An Open-Label, Phase 2, Pilot Study Investigating the Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Oral Treatment With the BTK Inhibitor PRN1008 in Patients With Newly Diagnosed or Relapsing Pemphigus Vulgaris
Phase: PHASE2
Conditions: Pemphigus Vulgaris
Sponsor: Principia Biopharma, a Sanofi Company

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005 Version 7.0 
Principia Biopharma Australia Pty Ltd. 
19 March 2019 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
An Open-Label, Phase 2, Pilot Study Investigating the Safety, 
Clinical Activity, Pharmacokinetics, and Pharmacodynamics of 
Oral Treatment with the BTK Inhibitor PRN1008 in Patients with 
Newly Diagnosed or Relapsing Pemphigus Vulgaris 
Protocol No.: 
PRN1008-005 
Development Phase: 
Phase 2 
Investigational Product: 
PRN1008 
No.: (IND/CTD/CTN) 
EudraCT No. 2015-003564-37 
Protocol Date: 
19 March 2019, Version 7.0 
Sponsor: 
Principia Biopharma Australia Pty Ltd 
Level 29, 525 Collins Street 
Melbourne, VIC 3000 
Australia 
Principia Biopharma Inc. 
220 East Grand Avenue 
South San Francisco 
CA 94080 
USA 
Sponsor's Medical 
 
Monitor:  
CONFIDENTIALITY STATEMENT 
This document contains confidential information. It is provided for the sole use of the principal 
investigator, subinvestigators, staff, institutional review boards, human research ethics 
committees, and regulatory authorities. By accepting this document, you agree to maintain the 
information as confidential and to use it only for the purpose of conducting or reviewing the 
study protocol. 
NCT02704429

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
Page 2 of 93 
PROTOCOL SIGNATURE PAGE 
Product Name: 
PRN1008 
Version Number: 
7.0 
Release Date:  
19 March 2019 
 
The undersigned confirms that this Protocol is accurate. 
 
 
Signed: 
 

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
Page 3 of 93 
PROTOCOL ACCEPTANCE PAGE 
PROTOCOL NO.:  
PRN1008-005 
 
PROTOCOL TITLE: 
An Open-Label, Phase 2, Pilot Study Investigating the Safety, 
Clinical Activity, Pharmacokinetics, and Pharmacodynamics of 
Oral Treatment with the BTK Inhibitor PRN1008 in Patients with 
Newly Diagnosed or Relapsing Pemphigus Vulgaris 
 
 
PROTOCOL DATE: 
Amendment 7, 19 March 2019 
 
By signing this protocol acceptance page, I confirm that I have read, understood, and agree to 
conduct the study in accordance with the current protocol. 
 
 
 
 
Principal Investigator Name (Printed) 
 
 
 
 
Principal Investigator Signature 
 
Date 
 

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
Page 4 of 93 
Please return original Protocol Acceptance to Principia Biopharma Australia Pty Ltd. or 
designee. Please retain a copy for your study files. 
This study is to be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, The International Conference on Harmonization (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Directive 2001/20/EC and 2005/28/EC, and the 
Title 21 Code of Federal Regulations Parts 50, 54, 56, 312, and 314, where appropriate. 
The study protocol and any amendments are to be reviewed by a Human Research Ethics 
Committee (HREC) before implementation. 
Written informed consent is to be obtained from each study participant prior to the conduct of 
any procedures which exceed or differ from standard practice at the study site. 
Confidential information contained in this document will not be used for any purpose other than 
the evaluation or conduct of the clinical investigation without prior written consent of Principia 
Biopharma Australia Pty Ltd. 

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
PROTOCOL ACCEPTANCE PAGE ..............................................................................................3 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF APPENDICES ..................................................................................................................9 
TABLE OF TABLES ......................................................................................................................9 
TABLE OF FIGURES .....................................................................................................................9 
STUDY SYNOPSIS ......................................................................................................................10 
GLOSSARY OF ABBREVIATIONS AND TERMS ...................................................................20 
1 
BACKGROUND AND SCIENTIFIC RATIONALE FOR THE TREATMENT OF 
PEMPHIGUS WITH PRN1008 .........................................................................................22 
1.1 
Background ............................................................................................................22 
1.2 
Rationale for PRN1008 Treatment in Pemphigus .................................................22 
1.3 
Summary of PRN1008 Animal Toxicity Studies ...................................................23 
1.3.1 
13-week GLP Toxicology .......................................................................23 
1.3.2 
6 and 9-month GLP Toxicology .............................................................24 
1.3.3 
Reproductive and Fertility Studies..........................................................24 
1.4 
Summary of PRN1008 Clinical Experience ..........................................................25 
1.4.1 
Experience in Healthy Volunteer Phase 1 Studies ..................................25 
1.4.2 
Experience in Pemphigus Patients in Study PRN1008-005 ...................27 
1.5 
Clinical Pharmacology of PRN1008 ......................................................................29 
1.5.1 
Pharmacokinetics in Healthy Volunteers ................................................29 
1.5.2 
Pharmacokinetics and BTK Occupancy in Pemphigus Patients .............29 
1.5.3 
BTK Occupancy in Patients with Pemphigus .........................................30 
2 
RATIONALE AND JUSTIFICATION FOR THE STUDY AND THE STUDY 
DESIGN .............................................................................................................................32 
2.1 
Rationale for the Study Design ..............................................................................32 
2.2 
Selection of the Starting Clinical Dose of PRN1008 in Pemphigus ......................32 
2.3 
Overall Risk/Benefit Assessment ..........................................................................33 
2.4 
Drug-Drug Interaction Potential ............................................................................33 
3 
OBJECTIVES OF THE STUDY .......................................................................................35 
3.1 
Primary Objectives .................................................................................................35 
3.2 
Secondary Objective ..............................................................................................35 
3.3 
Exploratory Objective ............................................................................................35 
4 
INVESTIGATIONAL PLAN ............................................................................................36 
4.1 
Overall Study Design and Plan ..............................................................................36 
4.2 
Number of Participants ..........................................................................................36 
4.3 
Study Duration and Duration of Subject Participation ..........................................36 

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4.4 
End of Study Definition .........................................................................................36 
4.5 
PRN1008 Administration.......................................................................................37 
4.5.1 
Rationale for PRN1008 Dosage Selection ..............................................37 
4.5.2 
Concomitant Medications .......................................................................37 
4.6 
PRN1008 Intrapatient Dose Adjustment ...............................................................38 
5 
PROTOCOL DEVIATIONS .............................................................................................40 
6 
STUDY POPULATION ....................................................................................................41 
6.1 
Inclusion Criteria (Part A and Part B unless noted below) ....................................41 
6.2 
Exclusion Criteria ..................................................................................................41 
6.3 
Prior and Concomitant Therapy .............................................................................43 
6.3.1 
Prior Therapy ..........................................................................................43 
6.3.2 
Concomitant Therapy..............................................................................44 
7 
LIST OF SCREENING ASSESSMENTS .........................................................................45 
8 
LIST OF STUDY ASSESSMENTS ..................................................................................46 
8.1 
Clinical Assessments Part A and B ........................................................................46 
8.2 
Laboratory Assessments Part A and B ...................................................................46 
8.3 
Safety and Tolerability Assessments .....................................................................47 
9 
STUDY TREATMENT .....................................................................................................48 
10 
IDENTITY OF INVESTIGATIONAL PRODUCT ..........................................................49 
10.1 
Formulation ............................................................................................................49 
10.2 
Packaging ...............................................................................................................49 
10.3 
Storage and Handling .............................................................................................49 
10.4 
Drug Accountability...............................................................................................49 
10.5 
Destruction of Investigational Product ..................................................................50 
11 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................51 
11.1 
Primary Outcome Measures ...................................................................................51 
11.1.1 
Safety ......................................................................................................51 
11.1.2 
Efficacy ...................................................................................................51 
11.2 
Secondary Outcome Measures ...............................................................................51 
11.3 
PK/PD Outcome Measures ....................................................................................52 
11.3.1 
PK Outcome Measures ...........................................................................52 
11.3.2 
PD Outcome Measures ...........................................................................52 
11.3.3 
Exploratory PK/PD Analysis ..................................................................52 
11.4 
Determination of Sample Size ...............................................................................52 
11.5 
Analysis Populations ..............................................................................................52 
11.5.1 
Screening Population ..............................................................................52 
11.5.2 
Safety Analysis Population .....................................................................52 
11.5.3 
Efficacy Analysis Population ..................................................................52 

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Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
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11.5.4 
Pharmacokinetic Analysis Population ....................................................53 
11.6 
Randomization and Blinding Procedures ...............................................................53 
11.7 
Subject Numbers and Treatment Assignments ......................................................53 
11.8 
Subject Disposition, Subject Replacement, and Demographics and Baseline 
Characteristics ........................................................................................................53 
11.8.1 
Disposition ..............................................................................................53 
11.8.2 
Replacement of Subjects .........................................................................53 
11.8.3 
Demographics and Baseline Characteristics ...........................................53 
11.9 
Efficacy Analysis ...................................................................................................54 
11.9.1 
Subject Response and Disease Progression ............................................54 
11.10 Safety Analysis ......................................................................................................54 
11.10.1 Adverse Events .......................................................................................54 
11.10.2 Clinical Laboratory Tests ........................................................................54 
11.10.3 Vital Signs ...............................................................................................55 
11.10.4 Concomitant Medications .......................................................................55 
11.11 Pharmacokinetics/Pharmacodynamics Analyses ...................................................55 
11.11.1 Missing PK/PD Values ...........................................................................55 
11.12 Statistical and Analytical Methods ........................................................................55 
11.12.1 Descriptive Summaries and Inference ....................................................55 
11.12.2 Exploratory Analyses ..............................................................................56 
11.12.3 Interim Analysis ......................................................................................56 
12 
SAFETY AND TOXICITY MANAGEMENT .................................................................57 
12.1 
Safety Monitoring Committee ...............................................................................57 
12.2 
Adverse Event Collection Period ...........................................................................57 
12.3 
Clinical Adverse Events .........................................................................................57 
12.4 
Adverse Event Intensity Grading ...........................................................................59 
12.5 
Adverse Event Relationship to Study Drug ...........................................................59 
12.6 
Treatment and Follow-Up of Adverse Events .......................................................59 
12.7 
Laboratory and ECG Abnormalities ......................................................................60 
12.7.1 
Follow-Up of Abnormal Laboratory Test Values ...................................60 
12.8 
Serious Adverse Event (SAE) Reporting ...............................................................60 
12.8.1 
SAE Definitions ......................................................................................60 
12.8.2 
SAE Reporting ........................................................................................61 
12.8.3 
Other Safety Findings Requiring Expedited Reporting ..........................62 
12.9 
Pregnancy ...............................................................................................................62 
13 
DATA QUALITY ASSURANCE .....................................................................................63 
13.1 
Assignment of Preferred Terms and Original Terminology ..................................63 
14 
ETHICAL ASPECTS ........................................................................................................64 

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14.1 
Local Regulations/Declaration of Helsinki ............................................................64 
14.2 
Subject Informed Consent......................................................................................64 
14.3 
Institutional Review Board Review .......................................................................64 
14.4 
Conditions for Modifying the Protocol ..................................................................65 
14.5 
Conditions for Terminating the Study ...................................................................65 
14.6 
Financial Disclosure ...............................................................................................65 
15 
STUDY DOCUMENTATION, MONITORING, CASE REPORT FORMS, AND 
RECORD RETENTION REQUIREMENTS ....................................................................66 
15.1 
Investigator's File/Retention of Records ................................................................66 
15.2 
Source Documents and Background Data .............................................................66 
15.3 
Audits and Inspections ...........................................................................................67 
15.4 
Case Report Forms .................................................................................................67 
15.5 
Study Monitoring ...................................................................................................67 
15.6 
Confidentiality of Clinical Trial Documents and Participants' Medical 
Records ..................................................................................................................67 
15.7 
Clinical Study Report .............................................................................................68 
15.8 
Publication of Data and Protection of Trade Secrets .............................................68 
16 
STUDY ADMINISTRATIVE PROCEDURES ................................................................69 
16.1 
Subject Recruitment Procedures ............................................................................69 
16.2 
Subject Enrollment Procedures ..............................................................................69 
16.3 
Patient Premature Withdrawal – Definition ...........................................................69 
16.4 
Procedures for Patients Who Withdraw from the Study ........................................69 
16.5 
Treatment Compliance ...........................................................................................70 
16.6 
Recording of AEs on the CRF ...............................................................................70 
16.7 
Physical Examination Procedures ..........................................................................70 
16.8 
Vital Signs Procedures ...........................................................................................71 
16.9 
Body Weight ..........................................................................................................71 
16.10 ECG Procedures .....................................................................................................71 
16.11 Laboratory Test Procedures ...................................................................................71 
16.11.1 Recording of Laboratory Test Results on the CRF .................................72 
16.12 Recording of Concomitant Medications on the CRF .............................................72 
17 
REFERENCES ..................................................................................................................73 
 

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LIST OF APPENDICES 
APPENDIX 1A 
Corticosteroid Rescue Criteria and Treatment Protocol (Part A) ....................75 
APPENDIX 1B 
Corticosteroid Rescue Criteria and Treatment Protocol (Part B) ....................77 
APPENDIX 2 
Strong And Moderate Cyp3a Inhibitors And Inducers ....................................79 
APPENDIX 3 
Sensitive CYP3A Substrates Including Those with Narrow Therapeutic 
Index ................................................................................................................80 
APPENDIX 4 
Schedule of Assessments .................................................................................81 
APPENDIX 5 
Pemphigus Disease Activity and Quality of Life Evaluation 
Instruments:  ABQOL, Tabqol, PDAI, ABSIS ................................................85 
APPENDIX 6 
Simple Nutritional Appetite Questionnaire (SNAQ) .......................................92 
APPENDIX 7 
Corticosteroid Taper Protocol ..........................................................................93 
 
TABLE OF TABLES 
Table 1 
TEAEs Reported by More than One Patient (N=21) .......................................29 
Table 2 (Part A) General Dose Adjustment Guidelines for Dose Selection in the First 
4 Weeks ............................................................................................................39 
Table 3 (Part B) 
General Dose Escalation Guidelines ................................................................39 
Table 4 
Dose Escalation Rules Part B ..........................................................................77 
 
TABLE OF FIGURES 
Figure 1 
Individual and Mean BTK Occupancy Data from HV Study 
PRN1008-001 with the Liquid Formulation of PRN1008* .............................26 
Figure 2 
PDAI and Clinical Response Patient Profiles of 5 Patients on Zero or 
Doses of CS ≤ 5 mg .........................................................................................27 
Figure 3 
Timing of Individual Clinical Responses (Day 15 to 29 circled) N=21 ..........28 
Figure 4 
Distribution of Plasma Concentrations at BTK Occupancy Timepoints .........30 
Figure 5 
BTK Occupancies (Mean and Standard Deviation) Based on 
Approximate Timepoints Following Dosing ...................................................31 
 

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Principia Biopharma Australia Pty Ltd.  
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STUDY SYNOPSIS 
Study Title: 
An Open-Label, Phase 2, Pilot Study Investigating the Safety, Clinical 
Activity, Pharmacokinetics, and Pharmacodynamics of Oral Treatment with 
the BTK Inhibitor PRN1008 in Patients with Newly Diagnosed or Relapsing 
Pemphigus Vulgaris 
Study Number: 
PRN1008-005 
Indication: 
Pemphigus: Pemphigus Vulgaris (PV) 
Background: 
PV, which is characterized by intraepidermal blisters in skin and mucosae, is 
known to be driven by autoantibodies to epidermal proteins and is responsive 
acutely to the anti-inflammatory effects of corticosteroids and chronically to 
B-cell depletion by anti-CD20 therapy. Principia Biopharma has developed a 
novel, highly selective, small molecule inhibitor of non-T cell white blood 
cell signaling (via B- cell receptor, FCɣR, FcεR signaling of the Bruton’s 
tyrosine kinase, i.e., BTK, pathway). In naturally occurring canine 
pemphigus foliaceus (PF), PRN1008, rapidly reversed disease without the 
need for corticosteroid treatment. In Phase 1 studies with 114 healthy 
volunteers, target BTK occupancy levels were safely and consistently 
exceeded, suggesting PRN1008 may be highly effective in human 
pemphigus and other autoimmune diseases. 
 
 
 
 
 
 
 
 
Refer to PRN1008 Investigators’ Brochure, for additional information. 
Study Sites: 
Multiple international sites 
Study Phase: 
Phase 2 

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
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Study Objectives: 
Primary Objectives: 
• 
To evaluate the clinical safety of PRN1008 in patients with PV over a 
12-week (Part A) or 24-week (Part B) treatment period 
• 
To evaluate the clinical activity of PRN1008 in patients with PV, per 
criteria in the European Academy of Dermatology and Venereology 
(EADV) 2014 Pemphigus S2 Guideline (Hertl et al. 2015)* 
*As modified to define CR without 2-month durability definition 
Secondary Objective: 
• 
To evaluate the pharmacokinetics (PK) and the pharmacodynamics (PD) 
of PRN1008 in patients with PV 
Exploratory Objective: 
• 
To evaluate the relationship of PK and PD to each other and to efficacy 
and safety in this patient population 
Study Design: 
Part A: 
Open-label cohort study, with intrapatient dose-adjustment based on clinical 
response and BTK occupancy, and with conventional immunosuppressive 
“rescue treatment”, if indicated. 
Initial dosing will be 400 mg twice daily (bid). The duration of study therapy 
will be 12 weeks starting on Day 1 and ending on study Day 84 (total 
duration of individual subject participation is 28 weeks). 
Part B: 
Initial dosing will be 400 mg once daily (qd), with intra-patient dose 
escalation to 400 mg bid allowed at or after the Week 3 visit for insufficient 
clinical response (and then again to 600 mg bid if necessary at or after the 
Week 5 visit). The duration of study therapy will be 24 weeks starting on 
Day 1 and ending on study Day 169 (total duration of individual subject 
participation is approximately 32 weeks). 
Both Parts: 
The first dose on Day 1 of Week 1 will be supervised in the clinic and the 
patient observed for approximately 2 hours, at which time a PK/PD sample 
will be drawn. Day 2 study medication will be withheld in the morning in 
order to gain the trough BTK occupancy approximately 12 (when bid 
dosing) or approximately 24 hours (when qd dosing) after the prior dose. 
Where follow-up is not feasible the next day, another day in the first week of 
treatment may be used to get trough occupancy instead, again withholding 
dose on the morning of that day to get an occupancy measurement close to 
12 (when bid dosing) or approximately 24 (when qd dosing) hours post dose. 
At other follow-up visits, BTK occupancy can be measured at any time after 
the usual morning dose of PRN1008. 
The maximum dose of PRN1008 in this study, after dose adjustment, will be 
600 mg bid. 

