An Open Label, Single-Dose, Single-Period Study Designed to Assess the Mass Balance Recovery, Metabolite Profile and Metabolite Identification of [14C]-Rencofilstat in Healthy Male Subjects
Phase: EARLY_PHASE1
Conditions: NASH With Fibrosis
Sponsor: Hepion Pharmaceuticals, Inc.

Doc No:DOC-61548    
  Doc Name:QSC204643 Clinical Protocol 
Project Number:204643        
   Version:3.0        
Status:Approved 
CLINICAL STUDY PROTOCOL 
An Open Label, Single-Dose, Single-Period Study Designed to 
Assess the Mass Balance Recovery, Metabolite Profile and 
Metabolite Identification of [14C]-Rencofilstat in Healthy Male 
Subjects  
Short Study Title: Single Dose ADME Study of [14C]-Rencofilstat 
in Healthy Male Subjects 
Quotient Sciences Study Number: 
QSC204643 
Sponsor Study Number: 
HEPA-CRV431-105 
EudraCT Number: 
2022-003789-20 
IRAS ID 
1007072 
Clinical Study Site: 
Quotient Sciences 
Mere Way 
Ruddington Fields 
Ruddington 
Nottingham NG11 6JS, UK 
Tel: +44 (0)115 974 9000 
Sponsor: 
Hepion Pharmaceuticals, Inc 
399 Thornall Street, First Floor 
Edison 
New Jersey 
08837 
Tel: +1 732-902-4000 
Date of Protocol: 
22 Mar 2023 
Status of Protocol: 
Version 3.0 
SPONSOR/QUOTIENT SCIENCES CONFIDENTIAL 
This clinical protocol may not be reproduced or communicated to a third party 
without the written permission of Hepion Pharmaceuticals, Inc. 

Sponsor/Quotient Sciences Confidential 
 
 
 
Protocol HEPA-CRV431-105 (QSC204643) Version 3.0 
22 Mar 2023 
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Document History 
Protocol Version Number 
Classification 
Date  
Version 3.0 
Non-Substantial Amendment 
22 Mar 2023 
Version 2.0 
Non-Substantial Amendment 
10 Mar 2023 
Version 1.0 
Original Protocol 
21 Dec 2022 
Details of the amendments can be found in Appendix 3. 
 

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Study Contacts 
Principal Investigator: 
Litza McKenzie MBChB, BScMedSci (Hons)  
Quotient Sciences 
Mere Way 
Ruddington Fields 
Ruddington 
Nottingham NG11 6JS, UK 
Tel: +44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Sub-Investigators: 
Sharan Sidhu MBChB, BAO, MRCS, MFPM 
Philip Evans MBChB, MRCS (Ed) 
Stuart Mair MBChB, DRCOG, DCPSA, FFPM 
Nand Singh BSc, MD, DPM, MFPM 
Martina Fieldingova MUDr 
Elizabeth Maria van Niekerk MBChB, DipPalMed 
Somasekhara Menakuru MBBS, MS, MRCS, DPM, 
MFPM 
David Everton BSc, MBBS 
Courtney Krstic BMedSci, BMBS (Hons)  
Lena Chen BSc (Hons), MBBS, MRCGP 
Nicholas Akam BMedSci, BMBS, MRCGP  
Daniel Pickering BMBS, BMedSci, PhD 
Mohamed Abokhwat MBBCH 
Quotient Sciences Tel:  
+44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Project Manager: 
Kirsty Webster BSc (Hons) 
Quotient Sciences 
Tel: +44 (0)115 974 9000 
Study Monitor: 
Details will be provided in the Communication Plan 
Medical Monitor: 
Bionical Emas 
Suite 209 
Spirella Building 
Bridge Road 
Letchworth Garden City 
Hertfordshire, SG6 4ET, UK 
Tel: +44 (0)1462 424 400 
Pharmacovigilance 
Provider: 
Details will be provided in the Communication Plan 
ARSAC Practitioner: 
Stuart Mair MBChB, DRCOG, DCPSA, FFPM 
Tel: +44 (0)115 974 9000  
Email: stuart.mair@quotientsciences.com 
Central Laboratory: 
The Doctors Laboratory 
The Halo Building 
1 Mabledon Place 
London WC1H 9AX 
Tel: + 44 (0)207 3077 404 

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Bioanalytical Laboratory, 
Mass Balance and 
Metabolism Laboratory: 
Pharmaron UK   
Pegasus Way 
Crown Business Park 
Rushden  
Northamptonshire NN10 6ER, UK 
Tel: +44 (0)1933 319 900 

Protocol HEPA-CRV431-105 (QSC204643) Version 3.0 
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1 Table of Contents 
1 
Table of Contents ............................................................................................ 5 
2 
List of Tables and Figures ............................................................................... 9 
2.1 
Table of In-Text Tables ...................................................................... 9 
2.2 
Table of In-Text Figures ..................................................................... 9 
3 
Synopsis ....................................................................................................... 10 
4 
List of Abbreviations ...................................................................................... 14 
5 
Background Information ................................................................................ 16 
5.1 
Introduction ...................................................................................... 16 
5.2 
Investigational Medicinal Product .................................................... 17 
5.3 
Previous Study Findings .................................................................. 17 
5.3.1 
Non-clinical Findings ....................................................................... 18 
5.3.2 
Clinical Findings .............................................................................. 19 
6 
Rationale ....................................................................................................... 22 
6.1 
Study Rationale ............................................................................... 22 
6.2 
Dose Rationale ................................................................................ 22 
6.3 
Population Rationale ....................................................................... 22 
6.4 
Risks and Benefits ........................................................................... 23 
6.4.1 
Risks Associated with Rencofilstat Administration ........................... 23 
6.4.2 
Risks Associated with Administration of Radioactivity ...................... 25 
6.4.3 
COVID-19 Related Risks and Risk Mitigation Measures .................. 25 
6.4.4 
General Risks and Overall Risk-Benefit Assessment ....................... 26 
7 
Objectives and Endpoints .............................................................................. 27 
8 
Study Design ................................................................................................. 27 
8.1 
Study Plan ....................................................................................... 27 
8.2 
Criteria for In-Study Decisions ......................................................... 29 
8.3 
Subject Withdrawal .......................................................................... 29 
8.4 
Subject Replacement ...................................................................... 30 
8.5 
Stopping Criteria .............................................................................. 30 
8.6 
Study Termination ........................................................................... 31 
8.7 
Lost to Follow-up ............................................................................. 31 
8.8 
Treatment Assignment..................................................................... 32 
8.8.1 
Subject Numbers ............................................................................. 32 
8.8.2 
Blinding ........................................................................................... 32 
9 
Selection of Subjects ..................................................................................... 32 
9.1 
Informed Consent ............................................................................ 32 
9.2 
Inclusion Criteria .............................................................................. 32 
9.3 
Exclusion Criteria ............................................................................. 33 
9.4 
Contraception and Restrictions ........................................................ 34 
9.4.1 
Sperm Donation............................................................................... 35 
9.5 
Pregnancy ....................................................................................... 35 
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9.6 
Additional Study Restrictions ........................................................... 35 
10 
Study Procedures .......................................................................................... 36 
10.1 
Screening ........................................................................................ 36 
10.1.1 
Subject Re-Screening ...................................................................... 36 
10.2 
Admission and Pre-dose Procedures ............................................... 36 
10.3 
Study Day Procedures ..................................................................... 37 
10.3.1 
Blood Volume .................................................................................. 37 
10.3.2 
Timing of Procedures ...................................................................... 37 
10.3.3 
Discharge from the Clinical Unit ....................................................... 37 
10.3.4 
Return Visits .................................................................................... 38 
10.3.5 
Medical Supervision ........................................................................ 38 
11 
Dosing of Subjects ........................................................................................ 38 
11.1 
Food and Fluid Intake ...................................................................... 38 
11.2 
Administration of Test Preparations ................................................. 38 
11.3 
Dosing Compliance ......................................................................... 39 
11.4 
Prior and Concomitant Medications ................................................. 39 
12 
Assessment of Efficacy ................................................................................. 39 
13 
Assessment of Mass Balance, Pharmacokinetics, Metabolite Profiling 
and Identification, and Pharmacodynamics ................................................... 39 
13.1 
Assessment of Mass Balance, Pharmacokinetic, and 
Metabolite Profiling and Identification .............................................. 39 
13.1.1 
Pharmacokinetic and Metabolite Profiling and Identification 
Blood Sampling ............................................................................... 40 
13.1.2 
Mass Balance and Metabolite Profiling and Identification Urine 
Sampling ......................................................................................... 40 
13.1.3 
Mass Balance and Metabolite Profiling and Identification 
Faecal Sampling .............................................................................. 41 
13.1.4 
Unexpected Sources of Elimination ................................................. 41 
13.2 
Assessment of Pharmacodynamics ................................................. 41 
14 
Assessment of Safety ................................................................................... 41 
14.1 
Definition and Classification of Adverse Events ............................... 41 
14.2 
Assessment of Causality ................................................................. 42 
14.3 
Recording Adverse Events .............................................................. 42 
14.4 
Serious Adverse Events .................................................................. 42 
14.4.1 
Definition of Serious Adverse Events ............................................... 42 
14.4.2 
Definition of Suspected Unexpected Serious Adverse 
Reactions ........................................................................................ 43 
14.5 
Laboratory Measurements ............................................................... 43 
14.5.1 
Haematology and Clinical Chemistry ............................................... 43 
14.5.2 
Virology ........................................................................................... 43 
14.5.3 
Urinalysis ......................................................................................... 44 
14.5.4 
Drug Screen .................................................................................... 44 
14.5.5 
Alcohol Breath Test ......................................................................... 44 
14.5.6 
Carbon Monoxide Breath Test ......................................................... 44 
14.5.7 
SARS-CoV-2 Tests (If Required) ..................................................... 44 
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14.5.8 
Abnormal Laboratory Findings ......................................................... 44 
14.6 
Vital Signs Measurements ............................................................... 45 
14.7 
ECG Measurements ........................................................................ 45 
14.8 
Body Weight, Height and BMI .......................................................... 45 
14.9 
Physical Examination ...................................................................... 46 
14.10 
Additional Safety Procedures........................................................... 46 
15 
Statistics and Data Analysis .......................................................................... 46 
15.1 
Sample Size Justification ................................................................. 46 
15.2 
Data Management ........................................................................... 46 
15.3 
Mass Balance, Pharmacokinetic, and Metabolite Profiling and 
Identification Data Analysis .............................................................. 47 
15.3.1 
Mass Balance Data Analysis ........................................................... 47 
15.3.2 
Pharmacokinetic and Total Radioactivity Data Analysis ................... 47 
15.3.3 
Metabolite Profiling and Identification .............................................. 48 
15.4 
Statistical Data Analysis .................................................................. 48 
15.5 
Interim Analysis ............................................................................... 49 
16 
Safety Reporting to Regulatory Authorities and Ethics Committees............... 49 
16.1 
Events Requiring Expedited Reporting ............................................ 49 
16.2 
Urgent Safety Measures .................................................................. 49 
16.3 
Reporting ......................................................................................... 50 
16.3.1 
Reporting Serious Adverse Events .................................................. 50 
16.3.2 
Reporting of Suspected Unexpected Serious Adverse 
Reactions ........................................................................................ 50 
16.3.3 
Expedited Reporting of Events ........................................................ 50 
16.3.4 
Reporting of Urgent Safety Measures .............................................. 51 
16.3.5 
Reporting of COVID-19 Vaccine-Related Adverse Events ............... 51 
16.4 
Serious Breaches ............................................................................ 51 
17 
Protocol Amendments and Deviations ........................................................... 51 
17.1 
Amendments ................................................................................... 51 
17.2 
Protocol Deviations .......................................................................... 51 
18 
Regulatory ..................................................................................................... 52 
18.1 
Compliance ..................................................................................... 52 
18.2 
MHRA and Ethical Approval ............................................................ 52 
18.3 
Administration of Radiation .............................................................. 52 
18.4 
Source Data .................................................................................... 53 
18.5 
Declaration of the End of the Study ................................................. 53 
18.6 
Document Storage and Archiving .................................................... 53 
18.7 
Protection of Personal Data and Confidentiality ............................... 53 
18.8 
Data Security Breach ....................................................................... 54 
19 
Quality Control and Quality Assurance .......................................................... 54 
19.1 
Monitoring........................................................................................ 54 
20 
Finance and Insurance .................................................................................. 55 
21 
Publication .................................................................................................... 55 
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22 
References ..................................................................................................... 55 
Appendix 1 
Clinical Laboratory Parameters ......................................................... 58 
Appendix 2 
Schedule of Assessments ................................................................. 59 
Appendix 3 
Protocol Amendment Summary of Changes ..................................... 62 
 

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2 List of Tables and Figures  
2.1 
Table of In-Text Tables 
Table 1 
Investigational Medicinal Product ............................................................... 17 
Table 2 
Summary of Whole Blood Rencofilstat Pharmacokinetic Parameters 
Following Single Oral Doses (SAD, PK Population) .................................. 21 
Table 3 
Mass Balance Parameters ......................................................................... 47 
Table 4 
Whole Blood Pharmacokinetic Parameters ................................................ 47 
 
2.2 
Table of In-Text Figures 
Figure 1 
Study Sequence ......................................................................................... 29 
 
 

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3 Synopsis 
 
Sponsor:  
Hepion 
Pharmaceuticals, Inc. 
 
Drug Substance:  
[14C]-rencofilstat 
EudraCT No.: 
2022-003789-20 
IRAS ID: 
1007072 
Title of Study: 
An Open Label, Single-Dose, Single-Period Study Designed to Assess the Mass Balance 
Recovery, Metabolite Profile and Metabolite Identification of [14C]-Rencofilstat in Healthy 
Male Subjects. 
Principal Investigator:  
Litza McKenzie MBChB, BScMedSci (Hons) 
Study Centre: 
Quotient Sciences, Mere Way, Ruddington Fields, Ruddington, Nottingham, NG11 6JS, 
UK 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary  
 
To determine the mass balance recovery after a 
single oral dose of carbon-14 ([14C])-rencofilstat 
 
Mass balance recovery of total radioactivity (TR) in 
all excreta (urine and faeces): CumAe and 
Cum%Ae 
To determine % parent drug unchanged versus 
metabolites 
Parent to total radioactivity ratio for whole blood 
based on AUC 
To perform metabolite profiling and structural 
identification from whole blood, urine and faecal 
samplesa 
Collection of whole blood, urine and faeces 
samples 
for 
metabolite 
profiling, 
structural 
identification, and quantification analysis 
Secondary 
To determine the routes and rates of elimination of 
[14C]-rencofilstat 
 
Mass balance recovery of TR in urine and faeces 
separately: Ae, %Ae, CumAe and Cum%Ae by 
interval 
To identify the chemical structure of each metabolite 
accounting for more than 10% of circulating TR or 
accounting for 10% or more of the dose in excreta 
Identification of the chemical structure of each 
metabolite accounting for more than 10% by AUC 
of circulating TR or accounting for 10% or more of 
the dose in excreta 
To evaluate the extent of distribution of TR into blood 
cells 
Evaluation of whole blood:plasma concentration 
ratios for TR 
To provide 
additional safety and tolerability 
information for rencofilstat 
To provide additional safety and tolerability 
information for rencofilstat by assessing: incidence 
of adverse events (AEs), physical examinations 
and change from baseline for vital signs, 
electrocardiograms (ECGs), and laboratory safety 
tests 
To further explore the oral pharmacokinetics (PK) of 
rencofilstat 
PK parameters for rencofilstat in whole blood and 
TR in plasma and whole blood following a single 
oral dose, including but not limited to: Tlag, Tmax, 
Cmax, 
AUC(0-last), 
AUC(0-inf), 
AUC(0-24), 
Lambda-z, T1/2, CL/F, Vz/F, MRT(0-last) and 
MRT(0-inf) as applicable 
a Metabolite profiling and identification will be reported separately from the clinical study report as a 
standalone document. 
Methodology: 
This is a single centre, open-label, non-randomised, single period, single dose study in 
healthy male subjects. It is planned to enrol a single cohort of 6 subjects.  

