Clinical trial NCT05181085
Conditions: Short Bowel Syndrome Parenteral Nutrition Associated Liver Disease
Sponsor: NorthSea Therapeutics B.V.
Start date: 2021-11-11; Completion date: 2022-05-27
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A double-blind, randomized, placebo controlled, single and multiple oral dose study to assess safety and tolerability of single and multiple doses of NST-6179 in healthy male and female subjects.

Detailed description:

Arms: arm 1: double blind, single ascending and multiple ascending dose, sequential group design arm 2: matched placebo arm
Interventions: intervention 1: NST 6179 intervention 2: Placebo
Intervention descriptions: intervention 1: orally administered, fully synthetic medium chain fatty acid (MCFA) analogue intervention 2: inactive analogue

Protocol documents:
Prot_000.pdf: 
TITLE PAGE 
Protocol 
A Phase 1, First Time in Human Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of NST-6179 in Healthy Subjects 
Protocol Status: Final 
Protocol Date: 11 July 2022 
Protocol Version: 5 
Investigational Medicinal Product: NST-6179 
Protocol Reference Number: NST-6179-01 
Labcorp Drug Development Study Number: 8462139 
EudraCT Number: 2021-000839-31 
Sponsor: 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Study Site: 
Labcorp Clinical Research Unit (CRU) Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Sponsor Signatories: 
Dr Stephen Rossi, PharmD 
Dr Stephen Harrison, MD 
Principal Investigator: 
Dr Jim Bush, MBChB, PhD, MRCS, 
FFPM, GFMD 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 


Protocol 
CONFIDENTIAL 
Labcorp Study: 8462139 
Protocol Reference: NST-6179-01 
Protocol Version 5, 11 July 2022 
Page 2 of 116 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
Dr Stephen Rossi, PharmD 
Date 
Chief Development Officer 
NorthSea Therapeutics B.V. 
Dr Stephen Harrison, MD 
Date 
Chief Medical Officer 
NorthSea Therapeutics B.V. 
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Protocol 
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Labcorp Study: 8462139 
Protocol Reference: NST-6179-01 
Protocol Version 5, 11 July 2022 
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INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Dr Jim Bush, MBChB, PhD, MRCS
Date 
FFPM, GFMD 
VP CPS Medical Services 
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Protocol 
CONFIDENTIAL 
Labcorp Study: 8462139 
Protocol Reference: NST-6179-01 
Protocol Version 5, 11 July 2022 
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RATIONALE FOR PROTOCOL AMENDMENT 
In order to increase the overall extent of exposure without exceeding the pharmacokinetic 
(PK) stopping criteria, twice daily (BID) dosing is planned to be investigated within Part B of 
the study. The dose selected per dosing occasion in Part B will not exceed a single dose 
shown to be safe and well tolerated in Part A.  
Due to the rapid elimination of NST-6179, no accumulation is expected following BID 
dosing. However, to enhance safety, a requirement for sentinel dosing in Part B has been 
added for BID dose regimens where the total daily dose exceeds the highest single dose 
evaluated in Part A. Relevant clinical PK and clinical safety data from previous cohorts in 
this study have been added to support these changes. 
Clarifications have been added regarding dose administration in the fasted state for a BID 
dosing regimen and the schedule of assessments for Part B has been updated to include 
options for BID dosing. 
Additionally, the option for the collection of a pharmacogenomics (PGx) blood sample from 
each subject has been added along with an associated exploratory objective and endpoint. 
Nonclinical studies show that the principal route of the hepatic metabolism of NST-6179 
in vitro is catalysed by cytochrome P450 (CYP)2C9 which is a polymorphic enzyme. Blood 
samples for PGx analyses will be collected to explore the contribution of common gene 
variants, such as CYP2C9, to the variability in PK profiles between subjects in vivo. The 
optional collection of the PGx blood sample will apply to all subjects in the study, in the case 
that subjects have already been dosed and/or discharged they will be contacted and asked if 
they would be willing to return to the CRU and consent to have this sample collected.  
The major and minor changes implemented in this amendment are summarised in 
Appendix 7. 


Protocol 
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Protocol Reference: NST-6179-01 
Protocol Version 5, 11 July 2022 
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STUDY IDENTIFICATION 
Sponsor 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Sponsor’s Study Contact 
Kathline Kim 
Senior Clinical Trial Manager 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Tel: +1 510 282 3024 
Email: kathline.kim@northseatherapeutics.com 
Study Director 
Dr Stephen Rossi, PharmD 
Chief Development Officer 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Tel: +1 415 572 0596 
Email: stephen.rossi@northseatherapeutics.com 
Sponsor’s Medical Contact 
Dr Stephen Harrison, MD 
Chief Medical Officer 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Tel: +1 210 288 586844 
Email: stephen.harrison@northseatherapeutics.com 
Study Site 
Labcorp Clinical Research Unit (CRU) Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
Dr Jim Bush, MBChB, PhD, MRCS, FFPM, GFMD 
VP CPS Medical Services 
Labcorp CRU Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Tel: +44 (0) 113 301 3644 
Tel (after hours): +44 (0) 113 301 3500 


Protocol 
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Labcorp Study: 8462139 
Protocol Reference: NST-6179-01 
Protocol Version 5, 11 July 2022 
Page 6 of 116 
Project Physician 
Dr Samuel Israel, MB:BS, MRCOG, FRCOG 
Labcorp Research Physician 
Covance CRU Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Tel: +44 (0) 113 301 3527 
Clinical Laboratory 
Labcorp Early Development Laboratories Ltd. 
Otley Road 
Harrogate, HG3 1PY 
United Kingdom 
Bioanalytical Laboratory 
LGC 
Newmarket Road 
Fordham 
Cambridgeshire, CB7 5WW 
United Kingdom 
Statistician 
Izabela Antys, BSc MSc GradStat 
Labcorp Drug Development 


Protocol 
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Labcorp Study: 8462139 
Protocol Reference: NST-6179-01 
Protocol Version 5, 11 July 2022 
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SYNOPSIS 
Study Title 
A Phase 1, First Time in Human Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of NST-6179 in Healthy Subjects 
Objectives 
The primary objectives of the study are: 
x to assess the safety and tolerability of single and multiple oral doses of NST-6179 in 
healthy male and female subjects 
The secondary objective of the study is: 
x to evaluate the single and multiple oral dose pharmacokinetics (PK) of NST-6179 in 
healthy male and female subjects 
The exploratory objectives of the study are: 
x to collect data to assess the relationship between NST-6179 concentrations and QT 
interval corrected for heart rate (QTc) in healthy male and female subjects 
x to evaluate the metabolite profile of NST-6179 in healthy male and female subjects. 
x to evaluate the effect of pharmacogenomics on the PK of NST-6179 in healthy male 
and female subjects. 
Study Design 
This will be a partly double-blind, randomised, placebo-controlled, single and multiple oral 
dose study conducted in 2 parts. Part A and Part B will be double-blind, randomised, 
placebo-controlled, with subjects receiving single (Part A) and multiple (Part B) oral doses. 
Part A will comprise a double-blind, single-ascending dose, sequential-group design. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only. 
Subjects will reside at the study site from Day -1 (the day before dosing) to Day 4 of each 
treatment period, as applicable. All subjects will return for a follow-up visit 10 to 14 days 
after their final dose. 
All groups in Part A will be divided into 2 sub-groups, with each sub-group being dosed 
24 hours apart. The first sub-group will comprise 2 subjects, with 1 subject receiving 
NST-6179 and 1 subject receiving placebo. The second sub-group will comprise 6 subjects, 
with 5 subjects receiving NST-6179 and 1 subject receiving placebo. 
There will be a minimum of 7 days between dose escalations for each group in Part A. 


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Part B will comprise a double-blind, multiple-ascending dose, sequential-group study design. 
Part B may start in parallel with Part A provided the exposure is not predicted to exceed an 
exposure shown to be safe and well tolerated in Part A. 
Each subject will participate in 1 treatment period only and reside at the study site from 
Day -1 until the morning of Day 16. All subjects will return for a follow-up visit 10 to 
14 days after their final dose. 
In each of Groups B1 to B4, 8 subjects will receive NST-6179 and 2 subjects will receive 
placebo. For all subjects, dosing is planned to be once daily (QD) on Days 1 to 14, inclusive. 
However, dosing frequency and duration in Part B may be changed following review of data 
from groups in Part A or earlier groups in Part B. The dose regimen will comprise no less 
than once every 2 days and will not exceed 4-times-daily dosing. There will be a minimum of 
14 days between dose escalations for each group. The dose selected on each dosing occasion 
in Part B will not exceed a single dose shown to be safe and well tolerated in Part A. Sentinel 
dosing will be implemented for any groups in Part B for which the total daily dose exceeds 
the highest single dose evaluated in Part A (eg, 1000 mg BID for which the total daily dose of 
2000 mg has not been administered as a single dose in Part A), whereby an initial cohort of 
2 subjects (1 active and 1 placebo) will be dosed on 1 day and, providing no safety concerns 
arise, the remaining cohort of 8 subjects (7 active and 1 placebo) will be dosed after at least 
72 hours.  
Number of Subjects 
Part A: it is planned to study 48 subjects in 6 groups (Groups A1 to A6). If additional groups 
are studied, up to 72 subjects will be studied in 9 groups (Groups A1 to A9). 
Part B: it is planned to study 40 subjects in 4 groups (Groups B1 to B4). If additional groups 
are studied, up to 70 subjects will be studied in 7 groups (Groups B1 to B7). 
Diagnosis and Main Criteria for Inclusion 
In Part A and Part B, healthy male and female subjects aged between 18 and 65 years 
(inclusive) with a body mass index between 18.0 and 32.0 kg/m2 (inclusive). 
Investigational Medicinal Products, Dose, and Mode of Administration 
10 mg and 100 mg NST-6179 capsules. 
Proposed dose levels for Part A: 50 mg for Group A1; subsequent dose levels are to be 
determined following satisfactory review by the sponsor and investigator of the safety and 
tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours 
post-final dose) from the previous dose group. 
Proposed dose levels for Part B: the dose levels, dosing frequency, and dosing duration will 
be decided, in consultation with the sponsor, on the basis of data from Part A of the study or 
earlier groups in Part B. The dose of NST-6179 per dosing occasion in Part B  will not 
exceed a single dose shown to be safe and well tolerated in Part A. 


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Administration route: oral. 
Reference Product and Mode of Administration for Part A and Part B 
Reference product: placebo capsules. 
Administration route: oral. 
Duration of Subject Participation in the Study 
Part A 
Planned screening duration: approximately 4 weeks. 
Planned study duration (screening to follow-up): approximately 6 weeks. 
Part B 
Planned screening duration: approximately 4 weeks. 
Planned study duration (screening to follow-up): approximately 8 weeks. 
Endpoints 
Pharmacokinetics 
Blood and urine samples will be collected for the analysis of plasma and urinary 
concentrations of NST-6179. Pharmacokinetic parameters will be derived by 
non-compartmental analysis. For Part A, the PK parameters will include area under the 
concentration-time curve (AUC) from time zero to infinity (AUC0-), area under the 
concentration-time curve from time zero to infinity normalised by dose (AUC0-/dose), area 
under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (AUC0-tlast), area under the concentration-time curve from time zero to the time 
of the last quantifiable concentration normalised by dose (AUC0-tlast/dose), maximum 
observed concentration (Cmax), Cmax normalised by dose (Cmax/dose), time of the maximum 
observed concentration (tmax), apparent terminal elimination half-life (t½), apparent total 
clearance (CL/F), apparent volume of distribution (Vz/F), amount of drug excreted (Ae), 
percentage of dose excreted unchanged (fe), and renal clearance (CLR). In Part B, the PK 
parameters will include: area under the concentration-time curve over a dosing interval 
(AUC0-Ĳ), AUC time zero to 24 hours postdose (AUC0-24, derived as AUC0-Ĳ*2 for a BID 
dosing regimen at steady state), area under the concentration-time curve over a dosing 
interval normalised by dose (AUC0-Ĳ/dose), AUC0- (Day 1 only), AUC0-/dose (Day 1 only), 
Cmax, Cmax/dose, tmax, t½, CL/F, Vz/F, minimum observed concentration (Cmin), observed 
accumulation ratio based on AUC0-Ĳ (RAAUC0-Ĳ), and observed accumulation ratio based on 
Cmax (RACmax). Other PK parameters may also be added. 


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Protocol Version 5, 11 July 2022 
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Safety 
Adverse events (AEs), clinical laboratory evaluations (haematology, clinical chemistry, 
coagulation, and urinalysis), 12-lead electrocardiogram (ECG) parameters, vital signs 
measurements, and physical examinations. 
Exploratory 
Continuous 12-lead ECG data will be collected for the future assessment of the NST-6179 
concentration-QTc response relationship following single oral doses of NST-6179. 
For the highest planned QD dose group in Part B, additional samples will be taken for the 
identification of metabolites of NST-6179. 
Optional pharmacogenomics samples will be collected from subjects that consent, for the 
determination of common gene variants (ie, cytochrome P450 2C9), that may have an effect 
on the PK of NST-6179. 
Statistical Methods 
Pharmacokinetics 
Non-compartmental PK analysis will be performed on individual plasma and urine 
concentration data, using commercial software such as Phoenix® WinNonlin®. 
The PK concentrations and parameters will be listed and summarised using descriptive 
statistics. 
A statistical analysis will be conducted to investigate the dose proportionality of AUC0-tlast, 
AUC0-, and Cmax on Day 1 in Part A and AUC0-Ĳ and Cmax on Day 14 in Part B. The PK 
parameters will be analysed using a power model. However, if the assumption of linearity is 
ruled unacceptable for any PK parameter, its corresponding PK parameter normalised by 
dose administered will be natural log-transformed and analysed using an analysis of variance 
model. 
Safety 
Safety parameters will be listed and summarised using descriptive statistics. No formal 
statistical analysis of safety data is planned. 


Protocol 
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Protocol Reference: NST-6179-01 
Protocol Version 5, 11 July 2022 
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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
RATIONALE FOR PROTOCOL AMENDMENT ...................................................................4 
STUDY IDENTIFICATION .....................................................................................................5 
SYNOPSIS .................................................................................................................................7 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF TABLES AND FIGURES........................................................................................14 
LIST OF ABBREVIATIONS ..................................................................................................15 
1. 
INTRODUCTION ...........................................................................................................17 
1.1. 
Overview ................................................................................................................17 
1.2. 
Summary of Non-clinical Pharmacology ...............................................................17 
1.3. 
Summary of Safety Pharmacology ........................................................................18 
1.4. 
Summary of Toxicology ........................................................................................18 
1.4.1. 
28-day Oral (Gavage) Administration Toxicity Study in the Rat 
Followed by a 2-week Recovery Period ......................................................18 
1.4.2. 
4-week Oral (Gavage) Toxicity and Toxicokinetic Study in the Monkey 
with a 2-week Recovery Period ...................................................................20 
1.4.3. 
13-week Oral (Gavage) Toxicity and Toxicokinetic Study in the 
Monkey with a 2-week Recovery Period .....................................................21 
1.4.4. 
13-week Oral (Gavage) Administration Toxicity Study in the Mouse 
(Labcorp Study Number 8423764; ongoing) ...............................................22 
1.5. 
Summary of Non-clinical Pharmacokinetics .........................................................24 
1.5.1. 
Rat ................................................................................................................24 
1.5.2. 
Monkey ........................................................................................................25 
1.5.3. 
Mouse ...........................................................................................................26 
1.6. 
Summary of Clinical Experience ...........................................................................27 
1.6.1. 
Phase 1 Single Ascending Dose and Multiple Ascending Dose Study in 
Healthy Subjects (Study NST-6179-01, ongoing) .......................................27 
1.7. 
Study Rationale ......................................................................................................29 
1.8. 
Benefit-risk Assessment .........................................................................................29 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................30 
2.1. 
Objectives ..............................................................................................................30 
2.2. 
Endpoints ...............................................................................................................30 
2.2.1. 
Primary Endpoints .......................................................................................30 
2.2.2. 
Secondary Endpoints ...................................................................................30 
2.2.3. 
Exploratory Endpoints .................................................................................32 
3. 
INVESTIGATIONAL PLAN ..........................................................................................32 


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3.1. 
Overall Study Design and Plan ..............................................................................32 
3.1.1. 
Part A ...........................................................................................................32 
3.1.2. 
Part B ...........................................................................................................35 
3.2. 
Study Start and End of Study Definitions ..............................................................36 
3.3. 
Additional Groups ..................................................................................................36 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................37 
3.4.1. 
Dose Interval Between Subjects ..................................................................38 
3.5. 
Selection of Doses in the Study .............................................................................38 
3.6. 
Dose Escalation ......................................................................................................40 
3.7. 
Dose Escalation Stopping Criteria .........................................................................41 
4. 
SELECTION OF STUDY POPULATION .....................................................................42 
4.1. 
Inclusion Criteria ...................................................................................................42 
4.1.1. 
Part A and Part B .........................................................................................42 
4.2. 
Exclusion Criteria ..................................................................................................42 
4.2.1. 
Part A and Part B .........................................................................................42 
4.3. 
Generic Screening ..................................................................................................44 
4.4. 
Subject Number and Identification ........................................................................44 
4.5. 
Subject Withdrawal and Replacement ...................................................................44 
4.6. 
Study Termination .................................................................................................45 
5. 
STUDY TREATMENTS .................................................................................................45 
5.1. 
Description, Storage, Packaging, and Labelling ....................................................45 
5.2. 
Study Treatment Administration ............................................................................46 
5.3. 
Randomisation .......................................................................................................46 
5.4. 
Blinding..................................................................................................................47 
5.5. 
Treatment Compliance ...........................................................................................47 
5.6. 
Drug Accountability...............................................................................................47 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................48 
6.1. 
Concomitant Therapies ..........................................................................................48 
6.2. 
Diet .........................................................................................................................48 
6.3. 
Smoking .................................................................................................................49 
6.4. 
Exercise ..................................................................................................................49 
6.5. 
Blood Donation ......................................................................................................49 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................49 
7.1. 
Pharmacokinetic Assessments ...............................................................................50 
7.1.1. 
Sample Collection and Processing for Pharmacokinetic Assessment .........50 
7.1.2. 
Sample Collection and Processing for Metabolite Identification ................50 
7.1.3. 
Analytical Methodology ..............................................................................50 
7.1.4. 
Sample Collection and Processing for Pharmacogenomics .........................51 
7.2. 
Safety and Tolerability Assessments .....................................................................51 


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7.2.1. 
Adverse Events ............................................................................................51 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................51 
7.2.3. 
Vital Signs ....................................................................................................52 
7.2.4. 
Electrocardiogram ........................................................................................52 
7.2.5. 
Physical Examination...................................................................................53 
7.2.6. 
Body Weight ................................................................................................53 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................53 
8.1. 
Determination of Sample Size ...............................................................................53 
8.2. 
Analysis Populations ..............................................................................................54 
8.2.1. 
Pharmacokinetic Population ........................................................................54 
8.2.2. 
Safety Population .........................................................................................54 
8.3. 
Pharmacokinetic Analyses .....................................................................................54 
8.4. 
Safety Analysis ......................................................................................................54 
8.5. 
Interim Analysis .....................................................................................................54 
9. 
REFERENCES ................................................................................................................54 
10. APPENDICES .................................................................................................................56 
Appendix 1: Adverse Event Reporting ..............................................................................57 
Appendix 2: Clinical Laboratory Evaluations ...................................................................61 
Appendix 3: Total Blood Volume ......................................................................................62 
Appendix 4: Contraception Guidance ................................................................................65 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................68 
Appendix 6: Schedule of Assessments ..............................................................................72 
Appendix 7: Summary of Amended Protocol Changes .....................................................79 
 
 
 


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LIST OF TABLES AND FIGURES 
Table 1: 
Group Assignment in the 13-week Oral (Gavage) Administration 
Toxicity Study in the Mouse (Labcorp Study Number 8423764) .............23 
Table 2: 
Summary of the NST-6179 Toxicokinetic Parameters in the Mouse on 
Day 1 in the 13-week Oral (Gavage) Administration Toxicity Study 
(Labcorp Study Number 8423764) ...........................................................24 
Table 3: 
Summary of the NST-6179 Toxicokinetic Parameters in Rat ...................25 
Table 4: 
Summary of the NST-6179 Toxicokinetic Parameters in Monkey ...........26 
Table 5: 
Pharmacokinetic Parameters of NST-6179 in the Mouse following a 
Single Dose of 70 mg/kg ...........................................................................26 
Table 6: 
Geometric Mean (%CV) PK Parameters of NST-6179 Following 
Single Oral Administration of NST-6179 Under Fasting Conditions 
(Part A) ......................................................................................................28 
Table 7: 
Geometric Mean (%CV) PK Parameters of NST-6179 Following 
Repeated Oral Administration of NST-6179 Under Fasting Conditions 
(Part B) ......................................................................................................28 
Table 8: 
Investigational Medicinal Product Dose Levels for Parts A and B ...........40 
 
Figure 1: 
Study Schematic (Part A) for Groups A1 to A6 ........................................33 
Figure 2: 
Planned Dose Levels for Part A .................................................................34 
Figure 3: 
Study Schematic for Part B ........................................................................36 
Figure 4: 
Planned Dose Levels for Part B .................................................................36 
 


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LIST OF ABBREVIATIONS 
Abbreviation Definition 
AE 
adverse event 
Ae 
amount of drug excreted 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AM 
morning 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-f 
area under the concentration-time curve from time zero to infinity 
AUC0-24 
area under the concentration-time curve from time zero to 24 hours 
postdose 
AUC0-tlast 
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration 
AUC0-Ĳ 
area under the concentration-time curve over a dosing interval 
BID 
twice daily 
BMI 
body mass index 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
CL/F 
apparent total clearance 
CLR 
renal clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organisation 
CRU 
Clinical Research Unit 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
fe 
percentage of drug excreted 
FO 
fish oil 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HED 
human equivalent dose 
hERG 
human ether-à-go-go-related gene 
ICF 
informed consent form 


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ICH 
International Council for/Conference on Harmonisation 
IFALD 
intestinal failure-associated liver disease 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IUD 
intrauterine device 
MCFA 
medium chain fatty acid 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MTD 
maximum tolerated dose 
NOAEL 
no-observed-adverse-effect level 
PGx 
pharmacogenomic 
PK 
pharmacokinetic(s) 
PM 
evening 
PNALD 
parenteral nutrition associated liver disease 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RAAUC0-Ĳ 
observed accumulation ratio based on AUC0-Ĳ 
RACmax 
observed accumulation ratio based on Cmax 
SAE 
serious adverse event 
t½ 
apparent terminal elimination half-life 
TK 
toxicokinetic(s) 
tmax 
time of the maximum observed concentration 
TMF 
trial master file 
TPN 
total parenteral nutrition 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution 
 
 


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1. INTRODUCTION 
1.1. 
Overview 
NorthSea Therapeutics is developing NST-6179, a novel, orally administered, fully-synthetic 
medium chain fatty acid (MCFA) analogue for the treatment of intestinal failure-associated 
liver disease (IFALD), also known as parenteral nutrition associated liver disease (PNALD), 
and other potential indications. There are likely to be multiple mechanisms that contribute to 
the observed pharmacodynamic (PD) effects of NST-6179. NST-6179 is structurally based on 
a MCFA to maximise both portal vein uptake and passive absorption but is modified to resist 
rapid metabolism as an energy source. This combination of attributes may provide targeted 
therapy for the treatment of IFALD. 
Total parenteral nutrition (TPN) is a lifesaving therapy for individuals with intestinal failure 
caused by insufficient bowel length or function. Long-term TPN treatment is limited by 
potentially serious complications, including liver disease. In the United States, it is estimated 
that around 40,000 to 45,000 patients require long term TPN, of which approximately 20% 
progress to IFALD. The incidence of IFALD in patients receiving long-term TPN varies 
widely depending on the age group, from 15% to 40% in adults and 40% to 60% in infants 
and neonates. Approximately 22% of deaths in patients on long-term TPN are attributed to 
IFALD. Intestinal failure-associated liver disease development is characterised initially by 
intrahepatic cholestasis, and then by progressive fibrosis and ultimately cirrhosis over the 
course of several months. Current strategies to treat IFALD include lipid restriction, which 
carries the risk of essential fatty acid deficiency, or transition to high volumes of fish oil (FO) 
lipid emulsion per day based on the weight of an average adult. There is a population of 
patients who continue to develop IFALD despite having been weaned off and it has also been 
demonstrated that a significant percentage of patients fail therapy. As such, there is a need for 
alternative treatments for patients who may benefit from lower dose enterally administered 
therapies. 
This study will be the first time NST-6179 has been administered to humans. 
1.2. 
Summary of Non-clinical Pharmacology 
Three in vivo pharmacology studies were conducted. 
Non-clinical efficacy studies demonstrated that in murine models of IFALD, orally 
administered NST-6179 was absorbed enterally and led to preservation of normal liver 
architecture, as compared to vehicle groups, which developed significant steatosis. Hepatic 
lipidomic analysis confirmed a decrease in hepatic triglycerides (-55%) and cholesteryl ester, 
the main hepatic cholesterol storage depot. The results demonstrated that NST-6179 confers 
hepatoprotective properties in a murine model of TPN-induced liver injury. An additional 
study where the same model was used to investigate co-administration of NST-6179 with 
either Intralipid (Soybean [SO] oil) or Omegaven® (FO) demonstrated that the combination 
did not give rise to any detrimental effects in this model and as such suggests that NST-6179 
could be safely administered in combination with existing lipid emulsion therapy. 
Importantly, significant down-regulation of key genes regulating hepatic inflammation and 
fibrosis were also observed in a mouse model of fibrosing steatohepatitis in response to 


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over-nutrition. These results suggest NST-6179 as a potential treatment for patients with 
IFALD or who are at risk of developing IFALD. 
1.3. 
Summary of Safety Pharmacology 
Four safety pharmacology studies were completed (all conducted to Good Laboratory 
Practice [GLP]). 
In an in vitro human ether-à-go-go-related gene (hERG) assay, NST-6179 had no significant 
effect on hERG tail current up to 75 μM (maximum concentration tested and limit of 
solubility). 
Consistent with the findings from the hERG study, no effect on the cardiovascular 
parameters, electrocardiogram (ECG) parameters, or body temperature in the telemetered 
cynomolgus monkey were observed following NST-6179 at doses of 60 mg/kg, 175 mg/kg, 
and 500 mg/kg. It was therefore concluded that the no-observed-adverse-effect level 
(NOAEL) for NST-6179 in the monkey was 500 mg/kg due to no adverse findings on the 
cardiovascular system and on body temperature. In addition, no adverse findings were noted 
in the ECGs of monkeys treated for 28 days up to 350 mg/kg in the repeat-dose toxicity study 
(Section 1.4.2). 
In an Irwin’s test in the Han Wistar rat, a single dose of NST-6179 at 100 mg/kg and 
245 mg/kg was not associated with any adverse (biologically significant) observations. 
Following single oral administration of 245 mg/kg NST-6179 in male rats, no adverse effects 
on the behavioural and physiological state of the rats were recorded; however, statistically 
significant reductions in locomotor activity and rearing were recorded at 2 hours postdose 
(not observed at the 100 mg/kg dose level). The NOAEL was considered to be 245 mg/kg, 
due to no adverse behavioural signs and the effects on locomotor activity and rearing were 
not considered to be adverse. 
A single dose study was performed to determine the potential effects of NST-6179 following 
single oral administration on respiratory rate, tidal volume, and minute volume in the rat. In 
this study, NST-6179 was administered at doses of 100 mg/kg, 245 mg/kg, and 600 mg/kg. 
The vehicle control was corn oil. There were no adverse or biologically relevant effects on 
respiratory rate, tidal volume, or minute volume. In addition, no significant adverse clinical 
signs were recorded in either the vehicle or any of the NST-6179-treated groups. Based on 
these findings, the NOAEL was 600 mg/kg. 
1.4. 
Summary of Toxicology 
Repeat-dose toxicology studies were conducted in rats and cynomolgus monkeys given oral 
NST-6179 for 28 days followed by a 2-week recovery period. 
1.4.1. 
28-day Oral (Gavage) Administration Toxicity Study in the Rat Followed by 
a 2-week Recovery Period 
NST-6179 was administered at doses of 100 mg/kg/day (low dose), 245 mg/kg/day 
(intermediate dose), and 600/450 mg/kg/day (high dose) to male and female rats. Animals in 
the high dose group were dosed 600 mg/kg/day on Days 1 and 2 of the dosing phase, 


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followed by a 2-day washout period and recommenced dosing at 450 mg/kg/day from Day 5 
of the dosing phase. At a dose level of 600 mg/kg/day, there were observations of decreased 
activity on Days 1 and 2, and ataxia, shallow respiration, splayed gait, decreased body tone, 
vocalisation, piloerection, and partially closed eyes on Day 2. The severity of these findings 
resulted in the suspension of administration of 600 mg/kg/day and the high dose was reduced 
to 450 mg/kg/day. The vehicle control article in this study was corn oil. Assessment of 
toxicity was based on mortality, clinical and postdose observations, body weights, food 
consumption, ophthalmic observations, and clinical and anatomic pathology. 
There were no clinical observations of concern following administration up to 450 mg/kg/day 
(reduced high dose) and there were no effects on body weights for female dose groups and no 
ophthalmic findings in animals of either sex administered NST-6179. 
Daily oral gavage administration of 100 mg/kg/day, 245 mg/kg/day or 600/450 mg/kg/day 
NST-6179 was tolerated at 100 mg/kg/day and 245 mg/kg/day, with no notable clinical 
observations or postdose observations in either dose group and only a slight reduction in body 
weight for males and slightly increased food consumption for females administered 
245 mg/kg/day. 
Administration of 600 mg/kg/day NST-6179 resulted in the premature sacrifice of 1 female 
rat and the death of 1 female rat with a range of adverse clinical observations and initial 
weight loss and reduced food consumption were noted for males. Due to these findings, the 
dose of 600 mg/kg/day was reduced to 450 mg/kg/day for the remaining animals. 
Once daily (QD) administration of 450 mg/kg/day also produced no in-life clinical 
observations, but males were observed with body weight losses. Findings related to an effect 
on the liver were observed in all NST-6179 dose groups and included diffuse hepatocyte 
hypertrophy and increased liver weights; these findings were observed in a dose-related 
manner and considered of a greater severity for males administered 600/450 mg/kg/day than 
animals administered lower doses of 100 mg/kg/day or 245 mg/kg/day, and correlated with 
increased alanine aminotransferase (ALT) activity across all dose levels, and alkaline 
phosphatase (ALP) activity at the 600/450-mg/kg/day dose level. Plasma drug levels were 
lower after repeated administration suggestive of metabolic induction. 
A dose level of 450 mg/kg/day resulted in several findings, but no single finding was 
considered adverse. Full reversibility of all findings, including the liver findings following 
administration of 450 mg/kg/day, indicated that any mild effects at this or lower doses would 
be fully reversible. 
Based on these findings, the NOAEL is 450 mg/kg/day. This dose level corresponded to 
mean maximum observed plasma concentration (Cmax) values of 95,400 ng/mL (males) and 
66,500 ng/mL (females), and mean area under the plasma concentration-time curve from time 
zero to 24 hours postdose (AUC0-24) values of 1,160,000 ng.h/mL (males) and 
1,030,000 ng.h/mL (females; Section 1.5.1). 


