRF Completion 
Guidelines document 
If the eCRF is not accessible 
A manual report is to be completed and sent to 
NorthAmerica_Medical@parexel.com or faxed 
to 1-781-434-5957 
If the eCRF, email, and fax are not available Contact the Parexel North America Safety Line 
via telephone at 1-781-434-5010 
An initial SAE/AESI Report may be sent without the Investigator’s signature but must be 
followed by a report signed by the Investigator within 48 hours of becoming aware of the event. 
Follow-up SAE/AESI reports must be submitted by the Investigator as new information becomes 
available within the same reporting timelines as initial reports. 
The Medical Monitors for this study may be contacted for advice or assistance. Contact details 
will be provided separately in a study contact list. 
10.18.6. 
 Severity of Adverse Events 
The severity of the AE will be graded by the Investigator according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (see 
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details). Only AEs not listed in the CTCAE should be graded with the ‘Equivalent To’ text 
in Table 3. 
Table 3: 
CTCAE (Version 5.0) AE Grading 
CTCAE Grade 
Equivalent To: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily activity 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated, although this 
could improve the overall well-being or symptoms of the 
participant. 
Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment 
or medical intervention is indicated in order to improve the 
overall well-being or symptoms; delaying the onset of 
treatment is not putting the survival of the participant at direct 
risk 
Grade 4 
Life-threatening/ 
disabling 
An immediate threat to life or leading to a permanent mental 
or physical condition that prevents work or performing normal 
daily activities; treatment or medical intervention is required 
in order to maintain survival 
Grade 5 
Death 
AE resulting in death 
Abbreviations: AE: adverse event, CTCAE: Common Terminology Criteria for Adverse Events. 
10.18.7. 
 Relationship of Adverse Events to Study Drug 
The Investigator will make a judgment regarding whether the AE was related to study drug, as 
outlined below: 
Definitely related: This category applies when, after careful medical consideration, there is 
almost no consideration of other causation. 
Probably related: There is a clinically plausible time sequence between onset of the AE and 
study drug administration. The AE is unlikely to be caused by a concurrent or underlying illness, 
other drugs, or procedures. If applicable, the AE follows a clinically consistent resolution pattern 
upon withdrawal of study drug. 
Possibly related: There is a clinically plausible time sequence between onset of the AE and 
study drug administration, but the AE could also have been caused by the concurrent or 
underlying illness, other drugs, or procedures. Information regarding study drug withdrawal may 
be lacking or unclear. “Possible” should be used when study drug administration is one of 
several biologically plausible causes of the AE. 
Unlikely related: The AE is most likely due to a cause not related to study intervention 
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Unrelated: Another cause of the AE is most plausible, and a clinically plausible temporal 
sequence is inconsistent with the onset of the AE and study intervention administration and/or a 
causal relationship is considered biologically implausible. 
For the purpose of regulatory reporting requirements, causal relationships of definite, probable, 
and possible will be considered treatment-related, while unlikely and unrelated will be 
considered not treatment-related. 
10.18.8. 
 Clinical Laboratory Adverse Events 
A clinical laboratory AE is any laboratory value that is deemed clinically significant by the 
Investigator and is accompanied by one of the following: 
• requires a medical intervention 
• requires a modification or interruption of study intervention 
• is accompanied by clinical symptoms 
Laboratory abnormalities that do not require medical intervention should not be recorded as AEs 
and will be captured and reported in the laboratory section of the clinical study report (CSR). If a 
medical intervention occurs, it should be recorded as a treatment with the abnormal laboratory 
finding as the AE (e.g., anemia with treatment required and blood transfusion recorded as a 
procedure; hyperglycemia with treatment required and change in insulin dose recorded on the 
concomitant medications eCRF). 
The Investigator should decide, based upon the AE criteria and the clinical condition of the 
participant, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. 
If, at the end of the treatment phase with the study intervention, there are pathological laboratory 
values that were not present at Baseline, further clinical or laboratory investigations should be 
performed until the values return to within reference range or until a plausible explanation (i.e., 
concomitant disease) is found for the pathologic laboratory values. 
10.19. 
Regulatory Aspects of Adverse Event Reporting 
The Investigator must promptly report to his or her Institutional Review Board (IRB) all 
unanticipated problems involving risks to participants.  
The Sponsor or designee will promptly notify FDA and all participating Investigators in a safety 
report of potential serious risks deriving from this clinical study or any other sources in 
accordance with 21 Code of Federal Regulations (CFR) 312.32. 