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Each subject will receive a single 225 mg oral dose of [14C]-rencofilstat 
self-microemulsifying drug delivery system oral emulsion (not more than [NMT] 
6.4 MBq), in the fasted state. 
Study Design: 
Subjects will undergo preliminary screening procedures for the study at the screening 
visit (Day -28 to Day -2). Subjects will be admitted in the evening on the day before 
dosing (Day -1). 
Whole blood, plasma, urine and faeces samples will be collected at regular intervals for 
PK analysis, TR analysis, metabolite profiling, mass balance and safety as applicable, 
from pre-dose to discharge from the clinical unit. Urine and faeces samples may be 
collected at return visits or home visits if mass balance criteria has not been met by a 
subject.  
Subjects will be dosed on the morning of Day 1 following an overnight fast (minimum 8 h) 
and will remain resident in the clinical unit until up to 504 h after dosing (up to Day 22).  
It is planned that subjects will be released as a group when all subjects have achieved a 
mass balance cumulative recovery of >90% or if <1% of the dose administered has been 
collected in urine and faeces within two separate, consecutive 24 h periods. This may 
result in the subjects being discharged as a group prior to completion of the planned 
residency period.  
If the mass balance criteria are achieved during the planned residency period, collection 
of all samples (blood, urine and faeces) will be stopped once the current 24 h collection 
period is complete, and subjects will undergo discharge assessments. 
If the mass balance criteria have not been met by all subjects on the morning of Day 22, 
the residency period for the subjects not achieving the mass balance criteria may be 
extended up to a maximum of 96 h (Day 26; 600 h post-dose). Only urine and/or faecal 
samples will be collected during the extended residency period.  
If the mass balance criteria have not been met by all subjects on the morning of Day 26, 
subjects not achieving the release criteria may be required to make up to 2 return visits 
(each of 24 h duration) at (nominally) Day 28 (+2 days) and Day 35 (±2 days) for 
additional collection of excreta samples (urine and/or faecal samples). 
If the mass balance criteria have not been met following the return visits, then home 
collections of urine and/or faeces may be requested at the discretion of the investigator 
for individual subjects. 
Number of Subjects Planned: 
It is planned to enrol 6 healthy male subjects to ensure data in a minimum of 4 subjects. 
No replacement subjects are planned for this study.  
Duration of Study: 
Subjects will receive 1 single administration on a single occasion. The estimated time 
from screening until the end of the study is approximately up to 8 weeks (9 weeks if 
return visits are required). 
Main Inclusion Criteria: 
Healthy males aged 30 to 65 years inclusive at the time of signing informed consent. 
Body mass index of 18.0 to 35.0 kg/m2 as measured at screening. 
Investigational Medicinal Product, Dose and Mode of Administration: 
The following IMP will be used in this clinical study. 
IMP Name 
Dose 
Route of Administration 
[14C]CRV431 SMEDDS Concentrate for 
Oral Emulsion, 225 mg (NMT 6.4 MBq) 
225 mg 
Oral administration, Fasted 
14C: carbon-14, MBq: megabecquerel, NMT: not more than 

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Immediately after administration of the oral solution, the dosing vessel will be rinsed with 
water and subjects will consume the rinse solution. Subjects will then consume further 
water to a total volume of 240 mL (including the dosing volume and volume used to rinse 
the dosing vessel). 
Mass Balance Assessments: 
Mass balance of TR in urine and faeces (and emesis, if applicable) will be calculated by 
Quotient Sciences for the parameters below. 
Parameter 
Definition 
Ae(urine) 
amount of TR excreted in urine 
%Ae(urine) 
amount of TR excreted in urine expressed as a percentage of the radioactive dose 
administered 
CumAe(urine) 
cumulative amount of TR excreted in urine 
Cum%Ae(urine) 
cumulative amount of TR excreted in urine expressed as a percentage of the 
radioactive dose administered 
Ae(faeces) 
amount of TR eliminated in faeces 
%Ae(faeces) 
amount of TR eliminated in faeces expressed as a percentage of the radioactive 
dose administered 
CumAe(faeces) 
cumulative amount of TR eliminated in faeces 
Cum%Ae(faeces) 
cumulative amount of TR eliminated in faeces expressed as a percentage of the 
radioactive dose administered 
Ae(total) 
amount of TR excreted in urine and faeces combined 
%Ae(total) 
amount of TR excreted in urine and faeces combined expressed as a percentage of 
the radioactive dose administered 
CumAe(total) 
cumulative amount of TR excreted in urine and faeces combined 
Cum%Ae(total) 
cumulative amount of TR excreted in urine and faeces combined expressed as a 
percentage of the radioactive dose administered 
Pharmacokinetic and Total Radioactivity Assessments: 
Whole blood concentration-time data for rencofilstat will be analysed by Quotient 
Sciences using Phoenix WinNonlin v8.3 or a more recent version (Certara USA, Inc., 
USA) and appropriate non-compartmental techniques to obtain estimates of the following 
PK parameters, where possible and appropriate. 
Parameter 
Definition 
Tlag 
Time prior to the first measurable concentration 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-24) 
Area under the curve from time 0 to 24 h post-dose 
AUC(0-last) 
Area under the curve from time 0 to the time of last measurable 
concentration 
AUC(0-inf) 
Area under the curve from time 0 extrapolated to infinity 
AUCextrap 
Area under the curve from time of the last measurable concentration to 
infinity as a percentage of the area under the curve extrapolated to infinity 
AUC ratio 
Parent to total radioactivity ratio for whole blood based on AUC 
T1/2  
Terminal elimination half-life 
Lambda-z 
First order rate constant associated with the terminal (log-linear) portion of 
the curve 
CL/F 
Total body clearance calculated after a single extravascular administration 
where F (fraction of dose bioavailable) is unknown 
Vz/F 
Apparent volume of distribution based on the terminal phase calculated using 
AUC(0-inf) after a single extravascular administration where F (fraction of 
dose bioavailable) is unknown 
MRT(0-last) 
Mean residence time from time 0 to time of the last measurable 
concentration  

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Parameter
Definition
MRT(0-inf)
Mean residence time from time 0 extrapolated to infinity 
In addition, whole blood-to-plasma TR concentration ratios will be calculated. 
Metabolite Profiling and Identification Assessment: 
Metabolite profiling of whole blood, urine and faeces will be performed using liquid 
chromatography-radio-detection with subsequent mass spectrometry where appropriate. 
Identification of the chemical structure of each metabolite accounting for greater than 
10% of circulating radioactivity in whole blood (“AUC pool”) and accounting for greater 
than 10% of the dose in the urine and faeces (from urine pools and faeces homogenate 
pools) will be performed. These aspects will be reported separately from the clinical study 
report as a standalone document. 
Safety Assessments: 
The safety assessments to be conducted are: 
•
AE monitoring
•
Single 12-lead ECGs
•
Vital signs
•
Clinical laboratory tests (clinical chemistry, haematology and urinalysis)
•
Physical examinations
Statistical Methodology: 
No formal statistical analysis will be performed for this study. Descriptive statistics 
(eg mean, median, standard deviation, minimum, maximum and number of subjects with 
an observation [n]) are considered adequate for a study of this type. Additional statistics 
will be provided for PK-related data, including coefficient of variation (CV%), geometric 
mean and geometric CV%. 
Sample Size and Power: 
The study is exploratory and no formal sample size calculation has been made. Based 
on experience from previous studies of a similar design, a total of 6 subjects are to be 
enrolled and a minimum of 4 evaluable subjects are considered sufficient. An evaluable 
subject is defined as a subject who has provided mass balance and PK samples for up 
to 21 days after drug administration or have demonstrated >90% mass balance recovery 
or have <1% of the administered dose eliminated in excreta for two consecutive days, 
whichever is sooner. 

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4 List of Abbreviations 
Abbreviation 
Definition 
14C 
carbon-14 
ADME 
absorption, metabolism, distribution and elimination 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARSAC 
Administration of Radioactive Substances Advisory 
Committee 
BCRP 
breast cancer resistance protein 
BMI 
body mass index 
CLcr 
creatinine clearance 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID-19 
Coronavirus Disease 2019 
CsA 
cyclosporine A 
CSPM 
Clinical Sample Processing Manual 
CV% 
coefficient of variation 
CYP450 
cytochrome P450 
Cyp A 
cyclophilin A 
Cyp B 
cyclophilin B 
Cyp D 
cyclophilin D 
DDI 
drug-drug interaction 
DMP 
data management plan 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
GCP 
good clinical practice 
GLP 
good laboratory practice 
HBsAg 
hepatitis B surface antigen 
HCC 
Hepatocellular carcinoma 
HCV Ab 
hepatitis C virus antibody 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IMP 
investigational medicinal product 

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ISF 
Investigator Site File 
MAD 
multiple ascending dose 
MATE 
Multidrug and toxin extrusion protein 
MHRA 
Medicines and Healthcare products Regulatory 
Agency 
NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Non-alcoholic Steatohepatitis 
NMT 
not more than 
NOAEL 
no-observed-adverse-effect-level 
OAT 
(human) organic ion transporter 
PgP 
P-glycoprotein 
PIS 
Participant Information Sheet 
PK 
pharmacokinetic(s) 
QA 
quality assurance 
QD 
once daily 
QTcF 
Corrected QT interval by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
SAD 
single ascending dose 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SMEDDS 
self-microemulsifying drug delivery system 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TDF 
tenofovir disoproxil fumarate 
TK 
toxicokinetic 
TR 
total radioactivity 
TV 
tidal volume 
 
The mass balance and pharmacokinetic definitions used in this study are presented in 
Section 15.3.1 and Section 15.3.2.

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5 Background Information 
5.1 
Introduction  
Rencofilstat, previously known as CRV431, is a non-immunosuppressive cyclosporine A 
(CsA) analogue being developed by Hepion Pharmaceuticals, Inc. for the treatment of 
fibrotic diseases, including Non-alcoholic Steatohepatitis (NASH) and Hepatocellular 
Carcinoma (HCC).  
The molecular action of CRV431 is binding and inhibition of cellular enzymes called 
cyclophilins. Cyclophilins are peptidyl prolyl isomerases that catalyse changes in the 
isomeric conformation (cis and trans) of peptide bonds between prolines and adjacent 
amino acids. Cyclophilins are involved in diverse cellular process, including intracellular 
signalling and inflammation (Cyclophilin A [Cyp A]), protein folding and secretion 
(Cyclophilin B [Cyp B]), and regulation of mitochondrial permeability transition pores 
(Cyclophilin D [Cyp D]), which protect cells in response to injury. 
Cyclophilins were first characterized through the discovery that cyclosporine A (CsA), a 
drug used for prevention of organ graft rejection, exerts its immunosuppressive activity 
by a two-step mechanism involving inhibition of Cyp A and calcineurin [1],[2],[3],[4]. 
Researchers have chemically modified CsA to diminish its calcineurin binding and 
thereby reduce its immunosuppressive properties while retaining its binding and 
inhibition of cyclophilins. This class of compounds is known as “non-immunosuppressive 
CsA analogues,” and includes rencofilstat. The safety and efficacy of this class of drug 
has been demonstrated by the partial clinical development of alisporivir wherein the 
compound was administered to over 2000 subjects [5],[6],[7]. 
Rencofilstat displays the basic functional characteristics of the family – high potency 
cyclophilin inhibition but low immunosuppressive activity – but it also possesses distinct 
properties that distinguish it from other compounds in the class such as increased 
solubility and less interaction with membrane transporters. The functional distinctiveness 
of rencofilstat derives in part from its unique modifications at amino acids 1 and 3, in 
comparison to most other non-immunosuppressive CsA analogues which are modified 
at amino acid positions 3 and 4. 
Non-alcoholic fatty liver disease (NAFLD) and its more severe form, NASH are significant 
health burdens with prevalence increasing throughout the world. NAFLD is characterized 
by fat accumulation in the liver and often is associated with obesity, insulin resistance, 
dyslipidaemia and other aspects of metabolic syndrome. NASH shares these 
characteristics but additionally is characterized by liver inflammation and fibrosis. 
Extensive fibrosis in the absence of compensatory fibrolysis leads to scarring and 
cirrhosis and an increased likelihood of developing complications such as HCC, with an 
annual incidence of 0.5% to 2.6% [8]. HCC represents more than 80% of the primary 
liver cancers. 
Worldwide NAFLD prevalence is 25% with the highest rates in the Middle East and South 
America. NASH affects between 1.5% and 6.5% of the global population. In the US, 
NAFLD prevalence is projected to increase from 83 million people in 2015 to 101 million 
people in 2030, with 33% of the population over the age of 15 impacted. The incidence 
of NASH and HCC are expected to similarly increase resulting in an excess 800,000 liver 
deaths during this period [9]. There are currently no US Food and Drug Administration 
(FDA) or UK Regulatory authority approved drugs for NASH, and metabolism-regulating 
drugs are largely not efficacious. Most drugs currently under development target 
metabolic disease rather than fibrosis. Multiple cyclophilin isoforms potentially contribute 

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to NASH pathophysiology, including Cyp A, Cyp B, and Cyp D, by participating in energy 
and lipid metabolic activities, regulation of hepatocyte death, inflammation, and fibrosis 
[10]. 
Reduction of liver steatosis, hepatocyte death, inflammation, and especially fibrosis are 
the primary outcomes being sought in NASH clinical trials. Achieving these endpoints is 
expected to alleviate the risks of advancing to compensated cirrhosis, decompensated 
cirrhosis, HCC, and liver failure [10]. 
5.2 
Investigational Medicinal Product 
The investigational medicinal product (IMP) that will be used in this clinical study is 
presented in Table 1. 
Table 1 
Investigational Medicinal Product 
IMP Name 
Dose 
Route of Administration 
[14C]CRV431 SMEDDS Concentrate 
for Oral Emulsion, 225 mg 
(NMT 6.4 MBq) 
225 mg 
Oral administration, Fasted 
14C: carbon-14, MBq: megabecquerel, NMT: not more than, SMEDDS: self-microemulsifying drug delivery 
system 
The 
carbon-14 
([14C])-rencofilstat 
(also 
referred 
to 
as 
[14C]CRV431) 
self-microemulsifying drug delivery system (SMEDDs) oral emulsion is an un-licensed 
medicinal product for use only in the proposed clinical trial.  
Only subjects enrolled in the study may receive study treatment and only authorised site 
staff may supply or administer study treatment. All study treatments will be stored in a 
secure, environmentally-controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
[14C]-rencofilstat will be manufactured in accordance with Good Manufacturing Practice 
(GMP) by Quotient Sciences. Where Quotient Sciences (hereafter referred to as 
Quotient) is manufacturing the final [14C]-rencofilstat SMEDDs oral emulsion, suitability 
of the manufacturing process will be documented in a Pharmaceutical Development and 
Control Strategy Report. 
IMP will be reconciled and destroyed in accordance with the study-specific quality 
agreement and technical addendum. 
5.3 
Previous Study Findings 
Full details of previous study findings can be found in the Investigator’s Brochure (IB) 
[11]. A summary of the non-clinical and clinical findings is provided below. 

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5.3.1 Non-clinical Findings 
Non-clinical Pharmacology 
Rencofilstat has been shown to bind specifically and with high potency to several human 
cyclophilin isoforms including Cyp A, Cyp B, Cyp D, and cyclophilin G. Across different 
species, organ types, and experimental systems, rencofilstat treatment resulted in 
therapeutic effects. Notably, rencofilstat decreased markers of inflammation and fibrosis 
in vitro, such as collagen and fibronectin secretion, and decreased liver fibrosis by 37% 
to 82% in disease models.  
Anti-neoplastic properties of rencofilstat were examined both in vitro and in vivo. 
Rencofilstat alone or in combination with other anti-cancer agents decreased growth of 
tumours and reduced tumour burden in mouse models.  
Rencofilstat demonstrated no indication of cytotoxicity, mitochondrial toxicity, 
immunosuppression, or off-target safety findings, consistent with long-term toxicology 
studies in rat and monkey that showed no rencofilstat-induced toxicity. 
Non-clinical Pharmacokinetics and Metabolism 
The PK characteristics of rencofilstat including drug absorption, distribution, and 
metabolism were determined in vitro and in rat and monkey. Seven-day, 30-day, 
26-week, and 39-week TK studies were conducted in rat and monkey.  
Whole blood is the preferred matrix as rencofilstat partitions primarily in red blood cells 
at concentrations ≤ 2 μM, and predominantly in the plasma fraction at 10 μM. Rencofilstat 
exhibited >96% plasma protein binding and is stable in rat, monkey and human whole 
blood and plasma for at least 8 h.  
Rencofilstat was predominantly metabolized by cytochrome P450 (CYP450) 3A4 into at 
least 12 distinct metabolites which is consistent with the reported metabolism of other 
cyclosporine analogues. Rencofilstat was not a significant inhibitor of any CYP450s and 
was not found to be an enzyme inducer.  
The pharmacokinetics (PK) of rencofilstat in rats and monkeys showed an increase in 
exposure with dose but appeared to reach a saturation point at the higher doses with a 
Tmax ranging from 1 to 8 h. 
Non-clinical Toxicology 
In both acute (30-day) and chronic (6- and 9-month) toxicology studies in rats and 
monkeys, rencofilstat was well tolerated and did not result in notable changes in weight, 
appetence, or clinical signs and symptoms.  
In rat, multiples of human exposure were up to 4.9-fold at the clinical dose of 75 mg and 
up to 3.4-fold relative to the 225 mg dose. In the monkey, multiples of human exposure 
were up to 5.4-fold at the clinical dose of 75 mg and 3.7-fold relative to the 225 mg dose.  
Genotoxicity studies included in vitro bacterial reverse mutation assay and mammalian 
chromosomal aberration test, and in vivo mammalian erythrocyte micronucleus test 
(conducted as part of the 30-day rat toxicity study). No genotoxicity findings were 
observed. 