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Corticosteroid 
Rescue Criteria 
Guidelines: 
Systemic corticosteroids will be avoided during PRN1008 therapy unless 
“rescue criteria” are triggered, or the patient enters the study on low-dose 
corticosteroids (i.e., ≤ 0.5 mg/kg). Corticosteroid rescue criteria are listed in 
Appendix 1. 
Outcome Measures: 
Primary Outcome Measures: 
Safety: 
The incidence of treatment-emergent AEs (TEAEs), including clinically 
significant changes in physical examination, laboratory tests, and vital signs. 
Efficacy: 
The proportion of subjects who are able to achieve control of disease activity 
(CDA) within 4 weeks of starting PRN1008 treatment without the need for 
doses of prednis(ol)one > 0.5 mg/kg. 
Secondary Outcome Measures:* 
• 
Proportion of subjects able to achieve CDA without corticosteroids 
within 4 weeks 
• 
Proportion of subjects able to achieve a complete response (CR) 
without corticosteroids within 12 weeks (and also 24 weeks in Part B) 
• 
Proportion of subjects able to achieve CR without the need for doses 
of prednis(ol)one of greater than 0.5mg/kg within 12 weeks (and also 
24 weeks in Part B) 
• 
Time to CDA 
• 
Time to CR 
• 
Time to end of consolidation phase 
• 
Time to relapse after PRN1008 treatment discontinuation 
• 
Cumulative corticosteroid usage over the first 12 weeks (and also 
24 weeks in Part B) 
• 
Change from baseline in Pemphigus Disease Area Index (PDAI) and 
Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) scores at 
each follow-up visit 
• 
Change from baseline in Autoimmune Bullous Diseases Quality of 
Life (ABQOL) and Treatment of Autoimmune Bullous Diseases 
Quality of Life (TABQOL) scores at each follow-up visit 
• 
Change from baseline in appetite (SNAQ score) at each follow-up visit 
*Clinical activity endpoints as defined by the EADV 2014 pemphigus S2 
guideline (Hertl et al. 2015) 
Pharmacokinetics Outcome Measure: 
• 
Plasma concentrations of PRN1008 at approximately the time of 
maximum concentration on Day 1 and at varied subsequent times 
during outpatient dosing 

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Pharmacodynamic Outcome Measures: 
• 
Percentage BTK occupancy in PBMCs at 2 & 24 hours after the first 
PRN1008 dose and at various subsequent times during outpatient 
dosing 
• 
Change from baseline in anti-dsg1-3 autoantibody levels by enzyme-
linked immunosorbent assay (ELISA) at various time points. 
Exploratory Outcome Measures: 
Exploratory PK/PD analysis will examine the effects, if any, of covariates on 
PK and/or PD, and the relationship between PK, PD, and efficacy in this 
population. 
Planned Number of 
Participants and 
Interim Analysis: 
 
 
Participant Selection 
Criteria: 
Inclusion Criteria Part A and Part B (unless noted below): 
1. 
Male or female patients, aged 18 to 80 years old, with biopsy-proven 
(positive direct immunofluorescence and appearance on H&E 
microscopy), mild-moderate PV in Part A (PDAI 8 to 45) and mild-
severe PV in Part B (PDAI 8 to 60) 
2. 
Newly diagnosed or relapsing patients for whom an initial period of 
PRN1008 monotherapy or combination therapy with low-dose 
corticosteroids (≤0.5 mg/kg of prednis[ol]one or equivalent), is judged 
clinically acceptable, provided tapering of the corticosteroid treatment 
regimen is anticipated with good clinical response to PRN1008 
3. 
BMI > 17.5 and < 40 kg/m2 Part A only  
4. 
Adequate hematologic, hepatic, and renal function (absolute neutrophil 
count ≥ 1.5 X 109/L, Hgb > 9 g/dL, platelet count ≥ 100 X 109/L, 
AST/ALT ≤ 1.5 x ULN, albumin ≥ 3 g/dL, creatinine ≤ ULN (Part A) 
and creatinine ≤ 1.5 x ULN (Part B) 
5. 
Female patients who are of reproductive potential must agree for the 
duration of active treatment in the study to use an effective means of 
contraception (hormonal contraception methods that inhibits ovulation, 
intrauterine device, intrauterine hormone-releasing system, bilateral 
tubal ligation, vasectomized partner, condoms or sexual abstinence). 
Unless surgically sterile, postmenopausal females should have 
menopause confirmed by FSH testing 
6. 
Able to provide written informed consent and agreeable to the schedule 
of assessments 
Exclusion Criteria Part A and Part B: 
1. Previous use of a BTK inhibitor.  
Patients enrolled in a previous version of this protocol who are 
still in their 12-week active treatment period with PRN1008 are 
eligible to continue treatment, initially with their current dose 
level, under this amended protocol for an additional 12 weeks, i.e. 

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24 weeks total, following review and signature of the EC 
approved patient’s consent. Patients who completed Part A and 
did not discontinue the study due to a medical condition that 
might compromise safety assessments or for a PRN1008 related 
adverse event may be screened for entry under Part B.  
2. 
Pregnant or lactating women 
3. 
ECG findings of QTc > 450 msec (males) or > 470 msec (females), 
poorly controlled atrial fibrillation (i.e. symptomatic patients or a 
ventricular rate above 100 beats/min on ECG), or other clinically 
significant abnormalities 
4. 
A history of malignancy of any type, other than surgically excised non-
melanoma skin cancers or in situ cervical cancer within 5 years before 
the day of dosing 
5. 
Use of immunologic response modifiers with the following periods 
prior to Day 1: as concomitant therapy, other immunologic response 
modifiers not detailed in this exclusion apart from corticosteroids; 1 
week: cyclophosphamide; 4 weeks: IVIG , Kinaret (anakinra) and 
Enbrel (etanercept); 12 weeks: Remicade (infliximab), Humira 
(adalimumab), Simponi (golimumab), Orencia (abatercept), Actemra 
(tocilizumab), Cimzia (certolizumab), Cosentyx (secukinumab), 
plasmapheresis; 6 months: Rituxan/MabThera (rituximab), 
ofatumumab, any other anti-CD20 antibody, other long-acting biologics 
6. 
More than 0.5 mg/kg of prednis(ol)one per day (“low dose 
corticosteroids”) within the two weeks prior to Day 1 
7. 
Use of proton pump inhibitor drugs such as omeprazole and 
esomeprazole (it is acceptable to change patient to H2 receptor blocking 
drugs prior to the first dose of PRN1008) 
8. 
Concomitant use of known strong-to-moderate inducers or inhibitors of 
CYP3A (Appendix 2) within 3 days or 5 half-lives (whichever is 
longer) of study drug dosing 
9. 
Use of CYP3A-sensitive substrate drugs (Appendix 3) with a narrow 
therapeutic index within 3 days or 5 half-lives (whichever is longer) of 
study drug dosing including, but not limited to, alfentanil, astemizole, 
cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, or terfenadine 
10. Has received any investigational drug (or is currently using an 
investigational device) within the 30 days before receiving the first dose 
of study medication, or at least 5 times the respective elimination half-
life time (whichever is longer) 
11. History of drug abuse within the previous 12 months 
12. Alcoholism or excessive alcohol use, defined as regular consumption of 
more than approximately 3 standard drinks per day 

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13. Refractory nausea and vomiting, malabsorption, external biliary shunt, 
or significant bowel resection that would preclude adequate study drug 
absorption 
14. History of anorexia nervosa or periods of three months or more of low 
body weight (BMI < 17.5) in the past 5 years 
15. Donation of a unit or more of blood or blood products within 4 weeks 
prior to Day 1 
16. History of solid organ transplant 
17. History of epilepsy or other forms of seizure in the last 5 years 
18. Positive for screening for HIV, hepatitis B (surface and core antibodies 
unrelated to vaccination), or hepatitis C (anti-HCV antibody confirmed 
with Hep C RNA) 
19. Positive interferon-gamma release assay (IGRA) (e.g., T-spot TB Test, 
QuantiFERON®-TB Gold, or QuantiFERON®-TB Gold Plus (QFT 
Plus), at Screening.  Unless, the patient has latent TB and all of the 
following 3 conditions are true: 
a) Chest X-ray does not show evidence suggestive of active 
tuberculosis (TB) disease 
b) There are no clinical signs and symptoms of pulmonary and/or extra-
pulmonary TB disease 
c) Documented receipt of one of the following prophylactic treatment 
regimens: 
i. Oral daily Isoniazid for 6 months 
or 
ii. Oral daily Rifampin (RIF) for 4 months 
or 
iii. Isoniazid and Rifapentine weekly for 3 months 
(3HP) 
On a case by case basis, after discussion and approval by the Sponsor, a 
local TB test that is negative and is considered equivalent to 1 of the 
above tests may be used for eligibility. For example, if a 
QuantiFERON®-TB Gold, or QuantiFERON-TB Gold Plus (QFT Plus) 
is positive and a local blood test or T-Spot TB test is negative, the 
patient may be enrolled using the local result upon approval of the 
Sponsor. 
20. History of serious infections requiring intravenous therapy with the 
potential for recurrence 
21. Live vaccine within 28 days prior to baseline or plan to receive one 
during the study 

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22. Any other clinically significant disease, condition, or medical history 
that, in the opinion of the Investigator, would interfere with subject 
safety, study evaluations, and/or study procedures 
Test Product and 
Method of Dosing 
PRN1008 300 mg and 100 mg tablets. Tablets should be taken with a glass of 
water and may be taken with or without food, i.e., a period of fasting is not 
required. 
Concomitant CYP3A 
Inducers or 
Inhibitors, Clinically 
Relevant CYP3A 
Substrate Drugs, 
Acid-Reducing Drugs 
and Anticoagulant 
Monitoring 
Inducers and inhibitors of Cytochrome P450 3A (CYP3A) should be 
avoided, as they may reduce or increase the exposure of PRN1008 
(Appendix 2) when administered concomitantly. 
PRN1008 is a moderate CYP3A inhibitor and can increase the exposure of 
drugs metabolized by CYP3A when administered concomitantly. Narrow 
therapeutic index CYP3A substrate drugs should be avoided (Appendix 3) 
and care should be taken with other drugs metabolized by the CYP3A. 
Clinically relevant CYP3A substrate drugs, (e.g. “sensitive substrate” listed 
in Appendix 3), should be managed by administering PRN1008 on a time 
schedule such that CYP3A substrate drugs can be given 2 hours or more 
after PRN1008. 
Proton pump inhibitors reduce the exposure of PRN1008 by approximately 
50% due to the effects of a lack of an acidic environment on tablet 
bioavailability. Therefore, subjects who are on proton pump inhibitors 
should be changed to H2 receptor blocking drugs or not enrolled in the study. 
PRN1008 should be given at least 2 hours before any dose of an H2 receptor 
blocking drug or any antacid. 
Anticoagulation with warfarin should be monitored actively in the first 
weeks of PRN1008 therapy, as the combination has not been studied 
previously (interaction is not suggested to be likely based on in vitro 
metabolism studies). 
Screening Procedures 
Part A and Part B: 
Up to 28 days before enrollment into the study, participants will be required 
to sign a consent form, after which screening assessments will be carried out 
as follows: 
• 
Review of medical history including concomitant medications 
• 
PDAI and ABSIS scoring 
• 
Review of inclusion and exclusion criteria 
• 
Measurement of height and weight 
• 
Physical examination 
• 
12-Lead ECG 
• 
Vital signs (blood pressure, heart rate, respiration rate and 
temperature) 
• 
Clinical laboratory testing (hematology, coagulation, serum chemistry 
and urinalysis) 
• 
HIV, hepatitis B (surface antigen and core antigen  and antibodies, 
hepatitis C (anti-HCV antibody confirmed with Hep C RNA) 

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• 
TB screen with T-spot TB Test, or QuantiFERON®-TB Gold test, or 
QuantiFERON®-TB Gold Plus (QFT Plus) 
• 
FSH (in postmenopausal women only who are not surgically sterile) 
• 
Pregnancy test in women of childbearing potential (serum test done at 
screening, urine dip test done at other time points) 
• 
Skin biopsy if not already performed: lesional for H&E staining, 
perilesional for direct immunofluorescence  
Randomization 
Procedure: 
Not applicable; the study is open-label.  
Study Assessments 
(see Schedule in 
Appendix 4): 
Part A: Patients will be screened within 28 days of dosing and will return for 
an end-of-study assessment 84 days after receiving their final dose of study 
drug. During the study, patients will return at specified times on an 
outpatient basis for assessment of vital signs, physical examination, 
assessment of AEs, assessment of concomitant medication use, assessment 
of clinical benefit, and provision of blood samples for PK and PD, and other 
clinical laboratory tests.  
Note: Patients who are currently enrolled in this PRN1008-005 study 
(Part A) and are in the 12-week active treatment period with PRN1008 are 
eligible to continue treatment at their current dose up to a total of 24 weeks 
active treatment, as a Part B patient, upon review and signature of the Part B 
EC-approved Patient Informed Consent Form. Patients that completed 
Part A of the trial are also eligible to be screened as a Part B patient, upon 
review and signature of the Part B EC-approved Patient Informed Consent 
Form. 
Part B: Patients will be screened within 28 days of dosing and will return for 
an end-of-treatment assessment on Day 169 after receiving their final dose of 
study drug on the morning of Day 169. They will return for follow up 28 days 
later for a final, follow up visit. During the study, patients will return at 
specified times on an outpatient basis for assessment of vital signs, physical 
examination, assessment of AEs, assessment of concomitant medication use, 
assessment of clinical benefit, and provision of blood samples for PK and 
PD, and other clinical laboratory tests. 
Clinical Assessments Part A and B: 
• 
Medical history, including evaluation of any on-study AEs and 
periodic vital signs (body temperature, heart rate, respiratory rate, 
blood pressure), concomitant medication use 
• 
At screening only: height and weight, full physical examination, and 
12-lead electrocardiogram (ECG) (an extra ECG may be taken at 
additional visits, if indicated) 
• 
Disease activity scores: PDAI, ABSIS (Appendix 5) 
• 
Standardized photography of the affected area (Optional) 
• 
Quality of Life Scores: ABQOL, TABQOL (Appendix 5) 
• 
SNAQ appetite questionnaire (Appendix 6) 

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Laboratory Assessments Part A and Part B: 
•
Hematology: hemoglobin, hematocrit, erythrocyte count (RBC’s), 
thrombocyte count (platelets), leukocyte count (WBCs) with 
differential in absolute counts (including neutrophils, eosinophils, 
basophils, lymphocytes, and monocytes)
•
Coagulation:  PT/INR, thrombin time, aPTT, fibrinogen level
•
Serum chemistry: Aspartate aminotransferase (AST), Alanine 
aminotransferase (ALT), Total, direct, and indirect bilirubin levels, 
Alkaline phosphatase (ALP), Albumin, Creatinine, Urea, Total 
Protein, Sodium, Chloride, Calcium, Phosphate, Potassium, Glucose 
(random), creatine phosphokinase (CPK) and thyroid stimulating 
hormone (TSH)
•
PK: Plasma PRN1008 concentration
•
PD: BTK occupancy in PBMCs and anti-desmoglein -1
and -3 autoantibody titers by ELISA
•
Urinalysis:  pH, specific gravity, protein, glucose, ketones, bilirubin, 
blood, nitrites, urobilinogen and leukocytes measured by dip stick
•
Serology:  HIV, Hepatitis B (surface antigen and core antigen and 
antibodies) and Hepatitis C and T-spot TB® Test, QuantiFERON®-
TB Gold, or QuantiFERON-TB Gold Plus (QFT Plus) testing at 
screening only
•
FSH for postmenopausal women who are not surgically sterile at 
screening only
•
Pregnancy test for women of childbearing potential 
Safety and 
Tolerability 
Assessments Part A 
and B: 
Specific assessments to evaluate treatment safety include the following: the 
frequency and type of AEs, clinical laboratory testing, SNAQ appetite 
questionnaire (Appendix 6) and vital signs.  
Patients will remain under observation in the clinic for 2 hours after 
administration of the first dose and until the PK/PD sample is drawn. 
A Safety Monitoring Committee (SMC) will regularly review and evaluate 
patient safety data including AEs, laboratory results, concomitant 
medications, dose modifications, and efficacy. 
Statistical Analysis: 
Clinical Activity: 
Given the natural history of PV to not remit spontaneously, a study of 
approximately 25 PV patients completing 12 weeks of treatment and 
approximately 25 PV patients completing 24 weeks of treatment with 
PRN1008 should determine a reasonable approximation of the responder rate 
and average time to response (e.g., estimated response rate of 50% with 80% 
CI of ± 13%). Where appropriate, patients from both parts will be combined 
in analysis. The results from this pilot study will be used to design 
confirmatory, pivotal clinical trials. Time course of changes in clinical and 
laboratory parameters will be described graphically, and at each visit using 
descriptive statistics. 

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Safety and Tolerability: 
Quantitative safety data will be summarized by descriptive statistics 
(arithmetic mean, standard deviation, median, minimum, and maximum) by 
dose level. Summaries will also be presented for the change from baseline, 
when appropriate.  
Pharmacokinetics and Pharmacodynamics: 
Individual and group PK and PD data will be summarized, displayed 
graphically, and by descriptive statistics for each visit, where measured. 
Study Duration: 
Approximately 48 months from the first subject treated to last subject 
completing, and 28 (Part A) – 32 (Part B) weeks per subject. 
 