 
 
 
 
 
 
 
 
 
 
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11. 
STATISTICAL METHODS 
11.1. 
General Considerations 
All statistical analyses will be performed using Version 9.4 or later of Statistical Analysis 
Software (SAS®). 
Data summaries will use descriptive statistics (n, mean, standard deviation [SD], median, 
minimum, and maximum) for continuous variables, and frequency and percentage for categorical 
and ordinal variables. Where there are missing values, the number missing will be presented 
without a percentage. All data collected will be included in by-participant data listings. 
11.2. 
Determination of Sample Size 
Approximately 75 participants will be randomized and allocated in a 1:1:1 ratio to receive 
bitopertin 20 mg QD, bitopertin 60 mg QD, or placebo.  
The primary efficacy endpoint is percent change from baseline in whole blood metal-free PPIX 
level at Day 
 Means of percent change from baseline values will be compared for each 
bitopertin dose group and placebo. Assuming the difference in mean percent change in PPIX 
between bitopertin and placebo is 30% with a corresponding pooled SD of 35%, a sample size of 
23 participants per group provides 80% power to detect a difference between each bitopertin 
dose group and placebo using a two-sample t-test with a 2-sided alpha=0.05. Assuming an 8% 
dropout rate, a total of 75 participants will be randomized. 
The key secondary efficacy endpoint is total hours of sunlight exposure to skin on days with no 
pain from 1000 to 1800 hours (10:00 AM to 6:00 PM) over 
 days. Means of total hours of 
sunlight exposure on days with no pain will be compared for each bitopertin dose group and 
placebo. Assuming the difference in means between bitopertin and placebo is 55 hours with a 
corresponding pooled SD of 67 hours, a sample size of 25 participants per group provides 80% 
power to detect a difference between each bitopertin dose group and placebo using a two-sample 
t-test with a 2-sided alpha=0.05.  
Given the nature of this phase 2 study, the sample sizes were calculated without a multiplicity 
adjustment for two dose comparisons versus placebo; however, a sequential testing strategy will 
be employed to control for testing of the primary endpoint followed by the key secondary 
endpoint as described in Section 11.9.2. 
11.3. 
Analysis Sets 
 
11.3.1. 
Intent-to-Treat Analysis Set 
To be included in the Intent-to-Treat (ITT) analysis set, participants must be ≥18 years of age at 
baseline and be randomized to study drug. 
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All analyses of the ITT analysis set will be based on each participant’s randomized treatment. If 
a participant is randomized according to the incorrect stratification, the participant will be 
analyzed under the randomized treatment for the stratum recorded in the randomization system. 
All efficacy analyses will be based on the ITT analysis set. 
11.3.2. 
Full Analysis Set 
To be included in the Full Analysis Set (FAS), participants must be ≥18 years of age at baseline, 
be randomized and take at least one dose of double-blind study drug, and have a baseline 
measurement and at least one post baseline measurement of the primary efficacy variable or key 
secondary efficacy variable. 
All analyses of the FAS will be based on each participant’s randomized treatment. If a 
participant is randomized according to the incorrect stratification, the participant will be 
analyzed under the randomized treatment for the stratum recorded in the randomization system. 
The FAS will be used for a sensitivity analysis of the primary and key secondary efficacy 
endpoints. 
11.3.3. 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set will include all participants in the FAS who meet the study 
eligibility requirements and have no major protocol deviations that affect the validity of the 
efficacy measurements. The PP Analysis Set will be used for a sensitivity analysis of the primary 
and key secondary efficacy endpoints. The criteria for inclusion in the PP Analysis Set will be 
finalized prior to study unblinding and detailed in the Statistical Analysis Plan (SAP). 
11.3.4. 
Safety Analysis Set 
All participants who are randomized and take at least one dose of double-blind study drug will be 
included in the Safety Analysis Set. Safety analyses will be based on the study drug that was 
dispensed to each participant.  
11.4. 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics for the Safety Analysis Set as well as ITT, FAS 
and PP Analysis Sets will be summarized overall and by treatment group using descriptive 
statistics. Demographic data will include but are not limited to sex, age (years), race/ethnicity, 
weight (kg), height (cm), and calculated BMI. Baseline characteristics will include all baseline 
PPIX measurements. 
11.5. 
Participant Disposition 
Frequencies and percentages will be displayed for the number of participants who: screened, 
failed screening, enrolled, were randomized, were treated, completed treatment, completed the 
study, discontinued treatment early, and withdrew from the study. The number and percentage of 
participants in each analysis set (ITT, FAS, PP, and Safety Analysis Sets) will be summarized. 