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In single- and repeat-dose toxicity studies in rats and monkeys, no mortality, clinical 
signs, changes in body weight, or genotoxicity were observed throughout the studies. 
The NOAEL for both rat and monkey was considered to be the highest dose level tested 
or the highest dose before plateau of exposure. 
5.3.2 Clinical Findings 
Rencofilstat PK parameters, safety, and efficacy in humans was investigated in three 
Phase 1 clinical studies and one Phase 2 clinical study. To date there have been no 
deaths or serious adverse events (SAEs). Most TEAEs were mild or moderate in severity 
and occurred at comparable rates between placebo and rencofilstat. There are two 
ongoing clinical studies in NASH subjects. 
Brief Safety Summary of Completed Clinical Studies 
During the first in human study of rencofilstat  in healthy volunteers (CRV431-101) there 
was no trend observed for adverse event (AE) reporting in relation to the rencofilstat 
dose. There were also no remarkable observations in the remaining safety assessments 
for vital signs, 12-lead ECGs, or safety laboratory measurements in this study. 
The result of CRV431-103 study in healthy volunteers indicated that rencofilstat does not 
alter the PK of midazolam or its metabolite, 1-hydroxymethyl midazolam. Midazolam and 
ketoconazole did alter the PK of rencofilstat, resulting in approximately 2-fold and 4-fold 
higher exposures, respectively. One subject was discontinued from study participation 
due to an AE of elevated alanine aminotransferase (ALT)/AST who was later determined 
to have infection with Coronavirus Disease 2019 (COVID-19). 
Administration of rencofilstat with a high fat meal in study CRV431-104 led to increases 
in Cmax, AUC(0-24), and AUC(0-inf) fed to fasted geometric mean ratios of 102.2%, 
114.5% and 132.9%, respectively. The upper bounds of the 90% confidence intervals 
extended beyond the 80-125% range for AUC(0-last) and AUC(0-inf), All AUC geometric 
mean ratios were outside of the 80–125% range, suggesting a high fat meal can increase 
the extent of rencofilstat exposure. Tmax increased from 1.5 to 1.8 h in the fasted and 
high fat groups, respectively, suggesting slightly delayed absorption. Mean half-life was 
approximately 22 h longer for subjects administered rencofilstat with food compared to 
subjects administered rencofilstat under fasted conditions, although inter-subject 
variability was considerably higher for the fed cohort. 
During CRV431-201 study, a multiple dose study in patients with NASH, two subjects 
discontinued the study treatment due to an AE; one subject experienced palpitations 
leading to discontinuation on study day 3 and another withdrew due to myalgia, migraine, 
and pyrexia on study day 7. A total of 21 (44.7%) subjects experienced 36 AEs, with 
most (69.4%) being unrelated to study treatment. A majority (97.2%) were mild to 
moderate in severity. One AE, constipation, was reported as severe (Grade 3), and there 
were no deaths or SAEs reported in the study. There were no AEs related to change in 
laboratory values, including liver biochemical markers, reported except for one subject 
with hypercholesterolaemia and one subject with a urinary tract infection. 
Overall, rencofilstat was deemed safe and well tolerated at all combinations tested to 
date in both healthy and NASH subjects. 

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Summary of Completed and Ongoing Clinical Studies to Date 
Study ID 
Phase 
Population 
Study Title 
Study design 
Dosing regimen 
Completed Clinical Studies 
CRV431-
101 
 
Phase 1 
Healthy 
Subjects 
A Randomized, Partially 
Blinded, Placebo-controlled, 
Ascending Sequential Dose 
Groups, Single Dose Study of 
the Safety, Tolerability and 
Pharmacokinetics of CRV431, 
Alone and in Combination with 
Tenofovir Disoproxil Fumarate 
and in Multiple Ascending 
Sequentially Dosed Healthy 
Subjects 
Randomised, 
subject-
blinded, 
placebo 
controlled 
ascending 
SAD and MAD 
Part 1 (SAD): 
75, 225, 375, or 
525 mg PO 
Part 2 (DDI): 
375 mg rencofilstat PO, 
300 mg TDF PO, or 
combination  
Part 3 (MAD): 
75, 150, 225, 300 or 
375 mg PO QD, 
28 days 
CRV431-
103  
 
Phase 1 
Healthy 
Subjects 
A Single Center, Open-Label, 
Phase 1 DDI Study to 
Evaluate the Pharmacokinetics 
of CRV431 in Normal Healthy 
Volunteer Subjects 
Randomised, 
open label, 
Phase 1, 
single-centre 
DDI study 
75 mg rencofilstat PO 
alone or in combination 
with 400 mg 
ketoconazole PO or 2 
mg midazolam IV 
CRV431-
104 
 
Phase 1 
Healthy 
Subjects 
A Single Center, Open-Label, 
Phase 1 Study to Evaluate the 
Pharmacokinetics of CRV431 
Under Fasted and Fed States 
in Normal Healthy Volunteer 
Subjects 
Open label, 
single dose 
225 mg PO 
CRV431-
201 
 
Phase 2a 
Presumed 
F2/F3 NASH 
Subjects 
AMBITION: A Phase 2a, Multi-
Center, Single-Blind, Placebo-
Controlled Study to Evaluate 
the Safety and Tolerability of 
CRV431 Dosed Once Daily in 
NASH Induced F2 and F3 
Subjects 
Multi-centre, 
single blind, 
placebo 
controlled 
75 mg or 225 mg PO 
QD,  
28 days 
Ongoing Clinical Studies 
CRV431-
207 
 
Phase 2b 
NASH 
Subjects 
ASCEND-NASH: A Phase 2B, 
Randomized, Multi-center, 
Double-blind, Placebo-
controlled Study to Evaluate 
the Efficacy and Safety of 
Rencofilstat in Adult Subjects 
with Nonalcoholic 
Steatohepatitis and Advanced 
Liver Fibrosis 
Multi-centre, 
double blind, 
placebo 
controlled 
75 mg, 150 mg and 
225 mg plus placebo, 
QD for 365 days PO  
 
CRV431-
210 
 
Phase 2 
NASH 
Subjects 
ALTITUDE-NASH: A Phase 2, 
Randomized, Multi-center, 
Open-label Study to Evaluate 
the Safety and Efficacy of 
Rencofilstat in Adult Subjects 
with Nonalcoholic 
Steatohepatitis Stage 3 
Fibrosis 
Multi-centre, 
open label 
75 mg, 150 mg and 
225 mg QD for 
120 days PO 
DDI: drug-drug interaction, MAD: Multiple Ascending Dose, SAD: Single Ascending Dose, TDF: tenofovir 
disoproxil fumarate 
Pharmacokinetics Summary of Single Ascending Doses in Healthy Volunteers 
PK analyses have been performed in all of the completed clinical trials to date. 
Rencofilstat PK have been consistent and repeatable in both healthy volunteer subjects 

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and presumed F2/F3 NASH subjects. As the current study is a single dose study, only 
single ascending dose (SAD) PK parameters are summarised here. 
In the CRV431-101 SAD part of the study, healthy volunteers received single doses of 
rencofilstat at 75, 225, 375, and 525 mg, or vehicle (liquid formulation), and PK was 
assessed for 6 days post-dose. Results demonstrated a plateauing of the apparent rate 
(Cmax) and extent (AUC) of rencofilstat exposure at dose levels above 225 mg. This 
was consistent with PK observations in rat and monkey that showed a plateau between 
middle and high dosing levels. 
Single dose PK of rencofilstat approximated first-order behaviour from 75 mg to 225 mg 
with decreasing exposure after 375 mg. Dose proportionality was initially greater than 
1:1 but decreased with the plateauing of exposure (Table 2).  
Table 2 
Summary of Whole Blood Rencofilstat Pharmacokinetic Parameters 
Following Single Oral Doses (SAD, PK Population) 
PK 
Parameters 
Rencofilstat 
75 mg (N=6) 
Rencofilstat 
225 mg (N=6) 
Rencofilstat  
375 mg (N=6) 
Rencofilstat  
525 mg (N=6) 
AUC(0-24) 
(ng.hr/mL) 
6048 ± 24.9 
17720 ± 27.8 
15670 ± 29.3 
18170 ± 18.2 
AUC(0-last) 
(ng.hr/mL) 
16620 ± 18.7 
53530 ± 32.4 
50640 ± 34.9 
62340 ± 24.2 
AUC(0-inf) 
(ng.hr/mL) 
20550 ± 18.1 
80030 ± 36.2 
79980 ± 50.2 
92870 ± 32.1 
Cmax  
(ng/mL) 
320.5 (32.0) 
1354 (15.5) 
1204 (58.3) 
1640 (15.0) 
Tmax 
(hr) 
2.99 
(2.00, 10.00) 
1.00 
(1.00, 2.00) 
1.00 
(1.00, 4.00) 
1.00 
(1.00, 100) 
T1/2 (hr) 
73.6 ± 15.2 
98.14 ± 17.96 
111.27 ± 37.25 
94.05 ± 17.87 
CL/F 
(L/hr) 
3.7 ± 0.7 
3.0 ± 0.9 
5.2 ± 2.7 
5.9 ± 1.6 
Vz/F (L) 
392.6 ± 115.50 
412.7 ± 144.0 
753.7 ± 244.7 
765.7 ± 136.9 
Cmax presented as geometric mean (geometric CV%). Tmax presented as median (minimum, maximum). 
Other parameters are presented as arithmetic mean ± SD. 
Safety Summary of Single Ascending Doses in Healthy Volunteers 
In the CRV431-101 SAD part of the study there were no deaths, SAEs, or subject 
discontinuations due to AEs in Part 1 of the study. Overall, a total of 20 AEs were 
experienced by 14 (47%) subjects following active treatment, with 3 (50%) subjects 
reporting 3 events following rencofilstat 75 mg, 1 (17%) subject reporting 5 events 
following rencofilstat 225 mg, 3 (50%) subjects reporting 3 events following rencofilstat 
375 mg, 3 (50%) subjects reporting 5 events following rencofilstat 525 mg, 4 (67%) 
subjects reporting 4 events following rencofilstat 375 mg ingested immediately following 
dilution, and 6 (60%) subjects reported 15 events following placebo.  
Mild constipation was the most commonly reported event, reported a total of 3 times by 
3 (10%) active-treatment subjects in Part 1 of the study, with 1 subject each reporting 
1 event following rencofilstat 375 mg, rencofilstat 525 mg, and rencofilstat 375 mg 
ingested immediately following dilution. The investigator considered all events to be 
possibly related to the study treatment. Each of the remaining AE terms were reported 
in ≤ 2 subjects (≤ 7%). 

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6 Rationale 
6.1 
Study Rationale 
This study aims to understand the absorption, distribution, metabolism and elimination 
(ADME) of rencofilstat in humans further through the assessment of the mass balance 
recovery after a single oral dose of [14C]-rencofilstat. The routes and rates of elimination 
of [14C]-rencofilstat will be determined and whole blood, urine and faecal samples will be 
used for metabolic profiling and structural identification. 
This is a single dose mass balance study of a single formulation, the study will be 
open-label and no randomisation is required. 
6.2 
Dose Rationale 
The Phase I clinical study found that rencofilstat was safe and well tolerated at single 
doses from 75 mg to 525 mg and at multiple doses of 75 mg to 375 mg, administered 
daily for 28 days.  
Systemic exposure of rencofilstat as measured by Cmax and AUC are approximately 
10 to 100-fold above the drug’s IC50 for inhibition of cyclophilins. Thus, the doses tested 
from the 75 mg dose upwards achieve systemic concentrations necessary to adequately 
engage the drug receptors at the site of action. Doses of 75 mg and 225 mg per day for 
28 days were studied in the Phase 2 study in patients with NASH. A dose of 225 mg has 
been chosen for this study as in previous clinical studies, rencofilstat systemic exposure 
has been found to plateau at doses equal to and higher than 225 mg. It is expected that 
225 mg will be the most efficacious dose and is currently the highest dose being 
evaluated in the Phase II clinical trials. 
The dose of radioactivity has been determined following review of human dosimetry 
calculations provided by UK Health Security Agency. The associated radiation exposure 
will fall within International Commission on Radiological Protection (ICRP) (1992) 
Guidelines for Category IIb studies (1 to 10 mSv). The dose of radioactivity will be no 
more than 6.4 MBq. 
To ensure that the [14C] drug product does not exceed the limit for radioactive dose 
approved by the Administration of Radioactive Substances Advisory Committee 
(ARSAC), the target specific activity of the drug substance will be set at 90% of 90% of 
the threshold radioactive dosing limit. This will allow for tolerances in the manufacturing 
processes for both drug substance and drug product thereby providing continued 
assurance for compliance with the ARSAC-approved limit for drug product radioactivity 
dose. 
6.3 
Population Rationale 
As this is a Phase I study assessing the ADME, PK and safety of rencofilstat, the most 
relevant population is healthy volunteers. Subjects who are non-smokers without a 
history of alcohol or drug abuse or regular co-medication are proposed to avoid 
interaction on drug metabolism and to avoid non-compliance.  
Data is not currently available from fertility and teratology studies with rencofilstat and 
subjects will be exposed to radiation; therefore, female subjects will not be enrolled in 
this study. 

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We acknowledge the ARSAC Notes for Guidance recommend that wherever possible, 
healthy subjects selected for research projects should be aged over 50 years [12]. 
However, the current study is designed to generate data for supporting the investigation 
of the human ADME of a drug, as well as generating samples for metabolite profiling and 
structural identification. 
There are two main reasons for generating these data within a clinical development 
programme. The first is to provide human metabolite data that can be used to interpret 
the metabolism profiles seen in the preclinical species employed in the longer-term 
toxicity studies, to ensure that there is adequate toxicology coverage for the safe 
development of the drug in patients. The second is to provide data to understand how 
the drug is processed in physiologically normal subjects, because understanding the 
routes of metabolism and elimination in a healthy population generates the appropriate 
data to guide the clinical pharmacology package required to fulfil the regulatory 
requirements of a New Drug Application.  
In order to address these two main aims of an ADME study, investigation of the drug 
under development is required in a population with normal physiological function, as it is 
recognised that certain physiological processes eg renal function, deteriorate with age 
and therefore it is preferable to use as healthy a population as possible, to mitigate 
against factors which may make interpretation of the data difficult. Also, healthy subjects 
as a trial population are ideal since they have a relatively stable physiological, 
biochemical and hormonal status, which removes any disease-related variations and 
variations due to concomitant medications. Therefore, given the aims of this ADME study 
our target age range for this study will be 30 to 65 years. 
In addition, the initial target indication of this drug is NASH and, therefore, the target age 
range for the indication is included in the proposed age range for the study.  
6.4 
Risks and Benefits 
6.4.1 Risks Associated with Rencofilstat Administration 
Rencofilstat, previously known as CRV431, has been studied in three Phase I studies in 
healthy volunteers (CRV431-101, CRV431-103, and CRV431-104) as well as in a 
Phase 2a study in NASH patients (CRV431-201). CRV431-101 was a first in human 
study of rencofilstat comprised of 1) a SAD study; 2) a DDI study between rencofilstat 
and TDF; and 3) a 28-day MAD study. There were no deaths or SAEs in any parts of the 
study.  
In Part 1, 20 AEs were experienced by 14 (47%) subjects following active treatment. The 
investigator assessed 18 events to be Grade 1, and 2 events to be Grade 2 in severity; 
9 events were possibly related to study treatment, and 11 events were assessed as 
unrelated to the study treatment. Mild constipation was the most commonly reported AE, 
by 3 (10%) active treatment subjects, with 1 subject each in the 375 mg, 525 mg, and 
375 mg (SMEDD ingested immediately following dilution) cohorts reporting 1 event each 
and was considered by the PI to be possibly related to the study. 
In Part 2 headache was the most reported AE, reported 11 times by 8 subjects (44%). 
Fatigue and oropharyngeal pain were reported 3 times by 3 subjects (17%); dyspepsia, 
myalgia, nausea, and dizziness were reported 2 times by 2 subjects (11%). Events were 
generally distributed across treatment conditions, with a moderate increase seen in AEs 
in the combination rencofilstat plus TDF treatment (12/18 subjects [67%]) than in 
rencofilstat (8/18 [44%]) or TDF (7/18 [39%]) alone. 