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GLOSSARY OF ABBREVIATIONS AND TERMS  
ABBREVIATION OR TERM 
DEFINITION 
ABSIS 
Autoimmune Bullous Skin Disorder Intensity Score 
ABQOL 
Autoimmune Bullous Diseases Quality of Life (assessment) 
AE 
Adverse event 
Ae 
Amount excreted unchanged in the urine 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BCR 
B-cell receptor 
BID 
Twice daily (morning and evening) 
BMI 
Body mass index 
BP 
Blood pressure 
BPM 
Beats per minute 
BTK 
Bruton’s Tyrosine Kinase 
CA 
Competent Authority 
CI 
Confidence Interval 
CLr 
Renal clearance 
Cmax 
Maximum observed plasma concentration 
CNS 
Clinical Network Services 
CPK 
Creatine phosphokinase 
CR 
Clinical Response 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for AEs 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DSG 
Desmoglein 
EC 
Ethics Committee (see also HREC) 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-Linked Immunosorbent Assay 
FSH 
Follicle Stimulating Hormone 
FDA 
Food and Drug Administration 
GLP 
Good Laboratory Practice 
H2 
Histamine two (receptor) 
HBsAg 
Hepatitis B surface antigen 
HPMC 
Hypromellose 
HCV 
Hepatitis C Virus 
HDL 
High density lipoprotein 
HDPE 
High-density polyethylene 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  

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ABBREVIATION OR TERM 
DEFINITION 
IMP 
Investigational medicinal product 
IR 
Immediate Release (tablet formulation) 
IRB 
Institutional Review Board (Human Research Ethics Committee) 
IVIG 
Intravenous immunoglobulin 
LDL 
Low density lipoprotein 
LPLV 
Last participant last visit  
LTFU 
Long-term Follow-up 
MAD 
Multiple ascending dose (trial) 
MedDRA 
Medical Dictionary for Regulatory Activities  
N 
Sample Size 
NOEL 
No observed effect level 
NOAEL 
No observed adverse effect level 
OTC 
Over the counter 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Pharmacodynamic 
PDAI 
Pemphigus Disease Area Index 
PF 
Pemphigus foliaceus 
PK 
Pharmacokinetic 
PO 
By Mouth 
PV 
Pemphigus vulgaris 
Q12H 
Every 12 hours 
QD 
Once a day 
QTc 
QT interval corrected for heart rate 
RA 
Rheumatoid arthritis 
RBC 
Red blood cell 
RR 
Resting Rate 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SD 
Standard Deviation 
SI 
Système international d’unités (International system of units) 
SMC 
Safety Monitoring Committee 
SoAT 
Schedule of Assessment Table 
SLE 
Systemic Lupus Erythematosus 
SNAQ 
Simplified Nutritional Appetite Questionnaire 
SSR 
Six-Month SUSAR Report 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TABQOL 
Treatment of Autoimmune Bullous Diseases Quality of Life (assessment) 
TB 
Tuberculosis 
TEAE 
Treatment-Emergent Adverse Event 
TGA 
Therapeutic Goods Administration 
Tmax 
Time of observed maximum plasma concentration 
TSH 
Thyroid stimulating hormone 
t½ 
Elimination half-life 
WBC 
White blood cell 
WHODD 
World Health Organisation Drug Dictionary 
XLA 
X-linked agammaglobulinemia 

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1 
BACKGROUND AND SCIENTIFIC RATIONALE FOR THE TREATMENT OF 
PEMPHIGUS WITH PRN1008 
1.1 
Background 
Bruton’s agammaglobulinemia tyrosine kinase (BTK) is an essential signaling element 
downstream of the B-cell receptor (BCR), Fc-gamma receptor (FcγR) and Fc-epsilon receptor 
(FcεR). BTK is a non-receptor tyrosine kinase and is a member of the TEC family of kinases. 
Inhibition of BTK activity in cells produces phenotypic changes consistent with blockade of the 
BCR. This activity results in the down-regulation of various B-cell activities including cell 
proliferation, differentiation, maturation, survival, and the up-regulation of apoptosis. BTK also 
regulates the activation of other hematopoietic cells, such as basophils, mast cells, macrophages, 
neutrophils, and platelets. It is not expressed in T cells, natural killer cells, and plasma cells 
(Sideras and Smith 1995; Mohamed, et al., 2009). A selective BTK inhibitor has the potential to 
target multiple pathways involved in inflammation and autoimmunity. These include modulation 
of BCR-mediated B-cell pathways, inhibition of FcγR-induced cytokine release from monocytes 
and macrophages, FcεR-induced mast cell degranulation, granulocyte migration and mediator 
release. These effects lead to the prediction that a BTK inhibitor could block the initiation and 
propagation of various inflammatory diseases and mitigate the resulting tissue damage. 
Important insights into BTK function come from loss of function analyses in humans and mice. 
Individuals with loss of function mutations in the BTK gene develop X-linked 
agammaglobulinemia (XLA) characterized by a complete absence of circulating B cells and 
plasma cells, and very low levels of immunoglobulins of all classes (Tsukada 1993, 
Vetrie 1993). This indicates the potential for BTK inhibition to suppress production of 
autoantibodies thought to be important in development of autoimmune diseases, such as 
pemphigus vulgaris (PV). These individuals have decreased humoral immunity and are 
susceptible to pyogenic bacterial as well as enterovirus infections, requiring treatment with 
intravenous immunoglobulin. However, inhibition of BTK in individuals with an intact immune 
system is not predicted to produce similar susceptibility to infection. 
Several orally administered BTK inhibitors, including ibrutinib (PCI-32765) and CC-292, are 
currently marketed or in clinical development for a range of indications. Ibrutinib has provided 
further clinical validation of the BTK target and was recently approved for human use in mantle 
cell lymphoma, Waldenström’s macroglobulinaemia, and chronic lymphocytic leukemia by the 
U.S. Food and Drug Administration (U.S. FDA), and has also demonstrated activity in other 
hematological malignancies (Wang 2013, Byrd 2013, Imbruvica Package Insert, 2015). CC-292 
has been reported to be well tolerated in a healthy volunteer population, at doses which provide 
100% occupancy of the BTK enzyme (Evans 2013). 
1.2 
Rationale for PRN1008 Treatment in Pemphigus 
PV is known to be driven by autoantibodies to epidermal proteins and is responsive acutely to 
the anti-inflammatory effects of corticosteroids and within 5 to 35 weeks to B- cell depletion by 
anti-CD20 therapy (Horvath et al. 2012). 

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PRN1008 is a novel, highly selective, small molecule inhibitor of non-T cell white blood cell 
signaling (via B- cell receptor, FCɣR, FcεR signaling of the Bruton’s tyrosine kinase, i.e., BTK, 
pathway).  
In Phase 1 studies with 114 healthy volunteers, target BTK occupancy levels were safely and 
consistently exceeded, suggesting PRN1008 at the planned dose levels may be highly effective in 
human pemphigus and other autoimmune diseases. 
As of January 18, 2018, PRN1008 had been administered to 21 patients with pemphigus 
(pemphigus vulgaris [PV] and pemphigus foliaceus [PF]), 18 of whom had 4 or more weeks of 
treatment with PRN1008. Of the 18 patients with efficacy data, 11 (61%) met the primary 
endpoint of “Control of Disease Activity” (CDA) on a CS dose of ≤ 0.5 mg/kg/day (low-dose 
CS) by the Week 5 visit. Three patients achieved CDA on no CS. Two patients required high-
dose CS temporarily during PRN1008 treatment due to worsening of disease activity. Four 
patients achieved complete remission (CR) on 1 to 20 mg/day of CS; 3 achieved CR at Week 13 
(25%) and one achieved CR at Week 21. PRN1008 has been well-tolerated in this study 
(see Section 1.4). 
Refer to PRN1008 Investigators’ Brochure for additional information. 
1.3 
Summary of PRN1008 Animal Toxicity Studies 
1.3.1 
13-week GLP Toxicology 
In the 13-week repeat-dose GLP toxicity studies with PRN1008, doses of up to 500 mg/kg/day 
and 300 mg/kg/day were given to rats and dogs, respectively. The No Observed Adverse Effect 
Level (NOAEL) in rats was considered to be 150 mg/kg/day and the NOAEL for male dogs was 
30 mg/kg/day. The NOAEL in female dogs is less than 30 mg/kg/day, based on body weight loss 
in one female administered 30 mg/kg/day. At doses above 150 mg/kg, the lungs of some rats 
showed increased macrophages and bronchoalveolar papillary hyperplasia. In dogs, PRN1008-
related findings considered potentially PRN1008-related were observed in the liver and 
lymphoid tissues. At doses above 30 mg/kg in dogs, changes in liver function (mainly ALT and 
AST), loss of appetite, and associated weight loss were observed. These observations are 
considered clinically significant and their assessment in human subjects is included in the study 
procedures in this clinical protocol. 
Orally administered PRN1008 did not affect the gross behavioral, physiological, or neurological 
state of rats at dose levels up to 500 mg/kg, and the NOAEL for effects on the cardiovascular and 
respiratory systems in dogs was considered to be 500 mg/kg. 
PRN1008 tested negative in a battery of in vitro and in vivo genotoxicity studies. 

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1.3.2 
6 and 9-month GLP Toxicology 
In the 6-month rat oral GLP toxicology study, the no-observed-adverse-related level (NOAEL) 
was 50 mg/kg/day in females (AUClast 5480 hr.ng/mL) and 150 mg/kg/day in males (AUClast 
5327 hr.ng/mL). The nature and severity of observed findings included lethality, decreased body 
weight gain, macroscopic and microscopic changes in the gastrointestinal tract, and neutrophilic 
inflammation in the brain. Adequate safety factors of ~4X are present to the rat NOAEL, 
assuming a maximum exposure in humans of 1360 ng.h/mL with a 600 mg bid dose, and 6X to 
the target exposure of 890 ng.h/mL with the 400 mg bid dose. 
In the 9-month dog oral GLP toxicology study, the NOAEL for male and female animals was 
30 mg/kg/day (AUClast 963 hr.ng/mL), based on body weight loss that required food 
supplementation and the euthanasia of one male dog dosed at 50mg/kg/day. The observed 
findings in the dog of appetite decrease, weight loss, and reversible changes in liver function are 
readily monitorable in human studies. 
1.3.3 
Reproductive and Fertility Studies 
1.3.3.1 
Embryo-Fetal Development Study in Rat  
There were no PRN1008-related external, visceral, or skeletal fetal malformations or variations, 
and there were no PRN1008-related effects on fetal ossification site averages. 
Pregnant female rats were given daily oral doses of 50, 150, or 300 mg/kg/day of PRN1008 from 
DG 7 through 17. The maternal NOAEL was determined to be 150 mg/kg/day based upon lower 
body weight/gain and food consumption. There were no PRN1008-related fetal development; or 
fetal external, visceral, or skeletal morphology changes. Therefore, the embryo/fetal 
development NOAEL was considered to be 300 mg/kg/day.  
1.3.3.2 
Embryo-Fetal Development Study in Rabbit  
There were no PRN1008-related external, visceral, or skeletal fetal malformations or variations, 
and there were no PRN1008-related effects on fetal ossification site averages. 
Pregnant female rabbits were given daily oral doses of 10, 30, or 100 mg/kg/day of PRN1008 
from DG 7 through 19. The maternal NOAEL was determined to be 30 mg/kg/day based upon 
lower body weight gain and food consumption at 100 mg/kg/day. There were no PRN1008-
related fetal development changes, and no fetal external, visceral, or skeletal morphology 
changes were observed. Therefore, the embryo/fetal development NOAEL was considered to be 
100 mg/kg/day. 
1.3.3.2.1 
Fertility and Early Embryonic Development in Rat  
Administration of PRN1008 in male rats resulted in an increased incidence of rales and reduced 
body weight, body weight gains, and food consumption. The NOAEL in males for general 
toxicity parameters was considered to be 150 mg/kg/day. There were no effects on mating, 

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fertility, reproductive organ weights, or sperm parameters in the treated males. The reproductive 
NOAEL in males was 300 mg/kg/day. 
Administration of PRN1008 in female rats resulted in reductions in body weights, body weight 
gains, and food consumption during the premating period and reductions in food consumption 
during the gestation period. The NOAEL for the females for maternal toxicity was considered to 
be 150 mg/kg/day. There were no effects on estrous cycling, mating, fertility, or ovarian and 
uterine parameters in the females. The reproductive and development NOAEL in females was 
300 mg/kg/day. 
Refer to PRN1008 Investigators’ Brochure, Section 4.4 and 6 5 for a more comprehensive 
preclinical safety summary. 
1.4 
Summary of PRN1008 Clinical Experience 
To date PRN1008 has been administered to 114 healthy adult volunteer subjects in five Phase I 
studies (PRN1008-001, PRN1008-002, PRN1008-004, PRN1008-006 and PRN1008-008) using 
four different formulations. Single doses, repeat single doses and periods of up to 11 days of 
once or twice daily dosing were studied. The maximum single dose administered was 1200 mg 
and the maximum multiday dose was 450 mg twice daily for 10 days (450 mg of the liquid 
formulation is equivalent to 648 mg of the IR tablet formulation). 
As of January 18, 2018, PRN1008 has been administered to 21 patients with pemphigus using 
the IR tablet formulation. Study PRN1008-005, is a Phase 2, open-label cohort study of 12 weeks 
of PRN1008 therapy, followed by 12 weeks of follow up, using a starting dose of 400 mg twice a 
day, with intra-patient dose-escalation based on clinical response and BTK occupancy up to a 
maximum dose of 600 mg twice a day (Part A of this protocol).  
This amendment 5.0, (Part B) allows 24 weeks of treatment followed by 4 weeks of follow-up. 
Initial dosing in Part B will be 400 mg once daily (qd), with intra-patient dose escalation to 
400 mg bid allowed at or after the Week 3 visit for insufficient clinical response (and then again 
to 600 mg bid if necessary at or after the Week 5 visit). 
A Phase 1/2 study of relapsing immune thrombocytopenia is enrolling patients at dose levels 
between 200 mg daily and 400 mg bid. 
1.4.1 
Experience in Healthy Volunteer Phase 1 Studies 
In Study PRN1008-001, volunteers received single oral doses of placebo (n = 6), 50 mg (n = 6), 
150 mg (n = 6), 300 mg (n = 6), 600 mg (n = 6), or 1200 mg (n = 6). The longest duration of 
treatment to date was in this same study, where subjects received 10 or 11 days of dosing, at dose 
regimens of placebo, 300 mg qd, 300 mg q12h, 600 mg qd, and 450 mg q12h (n = 8 per dose 
level). In Study PRN1008-002, a midazolam drug-drug interaction study, 12 subjects received 
single doses of 600 mg PRN1008. In both Study PRN1008-001 and Study PRN1008-002, 
PRN1008 was administered as a liquid formulation, under fasted conditions on all but one day. 
Study PRN1008-004 compared the relative bioavailability of the liquid formulation to a capsule 
formulation, whereby subjects (n = 12) received 300 mg single doses of both PRN1008 

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formulations. Study PRN1008-006 compared the relative bioavailability of the liquid 
formulation to a tablet formulation, whereby subjects (n = 12) received 300 mg single doses of 
both PRN1008 formulations, as well as the tablet after food and after several days of 
esomeprazole treatment. For additional details, refer to the PRN1008 Investigators’ Brochure.  
PRN1008 was safe and well tolerated at the dose levels tested). In these 114 Healthy Volunteer 
subjects, no severe AEs (AEs) or SAEs were reported, and no subjects required discontinuation 
or interruption of dosing. Reported AEs were mild or moderate in severity, with gastrointestinal 
AEs being most common (nausea/vomiting, loose stools) – predominantly with the liquid 
formulation. These AEs were more frequent at the 600 mg qd and 450 mg q12h doses. No 
clinically significant changes in laboratory parameters, vital signs, or ECG parameters were 
observed in 112/114 healthy volunteer subjects tested.  
In Study PRN1008-008 of single doses of 400 mg of tablet formulations, one healthy volunteer 
with a low-normal baseline neutrophil count of 2100/μL experienced a single laboratory reading 
of 800/μL during follow up five days after a series of 4 single doses, having had a single low 
count of 1200/μL four days earlier after the fourth dose. The single low count had returned to 
1900/μL when first remeasured four days later. In Study PRN1008-006, one subject had 
reversible, Grade 2 elevations of ALT during follow-up, associated with Grade 1 elevation of 
AST. 
Following single and multiple oral doses of PRN1008 in Study PRN1008-001, mean BTK 
occupancy in PBMCs of more than 70% was observed 4 hours or later following doses of 
300 mg or more on Day 1. Figure 1 shows clinically effective levels of BTK occupancy with a 
300 mg bid dose on Day 1, with slightly reduced interpatient variability, and slightly higher 
Hour-4 values, observed after multiple days of dosing. Three subjects with BTK occupancies at 
12 hours on Day 1 in the 40% range all had 12-hour occupancies above 60% by Day 10. 
Figure 1 
Individual and Mean BTK Occupancy Data from HV Study PRN1008-001 
with the Liquid Formulation of PRN1008* 
 
 
*Tablet equivalent doses are 428 mg twice daily after correction for relative bioavailability of ~70%.  
A second dose was not administered on Day 10. 
300mg 
bid
74±4
91±2
77±7
60±8

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1.4.2 
Experience in Pemphigus Patients in Study PRN1008-005 
1.4.2.1 
Efficacy 
As of January 18, 2018, PRN1008 had been administered to 21 patients with pemphigus 
(pemphigus vulgaris [PV] and pemphigus foliaceus [PF]), 18 of whom had 4 or more weeks of 
treatment. Of the 18 patients with efficacy data, 11 (61%) met the primary endpoint of “Control 
of Disease Activity” (CDA) on a CS dose of ≤ 0.5 mg/kg/day (low-dose CS) by the Week 5 visit. 
Three patients achieved CDA on no CS (Figure 2). Two patients required high-dose CS 
temporarily during PRN1008 treatment due to worsening of disease activity. Four patients 
achieved complete remission (CR) on 1 to 20 mg/day of CS; 3 achieved CR at Week 13 (25%) 
and one achieved CR at Week 21. Responses were seen in patients with both mild and moderate 
levels of initial disease (PDAI patient profiles, Figure 3). 
Figure 2 
PDAI and Clinical Response Patient Profiles of 5 Patients on Zero or Doses 
of CS ≤ 5 mg 
 
 
0
5
10
15
20
25
30
35
40
45
50
0
50
100
150
200
Days 
PDAI
total
activity
score
PRN1008 treatment
Post treatment follow up
First control of disease activity (CDA) no later CR
First control of disease activity (CDA) with later CR
First complete (clinical) remission (CR)
5mg
2.5mg
0mg
0mg
1mg
1mg
0mg

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Figure 3 
Timing of Individual Clinical Responses (Day 15 to 29 circled) N=21 
 
 
1.4.2.2 
Safety 
The following three serious adverse events (SAEs) have been reported in PV patients: a Grade 3 
event of cellulitis that led to hospitalization (considered by the investigator to be related to 
PRN1008), and two events considered unrelated to PRN1008 of 1) a Grade 3 event of 
“pancreatic pseudocyst – benign” that led to hospitalization and 2) a Grade 5 event of “acute 
respiratory failure - inflammation of an undiagnosed pulmonary sequestration-congenital” that 
led to hospitalization after one week of PRN1008 therapy and led to death following lung 
surgery more than a month after PRN1008 therapy was ceased. 
Table 1 shows treatment-emergent adverse events (TEAEs) reported by more than one patient by 
relatedness and severity. TEAEs reported by more than one patient deemed related to PRN1008 
are Grade 1 headache (10%), Grade 1 upper respiratory infection (10%) and Grade 1/2 dry 
mouth (10%). 
Two patients on chronic anticoagulation (warfarin and rivaroxaban) have been treated without 
bleeding complications. 
0
5
10
15
20
25
30
35
40
45
50
1
29
57
85
113
141
169
Days 
PDAI
total
activity
score
PRN1008 treatment
Post treatment follow up

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Table 1 
TEAEs Reported by More than One Patient (N=21) 
TEAE Term 
Related 
Grade 
Freq. (n, %) 
Pemphigus worsening 
No 
1-2 
4 (19%)* 
Headachea 
Yes/No 
1 
3 (14%)* 
Nausea 
Yes/No 
1 
2 (10%)* 
Upper respiratory tract infection 
Yes 
2 
2 (10%) 
Vomiting 
No 
1 
2 (10%) 
Dry mouth 
Yes 
1-2 
2 (10%)* 
TEAE = treatment-emergent adverse event 
a Two of three headaches were deemed related to PRN1008 therapy. 
*1 patient was at 500 mg bid, all other patients were at 400 mg bid 
 
Refer to PRN1008 Investigators’ Brochure for additional information. 
1.5 
Clinical Pharmacology of PRN1008 
1.5.1 
Pharmacokinetics in Healthy Volunteers 
With multiple dosing, the terminal half-life of PRN1008 is approximately 3 to 4 hours and the 
time of maximum concentration (Tmax) at therapeutic multiple doses of 1.5 to 2.0 hours. With 
300 mg bid of the liquid formulation, the accumulation ratio was 1.8 after 10 days of dosing. 
There is no effect of food on the AUC or Cmax of the tablet formulation although the Tmax is 
slightly delayed from 1.5 hours to approximately 2.5 hours. The volume of distribution is high 
(on the order of 2500 L) and plasma protein binding is 98% (PRN1008 Investigators’ Brochure). 
1.5.2 
Pharmacokinetics and BTK Occupancy in Pemphigus Patients 
In this Study PRN1008-005, PK sampling is being conducted in all patients for population PK 
analysis. Blood samples were drawn pre-dose and at 2 hours following PRN1008 administration 
on the first day of therapy, pre-dose on the second and seventh day of therapy, and then at 
random times following dosing at other study visits. Preliminary data suggest that plasma 
concentrations at 2 hours, steady state 2 hours, and pre-dose were generally consistent to those 
seen in Phase 1 studies, as corrected for formulation (Figure 4). 