 
 
 
 
 
 
 
 
 
 
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11.6. 
Study Treatment Compliance 
Compliance rates during the treatment period will be derived using the following formula: 
100*((Total number of tablets dispensed – Total number of tablets returned)/ 
(Expected number of tablets to be taken based on whether the participant is on full or half 
dose)). 
If a participant is lost to follow-up and does not return all unused tablets, it will be assumed that 
the participant did not take any tablets since the last visit date. 
Compliance rates will be presented for the Safety Analysis Set using summary statistics and 
percentage for the frequency distributions (0-<20%, 20-<40%, 40-<60%, 60-<80%, 80-<100%, 
100-<120%, and ≥120%) by treatment group and overall. Duration of treatment (in weeks) will 
be defined as: 
(date of last dose of study drug - date of first dose of study drug + 1)/7 
Duration of treatment will also be summarized by treatment group for the Safety Analysis Set. 
11.7. 
Efficacy Analysis 
All efficacy analyses will be performed based on the ITT. In addition, the primary and key 
secondary endpoint analyses will be conducted using the FAS and PP Analysis Sets. 
 
11.7.1. 
Primary Efficacy Analysis 
11.7.1.1. Primary Efficacy Endpoint: Percent Change from Baseline Metal-Free PPIX 
For the primary endpoint of percent change from baseline in whole blood metal-free PPIX level, 
a mixed model repeated measures (MMRM) analysis of covariance (ANCOVA) model will be 
fitted using all data as observed. The dependent variable is the percent change from baseline 
whole blood metal-free PPIX level for all post-baseline assessments for each participant. The 
model will include fixed effects for treatment, sunlight exposure time to prodromal symptom 
randomization stratification factor , baseline metal-free PPIX level, visit (Days 
 