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In Part 3, 2 subjects were discontinued due to AEs (1 due to urinary tract and yeast 
infections and 1 due to headache and lower abdominal pain). Only 3 AEs occurred in 
≥ 3 subjects: headache in 4 subjects (12%); fatigue, and diarrhoea in 3 subjects (9%). 
All events were Grade 1 or 2 in severity. There was no apparent relationship between 
rencofilstat dose level and AE frequency. 
Overall, there was no trend observed for AE reporting in relation to rencofilstat dose. 
There were no remarkable observations in the remaining safety assessments for vital 
signs, 12-lead ECGs, or safety laboratory measurements in this study.  
In study CRV431-103, there were no SAEs or deaths reported following treatment with 
75 mg rencofilstat alone or in combination with 400 mg ketoconazole or 2 mg midazolam. 
One patient discontinued study participation due to a TEAE of elevated ALT/AST and 
subsequent COVID-19 infection. Twenty-eight AEs were recorded for 12 subjects. 
Investigators assessed 21 AEs as Grade 1, 6 AEs as Grade 2, and 1 AE as Grade 3. 
The grade 3 AE, elevated ALT, was considered unrelated to study drug and instead 
related to COVID-19 infection. TEAEs reported in 2 or more subjects were nausea 
(4 subjects [14.8%], diarrhoea, dizziness, headache, alanine aminotransferase 
increased, and aspartate aminotransferase increased (2 subjects [7.4%]). There were 
no findings or changes from baseline observed in any of the laboratory parameters 
(haematology, coagulation, blood chemistry, urinalysis), vital signs, pulse oximetry or 
ECG that were deemed to be clinically significant by the investigator. 
In study CRV431-104, there was 1 AE related to clinically significant out-of-range vital 
signs (blood pressure increased) reported by 1 subject in the fed cohort. The AE was 
Grade 1 (mild) and judged by the Investigator as not related to study treatment. 
Overall, rencofilstat was safe and well tolerated at all combinations tested to date in 
healthy subjects. There are no important identified risks or potential identified risks from 
the rencofilstat development program.  
Non-clinical genotoxicity studies were all negative. These data presented a favourable 
safety profile for rencofilstat with acceptable safety margins that support the proposed 
clinical development program. No reproductive or developmental toxicity studies of 
rencofilstat have been performed as of the IB cut-off date of 01 Oct 2022. However, no 
females will take part in this study, and the male volunteers must agree to adhere to the 
contraception requirements defined in Section 9.4. No phototoxicity studies have been 
conducted on rencofilstat as of the IB cut-off date of 01 Oct 2022. Owing to the 
unavailability of phototoxicity data, subjects will be advised to minimise exposure to 
sunlight following dosing until discharge from the study (see Section 9.6). 
All formulation excipients are United States Pharmacopeia (USP) grade or National 
Formulary (NF) grade and therefore have a Generally Recognised As Safe (GRAS) 
designation. Consequently, it is deemed safe to use in this study.  
Given the current safety results, the benefit-risk is anticipated to be favourable at all dose 
levels tested. 

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6.4.2 Risks Associated with Administration of Radioactivity 
The dosage form will contain a radionuclide, not more than (NMT) 6.4 MBq 14C, so 
subjects will be exposed to ionising radiation. The effective dose that each subject will 
receive from 1 administration of 6.4 MBq 14C will not exceed 2.0 mSv. This is 
approximately 9 months of the average radiation exposure received in the UK each year 
(2.7 mSv; data obtained from UK Health Security Agency Ionising Radiation Exposure 
of the UK Population: 2010 Review [13]) and is slightly more (1.1 times) than the radiation 
dose that would result from 4 abdominal X-rays (0.47 mSv each). It is believed that any 
increase in the amount of radiation that is received above natural radiation carries a risk 
of later developing serious and possibly fatal conditions. The risk associated with the 
maximum possible dose of radiation in this study is very small indeed and is considered 
to be acceptable. 
Extrapolation of data from epidemiological studies of cancers induced by radiation 
exposure indicates that the risk factor for an adult UK population of both sexes (age 
range 18 to 64) is 5 × 10-2 per Sv [14]. From this it can be estimated that the lifetime risk 
of inducing a fatal cancer in a healthy individual from the total exposure of 2.0 mSv is 
approximately 1 in 10,000. The lifetime risk for being diagnosed with cancer in the UK is 
around 1 in 2 [15], indicating that this additional risk from this amount of radiation 
exposure is minimal. 
6.4.3 COVID-19 Related Risks and Risk Mitigation Measures 
The following risks and risk mitigating measures apply to the time in which the study is 
conducted during the COVID-19 pandemic.  
6.4.3.1 IMP Related Risk 
Against the background of the COVID-19 pandemic, the potential risk of a subject 
developing COVID-19 has been considered in terms of the risk-benefit evaluation. The 
mode of action of the IMP – as a cyclophilin inhibitor – has been considered alongside 
available pre-clinical and clinical data (including class effects) and it is considered that a 
subject would not be at increased risk of either becoming infected with severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2; the virus that causes COVID-19) or 
experiencing a more severe illness. That is, the IMP has no known immunomodulatory 
effect that would confer an increased risk to healthy subjects enrolled in the study. 
6.4.3.2 General COVID-19 Related Risk Mitigation Measures 
General risk mitigation against COVID-19 will be implemented in accordance with 
Quotient’s monitoring and prevention control measures. 
COVID-19 testing may be performed based on current infection rates and availability of 
tests. If required, it is planned that testing will comprise an antigen test performed on 
Day -1 prior to admission to the clinical unit and at return visits. Testing time points may 
be changed, and additional time points may be added throughout the study as required. 
The decision on COVID-19 testing and the definition of the testing time points are subject 
to change based on the current risk mitigation in place and will be agreed by the study 
team and documented in the Investigator Site File (ISF) via the Clinical Kick-Off Meeting 
minutes. 
The risk mitigation measures, where applicable, will be amended based on emerging 
government guidance. 

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6.4.3.3 COVID-19 Vaccine-Related Risk 
Approved (including health authority conditional marketing authorisation) COVID-19 
vaccines eg killed, inactivated, peptide, DNA and RNA vaccines may be permitted 
according to the investigator’s discretion and as per local guidance.  
Based on the mechanism of action of the IMP, as an inhibitor of cyclophilin, there is no 
perceived impact on the safety of the study subjects or on the study objectives for 
subjects who may receive these vaccines. It is also very unlikely that administration of 
the IMP would interfere with COVID19 vaccination response; however, no specific 
preclinical or clinical investigations have been conducted at this point with rencofilstat.  
6.4.4 General Risks and Overall Risk-Benefit Assessment  
Collecting a blood sample from a vein may cause pain, swelling, bruising, 
light-headedness, fainting, and very rarely, clot formation, nerve damage and/or infection 
at the site of the needle stick. 
During cannulation, more than one attempt may be needed to insert the cannula in a 
vein of a subject and it is possible that bruising and/or inflammation may be experienced 
at the site of cannulation.  
ECG stickers on the subjects' chests and limbs may cause some local irritation and may 
be uncomfortable to remove but subjects will be closely monitored to ensure any local 
irritation does not persist. 
There is no benefit to the subjects from taking part in this study. The development of a 
product to treat NASH and viral hepatitis-induced liver disease may be of benefit to the 
patients with these diseases. 
The overall risk benefit balance is therefore considered to be acceptable. 
 
 

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7 Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
 
To determine the mass balance recovery after a 
single oral dose of [14C]-rencofilstat 
 
Mass balance recovery of total radioactivity (TR) in 
all excreta (urine and faeces): CumAe and 
Cum%Ae 
To determine % parent drug unchanged versus 
metabolites 
Parent to total radioactivity ratio for whole blood 
based on AUC 
To perform metabolite profiling and structural 
identification from whole blood, urine and faecal 
samplesa 
Collection of whole blood, urine and faeces 
samples 
for 
metabolite 
profiling, 
structural 
identification, and quantification analysis 
Secondary 
To determine the routes and rates of elimination of 
[14C]-rencofilstat 
 
Mass balance recovery of TR in urine and faeces 
separately: Ae, %Ae, CumAe and Cum%Ae by 
interval 
To identify the chemical structure of each metabolite 
accounting for more than 10% of circulating TR or 
accounting for 10% or more of the dose in excreta 
Identification of the chemical structure of each 
metabolite accounting for more than 10% by AUC 
of circulating TR or accounting for 10% or more of 
the dose in excreta 
To evaluate the extent of distribution of TR into 
blood cells 
Evaluation of whole blood:plasma concentration 
ratios for TR 
To provide additional safety and tolerability 
information for rencofilstat 
To provide additional safety and tolerability 
information for rencofilstat by assessing: incidence 
of AEs, physical examinations and change from 
baseline for vital signs, ECGs, and laboratory safety 
tests 
To further explore the oral PK of rencofilstat 
PK parameters for rencofilstat in whole blood and 
TR in plasma and whole blood following a single 
oral dose, including but not limited to: Tlag, Tmax, 
Cmax, 
AUC(0-last), 
AUC(0-inf), 
AUC(0-24), 
Lambda-z, T1/2, CL/F, Vz/F, MRT(0-last) and 
MRT(0-inf) as applicable 
a Metabolite profiling and identification will be reported separately from the clinical study report as a 
standalone document. 
8 Study Design 
8.1 
Study Plan 
This is a single centre, open-label, non-randomised, single period, single dose study in 
healthy male subjects designed to assess the mass balance recovery, PK, metabolite 
profile and metabolite identification of rencofilstat. It is planned to enrol a single cohort 
of 6 subjects.  
All subjects will receive a single 225 mg oral dose of [14C]-rencofilstat, as a SMEDDS 
oral emulsion, containing NMT 6.4 MBq, in the fasted state.  
Subjects will undergo preliminary screening procedures for the study at the screening 
visit (Day -28 to Day -2). Subjects will be admitted in the evening on the day before 
dosing (Day -1). 
Whole blood, plasma, urine and faeces samples will be collected at regular intervals for 
PK analysis, TR analysis, metabolite profiling, mass balance and safety as applicable, 
from pre-dose to discharge from the clinical unit. Urine and faeces samples may be 
collected at return visits or home visits if mass balance criteria has not been met by a 
subject. 

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Subjects will be dosed on the morning of Day 1 following an overnight fast (minimum 8 h) 
and will remain resident in the clinical unit until up to 504 h after dosing (up to Day 22).  
It is planned that subjects will be released as a group when all subjects have achieved a 
mass balance cumulative recovery of >90% or if <1% of the dose administered has been 
collected in urine and faeces within two separate, consecutive 24 h periods. This may 
result in the subjects being discharged as a group prior to completion of the planned 
residency period.  
If the mass balance criteria are achieved during the planned residency period, collection 
of all samples (blood, urine and faeces) will be stopped once the current 24 h collection 
period is complete, and subjects will undergo discharge assessments. 
If the mass balance criteria have not been met by all subjects on the morning of 
Day 22, the residency period for the subjects not achieving the mass balance criteria 
may be extended up to a maximum of 96 h (Day 26; 600 h post-dose). Only urine and/or 
faecal samples will be collected during the extended residency period. 
If the mass balance criteria have not been met by all subjects on the morning of 
Day 26, subjects not achieving the release criteria may be required to make up to 
2 return visits (each of 24 h duration) at (nominally) Day 28 (+2 days) and 
Day 35 (±2 days) for additional collection of excreta samples (urine and/or faecal 
samples). 
If the mass balance criteria have not been met following the return visits, then home 
collections of urine and/or faeces may be requested at the discretion of the investigator 
for individual subjects. 
A subject will be considered evaluable if they have provided mass balance and PK 
samples for up to 21 days after drug administration or have demonstrated >90% mass 
balance recovery or have <1% of the administered dose eliminated in excreta for two 
consecutive days, whichever is sooner. 

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Figure 1 
Study Sequence 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 
 
Dose 
Day 1 
 
Discharge 
Day 22  
 
Or, if mass balance criteria are 
not met by Day 22a: 
Extended Residency Discharge 
Day 23, 24, 25 or 26 
 
And, if mass balance criteria 
are not met by Day 26b: 
Return Visit 
Day 28 (+2 days) 
 
And, if mass balance criteria 
are not met by Day 28b: 
Return Visit 
Day 35 (±2 days) 
a If all subjects have not achieved a mass balance cumulative recovery of >90% or if a total of <1% of the 
dose administered has not been collected in urine and faeces within 2 separate, consecutive 24 h periods 
on the morning of Day 22, the residency period for the subjects not achieving the mass balance criteria may 
be extended up to a maximum of 96 h (Day 26). Only urine and/or faecal samples will be collected during 
the extended residency period.  
b If the mass balance criteria have not been met by all subjects on the morning of Day 26, subjects not 
achieving the release criteria may be required to make up to 2 return visits (each of 24 h duration) at 
(nominally) Day 28 (+2 days) and Day 35 (±2 days) for additional collection of excreta samples (urine and/or 
faecal samples). If the mass balance criteria have not met following the return visits, then home collections 
of urine and/or faeces may be requested at the discretion of the investigator for individual subjects. 
8.2 
Criteria for In-Study Decisions 
Not applicable for this study. 
8.3 
Subject Withdrawal 
If a subject wishes to leave the study at any time, they will be permitted to do so. Every 
reasonable effort will be made by Quotient to complete a final assessment/discharge 
procedures. Quotient will advise the sponsor of the withdrawal of any subject from the 
study. 
Early withdrawal is defined as the date of the decision to withdraw the subject from the 
study. Subject completion is defined as the date of the last procedure conducted or last 
contact (eg unscheduled phone call or visit) for that subject. 

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Note that if a subject requests to leave the clinical unit earlier than the planned discharge 
time, eg due to unforeseen personal circumstances, they may be withdrawn from the 
study and may not be able to return to the clinical unit to complete the study. 
This is a single dose study, therefore, after an individual subject has received a dose of 
IMP, withdrawal of that subject from further dosing is not possible. Subjects will be 
monitored for the following criteria which may require their withdrawal from some or all 
study procedures if continuation is not in their best interests, except when the withdrawal 
is a result of withdrawal of consent:  
• 
Experiencing a serious or severe AE including but not limited to: 
− corrected QT interval by Fridericia’s formula (QTcF) of >500 msec or 
increase in QTcF interval of >60 msec from baseline (confirmed following 
a repeat ECG)  
− ALT concentration >3 × the upper limit of the reference range (confirmed 
following a repeat ALT blood test) 
• 
Termination of the study 
• 
Upon the subject’s request (withdrawal of consent) 
• 
Significant deviation from the protocol 
• 
Concurrent illness that would adversely affect subject safety or data integrity or 
requirement for prohibited medication 
• 
At the discretion of the investigator 
For the purpose of withdrawal criteria, baseline will be considered as the last available 
assessment prior to IMP dose. 
For a subject who withdraws because of an IMP-related AE, every effort will be made to 
ensure the subject completes follow-up procedures.  
Early withdrawal of consent by the subject to participate in any further activities will be 
distinguished from withdrawal for any of the other above reasons. 
8.4 
Subject Replacement 
No replacement subjects are planned for this study. 
8.5 
Stopping Criteria 
The study will be halted, and the risk to other subjects evaluated if any of the following 
criteria are met:  
• 
A serious adverse reaction (ie a SAE considered at least possibly related to the IMP 
administration) in one subject. 
• 
Severe non-serious adverse reactions (ie severe non-serious AE considered as, at 
least possibly related to the IMP administration) in two subjects in the same cohort, 
independent of within or not within the same system organ class. 
Relatedness to IMP will be determined by the investigator.  

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If the study is halted, a temporary halt will be submitted to the Medicines and Healthcare 
products Regulatory Agency (MHRA) and ethics committee (EC) in the form of a 
substantial amendment. The study may be resumed or terminated; however, it will not 
be resumed until a further substantial amendment to resume the study is submitted and 
approved by MHRA and EC. 
The ARSAC Practitioner will also be informed of the temporary halt. 
8.6 
Study Termination 
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the MHRA, 
EC, ARSAC practitioner or ARSAC. The ARSAC practitioner and ARSAC (if ARSAC 
research application has been submitted or approved) must be notified promptly, that the 
study will no longer be taking place. Notification of early termination should also be 
provided to the EC and MHRA within 15 days, clearly explaining the reasons for the 
termination. 
If the study is abandoned prior to commencement of any protocol activities, the 
investigator or sponsor must notify the EC, MHRA, ARSAC practitioner and ARSAC (if 
ARSAC research application has been submitted or approved) outlining the reasons for 
abandonment of the trial. 
New information regarding the safety of the IMP that indicates a change in the risk/benefit 
profile for the compound, such that the risk/benefit is no longer acceptable for subjects 
participating in the study may also mean termination of the study prior to dosing.  
Once exposure to dosing has begun, the study will be completed as planned unless the 
following criteria are satisfied that require a temporary halt or early termination of the 
study.  
• 
The occurrence of serious or severe AE(s), as defined in Section 8.5, if considered 
to be related to the IMP, as defined in Section 14.2, on the dosing day. 
• 
Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject safety. 
If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis described in Section 6.4 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances, 
termination can only take place with the agreement of the investigator and sponsor. The 
MHRA, EC, ARSAC practitioner and ARSAC will be informed of study termination. 
If it becomes necessary to consider termination of the study on the dosing day, dosing 
may be suspended pending discussion between the investigator, sponsor and ARSAC 
practitioner (where discussion is related to administration of radiation). Dosing will be 
stopped immediately on safety grounds. 
The study may be terminated or suspended at the request of the MHRA or EC. 
8.7 
Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to return for scheduled visits and 
cannot be contacted by the clinical unit.  

