A Randomised, Double-blind, Placebo-controlled, Study of the Safety, Tolerability, and Pharmacokinetics of AX-158 Following Administration of Single and, Multiple Ascending Oral Doses and Food Effect Sub-study in Healthy Male Volunteers
Phase: PHASE1
Conditions: Autoimmune Diseases
Sponsor: Artax Biopharma Inc

 
 
 
Artax Biopharma Inc 
Clinical Study Protocol 
Confidential 
RD675/34625  
AX-158-101 
Final 4.0 / 14 January 2022  
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
STUDY PROTOCOL 
 
STUDY TITLE: 
A Randomised, Double-blind, Placebo-controlled, Study 
of the Safety, Tolerability, and Pharmacokinetics of 
AX-158 Following Administration of Single and, Multiple 
Ascending Oral Doses and Food Effect sub-study in 
Healthy Male Volunteers. 
 
 
STUDY NUMBER: 
RD 675/34625 
 
AX-158-101 
 
 
EudraCT NUMBER: 
IRAS ID: 
2021-002541-16 
 
295109 
 
 
INVESTIGATIONAL 
MEDICINAL 
PRODUCT(s): 
• AX-158 5 mg Capsule 
• Placebo Capsule 
 
 
PLANNED STUDY 
DOSES: 
Part A - Single Ascending Dose (SAD)  
Part B - Food Effect 
Part C - Multiple Ascending Dose (MAD) 
 
 
PRINCIPAL 
INVESTIGATOR: 
Dr Annelize Koch 
Simbec-Orion  
Merthyr Tydfil 
CF48 4DR, UK 
STUDY SPONSOR: 
Artax Biopharma Inc 
SPONSOR’S 
RESPONSIBLE 
PHYSICIAN: 
Dr Richard Polisson  
Artax Biopharma, Inc 
One Broadway 
14th Floor 
Cambridge, MA  02142 
 
STUDY MONITOR: 
 
 
Simbec-Orion Clinical Development 
 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
SPONSOR LEGAL 
REPRESENTIVE: 
Orion LR 
Merthyr Tydfil Industrial Park, Pentrebach, 
Merthyr Tydfil, 
CF48 4DR, UK. 
ADDITIONAL 
DEPARTMENTS: 
Simbec-Orion Laboratory Services 
Merthyr Tydfil Industrial Park, Pentrebach, 
Merthyr Tydfil, 
CF48 4DR, UK. 
 
PROTOCOL FINALISATION STATEMENT 
 
This protocol is not considered final unless accompanied by an approval letter from the 
Research Ethics Committee and Notice of Acceptance from the relevant Competent 
Authority. 
 
Protocol Prepared by: AC 
 
 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
1 SIGNATURE PAGE 
 
I declare that I have read and understood this study protocol.  I agree to abide by this protocol 
(subject to any amendments agreed in writing between the Sponsor and Principal Investigator).  
Any changes in procedure will only be made if necessary, to protect the safety, rights, or 
welfare of the participants. 
 
STUDY SPONSOR: 
Richard Polisson, M.D 
Artax Biopharma, Inc 
One Broadway 
14th Floor 
Cambridge, MA 02142 
Signature: 
Date: 
  
617-368-0676 
email rpolisson@artaxbiopharma.com    
 
PRINCIPAL INVESTIGATOR: 
Dr Annelize Koch 
Simbec-Orion 
Merthyr Tydfil CF48 4DR 
UK  
Signature: 
Date: 
 
+44 (0)1443 690977 
email annelize.koch@simbecorion.com 
 
 
 
 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
2 PROTOCOL AMENDMENT/REVISION HISTORY 
Protocol 
Version/ 
Date 
Type of 
Amendment  
Amendment 
Rationale 
Sections Affected 
Summary of 
Amendment / Changes 
to the Protocol 
V1.0 26 
May 2021 
N/A 
N/A 
N/A 
N/A – Initial Version 
V2.0, 22 
June 2021 
N/A 
Response to 
MHRA Grounds 
for Non-
Acceptance 
Section 8.5 – 
Toxicology 
 
 
Section 10.3.4 - 
Progression from 
Dose Leader 
Group/Dose 
Escalation 
Stopping Criteria 
 
 
 
Section 10.8.7 – 
Selection of Doses 
in the Study  
- Section updated to 
include reference to pre-
defined exposure limits 
for Cmax & AUC0-24 as 
per MHRA request. 
 
- Stopping criteria for 
systemic 
exposure 
updated 
to 
include  
reference to pre-defined 
exposure limits for Cmax 
& 
AUC0-24 
as 
per 
MHRA request. 
 
 
- 
Additional 
text 
included as per MHRA 
request 
to 
clarify 
planned study doses in 
the 
context 
of 
the 
estimated 
human 
pharmacodynamic 
range. 
 
V3.0, 22 
October 
2021 
Non-Substantial 
To align with 
latest version of 
Simbec-Orion 
protocol template 
Section 3 – 
Synopsis 
 
 
Section 5 – 
Abbreviations 
 
 
 
 
 
 
Section 8.2 – 
Physical, 
Chemical and 
- Changes implemented 
to align with main body 
text 
 
- Abbreviations’ list 
updated to include 
additional abbreviations 
to align with latest 
version of Simbec-
Orion template 
 
 
- Capsule size updated 
from size 3 to size 2 
 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
Pharmaceutical 
Properties and 
Formulation 
 
Section 8.8 - 
Coronavirus 
Disease 2019 
(COVID-19) 
Risk/Benefit 
Assessment 
 
Section 10.3.1 – 
Dose Escalation 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 10.5 – 
Selection of 
Study Population 
 
Section 10.5.1 – 
Inclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
- Full definition of 
NHS, PPE & IMP 
added 
 
 
 
 
- Removal of term 
‘accrual’ in relation to 
dose escalation for 
review of PK and safety 
data. 
 
- Removal of term 
‘pharmacist’ and 
replaced with ‘IMP 
Management team’ 
 
- Addition of text to 
confirm that receipt of 
the signed dose 
escalation approval 
form will trigger the 
release of the IMP for 
the next dose level to 
the clinic. 
 
 
- Full definition of SI 
added 
 
 
- Criterion #11 updated 
to include full 
definition of QTcF 
 
- Criterion #12 updated 
to replace ‘pulse’ with 
‘heart rate’ as per latest 
version of Simbec-
Orion protocol template 
 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
 
 
 
 
 
Section 10.6.1 – 
Contraception 
 
 
 
 
 
 
 
 
 
 
Section 10.8.2 – 
Receipt and 
Storage  & 
Section 10.8.3 – 
Assembly and 
Release 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 10.8.11 - 
Blinding 
– Criterion #16 updated 
to include full 
definition for RT-PCR 
 
 
- Statement added to 
vasectomised partner 
contraception method to 
note that if there is no 
documentation to 
support the absence of 
sperm in the ejaculate, 
then condoms will still 
be required for these 
individuals. 
  
 
- Full definition of API 
added. 
 
- Revision of term ‘The 
Pharmacy’ to ‘IMP 
Management’ 
 
- Removal of reference 
to specific Simbec-
Orion SOP numbers 
and replaced with 
‘Simbec-Orion SOPs.’ 
 
- Revision of storage 
conditions for IMP 
from quarantine in a 
segregated, study 
specific area within the 
pharmacy to quarantine 
within a GMP area to 
facilitate circumstances 
where IMP may be 
stored within the 
clinical unit or other 
areas as needed. 
 
 
- Revision of term 
‘pharmacist’ to ‘IMP 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
 
 
 
Table 10.9.1 – 
Study Flow Chart 
– Part A Single 
Ascending Dose 
 
 
 
Table 10.9.2 – 
Study Flow Chart 
– Part B Food 
Effect 
 
 
 
Table 10.9.3 – 
Study Flow Chart 
– Part C Multiple 
Ascending Dose 
 
 
 
Section 10.9.2.4 - 
COVID-19 PCR 
Testing 
 
Section 10.9.2.5 - 
Drug of Abuse 
and Alcohol 
 
Section 10.9.5.1 – 
Adverse Events 
 
Section 
10.9.5.1.1.1 – 
Recording of 
Adverse Events 
 
Section 10.9.7 - 
Other Safety 
Assessments &  
Section 10.11.2 – 
Study Variables/ 
Endpoints &  
Management’ or ‘team’ 
where relevant. 
 
- Footnote #8 updated 
to replace ‘pulse’ with 
‘heart rate’ as per latest 
version of Simbec-
Orion protocol template 
 
 
- Footnote #8 updated 
to replace ‘pulse’ with 
‘heart rate’ as per latest 
version of Simbec-
Orion protocol template 
 
 
- Footnote #9 updated 
to replace ‘pulse’ with 
‘heart rate’ as per latest 
version of Simbec-
Orion protocol template 
 
 
– Full definition of RT-
PCR removed 
 
 
– Full definition of 
DOA removed 
 
 
– Full definition of SI 
removed 
 
– Full definition of SAE 
removed 
 
 
 
– Vital signs parameters 
updated to replace 
‘pulse’ with ‘heart rate’ 
as per latest version of 
Simbec-Orion protocol 
template 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
Appendix 1 – 
Normal Ranges 
for Vital Signs 
and ECG 
Parameters 
 
V4.0 
14/January 
2022 
Substantial  
Updates to study 
design 
Protocol Section 
3 – Synopsis 
 
Protocol Section 
5 – Abbreviations 
 
 
 
Protocol Section 
8.8 - Coronavirus 
Disease 2019 
(COVID-19) 
Risk/Benefit 
Assessment 
 
 
 
 
Protocol Section 
10.2 – Adaptive 
Elements 
 
 
 
 
Protocol Section 
10.5.1 – Inclusion 
Criteria 
 
Table 10.9.1, 
10.9.2, 10.3.3 – 
Study Flow 
Charts  
 
 
 
 
Protocol Section 
10.9.6 – COVID-
19 Testing  
 
 
 
 
 
 
 
 
 
Risk/benefit assessment 
updated to reflect the 
requirement for all 
participants enrolled 
into the study to be 
fully vaccinated against 
COVID-19 as per the 
current Welsh/UK 
Government guidelines 
 
Adaptive design 
elements updated to 
indicate that the timing 
of exploratory PD 
samples in both Part A 
and Part C. 
 
Criterion #16 updated 
New criterion #17 
 
 
Flow chart updated to 
include timepoints for 
exploratory PD 
sampling 
Part C flow updated to 
capture additional 
COVID-19 tests 
 
Section updated to 
reference routine 
performance of Lateral 
Flow Testing 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
 
Table 10.9.4, 
10.9.6 Summary 
of Blood 
Volumes 
 
Protocol Section 
10.9.26 – Other 
Assessments 
 
 
Protocol Section 
10.10.1 - 
Summary of 
Source 
Documentation 
Location 
 
Protocol Section 
10.11.2 – Study 
Variables/Endpoi
nts 
 
Protocol Section 
10.11.8 – PK 
Data 
 
 
Blood volume updated 
to reflect addition of 
exploratory PD samples 
 
 
New section added to 
describe the procedures 
for collection of 
exploratory PD samples 
 
Addition of reference to 
PD sample collection 
 
 
 
 
 
Endpoints for derived 
plasma PK for all study 
parts updated to include 
AUC0-24 
 
Text updated to include 
AUC0-24 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
3 SYNOPSIS 
NAME OF COMPANY: Artax Biopharma Inc 
NAME OF INVESTIGATIONAL MEDICINAL PRODUCT: AX-158, Placebo 
NAME OF ACTIVE INGREDIENT: AX-158 
TITLE OF STUDY: A Randomised, Double-blind, Placebo-controlled, Study of the Safety, Tolerability, and 
Pharmacokinetics of AX-158 Following Administration of Single and, Multiple Ascending Oral Doses and 
Food Effect sub-study in Healthy Male Volunteers. 
PRINCIPAL INVESTIGATOR: Dr Annelize Koch 
STUDY CENTRE: 
Simbec-Orion Clinical Pharmacology  
Merthyr Tydfil, CF48 4DR, UK 
CLINICAL PHASE: I 
OBJECTIVES:  
Primary Objective  
• 
To assess the safety and tolerability of single and multiple ascending doses of AX-158 when 
administered to healthy participants (Part A and Part C).  
Secondary Objective 
• 
To investigate the PK of single and multiple doses of AX-158 in healthy participants (Part A and Part 
C). 
• 
To investigate any food effect on the PK of AX-158 following oral administration of a single dose to 
healthy participants (Part B).  
METHODOLOGY:  
This is a phase I, randomised, double-blind, placebo-controlled study to investigate the safety, tolerability, and 
PK of AX-158 in healthy male participants following single (Part A) and multiple (Part C) ascending doses 
including food effect (Part B). 
 
The study will be conducted in three parts (Part A, Part B and Part C). 
 
Part A (SAD) will enrol 8 participants per cohort randomised (3:1) to receive AX-158 (6 participants) or placebo 
(2 participants). Part A will follow a single ascending dose (SAD) design with all participants receiving one 
dose of AX-158 (or placebo) in the fasted state.  
 
Part B (Food Effect) will be conducted in 8 participants in a cross-over manner; each participant will receive 
AX-158 in the fed and fasted state.  
 
Part C (MAD) will enrol 8 participants pre cohort randomised to (3:1) to receive AX-158 (6 participants) or 
placebo (2 participants). Part C will follow a multiple ascending dose (MAD) design with participants receiving 
AX-158 (or placebo) once daily for 10 consecutive days, in a fed or fasted state (depending on the outcome of 
the Part B (Food Effect). Doses, dosing duration and dose regimen (i.e., q.i.d., b.i.d., t.i.d.) of AX-158 and 
matching placebo for Part C may be modified based on all available safety, tolerability, and PK data and applied 
to additional MAD cohorts. Each participant will participate in only one cohort and in one of the study parts. 
 
Part A (SAD) will be conducted in up to forty (40) participants (5 cohorts of 8 participants). An additional two 
cohorts of eight (8) participants each (up to 16 additional participants total) may be investigated if required. Part 
B (Food Effect) will be conducted in 8 participants in a cross-over manner. Part C (MAD) will be conducted in 
up to twenty-four (24) participants (3 cohorts of 8 participants). An additional two cohorts of eight (8) 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
participants each (up to 16 additional participants total) may be investigated if required. Each participant will 
be assigned to only one study part and within each part, assigned to one cohort. 
 
Participants in Part A (SAD) will undergo a screening period (Day -28 to Day -2), an in-house treatment period 
comprising 4 overnight stays (from Day -1 to Day 4) and a follow up visit 5-7 days following administration of 
AX-158 or placebo. 
 
Participants in Part B (Food Effect) will undergo a screening period (Day -28 to Day -2), two in-house treatment 
periods comprising of 4 overnight stays (from Day -1 to Day 4) separated by a minimum of 7 days between 
doses and a follow up visit 5-7 days following the final administration of AX-158. 
 
Participants in Part C (MAD) will undergo a screening period (Day -28 to Day -2), an in-house treatment period 
comprising 13 overnight stays (from Day -1 to Day 13) and a follow up visit 5-7 days following the final 
administration of AX-158 or placebo. 
 
This study is designed to be adaptive, and the following elements may be revised based on emerging clinical 
safety and PK data during the course of the trial without a substantial amendment: 
 
• 
Following review of the Part B Food effect cohort PK data, participants in Part C cohorts may be 
administered AX-158 under fasted or fed conditions, as deemed appropriate, pending DERC 
determination of any appreciable impact of food effect of AX-158. If food effect is seen, cohorts in 
Part C could be dosed with a standardised meal (as opposed to the high-fat breakfast). This decision 
will be documented in the Food Effect Cohort Dose Escalation Review meeting minutes. 
• 
The timing, type, and number of safety, PK assessments may be modified (without extending the 
duration of the study).  
• 
A minimum washout of 7 days is expected within Part B but may be extended based on emerging safety 
and PK data to 14 days. 
• 
The number and/or volume of blood samples per assessment may be increased as long as the total 
volume of blood drawn for a participant does not exceed 10% of the pre-specified total blood volume 
or surpass 500 mL (except when extra blood samples need to be taken for safety reasons). 
• 
In Part C (MAD), it is planned to dose AX-158 or placebo once daily for at least 10 consecutive days; 
doses dosing duration and dose regimen (i.e., q.i.d., b.i.d, t.i.d) of AX-158 and matching placebo for 
Part C may be modified based on all available safety, tolerability, and PK data and applied to additional 
MAD cohorts up to a maximum of 14 days.  
• 
Dose levels/dosing regimen may be adjusted lower based on emerging safety and PK data. 
• 
Additional dose level(s) may be examined if deemed safe and appropriate. These cohorts will enrol 8 
participants (for SAD cohorts) and up to 8 participants (for MAD cohorts).  
• 
Currently it is planned that in order to dose escalate between cohorts and between study parts, PK data 
from up to the 24 hr post-last time point in all parts and 72 hr post-last dose safety data is required. 
However, if during the course of dose escalation, it is determined necessary to do so, then dose 
escalation procedures may be extended in order to include additional PK data up to the 72 hr post-last 
dose time point in all study parts. 
• 
Exploratory PD samples will be taken pre-dose  in Part A (SAD) and Part C (MAD) additional 
sample(s) will be taken based on emerging data.  The total blood volume will not exceed 500mL. 
 