and 
 and visit-by-treatment interaction and a random effect for the participant. The mixed 
model will utilize restricted maximum likelihood estimation with the Kenward-Roger method 
used to compute the denominator degrees of freedom for tests of fixed effects. The model will 
assume an unstructured covariance matrix. If the model does not converge under the unstructured 
covariance matrix, alternative covariance structures will be used until convergence is reached 
based on an ordered list of pre-specified covariance structures which will be documented in the 
SAP. If a structured covariance is used, then a robust sandwich estimator will be utilized for 
estimating the variance of the treatment effect estimate. 
The primary efficacy analysis will be based on comparisons of bitopertin and placebo at the 
Day 
 visit. From the MMRM model, the Day 
 pairwise differences between least square 
(LS) means of bitopertin treatment groups and placebo will be presented along with the 
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corresponding 95% CIs and 2-sided p-values. This analysis will be repeated for the FAS and PP 
Analysis Set. 
The primary estimand for this study is the difference in LS means of bitopertin and placebo with 
respect to percent change from baseline in whole blood metal-free PPIX level at Day 
 based 
on the primary endpoint MMRM model fitted to the ITT. There will be no adjustments made for 
the use of prohibited therapies or other intercurrent events. The p-values associated with the 
primary estimand will be used to test the formal hypotheses of this study, that mean percent 
change from baseline to Day 
 whole blood metal-free PPIX level for each dose of bitopertin 
is different from that of placebo. All other p-values to be displayed will be considered descriptive 
and will not be used for formal hypothesis testing. 
Since this endpoint may be skewed, a Kruskal-Wallis test will be used to test the treatment effect 
as a sensitivity analysis. The 2-sided p-values will be presented. The Hodges–Lehmann estimates 
of the median differences between the bitopertin treatment groups and placebo, and their 95% 
CIs, will also be presented. 
11.7.2. 
Key Secondary Efficacy Analysis 
The key secondary endpoint for this study is total hours of sunlight exposure on days with no 
pain from 1000 to 1800 hours (10:00 AM to 6:00 PM) summed over the entire treatment period 
from randomization to Day 
 An ANOVA model will be used for the ITT with effects for 
randomized treatment group and  the sunlight exposure time to prodromal symptom 
randomization stratification factor. Pairwise differences between LS means of bitopertin 
treatment groups and placebo will be presented along with the corresponding 95% CIs and 
2--sided p-values. This analysis will be repeated for the FAS and PP analysis set. 
Since a highly skewed distribution for this endpoint is expected, a Kruskal-Wallis test will be 
used to test the treatment effect as a sensitivity analysis. The 2-sided p-values will be presented. 
The Hodges–Lehmann estimates of the median differences between the bitopertin treatment 
groups and placebo, and their 95% CIs will also be presented. 
11.7.3. 
Secondary Efficacy Analyses 
Two-week averages of daily sunlight exposure time (minutes) prior to first prodromal symptom 
(e.g., burning, tingling, itching, or stinging) associated with sunlight exposure between 1 hour 
post-sunrise and 1 hour pre-sunset will be calculated for the 2 weeks immediately prior to 
randomization (baseline) and for the treatment period from randomization to Day 
 visit for 
each participant (see Appendix 4, Appendix 5). An MMRM ANCOVA model for the change 
from baseline will be fitted for this endpoint with fixed effects for randomized treatment, 
timepoint (2-week intervals), timepoint-by-treatment interaction,  sunlight exposure time to 
prodromal symptom randomization stratification factor and the corresponding baseline as a 
covariate. An unstructured within -participant covariance structure will be specified as the first 
choice. If the model converges, the Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. If the model does not converge under the unstructured 
covariance matrix, alternative covariance structures will be used until convergence is reached 
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based on an ordered list of pre-specified covariance structures which will be documented in the 
SAP. If a structured covariance is used, then a robust sandwich estimator will be utilized for 
estimating the variance of the treatment effect estimate. From the model, the differences between 
LS means of bitopertin groups and placebo will be presented for the 2-week interval ending in 
Day 
 along with the corresponding 95% CIs and 2-sided p-values. 
Percent Change from baseline in total PPIX concentration and change from baseline in plasma 
PPIX concentration will be analyzed in the same manner as the primary endpoint. 
Pain intensity of phototoxic reactions is captured daily according to a Likert scale (0-10) on the 
Sun Exposure Diary (Appendix 4).  Pain intensity will be analyzed as a total severity score 
whereby all as-observed pain scores will be summed over the entire treatment period from 
randomization to Day 
  Additionally, the maximum pain intensity post day 
 through end of 
study will be summarized.  An ANOVA model will be used for the ITT population with effects 
for randomized treatment group and the sunlight exposure time to prodromal symptom 
randomization stratification factor. Pairwise differences between LS means of bitopertin 
treatment groups and placebo will be presented along with the corresponding 95% CIs and 2-
sided p-values. This analysis will be repeated for the FAS and PP analysis set. 
11.8. 
Safety Analyses 
Safety data will include AEs, physical examination results, vital signs, 
, and 
clinical laboratory measurements. Observed data will be listed by participant and summarized 
using descriptive statistics by treatment group. 
11.8.1. 
Clinical Laboratory Tests 
Clinical laboratory parameters will be measured at baseline and post-baseline visits. Each 
continuous laboratory variable will be summarized as changes from baseline by treatment group. 
Laboratory data will also be classified as low, normal, or high relative to the parameter’s 
reference range. Laboratory abnormalities for each treatment group will be summarized using 
shift tables. 
11.8.2. 
Adverse Events 
AEs will be mapped to preferred term and body system using the Medical Dictionary for 
Regulatory Activities (MedDRA). 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. The 
number and percentage of participants reporting TEAEs will be summarized for each treatment 
group by MedDRA system organ class and preferred term, by severity, and by relationship to 
study drug (drug-related TEAEs versus TEAEs not related to study drug). Drug-related TEAEs 
will be considered those to be at least possibly related to study drug based on the Investigator’s 
assessment. The number and percentage of participants reporting SAEs, and the number and 
percentage of participants reporting AEs leading to study drug discontinuation will also be 
summarized for each treatment group by MedDRA system organ class and preferred term. 
11.8.3. 
Physical Examination and Vital Signs 
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The number and percentage of participants with physical examination abnormalities at each visit 
will be summarized and presented for each body system by treatment group. A listing of 
abnormalities will also be provided. 
Vital signs data will be summarized as changes from baseline and will be classified as low, 
normal, or high based on reference ranges pre-specified in the SAP. Vital sign abnormalities for 
each treatment will be summarized using shift tables. 
11.8.4. 
Prior Medications, Concomitant Medications and Procedures 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD), and concomitant medical procedures will be coded using MedDRA. The incidence 
of prior medications, concomitant medications, and concomitant medical procedures will be 
summarized using frequencies and percentages. 
11.8.5. 
Pharmacokinetics 
Trough plasma study drug levels as well as PK parameters will be listed and summarized by dose 
group using descriptive statistics. 
11.9. 
Other Statistical Issues 
11.9.1. 
Significance Levels 
All tests will be 2-tailed, using an overall 0.05 level of significance. All CIs will be 2-sided, 95% 
CIs. 
11.9.2. 
Multiple Comparisons/Multiplicity 
Given the nature of this phase 2 study, no adjustment for multiple comparisons of the primary 
endpoint will be made to account for multiple dose comparisons (i.e., there are two bitopertin 
groups being tested vs. placebo). Each bitopertin group comparison versus placebo will be tested 
using an α = 0.05. 
If and only if the comparison of the primary endpoint for a bitopertin group and placebo meets 
statistical significance at α = 0.05, will the key secondary endpoint be tested for that same 
bitopertin group and placebo.  In this way, the testing from the primary analysis to the secondary 
follows a hierarchical sequential design. 
All p-values to be presented for the rest of the secondary endpoints will be considered 
descriptive.  
11.9.3. 
Missing Data 
Participants who discontinue the study prematurely will not be replaced but will be encouraged 
to remain in the study and follow the schedule of assessments even if they meet study drug 
discontinuation criteria. To the extent possible, attempts will be made to minimize the amount of 
missing data through measures planned in the study conduct. However, if missing data are 
present, they will be handled as follows, for the primary efficacy endpoint: 