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1.4.2. 
4-week Oral (Gavage) Toxicity and Toxicokinetic Study in the Monkey with a 
2-week Recovery Period 
NST-6179 was administered at doses of 60 mg/kg/day (low dose), 175 mg/kg/day 
(intermediate dose), and 500/350 mg/kg/day (high dose) to male and female monkeys. 
Animals were dosed via oral gavage QD for 28 days at a volume of 5 mL/kg. Animals in the 
high dose group were dosed at 500 mg/kg/day from Day 1 to Day 6 of the dosing phase, 
followed by a 30-day washout period and recommenced dosing at 350 mg/kg/day for 
28 days. At a dose level of 500 mg/kg/day, there were observations of decreased activity, 
ataxia, semi-closed eyes, hunched posture, and vomiting. The severity of these findings and 
2 mortalities resulted in suspension of administration of 500 mg/kg/day, and the high dose 
was reduced to 350 mg/kg/day. The vehicle control article in this study was corn oil. 
Assessment of toxicity was based on mortality, clinical and postdose observations, body 
weights, food consumption, ophthalmic observations, ECG, and clinical and anatomic 
pathology. 
One male administered 500 mg/kg/day died following sedation due to the severity of clinical 
observations, which included a severe reduction in activity on Day 2 of dosing. One female 
administered 500 mg/kg/day was found dead on Day 7 of dosing. Observations noted for this 
animal on Day 6 of dosing included reduced activity. Administration of 500 mg/kg/day 
resulted in postdose observations of decreased activity, ataxia, semi-closed eyes, hunched 
posture, and vomiting. The severity of these findings and 2 mortalities resulted in suspension 
of administration of 500 mg/kg/day after 6 days, and the high-dose level was reduced to 
350 mg/kg/day following a 30-day wash-out period. Administration of 350 mg/kg/day was 
only associated with transient, mild, and occasional postdose observations of decreased 
activity, hunched posture, and vomiting that diminished throughout the 28 days of dosing. 
Administration of 350 mg/kg/day or 500 mg/kg/day resulted in increased body weight losses 
(up to 6.6% and 6.8% for males and females, respectively, at the 350-mg/kg/day dose level, 
and up to 5.9% and 5.2% for males and females, respectively, at the 500-mg/kg/day dose 
level) over the relevant dosing periods. 
Clinical chemistry changes observed during Week 4 of the dosing phase included a slightly 
increased ALT for both sexes administered 350 mg/kg/day (10.6% and 24.1% for males and 
females, respectively) and males administered 175 mg/kg/day (14.9%). In addition, there was 
increased triglyceride levels for both sexes administered 350 mg/kg/day (84.2% and 21.3% 
for males and females, respectively) and females administered 175 mg/kg/day (12.9%) when 
compared with predose results. Triglyceride levels remained increased for animals 
administered 350 mg/kg/day (by 65.8% and 29.8% for males and females respectively when 
compared to predose values) at the end of the recovery phase, with ALT activity no longer 
increased for animals administered 350 mg/kg/day. 
Daily oral gavage administration of NST-6179 at doses of 60 mg/kg/day, 175 mg/kg/day, or 
350 mg/kg/day was well tolerated. Administration of 500 mg/kg/day was clearly not tolerated 
and resulted in the death of 1 male and 1 female, alongside severe adverse clinical 
observations of ataxia and decreased activity. Based on these findings, the NOAEL is 
considered to be 350 mg/kg/day. This dose level corresponded to mean Cmax values of 


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145,000 ng/mL (males) and 59,100 ng/mL (females), and mean AUC0-24 values of 
638,000 ng.h/mL (males) and 440,000 ng.h/mL (females). 
1.4.3. 
13-week Oral (Gavage) Toxicity and Toxicokinetic Study in the Monkey with 
a 2-week Recovery Period 
This is an ongoing study objective to evaluate the toxicity and determine the toxicokinetics 
(TK) of NST-6179 when administered daily via oral gavage to the monkey for at least 
13 weeks and to assess the reversibility or persistence of any effects after a 4-week recovery 
phase following doses of 60 mg/kg/day (low dose), 210 mg/kg/day (intermediate dose), and 
350 mg/kg/day (high dose). The purpose of the study is to establish dose levels for future 
long term toxicity studies. A high dose level of 350 mg/kg/day was selected based on results 
from a 28-day repeat dose toxicity study (Covance study 8423746). An original high dose of 
500 mg/kg/day was not tolerated, resulting in two early sacrifices and postdose observations 
of decreased activity, ataxia, semi-closed eyes, hunched posture, and vomiting. Following a 
30-day washout period, a revised high dose level of 350 mg/kg/day was investigated over 
28 days, which was tolerated with no mortality and transient mild and occasional postdose 
observations of decreased activity, hunched posture, and vomiting that diminished throughout 
the 28 days dosing. An intermediate dose level of 210 mg/kg/day was selected as an 
alternative high dose level for future studies if the selected high dose level was not tolerated. 
A low dose level of 60 mg/kg/day was expected to be tolerated in-life, with no postdose 
observations or body weight effect noted following 28 days repeat administration at this dose 
level during the previous toxicity study. The cynomolgus monkey was selected as the 
relevant species because of the similarity of monkeys to humans in species specific 
cross-reactivity of test article. An in vitro metabolism study (Covance study 8423743) 
indicated the cynomolgus monkey is the preferred choice of large animal species due to the 
presence of specific human metabolites, which are not present in other species. 
Animals were dosed through Day 15 and NST-6179 was generally well tolerated with only 
mild spurious vomiting and an 8% decrease in bodyweight observed in the early stages, both 
of which returned to baseline status over time. No other relevant clinical findings have been 
observed to date at any dose level in either male or female monkeys. However, there were 
subsequently 2 events of note in the high-dose cohort (350 mg/kg/day). The first event 
occurred on Day 16 in which a single female monkey was found dead following dosing on 
Day 15. The decedent female appeared to be in general good health and displayed no clinical 
signs up through and postdose on Day 15. A macroscopic post-mortem examination showed 
no advanced autolysis at macroscopic post-mortem indicating the female died relatively soon 
prior to the post-mortem examination and at a timeframe when minimal drug concentrations 
levels would have been present. Microscopically, minimal alveolar/interstitial inflammation 
was noted, consistent with post aspiration effects but not the cause of mortality. The majority 
of tissues were well preserved with some autolysis noted in the gall bladder and 
gastrointestinal tract and to a lesser extent liver, pancreas, and salivary glands. No 
pre-existing comorbid conditions were identified as a potential cause of death. Clinical 
chemistry and urinalysis parameters were all normal or with minimal changes; none of which 
were felt to be clinically relevant. Assessment of the decedents ECG indicated minor 
anomalies considered not clinically relevant. As of this time, there is no clear indication of 
the cause of death but the examinations to date do not show any evidence of direct tissue 
injury or toxicity associated with NST-6179. 


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The second event occurred in the high-dose cohort (350 mg/kg/day) where a male monkey 
was found in a moribund condition 4 hours after dosing and euthanized on Day 87. This male 
was in good health throughout the study and prior to the last dose on Day 87. The 
investigation into the cause of death is still ongoing as well as an assessment of the remaining 
animals in the high-dose cohort. However, the initial assessment from the study pathologist 
determined that the microscopic findings were common background changes in this strain of 
monkey. However, there was moderate bilateral tubular nephropathy in the kidney which 
could be possibly related to the cause of death but will be confirmed with further 
investigations of this animal and the others in the cohort. No other clinical or laboratory 
findings revealed any clear signs of drug toxicity that would lead to death. 
A review of the data from the prior 28-day repeat dose oral toxicity study in monkeys 
established 350 mg/kg/day was the NOAEL level (Covance 8423746). No clinical signs and 
symptoms or mortality were observed at this dose level. Importantly, dosing in the monkey 
13-week study is now complete. NST-6179 was well tolerated in all other surviving male and 
female high dose monkeys. The low (60 mg/kg/day) and medium (210 mg/kg/day) doses 
were well-tolerated throughout the study period with no notable events. Both of the events in 
the high-dose group were at exposures far exceeding the exposure of the likely doses in the 
Phase 1 study. In addition, there was no clear drug-related effect with the first monkey and 
the second event occurred at a duration much longer than the maximal 14-day duration in the 
Phase 1 study. 
1.4.4. 
13-week Oral (Gavage) Administration Toxicity Study in the Mouse 
(Labcorp Study Number 8423764; ongoing) 
A 13-week oral toxicity study in the mouse conducted under GLP is currently ongoing to 
determine dose level selection in a subsequent 2-year carcinogenicity study as well as 
evaluating TK at Day 1 and Day 90 of the study. 
The maximum dose levels administered in the 13-week study were based on a previous 
mouse dose range finding study which was conducted to establish the maximum tolerated 
oral dose (MTD) in male and female mice. This study established an MTD of 250 mg/kg in 
female mice and an MTD of 200 mg/kg/day in male mice. These dose levels were tolerated 
for 21 days without mortality or adverse clinical signs. The selected low dose level of 
70 mg/kg/day is the approximate effective dose. The intermediate dose levels in males and 
females represent the mid-point between 70 mg/kg/day and 200 mg/kg/day (males) and 
250 mg/kg/day (females). 
Group assignment is indicated in Table 1. 


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Table 1: 
Group Assignment in the 13-week Oral (Gavage) Administration Toxicity 
Study in the Mouse (Labcorp Study Number 8423764) 
Groupa 
Subgroup 
Dose Levelb
(mg/kg/day) 
Dose 
Concentrationb 
(mg/mL) 
Number of Animals 
Males 
Females 
1 (Control) 
1 (Toxicity) 
0 
0 
12 
12 
2 (Toxicokinetic) 
0 
0 
3 
3 
2 (Low) 
1 (Toxicity) 
70 
7 
12 
- 
1 (Toxicity) 
70 
7 
-
12
2 (Toxicokinetic) 
70 
7 
18 
-
2 (Toxicokinetic) 
70 
7 
-
18
3 (Intermediate) 
1 (Toxicity) 
135 
13.5 
12 
- 
1 (Toxicity) 
160 
16 
-
12
2 (Toxicokinetic) 
135 
13.5 
18 
-
2 (Toxicokinetic) 
160 
16 
-
18
4 (High) 
1 (Toxicity) 
200 
20 
12 
- 
1 (Toxicity) 
250 
25 
-
12
2 (Toxicokinetic) 
200 
20 
18 
-
2 (Toxicokinetic) 
250 
25 
-
18
a. Group 1 administered vehicle control only (corn oil).
b. Animals dosed at a volume of 10 mL/kg.
On Day 1 of dosing in the 13-week study all mice were dosed by oral gavage at the doses 
outlined above. No adverse effects were observed at the low and intermediate dose levels. At 
the high dose levels, approximately 22 hours after the first dose, 1 male and 2 females were 
found dead. Additionally, 1 female displayed clinical signs of ataxia, reduced activity, 
hunched posture, and tremors leading to the animal being euthanized. Eight days after the 
first dose, 1 female was euthanized due to immobility of the hind limbs. Dosing was 
suspended at the high dose level after the events in the first 4 animals. These events occurred 
at the end of the dosing interval therefore are not considered to correlate with Cmax of 
NST-6179. However, continued dosing in the high dose level cohort was suspended and new 
dosing levels were evaluated the study. 
Macroscopic examination of major organs and tissues in decedents did not reveal any 
changes that could be related to drug treatment or mis-dosing via gavage. A full 
histopathology report of decedents is pending but TK analysis indicates drug exposure at the 
well-tolerated intermediate dose levels is greater than the current stopping rules. At the high 
dose level, drug exposure is substantially above the current stopping rule area under the 
concentration-time curve (AUC) of 358,000 ng.h/mL from the 28-day monkey toxicity study. 
The Day 1 TK parameters in the mouse are presented in Table 2. 


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Table 2: 
Summary of the NST-6179 Toxicokinetic Parameters in the Mouse on 
Day 1 in the 13-week Oral (Gavage) Administration Toxicity Study 
(Labcorp Study Number 8423764) 
Group 
Dose 
(mg/kg) 
Sex 
AUC0-24 
(ng.h/mL) 
Low 
70 
Male 
229,000 
70 
Female 
317,000 
Intermediate 
135 
Male 
400,000 
160 
Female 
587,000 
High 
200 
Male 
503,000 
250 
Female 
988,000 
Abbreviations: AUC0-24 = area under the plasma concentration-time curve from time zero to 24 hours postdose. 
Based on these data, the dose levels were adjusted to account for the necessitated decrease in 
high dose group while maintaining an adequate dose separation between the 3 dosing cohorts. 
The adjusted dose levels for both males and females are 70 mg/kg/day, 120 mg/kg/day, and 
170 mg/kg/day, with the adjustments made in the ongoing low and intermediate dose cohorts 
and a new cohort initiated at the high dose level. 
The observed adverse events (AEs) in the mouse have been considered and, as TK data 
indicate AEs on Day 1 correlate with exposure (AUC) substantially above the current 
stopping rule, are not considered to be clinically relevant. 
1.5. 
Summary of Non-clinical Pharmacokinetics 
1.5.1. 
Rat 
Toxicokinetic  parameters in rats following a single dose and repeated dosing for 28 days are 
presented in Table 3. 
Exposure to NST-6179, as assessed by Cmax and AUC0-24, increased with increasing dose 
level and decreased between Day 1 and Week 4, which was consistent with hepatocellular 
hypertrophy and suggestive of metabolic induction. 


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Table 3: 
Summary of the NST-6179 Toxicokinetic Parameters in Rat 
Day 
Dose 
(mg/kg/day) 
Sex 
AUC0-24 
(ng.h/mL) 
Cmax 
(ng/mL) 
tmax 
(hours) 
t½ 
(hours) 
1 
100 
Male 
292,000 
44,400 
0.500 
6.68 
Female 
288,000 
56,200 
0.500 
5.00 
Male and female 
290,000 
50,300 
0.500 
5.73 
245 
Male 
726,000 
124,000 
0.500 
6.41 
Female 
849,000 
143,000 
0.500 
4.32 
Male and female 
788,000 
134,000 
0.500 
5.23 
600a 
Male 
2,000,000 
274,000 
0.500 
NR 
Female 
1,950,000 
298,000 
0.500 
NR 
Male and female 
1,990,000 
286,000 
0.500 
NR 
28 
(Week 4) 
100 
Male 
221,000 
20,100 
0.500 
2.21 
Female 
189,000 
17,400 
4.00 
3.07 
Male and female 
205,000 
16,900 
4.00 
2.62 
245 
Male 
670,000 
86,100 
0.500 
2.38 
Female 
756,000 
82,200 
1.00 
3.18 
Male and female 
713,000 
66,800 
0.500 
2.78 
450a 
Male 
1,160,000 
95,400 
0.500 
2.32 
Female 
1,030,000 
66,500 
9.00 
NR 
Male and female 
1,090,000 
69,400 
0.500 
3.07 
Abbreviations: AUC0-24 = area under the plasma concentration-time curve from time zero to 24 hours postdose; 
Cmax = maximum observed plasma concentration; NR = not reported; t½ = apparent plasma terminal elimination half-life; 
TK = toxicokinetic(s); tmax = time of the maximum observed plasma concentration. 
NOTE: combined male and female parameters were calculated by combining concentration data for all animals (male and 
female) at each dose level on each interval and using these data as a separate composite profile for TK analysis. These 
parameters are not an average of the values calculated for males and females separately. 
a. Animals in the high dose group were dosed 600 mg/kg/day on Days 1 and 2 of the dosing phase, underwent a 2-day 
washout period and recommenced dosing at 450 mg/kg/day from Day 5 of the dosing phase. 
1.5.2. 
Monkey 
Toxicokinetic parameters in cynomolgus monkeys following a single dose and repeated 
dosing for 28 days are presented in Table 4. 
Exposure to NST-6179, as assessed by Cmax and AUC0-24 values, increased with the 
increasing dose level and in general decreased between Day 1 and Week 4 of the dosing 
phases suggesting some metabolic induction, consistent with the increased liver weight and 
microscopic findings of minimal hepatocyte hypertrophy. 


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Table 4: 
Summary of the NST-6179 Toxicokinetic Parameters in Monkey 
Day 
Dose 
(mg/kg/day) 
Sex 
AUC0-24 
(ng.h/mL) 
Cmax 
(ng/mL) 
tmax 
(hours) 
t½ 
(hours) 
1 
60 
Male 
116,000 
57,600 
0.500 
2.37 
Female 
121,000 
93,300 
0.500 
2.28 
Male and female 
119,000 
75,400 
0.500 
2.33 
175 
Male 
403,000 
111,000 
0.500 
4.95 
Female 
518,000 
155,000 
1.00 
2.37 
Male and female 
461,000 
133,000 
1.00 
3.66 
500 
(Phase 1)a 
Male 
2,080,000 
323,000 
2.00 
3.34 
Female 
2,300,000 
320,000 
2.00 
3.67 
Male and female 
2,190,000 
322,000 
2.00 
3.45 
350 
(Phase 2)a 
Male 
990,000 
228,000 
1.00 
5.23 
Female 
976,000 
165,000 
1.00 
3.18 
Male and female 
983,000 
196,000 
1.00 
4.54 
28 
(Week 4) 
60 
Male 
92,600 
52,000 
1.00 
4.50 
Female 
98,800 
72,400 
0.500 
3.13 
Male and female 
95,700 
62,200 
0.500 
3.96 
175 
Male 
133,000 
40,900 
0.500 
3.31 
Female 
358,000 
147,000 
1.00 
4.38 
Male and female 
245,000 
94,000 
1.00 
3.85 
350 
(Phase 2)a 
Male 
638,000 
145,000 
1.50 
4.72 
Female 
440,000 
59,100 
3.50 
3.95 
Male and female 
539,000 
102,000 
2.00 
4.28 
Abbreviations: AUC0-24 = area under the plasma concentration-time curve from time zero to 24 hours postdose; 
Cmax = maximum observed plasma concentration; QD = once daily; t½ = apparent plasma terminal elimination half-life; 
TK = toxicokinetic(s); tmax = time of the maximum observed plasma concentration. 
NOTE: combined male and female parameters were calculated by combining concentration data for all animals (male and 
female) at each dose level on each interval and using these data as a separate composite profile for TK analysis. These 
parameters are not an average of the values calculated for males and females separately. 
a. Animals administered 500 mg/kg/day from Days 1 through 6 of the dosing phase (Phase 1) underwent a 30-day washout 
period and recommenced dosing with a dose level of 350 mg/kg/day (Phase 2) for 28 days (500/350 mg/kg/day). 
1.5.3. 
Mouse 
NST-6179 was administered as a single dose of 70 mg/kg to mice (the approximate effective 
dose), and the mean pharmacokinetic (PK) parameters are summarised in Table 5. 
Table 5: 
Pharmacokinetic Parameters of NST-6179 in the Mouse following a Single 
Dose of 70 mg/kg 
Sex 
Dose Level 
(mg/kg) 
Cmax 
(ng/mL) 
tmax 
(hours) 
AUC0-24 
(ng.h/mL) 
AUC0- 
(ng.h/mL) 
t½ 
(hours) 
Male 
70 
36,900 
0.500 
188,000 
227,000 
7.71 
Female 
70 
43,800 
0.500 
190,000 
NR 
11.2 
Abbreviations: AUC0- = area under the concentration-time curve from time zero to infinity; AUC0-24 = area under the 
plasma concentration-time curve from time zero to 24 hours postdose; Cmax = maximum observed plasma concentration; 
NR = not reported; t½ = apparent plasma terminal elimination half-life; tmax = time of the maximum observed plasma 
concentration. 


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This single dose PK study in the mouse at the approximate effective dose of 70 mg/kg 
indicated high plasma maximum concentrations and systemic exposure (as assessed by Cmax 
and AUC0-24). NST-6179 was absorbed with the median time of the maximum observed 
concentration (tmax) occurring at 0.5 hours postdose in both male and female animals. Mean 
values for apparent terminal elimination half-life (t½) were 7.71 hours and 11.2 hours for 
male and female animals, respectively. Sex ratios (male/female) for Cmax and AUC0-24 were 
0.842 and 0.989, respectively, indicating no notable difference in PK between male and 
female animals. Toxicokinetics in the 28-day rat and monkey studies indicated NST-6179 
maximum plasma concentrations and systemic exposure were notably higher than the mouse. 
1.6. 
Summary of Clinical Experience 
1.6.1. 
Phase 1 Single Ascending Dose and Multiple Ascending Dose Study in 
Healthy Subjects (Study NST-6179-01, ongoing) 
The study remains blinded to treatment assignment for individual subjects. However, clinical 
PK and safety are available from the completed cohorts and are presented here to support the 
continued dose escalation in this ongoing study. 
1.6.1.1. 
Clinical Pharmacokinetics 
The PK data of NST-6179 were evaluated for all completed dosing cohorts and reviewed as 
part of the dose escalation meetings for both the single and repeated dose cohorts. Single 
doses of 50 mg, 200 mg, 400 mg, 600 mg, and 1000 mg were tested under fasted conditions. 
Repeat dosing performed under fasting conditions at the 200 mg, 400 mg, and 1000 mg 
dosing levels QD for 14 days. Standard PK parameters, accumulation ratio and dose 
proportionality were evaluated as appropriate. The PK parameters are presented for the 
completed single and repeated dose cohorts in Table 6 and Table 7, respectively. 


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Table 6: 
Geometric Mean (%CV) PK Parameters of NST-6179 Following Single 
Oral Administration of NST-6179 Under Fasting Conditions (Part A) 
Parameter 
(Units) 
NST-6179 
50 mg 
200 mg 
400 mg 
600 mg 
1000 mg 
Cohort 
A1 
A2 
A3 
A4 
A5 
 
N=6 
N=6 
N=6 
N=6 
N=6 
AUC0-tlast 
(ng*h/mL)  
2490 (22.3) 
10400 (29.0) 
27200 (20.5) 
39900 (23.0) 
71400 (17.2) 
AUC0-
(ng*h/mL)  
2680 (16.4) 
10500 (28.6) 
27200 (20.5) 
40000 (23.0) 
71500 (17.2) 
AUC0-24 
(ng*h/mL)  
2680 (16.4) 
10500 (28.6 
27200 (20.5) 
40000 (23.0) 
71400 (17.2) 
Cmax (ng/mL)  
1100 (54.7) 
4880 (49.9) 
13200 (29.2) 
18300 (33.7) 
26900 (33.7) 
tmaxa (h)  
1.50 
(1.00–4.00) 
1.75 
(1.00-4.00) 
2.00 
(1.50-3.00) 
1.50 
(0.500-2.00) 
2.00 
(1.00-3.00) 
t½ (h)  
0.844 (8.6) 
1.05 (59.2) 
1.38 (40.4) 
1.71 (50.2) 
2.91 (76.2) 
a Median (min-max) presented.  
N = number of subjects. 
Table 7: 
Geometric Mean (%CV) PK Parameters of NST-6179 Following 
Repeated Oral Administration of NST-6179 Under Fasting Conditions 
(Part B) 
Parameter 
(Units) 
NST-6179 
200 mg QD 
400 mg QD 
1000 mg QD 
Cohort 
B1 
B2 
B3 
 
Day 1 
Day 14 
Day 1 
Day 14 
Day 1 
Day 14 
 
N=8 
N=8 
N=8 
N=8 
N=8 
N=8 
AUC0-Ĳ a 
(ng*h/mL)  
11300 
(41.5) 
12900 
(31.6) 
21900 
(36.6) 
24700 
(26.7) 
71100 
(16.0) 
85700 
(19.8) 
AUC0- 
(ng*h/mL)  
11300 
(41.4) 
NA 
21900 
(36.6) 
NA 
71100 
(16.0) 
NA 
Cmax (ng/mL)  
5690 (51.0) 6920 (28.0) 
10500 
(60.4) 
10000 
(34.9) 
29100 
(25.3) 
31800 
(39.9) 
tmaxb (h)  
1.25 
(1.00-3.00) 
1.25 
(1.00-2.00) 
2.00 
(1.00-3.00) 
1.50 
(1.00-3.00) 
2.00 
(1.00-4.00) 
2.00 
(1.00-2.00) 
t½ (h)  
1.04 
(37.2) 
1.01 
(16.6) 
1.19 
(31.5) 
1.64 
(113.0) 
2.33 
(56.5) 
3.22 
(20.0) 
Cmin (ng/mL)  
NA 
NC 
NC 
NC 
NA 
8.10 (28.9) 
RAAUC0-Ĳ 
NA 
1.14 (15.5) 
NA 
1.13 (18.7) 
NA 
1.21 (17.6) 
RACmax  
NA 
1.22 (32.3) 
NA 
0.953 
(46.7) 
NA 
1.09 (39.9) 
Note: Cmin values are NC because the minimum concentration in all profiles was 0, and geometric mean was not calculated. 
a Refers to a AUC0-24 for Day 1. 
b Median (min-max) presented. 
N = number of subjects; NA = not applicable; NC = not calculated; QD = once daily; RA = accumulation ratio. 
To date, none of the subjects receiving single or repeat administration of NST-6179 have 
exceeded the PK stopping criteria. Following single administration of 1000 mg NST-6179 
(Cohort A5), the highest individual systemic NST-6179 exposure represented 73.8% and 
25.2% of the stopping criteria for Cmax and AUC0-24, respectively. Following repeat 


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administration of 1000 mg NST-6179 QD for 14 days (Cohort B3), the highest individual 
systemic NST-6179 exposure represented 88.2% and 34.1% of the PK stopping criteria, 
based on Cmax and AUC0-24, respectively. 
Overall, PK across the dose range of 50 to 1000 mg was generally consistent, with median 
tmax between 1 to 2 hours postdose, estimates for t1/2 in the range of 1 to 3 hours, and no 
evidence of accumulation following QD administration. From 50 to 1000 mg, AUC and Cmax 
increased in a manner that was generally proportional (or slightly more than proportional) to 
the increase in dose; as dose increased by 20-fold, geometric mean Cmax and AUC0- 
increased by 24- to 26-fold, respectively. 
1.6.1.2. 
Clinical Safety 
A total of 70 subjects have been exposed to either NST-6179 or matched placebo in single 
doses up to 1000 mg and as multiple doses up to 1000 mg QD for 14 days. The study is 
ongoing and remains blinded, but analysis of the adverse events (AEs) has been performed as 
part of dose escalation reviews. A total of 89 AEs were reported in 31 subjects during the 
study period, the majority of which were mild (77 of the 89 AEs) and considered not related 
to NST-6179 treatment (54 of the 89 AEs). There were no severe or serious AEs reported 
during the study period. The most common AE (greater than 2 subjects) considered to be 
related to NST-6179 treatment was headache; 15 AEs reported by 7 subjects. There were no 
clinically significant changes or abnormalities in laboratory parameters, vital signs, ECG 
parameters, or physical examinations recorded at for any of the doses of NST-6179 
administered. In summary, NST-6179 appears to be safe and well tolerated at single doses up 
to 1000 mg and repeated doses of 1000 mg QD for up to 14 days. 
1.7. 
Study Rationale 
This is the first time NST-6179 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when NST-6179 is administered orally as single 
and multiple doses to healthy subjects. This information will help establish the doses and 
dosing regimen suitable for future studies in patients. 
1.8. 
Benefit-risk Assessment 
Subjects in the current study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study. The risks of participation are 
primarily those associated with adverse reactions to the study treatment, although there may 
also be some discomfort from collection of blood samples and other study procedures. 
The events observed in the toxicology studies to date are also considered in determining the 
overall benefit-risk of the Phase 1 study. All events occurred in these specific studies at 
systemic exposure exceeding the current established stopping rules. Based on the observed 
drug exposure, a significant safety margin exists for both the relevant species, as well as the 
mice in the carcinogenicity dose ranging study, at the proposed initial human dose of 50 mg. 
Therefore, the risk-benefit of conducting this first-in-human study remains unchanged and 
proposed stopping rules remain supported by data from the mouse, rat, and monkey. 