The clinical phase is anticipated to take place between Q3 2021 (first participant first visit) and Q2 2022. The 
conclusion of the study is defined as last participant last visit (in Part C). The study will take place in the Clinical 
Unit of Simbec-Orion Clinical Pharmacology under full medical and nursing supervision.  
 
A schedule of all study assessments is provided in Table 10.9.1 (Part A SAD), Table 10.9.2 (Part B Food Effect) 
and Table 10.9.3 (Part C MAD). 
NUMBER OF PARTICIPANTS:  
Up to 104 healthy male participants may be enrolled into the study.  

 
 
 
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• 
Part A: 40 participants (5 cohorts of 8 participants each). An additional 2 cohorts of 8 
participants each may be investigated if required (max. 16 additional participants).  
• 
Part B: 8 participants (1 cohort of 8 participants).  
• 
Part C: 24 participants (3 cohorts of 8 participants each). An additional 2 cohorts of 8 
participants each may be investigated if required (max. 16 additional participants). 
MAIN INCLUSION CRITERIA:  
1. Healthy Male participant, between 18 and 50 years of age, inclusive. 
2. Male participant (and partner of childbearing potential) willing to use a highly effective method of 
contraception in addition to a condom, if applicable (unless anatomically sterile or where 
abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the participant) 
from first dose until 4 months after last dose of IMP. 
3. Participant 
with 
a 
body 
mass 
index 
(BMI) 
of 
18-30kg/m2. 
BMI = body weight (kg) / [height (m)]2. 
4. No clinically significant history of previous allergy / sensitivity to AX-158 or any of the excipients 
contained within the IMP. 
5. Participant with no history of autoimmune disease, cardiac disease, kidney disease or any food 
intolerance. 
6. No clinically significant abnormal test results for serum biochemistry, haematology and/or urine 
analyses within 28 days before the first dose administration of the IMP. 
7. Total serum bilirubin, alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine 
transaminase (ALT) ≤ 1.5 x upper limit of normal (ULN). If total bilirubin is above the upper limit 
of normal and is then fractionated, direct bilirubin must be within normal limits. 
8. Total serum Testosterone levels 2 x above the lower limit of the normal range within 28 days 
before the first dose administration of the IMP. 
9. Participant with a negative urinary drugs of abuse (DOA) screen (including alcohol) test results, 
determined within 28 days before the first dose administration of the IMP (N.B.: A positive test 
result may be repeated at the Investigator’s discretion). 
10. Participant with negative human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg)) and hepatitis C virus antibody (HCV Ab) test results at Screening. 
11. No clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined within 28 
days before first dose of IMP including a QRS > 120ms, PR interval > 220ms and QT interval 
corrected using Fredericia’s formula (QTcF) > 450ms. 
12. No clinically significant abnormalities in vital signs (e.g., blood pressure/heart rate, respiration 
rate and oral temperature) determined within 28 days before first dose of IMP. 
13. Participant must be available to complete the study (including all follow-up visits). 
14. Participant must satisfy an Investigator about his fitness to participate in the study. 
15. Participant must provide written informed consent to participate in the study. 
16. Participants with a negative COVID-19 test on admission. 
17. Participants who are considered fully vaccinated to COVID-19 as per the current Welsh/UK 
Government guidelines. 
MAIN EXCLUSION CRITERIA:  
1. A clinically significant history of gastrointestinal disorder likely to influence IMP absorption. 

 
 
 
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2. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements 
within 28 days or 5 half-lives (whichever is longer) prior to the first dose of IMP. Occasional use 
of paracetamol will be allowed. 
3. Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular, or metabolic 
dysfunction. 
4. A clinically significant history of drug or alcohol abuse (defined as the consumption of more than 
14 units [for male and female participants] of alcohol a week) within the past two years.  
5. Inability to communicate well with the Investigators (i.e., language problem, poor mental 
development, or impaired cerebral function). 
6. Participation in a New Chemical Entity (NCE) clinical study within the previous 3 months or five 
half-lives, whichever is longer, or a marketed drug clinical study within the 30 days or five half-
lives, whichever is longer, before the first dose of IMP. (Washout period between studies is defined 
as the period of time elapsed between the last dose of the previous study and the first dose of the 
next study). 
7. Donation of 450 mL or more blood within the 3 months before the first dose of IMP. 
8. Vegans, vegetarians, or other dietary restrictions (e.g., restrictions for medical, religious, or 
cultural reasons, etc), which would prevent participants from consuming a high-fat breakfast or 
standardised meal. 
9. Users of nicotine products i.e., current smokers or ex-smokers who have smoked within the 6 
months prior to screening or users of cigarette replacements (i.e., e-cigarettes, nicotine patches or 
gums). 
10. Participants who have received a COVID-19 vaccine injection within 28 days prior to the first dose 
of IMP.  
IMP ADMINISTRATION:  
Part A 
The following IMPs will be administered: 
• 
AX-158 capsules 
• 
Matching placebo  
The IMPs will be administered fasted (after an overnight fast of at least 10 h) with 240 mL water. More water 
may be provided (except PK days) if needed and the actual water taken with dose administration will be recorded 
in the eCRF. 
 
Part B 
Each participant will receive the following IMP over 2 treatment periods (1/period) in accordance with the 
randomisation code: 
• 
AX-158 capsules 
The IMP will be administered in either the fed or fasted (after an overnight fast of at least 10h or following 
consumption of a high-fat breakfast) state in accordance with the randomisation with 240 mL of water. More 
water may be provided (except PK days) if needed and the actual water taken with dose administration will be 
recorded in the eCRF. 
 
Part C 
The following IMPs will be administered: 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
• 
AX-158 capsules 
• 
Matching placebo  
The IMPs will be administered fasted (after an overnight fast of at least 10 h) with 240 mL water. More water 
may be provided (except PK days) if needed and the actual water taken with dose administration will be recorded 
in the eCRF. Participants must remain sitting for at least 1 h after dose. If food effect is observed, cohorts in Part 
C could be dosed with a standardised meal (as opposed to the high-fat breakfast). 
STUDY VARIABLES/ENDPOINTS: 
PK 
Part A 
The following plasma PK endpoints will be derived: Cmax, Tmax, λz, t1/2, AUC0-24, AUC0-t, AUC0-inf, 
AUC%extrapolated, CL/F, Vz/F. 
Part B 
The following plasma PK endpoints will be derived: Cmax, Tmax, Tlag, λz, t1/2, AUC0-24, AUC0-t, AUC0-inf, 
AUC%extrapolated, CL/F, Vz/F. 
Part C 
The following plasma PK endpoints will be derived on Day 1: Cmax, Tmax and AUC0-24, (AUC0-τ will also be 
derived if dosing interval other than q.d.).  
The following plasma PK endpoints will be derived on Final Dosing Day: Cmax, Tmax, λz, t1/2, AUC0-24, (AUC0-τ 
will also be derived if dosing interval other than q.d), AUC0-t, AUC0-inf, AUC%extrapolated, CL/F and Vz/F.  
The following urine PK parameters will be derived on Day 1 and Final Dosing Day: Ae, Ae%, CLR. 
Steady-State: For each dose level, log-transformed trough concentration levels at pre-dose day 5 will be 
subjected to a mixed effects analysis of variance (ANOVA) with study day as a fixed effect and participant as a 
random effect in order to establish whether and when steady-state has been attained for each dose level. Back-
transformed ratios for the comparisons of each consecutive day (i.e., Day 3/Day 2) will be presented along with 
corresponding 90 % CI. 
Accumulation: For each dose level, log-transformed Cmax and AUC0-τ values on Day 1 and Final Dosing Day 
(Day 10) will be subjected to an ANOVA with study day as a fixed effect and participant as a random effect. 
For comparison, point estimates and 90 % CI for the difference between Final Dosing Day (Day 10) and Day 1 
will be constructed using the residual mean square error obtained from the ANOVA for each dose level. The 
point and interval estimates will then be back transformed to give estimates of the ratios of the geometric least 
squares means and corresponding 90 % CI. 
Safety Part A, B and C 
• 
AEs.  
• 
Laboratory safety (biochemistry, haematology, coagulation, and urinalysis). 
• 
Vital signs (systolic/diastolic blood pressure, heart rate, oral body temperature and respiratory rate). 
• 
12-lead ECG (Heart rate, PR interval, QRS width, RR interval, QT interval and QT interval corrected 
using Fredericia’s formula (QTcF). 
STATISTICAL METHODS:    
There will be no formal hypothesis testing. All descriptive statistical analyses will be performed using the most 
recently released and available SAS® statistical software, unless otherwise noted. Continuous variables will be 
summarised by descriptive statistics (sample size [n], mean, standard deviation [SD], median, minimum, and 
maximum). Categorical variables will be summarised in frequency tables (n, frequencies, and percentages). 
Individual participant data will be presented in listings. Missing data will not be imputed unless otherwise stated. 
There will be a detailed description of participant disposition; participant demographics and baseline 

 
 
 
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characteristics will be summarised. PK data will be presented descriptively and graphically. A review of safety 
data and available preliminary PK data will be conducted by the DERC. A statistical analysis plan (SAP) will 
fully describe the planned analyses for this study. 
DURATION OF STUDY: 
Part A: approximately 6 weeks for each individual (from the screening to 
post-study follow-up). 
Part B: approximately 8 weeks for each individual (from the screening to 
post-study follow-up). 
Part C: approximately 7 weeks for each individual (from the screening to 
post-study follow-up). 
 

 
 
 
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4 TABLE OF CONTENTS 
1 
SIGNATURE PAGE ................................................................................. 3 
2 
PROTOCOL AMENDMENT/REVISION HISTORY ............................. 4 
3 
SYNOPSIS .............................................................................................. 10 
4 
TABLE OF CONTENTS ........................................................................ 16 
5 
ABBREVIATIONS USED IN THE PROTOCOL TEXT ...................... 21 
6 
ETHICS ................................................................................................... 24 
6.1 
Research Ethics Committee or Institutional Review Board .................... 24 
6.2 
Ethical Conduct of the Study ................................................................... 24 
6.3 
Participant Information and Consent ....................................................... 24 
7 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
 ................................................................................................................. 26 
7.1 
Study Personnel ....................................................................................... 26 
7.2 
Indemnity Arrangements ......................................................................... 26 
8 
INTRODUCTION ................................................................................... 27 
8.1 
Summary .................................................................................................. 27 
8.2 
Physical, Chemical and Pharmaceutical Properties and Formulation ..... 27 
8.3 
Nonclinical Pharmacology ....................................................................... 28 
8.4 
Nonclinical Pharmacokinetics ................................................................. 28 
8.5 
Toxicology ............................................................................................... 29 
8.6 
Clinical Experience .................................................................................. 31 
8.7 
Risk Assessment ...................................................................................... 31 
8.8 
Coronavirus Disease 2019 (COVID-19) Risk/Benefit Assessment ........ 32 
9 
STUDY OBJECTIVES ........................................................................... 34 
9.1 
Primary Study Objective .......................................................................... 34 
9.2 
Secondary Study Objective ...................................................................... 34 
10 
INVESTIGATIONAL PLAN .................................................................. 35 
10.1 
Overall Study Design and Plan ................................................................ 35 
10.2 
Adaptive Elements ................................................................................... 39 
10.3 
Dose Escalation Procedures and Stopping Criteria ................................. 40 
10.3.1 
Dose Escalation Procedures ..................................................................... 40 
10.3.2 
Stopping Criteria ...................................................................................... 40 

 
 
 
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10.3.3 
General Stopping Criteria ........................................................................ 40 
10.3.4 
Progression from Dose Leader Group/Dose Escalation Stopping Criteria
 ................................................................................................................. 41 
10.4 
Discussion of Study Design, including the Choice of Control Groups ... 42 
10.5 
Selection of Study Population ................................................................. 42 
10.5.1 
Inclusion Criteria ..................................................................................... 43 
10.5.2 
Exclusion Criteria .................................................................................... 44 
10.6 
Additional Advice and Restrictions for Study Population ...................... 45 
10.6.1 
Contraception ........................................................................................... 45 
10.6.2 
Sperm Donation ....................................................................................... 46 
10.6.3 
Phototoxicity ............................................................................................ 46 
10.6.4 
Diet and Fluid Restrictions ...................................................................... 46 
10.6.5 
Meal Times/Fasts ..................................................................................... 46 
10.6.6 
Fluid Intake .............................................................................................. 47 
10.6.7 
Alcohol Intake ......................................................................................... 47 
10.6.8 
Caffeine .................................................................................................... 47 
10.6.9 
Poppy and Sesame Seeds ......................................................................... 47 
10.6.10 
Grapefruit Juice and Other Restrictions .................................................. 47 
10.7 
Other Life-Style Restrictions ................................................................... 47 
10.7.1 
Strenuous Exercise ................................................................................... 47 
10.7.2 
Blood Donation ........................................................................................ 47 
10.7.3 
Exposure to Sunlight ................................................................................ 48 
10.7.4 
Removal of Participants from Therapy or Assessment ........................... 48 
10.8 
Investigational Medicinal Product ........................................................... 48 
10.8.1 
Identity ..................................................................................................... 48 
10.8.2 
Receipt and Storage ................................................................................. 49 
10.8.3 
Assembly and Release ............................................................................. 49 
10.8.4 
Administration ......................................................................................... 49 
10.8.5 
Return/Destruction ................................................................................... 50 
10.8.6 
Method of Assigning Participants to Treatment Groups ......................... 50 
10.8.7 
Selection of Doses in the Study ............................................................... 51 
10.8.8 
Dose Range to be Investigated ................................................................ 52 
10.8.9 
Dose Escalation Increments ..................................................................... 53 

 
 
 
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10.8.10 
Timing of Dose for Each Participant ....................................................... 53 
10.8.11 
Blinding ................................................................................................... 53 
10.8.12 
Prior and Concomitant Therapy ............................................................... 54 
10.8.13 
Treatment Compliance ............................................................................. 55 
10.9 
Efficacy and Safety Variables ................................................................. 55 
10.9.1 
Efficacy and Safety Measurements Assessed and Flow Chart ................ 55 
10.9.2 
Demographic and Background Assessments ........................................... 62 
10.9.3 
Demographics .......................................................................................... 62 
10.9.4 
Medical History and Concurrent Conditions ........................................... 62 
10.9.5 
Virology Tests ......................................................................................... 62 
10.9.6 
COVID-19 Testing .................................................................................. 62 
10.9.7 
Drugs of Abuse (including Alcohol and Cotinine) .................................. 62 
10.9.8 
Compliance with Inclusion/Exclusion Criteria ........................................ 62 
10.9.9 
Efficacy Assessments .............................................................................. 63 
10.9.10 
Safety Assessments .................................................................................. 63 
10.9.11 
Adverse Events ........................................................................................ 63 
10.9.12 
Recording of Adverse Events .................................................................. 63 
10.9.13 
Grades of Adverse Event Severity ........................................................... 64 
10.9.14 
Definitions of Adverse Event Causality .................................................. 64 
10.9.15 
Serious Adverse Events ........................................................................... 64 
10.9.16 
Monitoring of Participants with Adverse Events ..................................... 66 
10.9.17 
Pregnancy ................................................................................................ 66 
10.9.18 
Laboratory Safety Assessments ............................................................... 66 
10.9.19 
Other Safety Assessments ........................................................................ 67 
10.9.20 
Appropriateness of Measurements .......................................................... 68 
10.9.21 
Primary Efficacy Variable(s) ................................................................... 71 
10.9.22 
Drug Concentration Measurements ......................................................... 71 
10.9.23 
Pharmacokinetic Blood Sampling ........................................................... 71 
10.9.24 
Pharmacokinetic Urine Collection ........................................................... 72 
10.9.25 
Pharmacodynamic Assessments .............................................................. 72 
10.9.26 
Other Assessments ................................................................................... 72 
10.10 
Data Quality Assurance ........................................................................... 72 

 
 