 
 
 
 
 
 
 
 
 
 
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For the primary analysis of whole blood metal-free PPIX levels, inference will be performed in 
three steps. In step 1, missing data will be imputed with multiple imputation (MI) using SAS 
PROC MI. The MCMC option in PROC MI will be used for imputing the percent change from 
baseline in whole blood metal-free PPIX levels over time, including baseline as a covariate in the 
imputation model. Since classification variables such as treatment group cannot be included in 
the MCMC statement directly, a BY statement will be included in the PROC MI code to provide 
separate imputation models for each treatment group. If convergence is not attained, the 
regression option in PROC MI will be utilized for imputation. The output from PROC MI will be 
a data set containing multiple repetitions of the original data set, along with the newly imputed 
values. A minimum of 30 repetitions will be performed. 
In step 2 of the primary analysis, each MI repetition will be analyzed separately to test the 
equality of the overall percent change from baseline means of the treatment groups and the 
placebo group. In step 3, the results from each separate analysis in step 2 will be pooled using 
SAS PROC MIANALYZE. The pooled results will contain the estimate for the mean difference 
between bitopertin treatment groups and placebo for the percent change from baseline in whole 
blood metal-free PPIX levels at Day 121, as well as the corresponding standard error, 95% CI, 
and p-value.  
If the primary analysis renders a significant treatment difference, a tipping point analysis will be 
performed in order to examine the sensitivity of inferences to departures from the missing at 
random (MAR) assumption. Details will be provided in the SAP and a summary is provided 
below: 
As missing values following early discontinuations may not be consistent with a MAR 
assumption, a sensitivity analysis using multiple imputation under a missing not at random 
(MNAR) assumption will be performed searching for a tipping point that reverses the primary 
analysis conclusion. The imputed values will be made worse by adding a delta defined as k times 
the treatment difference between the bitopertin and placebo values obtained from the MI MAR 
analysis, where k is a shift parameter that is incremented in order to identify the point at which 
the primary analysis result becomes non-significant (the tipping point). Consideration will then 
be given to how plausible the imputed values are at the tipping point. If not plausible, then the 
conclusion for the primary analysis under the MAR assumption is supported. 
Given the key secondary endpoint is total hours of sunlight exposure on days with no pain from 
1000 to 1800 hours (10:00 AM to 6:00 PM) summed over the entire treatment period from 
randomization to Day 121, participants with missing data for any given day and for any reason 
(including premature discontinuation) will be assumed to have no sunlight exposure (i.e., 0 
hours).  This methodology ensures missing data is treated conservatively. 
 