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More information about the known and expected benefits, risks, and reasonably anticipated 
AEs associated with NST-6179 may be found in the Investigator’s Brochure (IB).1 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objectives of the study are: 
x to assess the safety and tolerability of single and multiple oral doses of NST-6179 in 
healthy male and female subjects 
The secondary objective of the study is: 
x to evaluate the single and multiple oral dose PK of NST-6179 in healthy male and 
female subjects 
The exploratory objectives of the study are: 
x to collect data to assess the relationship between NST-6179 concentrations and QT 
interval corrected for heart rate (QTc) in healthy male and female subjects 
x to evaluate the metabolite profile of NST-6179 in healthy male and female subjects. 
x to evaluate the effect of pharmacogenomics (PGx) on the PK of NST-6179 in healthy 
male and female subjects. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
x incidence and severity of AEs 
x incidence of laboratory abnormalities, based on haematology, clinical chemistry, 
coagulation, and urinalysis test results 
x 12-lead ECG parameters 
x vital signs measurements 
x physical examinations. 
2.2.2. 
Secondary Endpoints 
The PK outcome endpoints of NST-6179 for Part A (single-ascending dose in healthy 
subjects) are as follows: 
x area under the concentration-time curve (AUC) from time zero to infinity (AUC0-) 
x area under the concentration-time curve from time zero to infinity normalised by dose 
(AUC0-/dose) 


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x area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (AUC0-tlast) 
x area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration normalised by dose (AUC0-tlast/dose) 
x Cmax 
x Cmax normalised by dose (Cmax/dose) 
x tmax 
x t½ 
x apparent total clearance (CL/F) 
x apparent volume of distribution (Vz/F) 
x amount of drug excreted (Ae) 
x percentage of dose excreted (fe) 
x renal clearance (CLR). 
The PK outcome endpoints of NST-6179 for Part B (multiple-ascending dose in healthy 
subjects) are as follows: 
x area under the concentration-time curve over a dosing interval (AUC0-Ĳ) 
x AUC from time zero to 24 hours postdose (AUC0-24, GHULYHGDV$8&ĲIRUD%,'
dosing regimen at steady state) 
x area under the concentration-time curve over a dosing interval normalised by dose 
(AUC0-Ĳ/dose) 
x AUC0- (Day 1 only) 
x AUC0-/dose (Day 1 only) 
x Cmax 
x Cmax/dose 
x tmax 
x t½ 
x CL/F 
x Vz/F 
x minimum observed concentration (Cmin) 
x observed accumulation ratio based on AUC0-Ĳ (RAAUC0-Ĳ) 
x observed accumulation ratio based on Cmax (RACmax). 
Other PK parameters may also be added. 


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2.2.3. 
Exploratory Endpoints 
Continuous 12-lead ECG data will be collected for the future assessment of the NST-6179 
concentration-QTc response relationship following single oral doses of NST-6179. 
For the highest planned QD dose group in Part B, additional samples will be taken for the 
identification of metabolites of NST-6179. 
Optional PGx samples will be collected from subjects that consent, for the determination of 
common gene variants (ie, cytochrome P450 2C9), that may have an effect on the PK of 
NST-6179. 
3. INVESTIGATIONAL PLAN 
This will be a partly double-blind, randomised, placebo-controlled, single and multiple oral 
dose study conducted in 2 parts. Part A and Part B will be double-blind, randomised, 
placebo-controlled, with subjects receiving single (Part A) and multiple (Part B) oral doses. 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Part A 
Part A will comprise a double-blind, single-ascending dose, sequential-group design. Overall, 
48 subjects will be studied in 6 groups (Groups A1 to A6), with each group consisting of 
8 subjects. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only. 
Subjects will reside at the study site from Day -1 (the day before dosing) to Day 4 of each 
treatment period, as applicable. 
All subjects will return for a follow-up visit 10 to 14 days after their final dose. 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 per period and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups A1 to A6, 6 subjects will receive NST-6179 and 2 subjects will receive 
placebo. 
Groups A1 to A6 
It is planned for each subject in Groups A1 to A6 to receive only a single dose of NST-6179 
or placebo during the study. Doses will be administered in the fasted state in accordance with 
a randomisation schedule on the morning of Day 1. 
Additional Groups (Groups A7 to A9) 
If it is decided to enrol additional groups (Section 3.3) fasting requirements, meal 
compositions, and timing of doses will be determined following review of the available PK 
data. 


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Sentinel Dosing 
All groups in Part A will be divided into 2 sub-groups, with each sub-group being dosed 
24 hours apart. The first sub-group will comprise 2 subjects, with 1 subject receiving 
NST-6179 and 1 subject receiving placebo. The second sub-group will comprise 6 subjects, 
with 5 subjects receiving NST-6179 and 1 subject receiving placebo. 
There will be a minimum of 7 days between dose escalations for each group in Part A. 
An overview of the study design is shown in Figure 1 and the planned dose levels are 
presented in Figure 2. A Schedule of Assessments is presented in Appendix 6. 
Figure 1: 
Study Schematic (Part A) for Groups A1 to A6 
 
Abbreviations: CRU = Clinical Research Unit; N = number of subjects. 
 
-28
Screening
Resident in 
the CRU
Follow-up
10 to 14 days 
postdose
-2
-1
1
2
3
4
NST-6179 (N = 6)
or placebo (N = 2)
in the fasted state


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Figure 2: 
Planned Dose Levels for Part A 
 
 
Abbreviations: N = number of subjects; PK = pharmacokinetic(s); TBD = to be determined. 
NOTE: dose levels may be adjusted based on the ongoing review of the safety, tolerability, and PK data. Doses will be administered in an escalating manner following satisfactory 
review by the sponsor and investigator of the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose) from the previous dose 
group. 


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The total planned duration of study participation for each subject (from screening through 
follow-up visit) is anticipated to be approximately 6 weeks. 
3.1.2. 
Part B 
Part B will comprise a double-blind, multiple-ascending dose, sequential-group study design. 
Overall, 40 subjects will be studied in 4 groups (Groups B1 to B4), with each group 
consisting of 10 subjects. Part B may start in parallel with Part A provided the exposure is not 
predicted to exceed an exposure shown to be safe and well tolerated in Part A. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the study site from Day -1 until the morning of Day 16. 
All subjects will return for a follow-up visit 10 to 14 days after their final dose. 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 per period and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups B1 to B4, 8 subjects will receive NST-6179 and 2 subjects will receive 
placebo. For all subjects, dosing is planned to be QD on Days 1 to 14, inclusive. However, 
dosing frequency and duration in Part B may be changed following review of data from 
groups in Part A or earlier groups in Part B (Section 3.4). The dose regimen will comprise no 
less than once every 2 days and will not exceed 4-times-daily dosing. The dosing duration 
will comprise no fewer than 7 consecutive days and will not exceed 28 consecutive days of 
dosing (Section 3.4). There will be a minimum of 14 days between dose escalations for each 
group in Part B. The dose selected on each dosing occasion in Part B will not exceed a single 
dose shown to be safe and well tolerated in Part A. Sentinel dosing will be implemented for 
any groups in Part B for which the total daily dose exceeds the highest single dose evaluated 
in Part A (eg, 1000 mg BID for which the total daily dose of 2000 mg has not been 
administered as a single dose in Part A), whereby an initial cohort of 2 subjects (1 active and 
1 placebo) will be dosed on 1 day and, providing no safety concerns arise, the remaining 
cohort of 8 subjects (7 active and 1 placebo) will be dosed after at least 72 hours.; 
Section 3.4).  
Up to 3 further groups of 10 subjects (8 active:2 placebo) may be included in Part B 
(Section 3.3). 
An overview of the study design is shown in Figure 3, and the planned dose levels are 
presented in Figure 4. A Schedule of Assessments is presented in Appendix 6. 


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Figure 3: 
Study Schematic for Part B 
 
Abbreviations: CRU = Clinical Research Unit; N = number of subjects; PK = pharmacokinetic(s); QD = once daily. 
NOTE: doses will be administered in an escalating manner following satisfactory review by the sponsor and investigator of 
the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose) from the 
previous dose group. 
a. Dosing is planned to be QD on Days 1 to 14, inclusive. However, dosing frequency and duration in Part B may be 
changed following review of data from groups in Part A or earlier groups in Part B. The dose regimen will comprise no 
less than once every 2 days and will not exceed 4-times-daily dosing. The dosing duration will comprise no fewer than 
7 consecutive days and will not exceed 28 consecutive days of dosing. 
Figure 4: 
Planned Dose Levels for Part B 
 
Abbreviations: N = number of subjects; PK = pharmacokinetic(s); QD = once daily. 
NOTE: doses will be administered in an escalating manner following satisfactory review by the sponsor and investigator of 
the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose) from the 
previous dose group. 
a. Dosing is planned to be QD on Days 1 to 14, inclusive. However, dosing frequency and duration in Part B may be 
changed following review of data from groups in Part A or earlier groups in Part B. The dose regimen will comprise no 
less than once every 2 days and will not exceed 4-times-daily dosing. The dosing duration will comprise no fewer than 
7 consecutive days and will not exceed 28 consecutive days of dosing. 
The total planned duration of study participation for each subject (from screening through 
follow-up visit) is anticipated to be approximately 8 weeks. 
A Schedule of Assessments is presented in Appendix 6. 
3.2. 
Study Start and End of Study Definitions 
The start of the study is defined as the date the first subject signs an informed consent form 
(ICF). The point of enrolment occurs at the time of subject number allocation. The end of the 
study is defined as the date of the last subject’s last assessment (scheduled or unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, and PK data, additional dose groups (where 
systemic exposure is not expected to exceed that stated in the dose escalation stopping criteria 
[Section 3.7] for Part A or for Part B where the dose of NST 6179 will not exceed a single 
-28
Screening
Resident in the 
CRU
Follow-up
10 to 14 days postdose
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
NST-6179 (N = 8) or
placebo (N =2) QDa


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dose shown to be safe and well tolerated in Part A) may be added to the study. Up to 3 further 
groups of 8 subjects (6 active:2 placebo) may be included in Part A, and up to 3 further 
groups of 10 subjects (8 active:2 placebo) may be included in Part B. There will be no further 
dose escalation in these additional groups if dose escalation stopping criteria have been met 
and a dose level cannot be repeated if it previously met a stopping criterion. The requirement 
for additional groups will be agreed with the sponsor and documented in the trial master file 
(TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For Part A and Part B of the study, a sequential-group, ascending-dose design has been 
chosen for safety reasons as NST-6179 is in the early stages of clinical development, with 
Part A of the study being the first time it will be administered to humans. Oral doses have 
been chosen for both parts of the study, as this is the intended clinical route of administration.  
For safety reasons, sentinel dosing will be used in Part A, such that 2 subjects (1 NST-6179 
and 1 placebo) will be dosed 24 hours before the remaining 6 subjects. Sentinel dosing is not 
considered necessary in Part B when the total daily exposure is not be predicted to exceed an 
exposure previously shown to be safe and well tolerated in Part A. Sentinel dosing will be 
implemented for any groups in Part B for which the total daily dose (based on multiple doses 
per day) exceeds the highest single dose evaluated in Part A (eg, 1000 mg BID for which the 
total daily dose of 2000 mg has not been administered as a single dose in Part A). 
It is the intent of Part B to dose subjects such that steady-state plasma levels of NST-6179 are 
achieved and maintained for several days. Based on the available non-clinical data, it is 
expected that this will be achieved following 14 days of QD dosing; however, a full review of 
all the safety, tolerability, and PK data from Part A will be performed to confirm the dose 
regimen for Part B. If the t½ of NST-6179 is shorter than predicted by the non-clinical data, 
up to 4-times-daily dosing over 7 days may be appropriate. If the t½ of NST-6179 is longer 
than predicted by the non-clinical data, QD dosing may be more appropriate over 28 days (as 
steady state will take longer to achieve). The dose regimen will comprise no less than once 
every 2 days and will not exceed 4-times-daily dosing. The dosing duration will comprise no 
fewer than 7 consecutive days and will not exceed 28 consecutive days of dosing. 
Details of the dosing regimen and duration used for Part B of the study will be documented in 
the TMF. 
Based upon the non-clinical data, the duration of each treatment period is considered 
adequate to achieve the study objectives. 
Part A and Part B will be double-blind and placebo-controlled in order to avoid bias in the 
collection and evaluation of data during its conduct. Placebo has been chosen as the control 
treatment to assess whether any observed effects are treatment-related or simply reflect the 
study conditions. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 


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Continuous 12-lead ECG monitoring will be included in this study in order to explore 
potential NST-6179 effects on the QT interval, with a view of supporting a potential thorough 
QT study waiver. 
3.4.1. 
Dose Interval Between Subjects 
Following thorough review of all available non-clinical data (pharmacological and 
toxicological), dosing at each dose level in Part A will be such that 2 subjects (1 NST-6179 
and 1 placebo) will be dosed 24 hours before the remaining 6 subjects. After dosing the first 
2 subjects on a separate day, a minimum of a 5-minute dosing interval for the remaining 
6 subjects in each dose-ascending group is considered acceptable. Continuation to dose the 
remaining 6 subjects will be at the investigator’s discretion. 
In Part B, a minimum of a 5-minute dosing interval between subjects in each group is 
considered acceptable. 
In Part B, for any groups for which the total daily dose exceeds the highest single dose evaluated 
in Part A (eg, 1000 mg BID for which the total daily dose of 2000 mg has not been administered 
as a single dose in Part A), dosing will be such that a cohort of 2 subjects (1 NST-6179 and 
1 placebo) will be dosed at least 72 hours before the remaining 8 subjects. 
3.5. 
Selection of Doses in the Study 
In the 28-day repeat dose toxicology studies, NOAELs in the rat and cynomolgus monkey 
were 450 mg/kg and 350 mg/kg, respectively. These correspond to human equivalent doses 
(HEDs) of: 
Rat: 
450 mg/kg × 0.16 = 72 mg/kg 
(equivalent to approximately 4320 mg in a 60-kg subject) 
Monkey: 
350 mg/kg × 0.32 = 112 mg/kg 
(equivalent to approximately 6720 mg in a 60-kg subject) 
Where 0.16 and 0.32 are conversion factors to extrapolate the animal dose to the HED based 
on body surface area.2 
The rat was the most sensitive species (ie, that with the lowest HED), and assuming a 10-fold 
safety margin, this equates to a maximum recommended starting dose (MRSD) of: 
72 mg/kg
10
 = 7.2 mg/kg 
or 
 
 
 
7.2 mg/kg × 60 kg = 432 mg in a 60-kg subject 
Compared to the HED for the NOAEL in the rat, the most sensitive species (ie, that with the 
lowest HED), a starting dose of 50 mg in Part A will correspond to a dose of: 
50 mg
60 kg  = 0.83 mg/kg in a 60-kg subject 


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and a safety margin of: 
72 mg/kg
0.83 mg/kg  = 87-fold 
The approximate effective dose of NST-6179 in an efficacy model in the mouse was 
70 mg/kg (Section 1.5.3), which corresponds to a HED of: 
Mouse: 
70 mg/kg × 0.08 = 5.6 mg/kg 
(equivalent to approximately 336 mg in a 60-kg subject) 
Where 0.08 is the conversion factor to extrapolate the animal dose to the HED based on body 
surface area.2 Compared to the HED for the approximate effective dose in the mouse (ie, dose 
shown to have pharmacological activity in the mouse model), a starting dose of 50 mg in 
Part A will be approximately 7-fold lower than a dose expected to have pharmacological 
activity: 
5.6 mg/kg
0.83 mg/kg  = 6.7-fold 
Evaluation of protein binding indicates the unbound drug fraction is 4% in mouse compared 
to 1.78% in human. The proposed starting dose based on unbound drug is therefore 
approximately 15 times lower than the effective dose. Although there is no empirical data 
that defines a pharmacologically inactive dose in the mouse it is considered unlikely that a 
human starting dose of 50 mg would elicit significant pharmacological activity, if any. 
Furthermore metabolism in vitro is notably lower in mouse compared to human. Exposure to 
parent drug in human is likely to be proportionately less than mouse based on equivalent 
doses. 
The proposed investigational medicinal product (IMP) dose levels are shown in Table 8. 
However, based on the ongoing review of the available safety, tolerability, and PK data, as 
applicable, doses may be adjusted. 


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Table 8: 
Investigational Medicinal Product Dose Levels for Parts A and B 
Study Part 
Group 
Subject Numbers 
Treatment Period 1 
Part A 
A1 
0101 – 0108 
50 mg or placebo 
A2 
0109 – 0116 
200 mg or placebo 
A3 
0117 – 0124 
400 mg or placebo 
A4 
0125 – 0132 
600 mg or placebo 
A5 
0133 – 0140 
1000 mg or placebo 
A6 
0141 – 0148 
TBD mg or placebo 
A7a 
0149 – 0156 
TBD 
A8a 
0157 – 0164 
TBD 
A9a 
0165 – 0172 
TBD 
Part B 
B1 
0201 – 0210 
200 mg or placebo QD 
B2 
0211 – 0220 
400 mg or placebo QD 
B3 
0221 – 0230 
1000 mg or placebo QD 
B4 
0231 – 0240 
TBD mg or placebo BID 
B5b 
0241 – 0250 
TBD 
B6b 
0251 – 0260 
TBD 
B7b 
0261 – 0270 
TBD 
Abbreviations: BID = twice daily; NA = not applicable; PK = pharmacokinetic(s); QD = once daily; TBD =to be determined. 
a. Following review of the safety, tolerability, and PK data, additional dose groups (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]) may be added to the study. Up to 
3 further groups of 8 subjects (6 active:2 placebo) may be included in Part A. 
b. Following review of the safety, tolerability, and PK data, additional dose groups (where the dose of NST 6179 will not 
exceed a single dose shown to be safe and well tolerated in Part A) may be added to the study. Up to 3 further groups of 
10 subjects (8 active:2 placebo) may be included in Part B. 
For Part B of the study, dose levels, dosing frequency, and dosing duration will be decided, in 
consultation with the sponsor, on the basis of data from Part A of the study or earlier groups 
in Part B. The dose of NST-6179 per dosing occasion in Part B will not exceed a single dose 
shown to be safe and well tolerated in Part A. 
Dose levels should not increase by more than 5-fold for predicted non-pharmacologically 
active dose levels and by 3-fold for doses above 300 mg (ie, the predicted pharmacologically 
active dose level). 
Dose levels may be increased, providing systemic exposure does not exceed that stated in the 
dose escalation stopping criteria (Section 3.7). 
Details of all doses administered in Part A and Part B of the study will be documented in the 
TMF. 
3.6. 
Dose Escalation 
Doses will be administered in an escalating manner following satisfactory review by the 
sponsor and investigator of the safety and tolerability data (up to 48 hours post-final dose) 
and plasma PK data (up to 24 hours post-final dose) from the previous dose group. Doses 
may be reduced and may be lower than the starting dose. There will be a minimum of 7 days 
between dose escalations in Part A and a minimum of 14 days between dose escalations in 
Part B to allow sufficient time for an adequate safety review for each respective part. 


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Dose escalation in both Part A and Part B will only occur if data from a minimum of 
6 subjects have been reviewed from the previous dose group, such that data from a minimum 
of 4 subjects who have received NST-6179 will be used to make the dose escalation decision. 
The justification for this is as follows: 
x The study treatment is of a known pharmacological class for which the on-target 
effects in humans are well characterised. Based upon non-clinical data, no clinically 
important off-target effects are expected within the proposed dose range. 
x A minimum of 4 subjects receiving the active drug is considered sufficient to 
characterise the safety profile and PK response to NST-6179. 
Between each dose escalation, the investigator will review all available data in a blinded 
manner to ensure it is safe to proceed with the planned dose escalation. An interim safety 
report, summarising results from all available safety assessments, will be sent to the sponsor 
prior to the start of each successive group/treatment period. Any clinically significant results 
will be discussed with the sponsor before dose escalation continues. Interim PK data will also 
be reviewed in terms of dose escalation and to confirm that the study design remains 
appropriate. In the event of a disagreement between the sponsor and investigator on the dose 
escalation decision, the decision of the investigator will be upheld. 
3.7. 
Dose Escalation Stopping Criteria 
The study will be halted if 1 or more subject experience a serious adverse event (SAE) that is 
considered to be related to IMP or 2 or more subjects in the same group experience severe 
AEs that are considered to be related to IMP. If, following an internal safety review, the 
sponsor deems it appropriate to restart the study, this can be done following approval of a 
substantial protocol amendment. Dosing of subjects, including any ongoing multiple-dose 
groups, will be stopped immediately if any of the dose escalation stopping criteria are met. 
In Part A and Part B, following consultation with the sponsor, dose escalation will stop if: 
x Clinically relevant signs or symptoms of similar nature occur in 2 or more subjects in 
a group that, in the opinion of the investigator, warrant stopping of dose escalation. 
x There is evidence of clinically significant increases in liver function tests defined as 
3 times the upper limit of normal (ULN) for aspartate aminotransferase (AST), ALT, 
ALP, or gamma-glutamyl transferase (GGT) or 2 times the ULN for total bilirubin in 
2 or more subjects in a group (confirmed with repeat testing). 
x Moderate nausea or vomiting that prevents subjects from eating a meal on 3 or more 
occasions on 2 consecutive days in 2 or more subjects in a group. 
x The systemic exposure for any individual subject is predicted to exceed an AUC0-24 of 
358,000 ng.hr/mL (based on the female cynomolgus monkey at the intermediate dose 
level of 175 mg/kg/day at Day 28) in the 28-day oral toxicity study and/or a Cmax of 
59,100 ng/mL (based on the female cynomolgus monkey kinetics at the NOAEL 
[350mg/kg/day at Day 28]). 


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4. SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
4.1.1. 
Part A and Part B 
Subjects must satisfy all of the following criteria at the screening visit unless otherwise 
stated: 
1. Males or females, of any race, between 18 and 65 years of age, inclusive. 
2. Body mass index between 18.0 and 32.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical 
history, physical examination, 12-lead ECG, vital signs measurements, and 
clinical laboratory evaluations (congenital non-haemolytic hyperbilirubinemia [eg, 
suspicion of Gilbert’s syndrome based on total and direct bilirubin] is not 
acceptable) at screening and/or check-in as assessed by the investigator (or 
designee). 
4. Females will not be pregnant or lactating, and females of childbearing potential 
and males will agree to use contraception as detailed in Appendix 4. 
5. Able to comprehend and willing to sign an ICF and to abide by the study 
restrictions. 
4.2. 
Exclusion Criteria 
4.2.1. 
Part A and Part B 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
screening visit unless otherwise stated: 
Medical Conditions 
1. Significant history or clinical manifestation of any metabolic, allergic, 
dermatological, hepatic, renal, haematological, pulmonary, cardiovascular, 
gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as 
determined by the investigator (or designee). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug 
compound, food, or other substance, unless approved by the investigator (or 
designee). 
3. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs (uncomplicated 
appendectomy and hernia repair will be allowed). 
4. Any of the following: 
a. QT interval corrected for heart rate using Fridericia’s method (QTcF) 
> 450 ms confirmed by repeat measurement. 
b. QRS duration > 110 ms confirmed by repeat measurement. 


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c. PR interval > 220 ms confirmed by repeat measurement. 
d. findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
e. history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalaemia, family history of long QT syndrome). 
5. Confirmed (eg, 2 consecutive measurements) systolic blood pressure 
> 140 mmHg or < 80 mmHg, diastolic blood pressure > 90 mmHg or < 45 mmHg, 
and pulse rate > 100 beats per minute (bpm) or < 40 bpm. 
6. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
Prior/Concomitant Therapy 
7. Administration of a Coronavirus Disease 2019 (COVID-19) vaccine in the past 
28 days prior to dosing. 
8. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days 
prior to dosing, unless deemed acceptable by the investigator (or designee). 
9. Use or intend to use any prescription medications/products other than hormone 
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptives within 14 days prior to dosing, unless deemed acceptable by the 
investigator (or designee). 
10. Use or intend to use slow-release medications/products considered to still be 
active within 14 days prior to check-in, unless deemed acceptable by the 
investigator (or designee). 
11. Use or intend to use any non-prescription medications/products including 
vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 
7 days prior to check-in, unless deemed acceptable by the investigator (or 
designee). 
Prior/Concurrent Clinical Study Experience 
12. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days prior to dosing. 
13. Have previously completed or withdrawn from this study. 
Diet and Lifestyle 
14. Alcohol consumption of > 14 units per week. One unit of alcohol equals ½ pint 
(285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits. 
15. Positive alcohol breath test result or positive urine drug screen (confirmed by 
repeat) at screening or check-in. 
16. History of alcoholism or drug/chemical abuse within 2 years prior to check-in. 
17. Use of tobacco- or nicotine-containing products within 3 months prior to check-in, 
or positive cotinine at screening or check-in. 


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18. Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or 
beverages within 7 days prior to check-in. 
Other Exclusions 
19. Receipt of blood products within 2 months prior to check-in. 
20. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to 
screening, or platelets from 6 weeks prior to screening. 
21. Poor peripheral venous access. 
22. Subjects who, in the opinion of the investigator (or designee), should not 
participate in this study. 
23. Mental incapacity or language barriers which preclude adequate understanding or 
cooperation, or unwillingness to comply with trial requirements. 
24. An employee of the sponsor or investigator or otherwise dependent on them. 
4.3. 
Generic Screening 
Subjects may previously have been screened on a generic basis to determine their eligibility 
for inclusion in Phase 1 clinical studies conducted at the study site. If generic screening was 
performed within the specified study screening window, selected study-specific procedures 
will be repeated either at an additional screening visit or on admission to the study site on 
Day -1. 
4.4. 
Subject Number and Identification 
Subjects will have a unique identification number used at screening. Subjects will be assigned 
a subject number at the time of their randomisation. Assignment of subject numbers will be in 
ascending order and no numbers will be omitted (eg, in Part A, Subjects 0101, 0102, etc; in 
Part B, Subjects 0201, 0202, etc). Replacement subjects (Section 4.5) will be assigned a 
subject number corresponding to the number of the subject he/she is replacing plus 1000 (eg, 
Subject 1101 replaces Subject 0101). 
Subjects will be identified by screening identification number or subject number only on all 
study documentation. A list identifying the subjects by subject number will be kept in the Site 
Master File. This list will only contain subject number, sex, age, year of birth, and Trial One 
ID of subjects (ie, Screening Number). No identifiable confidential information can be filed. 
4.5. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
x change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects subject safety as determined by the investigator (or designee) 
x non-compliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the investigator (or designee) 


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x any clinically relevant sign or symptom that, in the opinion of the investigator (or 
designee), warrants subject withdrawal. 
If a subject is withdrawn from dosing, the sponsor will be notified and the date and reason(s) 
for the withdrawal will be documented in the subject’s electronic case report form (eCRF). If 
a subject is withdrawn from the study, efforts will be made to perform all follow-up 
assessments, if possible (Appendix 6). Other procedures may be performed at the 
investigator’s (or designee’s) and/or sponsor’s discretion. If the subject is in-house, these 
procedures should be performed before the subject is discharged from the clinic. The 
investigator (or designee) may also request that the subject return for an additional follow-up 
visit. All withdrawn subjects will be followed until resolution of all their AEs or until the 
unresolved AEs are judged by the investigator (or designee) to have stabilised. 
Subjects who are withdrawn for reasons not related to study treatment may be replaced 
following discussion between the investigator and the sponsor. Subjects withdrawn as a result 
of AEs thought to be related to the study treatment will generally not be replaced. 
4.6. 
Study Termination 
The study may be discontinued at the discretion of the investigator (or designee), sponsor, or 
sponsor’s medical monitor if any of the following criteria are met: 
x AEs unknown to date (ie, not previously reported in any similar investigational study 
drug trial with respect to their nature, severity, and/or duration) 
x increased frequency, severity, and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at check-in as baseline signs and 
symptoms) 
x medical or ethical reasons affecting the continued performance of the study 
x difficulties in the recruitment of subjects 
x cancellation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labelling 
The IMPs (10 mg and 100 mg NST-6179 capsule and placebo) will be supplied by the 
sponsor (or designee), along with the batch/lot numbers and certificates of analysis. A 
certificate of release authorised by a Qualified Person from a listed country or United 
Kingdom will also be issued for the IMP. 
All IMPs will be stored at the study site at ambient temperature (< 30°C) in a location that is 
locked with restricted access. 
NST-6179 will be supplied as a solid in hard gelatine capsules, 10 mg or 100 mg. Placebo 
will be supplied in matching hard gelatine capsules. The 10-mg formulation contains 
NST-6179 drug substance formulated in microcrystalline cellulose and magnesium stearate. 