 
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10.11 
Statistical Methods and Determination of Sample Size .......................... 75 
10.11.1 
Statistical and Analytical Plan ................................................................. 75 
10.11.2 
Study Variables/Endpoints ...................................................................... 75 
10.11.3 
Analysis Sets ............................................................................................ 76 
10.11.4 
Description of Statistical Methods ........................................................... 76 
10.11.5 
Demographic and Background Data ........................................................ 76 
10.11.6 
Efficacy Data ........................................................................................... 77 
10.11.7 
Safety Data ............................................................................................... 77 
10.11.8 
PK Data .................................................................................................... 78 
10.11.9 
Other Data ................................................................................................ 80 
10.11.10 
Sample Size Calculation .......................................................................... 80 
11 
PRACTICAL CONSIDERATIONS ....................................................... 81 
11.1 
Storage of Data ........................................................................................ 81 
11.2 
Protocol Amendments ............................................................................. 81 
11.3 
Confidentiality ......................................................................................... 81 
11.4 
Study Report and Publication Policy ....................................................... 81 
11.5 
General Data Protection Regulation (GDPR) .......................................... 81 
12 
REFERENCES ........................................................................................ 83 
13 
APPENDIX 1: NORMAL RANGES FOR VITAL SIGNS AND ECG 
PARAMETERS ....................................................................................... 84 
14 
APPENDIX 2: DECLARATION OF HELSINKI (BRAZIL, 2013) ...... 85 
 

 
 
 
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TABLES 
 
Table 10.8.1 Identity of Investigational Medicinal Products ................................... 49 
Table 10.8.2 Summary of predicted human exposures and multiples of the HED ..... 52 
Table 10.9.1 Study Flow Chart – Part A Single Ascending Dose ........................... 56 
Table 10.9.2 Study Flow Chart – Part B Food Effect .............................................. 58 
Table 10.9.3 Study Flow Chart – Part C Multiple Ascending Dose ........................ 60 
Table 10.9.4 Part A (Single Ascending Dose) Summary of Blood Volume .............. 69 
Table 10.9.5 Part B (Food Effect) Summary of Blood Volume ................................. 70 
Table 10.9.6 Part C (Multiple Ascending Doses) Summary of Blood Volume ......... 71 
Table 10.10.1 Summary of Source Documentation Location .................................. 74 
 

 
 
 
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5 ABBREVIATIONS USED IN THE PROTOCOL TEXT 
• ABPI 
Association of the British 
 
Pharmaceutical Industry 
• ADME 
absorption, distribution, 
 
metabolism, and excretion 
• AE(s) 
adverse event(s) 
• Ae 
amount and cumulative 
 
amount of dose excreted in 
 
urine over each collection 
 
interval 
• Ae% 
% and cumulative % of dose 
 
excreted in urine over each 
 
collection interval 
• ALP 
alkaline phosphatase 
• ALT 
alanine transaminase 
• ANOVA 
analysis of variance 
• API 
active pharmaceutical 
 
ingredient 
• aPTT 
activated partial 
 
thromboplastin time 
• AST 
aspartate transaminase 
• AUC 
area under the concentration 
 
versus time curve  
• AUC0-24 
AUC from time zero to time 
 
24 h postdose 
• AUC0-inf 
AUC extrapolated to infinity 
 
from dosing time, based on 
 
the last measurable
 
concentration 
• AUC0-t 
AUC from the time of dosing 
 
to the time of the last 
 
measurable concentration 
• AUC0-τ 
AUC from 0 to τ, where τ is 
 
the dosing interval.  
• AUC%extrapolated  
residual area 
• BIA 
BioIndustry Association 
• BMI 
body mass index  
• bpm 
beat(s) per minute 
• Cmax 
maximum plasma 
 
concentration 
• Ca 
calcium 
• CCRA 
Clinical Contract Research 
 
Association  
• CI 
confidence interval 
• CK 
creatine kinase 
• Cl 
chloride 
• CL/F 
clearance 
• CLR 
renal clearance 
• cm 
centimetres  
• CNS 
central nervous system 
• COVID-19 
coronavirus disease 2019 
• CRF 
case report form 
• CRP 
c-reactive protein 
• CV% 
coefficient of variation 
• CYP 
Cytochrome 
• DERC  
Dose Escalation Review   
 
Committee  
• DMP  
Data Management Plan 
• DOA 
drugs of abuse 
• DoH 
Department of Health 
• EAE 
Experimental autoimmune 
 
encephalomyelitis 
• EC 
European Commission 
• eCRF 
electronic case report form 
• ECG 
electrocardiogram  
• EDTA 
ethylenediaminetetraacetic 
 
acid  
• EMA 
European Medicine Agency 
• EU 
European Union  
• FIH 
First in Human 
• g 
gramme(s) 
• GCP 
Good Clinical Practice 
• GDPR 
General Data Protection 
 
Regulation 
• GGT 
gamma glutamyltransferase 
• GLP 
Good Laboratory Practice 
• GMP 
Good Manufacturing Practice 
• h 
hour(s) 
• Hb 
haemoglobin 
• HBsAg 
hepatitis B surface antigen 
• HCV Ab 
hepatitis C virus antibody 
• HCO3 
bicarbonate 
• HED 
human equivalent dose 

 
 
 
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• HIV 
human immunodeficiency 
 
virus 
• HRA 
Health Research Authority 
• IB 
Investigator’s Brochure  
• ICF 
informed consent form 
• ICH 
International  Council on 
 
Harmonisation 
• IMP 
investigational medicinal 
 
product(s) 
• INR 
international normalised ratio 
• ISF 
Investigator site file 
• IUD 
intrauterine device(s)  
• IUS 
intrauterine system 
• K 
potassium 
• kel 
elimination rate constant 
• LC MS/MS 
liquid chromatography 
 
tandem mass spectrometry 
• LFT 
lateral flow test 
• LH 
luteinising hormone  
• LLOQ 
lower limit of quantification 
• Ltd 
Limited 
• MAD 
Multiple Ascending dose 
• MCH 
mean corpuscular 
 
haemoglobin 
• MCHC 
mean corpuscular 
 
haemoglobin concentration 
• MCV 
mean corpuscular volume 
• MedDRA 
Medical Dictionary for 
Regulatory Activities 
• m 
metre(s) 
• MHRA 
Medicines and Healthcare 
products Regulatory Agency 
• mg 
milligram(s) 
• mL 
millilitre(s) 
• min 
minute 
• mmHg 
millimetre(s) of mercury 
• ms 
millisecond(s) 
• MRSD 
maximum recommended 
 
starting dose 
• MTD 
maximum tolerated dose 
• N 
number dosed 
• n 
number of observations 
• Na 
sodium 
• NCE  
new chemical entity 
• NHS 
National Health Service 
• NOAEL 
no-observed-adverse-effect 
 
level 
• NRES 
National Research Ethics 
 
Committee 
• PBMC 
peripheral blood mononuclear 
 
cell  
• PCH 
Prince Charles Hospital 
• PCE 
polychromatic erythrocytes 
• PD 
pharmacodynamic 
• PK 
pharmacokinetic 
• PPE 
personal protective equipment 
• PT 
prothrombin time 
• PR interval 
time the electrical impulse 
 
takes to travel from the sinus 
 
node through the AV node 
 
and entering the ventricles; 
 
measured from the beginning 
 
of the P wave to the beginning 
 
of the QRS complex 
• PV 
pharmacovigilance 
• QC 
quality control 
• QD 
Once a day 
• QP 
qualified person 
• QRS 
QRS complex represents 
 
ventricular depolarisation 
• QT interval  
the time for both ventricular 
 
depolarisation and 
 
repolarisation to occur, and 
 
therefore roughly estimates 
 
the duration of an average 
 
ventricular action potential. 
• QTc 
corrected QT interval 
• QTcF 
corrected QT interval using 
 
Fridericia’s formula 
• R2 
coefficient of determination 
• RBC 
red blood cell(s) 
• RDW 
red blood cell distribution 
 
width 
• REC 
Research Ethics Committee 
• RR interval  
the time elapsed between two 
 
successive R waves 

 
 
 
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• RT-PCR 
reverse transcription 
 
polymerase chain reaction 
• s 
second(s) 
• SAD 
Single acceding dose 
• SAE 
serious adverse event 
• SAP 
statistical analysis plan 
• SAS 
statistical analysis software by 
 
SAS Institute Inc., USA 
• SD 
standard deviation 
• SG 
specific gravity 
• SHM  
Sample Handling Manual  
• SI  
Statutory Instrument 
• SmPC 
Summary of Product 
 
Characteristics 
• SOC 
system organ class 
• SOP 
standard operating 
 
procedure(s) 
• SUSAR 
suspected unexpected serious 
 
adverse reaction 
• t½ 
terminal elimination half-life 
• TCR 
T cell receptor 
• TEAE 
Treatment Emergent Adverse 
 
Event 
• Tmax 
the time to Cmax  
• THC 
tetrahydrocannabinoids  
• TMF 
trial master file 
• UK 
United Kingdom 
• USA 
United States of America 
• Vz/F 
volume of distribution 
• WBC 
white blood cell(s) 
• ºC 
degrees Celsius 
• % 
percent  

 
 
 
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6 ETHICS 
6.1 Research Ethics Committee or Institutional Review Board  
This study protocol will be submitted to the Research Ethics Committee (REC) for review and 
provision of a favourable opinion.  The favourable opinion of the REC must be obtained before 
commencement of any study procedures. 
The favourable opinion is conditional upon the Sponsor registering the clinical trial in a 
publicly accessible database, within 6 weeks of the first participant recruited or following 
confirmation of an appropriate Health Research Authority (HRA) deferral.   
All substantial protocol amendments must receive favourable opinion from the REC 
responsible for the study. Non-substantial amendments will not require prior favourable 
opinion by the REC. 
If the study is stopped due to adverse events (AEs) it will not be recommenced without 
reference to the REC responsible for the study. 
The outcome of the study (e.g., completed) will be reported to the REC responsible for the 
study within 90 days of completion of the last participant’s final study procedures. In the event 
of the study being prematurely terminated a report will be submitted to the REC responsible 
for the study within 15 days. 
A summary of the clinical study report will be submitted to the REC responsible for the study 
within 1 year of completion of the last participant’s final study procedures. 
The REC will be informed that Simbec-Orion is a commercial organisation and that the study 
is funded by Artax Biopharma Inc. The participants who take part in the clinical study will be 
paid for their inconvenience and have been informed that there will be no benefits gained by 
their participation. All potential conflicts of interest will be declared by the Investigators.  
6.2 Ethical Conduct of the Study 
The Principal Investigator shall be responsible for ensuring that the clinical study is performed 
in accordance with the Declaration of Helsinki (Brazil 2013) (APPENDIX 2: DECLARATION 
OF HELSINKI (BRAZIL, 2013). It will comply with International Council on Harmonisation 
(ICH) Good Clinical Practice (GCP) [2] and applicable regulatory requirements. 
6.3 Participant Information and Consent 
Potential participants who volunteer for participation in the study will be informed of the aims, 
methods, anticipated benefits and potential hazards of the study and any possible discomfort it 
may entail.  Information will be given in both oral and written form and in the manner deemed 
appropriate by the Clinical Unit standard operating procedures (SOPs). Each participant will 
also be informed of his/her right to withdraw from the study at any time, for any reason. 
A written explanation (participant information sheet) and informed consent form will be 
provided, and the participant will be allowed sufficient time to consider the study information. 
Prior to signing the informed consent form, the participant will be given an opportunity to 
discuss any issues concerning the study with an Investigator who has suitable knowledge of 
the study and will have all questions answered openly and honestly. 

 
 
 
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If the participant is willing to participate in the study, the informed consent form will be signed 
and personally dated by the participant and the person taking consent. The participant will 
receive a copy of the informed consent form together with the participant information sheet 
and the original signed informed consent form will be retained with the study records at the 
Investigator site.  In addition, the actions and completion of the consenting process will be 
recorded in the participant’s medical record (i.e., source document). 
 

 
 
 
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7 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The study will be performed at a single site, Simbec-Orion Clinical Pharmacology Unit.  The 
overall responsibility for the study will rest with the Principal Investigator, Dr Annelize Koch.  
The Project Manager will act on behalf of the Principal Investigator to ensure the smooth and 
efficient running of all aspects of the study. 
7.1 Study Personnel 
Contract Research Organisation: Simbec-Orion  
Principal Investigator: 
Dr Annelize Koch 
Project Manager (Main Contact):  
Adam Chessun 
Project Manager Deputy: 
Hannah Parry 
Pharmacokinetics (PK):  
Dr Danielle Francombe 
Data Management and Statistics: 
Simbec-Orion Biometrics 
Laboratory Services: 
Simbec-Orion Laboratory Services 
IMP Management: 
Dr Rebecca Price-Davies 
The Principal Investigator will delegate study-related activities according to staff 
responsibilities and job descriptions. This will be documented in a study-specific delegation of 
responsibilities form. 
 
Sponsor: Artax Biopharma Inc 
Project Manager (Main Contact): Andres Gagete 
Sponsor’s Responsible Physician: Richard Polisson  
Sponsor’s Legal Representative: Orion LR 
Monitor: Simbec-Orion Clinical Development  
Pharmacovigilance (PV): Simbec-Orion Clinical Development 
7.2 Indemnity Arrangements 
The Sponsor and Simbec-Orion carry insurance to pay compensation for injury, accident, ill 
health or death caused by participation in this study without regard to proof of negligence in 
accordance with the insurance and compensation in the event of injury in Phase I clinical trials 
2012, guidance issued by the Association of the British Pharmaceutical Industry (ABPI), the 
BioIndustry Association (BIA) and the Clinical Contract Research Association (CCRA) in 
consultation with the Department of Health (DoH) and the National Research Ethics Service 
(NRES). 

 
 
 
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8 INTRODUCTION 
8.1  Summary  
Artax Biopharma Inc is developing AX-158, a new chemical entity (NCE), for the treatment 
of autoimmune and inflammatory diseases such as psoriasis, multiple sclerosis, rheumatoid 
arthritis, and Crohn’s disease. These are diverse groups of diseases in which the adaptive 
immune system (particularly via T lymphocytes) attacks self-antigens in the body. These 
diseases are extremely relevant from both a social and economic point of view since their high 
incidence and chronic nature, represents a significant socio-economic burden for communities 
worldwide. 
The AX-158 therapeutic target is the T cell receptor (TCR) signalosome. The compound, 
through its direct interaction with Nck1, a component of the signalosome, selectively 
modulates self-directed T cell activation which is a cause of autoimmune disease.  
T cells can recognise foreign and self-antigens and trigger the immune response against them. 
Recognition of the antigen by the T cell is carried out by the TCR responsible for signal 
transmission to the cytoplasm. To become active, reactive T cells have to receive three signals: 
- Signal 1, derived from the TCR after antigen recognition. This signal is the initiation 
event of the immune response and the most relevant one. 
- Signal 2, derived from co-stimulatory receptor (CD28). 
- Signal 3, derived from cytokine receptors, which are responsible for T cell proliferation 
and differentiation into different types of effectors. 
 
T cells are a critical element of immunopathological response mechanisms. AX-158 is designed 
to centrally address autoimmune diseases by modulating the response of T cells by changing 
the strength of low avidity TCR signalling events that are responsible for T cell activation in 
autoimmune diseases while not interfering with normal strong responses to foreign antigen 
challenges.   
AX-158 did not suppress acute immune responses in pre-clinical murine models involving 
either the immune-dominant vaccinia peptide B8R or haptenated antigens. However, the effect 
of AX-158 on human immune surveillance, including the response to vaccination, is unknown. 
8.2  Physical, Chemical and Pharmaceutical Properties and Formulation 
AX-158 is a dark brown crystalline powder. The drug substance is filled into size 2 capsules 
which contain a minimum of 5 mg of AX-158 (dose assembled into single capsules per dose 
level for each cohort). The capsules are for oral administration.  
Please refer to the current version of the Investigators Brochure (IB)[1] and Investigational 
Medicinal Product Dossier (IMPD)[3] for detailed information about the pharmaceutical 

 
 
 
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properties, formulation, and data (including pharmacology and toxicology data) derived from 
the non-clinical investigations of AX-158. 
8.3  Nonclinical Pharmacology 
In vitro studies have demonstrated activity of AX-158 at key points in the T cell TCR signaling 
cascade (proximal to the TCR, at key integrator of TCR signaling Akt, and at resulting cytokine 
production). 
 
Rapid phosphorylation of ZAP70 (pZAP70) in human Jurkat cells was observed upon TCR 
stimulation with Anti-CD3 (OKT3) and assessed by commercial HTRF (homogenous Time 
Resolved Fluorescence) methodology (Cisbio). Treatment of cells with AX-158 potently 
modulated pZAP70 signaling. 
 
Rapid phosphorylation of Akt (S473) was observed in primary T cells (PBMC) using flow 
cytometry analysis to study impacted T cell subsets. AX-158 potently impacts phosphorylation 
of Akt (S473) in both CD4+ and CD8+ T cells following stimulation (Anti-CD3 / CD28). 
 