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Figure 4 
Distribution of Plasma Concentrations at BTK Occupancy Timepoints 
 
BTK = Bruton’s tyrosine kinase; SS = steady state 
 
1.5.3 
BTK Occupancy in Patients with Pemphigus 
Target occupancies, based on efficacy in animals and the levels reached with a liquid 
formulation dose of 300 mg q12h, were approximately 80% on Day 1, approximately 70% on 
Day 2 pre-dose (indicated as SS 12 hr), and approximately 90% at SS 2 hr (Figure 5). Thus, 
target occupancy levels are being reached in nearly all individuals with a 400 mg twice daily 
dose. 
1 s t D a y 2 h r
S S  2  h r
S S  1 2  h o u r 
1
1 0
1 0 0
1 0 0 0
plasma conc (ng/ml)
15 1.1
19 6.3
9.4 7

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Figure 5 
BTK Occupancies (Mean and Standard Deviation) Based on Approximate 
Timepoints Following Dosing 
 
BTK = Bruton’s tyrosine kinase; SS = steady state 
 
1 s t D a y   2  h r  
S S  2  h r  
S S  1 2  h r  
0
5 0
1 0 0
% Occupancy
8 5 .5 3
86 .5 8
88 .1 3

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2 
RATIONALE AND JUSTIFICATION FOR THE STUDY AND THE STUDY 
DESIGN 
2.1 
Rationale for the Study Design 
This open-label, pilot study is designed to explore the initial efficacy and safety of PRN1008 in 
PV and to enable the accurate design of pivotal randomized clinical trials which are to follow. 
An open-label design was chosen for several reasons: PV does not spontaneously remit so there 
is no placebo effect to account for; clinicians need to know when to use rescue corticosteroids, if 
necessary, in a timely manner; and lastly, the pilot nature of the investigation itself is best 
explored in an open-label fashion. 
Because of the ability to guide individualized dosing with BTK occupancy measurement, the use 
of which has been validated in a naturally occurring canine pemphigus study, this assay was used 
to supplement the clinical response assessments in making dose-adjustments in Part A. More 
than 95% of patients in Part A (20/21) had adequate BTK occupancies (mean 86% pre dose at 
steady-state). In Part B, the clinical efficacy of the 400 mg qd dose is being explored to see if 
lower BTK occupancies will still equate to clinical efficacy. For this reason, clinical response 
alone, and not BTK occupancies, is recommended to guide dose adjustment in Part B. 
Given the efficacy seen in this pemphigus study to date at varied clinical severities, and the 
updated, supporting, chronic, GLP toxicology (Section 1.3), there is clinical equipoise to study 
PRN1008 monotherapy (or with low dose CS) in patients with mild-to-severe (baseline PDAI 
8-60), corticosteroid-naïve or relapsing PV, with close observation and appropriate corticosteroid 
rescue protocols. 
2.2 
Selection of the Starting Clinical Dose of PRN1008 in Pemphigus 
400 mg bid (Part A): The 400 mg bid starting dose is based upon the dose known to produce 
~70% BTK occupancy at trough (~85% average occupancy over the day), as adjusted by results 
of the relative bioavailability study, where the tablet had ~70% of the exposure of the equal dose 
of the liquid formulation. Adequate BTK occupancies with 400 mg bid dosing of the IR tablet 
has been confirmed in nearly all of the 21 patients with pemphigus studied to date. To confirm 
achievement of target, BTK occupancy measurements after the first dose will be expeditiously 
processed and provided to the treating physician in time for a follow-up visit at Day 15 (Part A 
only). This dose level has adequate safety factors to exposures in chronic toxicology studies 
(Section 1.3). 
400 mg qd (Part B): In some but not all animal studies, a dose-response relationship between 
pre-dose BTK occupancy and clinical efficacy was observed. As it is unknown whether a once 
daily PRN1008 dose will provide adequate pharmacodynamics effect, a 400 mg qd dose is being 
tested in Part B, with the option to expeditiously dose-escalate to higher doses at or after the 
Week 3 visit. This dose level has adequate safety factors to exposures in chronic toxicology 
studies (Section 1.3). 
Please refer to Investigator Brochure, Section 5.5.3, for additional information.  

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2.3 
Overall Risk/Benefit Assessment 
Design summary: Study PRN1008-005, is a Phase 2, open-label, cohort study of 12 weeks of 
PRN1008 therapy, followed by 12 weeks of follow up, using a starting dose in Part A of 400 mg 
twice a day (bid), with intra-patient dose-escalation to a maximum dose of 600 mg twice a day. 
In Part B the starting dose is 400 mg once daily (qd) with intra-patient dose-escalation to 
400 mg bid allowed at or after the week 3 visit based upon insuffcient clinical response (and then 
again to 600 mg bid if necessary at or after the Week 5 visit). 
Safety Profile: The one patient with a related SAE of cellulitis and fever observed in a patient 
with a higher risk of infection underscores the likely, mechanism-based risk of infection during 
chronic treatment with a BTK inhibitor. 
Based on data from 21 patients in this Study PRN1008-005, as of January 18, 2018, PRN1008 
has been well tolerated using the IR tablet formulation in doses of up to 400 mg bid (n=19), 
500 mg bid (n=1) and 600 mg bid (n=1). No patients have discontinued PRN1008 therapy or 
dose-reduced due to treatment-related adverse events. 
Efficacy: High clinical response rates have been observed in the first 21 PV patients in this 
study, on a background of zero or low dose CS, using a starting dose of 400 mg bid. It is possible 
that a lower, once daily dose may have a greater benefit-risk relationship, and this is being 
explored in Part B. 
Risk/Benefit: Given the encouraging safety and efficacy profile of PRN1008, further exploration 
of minimally effective dose levels and longer durations of therapy is justified in pemphigus 
patients. The results of this study will be used to guide PRN1008 use in future patient studies. 
No risks other than those previously mentioned in the Investigator’s Brochure or in the summary 
of PRN1008 clinical experience described above are known at this time. Refer to PRN1008 
Investigators’ Brochure, Section 5.6.2, for additional information. 
2.4 
Drug-Drug Interaction Potential 
Based on in vitro data, CYP3A4 appears to be the major CYP isoform responsible for PRN1008 
metabolism, including first-pass metabolism through the intestinal wall and liver. Therefore, 
PRN1008 plasma exposures have the potential to be altered if co-administered with other agents 
which either inhibit or induce CYP3A, however this potential interaction has not been studied 
clinically to date. Concomitant use of strong and moderate inducers of CYP3A should be 
avoided until their effects on PRN1008 exposure have been studied (Appendix 2). 
A clinical drug-drug interaction study (PRN1008-002) was conducted to evaluate the effects of 
the liquid formulation of PRN1008 when administered simultaneously with midazolam, a probe 
CYP3A substrate. When co-administered with midazolam, midazolam plasma exposures 
increased approximately 3-fold. PRN1008 is therefore classified as a moderate inhibitor of 
CYP3A. As a result, sensitive CYP3A substrate drugs, particularly those with a narrow 
therapeutic index, should be avoided during treatment with PRN1008 (Appendix 2). Additional 
details are provided in the Investigator Brochure. PRN1008 does not appear to be an inducer of 
CYP isoenzymes. 

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Acid reducing drugs may reduce the bioavailability of PRN1008 tablets. Therefore, PRN1008 
should be administered 2 hours or more prior to such drugs. Proton pump inhibitors are not 
permitted during the study (they resulted in a 50% decrease in PRN1008 tablet exposure when 
administered concomitantly in Study PRN1008-006). 

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3 
OBJECTIVES OF THE STUDY 
3.1 
Primary Objectives 
• To evaluate the clinical safety of PRN1008 in patients with PV over a 12-week (Part A) or 
24-week (Part B) treatment period 
• To evaluate the clinical activity of PRN1008 in patients with PV, per criteria in the European 
Academy of Dermatology and Venereology (EADV) 2014 Pemphigus S2 Guideline 
(Hertl et al. 2015)* 
*As modified to define CR without 2-month durability definition 
3.2 
Secondary Objective 
• To evaluate the pharmacokinetics (PK) and the pharmacodynamics (PD) of PRN1008 in 
patients with PV 
3.3 
Exploratory Objective 
• To evaluate the relationship of PK and PD to each other and to efficacy and safety in this 
patient population 

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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a Phase 2, open-label, pilot cohort study. 
Part A: Initial PRN1008 dosing will be 400 mg (bid), with intrapatient dose adjustment up to 
600 mg (bid) based on BTK occupancy and clinical response, and corticosteroid rescue 
treatment, if indicated. Patients requiring corticosteroid rescue treatment will be treated 
according to criteria specified in Appendix 7 of the protocol.  
Part B: Initial PRN1008 dosing will be 400 mg (qd), with intra-patient dose escalation to 
400 mg bid allowed at or after Week 3 visit for insufficient clinical response (and then again to 
600 mg bid if necessary at or after Week 5 visit). 
4.2 
Number of Participants 
This study is planned to enroll up to 50 PV patients, with an interim analysis completed when 
6 subjects completed 4 weeks or more of therapy (Study PRN1008-005 Interim Analysis 
Report). 
4.3 
Study Duration and Duration of Subject Participation 
Part A: Subjects will receive twice-daily PRN1008 treatment for 12 weeks, starting on Day 1 
and ending on study Day 85, with a further 12 weeks of follow up (total duration of individual 
subject participation is approximately 28 weeks). 
Part B: Patients will receive once or twice-daily PRN1008 for 24 weeks, starting on Day 1 and 
ending on study Day 169, with a follow up visit 4 weeks later (a total duration of individual 
subject participation is approximately 32 weeks). 
Patients enrolled in a previous version of this protocol who are still in their 12-week 
active treatment period with PRN1008 are eligible to continue treatment, initially with 
their current dose level, under this amended protocol for an additional 12 weeks, i.e. 
24 weeks total, following review and signature of the EC approved patient’s consent see 
Section 6.1 Inclusion Criteria. 
The expected study duration is approximately 48 months from the first subject treated to the last 
subject completing Part B in the study.  
4.4 
End of Study Definition 
The end of the study is defined as the date of the final safety follow-up after the LPLV. 

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4.5 
PRN1008 Administration 
Part A: Initial PRN1008 dosing will be 400 mg bid. The maximum dose in this study, after dose 
adjustment, will be 600 mg bid. Clinical response and tolerability will be assessed at each visit. 
Dosing may be adjusted according to Section 4.6. 
Part B: Initial PRN1008 dosing will be 400 mg qd, unless patients previously initiated the study 
with a 12-week treatment period are on higher doses, in which case they will initially continue 
with their current dose level. The maximum dose in this study, after dose adjustment will be 
600 mg bid. Clinical response and tolerability will be assessed at each visit. Dosing may be 
adjusted according to Section 4.6. 
PRN1008 tablets should be taken with a glass of water and may be taken with or without food, 
i.e., a period of fasting is not required. 
4.5.1 
Rationale for PRN1008 Dosage Selection 
400 mg bid (Part A): The 400 mg bid starting dose is based upon the dose known to produce 
~70% BTK occupancy at trough (~85% average occupancy over the day), as adjusted by results 
of the relative bioavailability study, where the tablet had ~70% of the exposure of the equal dose 
of the liquid formulation. Adequate BTK occupancies with 400 mg bid dosing of the IR tablet 
has been confirmed in nearly all of the 21 patients with pemphigus studied to date. To confirm 
achievement of target, BTK occupancy measurements after the first dose will be expeditiously 
processed and provided to the treating physician in time for a follow-up visit at Day 15 (Part A 
only). This dose level has adequate safety factors to exposures in chronic toxicology studies 
(Section 1.3). 
400 mg qd (Part B): In some but not all animal studies, a dose-response relationship between 
pre-dose BTK occupancy and clinical efficacy was observed. As it is unknown whether a once 
daily PRN1008 dose will provide adequate pharmacodynamic effect, a 400 mg qd dose is being 
tested in Part B, with the option to expeditiously dose-escalate to higher doses at or after the 
Week 3 visit. This dose level has adequate safety factors to exposures in chronic toxicology 
studies (Section 1.3). 
Maximum dose of 600 mg bid: A dose level 50% higher than the target upper dose level of 
400 mg bid was arbitrarily chosen based on previous clinical safety data in healthy volunteers at 
higher exposures and adequate safety factors to exposure in animal toxicology studies. 
4.5.2 
Concomitant Medications 
• Other immunosuppressive medications are not permitted except for low-dose corticosteroids 
and when rescue immunotherapy is triggered. 
• Inducers and inhibitors of Cytochrome P450 3A (CYP3A) should be avoided as they may 
reduce or increase the exposure of PRN1008 (Appendix 2) when administered 
concomitantly. 

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• PRN1008 is a moderate CYP3A inhibitor and can increase the exposure of drugs 
metabolized by CYP3A when administered concomitantly. Narrow therapeutic index CYP3A 
substrate drugs should be avoided (Appendix 3) and care should be taken with other drugs 
metabolized by the CYP3A. 
• Clinically relevant 3A substrate drugs (e.g. “sensitive substrate” listed in Appendix 3) should 
be managed by administering PRN1008 on a time schedule such that CYP3A substrate drugs 
can be given 2 hours or more after PRN1008. 
• Acid reducing drugs may reduce the bioavailability of PRN1008 tablets. Therefore, 
PRN1008 should be administered 2 hours or more prior to such drugs. Proton pump 
inhibitors are not permitted during the study. 
4.6 
PRN1008 Intrapatient Dose Adjustment 
Part A: Initial PRN1008 dosing will be 400 mg bid, with intrapatient dose adjustment based on 
clinical response and tolerability, supplemented by BTK occupancy (Table 2).  
Part B: Initial PRN1008 dosing will be 400 mg qd, with intra-patient dose escalation to 400 mg 
bid allowed at or after Week 3 visit for insufficient clinical response (see Table 3) (and then 
again to 600 mg bid if necessary at or after Week 5 visit. Corticosteroid rescue treatment will be 
initiated, if indicated (Appendix 1). 
“Well tolerated” is defined as the absence of Grade 3 or greater gastrointestinal AEs, or Grade 2 
non-gastrointestinal AEs, including liver function changes, related to PRN1008 therapy. 
Investigators should use their judgment of the risk-benefit of continuing therapy by weighing the 
extent of clinical response, and AEs potentially related to PRN1008 therapy. In general, 
PRN1008 should be stopped and conventional therapy started when tolerability is poor and 
clinical response is also suboptimal. 

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Table 2 (Part A) 
General Dose Adjustment Guidelines for Dose Selection in the First 
4 Weeks  
Clinical 
Response 
Trough BTK 
Occupancy 
Tolerability* 
Action 
Responder 
400 mg bid 
≥ 50% 
Well Tolerated 
Maintain 400 mg bid 
Taper corticosteroids if used in combination 
Poorly Tolerated  
Reduce to 300 mg bid 
Taper corticosteroids if used in combination 
< 50% 
Well Tolerated 
Maintain 400 mg bid 
Taper corticosteroids if used in combination 
Poorly Tolerated  
Reduce to 300 mg bid 
Taper corticosteroids if used in combination 
Suboptimal 
Response  
400 mg bid 
≥ 50% 
Well Tolerated 
Follow rescue criteria if triggered, if not 
maintain dose at 400 mg bid 
Poorly Tolerated  
Follow rescue criteria if triggered, if not 
maintain dose at 400 mg bid if feasible 
< 50% 
Well Tolerated 
Follow rescue criteria if triggered, if not, 
increase dose to 600 mg bid 
Poorly Tolerated  
Follow rescue criteria if triggered, if not, 
increase dose to 600 mg bid if tolerability 
allows.  
* “Well tolerated” is defined as the absence of Grade 3 or greater gastrointestinal AEs, or Grade 2 non-
gastrointestinal AEs, including liver function changes, related to PRN1008 therapy. 
 
Table 3 (Part B) 
General Dose Escalation Guidelines 
Current Dose 
Inadequate Clinical Response* Dose-escalation Rules 
400 mg qd 
Increase to 400 mg bid (allowed at Week 3 visit or later)** 
400 mg bid 
Increase to 600 mg bid (allowed at Week 5 visit or later)** 
600 mg bid 
No dose increase possible. See Appendix 1B for corticosteroid rescue protocol 
* Investigator discretion: Generally, clinical response is shown by some improvement seen in first 2 weeks with 
CDA achieved by the Week 5 visit 
** Unless tolerability issues preclude dose-escalation 

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5 
PROTOCOL DEVIATIONS 
The Principal Investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations. Principia does not allow 
intentional or prospective deviations from the protocol unless necessary to eliminate an 
immediate hazard to study subjects. The Principal Investigator is responsible for immediately 
(within 24 hours) notifying Principia of a major protocol deviation to permit Principia to 
determine the impact of the deviation on the subject and/or the study:  
Primary Principia Contact: 
 
Secondary Principia Contact: 
 
 
The Principal Investigator is responsible for notifying Independent Ethics Committee 
(IEC)/Independent Review Board (IRB) regulatory authorities, and contract research 
organization (CRO) Clinical Monitors of all protocol deviations. 