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The 100-mg formulation contains NST-6179 only. The placebo contains microcrystalline 
cellulose and magnesium stearate. 
The bulk drug container and unit dose containers will be labelled in accordance with national 
laws and regulations. The IMPs will be transferred from bulk supplies into the subject’s dose 
container by qualified clinical staff. 
5.2. 
Study Treatment Administration 
Full details on dietary restrictions for dose administration are described in Section 6.2. 
Each dose of NST-6179 and placebo will be administered orally with approximately 240 mL 
of room temperature water. In Part A and on the days with intensive PK assessments in 
Part B, all doses will be administered after an overnight fast of at least 10 hours. With the 
exception of water given with the dose, subjects will not be allowed fluids from 1 hour prior 
to until 2 hours after dosing. 
For any groups in Part B where a BID dosing regimen will be implemented doses will be 
administered in the morning (AM) and evening (PM) separated by 12 ± 0.5 hours (except on 
Day 14, when only the AM dose will be administered). Dose administration will occur in the 
fasted state; subjects will fast for at least 10 hours prior to and for 4.5 hours after the morning 
(AM) dose on Day 1 and the final day of dosing.  For the Day 1 PM dose and all other dosing 
occasions subjects will fast for at least 2 hours prior to dosing and 2 hours after dosing.  
Subjects will be administered the IMP in numerical order while standing and will not be 
permitted to lie supine for 2 hours after dosing, except as necessitated by the occurrence of an 
AE(s) and/or study procedures. 
5.3. 
Randomisation 
The randomisation code will be produced by the statistics department at Labcorp Drug 
Development using a computer-generated pseudo-random permutation procedure. 
In Part A, 6 subjects per group will be randomly assigned to receive NST-6179 and 2 subjects 
per group will be randomly assigned to receive placebo. For all groups in Part A, sentinel 
dosing will occur whereby 2 subjects (1 active and 1 placebo) will be dosed on 1 day and, 
providing no safety concerns arise, the remaining 6 subjects (5 active and 1 placebo) will be 
dosed after 24 hours. 
In Part B, 8 subjects per group will be randomly assigned to receive NST-6179 and 2 subjects 
per group will be randomly assigned to receive placebo. If sentinel dosing will be 
implemented for any groups in Part B, 2 subjects (1 active and 1 placebo) will be randomised 
and dosed on Day 1, providing no safety concerns arise, the remaining cohort of 8 subjects 
(7 active and 1 placebo) will be dosed after at least 72 hours. 
Prior to the start of the study, a copy of the master randomisation code will be supplied to the 
study site pharmacy staff (in sealed envelopes) and the biopharmaceutical analyst(s) at the 
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5.4. 
Blinding 
Both Part A and Part B of the study will be conducted in a double-blind manner. Treatments 
will be administered in a double-blind manner, and subjects will remain blinded with regard 
to treatment throughout the study. 
The following controls will be employed to maintain the double-blind status of the study: 
x The placebo capsules will be identical in appearance to NST-6179. 
x The investigator and other members of staff involved with the study will remain 
blinded to the treatment randomisation code during the assembly procedure. 
x The investigator and other members of staff (with the exception of pharmacy staff) 
involved with the study will remain blinded to the treatment randomisation code 
during the conduct of the study. 
x Interim bioanalytical data will be provided to Labcorp CRU in a blinded manner. 
To maintain the blind, the investigator will be provided with a sealed randomisation code for 
each subject, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject 
safety or to support dose escalation decisions (in the event of treatment-related SAEs or 
severe AEs), the decision to unblind resides solely with the investigator. Whenever possible, 
and providing it does not interfere with or delay any decision in the best interest of the 
subject, the investigator will discuss the intended code-break with the sponsor. If it becomes 
necessary to break the code during the study, the date, time, and reason will be recorded in 
the subject’s source data and on the individual envelope and will be witnessed by a second 
person. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
x All doses will be administered under the supervision of suitably qualified study site 
staff. 
x Immediately after dose administration, visual inspection of the mouth and hands will 
be performed for each subject. 
x A predose and postdose inventory of IMP will be performed on the dose containers. 
5.6. 
Drug Accountability 
The investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the sponsor upon request. 


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For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the sponsor or disposed 
of by the study site, per the sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription or non-prescription medications/products 
during the study until the follow-up visit, unless the investigator (or designee) and/or sponsor 
have given their prior consent. 
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the investigator (or 
designee), unless its use is deemed necessary for treatment of an AE. Any medication taken 
by a subject during the course of the study and the reason for its use will be documented in 
the source data. 
A risk assessment has been performed and subjects will be permitted to receive a COVID-19 
vaccine after dosing, if required. The administration of a COVID-19 vaccine will be recorded 
as a concomitant medication. 
6.2. 
Diet 
While confined at the study site, subjects will receive a standardised diet (as per study site 
procedures) at scheduled times that do not conflict with other study-related activities. 
Subjects will be fasted (at least 8 hours) before collection of blood samples for clinical 
laboratory evaluations. 
On the days with intensive PK assessments, meals will be identical for each group. 
On Day 1 in Part A, subjects will be fasted for at least 10 hours prior to dosing until 
approximately 4 hours after dosing, when lunch will be provided (lunch times on Day 1 will 
be staggered between subjects to ensure this). With the exception of water given with the 
dose, subjects will not be allowed fluids from 1 hour prior to until 2 hours after dosing. Meals 
will be provided as appropriate at other times. Other than the fluid restrictions on dosing 
days, water will be freely available at all times. 
In Part B, on days with intensive PK assessments (eg, Days 1 and 14), subjects will be fasted 
for at least 10 hours prior to morning (AM) dosing until approximately 4.5 hours after 
morning (AM) dosing. On days without intensive PK assessments and for the Day 1 PM 
dose, subjects will also fast for at least 2 hours prior to dosing and 2 hours after dosing. Meals 
will be provided as appropriate at other times. With the exception of water given with the 


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dose, subjects will not be allowed fluids from 1 hour prior to dosing until 2 hours after 
dosing. Other than these fluid restrictions, water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to check-in until the follow-up visit. 
Caffeine-containing foods and beverages will not be allowed from 36 hours before check-in 
until discharge. 
Consumption of alcohol will not be permitted from 36 hours prior to check-in until discharge. 
Up to 2 units/day of alcohol are permitted from discharge until 36 hours before the follow-up 
visit or 36 hours before check-in in each treatment period. 
6.3. 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine-containing products within 
3 months prior to check-in until the follow-up visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before check-in until the 
follow-up visit and will otherwise maintain their normal level of physical activity during this 
time (ie, will not begin a new exercise program nor participate in any unusually strenuous 
physical exertion). 
6.5. 
Blood Donation 
Subjects are required to refrain from donation of blood from 3 months prior to screening, 
plasma from 2 weeks prior to screening, and platelets from 6 weeks prior to screening until 
3 months after the follow-up visit. 
7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and the other procedures to be performed at the same timepoint. 
The highest priority procedures will be performed closest to the nominal time. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
x dosing 
x blood samples (for NST-6179 assay) 
x ECG extractions 
x urine samples (for NST-6179 assay) 
x vital signs 
x any other procedures. 


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7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing for Pharmacokinetic Assessment 
Blood samples (approximately 1 × 2.0 mL) will be collected by venipuncture or cannulation 
at the times indicated in the Schedule of Assessments in Appendix 6. Furthermore, up to 
3 additional blood samples may be taken from each subject per treatment period/PK sampling 
day, with the maximum volume of blood withdrawn per subject not exceeding the limit 
detailed in Appendix 3. Any changes to the scheduled times of PK assessments will be agreed 
with the sponsor and documented in the TMF. Samples taken from subjects who received 
placebo will not be analysed. 
Procedures for collection, processing, and shipping of PK blood samples will be detailed in a 
separate document. 
Urine samples will be collected over the time intervals indicated in the Schedule of 
Assessments in Appendix 6. Procedures for collection, processing, and shipping of urine 
samples will be detailed in a separate document. 
7.1.2. 
Sample Collection and Processing for Metabolite Identification 
For subjects in the highest QD dose group in Part B, blood samples (approximately 
1 × 2.0 mL) for metabolite identification will be collected by venipuncture or cannulation at 
the times indicated in the Schedule of Assessments in Appendix 6. Samples taken from 
subjects who received placebo will not be analysed. Furthermore, up to 3 additional blood 
samples may be taken from each subject per treatment period/PK sampling day, with the 
maximum volume of blood withdrawn per subject not exceeding the limit detailed in 
Appendix 3. 
Procedures for collection, processing, and shipping of blood samples for metabolite 
identification will be detailed in a separate document. 
Urine samples will be collected over the time intervals indicated in the Schedule of 
Assessments in Appendix 6. Procedures for collection, processing, and shipping of urine 
samples will be detailed in a separate document. 
7.1.3. 
Analytical Methodology 
Plasma and urine concentrations of NST-6179 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate documents. 
For the highest QD dose group in Part B, an exploratory analysis of NST-6179 metabolites in 
plasma and urine may be performed utilising the blood and urine samples collected for PK 
evaluation. 


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7.1.4. 
Sample Collection and Processing for Pharmacogenomics 
An optional blood sample (approximately 1 × 6 mL ) for PGx testing may be collected, if the 
subject consents, by venipuncture or cannulation at the times indicated in the Schedule of 
Assessments in Appendix 6. 
Samples will be kept for future research and will be stored at the Sponsor designated storage 
facility. The manager of these samples will ensure that they are properly used throughout 
their usable life and will destroy the samples at the end of the scheduled storage period, no 
longer than 25 years after the end of the study or the maximum period allowed by applicable 
law. 
Further details of sample collection, processing, and storage will be provided in a separate 
document. 
7.2. 
Safety and Tolerability Assessments 
7.2.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to final 
discharge from the study. Subjects will be observed for any signs or symptoms and asked 
about their condition by open questioning, such as “How have you been feeling since you 
were last asked?”, at least once each day while resident at the study site and at each study 
visit. Subjects will also be encouraged to spontaneously report AEs occurring at any other 
time during the study. 
Any AEs and remedial action required will be recorded in the subject’s source data. The 
nature, time of onset, duration, and severity will be documented, together with an 
investigator’s (or designee’s) opinion of the relationship to study treatment. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the investigator (or designee) to 
have stabilised. This will be completed at the investigator’s (or designee’s) discretion. 
7.2.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations at the times 
indicated in the Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are 
listed in Appendix 2. The timing of clinical laboratory evaluations may be adjusted and/or 
additional clinical laboratory evaluations may be performed at other times if judged to be 
clinically appropriate or if the ongoing review of the data suggests a more detailed 
assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for a drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 


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in Appendix 6. For all female subjects, a pregnancy test will be performed at the times 
indicated in the Schedule of Assessments in Appendix 6. 
An investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
7.2.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and oral body temperature will be 
assessed at the times indicated in the Schedule of Assessments in Appendix 6. Vital signs 
may also be performed at other times if judged to be clinically appropriate or if the ongoing 
review of the data suggests a more detailed assessment of vital signs is required. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. All subsequent measurements will be performed singly and 
repeated once if outside the relevant clinical reference ranges. Oral body temperature will be 
measured singly. 
Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. 
In the event orthostatic measurements are required (if deemed clinically appropriate by an 
investigator or designee), the supine blood pressure and pulse rate will be measured after the 
subject has been supine for at least 5 minutes. The subject will then stand for at least 
2 minutes and the standing blood pressure and pulse rate will be measured. 
7.2.4. 
Electrocardiogram 
7.2.4.1. 
12-lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes at the times indicated in the Schedule of Assessments in Appendix 6. Single 
12-lead ECGs will be repeated once if either of the following criteria apply:
x
QTcF value > 500 ms
x
QTcF change from the baseline (predose) is > 60 ms.
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG. 
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. All subsequent measurements will be performed singly and repeated once if outside 
the relevant clinical reference ranges. 
7.2.4.2. 
Telemetry 
Cardiac rhythm will be monitored by telemetry at the times indicated in the Schedule of 
Assessments in Appendix 6. 


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Telemetry is not planned for Part B of the study but may be implemented if any clinically 
significant findings are identified in the data from Part A. 
7.2.4.3. 
Continuous 12-lead Electrocardiogram Monitoring 
Continuous 12-lead ECG monitoring using a digital recorder will take place at the times 
indicated in the Schedule of Assessments in Appendix 6. Continuous 12-lead ECG 
monitoring may be added to Part B; if added, the details will be documented and filed in the 
TMF. 
All continuous 12-lead ECG data collected will be archived without extraction or analysis 
and will not be reported in the scope of this study. 
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint (each extraction will last for 5 minutes). 
Environmental distractions (eg, television, radio, conversation) should be avoided during the 
pre-ECG resting period and during ECG recording. 
When coinciding, vital signs assessments and PK sampling should always be performed after 
the ECG extraction time window. If a separate ECG machine is being used for safety 
assessments described in Section 7.2.4.1, that machine should be in place prior to the 
extraction window to permit safety ECGs to be recorded irrespective of the extraction 
window. If the machine is not in place prior to the extraction window, safety ECGs must be 
recorded after the extraction window. If an integral system is used, safety ECGs may be 
recorded irrespective of the extraction window. 
7.2.5. 
Physical Examination 
A full physical examination will be performed at screening and follow-up, and a 
symptom-directed physical examination will be performed at all other timepoints specified in 
the Schedule of Assessments in Appendix 6. 
7.2.6. 
Body Weight 
Body weight (in underclothes) will be recorded at the times indicated in the Schedule of 
Assessments in Appendix 6. 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time NST-6179 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. 


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8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of active study 
treatment (NST-6179) and have at least 1 quantifiable PK concentration. 
8.2.2. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of study treatment 
(NST-6179 or placebo). 
8.3. 
Pharmacokinetic Analyses 
Non-compartmental PK analysis will be performed on individual plasma and urine 
concentration data, using commercial software such as Phoenix® WinNonlin®. 
The PK concentrations and parameters will be listed and summarised using descriptive 
statistics.A statistical analysis will be conducted to investigate the dose proportionality of 
AUC0-tlast, AUC0-, and Cmax on Day 1 in Part A and AUC0-Ĳ and Cmax on Day 14 in Part B. 
The PK parameters will be analysed using a power model. However, if the assumption of 
linearity is ruled unacceptable for any PK parameter, its corresponding PK parameter 
normalised by dose administered will be natural log-transformed and analysed using an 
analysis of variance model. 
A subject may be excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2-times median time to maximum 
concentration. 
8.4. 
Safety Analysis 
Safety parameters will be listed and summarised using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
If conducted, the results from the cardiodynamic ECG assessment will be reported separately. 
Further detail of the analyses will be covered by the standard operating procedures (SOPs) 
and/or the analysis plan of the cardiac vendor. 
8.5. 
Interim Analysis 
No formal interim analyses are planned for this study. 
9. REFERENCES 
1. NorthSea Therapeutics B.V. NST-6179 – Investigator’s Brochure. (Version 1.0). 
09 March 2021. 
2. Food and Drug Administration. Guidance for Industry: Estimating the Maximum Safe 
Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers 


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[Internet]. Food and Drug Administration; 2005. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm078932.pdf 
 


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10. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product, which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavourable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study treatment, whether or not related to the 
study treatment. 
Assessment of Severity 
The investigator will be asked to provide an assessment of the severity of the AE using the 
following categories: 
x Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
x Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
x Severe: Interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
Relationship to Study Treatment 
The investigator (or designee) will make a determination of the relationship of the AE to the 
study treatment using a 2-category or binary approach system according to the following 
guidelines: 
x Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
x Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesised 
cause-effect relationship, and (if appropriate) reappears when the drug is reintroduced. 
Follow-up of Adverse Events 
Every reasonable effort will be made to follow up with subjects who have AEs. Any subject 
who has an ongoing AE that is related to the investigational medicinal product (IMP) or study 
procedures at the follow-up visit will be followed up, where possible, until resolution or until 
the unresolved AE is judged by the investigator (or designee) to have stabilised. This will be 
completed at the investigator’s (or designee’s) discretion. Any subject who has an ongoing 
AE that is not related to the IMP or study procedures at the follow-up visit can be closed out 
as ongoing at the investigator’s discretion. 


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Adverse Drug Reactions 
All noxious and unintended responses to an IMP (ie, where a causal relationship between an 
IMP and an AE is at least a reasonable possibility) related to any dose should be considered 
adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases 
or for modification of physiological function is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (eg, Investigator’s 
Brochure [IB] for an unapproved IMP). 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose either: 
x results in death 
x is life-threatening 
x requires inpatient hospitalisation or prolongation of existing hospitalisation 
x results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
x results in a congenital anomaly/birth defect 
x results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered SAEs when, based upon appropriate medical judgement, 
they may jeopardise the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
Instances of death or congenital abnormality, if brought to the attention of the investigator at 
any time after cessation of the study treatment and considered by the investigator to be 
related to the study treatment, will be reported to the sponsor. 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event as it 
occurred (ie, does not include a reaction that might have caused death if it had occurred in a 
more serious form). For instance, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 


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Definition of Hospitalisation 
Adverse events requiring hospitalisation should be considered serious. In general, 
hospitalisation signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the study site. When in doubt as to whether hospitalisation occurred or 
was necessary, the AE should be considered as serious. 
Hospitalisation for elective surgery or routine clinical procedures, which are not the result of 
an AE, need not be considered AEs and should be recorded on a clinical assessment form and 
added to the electronic case report form (eCRF). If anything untoward is reported during the 
procedure, this must be reported as an AE and either ‘serious’ or ‘non-serious’ attributed 
according to the usual criteria. 
Serious Adverse Event Reporting 
Emas Pharma Limited, Trading as Bionical Emas, Hertfordshire, United Kingdom is 
responsible for coordinating the reporting of SAEs in accordance with the European Directive 
2001/20/EC. 
The investigator will complete an SAE report form and forward it by email 
(drug.safety@bionical-emas.com) to Emas Pharma Limited and the sponsor immediately 
(within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Emas Pharma Limited include the following: 
x Prepare an SAE Management Plan prior to the start of the study. Where this plan 
differs from the applicable Clinical Research Unit (CRU) standard operating 
procedure (SOP) on SAE reporting, the SAE Management Plan will always take 
precedence. 
x Receive and review SAE report forms from the CRU and inform the sponsor of the 
SAE within 1 working day of the initial notification to Emas Pharma Limited. Emas 
Pharma Limited will delete any information from the SAE report forms that may 
identify the subject. 
x Write case narratives and enter the case into the safety database as defined in the SAE 
Management Plan. 
x Produce appropriate reports of all suspected unexpected serious adverse reactions and 
forward to the institutional review board (IRB)/ethics committee (EC), MHRA, 
investigator, and the sponsor within the timeframes stipulated in the Clinical Trials 
Directive Guideline (ENTR/CT 3). 
The responsibility for reporting SAEs will be transferred to the sponsor 28 days after the end 
of the study. 


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Pregnancy 
Pregnancy (maternal or paternal exposure to study treatment) does not meet the definition of 
an AE. However, to fulfil regulatory requirements any pregnancy should be reported by the 
investigator to Emas Pharma Limited and the sponsor immediately (within 24 hours) upon 
becoming aware of the pregnancy, by completing a Pregnancy report form and forwarding by 
email to drug.safety@bionical-emas.com. The pregnancy will be followed up to collect data 
on the outcome for both mother and foetus. 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Haematology: 
Urinalysis: 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase (GGT) 
Glucose 
Inorganic phosphate 
Potassium 
Sodium 
Total bilirubin 
Total CO2 
Total protein 
Uric acid 
Haematocrit 
Haemoglobin 
Mean cell haemoglobin 
Mean cell haemoglobin concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential: 
    Basophils 
    Eosinophils 
    Lymphocytes 
    Monocytes 
    Neutrophils 
Blood 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination 
Coagulation profile: 
Activated partial thromboplastin 
time (aPTT) 
International normalized ratio 
(INR) 
Prothrombin time (PT) 
Drug screen: 
Hormone panel - females 
only: 
Including but not limited to: 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/cannabinoids 
Tricyclic antidepressants 
Cotinine test 
Follicle-stimulating hormone 
(FSH)a 
Serum pregnancy test (human 
chorionic gonadotropin)b 
Urine pregnancy testb 
Serology:a 
Anti-hepatitis B surface antibody 
Hepatitis B surface antigen (HBsAg) 
Hepatitis C antibody 
Human immunodeficiency virus 
(HIV-1 and HIV-2) antibodies and 
p24 antigen 
Fasting Lipid Panel 
(Cohorts B4 onwards): 
Low-density lipoprotein 
cholesterol (LDL-c) 
High-density lipoprotein 
cholesterol (HDL-c) 
Very low-density lipoprotein 
(VLDL) 
Total Cholesterol 
Triglycerides (TG) 
Apolipoprotein (Apo) A1 
ApoB 
ApoC3 
a. Performed at screening only. 
b. For all female subjects, performed in serum at screening and in urine at all other times. A positive urine pregnancy test 
will be confirmed with a serum pregnancy test. 


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Appendix 3: Total Blood Volume 
Part A 
The following blood volumes will be withdrawn for each subject: 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory evaluationsa 
7.5 
5 
37.5 
Serology 
3.5 
1 
3.5 
Coagulation 
1.8 
5 
9.0 
NST-6179 pharmacokineticsb 
2.0 
19 
38.0 
Pharmacogenomicsc  
6.0 
1 
6.0 
Total: 
94.0 
Abbreviation: FSH = follicle-stimulating hormone. 
a. Includes pregnancy and FSH tests. 
b. Includes 3 additional samples that may be taken. 
c. This is an optional sample, which may be collected with the subject’s consent. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 140 mL. 


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Part B 
The following blood volumes will be withdrawn for each subject not participating in a group 
with metabolite identification: 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory evaluationsa 
7.5 
7 
52.5 
Serology 
3.5 
1 
3.5 
Coagulation 
1.8 
7 
12.6 
NST-6179 pharmacokineticsb 
2.0 
35 
70.0 
Pharmacogenomicsc  
6.0 
1 
6.0 
Fasting lipid panel 
2.5 
3 
7.5 
Total: 
152.1 
Note: Increased dosing frequency may require 2 to 3 additional PK sample collections, however, the maximum blood 
volume collected will not exceed 190 mL. 
Abbreviation: FSH = follicle-stimulating hormone; PK = pharmacokinetic(s). 
a. Includes pregnancy and FSH tests. 
b. Includes 3 additional samples (per PK sampling day) that may be taken. 
c. This is an optional sample, which may be collected with the subject’s consent. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 190 mL. 


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The following blood volumes will be withdrawn for each subject participating in a group with 
metabolite identification: 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory evaluationsa 
7.5 
7 
52.5 
Serology 
3.5 
1 
3.5 
Coagulation 
1.8 
7 
12.6 
NST-6179 pharmacokineticsb 
2.0 
35 
70.0 
Metabolite identificationb 
2.0 
35 
70.0 
Pharmacogenomicsc  
6.0 
1 
6.0 
Total: 
214.6 
Abbreviation: FSH = follicle-stimulating hormone; PK = pharmacokinetic(s). 
a. Includes pregnancy and FSH tests. 
b. Includes 3 additional samples (per PK sampling day) that may be taken. 
c. This is an optional sample, which may be collected with the subject’s consent. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 270 mL. 


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Appendix 4: Contraception Guidance 
Definitions 
Female of Childbearing Potential: premenopausal female who is anatomically and 
physiologically capable of becoming pregnant following menarche. 
Female of Non-childbearing Potential: 
1. Surgically sterile: female who is permanently sterile via hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy by reported medical history and/or 
medical records. Surgical sterilisation to have occurred a minimum of 6 weeks, or 
at the investigator’s discretion, prior to screening. 
2. Postmenopausal: females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) level of  40 mIU/mL. The amenorrhea should not be induced by 
a medical condition such as anorexia nervosa, hypothyroid disease or polycystic 
ovarian disease, or by extreme exercise. It should not be due to concomitant 
medications that may have induced the amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormones, anti-oestrogens, or selective 
oestrogen receptor modulators. Females on hormone replacement therapy with 
FSH levels < 40 mIU/mL may be included at the discretion of the investigator. 
Females aged > 60 years old whose FSH values are not  40 mIU/mL may be 
included at the discretion of the investigator and in consultation with the sponsor. 
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Subjects 
Female subjects who are of non-childbearing potential will not be required to use 
contraception. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary and 1 secondary method) of birth control from the time of signing the informed 
consent form (ICF) until 90 days after the follow-up visit. Primary (non-barrier) methods of 
contraception include: 
x hormonal injection (as prescribed) 
x combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
x combined hormonal patch (as prescribed) 
x combined hormonal vaginal ring (as prescribed) 
x surgical method performed at least 3 months prior to the screening visit: 
o 
bilateral tubal ligation 


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o 
Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes 
x hormonal implant 
x hormonal or non-hormonal intrauterine device (IUD) 
x vasectomised male partner (sterilisation performed at least 90 days prior to the 
screening visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject). 
Secondary (barrier) methods of contraception include: 
x male condom with spermicide 
x female condom with spermicide 
x over-the-counter sponge with spermicide 
x cervical cap with spermicide (as prescribed) 
x diaphragm with spermicide (as prescribed). 
Female subjects of childbearing potential should refrain from donation of ova from check-in 
(Day -1) until 90 days after the follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from check-in until 90 days after the follow-up 
visit. Acceptable methods of contraception for female partners include: 
x hormonal injection 
x combined oral contraceptive pill or progestin/progestogen-only pill 
x combined hormonal patch 
x combined hormonal vaginal ring 
x surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion]) 
x hormonal implant 
x hormonal or non-hormonal IUD 
x over-the-counter sponge with spermicide 
x cervical cap with spermicide 
x diaphragm with spermicide. 


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An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male subjects (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the time 
of the first dose until 90 days after the follow-up visit. Male subjects are required to refrain 
from donation of sperm from check-in until 90 days after the follow-up visit. 
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a 
subject who is abstinent at the time of signing the ICF becomes sexually active, they must 
agree to use contraception as described previously. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 


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Appendix 5: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
x Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
x Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
x Applicable laws and regulations. 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s Brochure 
(IB), and other relevant documents must be submitted to an institutional review board 
(IRB)/ethics committee (EC) by the investigator and reviewed and approved by the IRB/EC 
before the study is initiated. 
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require IRB/EC and regulatory authority (as locally required) approval 
before implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any non-substantial changes, as defined 
by regulatory requirements. 
The investigator will be responsible for the following: 
x Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC. 
x Notifying the IRB/EC of serious adverse events (SAEs) or other significant safety 
findings as required by IRB/EC procedures. 
x Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European Directive 2001/20/EC for clinical studies (if applicable), and all other 
applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study treatments, procedures, and potential risks of the study. 
Subjects will be instructed that they are free to obtain further information from the 
investigator (or designee) and that their participation is voluntary and they are free to 


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withdraw from the study at any time. Subjects will be given an opportunity to ask questions 
about the study prior to providing consent for participation. 
Following discussion of the study with study site personnel, subjects will sign the ICF in the 
presence of a suitably trained member of staff to indicate that they are freely giving their 
informed consent. A copy of the ICF will be given to the subject. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in electronic 
case report forms (eCRFs), study-related forms, study reports, or any related publications. 
Subject and investigator personal data will be treated in compliance with all applicable laws 
and regulations. In the event the study protocol, study report, or study data are included in a 
public registry, all identifiable information from individual subjects or investigators will be 
redacted according to applicable laws and regulations. 
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data 
may be examined by sponsor or contract research organisation (CRO) auditors or other 
authorised personnel appointed by the sponsor, by appropriate IRB/EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
x All relevant subject data relating to the study will be recorded on eCRFs unless 
directly transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF. 
x The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
x The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
x Labcorp Drug Development is responsible for the data management of this study 
including quality checking of the data. Predefined agreed risks, monitoring thresholds, 


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quality tolerance thresholds, controls, and mitigation plans will be documented in a 
project management plan. Additional details of quality checking to be performed on 
the data may be included in a data management plan. 
x A study monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorised site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
x Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator in the study site archive for at least 5 years after 
the end of the study unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR 
Part 11-compliant electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to Labcorp Drug Development electronically, will be integrated with the subject’s 
eCRF data in accordance with the data management plan. 
An eCRF must be completed for each enrolled subject who undergoes any screening 
procedures, according to the eCRF completion instructions. The sponsor, or CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 
the accuracy of the electronic data. The investigator will ensure that corrections are made to 
the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the investigator reviewed and approved the data 
on the eCRF, data queries, and site notifications. 
Publications 
Publications will be addressed in a separate agreement. The results of this study may be 
published or presented at scientific meetings. If this is foreseen, the investigator agrees to 
submit all manuscripts or abstracts to the sponsor before submission. This allows the sponsor 
to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 


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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 


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Appendix 6: Schedule of Assessments 


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Schedule of Assessments – Part A (Single Dose in Healthy Subjects) 
Study Procedures 
Screening 
(Day -28 to 
Day -2) 
Treatment Period 1 
Follow-up 
(10 to 14 days 
postdose) 
Day -1 
Days 1 to 4 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
Xa 
 
 
Urinary drug screen 
X 
X 
 
 
Alcohol breath test 
X 
X 
 
 
Urine cotinine test 
X 
X 
 
 
Serology 
X 
 
 
 
Pregnancy testb 
X 
X 
 
X 
FSHc 
X 
 
 
 
Height and body weight 
Xd 
X 
 
 
Study residency: 
 
 
 
 
Check-in 
 
X 
 
 
Check-out 
 
 
Day 4 
 
Non-residential visit 
X 
 
 
X 
Study treatment administration: 
NST-6179 or placebo 
 
 
Day 1 (0 hour) 
 
Pharmacokinetics: 
Blood sampling 
 
 
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose 
X 
Urine sampling 
 
 
Predose (spot collection) and 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 48 to 
72 hours postdose 
 
Safety and tolerability: 
Adverse event recording 
X 
X 
Ongoing 
X 
Prior/concomitant 
medication monitoring 
X 
X 
Ongoing 
X 


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Schedule of Assessments – Part A (Single Dose in Healthy Subjects) 
Study Procedures 
Screening 
(Day -28 to 
Day -2) 
Treatment Period 1 
Follow-up 
(10 to 14 days 
postdose) 
Day -1 
Days 1 to 4 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Predose and 48 hours postdose 
X 
Coagulation 
X 
X 
Predose and 48 hours postdose 
X 
Blood pressure, pulse rate, 
respiratory rate, and oral 
body temperature 
X 
 
Predose,e and 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose 
X 
12-lead ECG 
X 
 
Predose,e and 2, 4, 12, 24, 48, and 72 hours postdose 
X 
Telemetry 
 
 
From at least -1 hour predose to 4 hours postdose 
 
Continuous 12-lead ECGf 
 
 
3 (triplicate) continuous 12-lead extractions taken prior to dosing, and at 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose 
 
Full physical examination 
Xg 
 
 
X 
Symptom-directed physical 
examination 
 
 
Prior to discharge on Day 4 
 
Pharmacogenomics blood 
sample 
 
 
Predoseh 
 
Abbreviations: ECG = electrocardiogram; FSH = follicle-stimulating hormone. 
a. Interim medical history. 
b. Performed in serum at screening and in urine at all other times. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
c. Performed in all female subjects (to confirm postmenopausal status). 
d. Height measured at screening only. 
e. Predose assessments will take place within 2 hours prior to dosing. 
f. Monitor for 12-lead ECG recording will be worn from 2 hours predose to 25 hours postdose on Day 1. Prior to dosing, 3 (ie, triplicate) continuous 12-lead extractions are required. The 
predose extraction timepoints will be averaged for baseline. 
g. Performed between the screening visit and predose assessments. 
h. 
Optional sample; this sample is not time-sensitive, if not possible to collect predose on Day 1, it can be collected at any time during or after the course of the study. 
 