Cytokine production in primary T cells (PBMCs) was stimulated by Anti-CD3 activation of 
the TCR and assessed by flow cytometry. AX-158 potently modulated IL-2 production in 
CD4+ T Cells. AX-158 reduces intracellular IL-2 in primary CD4+ T cells following Anti-
CD3 stimulation of PBMCs as assessed by flow cytometry. 
8.4  Nonclinical Pharmacokinetics 
The results of safety pharmacology studies indicate that AX-158 has no effects on 
physiological, respiratory and CNS up to the maximum dose tested 180 mg/kg in rats, which 
is nearly 375 times the equivalent efficacy dose (1 mg/kg) on a body surface area basis in the 
EAE mouse model.  
 
The in vitro study on hERG clone cells showed that AX-158 is a week inhibitor of the hERG 
channel. The IC50 is 145 times higher than the peak free plasma concentration at the efficacious 
dose in EAE mouse model.  
   
Regarding in vivo cardiovascular parameters, a preliminary dog telemetry study was conducted 
in three unanaesthetised male beagle dogs and comprising three oral treatment groups: control 
(vehicle), 2 mg/kg AX-158 and 20 mg/kg AX-158. AX-158 at the dose of 2 mg/kg and 20 
mg/kg did not affect heart rate, body temperature and ECG parameters when compared to the 
vehicle.  At the low dose of 2 mg/kg, no changes in mean, systolic, and diastolic arterial blood 
pressure were observed. At the high dose of 20 mg/kg, a statistically significant increase in 
diastolic arterial blood pressure was observed in each of the 3 test animals (mean 38% maximal 
increase from pre-dose baseline and 26% higher compared to vehicle treatment), which in each 
case resolved by 16 hours post-dosing. No noticeable change in the sympatho-vagal balance 
attributed to AX-158 was seen at either dose. Dosing confirmation samples indicated that the 
plasma concentration at 20 mg/kg dose level was 4.5 µg/mL at 4 h post dose.    

 
 
 
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In view of this unexpected finding, an extended battery of haemodynamic and cardiovascular 
studies was performed, including: a non-good laboratory practice (GLP) telemetry study in 
conscious dogs via IV dosing 10 mg/kg (estimated peak plasma concentration: 18-20 µg/mL), 
a non-GLP study in anaesthetised rats via IV dosing up to 9 mg/kg  (plasma concentration not 
measured, however rats given at 2 mg/kg IV showed peak plasma concentrations around  12 
µg/ml then it could be estimated that rats given 9 mg/kg would have been exposed at least at 
3-4 times this concentration ), a non-GLP telemetry study in conscious minipigs via oral dosing 
up to 100 mg/kg (measured peak plasma concentration: 3.3 µg/mL) and a GLP telemetry study 
in conscious minipigs via oral dosing up to 300 mg/kg (estimated peak plasma concentration: 
14 µg/ml).  None of the studies showed any change of biological significance in heart rate, 
arterial blood pressure or electrocardiographic activity. The increase in blood pressure 
observed in dogs via oral dosing at 20 mg/kg could not be reproduced.  
Collectively, data from 4 studies in 3 different species did not show changes in blood pressure 
even at doses that resulted in peak plasma concentrations 3-4 times the concentration achieved 
in the dog study where blood pressure was increased. Therefore, the accumulated data allows 
suggesting that the effect observed in dogs was incidental and non-reproducible. 
 
Overall, single oral and intravenous dose studies were performed in several species to 
characterise its pharmacokinetics and bioavailability of AX-158. The bioanalytical methods 
for rat and minipig were validated according to FDA and EMA guidelines for the toxicokinetic 
assessment incorporated in the repeated dose toxicology studies. Plasma in vitro protein 
binding was determined in the species used in the preclinical studies and in human. AX-158 
metabolic profile was evaluated in vivo in rat, dog, minipig and in vitro using primary 
hepatocyte in humans and no in vitro CYP inhibition was observed. 
8.5  Toxicology 
In rats the maximum tolerated dose (MTD) following three consecutive days of oral 
administration of AX-158 was determined to be 300 mg/kg/day. A subsequent dose range 
finding study was conducted with doses up to 180 mg/kg/day for 14 days whereby the MTD 
was determined to be 180 mg/kg. A 28-day GLP toxicity study was carried out with doses up 
to 180 mg/kg/day by oral route. The studies elicited a decrease in the size of testes, 
epididymides, seminal vesicles and coagulating glands at doses ≥ 50 mg/kg/day. The changes 
in testes and epididymides were microscopically associated with degeneration/atrophy of 
seminiferous tubules of testes and cell debris/decreased sperm in lumen of epididymides. 
However, there were no associated microscopic changes in seminal vesicles and coagulating 
glands. These changes were observed to be partially reversible in recovery animals. Test item 
related perivascular inflammation at the base of heart involving the tunica adventitia of aorta 
and surrounding brown adipose tissue was noted at ≥50 mg/kg/day in both sexes and a single 
incidence in recovery group female animal. Chronic inflammation was observed with the 
presence of mononuclear cells and fibroblasts. The NOAEL in rat in the 28-day study was 15 
mg/kg/day. 
 
In minipigs, a MTD study achieving doses up to 600 mg/kg was performed by oral route. The 
MTD was >600 mg/kg. A 14 days DRF study was subsequently performed at 300 and 600 
mg/kg. The MTD following 14 consecutive days of oral administration was considered to be 

 
 
 
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300 mg/kg/day. A 28-day oral repeated dose study was performed at 30, 100 and 300 
mg/kg/day with 14 days of recovery period (Study A3674). The NOAEL in females was 
defined at the highest dose tested (300 mg/kg/day), while treatment-related reduction in the 
absolute and relative testes weight, correlated with treatment-related microscopic observations 
such as testicular hypoplasia/atrophy were observed in all male animals and not normalized 
after the recovery period. A second 28-day oral study only in males at 5, 15, and 50 mg/kg/day 
with a 10 week recovery period has been performed accordingly at lower doses in order to 
determine the NOAEL (Study A4211). As referenced in the histopathological report, testicular 
hypoplasia/atrophy is a common finding in male minipigs that appears in a spontaneous manner 
making it difficult to discriminate between test item-related effects and background noise from 
the species. For that reason, in the new study a few modifications were made to tackle this 
issue: 
 
- Higher number of animals per group were used (increased from 3 to 5) in order to 
provide additional statistical power to the study.  
- In addition, animals included on the study were screened using ultrasound to discard 
those showing detectable testicular damage/alteration.  
- Finally, this study included animals one month older than those from the previous GLP 
study in order to maximize the chances of them reaching sexual maturity. 
 
As a result, findings were observed at all dose levels in this new study were indistinguishable 
from those of including the control group and therefore where testicular alterations where 
indeed more severe than those on the treated animals. Therefore, considered not treatment 
related but incidental. Recovery animals also showed no alterations. Accordingly, the highest 
dose level at 50 mg/kg was selected as the NOAEL.  
 
It is important to note that current NOAEL is higher than the previous GLP study LOAEL 
which was defined at 30 mg/kg. In addition, the 50 mg/kg (NOAEL) and the 30 mg/kg 
(LOAEL) levels from the two different studies showed similar exposures in terms of AUClast 
at the end of the treatment (66.72 µg.h/mL and 60.101 µg.h/mL respectively) and yet it was 
not possible to reproduce the testicular damage on the second GLP study at 50 mg/kg.  
 
Overall, minipig NOAEL definitions are presented as follows merging the available data from 
the two GLP studies: 
 
- Female NOAEL for minipig was stablished at 300 mg/kg, the highest dose examined 
in the first GLP study. 
- For the male minipig, testicular findings were considered as treatment related in study 
A3674 because of an apparent dose-dependent relationship. However, in study A4211 
with added statistical power and pre-screening of animals for sexual maturity, findings 
were considered an expression of spontaneous and/or incidental pathology.  
- Although the results of both studies allow the assumption that findings in testes 
observed in study A3674 could be regarded as spontaneous and within the biological 
interindividual variability, there is not sufficient information at this time to discard a 
treatment related effect, as in rats, therefore an overall NOAEL of 15 mg/kg/day is 
selected, which results from the integrated assessment of the 2 minipig studies.    

 
 
 
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A complete standard genotoxicity package according to ICH M3 was performed, 
demonstrating that AX-158 was not mutagenic in the Bacterial Reverse Mutation Assay up to 
the highest recommended concentration of 5000 µg/plate. AX-158 was neither clastogenic up 
to the maximum non-cytotoxic concentration of 27 μg/mL in cultured human peripheral blood 
lymphocytes, either in the presence or in the absence of metabolic activation, higher 
concentrations showed remarkable cytotoxicity. Finally, AX-158 did not induce significant 
increases in micronucleated PCE in male and female Sprague Dawley rats when orally 
administered up to the MTD (500 mg/kg/day).  
 
On the basis of the above, the defined exposure limits for this study are set as the following: 
Cmax = 3.26 μg/mL & AUC0-24 = 14.859 μg*h/mL. 
8.6 Clinical Experience 
There has been no clinical experience with AX-158 to date. AX-158-101 is a first in human 
(FIH) clinical study. 
8.7 Risk Assessment 
The risk of this proposed Phase I study is considered acceptable given that: 
• There were no adverse events seen in non-clinical species above the NOAEL which 
warrant specific monitoring of participants.  
• The proposed starting dose of AX-158 in humans (5 mg/day) is 29 times lower than the 
HED of NOAEL from the most sensitive species (the rat) and the starting dose is 
predicted to achieve total exposures 3x-fold lower than the lowest efficacious exposure 
achieved in the mouse at 1 mg/kg, an approximately 121-fold lower total Cmax, and 69-
fold lower total AUC than exposure achieved at the NOAEL in rats and 78-fold lower 
total male Cmax, and 41-fold lower total AUC than exposure achieved at the NOAEL in 
minipigs. 
• The starting dose in Part C (multiple ascending dose [MAD]) will not exceed the 
highest dose examined in the preceding completed Part A (single ascending dose 
[SAD]) cohorts or a level expected to exceed the highest AX-158 exposure (Cmax and 
AUC0-24) observed from preceding Part A (SAD) cohorts. 
• For each SAD and MAD cohort, 2 sentinel participants (1 active, 1 placebo) will be 
dosed and monitored for 24 h prior to dosing the rest of the cohort. 
• In Part A (SAD), dose escalation will be done in a stepwise, controlled manner, with 
dose escalation only being permitted after full evaluation of up to 24 h PK and 72 h 
safety data from the previous cohort by the Dose Escalation Review Committee 
(DERC). 
• In Part C (MAD) dose escalation will be done in a stepwise, controlled manner, with 
dose escalation only being permitted after full evaluation of up to 10 days PK and safety 
data from the previous cohort by the DERC.   
• The study is being conducted in a Medicines and Healthcare products Regulatory 
Agency (MHRA) accredited Phase I unit. 

 
 
 
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Further details of the non-clinical studies and a summary of the known and potential risks and 
benefits to human participants of AX-158 can be found in the Investigator’s Brochure (IB)[2]. 
The study will be conducted in compliance with the protocol, GCP and the applicable 
regulatory requirement(s), as indicated within Section 6.2.5 of the ICH GCP E6 (R2) 
guidelines[2]. 
 
8.8 Coronavirus Disease 2019 (COVID-19) Risk/Benefit Assessment 
This study is to be conducted in healthy adult participants who are deemed not to be at higher 
risk of COVID-19 as per the latest version of the National Health Service (NHS) Guidance 
(https://www.nhs.uk/conditions/coronavirus-covid-19/people-at-higher-risk/whos-at-higher-
risk-from-coronavirus/. 
The safety of the participant is the primary concern; this study is to be conducted at Simbec-
Orion Clinical Pharmacology Unit which is a Phase I accredited unit with extensive experience 
in conducting Phase I trials of similar design. Simbec-Orion prioritise the health and wellbeing 
of their clinical trial participants and, as such, have implemented a number of COVID-19 
policies and risk mitigating actions. Prior to attendance at site, participants will be contacted to 
ensure they are not displaying any COVID-19 symptoms; Site COVID-19 policies will be 
explained to them at this time. Where appropriate perspex screens are in place and appropriate 
social distancing is enforced, when this is not possible, appropriate personal protective 
equipment (PPE) will be worn.  
Simbec-Orion Clinical Pharmacology unit is a dedicated trial facility and, as such, staffing 
levels will not be affected by the potential burden presented by COVID-19 to other medical 
facilities. All employees present at the clinical site are aware of the COVID-19 specific 
working requirements and will work to the relevant ‘Working Safely’ Policy.    
Medicines and Healthcare products Regulatory Agency (MHRA) Phase I Accreditation 
requirement No. 3 details the requirement for an agreement with a local hospital for supporting 
emergencies arising from the clinical trials performed by Simbec-Orion, this agreement is in 
place with Cwm Taf Morgannwg University Health Board and Prince Charles Hospital (PCH) 
for this purpose. Cwm Taf Morgannwg University Health Board and PCH have confirmed 
capacity to support any acute serious AEs (SAEs) during the COVID-19 pandemic (details 
contained within the latest version of the Simbec-Orion Clinical General Risk Assessment. 
AX-158 did not suppress acute immune responses in pre-clinical murine models involving 
either the immune-dominant vaccinia peptide B8R or haptenated antigens. However, the effect 
of AX-158 on human immune surveillance, including the response to vaccination, is unknown. 
All participants will remain in-house for the duration of the study under the medical supervision 
of the PI throughout. 
 
In addition, the sponsor has conducted a risk assessment in consideration of the ongoing 
COVID-19 vaccine deployment programme including assessment of the potential risks 
associated with concomitant vaccination whilst participating in this trial. 
 

 
 
 
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The sponsor has determined that the outcome of the risk assessment undertaken in conjunction 
with the study team is as follows. Knowledge on the Investigational Medicinal Product (IMP) 
is currently insufficient to assess the potential impact of IMP on the efficacy of COVID-19 
vaccination or to assess the impact of COVID vaccination on IMP safety. If given 
concomitantly, it could possibly be difficult to discriminate if the AEs observed during the 
study are due to the IMP or due to COVID-19 vaccine. In addition, the study participants are 
young healthy volunteers, by definition without any co-morbidity, and are in consequence in a 
category of subjects without any immediate risk of developing a severe form of COVID-19, 
and not considered the top priority for the UK vaccine campaign.  
 
Therefore, participants will be required to be fully vaccinated according to current Welsh / UK 
government guidelines prior to admission into the study. Participants are not permitted to have 
their COVID-19 vaccine injections (boosters) whilst in the study (from 28 days prior to dosing 
to completion of final post-study follow up procedures). Participants will be informed that if 
they are invited to receive a COVID-19 vaccination during the study and wish to receive the 
vaccine that they will be withdrawn from participation in the study. The investigator will check 
that any participants who may have a pre-booked appointment for a COVID-19 vaccination, 
are not in breach of this requirement. 
 
Both the Study and Site Risk Assessments will be continually monitored and updated 
throughout the trial, and it is currently deemed acceptable to conduct the trial without it 
impacting or being impacted by the COVID-19 pandemic.  
 
 
 

 
 
 
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9 STUDY OBJECTIVES 
9.1 Primary Study Objective 
• To assess the safety and tolerability of single and multiple ascending doses of AX-158 
when administered to healthy participants (Part A and Part C).  
9.2 Secondary Study Objective 
• To investigate the PK of single and multiple doses of AX-158 in healthy participants 
(Part A and Part C). 
• To investigate any food effect on the PK of AX-158 following oral administration of a 
single dose to healthy participants (Part B).  
 