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6 
STUDY POPULATION 
The study population is male or female patients with newly diagnosed (i.e., naïve to an effective 
induction treatment regimen) or relapsing, biopsy-proven, mild to severe PV (PDAI 8-60), for 
whom an initial period of PRN1008 monotherapy is judged clinically acceptable. 
Because patients without mucosal involvement but with a medical history suggestive of PV are 
allowed into the study, some patients with clinical features suggestive of the pemphigus foliaceus 
(PF) variant of the disease may be enrolled. 
6.1 
Inclusion Criteria (Part A and Part B unless noted below) 
1. 
Male or female patients, aged 18 to 80 years old, with biopsy-proven (positive direct 
immunofluorescence and appearance on H&E microscopy), mild-moderate PV in Part A 
(PDAI 8 to 45) and mild-severe PV in Part B (PDAI 8 to 60) 
2. 
Newly diagnosed or relapsing patients for whom an initial period of PRN1008 monotherapy 
or combination therapy with low-dose corticosteroids (≤0.5 mg/kg of prednis[ol]one or 
equivalent), is judged clinically acceptable, provided tapering of the corticosteroid treatment 
regimen is anticipated with good clinical response to PRN1008 
3. 
BMI > 17.5 and < 40 kg/m2 Part A only  
4. 
Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥ 1.5 X 109/L, 
Hgb > 9 g/dL, platelet count ≥ 100 X 109/L, AST/ALT ≤ 1.5 x ULN, albumin ≥ 3 g/dL, 
creatinine ≤ ULN (Part A) and creatinine ≤ 1.5 x ULN (Part B) 
5. 
Female patients who are of reproductive potential must agree for the duration of active 
treatment in the study to use an effective means of contraception (hormonal contraception 
methods that inhibits ovulation, intrauterine device, intrauterine hormone-releasing system, 
bilateral tubal ligation, vasectomized partner, condoms or sexual abstinence). Unless 
surgically sterile, postmenopausal females should have menopause confirmed by FSH 
testing. 
6. 
Able to provide written informed consent and agreeable to the schedule of assessments. 
6.2 
Exclusion Criteria 
1. 
Previous use of a BTK inhibitor 
Patients enrolled in a previous version of this protocol who are still in their 12-week 
active treatment period with PRN1008 are eligible to continue treatment, initially with 
their current dose level, under this amended protocol for an additional 12 weeks, i.e. 
24 weeks total, following review and signature of the EC approved patient’s consent. 
Patients who completed Part A and did not discontinue the study due to a medical condition 
that might compromise safety assessments or for a PRN1008 related adverse event may be 
screened for entry under Part B.  
2. 
Pregnant or lactating women 

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3. 
ECG findings of QTc > 450 msec (males) or > 470 msec (females), poorly controlled atrial 
fibrillation (i.e. symptomatic patients or a ventricular rate above 100 beats/min on ECG), or 
other clinically significant abnormalities 
4. 
A history of malignancy of any type, other than surgically excised non-melanoma skin 
cancers or in situ cervical cancer within 5 years before the day of dosing 
5. 
Use of immunologic response modifiers with the following periods prior to Day 1: as 
concomitant therapy, other immunologic response modifiers not detailed in this exclusion 
apart from corticosteroids; 1 week: cyclophosphamide; 4 weeks: IVIG, Kinaret (anakinra) 
and Enbrel (etanercept); 12 weeks: Remicade (infliximab), Humira (adalimumab), Simponi 
(golimumab), Orencia (abatercept), Actemra (tocilizumab), Cimzia (certolizumab), 
Cosentyx (secukinumab), plasmapheresis; 6 months: Rituxan/MabThera (rituximab), 
ofatumumab, any other anti-CD20 antibody, other long-acting biologics 
6. 
More than 0.5 mg/kg of prednis(ol)one per day (“low dose corticosteroids”) within the two 
weeks prior to Day 1 
7. 
Use of proton pump inhibitor drugs such as omeprazole and esomeprazole (it is acceptable 
to change patient to H2 receptor blocking drugs prior to the first dose of PRN1008) 
8. 
Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A 
(Appendix 2) within 3 days or 5 half-lives (whichever is longer) of study drug dosing 
9. 
Use of CYP3A-sensitive substrate drugs (Appendix 3) with a narrow therapeutic index 
within 3 days or 5 half-lives (whichever is longer) of study drug dosing including, but not 
limited to, alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine 
10. Has received any investigational drug (or is currently using an investigational device) within 
the 30 days before receiving the first dose of study medication, or at least 5 times the 
respective elimination half-life time (whichever is longer) 
11. History of drug abuse within the previous 12 months 
12. Alcoholism or excessive alcohol use, defined as regular consumption of more than 
approximately 3 standard drinks per day 
13. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel 
resection that would preclude adequate study drug absorption 
14. History of anorexia nervosa or periods of three months or more of low body weight 
(BMI < 17.5) in the past 5 years 
15. Donation of a unit or more of blood or blood products within 4 weeks prior to Day 1 
16. History of solid organ transplant 
17. History of epilepsy or other forms of seizure in the last 5 years 
18. Positive for screening for HIV, hepatitis B (surface and core antibodies unrelated to 
vaccination), or hepatitis C (anti-HCV antibody confirmed with Hep C RNA) 

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19. Positive interferon-gamma release assay (IGRA) (e.g., T-spot TB Test, QuantiFERON®-TB 
Gold, or QuantiFERON®-TB Gold Plus (QFT Plus) at Screening.  Unless, the patient has 
latent TB and all of the following 3 conditions are true: 
a. Chest X-ray does not show evidence suggestive of active tuberculosis (TB) disease 
b. There are no clinical signs and symptoms of pulmonary and/or extra-pulmonary 
TB disease 
c. Documented receipt of one of the following prophylactic treatment regimens: 
i. 
Oral daily Isoniazid for 6 months 
or 
ii. 
Oral daily Rifampin (RIF) for 4 months 
or 
iii. 
Isoniazid and Rifapentine weekly for 3 months (3HP) 
On a case by case basis, after discussion and approval by the Sponsor, a local TB test that is 
negative and is considered equivalent to 1 of the above tests may be used for eligibility. For 
example, if a QuantiFERON®-TB Gold, or QuantiFERON-TB Gold Plus (QFT Plus) is 
positive and a local blood test or T-Spot TB test is negative, the patient may be enrolled 
using the local result upon approval of the Sponsor. 
 
 
20. History of serious infections requiring intravenous therapy with the potential for recurrence 
21. Live vaccine within 28 days prior to baseline or plan to receive one during the study 
22. Any other clinically significant disease, condition, or medical history that, in the opinion of 
the Investigator, would interfere with subject safety, study evaluations, and/or study 
procedures 
6.3 
Prior and Concomitant Therapy 
6.3.1 
Prior Therapy 
Not Permitted: 
Use of immunologic response modifiers within the following periods prior to Day 1:  
• One week for cyclophosphamide 
• Four weeks for Kinaret® (anakinra), intravenous gamma globulin (IVIG), and Enbrel® 
(etanercept) 
• 12 weeks for Remicade® (infliximab), Humira® (adalimumab), Simponi® (golimumab), 
Orencia® (abatercept), Actemra® (tocilizumab), Cimzia® (certolizumab), Cosentyx™ 
(secukinumab), plasmapheresis 

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• 6 months for Rituxan®/MabThera® (rituximab), ofatumumab, any other anti-CD20 
antibody, or any other long-acting biologic 
6.3.2 
Concomitant Therapy 
Not Permitted: 
• Concomitant use of immunosuppressant medication, other than low-dose corticosteroids, 
unless rescue criteria (Appendix 1) are triggered. 
• Concomitant use of known strong to moderate inducers or inhibitors of CYP3A (Appendix 2) 
within 14 days or 5 half-lives (whichever is longer) of dosing with PRN1008. 
• Use of CYP3A-sensitive substrate drugs (Appendix 3) with a narrow therapeutic index 
within 14 days or 5 half-lives (whichever is longer) of PRN1008 dosing including, but not 
limited to, alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine. 
• Proton pump inhibitors are not permitted. Esomeprazole was shown to reduce the exposure 
of PRN1008 by approximately 50%, presumably due to the effects of a lack of an acidic 
environment on tablet dissolution. Therefore, subjects who are on proton pump inhibitors 
should be changed to H2 receptor blocking drugs if possible or not enrolled in the study. 
Permitted: 
• The use of oral prednis(ol)one may be permitted in some circumstances. For admission to the 
study, doses of oral prednis(ol)one in the 2 weeks prior to Day 1 may be no higher than 
0.5 mg/kg per day (inhaled and mucosal [for symptomatic treatment of oral lesions] 
corticosteroids are allowed). Where patients enter the study on low-dose corticosteroids, the 
regimen should be maintained for the initial 2 weeks of PRN1008 therapy. At the Day 15 
review, a good clinical response to PRN1008 should allow the tapering of the corticosteroid 
to commence using the Werth taper (Appendix 7). At all times, the rescue criteria should be 
followed, as indicated (Appendix 1). In some circumstances, corticosteroids should be added 
or the dose increased, with or without cessation of PRN1008. 
• Clinically relevant 3A substrate drugs (e.g., “sensitive substrate” listed in Appendix 3) 
should be managed by administering PRN1008 on a time schedule such that CYP 3A 
substrate drugs can be given 2 hours or more after PRN1008. 
• H2 receptor blocking drugs and antacids are permitted provide PRN1008 is given at least 
2 hours beforehand. 
• Anticoagulation with warfarin should be monitored actively in the first weeks of PRN1008 
therapy, as the combination has not been studied previously. 

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7 
LIST OF SCREENING ASSESSMENTS 
The Schedule of Assessments is presented in Appendix 4. All participants must sign and date the 
most current Institutional Review Board (IRB)-approved written informed consent form before any 
study specific assessments or procedures are performed. An original signed consent form will be 
retained by the Investigator and the participant will be given a copy of the signed consent form. 
Participants must fulfill all entry criteria to be enrolled into the study. Participants who fail to meet 
the entry criteria may be rescreened once at the discretion of the Investigator. A record of 
eligibility screening documenting the Investigator’s assessment of each screened participant with 
regard to the protocol’s inclusion and exclusion criteria, including screen failures, is to be 
completed and signed by the Investigator or designee. Ethnicity of participants will be recorded, 
since this information might be important to evaluate a potential impact of ethnic factors on drug 
properties [see also ICH Guideline E5 (R1)]. 
Up to 28 days before enrollment in the study, participants will be required to sign a consent 
form, after which screening assessments will be carried out. After providing written informed 
consent, subjects will complete the Screening Assessments within 28 days before the first dose of 
PRN1008: 
• Review of medical history and concomitant medication 
• PDAI, ABSIS assessments 
• Review of inclusion and exclusion criteria 
• Measurement of height and weight  
• Physical examination 
• 12-Lead ECG 
• Vital signs (blood pressure, heart rate, respiration rate, and temperature) 
• Clinical laboratory testing (hematology, coagulation, serum chemistry, and urinalysis) 
• HIV, hepatitis B (surface antigen and core antigen and antibodies), hepatitis C (anti-HCV 
antibody confirmed with Hep C RNA)  
• TB screen with T-spot TB Test, QuantiFERON®-TB Gold, or QuantiFERON®-TB Gold 
Plus (QFT Plus) 
• Serum pregnancy test for females of child bearing potential 
• FSH (in postmenopausal women who are not surgically sterile only) 
• Skin biopsy if not already performed: lesional for H&E staining, perilesional for direct 
immunofluorescence 
 

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8 
LIST OF STUDY ASSESSMENTS  
The Schedule of Assessments is presented in Appendix 4. 
8.1 
Clinical Assessments Part A and B 
• Medical history, including evaluation of any on-study AEs and periodic vital signs (body 
temperature, heart rate, respiratory rate, blood pressure), concomitant medication use, full or 
abbreviated physical examination 
• At screening only: height and weight, full physical examination, and 12-lead 
electrocardiogram (ECG) (an extra ECG may be taken at additional visits, if indicated) 
• Disease activity scores (PDAI, Autoimmune Bullous Skin Disorder Intensity Score [ABSIS]) 
(Appendix 5) 
• Standardized photography of the affected area (Optional) 
• Autoimmune Bullous Diseases Quality of Life (ABQOL) and Treatment of Autoimmune 
Bullous Diseases Quality of Life (TABQOL) assessments (Appendix 5) 
• SNAQ appetite questionnaire (Appendix 6) 
8.2 
Laboratory Assessments Part A and B 
Note: Laboratory assessments will be performed at both central and local laboratories, if 
required. 
• Hematology: hemoglobin, hematocrit, erythrocyte count (RBCs), thrombocyte count 
(platelets), leukocyte count (WBCs) with differential in absolute counts (including 
neutrophils, eosinophils, basophils, lymphocytes, and monocytes) 
• Coagulation:  PT/INR, thrombin time, aPTT, fibrinogen level. 
• Serum Chemistry: Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), 
Total, direct, and indirect bilirubin levels, Alkaline phosphatase (ALP), Albumin, Creatinine, 
Urea, Total Protein, Sodium, Chloride, Calcium, Phosphate, Potassium, Glucose (random), 
creatine phosphokinase (CPK) and thyroid stimulating hormone (TSH) 
• PK: Plasma PRN1008 concentration  
• PD: 
- 
BTK occupancy in PBMCs at baseline (pre-dose), and 2 and 24 hours after the first dose, 
then at various times of the day during follow-up visits. For the Day 2 (24 hour) BTK 
occupancy, PRN1008 should be taken as usual in the evening (only if bid dosing) and the 
PRN1008 morning dose withheld in order to take the blood sample approximately 
12 hours after the prior evening dose (for bid dosing) or 24 hours after the last dose 
(for qd dosing). Where follow-up is not feasible on Day 2, another day in the first week 

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of therapy may be used to get trough occupancy instead. For all other visits, occupancy is 
measured at random times after the usual morning dose. 
- 
Anti-desmoglein-1 and -3 autoantibody titers by enzyme-linked immunosorbent assay 
(ELISA) 
• Urinalysis:  pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, 
urobilinogen and leukocytes measured by dipstick 
• Serology:  HIV, Hepatitis B and Hepatitis C and T-spot TB Test or QuantiFERON® TB 
testing or QuantiFERON®-TB Gold Plus (QFT Plus) at screening only 
• Pregnancy or FSH:  Serum pregnancy test for women of child bearing potential or serum 
FSH for post-menopausal females 
8.3 
Safety and Tolerability Assessments 
Specific assessments to evaluate treatment safety include the following: the frequency and type 
of AEs, clinical laboratory testing, SNAQ appetite questionnaire (Appendix 6) and vital signs. 
Patients will remain under observation in the clinic for 2 hours after administration of the first 
PRN1008 dose and until the PK sample is drawn (see also Section 12.1, Safety Monitoring 
Committee). 

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9 
STUDY TREATMENT 
Part A: Initial PRN1008 dosing will be 400 mg bid. The maximum dose in this study, after dose 
adjustment, will be 600 mg bid. Subjects will be treated with PRN1008 for a maximum of 
12 weeks. 
Patients enrolled in a previous version of this protocol who are still in their 12-week 
active treatment period with PRN1008 are eligible to continue treatment, initially with 
their current dose level, under this amended protocol for an additional 12 weeks, i.e. 
24 weeks total, following review and signature of the EC approved patient’s consent. 
Part B: Initial PRN1008 dosing will be 400 mg qd unless patients are eligible to roll from 
Part A to Part B. The maximum dose in this study, after dose adjustment, will be 600 mg bid. 
Subjects will be treated with PRN1008 for a maximum of 24 weeks. 
PRN1008 tablets should be taken with a glass of water, with or without food, i.e., a period of 
fasting is not required. 

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10 
IDENTITY OF INVESTIGATIONAL PRODUCT 
10.1 
Formulation 
Each PRN1008 film-coated tablet contains either 100 mg or 300 mg of PRN1008 drug 
substance. In addition, the tablet contains Microcrystalline Cellulose (filler), Crospovidone 
(disintegrant), Sodium Stearyl Fumarate (lubricant) and a non-functional film coating. 
The 100 mg tablet is a round shape and orange in color. The 300 mg tablet is an oval shape and 
white in color. 
10.2 
Packaging 
PRN1008 tablets are packaged in white high-density polyethylene (HDPE) bottles with child-
resistant induction-sealed caps. 
10.3 
Storage and Handling 
PRN1008 tablets are supplied in white plastic bottles with child-resistant induction-sealed caps 
or blister packs. The recommended storage condition is 2 to 25°C. Refer to product label for 
specific instructions. 
10.4 
Drug Accountability 
The Investigator or his/her designated representatives will dispense study drug per the Schedule 
of Assessments (Appendix 4). 
The Investigator is responsible for the control of drugs under investigation. Adequate records of 
the receipt (e.g., Drug Receipt Record) and disposition (e.g., Investigational Drug Dispensing 
Log) of the study drug must be maintained. The investigational Drug Dispensing Log must be kept 
current and should contain the following information: 
• The identification of the participant to whom the study drug was dispensed (for example 
subject identification number, participant initials, and date of birth) 
• The date(s), quantity, and lot number(s) of the study drug dispensed to the participant 
• The identification of the person who dispensed the study drug 
All records and drug supplies must be available for inspection by the Study Monitor at every 
monitoring visit. When the study is completed, the Investigator will return any used and unused 
study drug (e.g., empty, partially used, and unused containers), occluded labels (or the equivalent) 
to the Sponsor as requested. The completed Drug Dispensing Log and Drug Return Record(s) will 
be returned to the Local Sponsor. The Investigator's copy of the Drug Return Record(s) must 
accurately document the return of all study drug supplies to the Sponsor. 

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10.5 
Destruction of Investigational Product 
Local or institutional regulations may require immediate destruction of used investigational 
medicinal product for safety reasons. In these cases, it may be acceptable for investigational study 
center staff to destroy dispensed investigational product before a monitoring inspection, provided 
that source document verification is performed on the remaining inventory and reconciled against 
the documentation of quantity shipped, dispensed, returned, and destroyed, and provided that 
adequate storage and integrity of drug has been confirmed. Written authorization must be obtained 
from the Sponsor or Sponsor designee after final accountability prior to destruction. 
Unused study drug from the site that has not been stored properly should not be destroyed until the 
final report has been approved. 
Written documentation of destruction must contain the following: 
• Identity of investigational product(s) destroyed 
• Quantity of investigational product(s) destroyed 
• Date of destruction 
• Method of destruction 
• Name and signature of responsible person who destroyed the investigational products 
Investigational sites that do not have a procedure for destruction and appropriate disposal of 
investigational product, or cannot dispose of investigational product locally may request 
assistance and documentation for return to the Sponsor, or assignment to a local qualified vendor 
for destruction and disposal. 
 