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If a subject fails to return to the clinical unit for a required study visit: 
• 
The clinical unit must attempt to contact the subject and reschedule the missed visit 
as soon as possible. 
• 
Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (eg three telephone calls on three 
separate occasions and, if necessary, an email or letter to the participant’s last known 
email/postal address). These contact attempts should be documented in the 
subject’s source. 
• 
If the subject cannot be contacted, they will be considered lost to follow-up.  
8.8 
Treatment Assignment 
This is an open-label, non-randomised study, therefore a randomisation schedule will not 
be produced. Instructions to dispense and dose will be produced prior to dosing with 
IMP, which will dictate the order in which the treatments should be administered to each 
subject. The instructions to dispense and dose will be retained in the ISF. 
8.8.1 Subject Numbers 
Subject numbers will be allocated on the morning of dosing according to the code 001 to 
006 using the lowest number available.  
8.8.2 Blinding  
This is an open-label, non-randomised study and therefore blinding is not required. 
9 Selection of Subjects 
Subjects will be recruited from the Quotient panel or by direct advertising to the public. 
Before subjects are admitted to the clinical unit, The Over Volunteering Prevention 
System (TOPS) will be checked to ensure that each subject has not been dosed in a 
study within 90 days of the planned dosing date of this study.  
9.1 
Informed Consent 
Subjects will be provided with a written explanation of the study at least the day before 
the screening visit. Additionally, subjects may be provided with an information video 
before the screening visit that introduces them to the study. In the video and/or during 
the screening visit, a physician or nurse will explain to each subject the nature of the 
study, its purpose, expected duration and the benefits and risks involved in study 
participation. Subjects will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that carry out 
clinical studies nationally. Subjects will then be given the opportunity to ask questions 
and will be informed of their right to withdraw from the study without prejudice. After this 
explanation and before entering the study, the subject will voluntarily sign an informed 
consent form (ICF). Until written consent has been obtained from the subject no study 
specific procedure or investigation will be performed. If an amendment is made to the 
participant information sheet (PIS), participants will be re-consented to the most current 
version of the ICF(s) where appropriate. 
9.2 
Inclusion Criteria 
 Healthy males 
 Aged 30 to 65 years inclusive at the time of signing informed consent  

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 Body mass index (BMI) of 18.0 to 35.0 kg/m2 as measured at screening  
 Must be willing and able to communicate and participate in the whole study 
 Must have regular bowel movements (ie average stool production of ≥1 and 
≤3 stools per day) 
 Must provide written informed consent 
 Must agree to adhere to the contraception requirements defined in Section 9.4 
Inclusion criteria 1, 4, 5 and 7 from the list above will be re-assessed at admission or 
pre-dose. 
9.3 
Exclusion Criteria 
 Subjects who have received any IMP in a clinical research study within the 
90 days prior to Day 1, or less than 5 elimination half-lives prior to Day 1, 
whichever is longer 
 Subjects who are, or are immediate family members of, a study site or sponsor 
employee 
 Evidence or history of current SARS-CoV-2 infection within 4 weeks prior to IMP 
administration  
 History of any drug or alcohol abuse in the past 2 years prior to screening 
 Regular alcohol consumption in males >21 units per week (1 unit = ½ pint beer, 
or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on 
type) 
 A confirmed positive alcohol breath test at screening or admission 
 Current smokers and those who have smoked within the last 12 months prior to 
screening 
 A confirmed breath carbon monoxide reading of greater than 10 ppm at screening 
or admission 
 Current users of e-cigarettes and nicotine replacement products and those who 
have used these products within the last 12 months prior to screening 
 Radiation exposure, including that from the present study, excluding background 
radiation but including diagnostic x-rays and other medical exposures, exceeding 
5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally 
exposed worker, as defined in the Ionising Radiation Regulations 2017 [16], shall 
participate in the study 
 Subjects who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator or delegate at screening 
 Clinically significant abnormal clinical chemistry, haematology or urinalysis as 
judged by the investigator (laboratory parameters are listed in Appendix 1). 
Subjects known to have Gilbert’s syndrome are excluded 
 Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in 
Appendix 1) 
 Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) 
or human immunodeficiency virus (HIV) antibody results 
 Evidence of renal impairment at screening, as indicated by an estimated eGFR of 
<60 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI; 2009) equation 
 History of clinically significant cardiovascular, renal, hepatic, dermatological, 
chronic respiratory or gastrointestinal disease, malabsorptive, neurological or 
psychiatric disorder, as judged by the investigator 
 Serious adverse reaction or serious hypersensitivity to any drug or the formulation 
excipients  

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 Presence or history of clinically significant allergy requiring treatment, as judged 
by the investigator. Hay fever is allowed unless it is active 
 Donation of blood or plasma within the previous 3 months or loss of greater than 
400 mL of blood 
 Subjects who have taken known strong or moderate CYP3A4 inducers in the 
30 days before IMP administration 
 Subjects who are taking, or have taken, any prescribed or over-the-counter drug 
or herbal remedies (other than up to 4 g of paracetamol per day) in the 14 days 
before IMP administration (see Section 11.4). Exceptions may apply, as 
determined by the investigator, if each of the following criteria are met: medication 
with a short half-life if the washout is such that no pharmacodynamic activity is 
expected by the time of dosing with IMP; and if the use of medication does not 
jeopardize the safety of the trial subject; and if the use of medication is not 
considered to interfere with the objectives of the study 
 Subjects who have had a COVID-19 vaccine 7 days before dosing 
 Failure to satisfy the investigator of fitness to participate for any other reason 
Exclusion criteria 3, 6, 8, 9, 13, 18, 20, 21 and 22 from the list above will be re-assessed 
at admission/pre-dose.  
Healthy subjects who do not meet the inclusion/exclusion criteria for the study will not be 
enrolled. 
9.4 
Contraception and Restrictions 
Male Subjects with Partners of Childbearing Potential 
Male subjects who are sexually active with a partner of childbearing potential must use, 
with their partner, a condom plus an approved method of highly effective contraception 
from the time of informed consent until 111 days after IMP administration. This has been 
calculated based on 90 days (one cycle of spermatogenesis) plus 5 half-lives of the IMP. 
5 half-lives have been calculated as 21 days based on the mean half-life of 98.138 h 
observed in healthy volunteers at a single dose of 225 mg. 
The following methods are acceptable: 
• 
Partner’s use of combined (oestrogen and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation:  
− oral  
− intravaginal  
− transdermal  
• 
Partner’s use of progestogen-only hormonal contraception associated with inhibition 
of ovulation:  
− oral  
− injectable/implantable 
− intrauterine hormone-releasing system  
• 
Partner’s use of intrauterine device  
• 
Vasectomised 
• 
Partner’s bilateral tubal occlusion 
These contraception requirements are considered to be more conservative than the 
guidance issued by the Heads of Medicines Agency: Clinical Trials Facilitation Group 
[17]. 

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Males with Partners of Non-childbearing Potential 
There is a significant risk of drug exposure through the ejaculate (which also applies to 
vasectomised males) that might be harmful to sexual partners. Therefore, even if a male 
is sexually active with a partner of non-childbearing potential they will be required to use 
a condom from IMP administration until discharge from the study.  
All Subjects  
Alternatively, sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject. 
9.4.1 Sperm Donation 
Male subjects should not donate sperm for the duration of the study and for 111 days 
after IMP administration. 
9.5 
Pregnancy 
Subjects will be instructed that if their partner becomes pregnant during the study this 
should be reported to the investigator. The investigator should also be notified of 
pregnancy occurring during the study but confirmed after completion of the study. In the 
event that a subject’s partner is subsequently found to be pregnant after the subject is 
included in the study, then consent will be sought from the partner and, if granted, any 
pregnancy will be followed and the status of mother and/or child(ren) will be reported to 
the sponsor after delivery.  
A pregnancy notification form and follow-up will be completed. 
9.6 
Additional Study Restrictions 
The following additional restrictions will be in place for the duration of the study: 
1. Subjects must abstain from alcohol during the 24 h prior to screening and the 24 h 
prior to admission until discharge from the clinical unit 
2. Subjects must not drink liquids or eat food containing grapefruit, cranberry, 
caffeine or other xanthines from 24 h prior to admission until discharge from the 
clinical unit 
3. Subjects should refrain from eating food containing poppy seeds for 48 h prior to 
screening and for 48 h prior to admission until discharge from the clinical unit 
4. Subjects must not take part in any unaccustomed strenuous exercise from the 
72 h before the screening visit and then from 72 h prior to admission until 
discharge from the study  
5. Must not donate blood or plasma (outside of this study), from screening, 
throughout the study duration, and for at least 90 days following dose of IMP 
6. Due to the unavailability of phototoxic data for rencofilstat, subjects will be advised 
to minimise exposure to sunlight by spending a reduced amount of time 
outdoors/remaining inside the clinical unit during the residential periods of the 
study, wearing sunglasses and clothing that minimises exposure to sunlight and 
using sun cream on exposed areas when going outdoors. They will also be 
advised not to use sunbeds. This restriction will be advised from dosing until 
7 days post-dose  

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7. Subjects will not be permitted to shower for 24 h post-dose (to ensure the 
collection of all samples) 
The additional restrictions above are not exclusion criteria; if non-compliance occurs, a 
protocol deviation will be completed.  
10 Study Procedures 
Study procedures will be performed as detailed in the study schedule of assessments in 
Appendix 2, and in accordance with Quotient’s standard operating procedures (SOP)s 
unless otherwise stated in this protocol. 
10.1 Screening 
Within the 28 days preceding dosing, all subjects will be required to undergo a screening 
visit. Screening procedures will be carried out in accordance with the schedule of 
assessments in Appendix 2. 
If the start of the study is delayed for any reason so that the interval between screening 
and dosing exceeds 28 days, all or part of the screening procedures will be repeated at 
the discretion of the investigator. 
Screening safety procedures such as safety bloods, ECGs, vital signs, carbon monoxide 
breath tests, alcohol breath tests and urinalysis can be repeated as clinically indicated 
under the discretion of the investigator or sub-investigator if there is a concern regarding 
a subject’s safety or eligibility to participate in the trial. 
10.1.1 Subject Re-Screening 
This study permits the re-screening of a subject who has discontinued the study as a 
pre-treatment failure (ie subject has not been treated); the reason for failure must be 
temporary and expected to resolve. If re-screened, the subject must be re-consented. 
10.2 Admission and Pre-dose Procedures 
The identity of the subjects will be confirmed at admission and pre-dose.  
In addition, the ongoing eligibility of subjects will be re-assessed at admission/pre-dose, 
as described in Sections 9.2 and 9.3.  
Admission/pre-dose safety procedures such as safety bloods, ECGs, vital signs, 
urinalysis and drugs of abuse tests can be repeated as clinically indicated under the 
discretion of investigator or sub-investigator if there is a concern regarding a subject’s 
safety or eligibility to participate in the clinical trial. 
If dosing is delayed, subjects who have completed admission procedures do not need 
admission procedures to be repeated if dosing is within 2 days and the subjects have 
remained resident in the clinical unit. 
The subjects will be admitted to the clinical unit on the evening before dosing (Day -1).  
In addition, subjects may be required to visit the clinical unit on Day -1 prior to admission 
to the clinical unit for SARS-CoV-2 antigen tests (if required; see Sections 6.4.3.2 and 
14.5.7). Test results must be available prior to dosing. 

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The admission and pre-dose procedures are presented in Appendix 2. 
10.3 Study Day Procedures 
10.3.1 Blood Volume 
The total blood volume for each subject will not exceed 550 mL in a 4-week period.  
The first 0.5 mL of blood withdrawn via cannula will be discarded. 
10.3.2 Timing of Procedures 
There are times where the protocol requires more than one procedure to be completed 
at the same time point. In these instances, the following will apply to post-dose time 
points: 
• 
PK samples should take priority over other procedures scheduled at the same time 
point  
• 
ECGs should be taken prior to vital signs when both measurements are scheduled 
at the same time point  
• 
Other assessments, eg physical examinations, will be performed within the required 
time windows 
As guidance, the preferred order of assessments is: 
 
 
 
 
Nominal 
time 
 
 
ECGs 
 
Vitals 
 
PK blood 
sampling 
 
Other assessments 
eg physical 
examinations 
ECGs should be taken 
prior to vital signs when 
both measurements are 
scheduled at the same 
time point 
 
PK samples should take priority over 
other procedures scheduled at the 
same time point 
Other assessments will 
be performed within the 
required time windows 
 
All safety assessments will be timed and performed relative to the start of dosing. 
10.3.3 Discharge from the Clinical Unit 
A subject will be allowed to leave the premises without additional investigator or 
sub-investigator review, following completion of study-specific procedures providing that: 
• 
No AEs have been reported during the study visit  
• 
The subject responds in the affirmative when asked if they are feeling well 
Refer to Section 8.1 for further details of subject discharge.  
If any of these conditions are not met, then the subject will only be allowed to leave the 
clinical unit with the authorisation of the investigator or sub-investigator. 
There will be no continued provision of the study intervention or treatment for subjects 
as this study involves healthy volunteers only. 

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10.3.4 Return Visits 
If the mass balance criteria have not been met by the morning of Day 26, subjects not 
achieving the release criteria may be required to return to the clinical unit for up to 2 
return visits on Day 28 (+2 days; 648 h post-dose) and (if mass balance criteria are still 
not met by Day 28) Day 35 (±2 days; 816 h post-dose) for 24-h faeces and/or urine 
collections as described in Appendix 2. 
Refer to Section 8.1 for further details. 
10.3.5 Medical Supervision 
A physician will be responsible for the clinical aspects of the study and will be available 
at all times during the study. In accordance with the current Association of the British 
Pharmaceutical Industry guidelines [18], each subject will receive a card stating the 
telephone number of the investigator and the 24/7 contact details of the Quotient’s on-call 
physician. 
11 Dosing of Subjects 
11.1 Food and Fluid Intake 
Subjects will be allowed water up to 1 h before the scheduled dosing time and will be 
provided with 240 mL of water at 1 h post-dose (to ensure adequate hydration), and 
thereafter water will be allowed ad libitum after 1 h post-dose. Decaffeinated fluids will 
be allowed ad libitum from lunch time on the day of dosing. 
If, for technical reasons, dosing is delayed for more than 2 h beyond the expected dosing 
time, subjects will receive 200 mL of an electrolyte drink (eg Lucozade Sport) at the 
originally scheduled dosing time, or earlier if possible. 
The calorie/fat content of meals are not required to be controlled. Subjects will be 
provided with a standardised menu.  
Subjects will be provided with a light snack and then fast from all food and drink (except 
water) for a minimum of 8 h on the day prior to dosing until approximately 4 h post-dose 
at which time lunch will be provided. An evening meal will be provided at approximately 
10 h post-dose and an evening snack at approximately 14 h post-dose. On subsequent 
days, meals will be provided at appropriate times. 
If an individual subject has not experienced a bowel movement in any 36 h period 
post-dose, fluid intake should be increased and administration of a mild laxative (eg 
prune juice or a mild stool softener) should be implemented. 
11.2 Administration of Test Preparations 
Specific details of the IMP and doses to be administered are provided in Section 5.2 and 
Section 8.1, respectively. Subjects will be dosed on the morning of Day 1.  
The exact time of dosing will be decided based on logistics and will be documented in 
the source.  
Subjects will receive 1 single administration on a single occasion. 

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Immediately after administration of the oral emulsion, the dosing vessel will be rinsed 
with water and subjects will consume the rinse solution. Subjects will then consume 
further water to a total volume of 240 mL (including the dosing volume and volume used 
to rinse the dosing vessel). 
11.3 Dosing Compliance 
During all clinical phases of the study, subjects will be observed by study staff to assure 
compliance to all study procedures, including dose administration.  
Mouth checks will be conducted after dosing to ensure the emulsion has been 
swallowed.  
The date and time that each subject is dosed will be recorded in the subject’s source 
data. Any violation of compliance will require evaluation by the investigator and sponsor 
to determine if the subject can continue in the study. 
11.4 Prior and Concomitant Medications 
No prescribed, over-the-counter medication or herbal remedies will be permitted from 
14 days before IMP administration until discharge from the study except up to 4 g of 
paracetamol per day and those deemed necessary by the investigator to treat AEs (see 
also Section 9.3).  
In addition, no strong or moderate CYP3A4 inducers will be permitted from 30 days 
before IMP administration until discharge from the study. 
Any medications used will be recorded in the source. 
Subjects are not permitted to receive the COVID-19 vaccine within 7 days prior to 
administration of IMP, so that by the time of dosing any effects of the vaccine (eg, 
pyrexia, fatigue, pain/stiffness at site of injection) are likely to have abated. Subjects will 
be permitted to have the vaccination when discharged from the clinical unit. 
Emergency equipment and drugs will be available within the clinical unit as per current 
standard procedures. In the unlikely event that they are required, their use will be 
documented. 
12 Assessment of Efficacy 
Not applicable for this Phase I study.  
13 Assessment of Mass Balance, Pharmacokinetics, Metabolite 
Profiling and Identification, and Pharmacodynamics 
13.1 Assessment of Mass Balance, Pharmacokinetic, and Metabolite Profiling and 
Identification 
Mass balance, PK, and metabolite profiling and identification assessments will be 
performed as detailed in the study schedule of assessments in Appendix 2. 