 
 
 
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10 INVESTIGATIONAL PLAN 
10.1 Overall Study Design and Plan 
This is a phase I, randomised, double-blind, placebo-controlled study to investigate the safety, 
tolerability, and PK of AX-158 in healthy male participants following single (Part A) and 
multiple (Part C) ascending doses including food effect (Part B). 
The study will be conducted in three parts (Part A, Part B and Part C). 
Part A (SAD) will enrol 8 participants per cohort randomised (3:1) to receive AX-158 (6 
participants) or placebo (2 participants). Part A will follow a single ascending dose (SAD) 
design with all participants receiving one dose of AX-158 (or placebo) in the fasted state. Part 
B (Food Effect) will be conducted in 8 participants in a cross-over manner; each participant 
will receive AX-158 in the fed and fasted state. Part C (MAD) will enrol 8 participants per 
cohort randomised to (3:1) to receive AX-158 (6 participants) or placebo (2 participants). 
Part C will follow a MAD design with participants receiving AX-158 (or placebo) once daily 
for 10 consecutive days, in a fed or fasted state (depending on the outcome of the Part B Food 
Effect). Doses, dosing duration and dose regimen (i.e., q.i.d., b.i.d., t.i.d.) of AX-158 and 
matching placebo for Part C may be modified based on all available safety, tolerability, and 
PK data and applied to additional MAD cohorts. 
Up to one hundred and four (104) healthy participants are planned to be enrolled in this 3-part, 
multi cohort study. Part A (SAD) will be conducted in up to forty (40) participants (5 cohorts 
of 8 participants). Part B (Food Effect) will be conducted in 8 participants in a cross-over 
manner. Part C (MAD) will be conducted in up to twenty-four (24) participants (3 cohorts of 8 
participants). Each participant will be assigned to only one study part and within each part, 
assigned to only one cohort. 
Participants in Part A (SAD) will undergo a screening period (Day -28 to Day -2), an in-house 
treatment period comprising 4 overnight stays (from Day -1 to Day 4) and a follow up visit 5-
7 days following administration of AX-158 or placebo. 
Participants in Part B (Food Effect) will undergo a screening period (Day -28 to Day -2), two 
in-house treatment periods comprising of 4 overnight stays (from Day -1 to Day 4) separated 
by a minimum of 7 days between doses and a follow up visit 5-7 days following the final 
administration of AX-158. 
Participants in Part C (MAD) will undergo a screening period (Day -28 to Day -2), an in-house 
treatment period comprising 13 overnight stays (from Day -1 to Day 13) and a follow up visit 
5-7 days following the final administration of AX-158 or placebo. 
For Part A (SAD) and Part C (MAD), a dose leader design will be implemented with 2 
participants being dosed on the first dosing day of each cohort. Of these 2, 1 will be on active 
drug and 1 on placebo. The remainder of the cohort will be dosed at least 24 h later pending an 
acceptable safety profile in the dose-leader group and will contain at least 1 additional placebo 
participant. This design allows maintenance of the “blind” while also staggering ongoing 
exposure within the MAD phase. 
In both Part A (SAD) and Part C (MAD), sequential cohorts will be exposed to increasing doses 
of AX-158. Prior to dose escalation between cohorts, safety and PK data from the previous 

 
 
 
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cohort will be reviewed by the DERC to determine whether it is appropriate to proceed to the 
next cohort/dose level. 
The maximum dose level administered will not exceed a level anticipated to result in plasma 
exposures greater than those seen at the NOAEL, without prior approval by the REC and 
MHRA, as per Section 6.4.4 of the ICH E6 (R2) guidelines[2]. 
The clinical phase is anticipated to take place between September 2021 and May 2022.  The 
conclusion of the study is defined as last participant last visit. 
The study will take place in the Clinical Unit of Simbec-Orion Clinical Pharmacology (Clinical 
Unit) under full medical and nursing supervision. 
A schedule of all study assessments is provided in Table 10.9.1, Table 10.9.2 and Table 10.9.3.  
Part A (SAD) 
Up to 5 dose levels of AX-158 are planned to be investigated in Part A of the study (with an 
option to include additional dose levels to a maximum of 2 cohorts). Each cohort will follow a 
dose-leader schedule; two participants (one randomised to receive placebo and one randomised 
to receive AX-158) will be dosed in a blinded manner at least 24 hours prior to the remainder 
of the cohort. In the absence of any safety concerns in these first 2 participants, dosing of the 
remainder of the cohort will proceed on a parallel study schedule. 
The lowest dose of AX-158 will be evaluated first; refer to Section 10.8.7 for further details; 
dose administration in the subsequent cohort will only proceed after blinded review of available 
safety and PK data from a minimum of six (6) evaluable participants in the preceding cohort 
by the DERC; see Section 10.3 for full details. The maximum dose investigated will not exceed 
a level anticipated to result in a Cmax or AUC0-24 exceeding those observed at NOAEL levels in 
the most relevant non-clinical species without prior approval by the REC and MHRA (via 
substantial amendment). The study may be discontinued at any time if any unacceptable safety 
findings are identified (as determined by PI and Sponsor). 
Screening (Days -28 to Day -2) 
Screening assessments will be performed from Day -28 to Day -2 to ensure the eligibility of 
participants. Assessments will be performed as per Table 10.9.1 
Treatment Period (Day -1 to Post-Treatment 3 (i.e., Day 4)) 
Participants will be admitted to the Clinical Unit on the morning of Day -1 with confirmation 
of eligibility and baseline assessments performed as per Table 10.9.1. Randomisation will 
occur prior to dose on Day 1. 
After an overnight fast of at least 10 h, dose administration will occur on the morning of Day 
1. Fasting will continue until 4 h post-dose; a standardised meal will then be provided. Clinical 
and laboratory assessments of safety, tolerability and PK variables will be conducted 
throughout the in-house period as per Table 10.9.1. Participants will be discharged from the 
clinical unit following completion of 72 h post-dose assessments providing there are no 
ongoing safety concerns; participants may be monitored as an outpatient where the PI (or 
delegate) deems this to be appropriate. 
A follow-up visit will be conducted 5-7 days following the first dose of AX-158 or placebo 
(i.e., Day 8) as per Table 10.9.1.  

 
 
 
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Post-Study Follow Up Visit (5-7 days after last dose of IMP (i.e., Day 8)). 
For participants in all SAD cohorts, a follow-up visit will be conducted 5-7 days following last 
IMP or placebo administration (i.e., Day 8). If all follow-up assessments (Table 10.9.1) are 
satisfactory the PI (or delegate), will discharge the participant from the study. If any AEs are 
ongoing, or any assessments are not satisfactory, participants may be recalled to the unit for 
follow-up assessments until the PI (or delegate) is satisfied the participant is medically stable 
and may be discharged from the study. Participants will be advised to return or contact the unit 
at any time if they may be experiencing any adverse effects. 
Following DERC review of data from Part A, the dose for participants in Part B will be 
determined. 
Part B (Food Effect) 
The dose to be evaluated in the food-effect cohort will be determined based on review of all 
available safety, tolerability, and PK data from Part A. Participants in the food-effect cohort 
will receive AX-158 administered under both fasted and fed conditions. 
Where receiving a dose in the fed state, participants will be provided the standard FDA high 
fat breakfast[5] which should be consumed within 30 minutes (mins) or less, with study drug 
administration occurring approximately 30 mins after the start of the meal. Fasting will 
recommence until 4 h post-dose; a standardised meal will then be provided.  
Participants will be discharged from the clinical unit following completion of 72 h post-dose 
assessments providing there are no ongoing safety concerns; participants will be monitored as 
an outpatient. 
Treatment Periods (Day -1 to Day 4): Participants will receive a single dose of AX-158 over 
2 treatments periods in fed/fasted conditions (1 condition per period). Each treatment period 
will be approximately 4 days duration, from the morning before dosing (Day -1) until 72 h 
post-dose (Day 4). During each treatment period, participants will receive a single dose of AX-
158 following an overnight fast of at least 10 h OR following consumption of a high-fat 
breakfast over 2 treatment periods (1 per period). When receiving AX-158 in the fed state, 
following an overnight fast of at least 10 h, participants will be provided the standard FDA 
high fat breakfast which will be served and consumed within 30 mins. AX-158 should be 
administered 30 mins after the start of the meal. At both treatment periods, fasting will 
continue/recommence until 4 h post-dose; a standardised meal will then be provided. 
Participants will be discharged 72 h post-dose. PK samples will be collected pre-dose and up 
to 72 h post-dose for the measurement of AX-158. Safety will also be evaluated at time points 
specified in Table 10.9.2. There will be at least 7 days between dose administrations. 
Following DERC review of data from Part B, the dose for participants in Part C will be 
determined, and cohorts in Part C may be administered AX-158 under fasted or fed conditions 
as deemed appropriate, pending DERC determination of any appreciable impact of food on the 
absorption, distribution, metabolism, and excretion (ADME) of AX-158. 
A follow-up visit will be conducted 5-7 days following last IMP administration. If all follow-
up assessments (Table 10.9.2) are satisfactory the PI (or delegate), will discharge the 
participant from the study. If any AEs are ongoing, or any assessments are not satisfactory, 
participants may be recalled to the unit for follow-up assessments until the PI (or delegate) is 

 
 
 
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satisfied the participant is medically stable and may be discharged from the study. Participants 
will be advised to return or contact the unit at any time if they may be experiencing any adverse 
effects. 
Part C (MAD) 
Part C will be initiated following review of all available safety, tolerability, and PK data from 
Part A (SAD) and Part B (Food Effect) to determine the appropriate AX-158 dose and dosage 
regimen to be evaluated in the initial MAD cohort; the starting dose in Part C will not exceed 
the highest dose level examined in the preceding completed Part A cohorts or a dose level 
expected to exceed the highest AX-158 exposure (Cmax and AUC0-24) observed from preceding 
Part A cohorts. It is planned to dose AX-158 or placebo once daily for at least 10 consecutive 
days; doses, dosing duration and dose regimen (i.e., q.i.d., b.i.d., t.i.d.) of AX-158 and matching 
placebo for Part C may be modified based on all available safety, tolerability, and PK data and 
applied to additional MAD cohorts. The maximum dose will not exceed a level anticipated to 
result in a Cmax or AUC0-24 exceeding those observed at NOAEL levels in the most relevant 
non-clinical species without prior approval by the REC and MHRA (via substantial 
amendment).  
Up to 3 dose levels of AX-158 are planned to be investigated in Part C of the study (with an 
option to include additional dose levels to a maximum of 2 cohorts). Each cohort will follow a 
dose-leader schedule in which two participants (one randomised to receive placebo and one 
randomised to receive AX-158) will be dosed at least 24 h prior to the remainder of the cohort 
allowing for review of emerging safety and tolerability data from this dose-leader group on an 
ongoing basis and to avoid dosing all participants in a cohort simultaneously.  
The lowest dose level of AX-158 will be evaluated first; dose administration in the subsequent 
cohorts will only proceed after blinded safety, tolerability, and PK data from a minimum of 6 
evaluable participants in the preceding cohort have been reviewed by the DERC; see Section 
10.3 for full details). The study part may be discontinued at any time if any unacceptable safety 
findings are identified (as determined by PI and Sponsor).  
Screening (Days -28 to Day -2) 
Screening assessments will be performed from Day -28 to Day -2 to ensure the eligibility of 
participants. Assessments will be performed as per Table 10.9.3. 
In-patient Period (Day -1 to Post-Treatment 3 (i.e., Day 13)) 
Participants will be admitted to the Clinical Unit on the morning of Day-1 with confirmation 
of eligibility and baseline assessments performed as per Table 10.9.3. Randomisation will 
occur prior to dose on Day 1. An evening snack will be consumed at least 10 h before each 
dose administration. After an overnight fast of at least 10 h, dose administration will occur each 
day, on the morning of Day 1 to Final Dosing Day (planned as Day 10). It is planned to 
administer doses in Part C in a fasted state, however following review of Part B food-effect 
data, the dose may be administered in a fed state with a standardised meal. Fasting will continue 
until 4 h post-dose; a standardised meal will then be provided. Clinical and laboratory 
assessments of safety, tolerability and PK variables will be conducted throughout the in-house 
period as per Table 10.9.3. 

 
 
 
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Participants will be discharged from the Clinical Unit on Post-Treatment (i.e., Day 13) 
following the completion of the 72 h post-last dose assessments providing there are no ongoing 
safety concerns.   
Post-Study Follow Up Visit (5-7 days after final dose of IMP i.e., Day 17). 
For participants in all MAD cohorts, a follow-up visit will be conducted 5-7 days following 
last IMP or placebo administration. If all follow-up assessments (Table 10.9.3.) are satisfactory 
the PI (or delegate), will discharge the participant from the study. If any AEs are ongoing, or 
any assessments are not satisfactory, participants may be recalled to the unit for follow-up 
assessments until the PI (or delegate) is satisfied the participant is medically stable and may be 
discharged from the study. Participants will be advised to return or contact the unit at any time 
if they may be experiencing any adverse effects. 
10.2 Adaptive Elements 
This study is designed to be adaptive, and the following elements may be revised based on 
emerging clinical safety and PK data throughout the course of the trial without a substantial 
amendment: 
 
• Following review of the Part B Food effect cohort PK data, participants in Part C 
cohorts may be administered AX-158 under fasted or fed conditions, as deemed 
appropriate, pending DERC determination of any appreciable impact of food effect of 
AX-158. If food effect is seen, cohorts in Part C could be dosed with a standardised 
meal (as opposed to the high-fat breakfast). This decision will be documented in the 
Food Effect Cohort Dose Escalation Review meeting minutes. 
• The timing, type, and number of safety, PK assessments may be modified (without 
extending the duration of the study).  
• A minimum washout of 7 days is expected within Part B but may be extended based on 
emerging safety and PK data to 14 days. 
• The number and/or volume of blood samples per assessment may be increased as long 
as the total volume of blood drawn for a participant does not exceed 10% of the pre-
specified total blood volume or surpass 500 mL (except when extra blood samples need 
to be taken for safety reasons). 
• In Part C (MAD), it is planned to dose AX-158 or placebo once daily for at least 10 
consecutive days; doses dosing duration and dose regimen (i.e., q.i.d., b.i.d, t.i.d) of 
AX-158 and matching placebo for Part C may be modified based on all available safety, 
tolerability, and PK data and applied to additional MAD cohorts up to a maximum of 
14 days.  
• Dose levels/dosing regimen may be adjusted lower based on emerging safety and PK 
data. 
• Additional dose level(s) may be examined if deemed safe and appropriate. These 
cohorts will enrol 8 participants (for SAD cohorts) and up to 8 participants (for MAD 
cohorts).  
• Currently it is planned that in order to dose escalate between cohorts and between study 
parts, PK data from up to the 24 hr post-last time point in all parts and 72 hr post-last 
dose safety data is required. However, if during the course of dose escalation, it is 

 
 
 
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determined necessary to do so, then dose escalation procedures may be extended in 
order to include additional PK data up to the 72 hr post-last dose time point in all study 
parts. 
• Exploratory PD samples will be taken pre-dose in Part A (SAD) and Part C (MAD) 
additional sample(s) will be taken based on emerging data.  The total blood volume will 
not exceed 500mL. 
10.3 Dose Escalation Procedures and Stopping Criteria 
10.3.1 Dose Escalation Procedures  
Following completion of each cohort, a summary of all relevant safety AEs, ECG, vital signs, 
laboratory assessments up to 72 h post dose) and PK data (up to 24 h post-dose for Part A & 
Part B and 10 days for Part C) will be produced on behalf of the Principal Investigator. Planned 
doses may be modified following a review of emerging data. Progression to the next SAD dose 
level and dose selection will be based on the available safety and PK data from at least 6 
evaluable participants from the preceding dose level. Progression to the next MAD dose level 
and dose selection will be based on the available safety and PK data from at least 6 evaluable 
participants from the preceding dose level. An evaluable participant is defined as a participant 
who has received the planned dose (active or placebo) and has sufficient PK samples to 
estimate Cmax and AUC0-24. Dose escalation will be dependent upon generation of acceptable 
safety (and PK) data. If it is not appropriate to escalate the dose according to the proposed dose 
escalation schedule, then the same dose, an intermediate dose or a lower dose may be given 
following discussion between the Sponsor and the Principal Investigator (or deputy) if no 
stopping criteria are met.   
There will be a Telephone Conference at a pre-appointed time to involve the Simbec-Orion 
Project Manager and Principal Investigator (or deputy) and the Sponsor’s representative(s), 
including the Sponsor's Responsible Physician. After discussion of all the data, the decision 
will be made whether to dose escalate and a written document (dose escalation approval form) 
signed by the Principal Investigator (or deputy) and Sponsor will be produced ratifying that 
decision. Full minutes, to be agreed by all parties, will be produced for each discussion 
regarding dose escalation and filed in the Investigator Site File. A copy of the signed dose 
escalation approval form will be provided to the Simbec-Orion IMP Management team to allow 
the release of the next dose level of IMP to the clinic.  
Dose escalation stopping criteria are detailed in Section 10.3.4 
10.3.2 Stopping Criteria 
10.3.3 General Stopping Criteria 
The study will be discontinued if any unacceptable safety findings are identified.  This decision 
will be made jointly by the Principal Investigator (or deputy) and the Sponsor.  A written 
document signed by the Principal Investigator (or deputy) and Sponsor will be produced 
ratifying the decision. 
Individual participants may also be withdrawn for any of the reasons outlined in Section 10.7.4. 