 


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Schedule of Assessments – Part B (Multiple Dose in Healthy Subjects) 
Study Procedures 
Screening 
(Day -28 to 
Day -2) 
Day -1 
Days 1 to 16 
Follow-up 
(10 to 14 days 
post-final dose) 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
Xa 
 
 
Urinary drug screen 
X 
X 
 
 
Alcohol breath test 
X 
X 
 
 
Urine cotinine test 
X 
X 
 
 
Serology 
X 
 
 
 
Pregnancy testb 
X 
X 
 
X 
FSHc 
X 
 
 
 
Height and body weight 
Xd 
X 
 
 
Study residency: 
Check-in 
 
X 
 
 
Check-out 
 
 
Day 16 (48 hours post-final dose) 
 
Non-residential visit 
X 
 
 
X 
Study treatment administration: 
NST-6179 or placebo 
 
 
QD dosing: 
Day 1 to 14 (0 hour) 
 
BID dosing:g 
Days 1 to 13 BID (0 hour [AM dose] and 12±0.5 hours later [PM dose]); Day 14 
(0 hour [AM dose] only) 
 


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Schedule of Assessments – Part B (Multiple Dose in Healthy Subjects) 
Study Procedures 
Screening 
(Day -28 to 
Day -2) 
Day -1 
Days 1 to 16 
Follow-up 
(10 to 14 days 
post-final dose) 
Pharmacokinetics: 
Blood sampling 
 
 
QD dosing: 
Day 1: predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose 
Days 2, 4, 6, 8, 10, and 12: predose 
Day 14: predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours postdose 
 
BID dosing: 
Day 1: pre-AM dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose (pre-PM 
dose) 
Days 2, 4, 6, 8, and 10: pre-AM dose 
Day 12 and 13: pre-AM dose and pre-PM dose 
Day 14: pre-AM dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours 
postdose 
 
Urine sampling (PK for all 
dose groups and metabolite 
identification for highest 
planned QD dose group only) 
 
 
QD dosing: 
Day 1: predose (spot collection) and 0 to 4, 4 to 8, 8 to 12, 12 to 24 hours 
postdose 
Day 14: predose (spot collection) and 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 
48 hours postdose 
 
BID dosing: 
Day 1: pre-AM dose (spot collection) and 0 to 4, 4 to 8, and 8 to 12 hours 
postdose (pre-PM dose) 
Day 14: pre-AM dose (spot collection) and 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 
24 to 48 hours postdose 
 


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Schedule of Assessments – Part B (Multiple Dose in Healthy Subjects) 
Study Procedures 
Screening 
(Day -28 to 
Day -2) 
Day -1 
Days 1 to 16 
Follow-up 
(10 to 14 days 
post-final dose) 
Blood sampling for metabolite 
identification (for highest 
planned dose group only) 
 
 
QD dosing only: 
Day 1: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose 
Days 2, 4, 6, 8, 10, and 12: predose 
Day 14: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours postdose 
 
Safety and tolerability: 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
Prior/concomitant medication 
monitoring 
X 
X 
Ongoing 
X 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Days 1, 4, and 8: pre-AM dose 
Day 14: 48 hours postdose 
X 
Coagulation 
X 
X 
Days 1, 4, and 8: pre-AM dose 
Day 14: 48 hours postdose 
X 
Fasting lipid panelh 
 
 
Days 1, 7, and 14: pre-AM dose  
 
Blood pressure, pulse rate, 
respiratory rate, and oral body 
temperature 
X 
 
QD dosing: 
Day 1: predosee, and 1, 2, 4, and 12 hours postdose 
Days 2 to 14: predose and 4 hours postdose 
 
BID dosing: 
Day 1: pre-AM dose and 1, 2, 4, and 12 hours postdose (pre-PM dose) 
Days 2 to 14: pre-AM dose (0 hour) and 4 hours postdose 
X 


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Schedule of Assessments – Part B (Multiple Dose in Healthy Subjects) 
Study Procedures 
Screening 
(Day -28 to 
Day -2) 
Day -1 
Days 1 to 16 
Follow-up 
(10 to 14 days 
post-final dose) 
12-lead ECG 
X 
 
QD dosing: 
Day 1: predosee, and 2, 4, and 12 hours postdose 
Days 4, 7, and 10: predose 
Day 14: predose, 2, 4, 12, 24, and 48 hours postdose 
 
BID dosing: 
Day 1: pre-AM dose and 2, 4, and 12 hours postdose (pre PM dose) 
Day 4, 7, and 10: pre-AM dose 
Day 14: pre-AM dose and 2, 4, 12, 24, and 48 hours postdose 
X 
Full physical examination 
Xf 
 
 
X 
Symptom-directed physical 
examination 
 
 
Prior to discharge on Day 16 
 
Pharmacogenomics blood 
sample 
 
 
Predosei 
 
Abbreviations: AM = morning; ECG = electrocardiogram; FSH = follicle-stimulating hormone; PK = pharmacokinetic(s); PM = evening. 
a. Interim medical history. 
b. Performed in serum at screening and in urine at all other times. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
c. Performed in all female subjects (to confirm postmenopausal status). 
d. Height measured at screening only. 
e. Predose assessments will take place within 2 hours prior to dosing. 
f. Performed between the screening visit and predose assessments. 
g. For BID dosing, the AM and PM dosing time for each subject will be as consistent as possible for each day. 
h. Only for Cohorts B4 onwards. 
i. Optional sample; this sample is not time-sensitive, if not possible to collect predose on Day 1, it can be collected at any time during or after the course of the study. 


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Appendix 7: Summary of Amended Protocol Changes 
Version 4 to Version 5 
Major changes: 
1. Rationale for protocol amendment: This is a new section added to details the 
reasons this amendment has been issued. 
2. Section 1.6.1: This is a new section added to include relevant data from previously 
completed cohorts. This section includes subsections for clinical pharmacokinetic 
(Section 1.6.1.1) and clinical safety data (Section 1.6.1.2). 
3. Sections 2.1 and 2.2.3: Exploratory objective and endpoint added for the 
evaluation of the effect of pharmacogenomics on the pharmacokinetics of NST-
6179.  
4. Sections 2.2.3, 7.1.2: Clarified that additional samples for metabolite 
identification will be collected for the highest planned QD dose group. 
5. Sections 3.1.2, 3.3, 3.4, and 3.5: Dosing restriction was revised from an exposure 
basis to an established safe dose level basis, ie, the dose of NST-6179 
administered on each dosing occasion in Part B will not exceed a single dose 
previously shown to be safe and well tolerated in Part A. Clarified in the footnotes 
for Figures 3 and 4 that the dosing frequency and duration in Part B may be 
change from the planned QD dosing. 
6. Section 3.5: Table 7, previously Table 6, updated to present the doses which have 
already been administered in Parts A and B. 
7. Sections 3.1.2, 3.4, 3.4.1, and 5.3:To enhance subject safety, a requirement for 
sentinel dosing for groups in Part B for which the total daily dose exceeds the 
highest single dose evaluated in Part A was added. 
8. Section 5.2: Details for administration of a BID dosing regimen have been added. 
9. Section 5.2 and 6.2: Details for the administration of a BID dosing regimen under 
fasted conditions have been added. 
10. Section 7.1.4: This is a new section added to include the collection of an optional 
pharmacogenomics sample. 
11. Appendix 2: Fasting lipid panel parameters were added to Part B for Cohorts B4 
onwards. 
12. Appendix 3: The total blood volumes drawn for Part A were updated to include an 
additional sample for pharmacogenomics. The total blood volumes drawn for Part 
B, for both subjects participating and not participating in metabolite identification, 
were updated to include additional samples for pharmacogenomics. The total 
blood volumes drawn for subjects not participating in metabolite identification in 
Part B, has been updated to include samples for the fasting lipid panel. 
13. Appendix 6, Schedule of Assessment for Part A (Single Dose in Healthy 
Subjects): Added a row for the collection of an optional pharmacogenomics blood 
sample predose on Day 1, an associated footnote (h) was added to clarify that this 
sample could be collected at any time during or after the study. 


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14. Appendix 6, Schedule of Assessment for Part B (Multiple Dose in Healthy 
Subjects): Study procedures were modified in support of BID dosing as follows: 
a. Added BID dosing to study treatment administration, 12±0.5 hours apart, 
starting in the morning (AM) of Day 1, completing dosing with an AM 
dose on Day 14. The AM and PM dosing time for each subject will be as 
consistent as possible for each day.  
b. Pharmacokinetic blood sampling modified to add trough collections pre-
PM dose on Days 12 and 13 and a 16 hour postdose sample on Day 14. 
Added clarification that predose collections will take place pre-AM dose 
and the 12 hours postdose collection on Day 1 is to be collected pre-PM 
dose to enable these collections to reflect single dose analysis as for Part B 
QD dose groups.  
c. Urine sampling modified to remove the 12 to 24 hour postdose collection 
interval on Day 1 because this interval will be after the PM dose on Day 1, 
and therefore no longer relevant for comparison with Part B QD dose 
groups. Clarified that predose collections will take place pre-AM dose. 
Additionally, clarified that urine samples for metabolite identification will 
be collected for the highest planned QD dose group. 
d. Blood samples for metabolite identification samples will be collected for 
Part B QD dose groups only. 
e. Added clarification that coagulation, clinical chemistry, haematology, and 
urinalysis predose samples will be collected pre-AM dose to remain 
comparable to Part B QD dose groups. 
f. Added clarification that the vital signs and ECG predose assessments will 
be pre-AM dose and the 12-hour postdose assessments on Day 1 are to be 
performed pre-PM dose to remain comparable to Part B QD dose groups. 
g. Added a row for a fasting lipid panel assessment on Days 1, 7, and 14, an 
associated footnote (h) was added to clarify this assessment is only 
applicable to Cohorts B4 onwards. 
h. Added a row for the collection of an optional pharmacogenomics blood 
sample predose on Day 1, an associated footnote (i) was added to clarify 
that this sample could be collected at any time during or after the study. 
Minor changes: 
1. Added PK parameter specific to BID dosing (area under the plasma concentration 
time curve (AUC) from time zero to 24 hours postdose (AUC0-24, derived as 
AUC0-Ĳ*2 for a BID dosing regimen at steady state). 
2. A footnote was added to the blood volume tables for Part B in Appendix 3, noting 
that additional PK blood sample collections may be required due to increased 
dosing frequency but the maximum blood volume collected would not exceed 450 
mL. 
3. The synopsis was updated according to changes in the protocol body, as 
applicable. 


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4. The amendment/version number and date were updated throughout the protocol. 
5. Abbreviations were added and/or removed, as appropriate. 
6. Minor editorial updates were made. 
Version 3 to Version 4 
Major changes: 
1. Text in Section 1.4.3 amended to update the findings of the 13-week oral (gavage) 
toxicity and toxicokinetic study in the monkey with a 2-week recovery period 
(Covance study 8423746). 
2. Section 1.4.4 is a new section added to present the current results of the ongoing 
13-week oral (gavage) administration toxicity study in the mouse (Labcorp study 
8423764). 
3. Section 1.8 updated to clarify the risk-benefit of conducting this first-in-human 
study (NST-6179-001) remains unchanged and the proposed stopping rules 
remain supported by data from the mouse, rat, and monkey. 
4. Removal of food-effect cohort from Part A, and clarification that all doses in 
Part B will be administered in the fasted state. The way the molecule should not 
be affected significantly by food and so a food-effect evaluation is not considered 
necessary. 
5. Appendix 6, Schedule of Assessment for Part A updated to clarify the clinical 
chemistry, haematology, urinalysis, and coagulation assessment will be at 
48 hours postdose (previously 72 hours postdose). 
Minor changes: 
6. The synopsis was updated according to changes in the protocol body, as 
applicable. 
7. The amendment/version number and date were updated throughout the protocol. 
8. The header was updated to reflect Covance being rebranded as Labcorp. 
9. Abbreviations were added and/or removed, as appropriate. 
10. Minor editorial updates were made. 
A detailed summary of changes is presented below: 
For each section, deleted text is shown in strikethrough, and new text is shown in bold. 
Section 1.4.3: 13-week Oral (Gavage) Toxicity and Toxicokinetic Study in the Monkey with 
a 2-week Recovery Period 
Previously read: 
Animals were dosed through Day 15 and was NST-6179 generally well tolerated with only 
mild spurious vomiting and an 8% decrease in bodyweight observed in the early stages, both 
of which returned to baseline status over time. No other relevant clinical findings have been 
observed to date at any dose level in either male or female monkeys. However, on Day 16, a 


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single female monkey in the high dose group was found dead following dosing on Day 15. 
The decedent female appeared to be in general good health and displayed no clinical signs up 
through and postdose on Day 15. Dosing was temporarily held in the high dose female cohort 
and out of caution was restarted at a lower dose of 300 mg/kg/day and the frequency of 
postdose monitoring was increased. A macroscopic post-mortem examination showed no 
advanced autolysis at macroscopic post-mortem indicated the female died relatively soon 
prior to the post-mortem examination. Although an exact time of death cannot be established, 
the relative time frame of death was close to 24 hours after the Day 15 dose, when minimal 
drug concentrations levels would have been present. Microscopically, minimal 
alveolar/interstitial inflammation was noted which is consistent with post aspiration effects. 
However, the minimal severity and distribution is considered not to be the cause of mortality. 
The majority of tissues were well preserved but some autolysis was noted in the gall bladder 
and gastrointestinal tract and to a lesser extent liver, pancreas and salivary glands. Further 
detailed examination of the clinical condition and study data from the decedent animal was 
also reviewed to determine any underlying condition existed as a potential cause of death. 
Clinical chemistry and urinalysis parameters were all normal. Haematology parameters were 
all within normal limits, with the exception of minimal increases in white cells and absolute 
neutrophil count. However, no evidence of infection was noted associated with these 
elevations. A minimal decrease in red cells, haemoglobin and packed cell volume was noted. 
None of these changes were felt to be clinically meaningful nor contributory to the cause of 
death. Assessment of the decedents ECG indicated minor anomalies considered not clinically 
relevant. 
A review of the data from the prior 28-day repeat dose oral toxicity study in monkeys 
established 350 mg/kg/day was the NOAEL level (Covance 8423746). No clinical signs and 
symptoms or mortality was observed at this dose level. Importantly, in the ongoing 13-week 
study NST-6179 continues to be well tolerated in all other males and females at all dosages 
up to 28 days of dosing. In summary, all of the clinical and laboratory data preceding the 
event, as well as the post-mortem assessments, have been peer reviewed by two pathologists, 
both of whom concur with the observations and the lack of evidence of a drug-related event. 
Now reads: 
Animals were dosed through Day 15 and NST-6179 was generally well tolerated with only 
mild spurious vomiting and an 8% decrease in bodyweight observed in the early stages, both 
of which returned to baseline status over time. No other relevant clinical findings have been 
observed to date at any dose level in either male or female monkeys. However, there were 
subsequently 2 events of note in the high-dose cohort (350 mg/kg/day). The first event 
occurred on Day 16 in which a single female monkey was found dead following dosing on 
Day 15. The decedent female appeared to be in general good health and displayed no clinical 
signs up through and postdose on Day 15. A macroscopic post-mortem examination showed 
no advanced autolysis at macroscopic post-mortem indicating the female died relatively soon 
prior to the post-mortem examination and at a timeframe when minimal drug concentrations 
levels would have been present. Microscopically, minimal alveolar/interstitial inflammation 
was noted, consistent with post aspiration effects but not the cause of mortality. The majority 
of tissues were well preserved with some autolysis noted in the gall bladder and 
gastrointestinal tract and to a lesser extent liver, pancreas, and salivary glands. No 
pre-existing comorbid conditions were identified as a potential cause of death. Clinical 


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chemistry and urinalysis parameters were all normal or with minimal changes; none of 
which were felt to be clinically relevant. Assessment of the decedents ECG indicated minor 
anomalies considered not clinically relevant. As of this time, there is no clear indication of 
the cause of death but the examinations to date do not show any evidence of direct tissue 
injury or toxicity associated with NST-6179. 
The second event occurred in the high-dose cohort (350 mg/kg/day) where a male 
monkey was found in a moribund condition 4 hours after dosing and euthanized on 
Day 87. This male was in good health throughout the study and prior to the last dose on 
Day 87. The investigation into the cause of death is still ongoing as well as an assessment 
of the remaining animals in the high-dose cohort. However, the initial assessment from 
the study pathologist determined that the microscopic findings were common 
background changes in this strain of monkey. However, there was moderate bilateral 
tubular nephropathy in the kidney which could be possibly related to the cause of death 
but will be confirmed with further investigations of this animal and the others in the 
cohort. No other clinical or laboratory findings revealed any clear signs of drug toxicity 
that would lead to death. 
A review of the data from the prior 28-day repeat dose oral toxicity study in monkeys 
established 350 mg/kg/day was the NOAEL level (Covance 8423746). No clinical signs and 
symptoms or mortality were observed at this dose level. Importantly, dosing in the monkey 
13-week study is now complete. NST-6179 was well tolerated in all other surviving male 
and female high dose monkeys. The low (60 mg/kg/day) and medium (210 mg/kg/day) 
doses were well-tolerated throughout the study period with no notable events. Both of 
the events in the high-dose group were at exposures far exceeding the exposure of the 
likely doses in the Phase 1 study. In addition, there was no clear drug-related effect with 
the first monkey and the second event occurred at a duration much longer than the 
maximal 14-day duration in the Phase 1 study. 
Section 1.4.4 (new section): 13-week Oral (Gavage) Administration Toxicity Study in the 
Mouse (Labcorp Study Number 8423764; ongoing) 
A 13-week oral toxicity study in the mouse conducted under GLP is currently ongoing 
to determine dose level selection in a subsequent 2-year carcinogenicity study as well as 
evaluating TK at Day 1 and Day 90 of the study. 
The maximum dose levels administered in the 13-week study were based on a previous 
mouse dose range finding study which was conducted to establish the maximum 
tolerated oral dose (MTD) in male and female mice. This study established an MTD of 
250 mg/kg in female mice and an MTD of 200 mg/kg/day in male mice. These dose levels 
were tolerated for 21 days without mortality or adverse clinical signs. The selected low 
dose level of 70 mg/kg/day is the approximate effective dose. The intermediate dose 
levels in males and females represent the mid-point between 70 mg/kg/day and 
200 mg/kg/day (males) and 250 mg/kg/day (females). 
Group assignment is indicated in Table 1. 


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Table 1: 
Group Assignment in the 13-week Oral (Gavage) Administration Toxicity 
Study in the Mouse (Labcorp Study Number 8423764) 
Groupa 
Subgroup 
Dose Levelb 
(mg/kg/day) 
Dose 
Concentrationb 
(mg/mL) 
Number of Animals 
Males 
Females 
1 (Control) 
1 (Toxicity) 
0 
0 
12 
12 
2 (Toxicokinetic) 
0 
0 
3 
3 
2 (Low) 
1 (Toxicity) 
70 
7 
12 
- 
1 (Toxicity) 
70 
7 
- 
12 
2 (Toxicokinetic) 
70 
7 
18 
- 
2 (Toxicokinetic) 
70 
7 
- 
18 
3 
(Intermediate) 
1 (Toxicity) 
135 
13.5 
12 
- 
1 (Toxicity) 
160 
16 
- 
12 
2 (Toxicokinetic) 
135 
13.5 
18 
- 
2 (Toxicokinetic) 
160 
16 
- 
18 
4 (High) 
1 (Toxicity) 
200 
20 
12 
- 
1 (Toxicity) 
250 
25 
- 
12 
2 (Toxicokinetic) 
200 
20 
18 
- 
2 (Toxicokinetic) 
250 
25 
- 
18 
a. Group 1 administered vehicle control only (corn oil). 
b. Animals dosed at a volume of 10 mL/kg. 
On Day 1 of dosing in the 13-week study all mice were dosed by oral gavage at the doses 
outlined above. No adverse effects were observed at the low and intermediate dose 
levels. At the high dose levels, approximately 22 hours after the first dose, 1 male and 
2 females were found dead. Additionally, 1 female displayed clinical signs of ataxia, 
reduced activity, hunched posture, and tremors leading to the animal being euthanized. 
Eight days after the first dose, 1 female was euthanized due to immobility of the hind 
limbs. Dosing was suspended at the high dose level after the events in the first 4 animals. 
These events occurred at the end of the dosing interval therefore are not considered to 
correlate with Cmax of NST-6179. However, continued dosing in the high dose level 
cohort was suspended and new dosing levels were evaluated the study. 
Macroscopic examination of major organs and tissues in decedents did not reveal any 
changes that could be related to drug treatment or mis-dosing via gavage. A full 
histopathology report of decedents is pending but TK analysis indicates drug exposure 
at the well-tolerated intermediate dose levels is greater than the current stopping rules. 
At the high dose level, drug exposure is substantially above the current stopping rule 
area under the concentration-time curve (AUC) of 358,000 ng.h/mL from the 28-day 
monkey toxicity study. The Day 1 TK parameters in the mouse are presented in Table 2. 


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Table 2: 
Summary of the NST-6179 Toxicokinetic Parameters in the Mouse on 
Day 1 in the 13-week Oral (Gavage) Administration Toxicity Study 
(Labcorp Study Number 8423764) 
Group 
Dose 
(mg/kg) 
Sex 
AUC0-24 
(ng.h/mL) 
Low 
70 
Male 
229,000 
70 
Female 
317,000 
Intermediate 
135 
Male 
400,000 
160 
Female 
587,000 
High 
200 
Male 
503,000 
250 
Female 
988,000 
Abbreviations: AUC0-24 = area under the plasma concentration-time curve from time zero to 24 hours postdose. 
Based on these data, the dose levels were adjusted to account for the necessitated 
decrease in high dose group while maintaining an adequate dose separation between the 
3 dosing cohorts. The adjusted dose levels for both males and females are 70 mg/kg/day, 
120 mg/kg/day, and 170 mg/kg/day, with the adjustments made in the ongoing low and 
intermediate dose cohorts and a new cohort initiated at the high dose level. 
The observed adverse events (AEs) in the mouse have been considered and, as TK data 
indicate AEs on Day 1 correlate with exposure (AUC) substantially above the current 
stopping rule, are not considered to be clinically relevant. 
Section 1.7: Study Rationale 
Previously read: 
This is the first time NST-6179 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when NST-6179 is administered orally as single 
and multiple doses to healthy subjects. This information will help establish the doses and 
dosing regimen suitable for future studies in patients. The study will also investigate the 
effects of food on the PK of NST-6179 prior to patient studies. 
Now reads: 
This is the first time NST-6179 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when NST-6179 is administered orally as single 
and multiple doses to healthy subjects. This information will help establish the doses and 
dosing regimen suitable for future studies in patients. 
Section 1.8: Benefit-risk Assessment 
Previously read: 
Subjects in the current study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study. The risks of participation are 
primarily those associated with adverse reactions to the study treatment, although there may 
also be some discomfort from collection of blood samples and other study procedures. More 


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information about the known and expected benefits, risks, and reasonably anticipated adverse 
events (AEs) associated with NST-6179 may be found in the Investigator’s Brochure (IB).1 
Now reads: 
Subjects in the current study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study. The risks of participation are 
primarily those associated with adverse reactions to the study treatment, although there may 
also be some discomfort from collection of blood samples and other study procedures. 
The events observed in the toxicology studies to date are also considered in determining 
the overall benefit-risk of the Phase 1 study. All events occurred in these specific studies 
at systemic exposure exceeding the current established stopping rules. Based on the 
observed drug exposure, a significant safety margin exists for both the relevant species, 
as well as the mice in the carcinogenicity dose ranging study, at the proposed initial 
human dose of 50 mg. Therefore, the risk-benefit of conducting this first-in-human 
study remains unchanged and proposed stopping rules remain supported by data from 
the mouse, rat, and monkey. 
More information about the known and expected benefits, risks, and reasonably anticipated 
AEs associated with NST-6179 may be found in the Investigator’s Brochure (IB).1 
Section 2.1: Objectives 
Previously read: 
The secondary objectives of the study are: 
x to evaluate the single and multiple oral dose PK of NST-6179 in healthy male and 
female subjects 
x to determine the effect of food on the single oral dose PK of NST-6179 in healthy 
male and female subjects. 
Now reads: 
The secondary objective of the study is: 
x to evaluate the single and multiple oral dose PK of NST-6179 in healthy male and 
female subjects 
Section 2.2: Secondary Endpoints 
Previously read: 
The PK outcome endpoints of NST-6179 for Part A (single-ascending dose and food effect 
[fed versus fasted dietary status at dosing] in healthy subjects) are as follows: 


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Now reads: 
The PK outcome endpoints of NST-6179 for Part A (single-ascending dose in healthy 
subjects) are as follows: 
Section 3.1.1: Part A 
Previously read: 
Part A will comprise a double-blind, single-ascending dose, sequential-group design 
incorporating a food-effect evaluation. Overall, 48 subjects will be studied in 6 groups 
(Groups A1 to A6), with each group consisting of 8 subjects. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only, 
except for Group A3, where each subject will participate in 2 treatment periods separated by 
a minimum of 7 days. Subjects will reside at the study site from Day -1 (the day before 
dosing) to Day 4 of each treatment period, as applicable. It is the intent to conduct the 
assessment of the effect of food in Group A3; however, based on emerging data, this may be 
conducted in a different dose group in Part A. 
All subjects will return for a follow-up visit 10 to 14 days after their final dose. 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 per period and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups A1 to A6, 6 subjects will receive NST-6179 and 2 subjects will receive 
placebo. 
Groups A1, A2, and A4 to A6 
It is planned for each subject in Groups A1, A2, and A4 to A6 to receive only a single dose of 
NST-6179 or placebo during the study. Doses will be administered in the fasted state in 
accordance with a randomisation schedule on the morning of Day 1. 
Group A3 
It is planned for each subject in Group A3 to have the same treatment in both treatment 
periods, such that each subject will receive 2 single doses of NST-6179 or placebo during the 
study. On Day 1 in Treatment Period 1, doses will be administered in the fasted state in 
accordance with a randomisation schedule. On Day 1 in Treatment Period 2, doses will be 
given 30 minutes after starting a standard high-fat breakfast. Although a food-effect 
evaluation is planned to occur in Group A3, this may be subject to change based on emerging 
data. 
Additional Groups (Groups A7 to A9) 
If it is decided to enrol additional groups (Section 3.3), the effect of food on the PK of 
NST-6179 may further be evaluated as described for Group A3. However, fasting 
requirements, meal compositions, and timing of doses will be determined following review of 
the available PK data. 