 
 
 
 
 
 
 
 
 
 
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12. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
12.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
The ethical principles that have their origin in the Declaration of Helsinki, and that are consistent 
with International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH), all applicable local Good Clinical Practice (GCP) 
guidelines, and the applicable regulatory requirement(s).  
Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB by the Investigator and 
reviewed and approved by the IRB before the study is initiated. 
• Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/ IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB, and all other applicable local regulations. 
• Conduct the study in compliance with the protocol. Any deviation from the protocol must 
be documented. 
12.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 

 
 
 
 
 
 
 
 
 
 
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12.3. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her healthcare proxy and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their healthcare 
proxy will be required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. A participant who is rescreened is not required to sign another ICF if 
the rescreening occurs within 30 days from the previous ICF signature date. 
A copy of the ICF(s) must be provided to the participant or the participant’s healthcare proxy. 
12.4. 
Participant Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
The Investigator and Investigator’s staff shall maintain the confidentiality of all participant 
records. 
12.5. 
Dissemination of Clinical Study Data 
The Sponsor will comply with current regulatory requirements for disclosure and submission of 
study results. The Sponsor’s policy on publication of study results is described in Section 13. 
12.6. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible 

 
 
 
 
 
 
 
 
 
 
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for verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The Sponsor assumes accountability for trial-related duties and functions delegated to other 
individuals (e.g., contract research organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for at least 2 years after the last marketing application approval 
or 2 years after formal discontinuation of the clinical development of the investigational product 
or according to applicable regulatory requirement(s). If the Investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. The Sponsor must be notified immediately by telephone or e-mail and 
the notification confirmed in writing if a custodial change occurs. 
12.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Any electronic study data are to be entered into a secure, validated data processing system and a 
backup maintained. Any changes to electronic study data will be documented. 

 
 
 
 
 
 
 
 
 
 
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Definition of what constitutes source data can be found in ICH guidance for industry E6 Good 
Clinical Practice: Consolidated Guidance. 
12.8. 
Study and Site Opening and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor designee reserves the right to close a study site or terminate the study at any time 
for any reason (e.g., as necessary for participant safety) at the sole discretion of the Sponsor. 
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed. 
 Reasons for the early closure of a study site by the Sponsor may include but are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the Investigator. 
• Discontinuation of further study drug development. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
12.9. 
COVID-19 Mitigation Plan 
The protocol includes the following adaptations to minimize risk while prioritizing the overall 
well-being and best interests of all involved in the trial. This protocol was written considering the 
impact of COVID-19 on trial participants, site staff and Sponsor staff. With these priorities in 
mind, these protocol design modifications have been made, but will still permit assessment of 
safety and efficacy of bitopertin: 
• the number of study visits has been minimized to align with the trial endpoints 
• some visits may be remote, with conduct of the study procedures at the subject’s location 
In addition to the above items included in the protocol, ongoing risk assessments and monitoring 
of the COVID-19 situation will be conducted by the Sponsor with input from the local 
investigator at a site and country (if applicable) level. These ongoing assessments include 
changes to any of the following: 
• Potential impact on trial participants 

 
 
 
 
 
 
 
 
 
 
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• Potential impact on trial site staff 
• Potential impact on Sponsor/CRO staff conducting site monitoring and central review of 
data 
Other mitigation plans, as appropriate, may be instituted. 
12.10. 
Future Use of Stored Specimens and Data 
Blood and urine samples may be stored and used for future research to develop methods, assays, 
prognostics, and/or companion diagnostics related to EPP and related conditions, and/or to 
further understand the mechanism of action or safety of bitopertin. 
Samples may be stored for a maximum of 10 years following study closure. The collection, 
labelling, storage, and shipment of samples will be detailed in the Laboratory Manual. 

 
 
 
 
 
 
 
 
 
 
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13. 
PUBLICATION POLICY 
All information regarding bitopertin supplied by the Sponsor to the Investigator or generated as a 
result of any clinical studies is privileged and confidential information belonging to the Sponsor. 
The Investigator agrees to use Sponsor’s confidential information solely to accomplish the study 
and will not use such information for any other purposes without the prior written consent of 
Disc Medicine. It is understood that there is an obligation to provide the Sponsor with complete 
and accurate data obtained during the study. The information obtained from the clinical study 
will be used towards the development of bitopertin and may be disclosed by Disc Medicine to 
regulatory authority(ies), other investigators, corporate partners, or consultants as required. 
 