 
 
 
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10.3.4 Progression from Dose Leader Group/Dose Escalation Stopping Criteria 
If any of the below-listed criteria are met, further dosing or dose escalation between cohorts 
will be temporarily stopped pending evaluation of all available data: 
• ‘serious’ adverse reaction (i.e., a serious adverse event considered related to the IMP 
administration) in one participant, as defined in Section 10.9.11. 
• ‘severe’ non-serious adverse reactions (i.e., severe non-serious adverse events 
considered related to the IMP administration) in two participants in the same cohort, 
independent of within or not within the same system-organ-class, as defined in Section 
10.9.11. 
• 4 out of 8 participants in a cohort experience the same moderate or severe AE that is 
considered related to the IMP. 
• 1 or more participant in the cohort experiences a drug related SAE.  
• Any participant experiences a severe AE in any key safety variable (ECG, laboratory 
safety or vital signs) that in the opinion of the Investigator is at least possibly related to 
the IMP and may jeopardise the safety of the participants.  
• QTcF < 330 ms, QTcF > 500 ms or a QTcF increase of > 60 ms in any participant 
confirmed on 3 consecutive ECGs, at least 1 min a part. 
• Systemic exposure (Cmax and AUC) for a dose that is anticipated to exceed pre-
determined exposure limits based on preclinical toxicology data and/or already 
available human PK data i.e., Cmax = 3.26 μg/mL & AUC0-24 = 14.859 μg*h/mL. 
• Any other toxicity which in the opinion of the Principal Investigator and the medical 
monitors of CRO and Sponsor would preclude dosing additional participants at the 
indicated dose level.  
• Any of the following elevation in a liver function test result, must have a possible 
relationship to IMP, to be confirmed on repeat samples, and other potential causes (i.e., 
strenuous exercise, use of a concomitant medication, viral infection such as hepatitis A 
or cytomegalovirus) must have been excluded. 
o ALT or AST >3x ULN and (BIL-T >2x ULN or INR >1.5) * 
o ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) * 
 
*Dependent on availability of liver function test data, observation may be made following 
progression from dose leader group. Any findings and impact will be reviewed and 
implemented (where applicable) immediately.  
Individual participants may also be withdrawn for any of the reasons outlined in Section 10.7.4. 
If any of the above criteria are fulfilled, dose escalation will only proceed once an appropriate 
substantial amendment has been submitted and receives regulatory approval from the MHRA 
and approval from the REC associated with the study. 

 
 
 
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10.4 Discussion of Study Design, including the Choice of Control Groups  
This study will be conducted in three parts (Part A [SAD], Part B [Food Effect] and Part C 
[MAD]). Part A is a randomised, double-blind, placebo-controlled SAD study to assess the 
safety, tolerability, and pharmacokinetics of AX-158 in up to 40 healthy male participants. Two 
additional cohorts of 8 participants each may be investigated if required. Part B is a randomised 
two-way cross over food effect study of AX-158, participants will receive a single dose of AX-
158 in both the fed and fasted state to assess safety, tolerability, pharmacokinetics of AX-158. 
Part C is a randomised, double-blind, placebo-controlled MAD study to assess the safety, 
tolerability, and pharmacokinetics of AX-158 in up to 24 healthy male participants. Two 
additional cohorts of 8 participants each may be investigated if required. The study employs a 
SAD parallel-group design; corresponding placebo control will be administered in order to 
evaluate treatment-related effects. Safety and PK data from a minimum of 6 participants of 
each cohort will be required for data review prior to dose escalation. 
 
The design of this study is typical of that used for FIH studies with a “dose leader” design for 
built-in safety. A dose leader design will be implemented in which 2 participants (1 AX-158 
and 1 placebo) in each cohort will be dosed approximately 24 h before the remainder of the 
Cohort. Providing there are no safety concerns in the dose leader group (to the 24 h time-point), 
the remainder of the cohort (6 participants) will be dosed a day later and will be randomised in 
such a way that at least one further participant receives placebo. This design allows 
maintenance of the “blind” and is intended to reduce the number of participants simultaneously 
exposed to risk in order to better manage the safety aspects of the trial. 
10.5 Selection of Study Population 
Up to one hundred and four (104) participants are planned to be enrolled into Part A, B and C 
of the study. 
The study is to be conducted in healthy male participants; therefore, participants are not 
expected to derive any therapeutic benefit from taking part in the study.  A healthy participant 
population with carefully considered inclusion/exclusion criteria will avoid the potential for 
interaction of AX-158 with any underlying disease state or concomitant medication that it may 
be necessary for patients to take, while ensuring that participants are fit and well enough for 
participation in the study.   
AX-158 has not been previously administered to humans; therefore, its effects in humans are 
as yet unknown. 
The following eligibility criteria are designed to select participants for whom protocol 
treatment and procedures are considered appropriate.  All relevant medical and non-medical 
conditions should be taken into consideration when deciding whether this protocol is suitable 
for a particular participant. 
Deviations from inclusion and exclusion criteria are not allowed as deviations have the 
potential to impact the scientific integrity of the study, regulatory acceptability or participant 
safety as such deviations constitute a deliberate breach of Regulation 29 of Statutory Instrument 
(SI) 2004/1031. Therefore, adherence to the criteria as specified in the protocol is essential. 

 
 
 
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10.5.1 Inclusion Criteria 
To be confirmed at screening: 
1. Healthy Male participant, between 18 and 50 years of age, inclusive. 
2. Male participant (and partner of childbearing potential) willing to use a highly 
effective method of contraception in addition to a condom (see Section 10.6.1), if 
applicable (unless anatomically sterile or where abstaining from sexual intercourse 
is in line with the preferred and usual lifestyle of the participant) from first dose 
until 4 months after last dose of IMP. 
3. Participant with a body mass index (BMI) of 18-30kg/m2. (Inclusive) 
BMI = body weight (kg) / [height (m)]2. 
4. No clinically significant history of previous allergy / sensitivity to AX-158 or any 
of the excipients contained within the IMP. 
5. Participant with no history of autoimmune disease, cardiac disease, kidney disease 
or any food intolerance. 
6. No clinically significant abnormal test results for serum biochemistry, haematology 
and/or urine analyses within 28 days before the first dose administration of the IMP. 
7. Total serum bilirubin, alkaline phosphatase (ALP), aspartate transaminase (AST) 
and alanine transaminase (ALT) ≤ 1.5 x upper limit of normal (ULN). If total 
bilirubin is above the upper limit of normal and is then fractionated, direct bilirubin 
must be within normal limits. 
8. Total serum Testosterone levels 2 x above the lower limit of the normal range within 
28 days before the first dose administration of the IMP. 
9. Participant with a negative urinary drugs of abuse (DOA) screen (including alcohol) 
test results, determined within 28 days before the first dose administration of the 
IMP (N.B.: A positive test result may be repeated at the Investigator’s discretion). 
10. Participant with negative human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg)) and hepatitis C virus antibody (HCV Ab) test results at 
Screening. 
11. No clinically significant abnormalities in 12-lead electrocardiogram (ECG) 
determined within 28 days before first dose of IMP including a QRS > 120ms, PR 
interval > 220ms and QT interval corrected using Fredericia’s formula (QTcF) > 
450ms. 
12. No clinically significant abnormalities in vital signs (e.g., blood pressure/heart rate, 
respiration rate and oral temperature) determined within 28 days before first dose 
of IMP. 
13. Participant must be available to complete the study (including all follow-up visits). 
14. Participant must satisfy an Investigator about his fitness to participate in the study. 
15. Participant must provide written informed consent to participate in the study. 
16. Participants with a negative COVID-19 test on admission. 

 
 
 
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17. Participants who are considered fully vaccinated to COVID-19 as per the current 
Welsh/UK Government guidelines. 
 
To be re-confirmed on Day -1 / prior to first dose administration: 
1. Participant continues to meet all screening inclusion criteria. 
2. Participant with a negative urinary DOA screen (including alcohol) prior to first 
dose administration. 
3. Participants with a negative COVID-19 test on admission (if required). 
10.5.2 Exclusion Criteria 
To be confirmed at Screening: 
1. A clinically significant history of gastrointestinal disorder likely to influence IMP 
absorption. 
2. Use of prescription or non-prescription drugs, including vitamins, herbal and 
dietary supplements within 28 days or 5 half-lives (whichever is longer) prior to the 
first dose of IMP. Occasional use of paracetamol will be allowed 
3. Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular, or 
metabolic dysfunction. 
4. A clinically significant history of drug or alcohol abuse (defined as the consumption 
of more than 14 units [for male and female participants] of alcohol a week) within 
the past two years.  
5. Inability to communicate well with the Investigators (i.e., language problem, poor 
mental development, or impaired cerebral function). 
6. Participation in a New Chemical Entity (NCE) clinical study within the previous 3 
months or five half-lives, whichever is longer, or a marketed drug clinical study 
within the 30 days or five half-lives, whichever is longer, before the first dose of 
IMP. (Washout period between studies is defined as the period of time elapsed 
between the last dose of the previous study and the first dose of the next study). 
7. Donation of 450 mL or more blood within the 3 months before the first dose of 
IMP. 
8. Vegans, vegetarians, or other dietary restrictions (e.g., restrictions for medical, 
religious, or cultural reasons, etc), which would prevent participants from 
consuming a high-fat breakfast or standardised meal. 
9. Users of nicotine products i.e., current smokers or ex-smokers who have smoked 
within the 6 months prior to screening or users of cigarette replacements (i.e., e-
cigarettes, nicotine patches or gums). 
10. Participants who have received a COVID-19 vaccine injection within 28 days prior 
to the first dose of IMP.  

 
 
 
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To be re-confirmed at Day -1 / prior to first dose administration: 
1. Development of any exclusion criteria since the Screening visit. 
2. Use of prescription or non-prescription drugs, including vitamins, herbal and 
dietary supplements since Screening. 
3. Participation in a clinical study since the Screening visit. 
4. Donation of 450 mL or more blood since the Screening visit. 
10.6 Additional Advice and Restrictions for Study Population 
10.6.1 Contraception 
To prevent pregnancy, male participants (and partner of childbearing potential)  must be willing 
to use a highly effective method of contraception in addition to a condom, if applicable (unless 
partner is of non-childbearing potential or where abstaining from sexual intercourse was in-
line with the preferred and usual lifestyle of the participant [periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception]) from the first dose until 4 months after the last dose.   
Highly effective methods of contraception include: 
• Combined (oestrogen and progestogen containing) hormonal contraception (oral, 
intravaginal, and transdermal) associated with inhibition of ovulation,  
• Progestogen-only hormonal contraception (oral, injectable, and implantable) associated 
with inhibition of ovulation,  
• Intrauterine device (IUD),  
• Intrauterine hormone-releasing system (IUS),  
• Bilateral tubal occlusion,  
• Vasectomised participant (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate. In the absence of such documentation, condoms will 
be required).  
To prevent exposure of any partner (male or female) during non-vaginal intercourse to the 
semen from a male participant who has been exposed to the IMP, the following contraception 
must be used: 
• Condom.  
The chosen contraception method(s) must be followed from the first dose until at least 4 months 
after receiving the last dose of IMP. 
In addition, male participants must use a condom when engaging in sexual intercourse with a 
female who is pregnant or breastfeeding during the study. 

 
 
 
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10.6.2 Sperm Donation 
Participants must not donate sperm from the first dose and for at least 4 months after the last 
dose of IMP. 
10.6.3 Phototoxicity 
Data on the potential phototoxicity of AX-158 is not yet available. Participants should therefore 
avoid exposure to direct sunlight from the first dose and should remain within the Phase I unit 
until 24 hours after the (last) dose. 
10.6.4 Diet and Fluid Restrictions 
10.6.5 Meal Times/Fasts 
Participants should receive standardised meals (as determined by the clinical unit) scheduled 
at the same time for all participants in each cohort (relative to their dosing time).  
Participants will fast overnight for at least 10 h then - 
Lunch will be served: approximately 4 h post-dose. 
Dinner will be served: approximately 8 h post-dose. 
Snack will be served: approximately 12 h post-dose. 
Participants are required to fast for at least 8 h prior to laboratory sample collection for the 
following tests:  
For blood glucose tests (analysed in serum or plasma).  
Please refer to Table 10.9.1, Table 10.9.2 and Table 10.9.3. for scheduling of these tests. 
On all non-dosing study days, whilst resident in the Clinical Unit, meals will be served at 
standard times. 
Participants will choose meals from a standard menu while resident at the Clinical Unit. 
 
Part B Food-Effect:  
 
Participants will fast overnight for at least 10 h then –  
During the fed treatment period, participants will be provided with a high fat breakfast** to be 
consumed within 30 mins or less. The study drug should be administered approximately 30 
min after the start of the meal.  
**A high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie 
(approximately 800 to 1000 calories) meal is recommended as a test meal for food-effect 
bioavailability and fed bioequivalence studies. This test meal should derive approximately 150, 
250, and 500-600 calories from protein, carbohydrate, and fat, respectively. An example test 
meal consists of two eggs fried in butter, two strips of bacon, two slices of toast with butter, 
four ounces of hash brown potatoes and eight ounces of whole milk[5]. 

 
 
 
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If it is determined following review of the Food Effect Cohort data that all cohorts in Part C 
should be administered AX-158 in the fed state, the meal will comprise of a standardised meal 
as per the standard for the Clinical Unit. 
10.6.6  Fluid Intake 
No fluids (apart from water taken with the dose) are allowed from 1 h prior to dosing until 1 h 
afterwards.  Water is then allowed ad libitum and at least 240 mL should be consumed every 
4 h during waking hours. Squash/cordial/hot drinks (decaffeinated tea and coffee) are allowed 
from 4 h post-dose. 
10.6.7 Alcohol Intake 
The consumption of alcohol will be limited to a maximum of 2 units per day from 7 days prior 
to the first dose of IMP. Alcohol will be avoided completely for a period of not less than 2 days 
prior to the first dose of IMP and throughout the study period.  Any deviation outside this 
alcohol intake restriction will be assessed on a case-by-case basis at the Investigator’s 
discretion (provided the participant’s alcohol intake will not impact in the safety aspects and 
objectives of the study and the participant has a negative alcohol screen prior to dosing). 
10.6.8 Caffeine 
Food or drink containing caffeine, including coffee, tea, cola, energy drinks or chocolates will 
be avoided completely 2 days prior to dosing and whilst the participants are resident in the 
Clinical Unit (during each dosing period). 
10.6.9 Poppy and Sesame Seeds 
Participants will be advised that they must not eat food containing poppy and/or sesame seeds 
for 3 days before each visit to the Clinical Unit, as consumption of poppy and/or sesame seeds 
can lead to a positive opiate result in the drugs of abuse test. 
10.6.10Grapefruit Juice and Other Restrictions  
No food or drink containing grapefruit, cranberry, or Seville oranges (including marmalade and 
fruit juices), and/or food or drink, sweets, candies, or other confectionary containing liquorice 
will be allowed from 7 days before the first dose of IMP until the final study visit. 
10.7 Other Life-Style Restrictions 
10.7.1 Strenuous Exercise 
Strenuous exercise must be avoided completely from 3 days before the first dose of IMP until 
the final study visit. 
10.7.2 Blood Donation 
Participants will be advised that they should not donate blood for at least 3 months after the 
final study visit. 

 
 
 
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10.7.3 Exposure to Sunlight 
Participants should avoid exposure to direct sunlight from the first dose until 24 h after the (last) 
dose. 
10.7.4 Removal of Participants from Therapy or Assessment 
Each participant will be informed of their right to withdraw from the study at any time and for 
any reason. 
An Investigator will withdraw a participant from the study at any time for any of the following 
reasons: 
• If a participant experiences a serious or intolerable AE, that prevents them from 
continuing. 
• If a participant incurs a significant protocol violation which impacts on their safety 
or the scientific integrity of the study (this will be discussed on a case-by-case basis 
with the sponsor). 
• At the request of the Sponsor. 
• If it is considered that the participant’s health is compromised by remaining in the 
study or the participant is not sufficiently cooperative. 
• If a participant is lost to follow-up. 
The reasons for any participant withdrawal will be recorded on the study completion form of 
the electronic case report form (eCRF). 
If a participant is withdrawn or chooses to withdraw from the study for any reason every 
possible effort will be made to perform the evaluations described for the post-study follow-up 
(see Table 10.9.1, Table 10.9.2 and Table 10.9.3). The data collected from withdrawn 
participants will be included in the study report. 
In the event of any abnormalities considered to be clinically significant, participants will be 
followed-up with appropriate medical management until values are considered to be clinically 
acceptable.  Referral or collaborative care will be organised if considered necessary. 
Up to one hundred and four (104) participants are planned to be enrolled into the study.  
Participants who withdraw from the study before receiving any IMP will be replaced.  
Participants who are withdrawn from the study due to significant drug-related AEs will not be 
replaced.  Replacement of all other participants withdrawn from the study after receiving IMP 
will be decided on a case-by-case basis by the Principal Investigator (or deputy) and Sponsor. 
10.8 Investigational Medicinal Product  
10.8.1 Identity 
The identity of each IMP is detailed in Table 10.8.1 Identity of Investigational Medicinal 
Products. 