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Sentinel Dosing 
All groups in Part A will be divided into 2 sub-groups, with each sub-group being dosed 
24 hours apart. The first sub-group will comprise 2 subjects, with 1 subject receiving 
NST-6179 and 1 subject receiving placebo. The second sub-group will comprise 6 subjects, 
with 5 subjects receiving NST-6179 and 1 subject receiving placebo. For groups participating 
in a food-effect evaluation, sentinel dosing will only be utilised in Treatment Period 1 when 
NST-6179 or placebo are administered in the fasted state. 
There will be a minimum of 7 days between dose escalations for each group in Part A. 
An overview of the study design is shown in Figure 1 and Figure 2 and the planned dose 
levels are presented in Figure 3. A Schedule of Assessments is presented in Appendix 6. 
Now reads: 
Part A will comprise a double-blind, single-ascending dose, sequential-group design. Overall, 
48 subjects will be studied in 6 groups (Groups A1 to A6), with each group consisting of 
8 subjects. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only. 
Subjects will reside at the study site from Day -1 (the day before dosing) to Day 4 of each 
treatment period, as applicable. 
All subjects will return for a follow-up visit 10 to 14 days after their final dose. 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 per period and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups A1 to A6, 6 subjects will receive NST-6179 and 2 subjects will receive 
placebo. 
Groups A1 to A6 
It is planned for each subject in Groups A1 to A6 to receive only a single dose of NST-6179 
or placebo during the study. Doses will be administered in the fasted state in accordance with 
a randomisation schedule on the morning of Day 1. 
Additional Groups (Groups A7 to A9) 
If it is decided to enrol additional groups (Section 3.3) fasting requirements, meal 
compositions, and timing of doses will be determined following review of the available PK 
data. 
Sentinel Dosing 
All groups in Part A will be divided into 2 sub-groups, with each sub-group being dosed 
24 hours apart. The first sub-group will comprise 2 subjects, with 1 subject receiving 
NST-6179 and 1 subject receiving placebo. The second sub-group will comprise 6 subjects, 
with 5 subjects receiving NST-6179 and 1 subject receiving placebo. 


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There will be a minimum of 7 days between dose escalations for each group in Part A. 
An overview of the study design is shown in Figure 1 and the planned dose levels are 
presented in Figure 2. A Schedule of Assessments is presented in Appendix 6. 
Section 3.1.1: Part A 
Previously read: 
Figure: 1: Study Schematic (Part A) for Groups A1, A2, and A4 to A6 
Now reads: 
Figure 1: Study Schematic (Part A) for Groups A1 to A6 
Section 3.1.1: Part A 
Figure 2 removed. 


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Section 3.1.1: Part A 
Previously read: 
Figure 3: Planned Dose Levels for Part A 
 
Abbreviations: N = number of subjects; PK = pharmacokinetic(s); TBD = to be determined. 
NOTE: dose levels may be adjusted based on the ongoing review of the safety, tolerability, and PK data. Doses will be administered in an escalating manner following satisfactory review by the 
sponsor and investigator of the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose) from the previous dose group. 
Although the food-effect evaluation is planned to occur in Group A3, this may be subject to change based on emerging data and may be conducted in a different dose group in Part A. 
Now reads: 
Figure 2: Planned Dose Levels for Part A 
 
Abbreviations: N = number of subjects; PK = pharmacokinetic(s); TBD = to be determined. 
NOTE: dose levels may be adjusted based on the ongoing review of the safety, tolerability, and PK data. Doses will be administered in an escalating manner following satisfactory review by the 
sponsor and investigator of the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose) from the previous dose group. 


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Section 3.1.1: Part A 
Previously read: 
The total planned duration of study participation for each subject (from screening through 
follow-up visit) is anticipated to be approximately 6 weeks for subjects not participating in 
the food-effect evaluation, and approximately 8 weeks for those participating in the 
food-effect evaluation. 
Now reads: 
The total planned duration of study participation for each subject (from screening through 
follow-up visit) is anticipated to be approximately 6 weeks. 
Section 3.1.2: Part B 
Previously read: 
In each of Groups B1 to B4, 8 subjects will receive NST-6179 and 2 subjects will receive 
placebo. The dietary state for dosing in Part B will be subject to review of the PK data from 
the fed/fasted comparison in Part A or earlier groups in Part B. For all subjects, dosing is 
planned to be QD on Days 1 to 14, inclusive. However, the dietary state (including fasting 
requirements and meal compositions), dosing frequency, and dosing duration in Part B may 
be changed following review of data from groups in Part A or earlier groups in Part B 
(Section 3.4). The total daily dose administered will not be predicted to exceed an exposure 
shown to be safe and well tolerated in Part A. The dose regimen will comprise no less than 
once every 2 days and will not exceed 4-times-daily dosing. The dosing duration will 
comprise no fewer than 7 consecutive days and will not exceed 28 consecutive days of dosing 
(Section 3.4). There will be a minimum of 14 days between dose escalations for each group 
in Part B. 
Now reads: 
In each of Groups B1 to B4, 8 subjects will receive NST-6179 and 2 subjects will receive 
placebo. For all subjects, dosing is planned to be QD on Days 1 to 14, inclusive. However, 
dosing frequency and duration in Part B may be changed following review of data from 
groups in Part A or earlier groups in Part B (Section 3.4). The total daily dose administered 
will not be predicted to exceed an exposure shown to be safe and well tolerated in Part A. 
The dose regimen will comprise no less than once every 2 days and will not exceed 
4-times-daily dosing. The dosing duration will comprise no fewer than 7 consecutive days 
and will not exceed 28 consecutive days of dosing (Section 3.4). There will be a minimum of 
14 days between dose escalations for each group in Part B. 


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Section 3.3: Additional Groups 
Previously read: 
Following review of the safety, tolerability, and PK data, additional dose groups (where 
systemic exposure is not expected to exceed that stated in the dose escalation stopping criteria 
[Section 3.7]) may be added to the study. Up to 3 further groups of 8 subjects 
(6 active:2 placebo) may be included in Part A, and up to 3 further groups of 10 subjects 
(8 active:2 placebo) may be included in Part B. This may include additional groups in Part A 
to explore the effect of food (ie, additional 2-period groups). There will be no further dose 
escalation in these additional groups if dose escalation stopping criteria have been met and a 
dose level cannot be repeated if it previously met a stopping criterion. The requirement for 
additional groups will be agreed with the sponsor and documented in the trial master file 
(TMF). 
Now reads: 
Following review of the safety, tolerability, and PK data, additional dose groups (where 
systemic exposure is not expected to exceed that stated in the dose escalation stopping criteria 
[Section 3.7]) may be added to the study. Up to 3 further groups of 8 subjects 
(6 active:2 placebo) may be included in Part A, and up to 3 further groups of 10 subjects 
(8 active:2 placebo) may be included in Part B. There will be no further dose escalation in 
these additional groups if dose escalation stopping criteria have been met and a dose level 
cannot be repeated if it previously met a stopping criterion. The requirement for additional 
groups will be agreed with the sponsor and documented in the trial master file (TMF). 
Section 3.4: Discussion of Study Design, Including the Choice of Control Groups 
Previously read: 
For Part A and Part B of the study, a sequential-group, ascending-dose design has been 
chosen for safety reasons as NST-6179 is in the early stages of clinical development, with 
Part A of the study being the first time it will be administered to humans. Oral doses have 
been chosen for both parts of the study, as this is the intended clinical route of administration. 
A 2-period design has been chosen for the food-effect arm, as this gives a within-subject 
assessment of the influence of food on the PK of NST-6179 and so increases the power of the 
study for the given number of subjects. 
Now reads: 
For Part A and Part B of the study, a sequential-group, ascending-dose design has been 
chosen for safety reasons as NST-6179 is in the early stages of clinical development, with 
Part A of the study being the first time it will be administered to humans. Oral doses have 
been chosen for both parts of the study, as this is the intended clinical route of administration. 


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Section 3.4: Discussion of Study Design, Including the Choice of Control Groups 
Previously read: 
Based upon the non-clinical data, the duration of each treatment period is considered 
adequate to achieve the study objectives. Where applicable, an interval of at least 7 days 
between treatment periods in the food-effect arm is considered adequate to prevent carryover 
of NST-6179. 
Now reads: 
Based upon the non-clinical data, the duration of each treatment period is considered 
adequate to achieve the study objectives. 
Section 3.5: Selection of Doses in the Study 
Previously read: 
Table 4: Proposed Investigational Medicinal Product Dose Levels for Parts A and B 
Study Part 
Group 
Subject Numbers 
Treatment Period 1 
Treatment Period 2 
Part A 
A1 
0101 – 0108 
50 mg or placebo 
NA 
A2 
0109 – 0116 
TBD mg or placebo 
NA 
A3a 
0117 – 0124 
TBD mg or placebo(fasted) 
TBD mg or placebo (fed) 
A4 
0125 – 0132 
TBD mg or placebo 
NA 
A5 
0133 – 0140 
TBD mg or placebo 
NA 
A6 
0141 – 0148 
TBD mg or placebo 
NA 
A7b 
0149 – 0156 
TBD 
TBD 
A8b 
0157 – 0164 
TBD 
TBD 
A9b 
0165 – 0172 
TBD 
TBD 
Part B 
B1 
0201 – 0210 
TBD mg or placebo 
NA 
B2 
0211 – 0220 
TBD mg or placebo 
NA 
B3 
0221 – 0230 
TBD mg or placebo 
NA 
B4 
0231 – 0240 
TBD mg or placebo 
NA 
B5c 
0241 – 0250 
TBD 
NA 
B6c 
0251 – 0260 
TBD 
NA 
B7c 
0261 – 0270 
TBD 
NA 
Abbreviations: NA = not applicable; PK = pharmacokinetic(s); TBD =to be determined. 
a. Although a food-effect evaluation is planned to occur in Group A3, this may be subject to change based on emerging data 
and may be conducted in a different dose group in Part A. 
b. Following review of the safety, tolerability, and PK data, additional dose groups (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]) may be added to the study. Up to 
3 further groups of 8 subjects (6 active:2 placebo) may be included in Part A. This may include additional groups in 
Part A to explore the effect of food (ie, additional 2-period groups). 
c. Following review of the safety, tolerability, and PK data, additional dose groups (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]) may be added to the study. Up to 
3 further groups of 10 subjects (8 active:2 placebo) may be included in Part B. 


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Now reads: 
Table 6: Proposed Investigational Medicinal Product Dose Levels for Parts A and B 
Study Part 
Group 
Subject Numbers 
Treatment Period 1 
Part A 
A1 
0101 – 0108 
50 mg or placebo 
A2 
0109 – 0116 
TBD mg or placebo 
A3 
0117 – 0124 
TBD mg or placebo 
A4 
0125 – 0132 
TBD mg or placebo 
A5 
0133 – 0140 
TBD mg or placebo 
A6 
0141 – 0148 
TBD mg or placebo 
A7a 
0149 – 0156 
TBD 
A8a 
0157 – 0164 
TBD 
A9a 
0165 – 0172 
TBD 
Part B 
B1 
0201 – 0210 
TBD mg or placebo 
B2 
0211 – 0220 
TBD mg or placebo 
B3 
0221 – 0230 
TBD mg or placebo 
B4 
0231 – 0240 
TBD mg or placebo 
B5b 
0241 – 0250 
TBD 
B6b 
0251 – 0260 
TBD 
B7b 
0261 – 0270 
TBD 
Abbreviations: NA = not applicable; PK = pharmacokinetic(s); TBD =to be determined. 
a. Following review of the safety, tolerability, and PK data, additional dose groups (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]) may be added to the study. Up to 
3 further groups of 8 subjects (6 active:2 placebo) may be included in Part A. 
b. Following review of the safety, tolerability, and PK data, additional dose groups (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]) may be added to the study. Up to 
3 further groups of 10 subjects (8 active:2 placebo) may be included in Part B. 
Section 4.2.1: Part A and B 
Exclusion criterion #19 removed. 
Section 5.2: Study Treatment Administration 
Previously read: 
Each dose of NST-6179 and placebo will be administered orally with approximately 240 mL 
of room temperature water. In Part A, all doses will be administered after an overnight fast of 
at least 10 hours, with the exception of Group A3, where the dose given in Treatment 
Period 2 will be administered 30 minutes after starting a high-fat breakfast. With the 
exception of water given with the dose, subjects will not be allowed fluids from 1 hour prior 
to until 2 hours after dosing. The dietary status for dosing in Part B will be determined 
following review of the PK data from the fed/fasted comparison in Part A or earlier groups in 
Part B. 
Now reads: 
Each dose of NST-6179 and placebo will be administered orally with approximately 240 mL 
of room temperature water. In Part A and on the days with intensive PK assessments in 
Part B, all doses will be administered after an overnight fast of at least 10 hours. With the 


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exception of water given with the dose, subjects will not be allowed fluids from 1 hour prior 
to until 2 hours after dosing. 
Section 5.3: Randomisation 
Previously read: 
In Part A, 6 subjects per group will be randomly assigned to receive NST-6179 and 2 subjects 
per group will be randomly assigned to receive placebo. Subjects participating in a 
food-effect evaluation will receive the same treatment in Treatment Periods 1 and 2. For all 
groups in Part A, sentinel dosing will occur whereby 2 subjects (1 active and 1 placebo) will 
be dosed on 1 day and, providing no safety concerns arise, the remaining 6 subjects (5 active 
and 1 placebo) will be dosed after 24 hours. For groups participating in a food-effect 
evaluation, sentinel dosing will only be utilised in Treatment Period 1 when NST-6179 or 
placebo are administered in the fasted state. 
Now reads: 
In Part A, 6 subjects per group will be randomly assigned to receive NST-6179 and 2 subjects 
per group will be randomly assigned to receive placebo. For all groups in Part A, sentinel 
dosing will occur whereby 2 subjects (1 active and 1 placebo) will be dosed on 1 day and, 
providing no safety concerns arise, the remaining 6 subjects (5 active and 1 placebo) will be 
dosed after 24 hours. 
Section 6.2: Diet 
Previously read: 
On the days with intensive PK assessments (Day 1 for Part A and Days 1 and 14 for Part B), 
meals will be identical for each group with the exception of the high-fat breakfast for 
Group A3 (or any other group participating in a food-effect evaluation). 
Fasted doses: On Day 1 in Part A, subjects will be fasted for at least 10 hours prior to dosing 
until approximately 4 hours after dosing, when lunch will be provided (lunch times on Day 1 
will be staggered between subjects to ensure this). With the exception of water given with the 
dose, subjects will not be allowed fluids from 1 hour prior to until 2 hours after dosing. Meals 
will be provided as appropriate at other times. Other than the fluid restrictions on dosing 
days, water will be freely available at all times. 
Fed doses: Subjects in Group A3 (or any other group participating in a food-effect 
evaluation) in Treatment Period 2 will consume a high-fat breakfast (contents are detailed in) 
before dosing. Subjects should start the meal 30 minutes prior to administration of the IMP. 
Study subjects should eat this meal in 30 minutes or less. The drug product should be 
administered 30 minutes after the start of the meal. Subjects will be fasted for approximately 
4.5 hours after dosing. With the exception of milk given with the high-fat breakfast and water 
given with the dose, subjects will not be allowed fluids from 1 hour prior to until 2 hours 
after dosing 


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Table 5: 
High-fat Breakfast Content 
High-fat Breakfast 
120 g fried eggs (2 eggs) in vegetable oil 
50 g bacon (2 rashers) 
72 g toasted white bread (2 slices) 
13 g butter (2 pats) 
108 g hash brown (3 each) 
240 g whole milk 
Total calories: 973 kcal 
This high-fat meal contains the equivalent of approximately 150 protein calories, 
250 carbohydrate calories, and 500 to 600 fat calories. 
In Part B, the time interval between meals and dosing will be determined by the PK data from 
Part A and will be documented in the TMF. Meals will be provided as appropriate at other 
times. With the exception of water given with the dose, subjects will not be allowed fluids 
from 1 hour prior to dosing until 2 hours after dosing. Other than these fluid restrictions, 
water will be freely available at all times. 
Now reads: 
On the days with intensive PK assessments, meals will be identical for each group. 
On Day 1 in Part A, subjects will be fasted for at least 10 hours prior to dosing until 
approximately 4 hours after dosing, when lunch will be provided (lunch times on Day 1 will 
be staggered between subjects to ensure this). With the exception of water given with the 
dose, subjects will not be allowed fluids from 1 hour prior to until 2 hours after dosing. Meals 
will be provided as appropriate at other times. Other than the fluid restrictions on dosing 
days, water will be freely available at all times. 
In Part B, on days with intensive PK assessments, subjects will be fasted for at least 
10 hours prior to dosing until approximately 4 hours after dosing. Meals will be provided 
as appropriate at other times. With the exception of water given with the dose, subjects will 
not be allowed fluids from 1 hour prior to dosing until 2 hours after dosing. Other than these 
fluid restrictions, water will be freely available at all times. 
Section 8.3: Pharmacokinetic Analyses 
Previously read: 
A statistical analysis will be conducted to investigate the dose proportionality of AUC0-tlast, 
AUC0-, and Cmax on Day 1 in Part A and AUC0-Ĳ and Cmax on Day 14 in Part B. The PK 
parameters will be analysed using a power model. However, if the assumption of linearity is 
ruled unacceptable for any PK parameter, its corresponding PK parameter normalised by 
dose administered will be natural log-transformed and analysed using an analysis of variance 
model. 


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A statistical analysis will be conducted to investigate the food effect on the treatment for 
AUC0-tlast, AUC0-, Cmax, and tmax in Part A (food-evaluation group only). The natural 
log-transformed AUC0-tlast, AUC0-, and Cmax parameters will be analysed using a mixed 
model. The model will include actual treatment as fixed effect and subject as a random effect, 
where treatment includes the fasting status. The tmax parameter will be analysed using the 
Wilcoxon signed-rank test. 
Now reads: 
A statistical analysis will be conducted to investigate the dose proportionality of AUC0-tlast, 
AUC0-, and Cmax on Day 1 in Part A and AUC0-Ĳ and Cmax on Day 14 in Part B. The PK 
parameters will be analysed using a power model. However, if the assumption of linearity is 
ruled unacceptable for any PK parameter, its corresponding PK parameter normalised by 
dose administered will be natural log-transformed and analysed using an analysis of variance 
model. 
Appendix 3: Total Blood Volume 
Previously read: 
Part A 
The following blood volumes will be withdrawn for each subject not participating in a 
food-effect evaluation: 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory evaluationsa 
7.5 
5 
37.5 
Serology 
3.5 
1 
3.5 
Coagulation 
1.8 
5 
9.0 
NST-6179 pharmacokineticsb 
2.0 
19 
38.0 
Total: 
88.0 
Abbreviation: FSH = follicle-stimulating hormone. 
a. Includes pregnancy and FSH tests. 
b. Includes 3 additional samples that may be taken. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 140 mL. 
The following blood volumes will be withdrawn for each subject participating in a 
food-effect evaluation: 


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Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory evaluationsa 
7.5 
8 
60.0 
Serology 
3.5 
1 
3.5 
Coagulation 
1.8 
8 
14.4 
NST-6179 pharmacokineticsb 
2.0 
37 
74.0 
Total: 
151.9 
Abbreviation: FSH = follicle-stimulating hormone. 
a. Includes pregnancy and FSH tests. 
b. Includes 3 additional samples (per treatment period) that may be taken. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 205 mL. 
Now reads: 
Part A 
The following blood volumes will be withdrawn for each subject: 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory evaluationsa 
7.5 
5 
37.5 
Serology 
3.5 
1 
3.5 
Coagulation 
1.8 
5 
9.0 
NST-6179 pharmacokineticsb 
2.0 
19 
38.0 
Total: 
88.0 
Abbreviation: FSH = follicle-stimulating hormone. 
a. Includes pregnancy and FSH tests. 
b. Includes 3 additional samples that may be taken. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 140 mL. 
Appendix 6: Schedule of Assessments 
Reference to food-effect removed, and footnotes edited, as applicable. 
 


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Appendix 6: Schedule of Assessments 
Previously read: 
Schedule of Assessments – Part A (Single Dose in Healthy Subjects) 
Study Procedures 
Screening 
(Day -28 to 
Day -2) 
Treatment Period 1 (and 2 for Group A3)a 
Follow-up 
(10 to 14 days 
postdose) 
Day -1 
Days 1 to 4 
 
NST-6179 or placebo 
 
 
Day 1 (0 hour) (30 minutes after starting a high-fat breakfast in Treatment 
Period 2 for Group A3a) 
 
Safety and tolerability: 
 
 
 
 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Predose and 72 hours postdose 
X 
Coagulation 
X 
X 
Predose and 72 hours postdose 
X 
Now reads: 
Schedule of Assessments – Part A (Single Dose in Healthy Subjects) 
Study Procedures 
Screening 
(Day -28 to 
Day -2) 
Treatment Period 1 
Follow-up 
(10 to 14 days 
postdose) 
Day -1 
Days 1 to 4 
 
NST-6179 or placebo 
 
 
Day 1 (0 hour) 
 
Safety and tolerability: 
 
 
 
 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Predose and 48 hours postdose 
X 
Coagulation 
X 
X 
Predose and 48 hours postdose 
X 


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Version 2 to Version 3 
NST-6179 is a novel, orally administered, fully-synthetic medium chain fatty acid (MCFA) 
analogue which is being developed for the treatment or the treatment of Intestinal failure-
associated liver disease (IFALD), and other potential indications. Study NST-6179-01 is a 
Phase 1, first-in-human, randomised, placebo-controlled single- and multiple-ascending dose 
study to evaluate the safety, tolerability, and pharmacokinetics (PK) of NST-6179 (EudraCT 
Number: 2021-000839-31). The study was approved by the Medicines and Healthcare 
products Regulatory Agency (MHRA) on 28 May 2021 and by the Ethics Committee (EC) on 
28 May 2021. The completed non-clinical program primary pharmacology studies in relevant 
in vivo mouse models, safety pharmacology studies in vitro and in vivo in the rat and monkey, 
in vitro mouse, rat, rabbit, dog, monkey and human plasma protein binding, repeated dose (28 
day) toxicity study in the rat and monkey, and genotoxicity assessment. Further details of 
these studies are included in the Investigator Brochure (Version 1.0, 09 March 2021), all of 
which supported the initiation of the Phase 1, first-in-human clinical study. 
Subsequently, a 13-week repeat dose oral toxicity study in the monkey was initiated on 16 
June 2021 and is currently ongoing. Single daily oral doses of 0, 60, 210, or 350 mg/kg/day 
have been administered in both male and female monkeys and generally well tolerated to 
date. Mild spurious vomiting was observed at 350 mg/kg/day in both males and females, 
which declined in frequency over time. Additionally, an 8% decrease in bodyweight was also 
observed during the first week of dosing in both male and female animals at the high dose as 
well, which subsequently increased back to baseline at Day 7. No other relevant clinical 
findings have been observed to date at any dose level in either male or female monkeys. 
However, on Day 16, a single female monkey in the high dose group was found dead 
following dosing on Day 15. The decedent female appeared to be in general good health and 
displayed no clinical signs up through and postdose on Day 15. Dosing was temporarily held 
in the high dose female cohort and, out of caution, was restarted at a lower dose of 
300 mg/kg/day, as well as increasing the frequency of postdose monitoring. An investigation 
was initiated immediately which include an expedited macroscopic post-mortem examination 
and clinical pathology assessment as well as a review of all study data prior to the event for 
the decedent monkey and the other animals in the study. The Sponsor placed a temporary 
hold on the Phase 1 clinical study on 02 July 2021 with notification to the MHRA and EC in 
accordance with the required timelines. 
A macroscopic post-mortem examination was performed on the decedent female and all 
major organs and tissues were processed for histopathological examination. The absence of 
advanced autolysis at macroscopic post-mortem indicated the female died relatively soon 
prior to the post-mortem examination. Although an exact time of death cannot be established, 
the relative timeframe of death was close to 24 hours after the Day 15 dose, when minimal 
drug concentrations levels would have been present. Microscopically, minimal 
alveolar/interstitial inflammation was noted which is consistent with post-aspiration effects. 
However, the minimal severity and distribution is considered not to be the cause of mortality. 
The majority of tissues were well preserved but some autolysis was noted in the gall bladder 
and gastrointestinal tract and to a lesser extent liver, pancreas, and salivary glands. Although 
histopathological assessment has not identified the cause of death, there was no evidence of 
drug-related changes or injury. 


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Further detailed examination of the clinical condition and study data from the decedent 
animal was also reviewed to determine any underlying condition existed as a potential cause 
of death. Clinical chemistry and urinalysis parameters were all normal. Haematology 
parameters were all within normal limits, with the exception of minimal increases in white 
cells and absolute neutrophil count. However, no evidence of infection was noted associated 
with these elevations. A minimal decrease in red cells, haemoglobin and packed cell volume 
was noted. None of these changes were considered to be clinically meaningful nor 
contributory to the cause of death. Assessment of the decedents ECG indicated minor 
anomalies considered not clinically relevant. All of the clinical and laboratory data preceding 
the event, as well as the post-mortem assessments, have been peer reviewed by two 
pathologists, both of whom concur with the observations and the lack of evidence of a 
drug-related event. 
A review of the data from the prior 28-day repeat dose oral toxicity study in monkeys 
established 350 mg/kg/day was the no-observed-adverse-effect level (NOAEL) level 
(Covance: 8423746). No clinical signs and symptoms or mortality was observed at this dose 
level. Importantly, in the ongoing 13-week study, NST-6179 continues to be well tolerated in 
all other males and females at all dosages. 
In summary, the investigation will continue to attempt to establish a cause of death but as of 
this date there is no clear evidence that this was a drug-related event. However, in accordance 
with the temporary hold, all patient-related activities were stopped and no participant has 
been randomized or dosed with NST-6179 at this time. Additionally, the Sponsor is 
proposing the following changes to Study NST-6179-01 as a precaution in response to the 
observed event: 
1. Revision to Dose Escalation Stopping Criterion based on PK. 
The PK stopping rule in Protocol Version 2 (26 April 2021) was based on the 
female maximum observed concentration (Cmax) and area under the 
concentration-time curve from time zero to 24 hours postdose (AUC0-24) at the 
NOAEL in the cynomolgus monkey 28-day repeat dose oral toxicity study at the 
high dose level of 350 mg/kg/day, with values of 59,100 ng/mL for Cmax and 
440,000 ng.h/mL for AUC0-24. Although there is no clear relationship between 
drug treatment and mortality of the female monkey in the current study, we 
propose a revision to ensure the participant safety. The proposed revision 
incorporates the AUC0-24 in the female cynomolgus monkey at the intermediate 
dose level (175 mg/kg/day) in the 28-day oral toxicity study (AUC0-24 of 358000 
ng.hr/mL); a decrease from the current AUC0-24. In the 28-day oral monkey 
toxicity study, the Cmax in the female high dose 350 mg/kg/day (59,100 ng/mL) is 
lower than that at the low and intermediate dose levels of 60 mg/kg (Cmax of 
72,400 ng/mL) and 175 mg/kg (Cmax of 147,000 ng/mL) respectively. 
Additionally, no adverse observations have been recorded that correlate with Cmax, 
including the female mortality in the 13-week study. Therefore, no change to the 
Cmax stopping rule is proposed at this time. 
1. Decrease of Initial Proposed Human Starting Dose. 
The initial proposed human starting dose of 100 mg is well within the safety 
margins with projected exposures significantly lower than the proposed stopping 


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rules. However, we are proposing to decrease the starting dose to 50 mg to further 
mitigate any risk to study subjects. 
2. Removal of Part C. 
The inclusion of Part C (open-label, single oral dose study to evaluate the PK of 
NST-6179 in patients receiving home parenteral nutrition, for short bowel 
syndrome, but with a functional duodenum, was planned to be incorporated in a 
future substantial amendment). The initial study plan was to evaluate the safety, 
tolerability and PK of NST-6179 exposure in healthy subjects followed by an 
evaluation of relevant doses in the intended population. However, NorthSea 
Therapeutics believe it is prudent to evaluate additional 13-week toxicology data 
in the context of the healthy participant data prior to dosing in a patient 
population. Therefore, we are removing the patient cohort from the current 
single-ascending dose/multiple-ascending dose study. 
3. Update of Sponsor Signatory and Sponsor Project manager due to personnel 
changes. 
4. As of June 2021, there has been a name change with Covance being rebranded as 
Labcorp. 
Minor changes: 
5. The synopsis was updated according to changes in the protocol body, as 
applicable. 
6. The amendment/version number and date were updated throughout the protocol. 
7. The header was updated to reflect Covance being rebranded as Labcorp. 
8. Abbreviations were added and/or removed, as appropriate. 
A detailed summary of changes is presented below: 
For each section, deleted text is shown in strikethrough, and new text is shown in bold. 
Title 
Previously read: 
A Phase 1, First Time in Human Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of NST-6179 in Healthy Subjects and Patients Requiring Home Parenteral 
Nutrition (HPN) for Short Bowel Syndrome 
Now reads: 
A Phase 1, First Time in Human Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of NST-6179 in Healthy Subjects 
Title Page 
Previously read: 
Covance Study Number: 8462139 


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Now reads: 
Labcorp Drug Development Study Number: 8462139 
Title Page 
Previously read: 
Study Site: 
Covance Clinical Research Unit (CRU) Ltd. 
Now reads: 
Study Site: 
Labcorp Clinical Research Unit (CRU) Ltd. 
Title Page 
Previously read: 
Sponsor Signatory: 
Dr Patrick Round, MBBS, FFPM 
Now reads: 
Sponsor Signatories: 
Dr Stephen Rossi, PharmD 
Dr Stephen Harrison, MD 
SPONSOR APPROVAL 
Previously read: 
Sponsor Signatory: 
Dr Patrick Round, MBBS, FFPM 
Medical Director 
NorthSea Therapeutics B.V. 
Now reads: 
Sponsor Signatory: 
Dr Stephen Rossi, PharmD 
Chief Development Officer 
NorthSea Therapeutics B.V. 
Dr Stephen Harrison, MD 
Chief Medical Officer 
NorthSea Therapeutics B.V. 