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13.1.1 Pharmacokinetic and Metabolite Profiling and Identification Blood 
Sampling 
Venous blood samples will be collected from the subjects by a trained member of the 
clinical team. Consent will be collected from the subjects for use of these samples for the 
purposes of the proposed study. Samples will be processed to isolate plasma and PK 
analysis will be carried out on plasma (TR) and whole blood (rencofilstat, TR, metabolite 
profiling and identification) samples. 
Plasma and whole blood samples will be sent for laboratory testing in linked anonymised 
form (subject number only). This information is able to be linked directly to the volunteer 
by the Quotient research team and study monitor, however not by the laboratory staff or 
sponsor. 
Venous blood samples will be withdrawn via an indwelling cannula or by venepuncture 
according to the time schedule presented in Appendix 2. 
All PK and metabolite profiling and identification windows will be timed relative to the 
start of dosing. 
The acceptable deviations from the nominal blood sampling times are as follows: 
• 
The pre-dose samples will be taken ≤1 h before dosing 
• 
0 to 1 h post-dose samples will be taken within ± 2 min of the nominal post-dose 
sampling time  
• 
1.5 h to 12 h post-dose samples will be taken within ± 10 min of the nominal 
post-dose sampling time 
• 
16 h to 504 h post-dose samples (or up to 600 h post-dose if the residency period is 
extended) will be taken within ± 30 min of the nominal post-dose sampling time  
Samples will be collected into appropriate tubes as specified by the bioanalytical 
laboratory. Details of sample tubes and processing will be contained in the 
Clinical Sample Processing Manual (CSPM). 
Samples will be shipped to Pharmaron UK for the analysis of rencofilstat, metabolite 
profiling and TR. 
13.1.2 Mass Balance and Metabolite Profiling and Identification Urine Sampling 
Urine samples will be collected according to the time schedule presented in Appendix 2. 
A single urine sample will be taken at pre-dose (or the first void of the day). Where a 
sample is not provided, this will not be considered a deviation. All individual urine voids 
will be collected and shipped to the metabolism laboratory for analysis, according to 
Quotient’s SOPs, unless indicated otherwise by the sponsor. 
Consent will be collected from the subjects for use of these samples for the purposes of 
the proposed study. Samples will be collected into appropriate containers as specified 
by the bioanalytical laboratory. Details of sample containers and processing will be 
contained in the CSPM. 
Urine samples will be sent for laboratory testing in linked anonymised form (subject 
number). This information is able to be linked directly to the volunteer by the Quotient 
research team and study monitor; however, not by the laboratory staff or sponsor. 

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Samples will be shipped to Pharmaron for the analysis of metabolite profiling and TR. 
13.1.3 Mass Balance and Metabolite Profiling and Identification Faecal Sampling 
Faecal samples will be collected according to the time schedule presented in Appendix 2. 
The pre-dose faecal sample will be taken between admission and pre-dose. If a pre-dose 
faecal sample cannot be obtained, the subject will still be dosed. Where a sample is not 
provided, this will not be considered a deviation. 
Consent will be collected from the subjects for use of these samples for the purposes of 
the proposed study. Samples and toilet paper will be collected into appropriate 
pots/containers as specified by the metabolism laboratory. Details of sample containers 
and processing will be contained in the CSPM. 
Faecal samples will be sent for laboratory testing in linked anonymised form (subject 
number). This information is able to be linked directly to the volunteer by the Quotient 
research team and study monitor; however, not by the laboratory staff or sponsor. 
Samples will be shipped to Pharmaron for the analysis of TR and for metabolite profiling. 
13.1.4 Unexpected Sources of Elimination  
During the study, other accidental sources of elimination will be collected as voided (eg 
emesis). 
Samples will be shipped to the Pharmaron for the analysis of TR. 
13.2 Assessment of Pharmacodynamics 
Not applicable for this Phase I study. 
14 Assessment of Safety 
14.1 Definition and Classification of Adverse Events 
An AE is any untoward medical occurrence in a subject that occurs either before dosing 
(referred to as a pre-dose AE) or once a medicinal product has been administered, 
including occurrences which are not necessarily caused by or related to that product.  
An adverse drug reaction is any AE where a causal relationship with the IMP is at least 
a reasonable possibility (possibly related or related).  
AEs will be monitored from the time the subject signs the ICF until discharge from the 
study. The severity of AEs should be assessed as follows: 
Mild 
An AE that is easily tolerated by the subject, causes minimal discomfort and 
does not interfere with everyday activities 
Moderate An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed 
Severe 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed 

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14.2 Assessment of Causality 
Every effort should be made by the investigator to try to explain each AE and assess its 
relationship, if any, to the IMP. The temporal relationship of the event to IMP 
administration should be considered in the causality assessment (ie if the event starts 
soon after IMP administration and resolves when the IMP is stopped). 
Causality should be assessed using the following categories:  
Unrelated: 
Clinical event with an incompatible time relationship to IMP 
administration, and that could be explained by underlying 
disease or other drugs or chemicals or is incontrovertibly not 
related to the IMP 
Possibly related: 
Clinical event with a reasonable time relationship to IMP 
administration, and that is unlikely to be attributed to concurrent 
disease or other drugs or chemicals 
Related: 
Clinical event with plausible time relationship to IMP 
administration and that cannot be explained by concurrent 
disease or other drugs or chemicals 
The degree of certainty with which an AE is attributed to IMP administration (or 
alternative causes, eg natural history of the underlying disease, concomitant therapy) will 
be determined by how well the experience can be understood in terms of one or more of 
the following: 
• 
Known pharmacology of the IMP 
• 
Reactions of a similar nature have been previously observed with the IMP or this 
class of drug 
• 
The experience being related by time to IMP administration 
• 
Alternative cause 
14.3 Recording Adverse Events 
AEs (including SAEs) will be recorded from the time of providing written informed consent 
until discharge from the study. During each study visit the subject will be questioned 
directly regarding the occurrence of any adverse medical event according to the 
schedule in the source. All AEs, whether ascribed to study procedures or not, will be 
documented immediately in the subject’s source. This will include the date and time of 
onset, a description of the AE, severity, seriousness, duration, actions taken, outcome 
and an investigator’s current opinion on the relationship between the study drug and the 
event. A diagnosis and final opinion on the relationship between the study drug and the 
event will be provided at the end of the study by the investigator.  
Any subject who withdraws from the study due to an AE will be followed up until the 
outcome is determined and written reports are provided by the investigator. 
14.4 Serious Adverse Events 
14.4.1 Definition of Serious Adverse Events 
A SAE is defined as any untoward medical occurrence that at any dose:  
• 
Results in death 

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• 
Is life-threatening 
• 
Requires hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Consists of a congenital anomaly or birth defect 
• 
An important medical event as recognised by the investigator 
14.4.2 Definition of Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed 
to be related to an IMP and are both unexpected (ie the nature or severity is not expected 
from the information provided in the IB) and serious. SUSARs are subject to expedited 
reporting to the MHRA and EC and ARSAC practitioner (when related to radiation 
exposure) (see Section 16.3.2 for details on reporting SUSARs). 
14.5 Laboratory Measurements 
Venous blood and urine samples will be collected from the subjects by a trained member 
of the clinical team. Consent will be collected from the subjects for use of these samples 
for the purposes of the proposed study. 
Blood and urine samples are sent for laboratory testing in linked anonymised form 
(subject number, gender and date of birth for analytical reasons). This information is able 
to be linked directly to the volunteer by the Quotient research team and study monitor; 
however, not by the laboratory staff or sponsor. 
Safety laboratory tests and virology will be carried out on blood samples, and drugs of 
abuse tests and urinalysis will be carried out on urine samples. The research will not 
involve analysis or use of human DNA. 
Blood and urine samples results will be reviewed by a physician and acted upon before 
the subject is dosed or receives their next dose, or is released from the study, as is 
appropriate. A list of the laboratory parameters measured is presented in Appendix 1. 
14.5.1 Haematology and Clinical Chemistry 
Laboratory tests will be performed by The Doctors Laboratory according to the time 
schedule presented in Appendix 2. Blood samples will be collected and processed as 
detailed in the CSPM. Scheduled blood samples will be taken following a fast of at least 
8 h. 
The acceptable deviations from the nominal blood sampling time points for laboratory 
assessments are: 
• 
The pre-dose blood sample will be taken ≤2 h before dosing 
• 
Post-dose blood samples will be taken ± 1 h from the nominal blood sampling time 
eGFR will be calculated at screening by The Doctors Laboratory using CKD-EPI equation 
[19] for eligibility purposes. 
14.5.2 Virology 
HBsAg, HCV Ab and HIV 1 and 2 tests will be performed from the clinical chemistry 
sample (see Section 14.5.1 for sample collection and processing information). 

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14.5.3 Urinalysis 
Urinalysis will be performed on-site using a dipstick according to the time schedule 
presented in Appendix 2. Urine samples will be collected and processed as detailed in 
the CSPM. If microscopy is required, a urine sample (approximately 20 mL) will be taken 
from the urine collection for TR and metabolite profiling and identification and sent to The 
Doctors Laboratory, after the void has been weighed. 
The acceptable deviations from the nominal urine sampling time points for urinalysis are: 
• 
The pre-dose urine sample will be the first void of the day or a sample collected ≤3 h 
before dosing  
• 
Post-dose urine samples will be taken ± 2 h from the nominal urine sampling time 
14.5.4 Drug Screen 
A urine drug screen will be performed on-site using a point of care testing method 
(eg Alere Drug Screen Test Cup) according to the time schedule presented in 
Appendix 2. The sample will be collected and processed as detailed in the CSPM. 
Subjects will be screened for the drugs of abuse listed in Appendix 1.  
14.5.5 Alcohol Breath Test 
An alcohol breath test will be performed according to the time schedule presented in 
Appendix 2. A positive result will exclude the subject from dosing during that admission. 
14.5.6 Carbon Monoxide Breath Test 
A carbon monoxide breath test will be performed according to the time schedule 
presented in Appendix 2. A result of greater than 10 ppm will exclude the subject from 
the study. 
14.5.7 SARS-CoV-2 Tests (If Required) 
Testing for the SARS-CoV-2 virus may be performed based on current infection rates 
and availability of tests. Tests will be performed according to the time schedule presented 
in Appendix 2. The samples will be collected and processed as detailed in the CSPM. 
Testing time points may be changed and additional time points may be added throughout 
the study as required. The decision on COVID-19 testing and the definition of the testing 
time points are subject to change based on the current risk mitigation in place and will 
be agreed by the study team and documented in the ISF via the Clinical Kick-Off Meeting 
minutes. 
14.5.8 Abnormal Laboratory Findings 
In cases where laboratory findings are outside the normal range and the investigator 
believes that the results may be of clinical significance, repeat sampling may be 
requested as clinically indicated. If the abnormal finding is clinically significant, 
appropriate actions will be taken eg the subject will not be entered into the study or the 
subject may be withdrawn from the study. The subject will be referred to their general 
practitioner or other appropriate provider for further care if necessary. The same will 
apply if the results of the HBsAg, HCV Ab or HIV test are positive and in addition the 
investigator will ensure that adequate counselling is available if requested. 

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Abnormal results at follow-up assessments will also require repeat testing if the 
investigator believes the results may be of clinical significance. 
Any clinically significant abnormality, including changes from baseline, must be reported 
as an AE. 
Additional blood and/or urine samples may be taken for safety tests. Furthermore, 
additional assays outside those specified in the protocol may be performed for safety 
reasons as requested by the investigator or sub-investigator. 
14.6 Vital Signs Measurements 
Blood pressure and heart rate will be measured by an automated recorder after the 
subject has been in a supine position for a minimum of 5 min and oral temperature will 
be measured according to the time schedule presented in Appendix 2. The acceptable 
deviations from the nominal vital signs measurement time points are: 
• 
The pre-dose vital signs measurements will be taken ≤2 h before dosing 
• 
Post-dose vital signs measurements will be taken ± 15 min from the nominal 
post-dose time points 
• 
Discharge vital signs measurements will be taken ± 1 h from the nominal time point 
• 
For return visits vital signs measurements will be taken ± 2 h from the nominal return 
visit time point 
If a subject shows an abnormal assessment at any stage, repeat measurements may be 
made and the abnormality followed to resolution if required. Additional measurements 
may be taken as deemed necessary by the investigator or sub-investigator. 
Any clinically significant abnormality, including changes from baseline, must be reported 
as an AE. 
14.7 ECG Measurements 
Single 12-lead ECGs will be measured after the subject has been in the supine position 
for a minimum of 5 min according to the time schedule presented in Appendix 2. The 
acceptable deviations from the nominal ECG measurement time points are: 
• 
The pre-dose ECG measurements will be taken ≤2 h before dosing 
• 
Post-dose ECG measurements will be taken ± 15 min from the nominal post-dose 
time point  
• 
Discharge ECG measurements will be taken ± 1 h from the nominal time point 
If a subject shows an abnormal assessment at any stage, repeat measurements may be 
made and the abnormality followed to resolution if required. Additional measurements 
may be taken as deemed necessary by the investigator or sub-investigator. 
Any clinically significant abnormality, including changes from baseline, will be reported 
as an AE. 
14.8 Body Weight, Height and BMI 
The subject’s body weight and height will be measured and their BMI will be calculated 
according to the time schedule presented in Appendix 2. 

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14.9 Physical Examination 
Subjects will undergo a physical examination according to the time schedule presented 
in Appendix 2. 
In the targeted (symptom driven) physical examination, a physician will assess the 
subject; if the subject reports feeling unwell or has ongoing AEs, then the physician will 
examine the appropriate body system(s) if required. 
14.10 Additional Safety Procedures 
Additional non-invasive procedures that are already specified in the protocol may be 
performed, if it is believed that an important effect of the IMP(s) is occurring or may occur 
at a time when no measurements are scheduled, or if extra procedures are needed in 
the interests of safety. 
Additional blood samples for safety assessments may be taken if required by the 
investigator or sub-investigator at any point. 
15 Statistics and Data Analysis 
15.1 Sample Size Justification 
The study is exploratory and no formal sample size calculation has been made. Based 
on experience from previous studies of a similar design, a total of 6 subjects are to be 
enrolled and a minimum of 4 evaluable subjects are considered sufficient. 
15.2 Data Management 
Data management will be performed by Quotient. 
Study data will be managed using a validated electronic case report form (eCRF) 
database system and subjected to data consistency and validation checks. Data queries 
will be raised within the study eCRF database by data management staff and resolved 
with the assistance of clinical staff. 
AEs, medical histories and medications will be coded using the Medical Dictionary for 
Regulatory Activities (version to be specified in the Data Management Plan [DMP]) and 
the World Health Organization (WHO) Drug Dictionary Global Drug Reference (version 
to be specified in the DMP), respectively. An independent coding review will also be 
performed within the Data Sciences department. 
Clinical chemistry and haematology data (and other safety laboratory data) will be 
collected by a central laboratory (The Doctors Laboratory) and stored electronically in 
their clinical pathology system. The data will be transferred electronically to Quotient and 
all demographic details and sample dates will be cross-referenced with the 
corresponding data on the study database. All queries will be resolved with the 
assistance of laboratory staff, or if necessary, clinical staff.  
The database will be closed after all queries have been resolved. The database will be 
locked when all criteria listed in the DMP are met.  
Further details are addressed in the DMP. 