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11 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
11.1 
Primary Outcome Measures 
11.1.1 
Safety  
The incidence of treatment-emergent AEs (TEAEs), including clinically significant changes in 
physical examination, laboratory tests, and vital signs. 
11.1.2 
Efficacy  
The proportion of subjects who are able to achieve control of disease activity (CDA) within 
4 weeks of starting PRN1008 treatment without the need for doses of prednis(ol)one > 0.5 mg/kg.  
11.2 
Secondary Outcome Measures 
The following clinical activity endpoints* will be assessed: 
• Proportion of subjects able to achieve CDA without corticosteroids within 4 weeks 
• Proportion of subjects able to achieve a complete response (CR) without corticosteroids 
within 12 weeks (and 24 weeks in Part B) 
• Proportion of subjects able to achieve CR without the need for doses of prednis(ol)one of 
greater than 0.5mg/kg within 12 weeks (and 24 weeks in Part B) 
• Time to CDA 
• Time to CR 
• Time to end of consolidation phase 
• Time to relapse after PRN1008 treatment discontinuation 
• Cumulative corticosteroid usage over the first 12 weeks (and 24 weeks in Part B) 
• Change from baseline in Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous 
Skin Disorder Intensity Score (ABSIS) scores at each follow-up visit 
• Change from baseline in Autoimmune Bullous Diseases Quality of Life (ABQOL) and 
Treatment of Autoimmune Bullous Diseases Quality of Life (TABQOL) scores at each 
follow-up visit 
• Change from baseline in appetite (SNAQ score) at each follow-up visit 
*Clinical activity endpoints as defined by the EADV 2014 pemphigus S2 guideline (Hertl et al. 2015) with the 
exception that CR is defined as CR at a single point in time rather than present for ≥2 months 
 

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11.3 
PK/PD Outcome Measures 
11.3.1 
PK Outcome Measures 
• Plasma concentrations of PRN1008 at approximately the time of maximum concentration on 
Day 1 and at various subsequent times during outpatient dosing 
11.3.2 
PD Outcome Measures 
• Percentage BTK occupancy for individuals in peripheral blood mononuclear cells (PBMCs) 
at 2 & 24 hours after the first PRN1008 dose and at varied subsequent times during 
outpatient dosing 
• Change from baseline in anti-dsg1-3 autoantibody levels by ELISA at various time points 
11.3.3 
Exploratory PK/PD Analysis 
Exploratory PK/PD analysis will examine the effects, if any, of covariates on PK and/or PD, and 
the relationship between PK, PD, and efficacy in this population. 
11.4 
Determination of Sample Size 
Sample size for this pilot study was determined pragmatically by the number of subjects required 
to determine a preliminary safety profile and a point estimate for the primary endpoint of 
efficacy. If the clinical response rate is 50%, 25 subjects in each Part will result in an 80% CI of 
± 13%. Results from this pilot study will be used to design confirmatory clinical trials. 
11.5 
Analysis Populations 
Four study populations will be defined: Screening Population, Safety Population, Efficacy 
Population, and Pharmacokinetic Population. 
11.5.1 
Screening Population 
All participants who provide informed consent and have screening assessments evaluated for 
study participation are included in the Screening Population. 
11.5.2 
Safety Analysis Population 
All participants who have received at least one dose of PRN1008 will be included in the safety 
analysis. The Safety Analysis Population will be defined for all safety analyses. 
11.5.3 
Efficacy Analysis Population 
All patients who have received at least one dose of PRN1008 will be included in the efficacy 
analysis. Subject response and disease progression will be determined using PDAI, ABSIS, 
ABQOL, and TABQOL scores. Efficacy data will be presented in listings by subject and 
tabulated for each efficacy endpoint. Data may be combined where appropriate for Parts A 

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and B. Additional sub-group analyses (e.g. disease severity, dose group) may be performed as 
appropriate. 
11.5.4 
Pharmacokinetic Analysis Population 
A pharmacokinetic population will be defined for participants who provide adequate plasma 
concentration data to allow for PK analysis. Participants may be excluded from the PK population 
if they significantly violate the inclusion or exclusion criteria, deviate significantly from the 
protocol, or if data are unavailable or incomplete, all of which may influence the analysis. 
Excluded cases will be documented together with the reason for exclusion in the Clinical Study 
Report. 
11.6 
Randomization and Blinding Procedures 
Not applicable; the study is open-label. 
11.7 
Subject Numbers and Treatment Assignments 
As they are enrolled in the study, subjects will be assigned a unique consecutive number. 
The site, in conjunction with the Sponsor, will be responsible for assignment of all unique subject 
numbers and dose assignments. 
11.8 
Subject Disposition, Subject Replacement, and Demographics and Baseline 
Characteristics 
11.8.1 
Disposition 
The numbers of subjects enrolled, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated. The number of subjects in each analysis population will be 
reported overall. 
11.8.2 
Replacement of Subjects 
Participants prematurely discontinued from the study for non-safety reasons may be replaced at the 
discretion of the Sponsor, to ensure adequate numbers of evaluable participants. A patient is 
considered "evaluable" if they took one or more doses of the study drug. Each patient who 
provides informed consent will be assigned a unique subject identifier (USUBJID). Participants 
recruited to be replacement patients will be assigned the next available subject identifier. 
11.8.3 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics (pemphigus type, age, sex, race, ethnicity, weight, 
height, and body mass index) will be summarized for the Safety Population using descriptive 
statistics. No formal statistical analyses will be performed, and no inferential statistics reported. 
Prior and concomitant medications will be summarized overall, by dose level, and by the number 
and percentage of subjects taking each medication, classified using World Health Organization. 
Drug Dictionary Anatomical Therapeutic Chemical classes and preferred terms (WHODD). 

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Disposition, baseline demographics and subject characteristics will be summarized for the Safety 
Population. 
11.9 
Efficacy Analysis 
11.9.1 
Subject Response and Disease Progression 
Subject response and disease progression will be determined using PDAI, ABSIS, ABQOL, and 
TABQOL scores. Efficacy data will be presented in listings, by subject, and tabulated overall. 
Data may be combined where appropriate for Parts A and B. Additional sub-group analyses 
(e.g. disease severity, dose group) may be performed as appropriate. 
The PDAI, ABSIS, ABQOL, and TABQOL questionnaires are located in Appendix 5. 
11.10 Safety Analysis 
Quantitative safety data will be summarized by descriptive statistics (arithmetic mean, standard 
deviation, median, minimum, and maximum) by dose level. Summaries will also be presented 
for the change from baseline, when appropriate. All safety analyses will be based on the Safety 
Analysis Population. As appropriate, listings, summary tables and graphs (individual plots and/or 
mean plots) by period will be provided to the Investigator and to the SMC for safety and 
tolerability assessment. 
11.10.1 Adverse Events 
The original verbatim AE terms recorded on the participant’s case report form (CRF) by the 
Investigator will be standardized by the Local Sponsor by assigning preferred terms and system 
organ classes from the most recent available version of the Medical Dictionary for Drug 
Regulatory Affairs (MedDRA). 
AEs will be described by individual listings and frequency tables by preferred terms and body 
system. The NCI CTCAE, version 4.0 will be used for grading AEs. 
11.10.2 Clinical Laboratory Tests 
All clinical laboratory data will be stored in the database in the units in which they were reported. 
Normal ranges for the local laboratory parameters must be provided to Principia/designee before 
the study starts. Participant listings and summary statistics at each assessment time, including 
change from baseline, will be presented using the International System of Units (SI units; Système 
International d’Unités). Laboratory data not reported in SI units will be converted to SI units 
before analysis.  
Clinical laboratory results will be summarized descriptively for baseline and each time point. 
The numerical change from baseline to each time point will be computed. In addition, laboratory 
shift tables will be provided for all laboratory parameters where low/normal/high or abnormal/ 
normal status can be ascertained for shift from baseline to each time point. Listings of individual 
laboratory parameters by visit with normal ranges and abnormality assessments will also be 
completed by subject. 

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Scatter plots of the baseline value (x-axis) and end of study (y-axis) will be completed for each 
continuous clinical laboratory parameter. In addition, individual and group mean laboratory 
values over time (i.e., by visit) will also be completed to evaluate changes and trends in 
laboratory safety. Reference ranges will be highlighted on the plots to identify laboratory 
assessment out of range. Other graphical displays may be created as appropriate. 
11.10.3 Vital Signs 
Vital signs data will be presented by individual listings. Systolic blood pressure values < 90 or 
> 140 mmHg and diastolic blood pressure values < 60 or > 80 mmHg will be flagged as outside 
the normal range. Resting heart rate < 40 or > 100 beats per minute will be flagged as abnormal. 
Descriptive statistics of values and changes from baseline (mean, median, standard deviation) will 
be reported for quantitative variables separately for each period. In addition, tabular and graphical 
summaries will be used, as appropriate. 
11.10.4 Concomitant Medications 
The original terms recorded on the participants’ CRF by the Investigator for concomitant 
medications will be standardized by the Local Sponsor by assigning preferred terms from the 
WHODD (World Health Organization Drug Dictionary) drug terms dictionary for treatments or 
coded via generic name of the concomitant medication. 
Concomitant medications will be presented in summary tables and listings. 
11.11 Pharmacokinetics/Pharmacodynamics Analyses 
Individual and group PK and PD data will be summarized, displayed graphically, and by 
descriptive statistics for each visit where measured. Data will be summarized by descriptive 
statistics and related to clinical responses for each patient and as a group. PD and PD data 
will be pooled with data from other studies, and analyzed and reported separately. 
11.11.1 Missing PK/PD Values  
The methodology of handling missing PK/PD values in the analysis will be determined. 
11.12 Statistical and Analytical Methods 
11.12.1 Descriptive Summaries and Inference 
Descriptive summary statistics will be provided for the safety, PK, and PD variables. 
For continuous variables, these statistics will typically include the number of subjects, mean, 
standard deviation, median, minimum, and maximum. For categorical variables, these statistics 
will typically include the number and percentage of subjects in each category. Descriptive 
summaries will be completed by study part, cohort, and dose. 
Due to the small sample sizes, all p-values derived from inferential analyses will be considered 
informative. In general, all significant testing will be two-sided at significance level 0.05. 
All tests will be made without adjustment for multiplicity or multiple comparisons. 

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11.12.2 Exploratory Analyses 
Exploratory analyses not specified in the protocol or statistical analysis plans may be performed 
to further explore study results. 
11.12.3 Interim Analysis 
An interim analysis to evaluate safety, and to reevaluate sample size and other aspects of study 
design, was conducted for this study when 6 patients completed 4 weeks or more of PRN1008 
therapy (Part A only) (Study PRN1008-005 Interim Analysis Report). 

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12 
SAFETY AND TOXICITY MANAGEMENT 
This section provides detailed information on reporting requirements and interpretation of safety 
assessments for AEs and reporting requirements for serious SAEs. Guidance and reporting 
requirements for pregnancy are also provided. 
12.1 
Safety Monitoring Committee  
A Safety Monitoring Committee (SMC) will review the emerging safety data (TEAEs, safety 
labs), and efficacy, PD, and dose modification data approximately every 3 months within the 
first 6 months following the first subject enrolled in the study, and then with a frequency 
determined as appropriate by the SMC. The SMC members will include the Sponsor's Medical 
Monitor, a Principal Investigator, and a pemphigus clinical expert who is not an investigator in 
the study. The trial statistician will also participate in safety reviews. Documentation of the 
patient data reviewed at each meeting, including the individual SMC member’s confirmation of 
data review and the findings and actions of the SMC, will be included in the Trial Master File. 
SMC findings that impact the safety of patients in this study will be immediately reported to the 
local Competent Authority (CA) and Ethics Committee (EC). 
An SMC Charter outlining the SMC composition and responsibilities will be in place prior to the 
first scheduled meeting. 
12.2 
Adverse Event Collection Period 
The AE Collection Period begins at the time of the first screening/eligibility assessment and ends 
at the end of the study for each patient. 
12.3 
Clinical Adverse Events 
An AE is any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related to the 
product. All AEs encountered during the clinical study will be reported in detail in the source 
documents and documented in the CRF, from the date of participant consent throughout the 
follow-up visit.  
Pre-existing conditions that worsen during a study are to be reported as AEs, with the exception 
of the disease under study as it is expected that there may be variation in pemphigus disease 
activity, and this is captured in other measurements. 
The below guidelines should be followed when recording AEs: 
Medical terms: Whenever possible, use recognized medical terms when recording AEs on the 
AE CRF. Do not use colloquialisms or abbreviations. 

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Diagnosis: If known or suspected, record the diagnosis rather than component signs and 
symptoms on the AE CRF and SAE form (e.g., if a diagnosis is made of congestive heart failure, 
record congestive heart failure rather than the symptoms of dyspnea, rales, cyanosis). However, 
signs and symptoms that are considered unrelated to an encountered syndrome or disease should 
be recorded as individual AEs on the AE CRF or SAE form. 
Death: Death is an outcome of an event. The event that resulted in the death should be recorded 
and reported on the AE CRF and SAE form (except for sudden, unexplained death.) 
Surgical or diagnostic procedures: For medical or surgical procedures (e.g., colonoscopy, 
biopsy), the medical condition that led to the procedure is an AE. Elective procedures (e.g., 
vasectomy), planned hospitalizations, and procedures for treatment of conditions noted in the 
patient’s medical history that have not worsened (e.g., planned cataract surgery, hernia repair) 
are not considered AEs. 
Chronic disease: In the case of disease (excluding disease under study) that is progressing by 
episodes (chronic disease), if the disease is known when the participant enters the trial, only 
worsening (increased frequency or intensity of the episodes or attacks) will be documented as an 
AE. If the disease is detected during the trial, and if repeated episodes enable diagnosis of a 
chronic disease, the episodes will be entered with the diagnosis and start/stop dates grouped 
together, and clearly described in the source documents. 
Disease under study (Pemphigus): Unexpected progression, signs, or symptoms of the disease 
under study are not AEs and are not to be recorded on the AE page of the CRFs unless the event 
meets the definition of an SAE or is not consistent with the typical clinical course of the patient’s 
disease as established by the patient’s medical history.  Worsening of the disease under study or 
other disease-related symptoms should be recorded as an AE only if the event meets the 
definition of an SAE or is not consistent with the typical clinical course of the disease.  
Laboratory Out of Range Values: An isolated, out-of-range laboratory result in the absence of 
any associated, clinical finding may or may not be considered an AE; the Investigator’s 
evaluation should be based on a consideration of the overall clinical context. An out-of-range 
laboratory result will be considered clinically significant and recorded as an AE when it is part of 
a clinical abnormality requiring specific medical intervention or follow-up. The test will be 
repeated and the patient will be followed-up until the test value has returned to the normal range 
or baseline, or the Investigator has determined that the abnormality is chronic or stable. The 
Investigator will exercise medical judgment in deciding whether out-of-range values are 
clinically significant and document the assessment in the source records. 

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12.4 
Adverse Event Intensity Grading 
All clinical AEs encountered during the clinical study will be reported on the AE page of the 
CRF. Intensity of AEs will be graded based on the NCI CTCAE, Version 4.0 or higher and 
reported in detail as indicated on the CRF. For any AEs not found in the CTCAE, a description 
of intensity grading can be found below: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living. 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
12.5 
Adverse Event Relationship to Study Drug 
Investigators should use their knowledge of the study participant, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or not an 
AE is considered to be related to the study drug, indicating "yes" or "no" accordingly. 
The following guidance should be taken into consideration: 
• Temporal relationship of event onset to the initiation of study drug 
• Course of the event, considering especially the effects of dose reduction, discontinuation of 
study drug, or reintroduction of study drug (if applicable) 
• Known association of the event with the study drug or with similar treatments 
• Known association of the event with the disease under study 
• Presence of risk factors in the study participant or use of concomitant medications known to 
increase the occurrence of the event 
• Presence of non-treatment-related factors that are known to be associated with the occurrence 
of the event 
12.6 
Treatment and Follow-Up of Adverse Events 
SAEs for which the relationship to the study drug is “related”, should be followed up until they 
have returned to baseline status or stabilized. 

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If after follow-up, return to baseline status or stabilization cannot be established an explanation 
should be recorded on the CRF. 
12.7 
Laboratory and ECG Abnormalities 
Laboratory test results will be recorded on the laboratory results pages of the CRF, or appear on 
electronically produced laboratory reports, if applicable. 
Any treatment-emergent abnormal laboratory or ECG result which is clinically significant, i.e., 
meeting one or more of the following conditions, should be recorded as a single diagnosis on the 
AE page in the CRF: 
• Accompanied by clinical symptoms 
• Leading to a change in study drug (e.g. dose modification, interruption or permanent 
discontinuation) 
• Requiring a change in concomitant therapy (e.g., addition of, interruption of, discontinuation 
of, or any other change in a concomitant medication, therapy or treatment) 
Note: Any laboratory or ECG result abnormality fulfilling the criteria for a serious adverse event 
(SAE) should be reported as such, in addition to being recorded as an AE in the CRF. 
12.7.1 
Follow-Up of Abnormal Laboratory Test Values 
In the event of unexplained clinically significant abnormal laboratory test values, the tests should 
be repeated as soon as possible and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found. If a clear explanation is established, 
it should be recorded on the CRF. 
12.8 
Serious Adverse Event (SAE) Reporting 
12.8.1 
SAE Definitions 
An SAE is any experience (clinical AE or abnormal laboratory test) that suggests a significant 
hazard, contraindication, side effect, or precaution. An SAE must fulfill at least one of the 
following criteria at any dose level: 
• is fatal (results in the outcome death)* 
• is life-threatening 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is medically significant or requires intervention to prevent one or other of the outcomes listed 
above 

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Note that the term "sudden death" should only be used when the cause is of a cardiac origin as 
per standard definition. The terms "death" and "sudden death" are clearly distinct and must not be 
used interchangeably. 
12.8.2 
SAE Reporting 
Any clinical adverse event or abnormal laboratory test value that is serious and which occurs 
during the course of the study (as defined above), occurring from the enrollment visit (start of 
study screening procedures), including long term follow-up must be reported to: 
• The Local Sponsor (or designee) and monitor within 24 hours of the Investigator becoming 
aware of the event (expedited reporting). 
• The investigational site’s IRB by the investigator in accordance with their regulations. 
Initial notification of an SAE must be confirmed in24 hours from the time the investigational 
team first become aware of the event using the PPD RAVE system, if possible. Paper SAE report 
forms should only to be used when the PPD RAVE system is not accessible, and SAEs should be 
transferred into RAVE once the system is available. 
If PPD RAVE is not accessible, a written, narrative description of any SAE must be scanned and 
emailed to 1008005SAE@principiabio.com within 24 hours of awareness of the event. 
If paper SAE forms are used, copies of the initial and follow-up SAE report forms must be made 
and the originals retained of all information faxed to PPD in the Investigator Site File. 
As further information regarding the SAE becomes available, such follow-up information should 
be documented as an update in the RAVE system, or if RAVE is not accessible, on a new SAE 
report form, marked as a follow-up report and emailed to 1008005SAE@principiabio.com. 
After informed consent, but prior to initiation of study medications, only SAEs caused by a 
protocol-mandated intervention must be reported within 24 hours (e.g., SAEs related to invasive 
screening procedures such as biopsies, medication washout, or no treatment run-in). After first 
study medication, all SAEs must be reported within 24 hours. 
SAEs identified after a subject has exited the study, that the Investigator deems related to 
PRN1008 exposure, should be reported to the Sponsor as noted above. 
Unrelated SAEs must be collected and reported during the study and for up to 30 days after the 
last dose of study medication. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are reported to Investigators at 
each site and associated IRB when the following conditions occur: 
• The event is a SAE 
• There is a reasonable possibility that the event is an adverse reaction caused by the 
administered drug 

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• The adverse reaction is unexpected, that is to say, not foreseen in the Investigator’s Brochure 
• When all participants at a particular site are off treatment, as defined by the protocol, 
individual SUSAR reports will be forwarded to the site and its associated IRB on an 
expedited basis. 
Individual SUSARs considered to be a significant safety issue and/or which result in a change to 
the informed consent form will be reported in an expedited manner to all Investigators and IRBs. 
Reporting of any SAEs to applicable regulatory authorities will be the responsibility of the Local 
Sponsor in compliance with local regulations. 
12.8.3 
Other Safety Findings Requiring Expedited Reporting 
Significant safety findings will be reported to the Investigator by Principia or designee as 
obtained. The Investigator is responsible for reporting to the investigational site’s IRB in 
accordance with their regulations. Reporting to applicable regulatory authorities will be the 
responsibility of Principia (or designee) in compliance with local regulations. 
12.9 
Pregnancy 
Pregnancy in a Female Clinical Trial Participant: If a female clinical trial participant becomes 
pregnant during the study, she must be instructed to stop taking the study drug and immediately 
inform the Investigator. Pregnancies occurring up to 90 days after the completion of the study 
drug must also be reported to the Investigator. The participant should be counseled by a 
specialist, to discuss the risks of continuing with the pregnancy and the possible effects on the 
fetus. Monitoring of the participant should continue until the outcome of the pregnancy is 
known. The Investigator should report all pregnancies in clinical trial participants to the Sponsor 
within 24 hours of becoming aware of them, using the Clinical Trial Pregnancy Reporting Form. 
Pregnancy in the Partner of a Male Clinical Trial Participant: If the Investigator becomes aware 
of a pregnancy occurring in the partner of a participant participating in the study, the pregnancy 
should be reported to the Sponsor within 24 hours working day of obtaining written consent from 
the pregnant partner. The Investigator will make arrangements for the pregnant partner to be 
counseled by a specialist, to discuss the risks of continuing with the pregnancy and the possible 
effects on the fetus. Monitoring of the pregnant partner should continue until the outcome of the 
pregnancy is known. 
Note: The Pregnancy Reporting Form should only be completed by the Investigator if the 
pregnant partner has signed an Informed Consent Form “Information to Pregnant Partner of 
Participant.” 