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14. 
APPENDICES 
APPENDIX 1. 
Strong CYP3A4 Inhibitors and Inducers 
 
Strong Inhibitors 
Strong Inducers 
Atazanavir 
Apalutamide 
Ceritinib 
Carbamazepine 
Clarithromycin 
Enzalutamide 
Cobicistat and cobicistat-containing coformulations 
Fosphenytoin 
Darunavir 
Lumacaftor 
Idelalisib 
Lumacaftor-ivacaftor 
Indinavir 
Mitotane 
Itraconazole 
Phenobarbital 
Ketoconazole 
Phenytoin 
Levoketoconazole 
Primidone 
Lonafarnib 
Rifampin (rifampicin) 
Lopinavir 
 
Mifepristone 
 
Nefazodone 
 
Nelfinavir 
 
Ombitasvir-paritaprevir-ritonavir 
 
Ombitasvir-paritaprevir-ritonavir plus dasabuvir 
 
Posaconazole 
 
Ritonavir and ritonavir-containing coformulations 
 
Saquinavir 
 
Telithromycin 
 
Tucatinib 
 
Voriconazole 
 

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APPENDIX 2. 
Schedule of Assessments 
Procedure 
Screening 
Baseline 
Study Visitsa 
 
 
 
 
 
 
 
 
 
OL visits 
q 8 wks 
Visit Window 
- 
 
 
 
 
 
 
 
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Complete physical examination 
X 
 
 
 
 
 
 
X 
 
Targeted neurological 
examinationb 
X 
 
 
 
X 
 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and heightc 
X 
 
 
 
 
 
 
X 
 
Serum or urine pregnancy testd 
X 
X 
 
 
 
 
 
 
 
Genotyping (unless documented in 
medical history) 
Anytime during Screening or Treatment Period 
 
 
Randomizatione 
Xe 
Xe 
 
 
 
 
 
 
 
Pharmacokinetic samplingf 
 
 
 
 
 
 
 
 
 
Blood chemistryg 
X 
X 
 
X 
X 
X 
X 
X 
X 
Hematologyh 
X 
X 
 
X 
X 
X 
X 
X 
X 
Porphyrinsi 
X 
X 
 
X 
X 
X 
X 
X 
X 
Serology/Virologyj 
X 
 
 
 
 
 
 
 
 
Serum iron, TIBC, TSAT, ferritin 
 
X 
 
 
X 
 
X 
X 
X 
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Procedure 
Screening 
Baseline 
Study Visitsa 
 
 
 
 
 
 
 
 
 
(EOS) 
OL visits 
q 8 wks 
Visit Window 
- 
 
 
 
 
 
 
 
(±3) 
Urinalysis 
 
X 
 
 
X 
 
X 
X 
 
Light dosimeterk 
X 
Daily  
Daily sun exposure diaryk 
X 
Daily 
‘Sun Exposure Challenge 
Question’ – (time to prodrome)l  
X 
Weekly 
PRO questionnairesm 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
Adverse eventsn 
X 
X 
 
X 
X 
X 
X 
X 
X 
Study drug 
 
Daily dosing of study drug 
Xo 
X 
Study drug diaryp 
 
X 
X 
X 
X 
X 
X 
X 
X 
Exit interviewq 
 
 
 
 
 
 
 