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STUDY IDENTIFICATION 
Previously read: 
Sponsor’s Study Contact 
Lis Mable 
Project Manager 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Sponsor’s Medical Contact 
Dr Patrick Round, MBBS, FFPM 
Medical Director 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25 C6 
1105 BP, Amsterdam 
The Netherlands 
Tel (after hours): +44 (0)7979 502 770 
Study Site 
Covance Clinical Research Unit (CRU) Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
Dr Jim Bush, MBChB, PhD, MRCS, FFPM, GFMD 
VP CPS Medical Services 
Covance CRU Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Tel: +44 (0) 113 301 3644 
Tel (after hours): +44 (0) 113 301 3500 
Project Physician 
Dr Samuel Israel, MB:BS, MRCOG, FRCOG 
Clinical Research Physician 
Covance CRU Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Tel: +44 (0) 113 301 3527 
Clinical Laboratory 
Covance Clinical Pathology Services 
Otley Road 
Harrogate, HG3 1PY 
United Kingdom 
Statistician 
Izabela Antys, BSc MSc GradStat 
Covance Biometrics 


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Now reads: 
Sponsor’s Study Contact 
Kathline Kim 
Senior Clinical Trial Manager 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Tel: +1 510 282 3024 
Email: kathline.kim@northseatherapeutics.com 
Study Director 
Dr Stephen Rossi, PharmD 
Chief Development Officer 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Tel: +1 415 572 0596 
Email: stephen.rossi@northseatherapeutics.com 
Sponsor’s Medical Contact 
Dr Stephen Harrison, MD 
Chief Medical Officer 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Tel: +1 210 288 5868 
Email: stephen.harrison@northseatherapeutics.com 
Study Site 
Labcorp Clinical Research Unit (CRU) Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
Dr Jim Bush, MBChB, PhD, MRCS, FFPM, GFMD 
VP CPS Medical Services 
Labcorp CRU Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Tel: +44 (0) 113 301 3644 
Tel (after hours): +44 (0) 113 301 3500 
Project Physician 
Dr Samuel Israel, MB:BS, MRCOG, FRCOG 
Clinical Research Physician 
Labcorp CRU Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Tel: +44 (0) 113 301 3527 


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Clinical Laboratory 
Labcorp Early Development Laboratories Ltd. 
Otley Road 
Harrogate, HG3 1PY 
United Kingdom 
Statistician 
Izabela Antys, BSc MSc GradStat 
Labcorp Drug Development 
Section 1.3: Summary of Safety Pharmacology 
Previous read: 
Four safety pharmacology studies were conducted (all were conducted to Good Laboratory 
Practice [GLP]). 
Now reads: 
Four safety pharmacology studies were completed (all conducted to Good Laboratory 
Practice [GLP]). 
Section 1.4.3 (new section): 13-week Oral (Gavage) Toxicity and Toxicokinetic Study in the 
Monkey with a 2-week Recovery Period 
This is an ongoing study objective to evaluate the toxicity and determine the 
toxicokinetics (TK) of NST-6179 when administered daily via oral gavage to the monkey 
for at least 13 weeks and to assess the reversibility or persistence of any effects after a 
4-week recovery phase following doses of 60 mg/kg/day (low dose), 210 mg/kg/day 
(intermediate dose), and 350 mg/kg/day (high dose). The purpose of the study is to 
establish dose levels for future long term toxicity studies. A high dose level of 
350 mg/kg/day was selected based on results from a 28-day repeat dose toxicity study 
(Covance 8423746). An original high dose of 500 mg/kg/day was not tolerated, resulting 
in two early sacrifices and postdose observations of decreased activity, ataxia, semi-
closed eyes, hunched posture, and vomiting. Following a 30-day washout period, a 
revised high dose level of 350 mg/kg/day was investigated over 28 days, which was 
tolerated with no mortality and transient mild and occasional postdose observations of 
decreased activity, hunched posture, and vomiting that diminished throughout the 28 
days dosing. An intermediate dose level of 210 mg/kg/day was selected as an alternative 
high dose level for future studies if the selected high dose level was not tolerated. A low 
dose level of 60 mg/kg/day was expected to be tolerated in-life, with no postdose 
observations or body weight effect noted following 28 days repeat administration at this 
dose level during the previous toxicity study. The cynomolgus monkey was selected as 
the relevant species because of the similarity of monkeys to humans in species specific 
cross-reactivity of test article. An in vitro metabolism study (Covance study 8423743) 
indicated the cynomolgus monkey is the preferred choice of large animal species due to 
the presence of specific human metabolites, which are not present in other species. 
Animals were dosed through Day 15 and NST-6179 was generally well tolerated with 
only mild spurious vomiting and an 8% decrease in bodyweight observed in the early 
stages, both of which returned to baseline status over time. No other relevant clinical 


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findings have been observed to date at any dose level in either male or female monkeys. 
However, on Day 16, a single female monkey in the high dose group was found dead 
following dosing on Day 15. The decedent female appeared to be in general good health 
and displayed no clinical signs up through and postdose on Day 15. Dosing was 
temporarily held in the high dose female cohort and out of caution was restarted at a 
lower dose of 300 mg/kg/day and the frequency of postdose monitoring was increased. A 
macroscopic post-mortem examination showed no advanced autolysis at macroscopic 
post-mortem indicated the female died relatively soon prior to the post-mortem 
examination. Although an exact time of death cannot be established, the relative time 
frame of death was close to 24 hours after the Day 15 dose, when minimal drug 
concentrations levels would have been present. Microscopically, minimal 
alveolar/interstitial inflammation was noted which is consistent with post aspiration 
effects. However, the minimal severity and distribution is considered not to be the cause 
of mortality. The majority of tissues were well preserved but some autolysis was noted 
in the gall bladder and gastrointestinal tract and to a lesser extent liver, pancreas and 
salivary glands. Further detailed examination of the clinical condition and study data 
from the decedent animal was also reviewed to determine any underlying condition 
existed as a potential cause of death. Clinical chemistry and urinalysis parameters were 
all normal. Haematology parameters were all within normal limits, with the exception 
of minimal increases in white cells and absolute neutrophil count. However, no evidence 
of infection was noted associated with these elevations. A minimal decrease in red cells, 
haemoglobin and packed cell volume was noted. None of these changes were felt to be 
clinically meaningful nor contributory to the cause of death. Assessment of the 
decedents ECG indicated minor anomalies considered not clinically relevant. 
A review of the data from the prior 28-day repeat dose oral toxicity study in monkeys 
established 350 mg/kg/day was the NOAEL level (Covance 8423746). No clinical signs 
and symptoms or mortality was observed at this dose level. Importantly, in the ongoing 
13-week study, NST-6179 continues to be well tolerated in all other males and females at 
all dosages up to 28 days of dosing. In summary, all of the clinical and laboratory data 
preceding the event, as well as the post-mortem assessments, have been peer reviewed 
by two pathologists, both of whom concur with the observations and the lack of 
evidence of a drug-related event. 
Section 1.7: Study Rationale 
Previously read: 
This is the first time NST-6179 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when NST-6179 is administered orally as single 
and multiple doses to healthy subjects. In addition, this study aims to evaluate the PK of a 
single dose of NST-6179 in patients receiving home parenteral nutrition (HPN) for short 
bowel syndrome. This information, together with the PK data from healthy subjects, will help 
establish the doses and dosing regimen suitable for future studies in patients. The study will 
also investigate the effects of food on the PK of NST-6179 prior to patient studies. 


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Now reads: 
This is the first time NST-6179 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when NST-6179 is administered orally as single 
and multiple doses to healthy subjects. This information will help establish the doses and 
dosing regimen suitable for future studies in patients. The study will also investigate the 
effects of food on the PK of NST-6179 prior to patient studies. 
Section 2.1: Objectives 
Previously read: 
The primary objectives of the study are: 
x to assess the safety and tolerability of single and multiple oral doses of NST-6179 in 
healthy male and female subjects 
x to assess the safety and tolerability of single doses of NST-6179 in male and female 
patients receiving HPN for short bowel syndrome, but with a functional duodenum. 
The secondary objectives of the study are: 
x to evaluate the single and multiple oral dose PK of NST-6179 in healthy male and 
female subjects 
x to determine the effect of food on the single oral dose PK of NST-6179 in healthy 
male and female subjects 
x to evaluate the PK profile in male and female patients receiving HPN for short bowel 
syndrome, but with a functional duodenum. 
Now reads: 
The primary objectives of the study are: 
x to assess the safety and tolerability of single and multiple oral doses of NST-6179 in 
healthy male and female subjects 
The secondary objectives of the study are: 
x to evaluate the single and multiple oral dose PK of NST-6179 in healthy male and 
female subjects 
x to determine the effect of food on the single oral dose PK of NST-6179 in healthy 
male and female subjects. 
Section 3: Investigational Plan 
Previously read: 
This will be a partly double-blind, randomised, placebo-controlled, single and multiple oral 
dose study conducted in 3 parts. Part A and Part B will be double-blind, randomised, 


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placebo-controlled, with subjects receiving single (Part A) and multiple (Part B) oral doses. 
Part C will be open-label, non-randomised with patients receiving a single oral dose. 
Now reads: 
This will be a partly double-blind, randomised, placebo-controlled, single and multiple oral 
dose study conducted in 3 parts. Part A and Part B will be double-blind, randomised, 
placebo-controlled, with subjects receiving single (Part A) and multiple (Part B) oral doses. 
 


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Figure 3: Planned Dose Levels for Part A 
Previously read: 
 
Now reads: 
 


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Section 3.1.3: Part C 
Part C will be an open-label, single oral dose study to evaluate the PK of NST-6179 in 
patients receiving HPN for short bowel syndrome, but with a functional duodenum. Four to 
6 patients will be studied in a single group (Group C1). 
Part C will be described in a future substantial protocol amendment. 
Section 3.5: Selection of Doses in the Study 
Previously read: 
Compared to the HED for the NOAEL in the rat, the most sensitive species (ie, that with the 
lowest HED), a starting dose of 100 mg in Part A will correspond to a dose of: 
100 mg
60 kg  = 1.67 mg/kg in a 60-kg subject 
and a safety margin of: 
72 mg/kg
1.67 mg/kg  = 43-fold 
The approximate effective dose of NST-6179 in an efficacy model in the mouse was 
70 mg/kg (Section 1.5.3), which corresponds to a HED of: 
Mouse: 
70 mg/kg × 0.08 = 5.6 mg/kg 
(equivalent to approximately 336 mg in a 60-kg subject) 
Where 0.08 is the conversion factor to extrapolate the animal dose to the HED based on body 
surface area.2 Compared to the HED for the approximate effective dose in the mouse (ie, dose 
shown to have pharmacological activity in the mouse model), a starting dose of 100 mg in 
Part A will be approximately 3-fold lower than a dose expected to have pharmacological 
activity: 
5.6 mg/kg
1.67 mg/kg  = 3.4-fold 
Evaluation of protein binding indicates the unbound drug fraction is 4% in mouse compared 
to 1.78% in human. The proposed starting dose based on unbound drug is therefore 
approximately 9 times lower than the effective dose. Although there is no empirical data that 
defines a pharmacologically inactive dose in the mouse it is considered unlikely that a human 
starting dose of 100 mg would elicit significant pharmacological activity, if any. Furthermore 
metabolism in vitro is notably lower in mouse compared to human. Exposure to parent drug 
in human is likely to be proportionately less than mouse based on equivalent doses. 


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Now reads: 
Compared to the HED for the NOAEL in the rat, the most sensitive species (ie, that with the 
lowest HED), a starting dose of 50 mg in Part A will correspond to a dose of: 
50 mg
60 kg  = 0.83 mg/kg in a 60-kg subject 
and a safety margin of: 
72 mg/kg
0.83 mg/kg  = 87-fold 
The approximate effective dose of NST-6179 in an efficacy model in the mouse was 
70 mg/kg (Section 1.5.3), which corresponds to a HED of: 
Mouse: 
70 mg/kg × 0.08 = 5.6 mg/kg 
(equivalent to approximately 336 mg in a 60-kg subject) 
Where 0.08 is the conversion factor to extrapolate the animal dose to the HED based on body 
surface area.2 Compared to the HED for the approximate effective dose in the mouse (ie, dose 
shown to have pharmacological activity in the mouse model), a starting dose of 50 mg in 
Part A will be approximately 7-fold lower than a dose expected to have pharmacological 
activity: 
5.6 mg/kg
0.83 mg/kg  = 6.7-fold 
Evaluation of protein binding indicates the unbound drug fraction is 4% in mouse compared 
to 1.78% in human. The proposed starting dose based on unbound drug is therefore 
approximately 15 times lower than the effective dose. Although there is no empirical data 
that defines a pharmacologically inactive dose in the mouse it is considered unlikely that a 
human starting dose of 50 mg would elicit significant pharmacological activity, if any. 
Furthermore metabolism in vitro is notably lower in mouse compared to human. Exposure to 
parent drug in human is likely to be proportionately less than mouse based on equivalent 
doses. 


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Table 4: Proposed Investigational Medicinal Product Dose Levels for Parts A and B 
Previously read: 
Study Part 
Group 
Subject Numbers 
Treatment Period 1 
Treatment Period 2 
Part A 
A1 
0101 – 0108 
100 mg or placebo 
NA 
A2 
0109 – 0116 
TBD mg or placebo 
NA 
A3a 
0117 – 0124 
TBD mg or placebo (fasted) TBD mg or placebo (fed) 
A4 
0125 – 0132 
TBD mg or placebo 
NA 
A5 
0133 – 0140 
TBD mg or placebo 
NA 
A6 
0141 – 0148 
TBD mg or placebo 
NA 
A7b 
0149 – 0156 
TBD 
TBD 
A8b 
0157 – 0164 
TBD 
TBD 
A9b 
0165 – 0172 
TBD 
TBD 
Now reads: 
Study Part 
Group 
Subject Numbers 
Treatment Period 1 
Treatment Period 2 
Part A 
A1 
0101 – 0108 
50 mg or placebo 
NA 
A2 
0109 – 0116 
TBD mg or placebo 
NA 
A3a 
0117 – 0124 
TBD mg or placebo (fasted) TBD mg or placebo (fed) 
A4 
0125 – 0132 
TBD mg or placebo 
NA 
A5 
0133 – 0140 
TBD mg or placebo 
NA 
A6 
0141 – 0148 
TBD mg or placebo 
NA 
A7b 
0149 – 0156 
TBD 
TBD 
A8b 
0157 – 0164 
TBD 
TBD 
A9b 
0165 – 0172 
TBD 
TBD 
Section 3.7: Dose Escalation Stopping Criteria 
Previously read: 
x The systemic exposure for any individual subject is predicted to exceed a Cmax of 
59,100 ng/mL and/or an AUC0-24 of 440,000 ng.h/mL (based on the female monkey 
kinetics at the NOAEL [350mg/kg/day at Day 28] which is the lowest exposure seen 
in repeat dose toxicology). 
Now reads: 
x The systemic exposure for any individual subject is predicted to exceed an AUC0-24 of 
358,000 ng.hr/mL (based on the female cynomolgus monkey at the intermediate 
dose level of 175 mg/kg/day at Day 28) in the 28-day oral toxicity study and/or a 
Cmax of 59,100 ng/mL (based on the female cynomolgus monkey kinetics at the 
NOAEL [350 mg/kg/day at Day 28]). 


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Protocol Reference: NST-6179-01 
Protocol Version 5, 11 July 2022 
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Section 5.3: Randomisation 
Previously read: 
The randomisation code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. 
Now reads: 
The randomisation code will be produced by the statistics department at Labcorp Drug 
Development using a computer-generated pseudo-random permutation procedure. 
Section 5.4: Blinding 
Previously read: 
The following controls will be employed to maintain the double-blind status of the study: 
x The placebo capsules will be identical in appearance to NST-6179. 
x The investigator and other members of staff involved with the study will remain 
blinded to the treatment randomisation code during the assembly procedure. 
x The investigator and other members of staff (with the exception of pharmacy staff) 
involved with the study will remain blinded to the treatment randomisation code 
during the conduct of the study. 
x Interim bioanalytical data will be provided to Covance in a blinded manner. 
Now reads: 
The following controls will be employed to maintain the double-blind status of the study: 
x The placebo capsules will be identical in appearance to NST-6179. 
x The investigator and other members of staff involved with the study will remain 
blinded to the treatment randomisation code during the assembly procedure. 
x The investigator and other members of staff (with the exception of pharmacy staff) 
involved with the study will remain blinded to the treatment randomisation code 
during the conduct of the study. 
x Interim bioanalytical data will be provided to Labcorp CRU in a blinded manner. 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations (Data Quality 
Assurance) 
Previously read: 
The following data quality steps will be implemented: 
x Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality tolerance 


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Protocol Version 5, 11 July 2022 
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thresholds, controls, and mitigation plans will be documented in a project 
management plan. Additional details of quality checking to be performed on the data 
may be included in a data management plan. 
Now reads: 
The following data quality steps will be implemented: 
x Labcorp Drug Development is responsible for the data management of this study 
including quality checking of the data. Predefined agreed risks, monitoring thresholds, 
quality tolerance thresholds, controls, and mitigation plans will be documented in a 
project management plan. Additional details of quality checking to be performed on 
the data may be included in a data management plan. 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations (Investigator 
Documentation Responsibilities) 
Previously read: 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the data management plan. 
Now reads: 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to Labcorp Drug Development electronically, will be integrated with the 
subject’s eCRF data in accordance with the data management plan. 


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Protocol Reference: NST-6179-01 
Protocol Version 5, 11 July 2022 
Page 116 of 116 
Version 1 to Version 2 
At the request of the Medicines and Healthcare products Regulatory Agency (MHRA), the 
primary changes in this amendment are: 
1. Section 3.5 has been updated to clarify the starting dose is unlikely to be 
pharmacologically active. 
2. Section 3.7 has been updated to base the pharmacokinetic (PK) stopping criteria 
on the female monkey. 
Minor changes: 
1. The amendment/version number and date were updated throughout the protocol. 
A detailed summary of changes is presented below: 
For each section, deleted text is shown in strikethrough, and new text is shown in bold. 
Section 3.5: Selection of Doses in the Study 
Evaluation of protein binding indicates the unbound drug fraction is 4% in mouse 
compared to 1.78% in human. The proposed starting dose based on unbound drug is 
therefore approximately 9 times lower than the effective dose. Although there is no 
empirical data that defines a pharmacologically inactive dose in the mouse it is 
considered unlikely that a human starting dose of 100 mg would elicit significant 
pharmacological activity, if any. Furthermore metabolism in vitro is notably lower in 
mouse compared to human. Exposure to parent drug in human is likely to be 
proportionately less than mouse based on equivalent doses. 
Section 3.7: Dose Escalation Stopping Criteria 
Previously read: 
x The systemic exposure for any individual subject is predicted to exceed a Cmax of 
69,400 ng/mL and/or an AUC0-24 of 1,090,000 ng.h/mL (ie, systemic exposure will be 
no greater than the Cmax and AUC0-24 at the NOAEL with the lowest HED [rat]). 
Now reads: 
x The systemic exposure for any individual subject is predicted to exceed a Cmax of 
59,100 ng/mL and/or an AUC0-24 of 440,000 ng.h/mL (based on the female monkey 
kinetics at the NOAEL [350mg/kg/day at Day 28] which is the lowest exposure 
seen in repeat dose toxicology). 

SAP_001.pdf: 
 
 
TITLE PAGE 
Statistical Analysis Plan 
A Phase 1, First Time in Human Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of NST-6179 in Healthy Subjects 
SAP Status: Final 
SAP Version: 1.0 
SAP Date: 26AUG2022 
Investigational Medicinal Product: NST-6179 
Protocol Reference: NST-6179-01 
Labcorp Drug Development Study: 8462139 
 
 
Sponsor: 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Study Site: 
Labcorp Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
 
 
Principal Investigator: 
Dr Jim Bush, MBChB, PhD, MRCS, FFPM, 
GFMD 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 


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Protocol Reference: NST-6179-01 
Final Version 1.0, 26AUG2022 
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ST-AD-031 Version 02 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF IN-TEXT TABLES AND FIGURES ......................................................................... 3 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1. Primary Objective ........................................................................................................... 6 
2.2. Secondary Objective ....................................................................................................... 7 
2.3. Exploratory Objectives.................................................................................................... 7 
3. STUDY ENDPOINTS ........................................................................................................... 7 
3.1. Primary Endpoints ........................................................................................................... 7 
3.2. Secondary Endpoints ....................................................................................................... 7 
3.3. Exploratory Endpoints .................................................................................................... 8 
4. STUDY DESIGN................................................................................................................... 9 
4.1. Part A .............................................................................................................................. 9 
4.2. Part B ............................................................................................................................. 12 
5. SAMPLE SIZE JUSTIFICATION ...................................................................................... 13 
6. STUDY TREATMENTS ..................................................................................................... 13 
7. DEFINITIONS OF POPULATIONS .................................................................................. 14 
7.1. All Subjects Population ................................................................................................. 15 
7.2. Safety Population .......................................................................................................... 15 
7.3. Pharmacokinetic Population ......................................................................................... 15 
8. STATISTICAL METHODOLOGY .................................................................................... 15 
8.1. General .......................................................................................................................... 15 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ....................................................................................................................... 16 
8.1.2. Calculation of the Summary Statistics ................................................................... 16 
8.1.3. Triplicate Readings................................................................................................. 17 
8.1.4. Repeat and Unscheduled Readings ........................................................................ 17 
8.1.5. Definitions of Baseline and Change from Baseline ............................................... 17 
8.2. Subject Disposition and Population Assignment .......................................................... 18 
8.3. Screening Demographics .............................................................................................. 18 


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8.4. Prior and Concomitant Medication ............................................................................... 18 
8.5. Pharmacokinetic Assessments ...................................................................................... 19 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 19 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 23 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 24 
8.6. Safety and Tolerability Assessments ............................................................................ 25 
8.6.1. Adverse Events ....................................................................................................... 25 
8.6.2. Clinical Laboratory Parameters .............................................................................. 27 
8.6.3. Vital Signs Parameters ........................................................................................... 27 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 27 
8.6.5. Other Assessments ................................................................................................. 28 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 28 
9. INTERIM ANALYSES ....................................................................................................... 28 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 28 
11. REFERENCES .................................................................................................................. 28 
12. APPENDICES ................................................................................................................... 30 
Appendix 1: 
Document History ................................................................................ 30 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1: 
Presentation of Study Treatments in TFLs (Part A) ............................................. 14 
Table 2: 
Presentation of Study Treatments in TFLs (Part B) .............................................. 14 
 
Figure 1: 
Study Design (Part A) ........................................................................................... 10 
Figure 2: 
Planned Dose Levels (Part A) ............................................................................... 11 
Figure 3: 
Study Schematic (Part B) ...................................................................................... 13 
Figure 4: 
Planned Dose Levels (Part B) ............................................................................... 13 
 


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Protocol Reference: NST-6179-01 
Final Version 1.0, 26AUG2022 
Page 4 of 30 
 
ST-AD-031 Version 02 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
%AUCextrap 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
ADaM 
Analysis Data Model 
AE 
adverse event 
Aet1-t2 
amount of the dose administered recovered over the time interval t1 to 
t2 
ANOVA 
analysis of variance ANOVA 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
postdose 
AUC0-72 
area under the concentration-time curve from time 0 to 72 hours 
postdose  
AUC0-∞ 
area under the concentration-time curve from time 0 extrapolated to 
infinity 
AUC0-tlast 
area under the concentration-time curve from time 0 to the time of the 
last quantifiable concentration 
AUC0-τ 
area under the concentration-time curve over a dosing interval 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent total clearance  
CLR 
renal clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration in a dosing interval 
COVID-19 
coronavirus disease 2019 
CSR 
clinical study report 
CV 
coefficient of variation 
DAUC0-∞ 
AUC0-∞ normalised by dose administered 
DAUC0-tlast 
AUC0-tlast normalised by dose administered 
DAUC0-τ 
AUC0-τ normalised by dose administered 
DCmax 
Cmax normalised by dose administered 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
fet1-t2 
percentage of the dose administered recovered over the time interval t1 
to t2 
GLSM 
geometric least squares mean 


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Protocol Reference: NST-6179-01 
Final Version 1.0, 26AUG2022 
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ST-AD-031 Version 02 
ICH 
International Council for/Conference on Harmonisation 
ln 
natural log 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
not applicable 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R2-adj 
adjusted coefficient for determination of exponential fit 
RAAUC0-τ 
observed accumulation ratio based on AUC0-τ 
RACmax 
observed accumulation ratio based on Cmax 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDV 
source document verification 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tlast 
time of the last quantifiable concentration 
tmax 
time of the maximum observed concentration 
Vz/F 
apparent volume of distribution during the terminal phase  
WHODrug 
World Health Organization Drug Dictionary  
λz 
apparent terminal elimination rate constant 
λz Lower 
start of exponential fit 
λz N 
number of data points included in the log-linear regression 
λz Span Ratio 
time period over which λz was determined as a ratio of t1/2 
λz Upper 
end of exponential fit 
 


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Protocol Reference: NST-6179-01 
Final Version 1.0, 26AUG2022 
Page 6 of 30 
 
ST-AD-031 Version 02 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 4 
dated 06 October 2021) and electronic case report form (eCRF). Noting that later clinical 
study protocol (Final Version 5 dated 11 July 2022) was generated but never used for the 
study conduct.  
This SAP describes the planned analysis of the pharmacokinetic (PK) safety, and tolerability 
data from this study. A detailed description of the planned TFLs to be presented in the 
clinical study report (CSR) is provided in the accompanying TFL shells document.  
Continuous 12-lead electrocardiogram (ECG) data will be collected and stored for the future 
assessment of the NST-6179 concentration QT interval corrected for heart rate (QTc) 
response relationship following single oral doses of NST-6179. This data is not planned to be 
analysed by Labcorp Drug Development. If it decided to perform analysis on this data, this 
will be reported separately. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with NorthSea Therapeutics B.V. A limited amount of information 
about this study (eg, objectives, study design) is given to help the reader’s interpretation.  
This SAP must be finalised prior to any unblinding of study data for analysis purposes 
(interim or final). Additionally, the SAP and TFL shells should be finalised prior to any 
programming activities commencing.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with NorthSea Therapeutics B.V and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E3 guideline Structure and Content of Clinical Study 
Reports, ICH E8 guideline General Considerations for Clinical Trials, and ICH E9 guideline 
Statistical Principles for Clinical Trials.1,2,3 
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES 
2.1. Primary Objective 
The primary objective of the study is: 
● to assess the safety and tolerability of single and multiple oral doses of NST-6179 in 
healthy male and female subjects 


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2.2. Secondary Objective 
The secondary objective of the study is: 
● to evaluate the single and multiple oral dose PK of NST-6179 in healthy male and 
female subjects 
2.3. Exploratory Objectives 
The exploratory objectives of the study are: 
● to collect data to assess the relationship between NST-6179 concentrations and QT 
interval corrected for heart rate (QTc) in healthy male and female subjects 
● to evaluate the metabolite profile of NST-6179 in healthy male and female subjects. 
3. STUDY ENDPOINTS 
3.1. Primary Endpoints 
The primary safety endpoints for this study are as follows: 
● incidence and severity of adverse events (AEs) 
● incidence of laboratory abnormalities, based on haematology, clinical chemistry, 
coagulation, and urinalysis test results 
● 12-lead ECG parameters 
● vital signs measurements 
● physical examinations. 
3.2. Secondary Endpoints 
The PK outcome endpoints of NST-6179 for Part A (single ascending dose in healthy 
subjects) are as follows: 
● area under the concentration-time curve (AUC) from time 0 extrapolated to infinity 
(AUC0-∞) 
● AUC0-∞ normalised by dose administered (DAUC0-∞) 
● AUC from time 0 to the time of the last quantifiable concentration (AUC0-tlast) 
● AUC0-tlast normalised by dose administered (DAUC0-tlast) 
● maximum observed concentration (Cmax) 
● Cmax normalised by dose administered (DCmax) 


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● time of the maximum observed concentration (tmax) 
● apparent terminal elimination half-life (t1/2) 
● apparent total clearance (CL/F) 
● apparent volume of distribution during the terminal phase (Vz/F) 
● amount of the dose administered recovered over the time interval t1 to t2 (Aet1-t2) 
● percentage of the dose administered recovered over the time interval t1 to t2 (fet1-t2) 
● renal clearance (CLR). 
The PK outcome endpoints of NST-6179 for Part B (multiple ascending dose in healthy 
subjects) are as follows: 
● AUC over a dosing interval (AUC0-τ) 
● AUC0-τ normalised by dose administered (DAUC0-τ) 
● AUC0-∞ (Day 1 only) 
● DAUC0-∞ (Day 1 only) 
● Cmax 
● DCmax 
● tmax 
● t1/2 
● CL/F 
● Vz/F  
● minimum observed concentration in a dosing interval (Cmin) 
● observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
● observed accumulation ratio based on Cmax (RACmax). 
Other PK parameters may also be added. 
3.3. Exploratory Endpoints 
Continuous 12-lead ECG data will be stored for the future assessment of the NST-6179 
concentration-QTc response relationship following single oral doses of NST-6179. 