 
 
 
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Table 10.8.1 Identity of Investigational Medicinal Products  
IMP Name 
Strength 
Presentation/Form 
Route 
AX-158 
Minimum of 5 mg API 
per capsule 
Capsule 
Oral 
Matching Placebo (per capsule strength) 
N/A 
Capsule 
Oral 
10.8.2 Receipt and Storage 
The active pharmaceutical ingredient (API) (AX-158) will be supplied by the Sponsor. 
The Sponsor must notify the Principal Investigator, or the Project Manager, prior to dispatch 
of supplies, and of the anticipated date of their arrival.  API should arrive at the study site at 
least 4 weeks before the first dosing day.  The Sponsor shall address all supplies to: 
The Production Manager 
IMP Management 
Simbec-Orion  
Merthyr Tydfil Industrial Park 
Merthyr Tydfil CF48 4DR 
Upon receipt, supplies will be dealt with as per Simbec-Orion SOPs. Temperature monitors 
included with shipments will be downloaded. 
The API will be stored under quarantine, at 15-25oC in a secure, temperature-controlled GMP 
area. A sample will be taken and sent to Simbec-Orion’s contract laboratory to confirm identity. 
A Simbec-Orion Qualified Person (QP) will review the shipping documentation and certificate 
of analysis. The supplies will subsequently be removed from quarantine and approved for use. 
10.8.3 Assembly and Release 
The IMP will be assembled into unit doses by suitably trained Simbec-Orion staff according to 
Simbec-Orion SOPs.  
The IMP will be labelled as specified in Annex 13 (manufacture of IMPs) of the European 
Commission (EC) guide to Good Manufacturing Practice (GMP)[6]. 
The finished IMP will be certified by a Simbec-Orion QP and stored in a secure, temperature-
controlled GMP area according to  Simbec-Orion SOPs . 
10.8.4 Administration 
 
Part A 
The following IMPs will be administered: 
• AX-158 capsules 
• Matching placebo  
The IMPs will be administered fasted (after an overnight fast of at least 10 h) with 240 mL 
water. More water may be provided (except on PK days) if needed and the actual water taken 

 
 
 
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with dose administration will be recorded in the eCRF. Participants must remain in a sitting  
position for at least 1 h after dose. 
Part B 
Each participant will receive the following IMP over 2 treatment periods (1/period) in 
accordance with the randomisation code: 
• AX-158 capsules 
The IMP will be administered in either the fed or fasted (after an overnight fast of at least 10h 
or following consumption of a high-fat breakfast) state in accordance with the randomisation 
with 240 mL of water. More water may be provided (except on PK days) if needed and the 
actual water taken with dose administration will be recorded in the eCRF. There will be at 
least 7 days between doses. 
 
Part C 
The following IMPs will be administered: 
• AX-158 capsules 
• Matching placebo  
The IMPs will be administered fasted (after an overnight fast of at least 10 h) with 240 mL 
water. More water may be provided (except on PK days) if needed and the actual water taken 
with dose administration will be recorded in the eCRF. Participants must remain in a sitting 
position for at least 1 h after dose. If food effect is seen, cohorts in Part C could be dosed with 
a standardised meal (as opposed to the high-fat breakfast).  
For Part A (SAD) and Part C (MAD), a dose leader design will be implemented with 2 
participants being dosed on the first dosing day of each cohort.  Of these 2, 1 will be on active 
drug and 1 on placebo.  The remainder of the cohort will be dosed at least 24 h later pending 
an acceptable safety profile in the dose-leader group and will contain at least 1 additional 
placebo participant. This design allows maintenance of the “blind”. 
IMP administration will be documented in the eCRF. 
10.8.5 Return/Destruction 
All used IMP containers and unused IMP will be held under quarantine pending 
return/destruction.  
The Sponsor must provide approval for return/destruction of all remaining IMP within 8 weeks 
study completion. After this period, a charge for storage will be incurred.  
All returns will be arranged at the earliest available delivery date. For IMP destruction, the 
sponsor will receive the Certificate of Destruction 4 to 6 weeks from the date of removal from 
site. 
10.8.6 Method of Assigning Participants to Treatment Groups 
Participants will be allocated to treatment groups according to a randomisation code produced 
by Simbec-Orion using the PROC PLAN procedure of SAS® (the most up to date version will 

 
 
 
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be used and this will be documented in the Statistical Analysis Plan [SAP]). The randomisation 
code will include 2 dose-leaders (1 active:1 placebo) in each cohort (for Part A and Part C 
only).  
Participants will be numbered sequentially from 001 (i.e., 001, 002 etc.). Replacement 
participants will be assigned the same randomisation as the participant they are replacing, 
however, 100 will be added to the number (i.e., 101 would replace 001 etc.). 
10.8.7 Selection of Doses in the Study 
The starting dose of AX-158 for the FIH study is selected based on FDA (2005) and EMA 
(2017) guidelines using nonclinical PK and toxicological data. 
The NOAEL-based maximum recommended starting dose (MRSD) according to the FDA was 
calculated using the NOAEL from the rat, which was the most sensitive species. 
The NOAEL, as derived from the 28-day toxicology study in rats, was 15 mg/kg/day. The 
human equivalent dose (HED) was calculated as 15 mg/kg / 6.2 = 2.4 mg/kg. Applying a 
standard safety factor of 10 (per FDA guidance), and a standard body weight of 60 kg, the 
NOAEL based maximum recommended starting dose (MRSD) would be (2.4 x 60)/10 = 
14.4 mg. 
The efficacious dose in a murine EAE model treated for 23 days is 1 mg/kg. This dose 
corresponds to 0.69 µg/mL and 0.942 µg.h/mL Cmax and AUClast, respectively.  The MED dose 
in mouse at 1 mg/kg corresponds to a target AUCu= 942*0.27= 254 ng*h/mL. Assuming a 
0.22 unbound fraction for humans, this would correspond to a human AUC of 1150 ng*h/mL 
as per human efficacious dose projection modelling[1]. 
A dose of 15 mg AX-158 dosed QD would result in exposure in a range similar to mouse AUC 
at 1 mg/kg[1]. Nonetheless, a starting dose 3x below the projected efficacious dose in humans 
is proposed and therefore 5 mg is suggested as the starting dose in humans.  This approach 
meets the EMA Guideline on strategies to identify and mitigate risks for first-in-human and 
early clinical trials with investigational medicinal products, 2018 which states that the starting 
dose should be a dose expected to result in an exposure lower than pharmacology active dose. 
As this is a first-in-human study, it is acknowledged that only the selected starting dose for the 
first cohort (5 mg) in the Single Ascending Dose (SAD) part of the study (Part A) is fixed; all 
other dose levels to be evaluated in subsequent cohorts with Part A are subject to selection 
following dose escalation data review of PK and safety data from the previous cohorts. 
However, the anticipated doses for evaluation in the 5 cohorts of Part A of the study are as 
shown in Table 10.8.2 below,. 
   
The table summarises two scenarios where i) at least 3 of the proposed dose levels are expected 
to be above the efficacious exposure according to PK modelling and ii) all dose levels would 
be in the therapeutic range according to BSA conversion factors. 
 

 
 
 
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Table 10.8.2 Summary of predicted human exposures and multiples of the HED  
Human Phase I 
Proposed Dose 
Levels (mg) 
PK Modelling 
Human exposure vs 
Mouse MED (AUCs 
ug.h/ml) * 
BSA conversion 
Human Phase I (mg/kg) 
** 
Multiples 
of 
HED 
(0.083 mg/kg) from the 
EAE model (BSA basis) 
5 
0.38 
0.083 
1 
10 
0.77 
0.167 
2 
15 
1.17 
0.25 
3 
25 
1.87 
0.42 
5 
40 
3.04 
0.67 
8 
*Efficacious exposure 0.942 μg.h/mL. Values based on CERTARA projections **Assuming a 
60 kg average body weight. Dose levels expected to be within the therapeutic range based on 
both approaches are identified in bold and red. 
 
On the basis of the above table and a maximum proposed dose of 40 mg, it is anticipated that 
the maximum dose will fall within the estimated human pharmacodynamic dose range. 
Efficacy on the EAE model has been confirmed both at 1 and 10 mg/kg in mice which would 
correlate on a BSA basis to 5 and 50 mg in humans. Accordingly, it is considered that the 
planned doses up to and including the maximum planned dose will all fall under the estimated 
pharmacodynamic dose range.   
 
As detailed within Section 10.2, the proposed dose levels may be adapted and modified if the 
actual human exposure levels (evaluated following cohort dose escalation data review) are 
below the levels predicted by the PK modelling. This additional measure guarantees that the 
study includes representative dose levels within the pharmacodynamic range. If a higher dose 
than the proposed maximum dose of 40 mg is to be evaluated (following dose escalation data 
review), an estimation of AX-158 exposure will be performed in order to determine that this 
higher dose will not exceed the exposure limits as set within the protocol pre-defined stopping 
criteria (Cmax= 3.26 ug/mL; AUC= 14.859 μg.h/mL) or exceed the estimated human 
pharmacodynamic dose range. If it is determined that this higher dose will indeed exceed the 
exposure limits or exceed the estimated human pharmacodynamic dose range, an appropriate 
substantial amendment will be submitted for review and approval by the REC and MHRA and 
dosing will only proceed following receipt of approval of this substantial amendment. 
 
AX-158 will be given as a flat dose at each dose level, based on a 60 Kg volunteer. Eligible 
participants will be enrolled in sequential cohorts treated with AX-158, given as an oral capsule 
dose while being monitored for safety. 
10.8.8 Dose Range to be Investigated 
Part A (SAD): No dose level that is predicted to exceed either the Cmax or AUC0-24 seen at the 
NOAEL in the nonclinical studies will be administered in this study without prior approval, 
via substantial amendment, from REC and MHRA. During the study, PK data from the 
previous cohort/s, along with safety and tolerability information, will be used to aid dose 
selection and the magnitude of the dose increase for the next cohort.  

 
 
 
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Part B (Food effect): The dose level at which the food effect will be performed will be based 
on a review of all available safety and PK data from Part A and will not exceed a dose tolerated 
in Part A. 
Part C (MAD): The starting dose in Part C will not be expected to exceed the highest 
established AX-158 exposure (Cmax and AUC0-24) from Part A. Doses of AX-158 and matching 
placebo for Part C will be selected based on safety, tolerability and pharmacokinetic 
considerations from Part A (and where applicable previous cohort/s of Part C) which will be 
used to aid dose selection, magnitude of the dose increase for the next cohort and review of 
dosing regimen if appropriate. The maximum dose administered in a 24 h period will not 
exceed a level anticipated to result in a Cmax or AUC0-24 exceeding those observed at NOAEL 
levels in nonclinical species without prior approval by the REC and MHRA (via substantial 
amendment). 
10.8.9 Dose Escalation Increments 
The planned dose escalation for all cohorts (with the exception of Part A [SAD] Cohort 1) is 
up to a 2-fold increase of the previous dose level. In Part A, it is planned to investigate up to 5 
dose levels; however, it is possible that 2 additional dose level(s) may be investigated if 
justified based on available safety, tolerability, and PK data. In Part C, it is planned to 
investigate up to 3 dose levels; however, it is possible that 2 additional dose level(s) may be 
investigated if justified based on available safety and PK data. Dose escalation increments may 
vary from those planned but will not exceed 2-fold; the Sponsor and the Principal Investigator 
may decide not to proceed with further dose cohorts, to administer a lower or intermediate 
dose, to repeat a dose in subsequent cohorts or to proceed to a higher dose if at all. A dose level 
will not be repeated if dose escalation stopping criteria have been met at that dose level.  It is 
noted that escalation/continuation to the next dose level will not occur if any individual 
participant’s Cmax or AUC0-24 data exceeds those levels seen at the NOAEL in the most sensitive 
preclinical species, (AX-158 Cmax of 3.26 ug/mL and AUC of 14.859 µg*h/mL(males), or if 
they are anticipated to do so at the next dose level based on emerging PK data. 
10.8.10Timing of Dose for Each Participant 
Participants will be required to fast for at least 10 h overnight prior to each morning dose. The 
fast will be broken 4 h after dosing with a light lunch (see Section 10.6.5). If the study is to be 
performed during fed conditions, it is recommended that participants should start the meal 30 
minutes prior to administration of the drug product and eat this meal within 30 minutes. The 
caloric breakdown of the test meal should be provided in the study protocol, Section 10.6.5. 
For Part A (SAD) and Part C (MAD) two (2) dose leaders (1 active:1 placebo) will be dosed 
first in each cohort. The remainder of the cohort will be dosed at least 24 h later pending an 
acceptable safety profile in the dose-leader group. 
10.8.11Blinding 
A designated individual from the IMP Management Department at Simbec-Orion will generate 
the randomisation code under the guidance of a statistician.  All other site and Sponsor 
personnel involved in the study will be blinded with regards to the IMP being administered.  
The team responsible for the preparation of participant doses and emergency code break 

 
 
 
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envelopes will not be blinded and a copy of the original randomisation code will be issued to 
them for this purpose. 
The Simbec-Orion Bioanalytical Scientist will be provided with a copy of the randomisation 
code for the purposes of analysing samples.  The Bioanalytical Scientist will provide the drug 
concentration data for interim analysis and dose escalation data review in a re-coded participant 
number format, presented by dose level, in order to maintain the blind of study personnel. 
The Simbec-Orion Pharmacology team members will be provided with a copy of the 
randomisation code for the purposes of PK analysis.   
Participant doses: Once the randomisation code has been authorised as per Simbec-Orion 
SOPs, each participant dose will be packaged and labelled for individual participants by 
designated individuals from the IMP Management Department at Simbec-Orion on behalf of 
the Sponsor.  The QP checks that the active drug and placebo are indistinguishable as part of 
the QP certification process.  
Code break envelopes: Once the randomisation code has been authorised as per Simbec-Orion 
SOPs, the IMP Management team will produce individual sealed code-break envelopes that 
contain the treatment allocation(s) for each participant. The envelopes will be stored in a 
restricted access area.  A set of code break envelopes will also be provided to the Simbec-Orion 
Pharmacovigilance (PV) Department. 
Emergency unblinding: Where the site requires emergency access to an individual participant 
code Simbec-Orion will break the blind via the code break envelopes without prior consultation 
with the Sponsor. In such an event, the Sponsor will be notified as soon as possible via email.   
Non-emergency unblinding: If an Investigator believes that knowledge of the IMPs received 
by a participant is essential for appropriate treatment of an AE, the code will be broken via the 
code break envelopes. Where practical, the Investigator should ideally consult the Sponsor 
before breaking the code.  In any event, the Sponsor will be informed as soon as practical 
whenever the code has been broken for a participant.   
If the blind needs to be broken for an individual participant, the date and reason will be recorded 
in the participant’s eCRF. The Investigator will not reveal the unblinded treatment code to any 
other member of the clinical team involved in the study or to the Study Monitor. If the code is 
broken for any individual participant, the participant will be withdrawn from the study and the 
procedures accompanying withdrawal performed. If the code is broken without justification, 
this will be deemed a serious protocol deviation. 
10.8.12 Prior and Concomitant Therapy 
Prior Medication:  Prescription or non-prescription drugs, including vitamins, herbal and 
dietary supplements should not be taken within 28 days (or 5 half-lives (whichever is longer)) 
prior to the first dose of IMP, unless in the opinion of the Investigator and Sponsor's 
Responsible Physician the medication will not interfere with the study procedures or 
compromise participant safety.  Prescription or non-prescription drugs, including vitamins, 
herbal and dietary supplements taken during the 28 days before the first dose of IMP, and the 
reason for taking them, will be noted in the participant’s eCRF.  

 
 
 
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Participants should not receive a COVID-19 vaccine within 28 days prior to the first dose of 
IMP. 
Inclusion of participants who have taken prior medication will be reviewed on a case-by-case 
basis in relation to the safety aspects and objectives of this study.   
Concomitant Medication: Prescription or non-prescription drugs, including vitamins, herbal 
and dietary supplements should not be taken throughout the duration of the study, with the 
exception of paracetamol (which may be taken as an analgesic to a maximum of 2g in 24 h).  
Participants should not receive a COVID-19 vaccine from the first dose of IMP to completion 
of the post-study follow up visit. 
If intake of any prior or concomitant medication is necessary during the study, the daily dosage, 
duration, and reasons for administration will be recorded on the participant’s eCRF. 
10.8.13Treatment Compliance 
Each dose of IMP will be taken under supervision and a hand and mouth check conducted.  The 
exact dosing time for each participant will be recorded on the participant’s eCRF. 
10.9 Efficacy and Safety Variables 
10.9.1 Efficacy and Safety Measurements Assessed and Flow Chart 
A schedule of study assessments is provided in in Table 10.9.1, Table 10.9.2 and Table 10.9.3  
Simbec-Orion personnel who have been appropriately trained will carry out study procedures. 
Where more than 1 procedure is scheduled for the same time-point, the following order of 
priority will apply:  
1. PK blood sampling. Blood samples collected outside of the defined deviation windows 
will be recorded as protocol deviations: ± 1 minute for samples collected up to 45 minutes time-
point (inclusive) and ± 5 minutes for samples collected > 45 minutes time-point.  
2. Vital signs and 12-lead ECG (a window of ± 10 min in relation to the nominal time-point 
is allowed). 
3. Start or finish of urine collection interval (a window of ± 10 min in relation to the nominal 
time-point). 
All baseline assessments may be performed within the 1 h before dosing. 