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13 
DATA QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data, including data collection and 
management, will be described in the Data Management Plan. 
Accurate and reliable data collection will be assured by verification and cross–check of the CRF 
against the Investigator’s records by the study monitor (source document verification), and the 
maintenance of a study drug–dispensing log by the Investigator. 
Data for this study will be recorded in the study Electronic Data Capture (EDC) CRFs. The data 
will be entered by the study center from the source documents into the CRF or will be loaded 
from electronic files (e.g., safety lab data). In no case is the CRF to be considered as source data 
for this study. 
A comprehensive validation check program will verify the data and discrepancy reports will be 
generated accordingly for resolution by the Investigator. All discrepant data will be resolved in 
the EDC database and all data entered in the database will be independently compared with the 
original Investigator’s records. 
13.1 
Assignment of Preferred Terms and Original Terminology 
For classification purposes, preferred terms will be assigned to the original terms recorded on the 
CRF, using the most up to date version of the MedDRA for AEs, diseases and surgical and 
medical procedures, and the WHODD for drug and herbal treatments. 

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14 
ETHICAL ASPECTS 
This section provides information for the Investigator on the ethics requirements for the study, 
including subject informed consent, IRB/EC review of the study and study materials, and 
conditions for modifying or terminating the study. Requirements for financial disclosure for the 
Investigator are also described. 
14.1 
Local Regulations/Declaration of Helsinki 
The Investigator will ensure that this study is conducted in full conformance with the principles 
of the “Declaration of Helsinki” or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual. The study must 
fully adhere to the principles outlined in current “Guideline for Good Clinical Practice” ICH 
Tripartite Guideline or with local law if it affords greater protection to the participant. 
14.2 
Subject Informed Consent 
It is the responsibility of the Investigator, or a person designated by the Investigator 
[if acceptable by local regulations], to obtain signed and dated informed consent from each 
participant prior to participating in this study after adequate explanation of the aims, methods, 
objectives and potential hazards of the study. The Investigator or designee must also explain that 
the participants are completely free to refuse to enter the study or to withdraw from it at any 
time, for any reason. 
The CRFs for this study contain a field for documenting informed participant consent, and this 
must be completed appropriately. If new safety information results in significant changes in the 
risk/benefit assessment, the consent form should be reviewed and updated if necessary. All 
participants should be informed of the new information, given a copy of the revised form and 
give their consent to continue in the study. 
14.3 
Institutional Review Board Review 
This protocol and any accompanying material provided to the participant (such as participant 
information sheets or descriptions of the study used to obtain informed consent), as well as any 
advertising or compensation given to the participant, will be submitted by principal Investigator 
or coordinating Investigator to the relevant institutional IRB responsible for the investigational 
study.  
An approval letter or certificate (specifying the protocol number and title) from the IRB must be 
obtained before starting the study (initiation). The approval letter to the Investigator should 
specify the date on which the committee met and granted the approval. The Local Sponsor must 
also obtain relevant regulatory authority approvals before starting the study. 
Any modifications made to the protocol after receipt of the IRB approval must also be submitted 
by the principal Investigator or coordinating Investigator to the IRB in accordance with local 
procedures and regulatory requirements. The Local Sponsor must also obtain relevant regulatory 

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approval for protocol modifications according to the local regulations. The Local Sponsor will 
assist the Investigator in submitting the protocol to an appropriate IRB. 
14.4 
Conditions for Modifying the Protocol 
Any protocol modifications must be prepared and approved by a representative of The Sponsor. 
All protocol modifications must be submitted to the appropriate IRB for information and/or 
approval in accordance with local requirements, and to Regulatory Agencies if required. 
Approval must be obtained before any changes can be implemented, except for changes 
necessary to eliminate an immediate hazard to study participants, or when the change(s) involves 
only logistical or administrative aspects of the study [e.g., change in monitor(s), change of 
telephone number(s)]. 
14.5 
Conditions for Terminating the Study 
The Sponsor, the Investigator and the IRB responsible for the study reserve the right to terminate 
the study at any time. Should this be necessary, the parties will consult and arrange the 
termination procedures on an individual study basis. In terminating the study, the Sponsor and 
the Investigator will assure that adequate consideration is given to the protection of the 
participant’s interests. The appropriate IRB and Regulatory Agencies should be informed 
accordingly. 
14.6 
Financial Disclosure 
The Investigator(s) will provide the Sponsor with sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the appropriate regulatory authorities. The Investigator is responsible to promptly 
update any information provided to the Sponsor if relevant changes occur in the course of the 
investigation and for 1 year following the completion of the study (last participant, last visit). 

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15 
STUDY DOCUMENTATION, MONITORING, CASE REPORT FORMS, AND 
RECORD RETENTION REQUIREMENTS 
15.1 
Investigator's File/Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into two different separate categories (1) Investigator’s Study File, and 
(2) participant clinical source documents. 
The Investigator’s Study File will contain the protocol/amendments, CRF data and 
Discrepancies, IRB and regulatory authority approval with correspondence, sample informed 
consent, drug records, staff curriculum vitae and authorization forms and other appropriate 
documents/correspondence, etc. 
Participant clinical source documents independent of the CRF would include participant 
hospital/clinic records, physician’s and nurse’s notes, original laboratory reports, ECG, EEG, 
X-ray, pathology and special assessment reports, signed informed consent forms, consultant 
letters, and participant screening and enrollment logs.  
To comply with international regulations, the records should be retained by the investigator for at 
least 2 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing application in an ICH region, or until at least 2 years 
have elapsed since the formal discontinuation of clinical development of the investigational 
medicinal product. However, the investigator may need to retain these documents for a longer 
period if require by the local regulatory requirements or by agreement with the Sponsor. 
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site for any 
or all of the documents, special arrangements must be made between the Investigator and the 
Sponsor to store these in a sealed container(s) outside of the site so that they can be returned 
sealed to the Investigator in case of a regulatory audit. Where source documents are required for 
the continued care of the participant, appropriate copies should be made for storing outside of the 
site. 
15.2 
Source Documents and Background Data 
The Investigator shall supply the Sponsor on request with any required background data from the 
study documentation or clinic records. This is particularly important when CRFs are illegible or 
when errors in data transcription are suspected. In case of special problems and/or governmental 
queries or requests for audit inspections, it is also necessary to have access to the complete study 
records, provided that participant confidentiality is protected. 

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15.3 
Audits and Inspections 
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Sponsor or its designees, or to health 
authority inspectors after appropriate notification. The verification of the CRF data must be by 
direct inspection of source documents. 
15.4 
Case Report Forms 
The data collected in the source documents for this study will be entered into the study EDC 
CRF. An audit trail will maintain a record of initial entries and changes made; time and date of 
entry; and name of person making entry or change. For each participant enrolled, a CRF must be 
completed and signed by the Principal Investigator or authorized delegate from the study staff. 
If a participant withdraws from the study, the reason must be noted in the CRF. If a participant is 
withdrawn from the study because of a treatment-limiting adverse event, thorough efforts should 
be made to clearly document the outcome. 
The Investigator should ensure the accuracy, completeness and timeliness of the data reported to 
the Sponsor in the CRFs and in all required reports. 
15.5 
Study Monitoring 
It is understood that the responsible Sponsor study monitor (or designee) will contact and visit 
the Investigator regularly and will be allowed, on request, to inspect the various records of the 
study (CRFs and other pertinent data) provided that participant confidentiality is maintained in 
accordance with local requirements. 
It will be the monitor's responsibility to inspect the EDC CRFs at regular intervals throughout the 
study, to verify the adherence to the protocol and the completeness, consistency and accuracy of 
the data being entered on them. The monitor must verify that the participant received the 
assigned dose. The monitor should have access to laboratory test reports and other participant 
records needed to verify the entries in the EDC CRF. The Investigator (or deputy) agrees to 
cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. 
15.6 
Confidentiality of Clinical Trial Documents and Participants' Medical Records 
The Investigator must assure that participants’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. In the EDC CRF or other documents 
submitted to the Sponsor, participants should not be identified by their names, but by an 
identification code. 
The Sponsor already maintains rigorous confidentiality standards for clinical studies by “coding” 
(i.e. assigning a unique participant identification (ID) number at the Investigator site) all 
participants enrolled in Sponsor clinical studies. This means that participant names are not 
included in data sets that are transmitted to any Sponsor location.  

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15.7 
Clinical Study Report 
A Clinical Study Report will be written and submitted to relevant IRB/HREC/EC and regulatory 
authorities in accordance with local requirements. 
15.8 
Publication of Data and Protection of Trade Secrets 
It is anticipated that the results of this study may be published or presented at scientific meetings. 
Investigators cannot publish without prior written permission of the Sponsor. Authors must allow 
a reasonable period for manuscript review of at least 30 days. The Sponsor may delay 
publication for commercial reasons for up to 6 months. 

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16 
STUDY ADMINISTRATIVE PROCEDURES 
This section provides additional information on study-related administrative procedures, 
definitions, requirements, and record-keeping activities related to the study assessments 
described in Section 8. 
16.1 
Subject Recruitment Procedures 
Participants will be identified for potential recruitment by the Investigator using recruitment plan 
agreed upon with Principia, possibly including, but not limited to, a listing from study center, 
volunteer database, newspaper/radio/internet advertisement, or mailing list. 
16.2 
Subject Enrollment Procedures 
Participants cannot commence enrollment procedures until all entry criteria have been fulfilled. 
Where the clinical significance of an abnormal screening test result (lab or any other tests) is 
considered uncertain, the test may be repeated. 
The Investigator or designee will enter data for each enrolled participant in the study CRF and 
enter the corresponding number for allocation to the treatment groups in the appropriate place on 
each participant’s CRF. A participant enrollment and Identification Code List must be 
maintained by the Investigator or Pharmacist, or designee. 
Under no circumstances will participants who enroll in this study and complete treatment as 
specified be permitted to re-enroll in the study. 
16.3 
Patient Premature Withdrawal – Definition  
A patient who withdraws from the study before taking one or more doses of study drug is 
considered to have withdrawn from the study early. 
16.4 
Procedures for Patients Who Withdraw from the Study 
Participants have the right to withdraw from the study at any time for any reason. In the event 
that a participant decides to discontinue from the study, he/she should be asked if he/she can still 
be contacted for further information. The outcome of that discussion should be documented in 
both the medical records and in the CRF. 
When applicable, participants should be informed of circumstances under which their 
participation may be terminated by the Investigator without the participant's consent. The 
Investigator may withdraw participants from the study in the event of intercurrent illness, AEs, 
treatment failure after a prescribed procedure, lack of compliance with the study and/or study 
procedures or any other reasons where the Investigator feels it is in the best interest of the 
participant to be terminated from the study. 

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Reasons for withdrawal must be documented and explained to the participant. It is understood by 
all concerned that an excessive rate of withdrawals can render the study uninterpretable; 
therefore, unnecessary withdrawal of participants should be avoided. Should a participant decide 
to withdraw, all efforts should be made to complete and report the observations as thoroughly as 
possible, particularly the follow-up examinations. 
The Investigator should contact the participant or a responsible relative either by telephone 
(followed by registered mail) or through a personal visit to determine as completely as possible 
the reason for the withdrawal. A complete final evaluation at the time of the participant’s 
withdrawal should be made, with an explanation of why the participant is withdrawing from the 
study. If the reason for removal of a participant from the study is an AE, the principal specific 
event must be recorded on the CRF. The participant should be followed until the AE is resolved, 
if possible. 
16.5 
Treatment Compliance 
Accountability and participant compliance will be assessed by maintaining adequate study drug 
dispensing records and medication counts. The Investigator is responsible for ensuring that 
dosing is administered in compliance with the protocol. See Section 10.4 for instructions on 
Drug Accountability procedures. 
16.6 
Recording of AEs on the CRF 
All AEs encountered during the clinical study will be reported in detail in the source documents 
and documented in the CRF, from the date of participant consent throughout the follow-up visit. 
SAEs for which the relationship to test drug is considered “related”, should be followed up until 
they have returned to the baseline status or stabilized. If the cause of the AE is established, it 
should be described in detail, including supporting information, in the source documents and on 
the CRF. 
16.7 
Physical Examination Procedures 
At screening and follow-up visits, a complete physical examination will consist of checking the 
normality or abnormality of the following body systems: general appearance, skin, eyes, ears, 
nose, throat, heart, chest/breast, abdomen, neurological system, lymph nodes, spine and 
extremities (skeletal). 
An abbreviated physical examination will consist of checking the normality or abnormality of 
the following body systems: general appearance, abdomen, and cardiorespiratory examination. 
The results of the physical examination will be summarized as normal/abnormal. In case of 
abnormality, details will be recorded in the participant notes and in the CRF. 
Height will be recorded at screening only. 

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16.8 
Vital Signs Procedures 
Blood pressure (BP), pulse rate, body temperature and respiratory rate will be recorded at the 
time points specified in the Schedule of Assessments (Appendix 4). 
16.9 
Body Weight 
Body weight should be measured on the same digital clinic scale, after checking for accurate 
zero calibration each time. Weight is recorded in kg to one decimal place. 
16.10 ECG Procedures 
Single 12-lead ECG assessments will be obtained as specified in the Schedule of Assessments 
(Appendix 4) to confirm eligibility and to ensure real time safety evaluation of the participants in 
the study, as specified in the Schedule of Assessments. Unscheduled ECGs may be performed as 
clinically indicated and recorded in the eCRF. 
Participants should be in a resting position for at least 10 minutes prior to any measurement. 
Body position should also be consistently maintained for each ECG evaluation. In particular, 
changes in heart rate should be avoided. There should be no environmental distractions 
(TV, radio, conversation) during the pre-ECG rest and the ECG recording time. 
Heart rate (HR), QRS duration and respiratory rate (RR), and QT intervals will be recorded. 
Changes of the T-wave and U-wave morphology and overall ECG interpretation will be 
documented. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. 
For safety monitoring purposes, the Investigator must review, sign and date all ECG tracings. 
Paper copies will be kept at the study center with the participant's clinical file as part of the 
permanent record. The ECG intervals and interpretation will be recorded on the CRF. 
16.11 Laboratory Test Procedures 
The laboratory assessments will be performed at a central laboratory, with the provision for 
occasional local laboratory testing, if required. Laboratory safety tests shall be collected at time 
points specified in the Schedule of Assessments (Appendix 4). 
Additional blood or urine samples may be taken at the discretion of the Investigator if the results 
of any test fall outside the reference ranges, or clinical symptoms necessitate additional testing to 
monitor participant safety. Where the clinical significance of abnormal lab results is considered 
uncertain, screening lab tests may be repeated before randomization to confirm eligibility. In the 
event of unexplained abnormal clinically significant laboratory test values, the tests should be 
repeated immediately and followed up until they have returned to the normal range, are 
considered to be clinically stable, and/or an adequate explanation of the abnormality is found. 

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16.11.1 Recording of Laboratory Test Results on the CRF  
Results of clinical laboratory testing will be recorded on the CRF or be received as electronically 
produced laboratory reports submitted directly from the local or central laboratory, if applicable. 
The procedures for the collection, handling and shipping of laboratory samples will be specified 
in the Sample Collection, Handling and Logistics Manual. 
16.12 Recording of Concomitant Medications on the CRF 
All medications (prescription and over-the-counter [OTC]) taken within 28 days prior to study 
screening (reference Exclusion Criteria, Item #5) will be recorded in the CRF. 

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17 
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Relapsed Chronic Lymphocytic Leukemia. N Engl J Med., 369(1):32-42, 2013.  
Bizikova P, Olivry T, Mamo LB, Dunston SM. Serum autoantibody profiles of IgA, IgE and IgM 
in canine pemphigus foliaceus. Vet Dermatol 2014;25:471-e75. 
Bizikova P, Dean GA, Hashimoto T, Olivry T. Cloning and establishment of canine 
desmocollin-1 as a major autoantigen in canine pemphisgus foliaceus. Vet Immunol 
Immunopathol 2012;149:197-207. 
Development Report #DVR0210, A Pilot Study of the Efficacy of a Bruton’s Tyrosine Kinase 
Inhibitor (BTKi) in the Treatment of Dogs with Pemphigus Foliaceus (PF). Principia Biopharma, 
Inc., South San Francisco, CA, 94080, U.S.A. 
Evans EK, Tester R, Aslanian S, Karp R, Sheets M, Labenski MT, Witowski SR, Lounsbury H, 
Chaturvedi P, Mazdiyasni H, Zhu Z, Nacht M, Freed MI, Petter RC, Dubrovskiy A, Singh J, 
Westlin WF. Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of 
Activity in Mice and Humans. J Pharmacol Exp Ther, 346(2):219-28, 2013. 
Hertl, M., Jedlickova, H., Karpati, S., et al. (2015), Pemphigus. S2 Guideline for diagnosis and 
treatment – guided by the European Dermatology Forum (EDF) in cooperation with the 
European Academy of Dermatology and Venereology (EADV). Journal of the European 
Academy of Dermatology and Venereology, 29: 405–414. doi: 10.1111/jdv.12772. 
Horváth, B., Huizinga, J., Pas, H.H., Mulder, A.B., Jonkman, M.F., Low Dose rituximab is 
effective in pemphigus. Br J Dermatol. 166(2): 405-12, 2012.  
Imbruvica [package insert]. Pharmacyclics, Inc., Sunnyvale, CA; 2015. 
Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, Borradori L, et al. Consensus 
statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am 
Acad Dermatol. 2008;58:1043–6. 
Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, et al. Bruton's tyrosine kinase (Btk): 
function, regulation, and transformation with special emphasis on the PH domain. Immunol 
Rev 228, 58-73, 2009. 
PRN1008-005 Interim Analysis Report February 2017 
PRN1008 Investigator Brochure, Principia Biopharma. 
Principia Study PRN1008-006, data on file, 2016. 