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15.3 Mass Balance, Pharmacokinetic, and Metabolite Profiling and Identification 
Data Analysis 
15.3.1 Mass Balance Data Analysis  
The mass balance parameters presented in Table 3 will be calculated by Quotient using 
the concentration data for TR in urine and faeces (and emesis, if applicable) provided by 
Pharmaron.  
Table 3 
Mass Balance Parameters  
Parameter 
Definition 
Ae(urine) 
amount of TR excreted in urine 
%Ae(urine) 
amount of TR excreted in urine expressed as a percentage of the radioactive 
dose administered 
CumAe(urine) 
cumulative amount of TR excreted in urine 
Cum%Ae(urine) 
cumulative amount of TR excreted in urine expressed as a percentage of the 
radioactive dose administered 
Ae(faeces) 
amount of TR eliminated in faeces 
%Ae(faeces) 
amount of TR eliminated in faeces expressed as a percentage of the 
radioactive dose administered 
CumAe(faeces) 
cumulative amount of TR eliminated in faeces 
Cum%Ae(faeces) 
cumulative amount of TR eliminated in faeces expressed as a percentage of 
the radioactive dose administered 
Ae(total) 
amount of TR excreted in urine and faeces combined 
%Ae(total) 
amount of TR excreted in urine and faeces combined expressed as a 
percentage of the radioactive dose administered 
CumAe(total) 
cumulative amount of TR excreted in urine and faeces combined 
Cum%Ae(total) 
cumulative amount of TR excreted in urine and faeces combined expressed as 
a percentage of the radioactive dose administered 
Further analysis details will be included in the Reporting and Analysis Plan (RAP). 
15.3.2 Pharmacokinetic and Total Radioactivity Data Analysis 
The whole blood concentration data for rencofilstat and plasma and whole blood TR 
concentration data provided by Pharmaron will be analysed by Quotient, using 
Phoenix WinNonlin v8.3 or a more recent version (Certara USA, Inc., USA). 
Calculated rencofilstat concentrations may be corrected for specific activity of the 
administered radiolabelled oral dose by the Data Sciences department at Quotient. 
PK analysis of the whole blood concentration-time data obtained will be performed using 
appropriate non-compartmental techniques to obtain estimates of the PK parameters 
presented in Table 4 and where possible and appropriate. 
Table 4 
Whole Blood Pharmacokinetic Parameters 
Parameter 
Definition 
Tlag 
Time prior to the first measurable concentration 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-24) 
Area under the curve from time 0 to 24 h post-dose 
AUC(0-last) 
Area under the curve from time 0 to the time of last measurable concentration 
AUC(0-inf) 
Area under the curve from time 0 extrapolated to infinity 

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Parameter 
Definition 
AUCextrap 
Area under the curve from time of the last measurable concentration to infinity as a 
percentage of the area under the curve extrapolated to infinity 
AUC ratio 
Parent to total radioactivity ratio for whole blood based on AUC 
T1/2  
Terminal elimination half-life 
Lambda-z 
First order rate constant associated with the terminal (log-linear) portion of the curve 
CL/F 
Total body clearance calculated after a single extravascular administration where F 
(fraction of dose bioavailable) is unknown 
Vz/F 
Apparent volume of distribution based on the terminal phase calculated using AUC(0-
inf) after a single extravascular administration where F (fraction of dose bioavailable) 
is unknown 
MRT(0-last) 
Mean residence time from time 0 to time of the last measurable concentration  
MRT(0-inf) 
Mean residence time from time 0 extrapolated to infinity  
In addition, whole blood-to-plasma TR concentration ratios will be calculated. 
Further details of the PK data analysis will be included in the RAP. 
15.3.3 Metabolite Profiling and Identification  
Metabolite profiling of whole blood, urine and faeces will be performed using liquid 
chromatography-radio-detection with subsequent mass spectrometry where appropriate.  
Identification of the chemical structure of each metabolite accounting for greater than 
10% of circulating radioactivity in whole blood (“AUC pool”) and accounting for greater 
than 10% of the dose in the urine and faeces (from urine pools and faeces homogenate 
pools) will be performed.  
These aspects will be reported separately from the clinical study report as a standalone 
document. 
15.4 Statistical Data Analysis  
Production of summary tables, figures and listings for this study will be performed by 
Quotient using the statistical package SAS (v9.4 or more recent version).  
All safety, mass balance recovery and PK data will be listed. 
No formal statistical analysis will be performed for this study. Descriptive statistics 
(eg mean, median, standard deviation, minimum, maximum and number of subjects with 
an observation [n]) are considered adequate for a study of this type. Additional statistics 
will be provided for PK-related data, including coefficient of variation (CV%), geometric 
mean and geometric CV%.  
Populations and analysis sets will be determined for safety, PK and mass balance data 
after database lock when the relevant data are available, using the criteria defined in the 
RAP; the RAP will be signed off prior to database lock. 
Further details relating to the statistical analysis will be included in the RAP including the 
following: 
• 
Criteria to be used to define each of the population and analysis sets 
• 
Additional detail covering the analyses and/or description of primary and secondary 
analyses and safety data 

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• 
Handling of missing data, unused or spurious data 
• 
Handling of data from withdrawn subjects 
15.5 Interim Analysis 
No formal interim analyses are planned for this study. 
16 Safety Reporting to Regulatory Authorities and Ethics 
Committees 
16.1 Events Requiring Expedited Reporting 
SUSARs (Section 14.4.2) are subject to expedited reporting to the appropriate regulatory 
authority and EC and the ARSAC practitioner when related to radioactive exposure. 
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of an IMP or that would 
be sufficient to consider changes in the IMPs’ administration or in the overall conduct of 
the study, for instance: 
• 
An increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important 
• 
SAEs that occur after the subject has completed the clinical study where the sponsor 
considers them to be a SUSAR 
• 
New events related to the conduct of the study or the development of the IMPs and 
likely to affect the safety of the subjects, such as: 
− An SAE which could be associated with the study procedures and which 
could modify the conduct of the study 
− A major safety finding from a newly completed animal study (such as 
carcinogenicity) 
− Any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same IMPs in another country by the same sponsor 
16.2 Urgent Safety Measures 
If Quotient or any of its staff or contractors becomes aware of an actual or potential 
urgent safety issue, then the sponsor must be immediately contacted so that appropriate 
urgent safety measures can be agreed. An urgent safety issue is defined as:  
• 
An immediate hazard to the health or safety of subjects participating in a clinical study 
• 
A serious risk to human health or potentially a serious risk to human health 
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe 
conduct of the study or that pose a risk to study subjects. 
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, Quotient may take urgent safety measures before informing the 
sponsor, but the sponsor must be informed immediately after the hazard has resolved.  
The sponsor is responsible for informing the appropriate regulatory authorities, and the 
EC; the task of reporting urgent safety measures will be delegated to Quotient. 

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16.3 Reporting 
16.3.1 Reporting Serious Adverse Events 
The investigator must notify the study sponsor and pharmacovigilance provider of any 
SAE or serious adverse reaction immediately, and in all cases within 24 h of becoming 
aware of the event or reaction. A copy of the written report of the event should promptly 
be sent to the study sponsor for information purposes, in accordance with International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) guidelines for GCP [20]. 
16.3.2 Reporting of Suspected Unexpected Serious Adverse Reactions 
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible. 
16.3.3 Expedited Reporting of Events 
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible. 
Where expedited reporting is required, the following procedures should be followed. 
Fatal or life-threatening SUSARs 
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA as soon as possible, but no later than 7 calendar days after they first became 
aware of the reaction. Any additional relevant information should be sent within 8 days 
of the report. The task of reporting fatal or life-threatening SUSARs may be delegated to 
the pharmacovigilance provider.  
The sponsor is required to notify the EC of any fatal or life-threatening SUSAR as soon 
as possible, but no later than 7 calendar days after they first became aware of the 
reaction. Any additional relevant information should be sent within 8 days of the report. 
The task of reporting fatal or life-threatening SUSARs may be delegated to the 
investigator. 
The ARSAC Practitioner will be notified of any fatal or life-threatening SUSAR that is 
considered related to the exposure to radioactivity. 
Other SUSARs 
It is the responsibility of the sponsor to report other SUSARs to the MHRA as soon as 
possible, but no later than 15 calendar days after they first became aware of the reaction. 
The task of reporting other SUSARs may be delegated to the pharmacovigilance 
provider. 
The sponsor is required to notify the EC of other SUSARs as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction. The task of 
reporting other SUSARs may be delegated to the investigator. 
The ARSAC Practitioner will be notified of any SUSAR that is considered related to the 
exposure to radioactivity. 

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16.3.4 Reporting of Urgent Safety Measures 
Quotient is required to notify the MHRA and the EC of an urgent safety measure 
immediately by telephone and follow-up in writing within 3 calendar days from the date 
the measures are taken. 
16.3.5 Reporting of COVID-19 Vaccine-Related Adverse Events 
AEs considered by the investigator to be related to COVID-19 vaccines will be reported 
to the MHRA via the Yellow Card system. 
16.4 Serious Breaches 
It is the responsibility of the sponsor to notify the MHRA of any serious breach, which is 
likely to affect, to a significant degree, the safety or mental integrity of the subjects of the 
study or the scientific value of the study.  
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach. 
17 Protocol Amendments and Deviations 
17.1 Amendments 
After the protocol has been submitted to the MHRA and EC, any amendment must be 
agreed by the investigator after discussion with the sponsor and will be formally 
documented. 
All substantial amendments will be submitted to the MHRA and/or EC for approval and/or 
an opinion, respectively, as required by current regulations. Any amendments relating to 
the administration of radioactive substances will be reviewed by the ARSAC practitioner 
prior to submission to ARSAC as required by the current ARSAC Notes for Guidance 
[12]. The ARSAC practitioner will also be notified of any substantial amendments to the 
PIS and ICF and/or protocol. 
If the PIS and ICF are updated as a result of the substantial amendment, the new 
approved versions will be used to re-consent currently enrolled subjects and must be 
provided to newly enrolled subjects prior to their entry into the study. 
17.2 Protocol Deviations 
The study must be conducted in accordance with the Clinical Protocol. Should a protocol 
deviation occur, it must be promptly assessed in order to decide whether any of these 
non-compliances should be reported to the MHRA as a serious breach of GCP and the 
Clinical Protocol. 
Protocol waivers are not acceptable. 
Deviations from the protocol will be recorded in the source as noted by the clinical staff. 
If necessary, the sponsor will be informed of the deviation. 
Any protocol deviations assessed as major will be discussed with the sponsor in order 
to determine if the withdrawal criteria stated in Section 8.3 have been met. 

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18 Regulatory 
18.1 Compliance 
This study will be conducted in accordance with the protocol and with the following 
legislation: 
• 
ICH GCP Guidelines approved by the Committee for Medicinal Products for Human 
Use (CHMP) on 17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 
2002, Integrated Addendum E6 (R2) dated 09 Nov 2016 [20] 
• 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory Instruments 
2004 No. 1031 [21] 
• 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2006 No. 1928 [22] 
• 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984 [23] 
• 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2008 No. 941 [24] 
• 
The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations. 
Statutory Instruments 2019 No. 744 [25] 
• 
Health and Safety. The Ionising Radiations Regulations 2017. Statutory Instrument 
2017 No. 1075 [14]  
• 
Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. 
Statutory Instrument 2017 No. 1322 [16]  
In addition, the study will be performed according to the ethical principles outlined in the 
World Medical Association Declaration of Helsinki and its amendments [15]. 
18.2 MHRA and Ethical Approval 
Prior to the initiation of the study, the clinical trial of an investigational medicinal product 
(CTIMP) application, the protocol and associated documentation must be approved by 
the MHRA and given a favourable opinion by an EC. A copy of this written approval and 
any correspondence with the MHRA and EC will be available at the clinical site and will 
be provided to the sponsor.  
18.3 Administration of Radiation 
Dr Stuart Mair will be the ARSAC practitioner for this study, which includes the 
administration of radiation at Quotient. Administration will be conducted in accordance 
with Dr Mair’s current ARSAC practitioner licence and Quotient’s current ARSAC 
Employer licence. Additionally, a research application will be submitted to ARSAC to 
obtain approval for the conduct of the study before dosing. 
Before submitting to the ARSAC, a summary of available non-clinical tissue distribution 
and excretion information on [14C]-rencofilstat will be submitted to the Radiation 
Protection Division of UK Health Security Agency for human dosimetry calculations in 
order to facilitate the selection of the dose of radioactivity to be administered. The final 
report from the UK Health Security Agency will be included in the application to the 
ARSAC. 
The protocol will be reviewed and the final version will be approved by the ARSAC 
practitioner, Dr Stuart Mair. 

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18.4 Source Data 
A study-specific source document identification list will be finalised with the sponsor prior 
to the start of the clinical phase of the study. The document will identify what data should 
be considered source data for this study.  
For this study, electronic data capture will be used where possible and data will be 
automatically recorded into an eCRF. In instances where paper source documents are 
used, data to be transcribed into the eCRF will be identified using a Source Document 
Identification List, as governed by Quotient’s SOPs. 
18.5 Declaration of the End of the Study 
The end of the study is defined as the last visit of the last subject (eg discharge from the 
study). Any changes to this definition will be notified as a substantial amendment (see 
Section 17.1). 
The EC and MHRA should be notified of the conclusion of the study within 90 days of 
the end of the study, or within 15 days if the study is terminated early, clearly explaining 
the reasons for the termination. 
The ARSAC Practitioner will also be notified of the end of trial or early termination of the 
trial within an appropriate timeframe. 
18.6 Document Storage and Archiving 
All documentation and correspondence pertaining to the study (source data, raw data, 
letters etc) will be kept in accordance with the ICH guidelines for GCP 1996, updated 
2002, Integrated Addendum E6 (R2) dated 09 Nov 2016 (ICH GCP Section 4.9.5) [20], 
The Medicines for Human Use (Clinical Trials) Regulations 2004 [21], The Medicines for 
Human Use (Clinical Trials) Amendment Regulations 2006 [22],[23] and The Medicines 
for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations [25]. 
All study related documents will be retained for a minimum period of 15 years. After this 
time, the sponsor will be contacted to ascertain whether continued storage or destruction 
is required in accordance with current regulations. 
18.7 Protection of Personal Data and Confidentiality 
Personal data are securely stored to prevent unauthorised access, disclosure, 
dissemination, alteration or loss of information and unauthorised personal data 
processing. Access to personal information is restricted so that only personnel who are 
required to access personal data as part of their job role can do so. All personnel who 
access personal information are bound by a duty of confidentiality. 
Technical arrangements surrounding the electronic storage and use of data are as 
follows: 
• 
Computers storing electronic personal data are protected by antivirus software and 
the network on which computers are linked are protected by industry grade firewalls 
• 
Off-site personnel can only access networked computers through a virtual private 
network  
• 
Electronic access of data is limited according to user roles 
• 
All data are stored on password protected computers 

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Organisational arrangements are as follows: 
• 
All buildings are secured by key-card access 
• 
Manual files of personal data are stored within locked cabinets/restricted areas of the 
clinical unit that can only be accessed by authorised personnel 
• 
Data security and/or confidentiality provisions are utilised in agreements with third 
parties 
• 
Documented Back-up and disaster recovery procedures are in place 
• 
Internal audit and compliance functions provide regulatory oversight 
The personal data of volunteers will be pseudonymised in that they will only include 
health, initials, date of birth and demographics (gender and ethnicity) and cannot be 
linked back to the individual by the recipient. The sponsor shall be the data controller in 
respect of the personal data of the study subjects collected in connection with the study, 
and shall act in accordance with the relevant data protection laws in relation to the 
collection and processing of those personal data. The study subjects’ pseudonymised 
personal data shall be collected and processed for the purposes of the study and may 
also be added to research databases and used in the future by the sponsor and its 
affiliates for certain additional clinical research, for product regulation and safety 
reporting purposes and for ensuring compliance with legal requirements. The study 
subjects’ pseudonymised personal data may be processed for such purposes by other 
parties including: the sponsor’s affiliates and licensing partners, its business partners, 
regulatory agencies and other health authorities, and ECs. The study subjects’ 
authorisation for such use and disclosure shall be obtained by the study subjects signing 
the ICF for the study. 
Additionally, Quotient personnel are contractually bound by a duty of confidentiality and 
receive training on this matter. 
18.8 Data Security Breach 
Quotient has a comprehensive process in place for identifying, assessing, resolving and 
reporting any potential data security breach. All staff are trained in the identification of 
potential data security breaches. Potential breaches are managed by appropriately 
trained quality assurance (QA) personnel in accordance with Quotient’s SOPs. After 
robust assessment of data breaches, those deemed serious will be reported to the 
sponsor and Information Commissioner’s Office, as applicable. 
19 Quality Control and Quality Assurance 
Quality control of all data collected from this study will be performed in accordance with 
Quotient’s SOPs. This study (or elements thereof) may be subject to Quotient QA audit, 
in line with current internal auditing procedures. Similarly, the study (or elements thereof) 
may be subject to sponsor QA audit. 
19.1 Monitoring 
GCP requires that studies are adequately monitored. The sponsor should determine the 
appropriate extent and nature of monitoring. A study monitor, independent of Quotient, 
will be appointed to verify that the study is conducted in accordance with current GCP, 
regulatory requirements, the protocol and that the data are authentic, accurate and 
complete.  