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For the highest planned dose group in Part B, additional samples will be taken for the 
identification of metabolites of NST-6179. 
4. STUDY DESIGN  
This will be a partly double-blind, randomised, placebo-controlled, single and multiple oral 
dose study conducted in 2 parts. Part A and Part B will be double-blind, randomised, 
placebo-controlled, with subjects receiving single (Part A) and multiple (Part B) oral doses. 
4.1. Part A 
Part A will comprise a double-blind, single-ascending dose, sequential-group design. Overall, 
48 subjects will be studied in 6 groups (Groups A1 to A6), with each group consisting of 
8 subjects. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only. 
Subjects will reside at the study site from Day -1 (the day before dosing) to Day 4 of each 
treatment period, as applicable. 
All subjects will return for a follow-up visit 10 to 14 days after their final dose. 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 per period and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups A1 to A6, 6 subjects will receive NST-6179 and 2 subjects will receive 
placebo. 
Groups A1 to A6 
It is planned for each subject in Groups A1 to A6 to receive only a single dose of NST-6179 
or placebo during the study. Doses will be administered in the fasted state in accordance with 
a randomisation schedule on the morning of Day 1. 
Additional Groups (Groups A7 to A9) 
If it is decided to enrol additional groups, fasting requirements, meal compositions, and 
timing of doses will be determined following review of the available PK data. 
Sentinel Dosing 
All groups in Part A will be divided into 2 sub-groups, with each sub-group being dosed 
24 hours apart. The first sub-group will comprise 2 subjects, with 1 subject receiving 
NST-6179 and 1 subject receiving placebo. The second sub-group will comprise 6 subjects, 
with 5 subjects receiving NST-6179 and 1 subject receiving placebo. 
There will be a minimum of 7 days between dose escalations for each group in Part A. 
An overview of the study design is shown in Figure 1 and the planned dose levels are 
presented in Figure 2.  


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The total planned duration of study participation for each subject (from screening through 
follow-up visit) is anticipated to be approximately 6 weeks. 
Figure 1: Study Design (Part A) 
 
Abbreviations: CRU = Clinical Research Unit; N = number of subjects. 
 
 
 


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Figure 2: Planned Dose Levels (Part A) 
 
Abbreviations: N = number of subjects; PK = pharmacokinetic(s); TBD = to be determined. 
NOTE: dose levels may be adjusted based on the ongoing review of the safety, tolerability, and PK data. Doses will be administered in an escalating manner following satisfactory review by the 
sponsor and investigator of the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose) from the previous dose group


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4.2. Part B 
Part B will comprise a double-blind, multiple-ascending dose, sequential-group study design. 
Overall, 40 subjects will be studied in 4 groups (Groups B1 to B4), with each group 
consisting of 10 subjects. Part B may start in parallel with Part A provided the exposure is not 
predicted to exceed an exposure shown to be safe and well tolerated in Part A. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the study site from Day -1 until the morning of Day 16. 
All subjects will return for a follow-up visit 10 to 14 days after their final dose. 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 per period and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups B1 to B4, 8 subjects will receive NST-6179 and 2 subjects will receive 
placebo. For all subjects, dosing is planned to be once daily (QD) on Days 1 to 14, inclusive. 
However, dosing frequency and duration in Part B may be changed following review of data 
from groups in Part A or earlier groups in Part B. The dose regimen will comprise no less 
than once every 2 days and will not exceed 4-times-daily dosing. The dosing duration will 
comprise no fewer than 7 consecutive days and will not exceed 28 consecutive days of 
dosing. There will be a minimum of 14 days between dose escalations for each group in 
Part B. The total daily dose administered will not be predicted to exceed an exposure shown 
to be safe and well tolerated in Part A. 
Up to 3 further groups of 10 subjects (8 active:2 placebo) may be included in Part B. 
An overview of the study design is shown in Figure 3, and the planned dose levels are 
presented in Figure 4.  
The total planned duration of study participation for each subject (from screening through 
follow-up visit) is anticipated to be approximately 8 weeks. 


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Figure 3: Study Schematic (Part B) 
 
Abbreviations: CRU = Clinical Research Unit; N = number of subjects; PK = pharmacokinetic(s); QD = once daily. 
NOTE: doses will be administered in an escalating manner following satisfactory review by the sponsor and investigator of 
the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose) from the 
previous dose group. 
a. Dosing is planned to be QD on Days 1 to 14, inclusive. The dose regimen will comprise no less than once every 2 days 
and will not exceed 4-times-daily dosing. The dosing duration will comprise no fewer than 7 consecutive days and will 
not exceed 28 consecutive days of dosing. 
Figure 4: Planned Dose Levels (Part B) 
 
Abbreviations: N = number of subjects; PK = pharmacokinetic(s); QD = once daily. 
NOTE: doses will be administered in an escalating manner following satisfactory review by the sponsor and investigator of 
the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose) from the 
previous dose group. 
a. Dosing is planned to be QD on Days 1 to 14, inclusive. The dose regimen will comprise no less than once every 2 days 
and will not exceed 4-times-daily dosing. The dosing duration will comprise no fewer than 7 consecutive days and will 
not exceed 28 consecutive days of dosing. 
5. SAMPLE SIZE JUSTIFICATION  
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time NST-6179 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. 
6. STUDY TREATMENTS  
The study treatment names and ordering to be used in the TFLs for Part A are presented in 
Table 1 and for Part B in Table 2.  


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Table 1: 
Presentation of Study Treatments in TFLs (Part A)  
Group 
Study Treatment 
Order in TFLs 
A1 to A9 
Placeboa 
1 
A1 
TBD mg NST-6179 
2 
A2 
TBD mg NST-6179 
3 
A3 
TBD mg NST-6179 
4 
A4 
TBD mg NST-6179 
5 
A5 
TBD mg NST-6179 
6 
A6 
TBD mg NST-6179 
7 
A7b 
TBD mg NST-6179 
8 
A8b 
TBD mg NST-6179 
9 
A9b 
TBD mg NST-6179 
10 
a Placebo will be pooled across all groups 
b Optional group 
Table 2: 
Presentation of Study Treatments in TFLs (Part B)  
Group 
Study Treatment 
Order in TFLs 
B1 to B7 
Placeboa 
1 
B1 
TBD mg NST-6179 (QD) 
2 
B2 
TBD mg NST-6179 (QD) 
3 
B3 
TBD mg NST-6179 (QD) 
4 
B4 
TBD mg NST-6179 (QD) 
5 
B5b 
TBD mg NST-6179 (QD) 
6 
B6b 
TBD mg NST-6179 (QD) 
7 
B7b 
TBD mg NST-6179 (QD) 
8 
Abbreviations:  QD = once daily 
a Placebo will be pooled across all groups 
b Optional group 
All TFLs will be based on actual treatments (eg, if subject was assigned to receive placebo 
but was wrongfully dosed with active treatment they would be summarised and listed under 
active treatment). 
All dose levels described above are the potential dose levels, and therefore are subject to 
change. The TFLs will reflect the dose levels utilised in the study, and these will be displayed 
in increasing order.  
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those due to coronavirus disease 2019 (COVID-19) and 
related restrictions (see Section 8.1.1), will be considered prior to database lock for their 
importance and taken into consideration when assigning subjects to populations.  


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7.1. All Subjects Population  
The all subjects population will include all subjects who signed the informed consent form 
and had any study assessment recorded in the database per the protocol.  
7.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study treatment 
(NST-6179 or placebo).  
7.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of active study 
treatment (NST-6179) and have at least 1 valid PK concentration.  
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database, with the exception of medical 
history. Listings will include all subjects assigned to the all subjects population and include 
data up to the point of study completion or discontinuation. Subjects are generally considered 
to have completed the study if they complete the scheduled follow-up visit (rather than early 
termination visit). Any subject who discontinues the study will be identified accordingly in 
the listings. Summaries will include the subjects assigned to the relevant population based on 
data type.  
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if a new version is issued during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if a new version is issued 
during the study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if a new 
version is issued during the study). Pinnacle 21 Community Validator Version 4.0.1 (or 
higher if a new version is issued during the study) will be utilised to ensure compliance with 
CDISC standards.  
For all statistical analyses, the hypothesis testing will be 2-sided and carried out on 0.05 
significance level, unless specifically stated otherwise.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations. 
Where reference is made to ‘valid’ data, this refers to non-missing data which meet the 
predetermined criteria (eg, are not flagged for exclusion).  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, and changes from baseline.  


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All figures will be produced on linear-linear or discrete-linear scales, as applicable, unless 
specifically stated otherwise. 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions 
Due to COVID-19 and related restrictions, there is a high risk for impact to data integrity, 
with the recognised potential for: 
● Missed visits, caused by, for example: 
o Subject unable to travel to site due to restrictions, the need to quarantine, or 
COVID-19 infection 
o Subject unwilling to go to site due to fear of COVID-19 infection 
o Site postponing subject’s visit due to investigator not being available (eg, if they 
have been dispatched to hospital handling COVID-19 infections) 
● Site unable to replenish supply of investigational product 
● Incomplete data entry by sites due to limited resources to support study or no access to 
source documents or to eCRF 
● Outstanding source document verification (SDV) due to sponsor or country restrictions 
on remote SDV, or no or limited access to site(s) for on-site visits 
● Unanswered queries 
At the time of the reporting of the study results, all protocol deviations due to COVID-19 or 
related restriction will be assessed for their severity and impact on the analyses. If needed, 
appropriate statistical methods will be applied as a mitigating action (eg, data might be 
categorised into 2 analysis groups, with and without COVID-19 and related restrictions 
impact); however, this will exclude any imputations of the missing values. Any mitigating 
actions will be agreed with NorthSea Therapeutics B.V. in advance and identified in the CSR.  
8.1.2. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum.  


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● In general, as discontinuation data are not associated with any scheduled timepoint, 
they will be excluded from all calculations of summary statistics and statistical 
analyses. Exceptions may be made where justified.  
For categorical data the following rules will be applied:  
● For ordered categorical data (eg, AE severity), all categories between the possible 
minimum and maximum categories will be included, even if n = 0 for a given category.  
● For non-ordered categorical data (eg, race), only those categories for which there is at 
least 1 subject represented will be included; unless specifically stated otherwise.  
● Missing values will not be imputed, unless specifically stated otherwise. A ‘missing’ 
category will be included for any parameter for which information is missing. This will 
ensure that the population size totals are consistent across different parameters.  
8.1.3. Triplicate Readings  
For vital signs data only, where triplicate readings are taken, the median of triplicate readings 
will replace the separate individual triplicate readings in all calculations.  
For 12-lead ECG data only, where triplicate readings are taken, the mean of triplicate 
readings will replace the separate individual triplicate readings in all calculations.  
In case of incomplete triplicate readings (eg, only 2 out of 3 readings were recorded), the 
mean and/or medians will be calculated, as appropriate, based on the number of readings 
available.  
8.1.4. Repeat and Unscheduled Readings  
For vital signs and 12-lead ECG data only, any predose value recorded in addition to the 
original value or a postdose value recorded within 15 minutes of the original value will be 
defined as a repeat value; any postdose value recorded more than 15 minutes after the 
original value will be defined as an unscheduled value. For all other data types (eg, laboratory 
parameters), any value recorded in addition to the original value will be defined as an 
unscheduled value.  
The original value will be replaced by the last associated repeat value in all calculations, with 
the exception of the 12-lead ECG outlier analysis (see Section 8.6.4). 
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 8.1.5) and 12-lead ECG outlier analysis (see Section 8.6.4).  
8.1.5. Definitions of Baseline and Change from Baseline  
The baseline will be defined as the last value recorded prior to the first dose. If the date/time 
of the value is incomplete or missing, it will be excluded from the baseline calculation, unless 
the incomplete date/time indicates the value was recorded prior to the first dose. 


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Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the postdose timepoint.  
The summary statistics for change from baseline will be derived from individual subjects’ 
values (eg, mean change from baseline will be the mean of the individual changes from 
baseline for all subjects, rather than difference between the mean value at the postdose 
timepoint and mean value at baseline).  
See Section 8.1.4 for more detail on handling repeat and unscheduled readings in the 
calculations. See Section 8.1.3 for more detail on handling of triplicate readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment will be provided, based on the safety population.  
8.3. Screening Demographics  
The screening demographics including age, sex, race, ethnicity, height, body weight, and 
body mass index will be listed.  
A summary table by treatment will be provided, based on the safety population.  
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that starts during or after the first dose or starts but 
does not end prior to the first dose.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version March 2021 (or later if a new version is 
issued during the study; see the data management plan [DMP] for more details). Prior and 
concomitant medications will be listed.  


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8.5. Pharmacokinetic Assessments   
8.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma and urine 
concentrations of NST-6179 using noncompartmental methods in validated software program 
Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Part A - SAD 
Parameter 
Unitsa 
Definition 
Plasma PK Parameters 
AUC0-tlast 
h*ng/mL 
area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration (tlast)b 
AUC0-∞ 
h*ng/mL 
area under the concentration-time curve from time 0 extrapolated to 
infinityc 
AUC0-24 
h*ng/mL 
area under the concentration-time curve from time 0 to 24 hours 
postdose 
AUC0-72 
h*ng/mL 
area under the concentration-time curve from time 0 to 72 hours 
postdose (for calculation of CLR) 
%AUCextrap 
% 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
Cmax 
ng/mL 
maximum observed concentration 
tmax 
h 
time of the maximum observed concentration 
tlast 
h 
time of the last quantifiable concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance  
Vz/F 
L 
apparent volume of distribution during the terminal phase  
DAUC0-tlast 
h*ng/mL/mg AUC0-tlast normalised by dose administeredd  
DAUC0-∞ 
h*ng/mL/mg AUC0-∞ normalised by dose administeredd  
DCmax 
ng/mL/mg 
Cmax normalised by dose administeredd  
Urine PK Parameters 
Aet1-t2 
mg 
amount of the dose administered recovered over the time interval t1 
to t2, calculated for each interval from the start of the collection 
interval and from the start of the dosing interval (time 0) 
fet1-t2 
% 
percentage of the dose administered recovered over the time interval 
t1 to t2, calculated for each interval from the start of the collection 
interval and from the start of the dosing interval (time 0) 
CLR 
L/h 
renal clearance, calculated as Ae0-72/AUC0-72 or other appropriate 
collection interval 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b The AUC will be calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations (linear up/log down rule).  
c Based on the last observed quantifiable concentration 
d Calculated by dividing the parameter by the dose (mg)  


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Part B - MAD 
Parameter 
Unitsa 
Definition 
Plasma PK Parameters 
AUC0-τ 
h*ng/mL 
area under the concentration-time curve over a dosing interval, 
may be referred to AUC0-24 for Day 1b 
AUC0-∞ 
h*ng/mL 
area under the concentration-time curve from time 0 extrapolated 
to infinityc (Day 1 only) 
%AUCextrap 
% 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
(Day 1 only) 
Cmax 
ng/mL 
maximum observed concentration 
Cmin 
ng/mL 
minimum observed concentration in a dosing interval (Day 14 
only) 
tmax 
h 
time of the maximum observed concentration 
tlast 
h 
time of the last quantifiable concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance  
Vz/F 
L 
apparent volume of distribution during the terminal phase  
RAAUC0-τ 
NA 
observed accumulation ratio based on AUC0-τ 
RACmax 
NA 
observed accumulation ratio based on Cmax 
DAUC0-τ 
h*ng/mL/mg AUC0-τ normalised by dose administeredd  
DAUC0-∞ 
h*ng/mL/mg AUC0-∞ normalised by dose administeredd (Day 1 only) 
DCmax 
ng/mL/mg 
Cmax normalised by dose administeredd  
Urine PK Parameters 
Aet1-t2 
mg 
amount of the dose administered recovered over the time interval 
t1 to t2, calculated for each interval from the start of the 
collection interval and from the start of the dosing interval 
(time 0) 
fet1-t2 
% 
percentage of the dose administered recovered over the time 
interval t1 to t2, calculated for each interval from the start of the 
collection interval and from the start of the dosing interval 
(time 0) 
CLR 
L/h 
renal clearance, calculated as Ae/AUC using matched collection 
intervals; at steady state, collection intervals will be matched to 
the dosing interval 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b The AUC will be calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations (linear up/log down rule).  
c Based on the last observed quantifiable concentration 
d Calculated by dividing the parameter by the dose (mg) 
Additional PK parameters may be determined where appropriate. 


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The PK analysis will be carried out where possible using actual dose administered (mg) and 
actual postdose blood sampling times. If an actual time is missing, the sample concentration 
result will be treated as missing unless there is scientific justification to include the result 
using the nominal time.  
The parameters Cmax, Cmin, and tmax will be obtained directly from the concentration-time 
profiles. If Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence 
of Cmax. 
The accumulation ratio(s) (RAAUC0-τ and RACmax) will be calculated as follows: 
RAAUC0-τ = AUC0-τ profile day 14 / AUC0-τ profile day 1 
RACmax = Cmax profile day 14 / Cmax profile day 1 
The parameter AUC0-tlast or other common partial area may be used to determine RAAUC0-τ if 
AUC0-τ cannot be reliably calculated for the majority of subjects. 
8.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz for their calculation (eg, AUC0-∞, t1/2, CL/F, and Vz/F) will only be 
calculated if the R2-adj value of the regression line is ≥0.7. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio 
NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (ie, the difference between 
λz Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2 half-lives, the 
robustness of the t1/2 values will be discussed in the CSR. 


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8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive concentrations above the lower limit of quantification. If there are only 
3 consecutive concentrations, at least 1 should follow Cmax.  
If the extrapolated area is >30%, AUC0-∞ (and derived parameters) may be excluded from the 
summary statistics and statistical analysis at the discretion of the sponsor or 
pharmacokineticist.  
If AUC0-∞ cannot be determined reliably for all subjects and/or dose levels, an alternative 
AUC measure, such as AUC to a fixed timepoint or AUC0-tlast, may be used in the statistical 
analysis of dose proportionality.   
8.5.1.3. Calculation of NST-6179 Urinary Parameters  
The amount of the dose administered recovered (Ae) in urine as NST-6179 for each urine 
collection interval (t1-t2) will be calculated as the product of urine analyte concentration and 
urine volume. Where only urine sample weight is supplied, a specific gravity of 1 g/mL will 
be assumed, and it will be considered equivalent to urine volume.  
Cumulative Ae0-x h will be calculated by summing the Aet1-t2 values over the 0-x h interval, 
where x = the end of the last collection time interval. 
The percentage of the dose administered recovered over the time interval t1 to t2 (fet1-t2) as 
NST-6179 will be calculated for each urine collection interval as follows: 
fet1-t2 = (Aet1-t2 / dose) × 100 
Cumulative fe0-x h will be calculated by summing the fet1-t2 values over the 0-x h period in the 
same manner as cumulative Ae0-x h. 
Renal clearance (CLR) will be calculated over 0-t2 according to the following formula, where 
cumulative Ae and AUC are calculable to the same end time (t2): 
CLR = Ae0-t2 / AUC0-t2 
Alternatively, AUC0-∞ may be used if urinary excretion of the dose is considered to be 
complete and AUC0-∞ is well characterised. 
8.5.1.4. Criteria for Handling Concentration Below the Limit of Quantification or 
Missing Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQ concentrations will be treated as 
missing. The following rules apply to the specific situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 


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● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be 
set to missing for the calculation of the PK parameters, unless they are considered to be 
a true characteristic of the profile of the drug. 
● If a Day 1 predose plasma concentration is missing, it will be set to 0 by default within 
Phoenix WinNonlin. If a profile day 14 predose concentration is missing, it will be set 
to Cmin by default within Phoenix WinNonlin. 
Urine concentrations that are BLQ will be set to 0 for the calculation of Aet1-t2.  
8.5.1.5. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value on Day 1 will be considered anomalous and set 
to missing for the PK analysis. This will be set to 0 by default in Phoenix WinNonlin. 
8.5.2. Presentation of Pharmacokinetic Data 
All PK concentrations and parameters will be listed.  
Summary tables, arithmetic mean (+ standard deviation [SD]) figures, overlaying individual 
figures, and individual figures by treatment and time postdose will be provided for plasma 
PK concentrations. All figures will be produced on both linear-linear and linear-logarithmic 
scales, with the exception of figures across all days, which will be produced on the 
linear-linear scale only. The +SD bars will only be displayed on the linear-linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Separate summary tables by treatment and time 
interval will be provided for excretion parameters and cumulative excretion parameters. 
A subject may be excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2 times the median tmax.   
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the plasma concentration will be flagged in the listings. Individual concentrations deemed to 
be anomalous will be flagged in the listings. 
For plasma concentration data the following rules will apply: 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
● Arithmetic mean or median values that are BLQ will be presented as 0. 
Urine concentration data will be listed only. 


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For PK parameters the following rule will apply: 
● Geometric mean and coefficient of variation will not be calculated for discrete time 
parameters (ie, tmax or tlast). 
8.5.3. Pharmacokinetic Statistical Methodology  
A statistical analysis will be conducted to investigate the dose proportionality of AUC0-tlast, 
AUC0-∞, and Cmax on profile day 1 for Part A; AUC0-∞ and Cmax on profile day 1 and AUC0-τ 
and Cmax on profile day 14 for Part B (only for plasma NST-6179). 
The hypothesis testing will be 2-sided and carried out on 0.05 significance level. 
The PK parameters will be analysed using a power model4 that will have the following form: 
parameter = intercept × dose^slope × random error 
Using the natural log (ln) transformation,5 a power model can be expressed as a linear 
regression equation: 
ln(parameter) = intercept + slope × ln(dose) + random error 
For dose proportionality, the slope of the regression line is equal to 1; for dose independence, 
it is equal to 0.  
For each PK parameter separately, a pooled estimate (across all doses) of slope, 
corresponding 95% confidence interval (CI), and between-subject CV will be calculated. 
Figures (on the logarithmic-logarithmic scale) containing individual values, power model line 
(95% CI), and dose proportionality line (defined as the power model line with slope of 1) will 
be created for each PK parameter. Additionally, figures (on the logarithmic-linear scale) 
containing individual values and geometric means will be created for each corresponding PK 
parameter normalised by dose administered.  
The lack of fit test will be conducted for the statistical assessment of linearity assumption, 
and thus appropriateness of a power model. The lack of fit model will be the same as the 
power model fitted, but with dose included as additional fixed effect. The statistical 
assessment will rule the linearity assumption acceptable if the diagnostic plots appear 
reasonable and the lack of fit 2-sided p-value >0.05 (dose effect is not significant at the 0.05 
level of significance). The assessment of linearity assumption may also occur via visual 
examination of the figures by the pharmacokineticist. This assessment may override the 
statistical assessment; where this occurs, it will be detailed in the CSR.  
It will be concluded that PK parameter is dose proportional for the dose range studied if the 
assumption of linearity is ruled acceptable and the 95% CI for the slope spans 1.  
If the assumption of linearity is ruled unacceptable for any PK parameter, its corresponding 
PK parameter normalised by dose administered will be ln-transformed and analysed using an 
analysis of variance (ANOVA) model.6 The model will include dose as a factor.  


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For each PK parameter separately, the geometric least squares mean (GLSM) for each dose, 
p-values for the overall, and pairwise dose comparisons will be calculated. Residual plots will 
be produced to assess the adequacy of the model(s) fitted.  
Examples of the SAS code that will be used are as follows: 
Power Model Analysis  
proc mixed data = <data in> alpha = 0.05; 
 by parcat1n parcat1 pkday fast paramn param; 
 model lpk = ldose / cl residual ddfm = kr2; 
 ods output solutionf = <data out>; 
run; 
Power Model Analysis (Between-subject Variability) 
proc mixed data = <data in> covtest alpha = 0.05; 
 by parcat1n parcat1 pkday fast paramn param; 
 class ldose; 
 model lpk = ldose / cl residual ddfm = kr2; 
 ods output covparms = <data out>; 
run; 
(Note: Pooled Geometric CV (%) = 100*(sqrt(exp(estimate)-1))) 
Power Model Analysis (Lack of Fit Test) 
proc mixed data = <data in>; 
 by parcat1n parcat1 pkday fast paramn param; 
 class dose; 
 model lpk = ldose dose / htype = 1 ddfm = kr2; 
 ods output tests1 = <data out>; 
run; 
ANOVA Model Analysis 
proc mixed data = <data in> alpha = 0.05; 
 by parcat1n parcat1 pkday fast paramn param; 
 class dose; 
 model ldnpk = dose / cl residual ddfm = kr2; 
 lsmeans dose / cl pdiff;  
 ods output lsmeans = <data out>;  
 ods output diffs = <data out>; 
 ods output tests3 = <data out>; 
run; 
8.6. Safety and Tolerability Assessments  
8.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 24.0 (or higher if a new version is issued during the study; see the DMP for more 
details).  
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose, or starts prior to the first dose and increases in severity after the first dose.  


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A treatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment, as determined by the investigator.  
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
last associated dose for TEAEs only. Where the last associated dose is referring to the last 
dose received prior to the start of a TEAE.  
The frequency of subjects with TEAEs and the number of TEAEs will be summarised for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment  
● Treatment-related TEAEs by severity and treatment  
The frequency of subjects will be summarised separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  
For the AE data the following rules will apply:  
● For the derivation of treatment-emergent status (applicable to all AEs): If the start 
date/time of an AE is incomplete or missing, an AE will be assumed to not be a TEAE, 
unless the incomplete start date/time or the end date/time indicates an AE started after 
the first dose.  
● For the derivation of treatment-related status (applicable to TEAEs only): If the study 
treatment relationship for a TEAE is missing, a TEAE will be assumed to not be a 
treatment-related TEAE.  
● For the derivation of onset time (applicable to TEAEs only): If the start date/time of a 
TEAE is missing, onset time will not be calculated. If the start date/time of a TEAE is 
incomplete, where possible, the minimum possible onset time will be calculated and 
presented in ‘≥DD:HH:MM’ format (eg, if the date/time of the last associated dose is 
01MAY2019/08:00 and recorded start date/time of a TEAE is 03MAY2019, then the 
minimum possible onset time will be calculated by assuming a TEAE started at the first 
hour and minute of 03MAY2019 [03MAY2019/00:00], thus will be presented as onset 
time ≥01:16:00 in the listing). If the start date of a TEAE is the same as the date of the 
last associated dose but the start time of a TEAE is missing, an onset time will be 
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● For the derivation of duration (applicable to all AEs): If the end date/time of an AE is 
missing, duration will not be calculated. If the start or end date/time of an AE is 
incomplete, where possible, the maximum possible duration will be calculated and 
presented in ‘≤DD:HH:MM’ format (eg, if the start of an AE date/time is 
01MAY2019/08:00 and its recorded end date/time is 03MAY2019, then the maximum 
possible duration will be calculated by assuming an AE ended at the last hour and 
minute of 03MAY2019 [03MAY2019/23:59], thus will be presented as 
duration ≤02:15:59 in the listing). Any clock changes will be accounted for in the 
derivation.  
● For the calculation of TEAE summary statistics: If the severity of a TEAE is missing, 
that TEAE will be counted under the ‘missing’ category. 
● For the calculation of TEAE summary statistics: If a subject experienced multiple 
TEAEs with the same preferred term for the same treatment, this will be counted as 1 
TEAE for that treatment under the maximum severity recorded.  
8.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters will be listed; any value outside the clinical reference range 
will be flagged. Separate listings will be provided for any parameter for which there is any 
individual subject value outside the respective clinical reference range.  
Summary tables and boxplots by treatment and timepoint will be provided for clinical 
chemistry, haematology, and coagulation.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, all calculations, and presentation in the figures, <x and ≤x values 
will be set to half of x, whereas >x and ≥x values will be set to x.  
8.6.3. Vital Signs Parameters  
All vital signs parameters and their changes from baseline will be listed, as applicable; any 
value outside the clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided for all vital signs 
parameters and their changes from baseline, as applicable. 
8.6.4. 12-lead Electrocardiogram Parameters   
All 12-lead ECG parameters and their changes from baseline will be listed; any value outside 
the clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided for all 12-lead 
ECG parameters and their changes from baseline. 
An outlier analysis will be performed for QT interval corrected for heart rate using Bazett’s 
formula (QTcB) and QT interval corrected for heart rate using Fridericia’s formula (QTcF). 
The analysis will include all individual original, repeat, and unscheduled postdose values.  


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The maximum postdose values will be summarised by treatment according to the following 
categories:  
● ≤450 ms  
● >450 and ≤480 ms (all instances flagged in the listing)  
● >480 and ≤500 ms (all instances flagged in the listing)  
● >500 ms (all instances flagged in the listing)  
The maximum increases from baseline will be summarised by treatment according to the 
following categories:  
● ≤30 ms  
● >30 and ≤60 ms (all instances flagged in the listing)  
● >60 ms (all instances flagged in the listing) 
8.6.5. Other Assessments  
Medical history will not be listed.  
The continuous 12-lead ECG data will be recorded for this study, but if it is analysed in the 
future, it will be reported separately. 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.  
9. INTERIM ANALYSES  
No formal interim analyses are planned for this study. 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  
11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
2. ICH. ICH Harmonised Tripartite Guideline: General considerations for clinical trials (E8). 
17 July 1997.  


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3. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
4. Gough K, Hutchinson M, Keene O, et al. Assessment of dose proportionality: report from 
the statisticians in the pharmaceutical industry/Pharmacokinetics UK Joint Working 
Party. Drug Inf J. 1995;29(3):1039-1048. 
5. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
6. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
 


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12. APPENDICES 
Appendix 1: 
Document History 
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
NA = not applicable