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Page 74 of 93 
Rosenbach M, Murrell D, Bystryn JC, et al. Reliability and convergent validity of two outcome 
instruments for pemphigus. J Invest Dermatol 2009;129(10):2404–10.  
Sideras P and Smith CI. Molecular and cellular aspects of X-linked agammaglobulinemia. 
Adv Immunol, 59: 135-223, 1995. 
Tjokrowidjaja A, Daniel BS, Frew JW, Sebaratnam DF, Hanna AM, Chee S, Dermawan A, 
Wang CQ, Lim C, Venugopal SS, Rhodes LM, Welsh B, Nijsten T, Murrell DF. Br J Dermatol. 
2013 Nov;169(5):1000-6. 
Tsukada, S., Saffran, D. C., Rawlings, D. J., Parolini, O., Allen, R. C., Klisak, I., Sparkes, R. S., 
Kubagawa, H., Mohandas, T., Quan, S., and et al. Deficient expression of a B cell cytoplasmic 
tyrosine kinase in human X-linked agammaglobulinemia. Cell, 72: 279-290, 1993. 
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. U.S. 
Food and Drug Administration. 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm# Accessed 07 April 2016. 
Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., 
Kinnon, C., Levinsky, R., Bobrow, M., and et al. The gene involved in X-linked 
agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature, 361: 
226-233, 1993. 
Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, 
Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, 
Jedrzejczak WW, Johnson P, Spurgeon SE, Li L, Zhang L, Newberry K, Ou Z, Cheng N, Fang 
B, McGreivy J, Clow F, Buggy JJ, Chang BY, Beaupre DM, Kunkel LA, Blum KA. Targeting 
BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2013 
Jun 19. [Epub ahead of print]. 
Werth VP, Fivenson D, Pandya AG, et al. Multicenter randomized, double-blind, placebo-
controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase 
pemphigus vulgaris. Arch Dematol. 2008 Jan;144(1):25-32.  
Wilson MM, Thomas DR, Rubenstein LZ, Chibnall JT, Anderson S, Baxi A, Diebold MR, 
Morley JE. Appetite assessment: simple appetite questionnaire predicts weight loss in 
community-dwelling adults and nursing home residents. Am J Clin Nutr. 2005 
Nov;82(5):1074-81. 

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APPENDIX 1A 
CORTICOSTEROID RESCUE CRITERIA AND TREATMENT 
PROTOCOL (PART A) 
Systemic corticosteroids will be avoided during PRN1008 monotherapy unless these rescue 
criteria are triggered, as described below, or if patients enter the study on low doses (≤ 0.5 mg/kg 
mg per day). In each rescue scenario, the recommended method of corticosteroid taper is shown 
in Appendix 7. 
Rescue Criteria #1: Flare which, in the mind of investigator, is potentially life threatening  
• Commence conventional immunosuppressive therapy and discontinue PRN1008 
Rescue Criteria #2: Development of severe but not life-threatening PV (defined as PDAI 
score ≥ 45) at any time during PRN1008 therapy: 
• If most recent BTK trough occupancy was 50% or more, commence conventional 
immunosuppressive therapy and discontinue PRN1008 
• If most recent BTK trough occupancy was < 50% and PRN1008 dose has not been increased 
since last BTK assay, commence, or increase dose to, full-dose prednis(ol)one (1.0 mg/kg) 
orally and increase dose of PRN1008 by an amount agreed to with the Sponsor’s Medical 
Monitor. At next review: 
- 
If not responding, commence conventional immunosuppressive therapy and discontinue 
PRN1008 
- 
If responding, maintain or taper corticosteroids as clinically appropriate while 
maintaining PRN1008 treatment 
• If no BTK trough occupancy is available to guide therapy, maintain PRN1008, and 
commence, or increase to, full-dose prednis(ol)one (1.0 mg/kg) orally. Seek to expedite latest 
BTK trough occupancy test result or arrange for a new blood draw to measure BTK trough 
occupancy. At next review: 
- 
If not responding, commence conventional immunosuppressive therapy and discontinue 
PRN1008 
- 
If responding, maintain or taper corticosteroids as clinically appropriate while 
maintaining PRN1008 treatment (including adjust dose upwards if BTK trough 
occupancy < 50% in consultation with the Sponsor Medical Monitor) 

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Rescue Criteria #3: Patients with non-severe PV but who fail to achieve “Control of Disease 
Activity (CDA*)” by 4 weeks 
• If most recent BTK trough occupancy was 50% or more, commence, or increase dose to, low 
dose prednis(ol)one (0.5 mg/kg) orally. Review after another ~2 weeks: 
- 
If not responding, commence conventional immunosuppressive therapy and discontinue 
PRN1008 
- 
If responding, maintain or taper corticosteroids as clinically appropriate while 
maintaining PRN1008 treatment 
• If most recent BTK trough occupancy was < 50% and PRN1008 dose has not been increased 
since last BTK assay, increase dose of PRN1008 by an amount agreed to with the Sponsor’s 
Medical Monitor. At review after another ~2 weeks: 
- 
If not responding, commence, or increase dose to, low-dose prednis(ol)one (0.5 mg/kg) 
orally and maintain PRN1008 treatment. If a dose of ≥ 0.5 mg/kg is already in use, or if 
after further review the patient is still not responding, commence conventional 
immunosuppressive therapy and discontinue PRN1008. 
- 
If responding, maintain PRN1008 treatment and consider tapering of prednis(ol)one 
In each rescue scenario, the recommended method of corticosteroid taper is shown in 
Appendix 7. 
When patients enter the study on corticosteroids, the dose should be maintained for the initial 
2 weeks of PRN1008 therapy if possible in order to evaluate the additive effects of PRN1008. 
During this time and subsequently, the rescue criteria should be followed if indicated. In other 
words, in some circumstances the corticosteroid dose should be increased, with or without 
cessation of PRN1008. If patients respond well to PRN1008 without increasing the corticosteroid 
dose, the Werth taper (Appendix 7) should be commenced after four weeks of PRN1008 therapy. 
*As defined by the EADV 2014 Pemphigus S2 Guideline (Hertl et al. 2015) 
 
 

A Phase 2 Study of PRN1008 in Pemphigus 
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Page 77 of 93 
APPENDIX 1B 
CORTICOSTEROID RESCUE CRITERIA AND TREATMENT 
PROTOCOL (PART B) 
Systemic corticosteroids will be avoided during PRN1008 monotherapy unless these rescue 
criteria are triggered, as described below, or if patients enter the study on low doses (≤ 0.5 mg/kg 
mg per day). In each rescue scenario, the recommended method of corticosteroid taper is shown 
in Appendix 7. 
Rescue Criteria #1: Flare which, in the mind of investigator, is potentially life threatening  
• Commence conventional immunosuppressive therapy and discontinue PRN1008 
Rescue Criteria #2: Development of severe (defined as PDAI score ≥ 45) but not life-
threatening PV or clinically significant worsening of already severe PV during PRN1008 
therapy: 
• Commence, or increase dose to, full-dose prednis(ol)one (1.0 mg/kg) orally and increase 
dose of PRN1008 by an amount agreed to with the Sponsor’s Medical Monitor to a 
maximum of 600 mg bid. At next review: 
- 
If not responding, commence conventional immunosuppressive therapy and discontinue 
PRN1008 
- 
If responding, maintain or taper corticosteroids as clinically appropriate while 
maintaining PRN1008 treatment. 
Rescue Criteria #3: Patients with non-severe PV but who fail to achieve “Control of Disease 
Activity (CDA*)” by 4 weeks 
• If partially responding, increase dose of PRN1008 if not already maximal (Table 4), review 
in 1-2 weeks, and then consider additional CS up to a dose of 0.5 mg/kg. If subsequently 
responding, maintain PRN1008 treatment and taper prednis(ol)one. 
• If not responding, increase dose of PRN1008 if not already maximal (Table 4), review in 
1-2 weeks, and then consider additional CS up to a dose of 1.0 mg/kg. If subsequently 
responding, maintain PRN1008 treatment and taper prednis(ol)one. 
Table 4 
Dose Escalation Rules Part B 
Current Dose 
Inadequate Clinical Response1 Dose-Escalation Rules 
400 mg qd 
Increase to 400 mg bid (allowed at Week 3 visit or later)2 
400 mg bid 
Increase to 600 mg bid (allowed at Week 5 visit or later)2 
600 mg bid 
No dose increase possible. 
1. Investigator discretion: Generally, clinical response is shown by some improvement seen in first 2 weeks with 
CDA achieved by the Week 5 visit 
2. Unless tolerability issues preclude dose-escalation 
 

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Page 78 of 93 
In each rescue scenario, the recommended method of corticosteroid taper is shown in 
Appendix 7. 
When patients enter the study on corticosteroids, the dose should be maintained for the initial 
2 weeks of PRN1008 therapy if possible in order to evaluate the additive effects of PRN1008. 
During this time and subsequently, the rescue criteria should be followed if indicated. In other 
words, in some circumstances the corticosteroid dose should be increased, with or without 
cessation of PRN1008. If patients respond well to PRN1008 without increasing the corticosteroid 
dose, the Werth taper (Appendix 7) should be commenced after four weeks of PRN1008 therapy. 
* As defined by the EADV 2014 Pemphigus S2 Guideline (Hertl et al. 2015) 
 

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Page 79 of 93 
APPENDIX 2 
STRONG AND MODERATE CYP3A INHIBITORS AND 
INDUCERS 
 
Strong 
Moderate 
3A Inducers 
Avasimibe, carbamazepine, phenytoin, 
rifampin, St. John’s wort 
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
3A Inhibitors 
Boceprevir, 
clarithromycin, conivaptan, 
grapefruit juice, indinavir, itraconazole, 
ketoconazole,  
lopinavir/ritonavir, 
mibefradil,  
nefazodone, nelfinavir, 
posaconazole, ritonavir,  
saquinavir,  
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, Seville orange juice, 
grapefruit juice, 
imatinib, verapamil 
From:  Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. U.S. Food and 
Drug Administration.  

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Page 80 of 93 
APPENDIX 3 
SENSITIVE CYP3A SUBSTRATES INCLUDING THOSE WITH 
NARROW THERAPEUTIC INDEX 
3A Sensitive Substrate 
Subset with Narrow Therapeutic Index 
Alfentanil, aprepitant, budesonide, buspirone, 
conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, lopinavir, 
lovastatin, lurasidone, maraviroc, midazolam, 
nisoldipine, quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, tipranavir, 
triazolam, vardenafil 
Alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus,  
terfenadine 
From: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. U.S. Food and 
Drug Administration.  
 
 

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Page 81 of 93 
APPENDIX 4 
SCHEDULE OF ASSESSMENTS  
PART A: 12-WEEK TREATMENT/ 12-WEEK FOLLOW-UP: 
 
Screen 
Day 1, 
Week 1 
Pre-dose 
Day 1 
Week 1 
Post-doseg 
Day 2, 
Week 1a 
Day 15, 
Week 3 
+/- 3 days 
Day 29, 
Week 5 
+/- 3 days 
Day 57, 
Week 9 
+/- 7 days 
Day 85, 
Week 13 
+/- 7 days 
Day 113, 
Week 17 
+/- 7 days 
Day 141, 
Week 21 
+/- 7 days 
Day 169, 
Week 25 
+/- 7 days 
Unscheduled 
Visit 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam./med. 
History, PDAI and ABSIS 
X 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated physical exam, 
PDAI, ABSIS 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead) 
X 
 
 
 
 
 
 
 
 
 
 
(X)b 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
Hep B & C, HIV,  
T-spot TB Test, 
QuantiFERON®-TB Gold, 
QuantiFERON®-TB Gold 
Plus (QFT Plus) 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
X 
X 
 
 
 
X 
X 
X 
 
 
X 
 
Skin biopsyd 
X 
 
 
 
 
 
 
 
 
 
 
 
Hem, Coag, Chem 
Xe 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
FSHf 
X 
 
 
 
 
 
 
 
 
 
 
 
BTK occupancy sample 
 
Xg 
Xh 
X 
X 
X 
X 
X 
 
 
 
(X)b 
PK sample 
 
X 
Xh 
X 
X 
X 
X 
X 
 
 
 
(X)b 
Anti-DSG antibodies. 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Photography (Optional)i 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
ABQOL & TABQOL 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
SNAQ questionnaire 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AEs 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensed 
 
X 
 
 
 
X 
X 
 
 
 
 
 
Drug reconciliation 
 
 
 
 
X 
X 
X 
X 
 
 
 
 

A Phase 2 Study of PRN1008 in Pemphigus 
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Principia Biopharma Australia Pty Ltd.  
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Page 82 of 93 
Schedule of Assessments Footnotes: 
a. 
Withhold PRN1008 on morning of Day 2 until PK/PD measurement has been taken as close to 12 hours after second dose as possible. Where follow-up on Day 2 is not 
possible, PK/PD samples may be taken on another day in the first week of treatment. On all other days, instruct patient to take PRN1008 in the morning as 
usual prior to clinic and take note of the time taken. Extra PK/PD sample intended for 1 to 5 days after dose adjustment or to replace missing samples–not 
required for other extra visits.  
b. Only if clinically indicated. 
c. 
For women of childbearing potential only. Serum pregnancy test done at screening, urine dip test done at other time points. 
d. Performed only if no suitable prior biopsy. 
e. 
TSH and CPK taken as part of chemistry panel. 
f. 
To confirm postmenopausal status for women who are not surgically sterile only. 
g. Two-8mL pre-dose blood tubes to be collected at baseline to ensure sufficient samples for later time point assay calculations. 
h. 2 hours post-dose (+/- 15 mins) 
i. 
Photography is used to document skin disease changes; ideally in most patients. Strict masking of patient identity is required. 

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
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Page 83 of 93 
PART B:  SCHEDULE OF ASSESSMENTS (24-weeks Treatment/ 4-weeks Follow Up) 
 
Screen 
Day 1, 
Week 1 
Pre-dose 
Day 1 
Week 1 
Post-dosea 
Day 2, 
Week 1g 
Day 15, 
Week 3 
+/-3 days 
Day 29, 
Week 5 
+/-3 days 
Day 57, 
Week 9 
+/-7 days 
Day 85, 
Week 13 
+/-7 days 
Day 113, 
Week 17 
+/-7 days 
Day 141, 
Week 21 
+/-7 days 
Day 169, 
Week 25 
+/-7 days 
Day 197, 
Week 29 
+/-7 days 
Unscheduled 
Visit 
Informed Consentk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
exam/med.History PDAI, 
ABSIS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated physical 
exam., PDAI, ABSIS 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead) 
X 
 
 
 
 
 
 
 
 
 
 
 
(X)b 
Vital Signsj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hep B &C, HIV,  
T-spot TB Test, 
QuantiFERON®-TB 
Gold, QuantiFERON®-
TB Gold Plus (QFT Plus) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Skin biopsyd 
X 
 
 
 
 
 
 
 
 
 
 
 
Hem, Coag, Chem 
Xe 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSHf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BTK occupancy sample 
 
Xg 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) b 
PK sample  
 
X 
Xh 
Xa 
X 
X 
X 
X 
X 
X 
X 
 
(X) b 
Anti-DSG antibodies. 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Photography (Optional)i 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ABQOL & TABQOL 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SNAQ questionnaire 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensed 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Drug reconciliation 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Principia Biopharma Australia Pty Ltd.  
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Page 84 of 93 
Schedule of Assessments Footnotes: 
a. 
Withhold PRN1008 on morning of Day 2 until PK/PD measurement has been taken as close to 12 hours (when bid dosing) or 24 hours (when qd dosing) after the prior dose 
as possible. Where follow-up on Day 2 is not possible, PK/PD samples may be taken on another day in the first week of treatment. On all other days, instruct 
patient to take PRN1008 in the morning as usual prior to clinic and take note of the time taken. Extra PK/PD sample intended for 1 to 5 days after dose 
adjustment or to replace missing samples–not required for other extra visits. 
b. Only if clinically indicated. 
c. 
For women of childbearing potential only. Serum pregnancy test done at screening, urine dip test done at other time points. 
d. Performed only if no suitable prior biopsy. 
e. 
TSH and CPK taken as part of chemistry panel. 
f. 
To confirm postmenopausal status for women who are not surgically sterile only. 
g. Two-8mL pre-dose blood tubes to be collected at baseline to ensure sufficient samples for later time point assay calculations. 
h. 2 hours post-dose (+/- 15 mins) 
i. 
Photography is used to document skin disease changes; ideally in most patients. Strict masking of patient identity is required. 
j. 
Vital sign include blood pressure (BP), pulse rate, body temperature and respiratory rate and are recorded at the time points specified 
k.  The Schedule of Assessments has been revised to be consistent with the 24 week treatment duration and 4 week safety follow up assessments described in 
this protocol Version 5, Part B. Patients enrolled in an earlier protocol version (Part A) who are in the active12-week treatment period are eligible to 
continue treatment, initially at their current dose, for up to a total of 24 weeks active treatment upon review and signature of the Part B EC approved Patient 
Informed Consent Form, with procedures and tests per this Schedule. Patients that have completed Part A of the trial are also eligible to be screened as a 
Part B patient, upon review and signature of the Part B EC-approved Patient Informed Consent Form. 
 
 
 

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Principia Biopharma Australia Pty Ltd.  
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Page 85 of 93 
APPENDIX 5 
PEMPHIGUS DISEASE ACTIVITY AND QUALITY OF LIFE 
EVALUATION INSTRUMENTS:  ABQOL, TABQOL, PDAI, ABSIS 

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Page 88 of 93 
Treatment of Autoimmune Bullous Diseases Quality of Life Assessment (TABQOL) 

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
Page 89 of 93 
From: Tjokrowidjaja et al. 2013 

A Phase 2 Study of PRN1008 in Pemphigus 
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Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
Page 90 of 93 
Pemphigus Disease Activity Index (PDAI) (Murrell et al. 2008)  

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
Page 91 of 93 
Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) (Rosenbach et al. 2009) 

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
Page 92 of 93 
APPENDIX 6 
SIMPLE NUTRITIONAL APPETITE QUESTIONNAIRE (SNAQ) 
From Wilson et al., 2005 
 

A Phase 2 Study of PRN1008 in Pemphigus 
Protocol PRN1008-005, Version 7.0 
Principia Biopharma Australia Pty Ltd.  
19 March 2019 
 
Page 93 of 93 
APPENDIX 7 
CORTICOSTEROID TAPER PROTOCOL 
Maintain corticosteroid dose for 2 weeks after disease control has been achieved. 
Subsequently, reduce the corticosteroid dose by 15% every three weeks. 
-OR- 
 
 
From: Werth et al. 2008