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The investigator agrees to receive visits from a study monitor and provide assistance to 
verify protocol implementation, source completion and transcription of data into the 
eCRF, document storage and AE reporting. 
Quotient will extend the professional privilege of access to the subjects’ clinical source 
documents to the study monitor, EC, regulatory bodies or other authorised personnel (eg 
auditor) for the purposes of source data verification. 
Following completion of the study both study related documents and subject data may 
be sent to the sponsor at a location outside of the UK where data protection laws differ. 
In the interests of confidentiality, subjects will not be identified on any such documents 
or data, and specific subject consent for such a disposition will be obtained. 
20 Finance and Insurance 
The sponsor Hepion Pharmaceuticals, Inc has funded this study. A no-fault clinical trials 
insurance has been obtained by the sponsor. The sponsor insurance will compensate 
subjects in accordance with the Association of the British Pharmaceutical Industry 
Guidelines for Phase I Clinical Trials 2018 edition [18]. 
21 Publication 
Please refer to the Master Services Agreement for information on publication.  
Quotient shall have the right to publish the results of the research, subject to the 
sponsor’s prior written consent, which shall not be unreasonably withheld or delayed. 
Following the receipt of such consent, Quotient shall submit a copy of the proposed 
publication to the sponsor who shall have 30 days in which to request amendments 
thereto which, to the extent that such proposed amendments are reasonable, Quotient 
shall be obliged to incorporate prior to such publication. 
The sponsor undertakes that, prior to publication of any information, article, paper, report 
or other material concerning the research, it will submit a copy of such publication to 
Quotient who shall have 30 days in which to request amendments thereto which, to the 
extent that such proposed amendment are reasonable, the sponsor shall be obliged to 
incorporate prior to such publication. 
22 References 
[1] 
Handschumacher RE, Harding MW, Rice J, et al. Cyclophilin: a specific cytosolic 
binding protein for cyclosporin A. Science. 1984; 226(4674):544-547. 
[2] 
Swanson SK, Born T, Zydowsky LD et al. Cyclosporin mediated inhibition of 
bovine calcineurin by cyclophilins A and B. Proc Natl Acad Sci USA. 1992; 
89(9):3741-3745. 
[3] 
Liu J, Farmer JD Jr, Lane WS, et al. Calcineurin is a common target of 
cyclophilin-cyclosporin 
A 
and 
FKBP-FK506 
complexes. 
Cell. 
1991; 
66(4):807-815. 
[4] 
Clipstone NA and Crabtree GR. Identification of calcineurin as a key signalling 
enzyme in T-lymphocyte activation. Nature. 1992; 357(6380):695-697. 

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[5] 
Pawlotsky J-MM, Flisiak R, Sarin SK, et al. Alisporivir plus ribavirin, interferon 
free or in combination with pegylated interferon, for hepatitis C virus genotype 2 
or 3 infection. Hepatology. 2015; 62:1013–1023. 
[6] 
Zeuzem S, Flisiak R, Vierling JM, et al. Randomised clinical trial: Alisporivir 
combined with peginterferon and ribavirin in treatment-naïve patients with chronic 
HCV genotype 1 infection (ESSENTIAL II). Aliment Pharmacol Ther. 2015; 
42:829–844. 
[7] 
Buti M, Flisiak R, Kao JH, et al.  Alisporivir with peginterferon/ribavirin in patients 
with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed 
after prior interferon-based therapy: FUNDAMENTAL, a Phase II trial. J Viral 
Hepat. 2015; 22:596–606. 
[8] 
Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related 
HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol 
Hepatol. 2021; 18(4):223-238. 
[9] 
Estes C, Razavi H, Loomba R, et al. Modeling the epidemic of nonalcoholic fatty 
liver disease demonstrates an exponential increase in burden of disease. 
Hepatology. 2018; 67(1): 123–133. 
[10] 
Ure DR, Trepanier DJ, Mayo PR, et al. Cyclophilin inhibition as a potential 
treatment for nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 
2020; 29(2):163-178. 
[11] 
Hepion Pharmaceuticals, Inc. Investigational Brochure: Rencofilstat. Version 6.0. 
December 2022. 
[12] 
Notes for guidance on the clinical administration of radiopharmaceuticals and use 
of sealed radioactive sources. Administration of Radioactive Substances 
Advisory Committee. September 2021. 
[13] 
Ionising Radiation Exposure of the UK population: 2010 Review. Public Health 
England. April 2016. https://www.gov.uk/government/publications/ionising-
radiation-exposure-of-the-uk-population-2010-review. 
[14] 
Health and Safety. The Ionising Radiations Regulations 2017. Statutory 
Instrument 2017 No. 1075. 
[15] 
World Medical Association, Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects (and all subsequent amendments). 
[16] 
Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. 
Statutory Instrument 2017 No. 1322. 
[17] 
Heads of Medicines Agency: Clinical Trials Facilitation Group. Recommendations 
related to contraception and pregnancy testing in clinical trials. 21 Sep 2020. 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_gui
dance_Version_1.1_updated.pdf. 

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[18] 
Guidelines for Phase I Clinical Trials. Association of the British Pharmaceutical 
Industry Guidelines. London, UK; 2018 Edition (publication date 29 May 2018). 
[19] 
Levy AS, Stevens LA, Schmit CH et al A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009; 150(9): 604-612. 
[20] 
International Council for Harmonisation Good Clinical Practice (GCP) Guidelines 
approved by the Committee for Medicinal Products for Human Use (CHMP) on 
17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 2002, Integrated 
Addendum E6 (R2) dated 09 Nov 2016. 
[21] 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory 
Instruments 2004 No. 1031. 
[22] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2006 No. 1928. 
[23] 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984. 
[24] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2008 No. 941. 
[25] 
The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) 
Regulations. Statutory Instruments 2019 No. 744. 

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Appendix 1 Clinical Laboratory Parameters  
Haematology 
Clinical Chemistry 
Virology 
Urinalysis 
Drugs of Abuse 
Basophils 
Eosinophils 
Haematocrit  
(Packed Cell Volume- PCV) 
Haemoglobin 
Lymphocytes 
Mean Cell Haemoglobin (MCH) 
Mean Cell Haemoglobin 
Concentration (MCHC) 
Mean Cell Volume (MCV) 
Monocytes 
Neutrophils 
Platelet Count 
Red Blood Cell (RBC) Count  
White Blood Cell (WBC) Count 
 
Alanine Aminotransferase 
(ALT) 
Albumin 
Alkaline Phosphatase 
Aspartate Aminotransferase 
(AST) 
Bicarbonate 
Bilirubin (Total) 
Bilirubin (Direct; only if Total is 
elevated) 
Calcium 
Chloride 
Creatine Kinase (CK) 
Creatinine 
eGFR will be calculated at 
screening using CKD-EPI 
2009  
Gamma Glutamyl Transferase 
(GGT) 
Glucose 
Glucose (Fasting) 
Potassium 
Phosphate (Inorganic) 
Protein (Total) 
Sodium 
Urea  
Serum Cholesterol (fasted) 
High-Density Lipoprotein 
(HDL) 
Low-Density Lipoprotein (LDL) 
Triglycerides (TRI) 
Amylase 
Lipase 
Hepatitis B Surface Antigen 
Hepatitis C Virus Antibody 
HIV Antibody 
 
If Required: 
SARS-CoV-2 Antigen 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes 
Nitrites 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
At discretion of 
investigator based on 
urinalysis results 
Microbiology  
Urine Microscopy 
 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cocaine 
Marijuana/Cannabis 
Methadone 
Methamphetamine/ 
Ecstasy 
Morphine/Opiates 
Phencyclidine 
Tricyclic Antidepressants 
 

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Appendix 2 
Schedule of Assessments 
Study day 
-28 to 
-2 
-1 
 
1 
2 
3 
4 
5 
6 
7 
8 
 
Times after dosing (h) 
 
S 
Aa  Pa  
0 
0.5 
1 
1.5 
2 
3 
4 
6 
8 
12 16 
24 
48 
72 
96 
120 144 168 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, Height and BMI 
X 
Xc  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon Monoxide Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Antigend 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted (symptom driven) Physical 
Examinatione 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Blood Samplesf  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
eGFRg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Single 12-Lead ECGs 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Vital Signsh 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Adverse Events 
---------------------------------------------------------------------X---------------------------------------------------------------------→ 
Prior and Concomitant Medication  
---------------------------------------------------------------------X---------------------------------------------------------------------→ 
Mass Balance, PK and Met Prof and ID Assessments 
Whole Blood Samples for Rencofilstat 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Samples for TR 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole Blood Samples for TR 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole Blood Samples for Met Prof and ID 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
Urine Samples for TR and Met Prof and IDi 
 
 
---------------------------------------------------------------X------------------------------------------------------------------→ 
Faecal Samples for TR and Met Prof and IDj 
 
------------------------------------------------------------------X------------------------------------------------------------------→ 

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Appendix 2 
Schedule of Assessments (continued) 
Study day 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
28 (+2 
days) 
35 (±2 
days) 
Home 
Collectionsn 
Times after dosing (h) 
 
192 216 240 264 288 312 336 360 384 408 432 456 480 504k 
528l 
552l 
576l 
600l 
Return Visitsm 
General Assessments 
SARS-CoV-2 Antigend  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Safety Assessments 
Targeted (symptom driven) Physical 
Examinatione  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
 
 
 
Safety Labsf  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
 
 
 
Urinalysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
 
 
 
Single 12-Lead ECGs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
 
 
 
Vital Signsh  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
X 
X 
 
Adverse Events 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→ 
Prior and Concomitant Medication  
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→ 
Mass Balance, PK and Met Prof and ID Assessments 
Whole Blood Samples for 
Rencofilstat 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xp 
 
 
 
 
 
 
 
Plasma Samples for TR 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xp 
 
 
 
 
 
 
 
Whole Blood Samples for TR 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xp 
 
 
 
 
 
 
 
Whole Blood Samples for Met Prof 
and ID 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Urine Samples for TR and Met Prof 
and IDi 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→ 
Faecal Samples for TR and Met Prof 
and IDj 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→ 
A: admission; BMI: body mass index; ID: identification; Met Prof: Metabolite Profiling; P: pre-dose; PK: pharmacokinetic(s); S: screening; TR: total radioactivity 
a Eligibility will be re-assessed at admission/pre-dose 
b Update only 
c Weight only  
d Testing for SARS-CoV-2 may be performed based on current infection rates and availability of tests. If required, it is planned that testing will comprise an antigen test 
performed on Day -1 prior to admission to the clinical unit and at return visits. The decision on COVID-19 testing and the definition of the testing time points are subject to 
change based on the current risk mitigation in place and will be agreed by the study team and documented in the ISF via the Clinical Kick-Off Meeting minutes 
e Targeted (symptom driven) physical examination of the relevant body system(s) as clinically indicated, as per the investigator’s judgement 
f Haematology and clinical chemistry at each time point including virology at screening 
g eGFR will be calculated at screening using the CKD-EPI equation for eligibility purposes 

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h Blood pressure and heart rate will be measured at every time point; oral temperature will be checked at screening, pre-dose and at first return residential visit (Day 28 
+2 days) only 
i Urine will be collected for the following intervals: A single urine sample will be collected at pre-dose (or the first void of the day), then at: 0-12 h, 12-24 h and then for 24 h 
intervals until mass balance criteria have been met (see Section 8.1 for details of mass balance criteria) 
j Faeces will be collected at pre-dose (sample will be taken between admission and pre-dose), then at 24 h intervals until mass balance criteria have been met (see 
Section 8.1 for details of mass balance criteria) 
k Discharge from clinical unit. Discharge assessments will be performed at the time of actual discharge. It is planned that subjects will remain resident in the clinical unit 
until 504 h post-dose (Day 22). Subjects will be discharged from the clinical unit on Day 22 provided they have met the following mass balance discharge criteria: mass 
balance cumulative recovery of >90% OR <1% of the dose administered collected in urine and faeces within 2 separate, consecutive 24 h periods. It is also planned that 
subjects will be discharged from the clinical unit as a group if all subjects have achieved the mass balance discharge criteria 
l If mass balance discharge criteria have not been met by all subjects by Day 22, the residency period for the subjects not achieving the mass balance criteria may be 
extended up to a maximum of 96 h (Day 26). Urine and/or faeces will be collected during the additional residency period 
m If mass balance discharge criteria have not been met by all subjects by the end of the additional residency (Day 26), subjects not achieving the mass balance criteria 
may be required to make up to 2 return visits (each of 24 h duration) at (nominally) Day 28 (+2 days) and Day 35 (±2 days) for additional collection of excreta samples. 
Only urine and/or faeces will be collected during the return visits 
n If the mass balance criteria are not met following the return visits, then home collections of urine and/or faeces may be requested at the discretion of the investigator for 
individual subjects 
o In the event of early withdrawal, all safety discharge assessments should be completed 
p If the residency period for subjects not achieving the mass balance criteria is extended, a further sample will be taken at actual discharge 
 

Sponsor/Quotient Sciences Confidential 
 
Protocol HEPA-CRV431-105 (QSC204643) Version 3.0 
22 Mar 2023 
Page 62 of 64 
 
Appendix 3 
Protocol Amendment Summary of Changes 
Protocol Version 3.0 
In Protocol Version 2.0 (dated 10 Mar 2023), it was noted that there was a urinalysis 
sample taken at 4 h post-dose. This sample is not required clinically and would require 
an aliquot of urine to be removed from the mass balance urine collections at a key time 
point. The 24 h post-dose urinalysis sample is deemed adequate and clinically 
appropriate. Therefore, the 4 h post-dose urinalysis sample has been removed from the 
protocol. 
All relevant sections of the protocol have been updated, including: 
Document History Page; Appendix 2 Schedule of Assessments. 
As these changes do not significantly affect the scientific value of the trial, the safety or 
physical or mental integrity of the subjects of the trial, or the quality of the IMP, the 
amendment to the protocol is considered to be non-substantial. 
Protocol Version 2.0 
The 11 timepoints for the whole blood metabolite ID collections have been rearranged to 
occur over a longer duration of time to ensure that the study objectives will be met. 
Pharmaron provided adjustments to the timings of sample collection. The timings but not 
the number of samples or blood volumes have been updated.  
In Protocol Version 1.0 (dated 21 Dec 2022), the time points for whole blood metabolite 
ID collection were scheduled to be taken at pre-dose, 2, 4, 8, 12, 24, 48, 72, 96 120 and 
168 h post-dose. The protocol has been updated to remove samples taken at 4, 12, 72, 
96 and 168 h post dose and add samples at 192, 264, 312, 408 and 456 h post-dose. 
Therefore, the updated metabolite ID time points are as follows: pre-dose, 2, 8, 24, 48, 
120,192, 264, 312, 408 and 456 h post-dose. 
Additionally, it was noted that in the footnotes of Table 1 and the table ‘Investigational 
Medicinal Product, Dose and Mode of Administration’ in the synopsis, the IMP was 
incorrectly stated as a salt form. These footnotes have been removed. 
Furthermore, minor typographical corrections have been made. 
All relevant sections of the protocol have been updated, including: 
Document History Page; Synopsis; 5.1 Introduction; 5.2 Investigational Medicinal 
Product; Appendix 2 Schedule of Assessments. 
As these changes do not significantly affect the scientific value of the trial, the safety or 
physical or mental integrity of the subjects of the trial, or the quality of the IMP, the 
amendment to the protocol is considered to be non-substantial. 

Sponsor/Quotient Sciences Confidential 
Protocol HEPA-CRV431-105 (QSC204643) Version 3.0 
22 Mar 2023 
Page 63 of 64 
Signatures for Quotient Sciences 
CONFIDENTIALITY AND GCP COMPLIANCE STATEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
and any other product information provided by the sponsor. I agree to conduct this study 
in accordance with the requirements of this protocol and also protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements 
for
Pharmaceuticals for Human Use E6 (R2) Good Clinical Practice: Consolidated
Guideline.
•
All applicable laws and regulations, including, without limitation, data privacy laws
and regulations.
•
Regulatory requirements for reporting serious adverse events defined in Section 16.3
of this protocol.
Information taken from the study protocol may not be disseminated or discussed with a 
third party without the express consent of the sponsor.  
Litza McKenzie MBChB, BScMedSci (Hons) 
See electronic signature at the end of 
the document 
Principal Investigator 
Signature 
Senior Clinical Research Physician 
Date 

Sponsor/Quotient Sciences Confidential 
Protocol HEPA-CRV431-105 (QSC204643) Version 3.0 
22 Mar 2023 
Page 64 of 64 
Signatures for Sponsor 
Jill A Greytok 
Senior Director, Clinical Development 
Signature 
Hepion Pharmaceuticals, Inc. 
 
Date 
Patrick R Mayo BSc(Pharm), PhD, MTS 
SVP Clinical Pharmacology & Analytics 
Signature 
Hepion Pharmaceuticals, Inc. 
Date 
Todd Hobbs, MD 
Hepion Pharmaceuticals, Inc. 
Signature 
 
Date 
Daniel Trepanier, PhD  
Sr. Vice President, Drug Development 
Signature 
Hepion Pharmaceuticals, Inc. 
Date 
3/22/2023
3/22/2023
3/22/2023
3/22/2023

Document Approvals
Approved Date: 22 Mar 2023
Document Author(s):  Molly Boughey-Moore 
Approval Task
Verdict:  Approve
Litza McKenzie, Senior Clinical Research Physician
(Litza.McKenzie@quotientsciences.com)
Approval
22-Mar-2023 17:32:22 GMT+0000