X 
 
HBV = Hepatitis B virus; HCV = Hepatitis C virus; HIV = Human immunodeficiency virus; OL=open-label; PRO = Patient reported outcomes. 
Footnotes: 
a. 
After Day 1, all study visits may occur remotely with the exception of the Day 
 and EOS visits. 
b. 
A targeted neurologic exam that includes mental status, optical and eye movement cranial nerves (CNII, CNIII, CNIV, CNVI), motor function, gait, stance, and 
coordination will be performed.  
c. 
Height is only measured at Screening. 
d. 
For females of child-bearing potential, a pregnancy test must be performed. The preferred method is a urine screen, but a serum test may be performed if urine is not 
feasible. If the urine test is positive, a serum test must be performed to confirm. 
e. 
Participants randomized to treatment group upon confirmation of eligibility Day -1 or Day 1. 
f. 
Day : Pre-dose and 2±0.25, 4±0.25, 6±0.25 hours post-dose. Day : 24±1 hours post Day 1 dose, but prior to Day  dosing. Day 
 Pre-dose and 4±0.5 hours 
post-dose. 
g. 
Chemistry includes sodium, potassium, carbon dioxide (CO2), chloride, blood urea nitrogen (BUN), creatinine, glucose, calcium, alkaline phosphatase, total bilirubin, 
direct bilirubin, AST, ALT, GGT, and albumin. 
CCI
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C
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C
C
C
C
C
C
C
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h. 
Hematology parameters include a complete white blood cell count (WBC) with differential, red blood cell count (RBC), hemoglobin, hematocrit, platelet count, mean 
corpuscular hemoglobin (MCV), red cell distribution width, mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular hemoglobin (MCH). Special 
hematology parameters include reticulocyte (absolute) and reticulocyte %, and CHr. 
i. 
Porphyrins, including metal-free whole blood PPIX, metal-free erythrocyte PPIX, whole blood total PPIX, and plasma total PPIX. 
j. 
Includes hepatitis B surface antigen (HBV), hepatitis C virus (HBC), and human immunodeficiency virus (HIV). Results must be available before the first dose. 
k. 
Light dosimeter and daily sun exposure diary are to be completed for 2 weeks during Screening and daily during the double-blind treatment phase. Light dosimeter is 
optional during open-label phase.  
l. 
‘Sun Exposure Challenge Question’ (time to prodrome) is to be completed twice during Screening, if possible, and weekly thereafter (Appendix 5). 
m. Assessment tools: 
 
Appendix 6). 
n. 
Only SAEs and AEs related to study procedures are to be collected prior to first dose of study drug. AEs may be assessed by phone. 
o. 
Dosing may continue if participant continues on open-label study drug. 
p. 
A study drug diary will be dispensed to the subject at baseline. Subjects will bring their diary with them to each study visit.  Diary information will be reviewed and/or 
collected by the study team during study visits. 
q. 
Subjects who complete the double-blind treatment period will be invited to participate in an optional exit interview after the last double-blind period dose and before the 
first open label period dose. 
 
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APPENDIX 3. 
Clinical Laboratory Parameters 
Refer to Schedule of Assessments (Appendix 2) for sampling times. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 4. 
Sun Exposure Diary 
 
 
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APPENDIX 5. 
Sun Exposure Challenge Question  
 
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APPENDIX 6. 
 
 
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15. 
REFERENCES 
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Gonzalez FJ, Klaassen CD, Ma X. The essential role of the transporter ABCG2 in the 
pathophysiology of erythropoietic protoporphyria. Sci Adv. 2019 Sep;5(9):eaaw6127. 
2. Balwani M, Naik H, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, Phillips JD, 
Overbey JR, Wang B, Singal AK, Liu LU, Desnick RJ. Clinical, Biochemical, and 
Genetic Characterization of North American Patients with Erythropoietic Protoporphyria 
and X-linked Protoporphyria. JAMA Dermatol. 2017 Aug 01;153(8):789-796. 
3. Snast I, Kaftory R, Sherman S, Edel Y, Hodak E, Levi A, Lapidoth M. Acquired 
erythropoietic protoporphyria: A systematic review of the literature. Photodermatol 
Photoimmunol Photomed. 2020 Jan;36(1):29-33. 
4. Sachar M et al. Protoporphyrin IX: the Good, the Bad, and the Ugly. J Pharmacol Exp 
Ther. 2016;356(2):267-75. 
5. Phillips JD et al. Heme biosynthesis and the porphyrias. Mol Genet Metab. 
2019;128(3):164–177. 
6. Wulf HC, Nissen CV, Philipsen PA. Inactivation of protoporphyrin IX in erythrocytes in 
patients with erythropoietic protoporphyria: A new treatment modality. Photodiagnosis 
Photodyn Ther. 2020 Mar;29:101582 
7. Heerfordt IM et al. Patients with Erythropoietic Protoporphyria Have Reduced 
Protoporphyrin IX from Early in Pregnancy. Br J Dermatol. 2017;177:38-40. 
8. Cui, L., Hung, H.M., and Wang, S.J. “Modification of sample size in group sequential 
clinical trials.” Biometrics 55, pp. 853-857 (1999). 
9. Lawrence, J. and Hung, HMJ. Estimation and Confidence Intervals after Adjusting the 
Maximum Information. Biometrical Journal, 2003; 45 (2): 143-152.