 
 
 
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Table 10.9.1 Study Flow Chart – Part A Single Ascending Dose 
Visits1,2 
Screening 
Treatment Period 
Follow up 
In-house 
Days 
Day – 28 
to -2 
Day 
- 1 
Day 1 
Post-
Treatment 
1 (Day 2) 
Post-
Treatment 
2 (Day 3) 
Post-
Treatment 
3 (Day 4) 
5-7 days from 
last IMP dose 
Time (h) 
 
 
Pre- 
Dose 
0 
0.5 
0.75 
1h 
2h 
3h 
4h 
6h 
8h 
12h 
24h 
36h 
48h 
72h 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion3 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight/BMI
4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History & 
Concurrent 
Conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology Tests 
(HIV, HBsAg, 
HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and Alcohol 
Screen5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry 
X6 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Haematology  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Urinalysis  
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
Coagulation7 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs8 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X11 
X11 
12-Lead ECG9 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
X 
X 
X 

 
 
 
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Visits1,2 
Screening 
Treatment Period 
Follow up 
In-house 
Days 
Day – 28 
to -2 
Day 
- 1 
Day 1 
Post-
Treatment 
1 (Day 2) 
Post-
Treatment 
2 (Day 3) 
Post-
Treatment 
3 (Day 4) 
5-7 days from 
last IMP dose 
Time (h) 
 
 
Pre- 
Dose 
0 
0.5 
0.75 
1h 
2h 
3h 
4h 
6h 
8h 
12h 
24h 
36h 
48h 
72h 
 
Prior & 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dose IMP10 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling for 
PK 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Exploratory PD 
sample 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Flow Chart Footnotes: 
1 
All cohorts will complete only 1 Treatment Period. 
2 
Participants will be in the clinical unit for their in-house period from the morning before dosing (Day -1), until the completion of all the assessments on Post-Treatment 3 (Day 4). 
3 
Eligibility will be determined during screening. Continued eligibility will be confirmed on Day -1, and pre-dose Day 1. 
4 
Height measured at Screening only. 
5 
A urine sample will be used to screen for drugs of abuse (including alcohol and cotinine).   
6 
Total serum testosterone only required at screening. 
7 
Coagulation testing aPTT and PT 
8 
Vital signs include the following assessments: supine systolic and diastolic blood pressure, supine heart rate, respiration rate and oral temperature 
9 
12-lead ECG will be performed at screening, each period pre-dose and at 30 min, 4 h, 12 h, 24 h, 48 h and 72 h post-dose and at the post-study follow up visit. 
10 
IMP or placebo will be administered orally in a fasted state (after an overnight fast of at least 10 h) with 240 mL water. The fast will be broken 4 h post-dose with lunch.  
11 
Symptom directed 
12 
Cohort 3 onwards additional samples will be taken based on emerging data 
 
 

 
 
 
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Table 10.9.2 Study Flow Chart – Part B Food Effect 
Visits1,2 
Screening 
Treatment Periods 1 & 2 
Follow up 
In-house 
Days 
Day – 28 
to -2 
Day 
- 1 
Day 1 
Post-
Treatment 
1 (Day 2) 
Post-
Treatment 
2 (Day 3) 
Post-
Treatment 
3 (Day 4) 
5-7 days from last 
IMP dose 
Time (h) 
 
 
Pre- 
Dose 
0 
0.5 
0.75 
1h 
2h 
3h 
4h 
6h 
8h 
12h 
24h 
36h 
48h 
72h 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion3 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight/BMI4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History & 
Concurrent 
Conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology Tests 
(HIV, HBsAg, 
HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and Alcohol 
Screen5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry 
X6 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Haematology  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Urinalysis  
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
Coagulation7 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs8 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X11 
X11 
12-Lead ECG9 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
Prior & Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dose IMP10 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Visits1,2 
Screening 
Treatment Periods 1 & 2 
Follow up 
In-house 
Days 
Day – 28 
to -2 
Day 
- 1 
Day 1 
Post-
Treatment 
1 (Day 2) 
Post-
Treatment 
2 (Day 3) 
Post-
Treatment 
3 (Day 4) 
5-7 days from last 
IMP dose 
Time (h) 
 
 
Pre- 
Dose 
0 
0.5 
0.75 
1h 
2h 
3h 
4h 
6h 
8h 
12h 
24h 
36h 
48h 
72h 
 
Blood Sampling for 
PK 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study Flow Chart Footnotes: 
1 
All cohorts will complete Treatment Period 1 & 2. 
2 
For Treatment Periods 1 & 2, participants will be in the clinical unit for their in-house period from the morning before dosing (Day -1), until the completion of all the assessments on 
Post-Treatment 3 (Day 4). 
3 
Eligibility will be determined during screening. Continued eligibility will be confirmed on Day -1, and pre-dose Day 1 for Treatment Periods 1 & 2.  
4 
Height measured at Screening only. 
5 
A urine sample will be used to screen for drugs of abuse (including alcohol and cotinine).   
6 
Total serum testosterone only required at screening. 
7 
Coagulation testing aPTT and PT 
8 
Vital signs include the following assessments: supine systolic and diastolic blood pressure, supine heart rate, respiration rate and oral temperature 
9 
12-lead ECG will be performed at screening, each period pre-dose and at 30 min, 4 h, 12 h, 24 h, 48 h and 72 h post-dose and at the post-study follow up visit. 
10 
Participants will receive a single dose of AX-158 following an overnight fast of at least 10 h OR following consumption of a high-fat breakfast over 2 treatment periods (1 per period). 
AX-158 should be administered 30 mins after the start of the meal. 
11 
Symptom directed 
 
 

 
 
 
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Table 10.9.3 Study Flow Chart – Part C Multiple Ascending Dose 
Visits1 
Screening 
In-house 
 
Follow 
up 
Days 
Day – 28 
to -2 
Day - 1 
Day 1-4, Day 10-1315 
Day 5-9 
5-7 
days 
from 
last 
IMP 
dose 
Time (h) 
 
 
Pre- 
Dose 
0  
0.5 
0.75 
1h 
2h 
3h 
4h 
6h 
8h 
12h 
24h 
36h 
48h 
72h 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight/BMI3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History & 
Concurrent Conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology Tests (HIV, 
HBsAg, HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and Alcohol 
Screen4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X15 
 
Biochemistry 
X7 
X7,8 
 
 
 
 
 
 
 
 
 
 
 
X7,8 
 
 
X 
X6 
X 
Haematology  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X6 
X 
Urinalysis  
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X6 
X 
Coagulation5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X6 
X 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs9 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
Physical Examination 
X 
X13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
 
X13 
12-Lead ECG10 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
X 
X 
X6 
X 
Prior and Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dose IMP11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Blood Sampling for PK 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X14 
 

 
 
 
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Visits1 
Screening 
In-house 
 
Follow 
up 
Days 
Day – 28 
to -2 
Day - 1 
Day 1-4, Day 10-1315 
Day 5-9 
5-7 
days 
from 
last 
IMP 
dose 
Time (h) 
 
 
Pre- 
Dose 
0  
0.5 
0.75 
1h 
2h 
3h 
4h 
6h 
8h 
12h 
24h 
36h 
48h 
72h 
 
 
 
Urine Sampling for PK 
 
 
 
X12 
 
 
 
 
 
Exploratory PD sample 
 
 
X16 
 
 
 
 
Study Flow Chart Footnotes: 
1 
For each cohort participants will be in the clinical unit for their inpatient visit from the morning before dosing (Day -1), until the completion of all assessments on Day 13. 
2 
Eligibility will be determined during screening. Continued eligibility will be confirmed on Day -1, and pre-dose Day 1- 10 
3 
Height measured at Screening only. 
4 
A urine sample will be used to screen for drugs of abuse (including alcohol and cotinine). 
5 
Coagulation testing aPTT and PT 
6 
Pre dose on Day 7 only 
7 
Total serum testosterone required at screening, pre dose D-1 and on D11 
8 
Serum LH required at pre dose (D-1) and on D11 
9 
Vital signs include the following assessments: supine systolic and diastolic blood pressure, supine heart rate, respiration rate and oral temperature 
10 
12-lead ECG will be performed at screening, pre-dose and at 30 min, 4 h, 12 h, 24 h, 48 h and 72 h post-dose Days 1 and 10 and at the post-study follow up visit. 
11 
For all cohorts IMP or placebo will be administered orally in a fasted state (after an overnight fast of at least 10 h) with 240 mL water. The fast will be broken 4 h post-dose with lunch 
on Days 1-10. 
12 
Urine sampling: for AX-158: pre-dose and in intervals of 0-12, 12-24, 24-48 and 48-72 h post-dose on Day 1 and Day 10 
13 
Symptom Directed 
14 
Pre-dose trough sample day 5 only 
15 
COVID-19 test on day 8 and prior to check out. 
16 
Additional samples will be taken based on emerging data 
 
 

 
 
 
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10.9.2 Demographic and Background Assessments 
The following demographic and background assessments will be performed during the study 
at the time-points specified in in Table 10.9.1, Table 10.9.2 and Table 10.9.3  
10.9.3 Demographics 
Demographic data: age, year of birth, gender, race, ethnicity, height, weight, and BMI.  
Height in metres (to the nearest cm) and weight in kg (to the nearest 0.1 kg) in indoor clothing 
and without shoes will be measured.  BMI = body weight (kg)/[height (m)]2 will be calculated. 
10.9.4 Medical History and Concurrent Conditions 
Relevant medical history and current conditions will be recorded in the eCRF.   
10.9.5 Virology Tests 
Virology tests: HBsAg, HCV Ab and HIV test (antibodies to HIV-1 and HIV-2).  
Virology tests will be analysed from the same serum sample for biochemistry analyses at 
Screening by Simbec-Orion Laboratory Services, or at an appropriate referral laboratory, using 
an appropriate analyser/method(s) of analyses.   
10.9.6 COVID-19 Testing 
A nasopharyngeal and/or oropharyngeal swab will be collected. COVID-19 testing will be 
routinely performed via lateral flow tests however a RT-PCR test may be performed at the 
Principal Investigator’s discretion by Simbec-Orion Laboratories Services. 
10.9.7 Drugs of Abuse (including Alcohol and Cotinine) 
Urine DOA screen (including alcohol and cotinine): alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids/tetrahydrocannabinoids (THC), cocaine, cotinine, methadone, 
and opiates. 
A mid-stream urine sample will be collected into a universal collection/storage container. At 
protocol-defined time-points when both urinalysis and drugs of abuse/alcohol screening are 
required, all urine analyses will be performed from a single approximately 20 mL urine sample. 
Urine samples for DOA (including alcohol and cotinine) will be analysed by Simbec-Orion 
Laboratory Services, or at an appropriate referral laboratory, using an appropriate 
analyser/manual kit(s)/method(s) of analyses.  
Assessments of urine sample quality (i.e., urine sample verification/adulteration) will be 
performed by measuring urine creatinine for urine DOA. 
10.9.8 Compliance with Inclusion/Exclusion Criteria 
An Investigator will assess all participants against the study inclusion and exclusion criteria at 
Screening.  Compliance will be re-confirmed on Day -1/prior to dosing. 

 
 
 
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10.9.9 Efficacy Assessments 
Not applicable. 
10.9.10Safety Assessments 
The following safety assessments will be performed at the time-points specified in in Table 
10.9.1, Table 10.9.2 and Table 10.9.3 
10.9.11Adverse Events 
AEs and SAEs that occurred during the study along with their severity and relationship to study 
drug will be reported. 
An AE is defined as per SI 2004 No. 1031: 
Any untoward medical occurrence1 in a participant to whom a medicinal product has been 
administered, including occurrences which are not necessarily caused by or related to that 
product.2 
Notes: 
1 Whether subjective complaint or objective finding. 
2 An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporarily associated with the use of an IMP, 
whether or not considered related to the IMP. 
An unexpected adverse reaction is defined as: 
An adverse reaction, the nature, or severity of which is not consistent with the applicable 
product information (e.g., IB for an unapproved investigational product of summary of product 
characteristics (SmPC) for an authorised product). 
AEs will be monitored throughout the study from the signature of participant informed consent 
through to the post-study follow-up visit.  All AEs will be recorded, whether considered minor 
or serious, drug-related, or not. 
All abnormal laboratory findings considered to be clinically significant will be recorded as 
AEs. 
10.9.12Recording of Adverse Events 
All of the following details will be recorded in the participant’s eCRF for each AE: 
• Full description of AE. 
• Date and time of onset. 
• Ongoing (Yes/No) 
• End Date and time. 
• Severity of event to be assessed by an Investigator in accordance with the 
definitions below. 
• SAE (Yes/No) and seriousness criteria (if applicable) 

 
 
 
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• Relationship to IMP to be assessed by an Investigator in accordance with the 
definitions below. 
• Action taken (if any). 
• Outcome and details of any further follow-up. 
10.9.13 Grades of Adverse Event Severity 
The following grades will be used by an Investigator to describe the severity of AEs. 
The following are the only grades, which will be used to describe AE severity.  Only 1 severity 
grade will be used for each AE (e.g., mild - moderate is not acceptable). 
SEVERITY OF THE AE 
DEFINITION 
Mild  
The AE does not interfere with the participant’s daily routines.  It causes no 
more than slight discomfort or mild objective change in any of the safety 
parameters assessed during the study as determined by the Investigator. 
Moderate  
The AE interferes with some aspects of the participant’s daily routines or 
moderate objective change in any of the safety parameters assessed during 
the study as determined by the Investigator. 
Severe  
The AE causes inability to carry out the participant’s daily routine or severe 
objective change in any of the safety parameters assessed during the study as 
determined by the Investigator. 
10.9.14 Definitions of Adverse Event Causality 
The following definitions will be used by an Investigator to describe the relationship between 
an AE and the IMP. 
The following are the only definitions which will be used to describe the relationship between 
AEs and the IMP. Only 1 relationship definition will be used for each AE. 
RELATIONSHIP TO IMP 
DEFINITION 
Reasonable possibility 
• There is a reasonable possibility of the event being related to the IMP.  This 
might be temporal or due to a physiological or pharmacodynamic process. 
No reasonable possibility 
• No reasonable possibility of the event being related to the IMP, the IMP 
may not have been administered, no temporal relationship, and no known 
or understood physiological or pharmacological mechanism for the event 
to be related. 
10.9.15 Serious Adverse Events 
"SAE", "serious adverse reaction" or "unexpected serious adverse reaction" is defined in 
Statutory Instrument 2004 No. 1031 as any AE, adverse reaction, or unexpected adverse 
reaction, respectively, that 
a. results in death, 
Note: Death is an outcome (of an AE, of progressive disease, etc.) and not an AE in 
itself. 
b. is life-threatening, 

 
 
 
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A life-threatening event places the patient at risk of death at the time of the event. It 
does not refer to an event which hypothetically might have caused death if it were more 
severe. 
c. requires hospitalisation or prolongation of existing inpatients’ hospitalisation, 
“In-patient hospitalisation” means that the patient has been formally admitted to a 
hospital for medical reasons, for any length of time. It does not include presentation to 
or care within an emergency department. 
Complications that occur during hospitalisations are AEs. If a complication prolongs 
hospitalisation, it is an SAE. 
d. results in persistent or significant disability or incapacity, or 
e. consists of a congenital anomaly or birth defect. 
f. Is otherwise “medically significant” (e.g., that it does not meet preceding criteria, 
but is considered serious because treatment/intervention would be required to 
prevent one of the preceding criteria).  
Initial or follow-up SAE information must be reported within 24 h of knowledge by submitting 
an initial or follow-up SAE report via email or fax to Simbec-Orion PV: 
E mail: pharmacovigilance@SimbecOrion.com. 
SAE Fax: +44 (0)1753 695101; back up SAE Fax: +44 (0)1753 695124. 
SAE(s) will be collected throughout the study from the signature of participant informed 
consent through to the post-study follow-up visit. SAEs occurring after the follow-up period 
should be reported to the Sponsor if the investigator becomes aware of them. 
The SAE Form must be completed as fully as possible with information relevant to the SAE(s) 
being reported. If it is not possible to complete all sections of the SAE Form within 24 hours, 
transmission of the form must not be delayed, and the outstanding information should be sent 
on a follow-up SAE Form.  
Simbec-Orion PV will notify the Sponsor and relevant personnel of the SAE via e mail within 
1 business day of receipt of the initial SAE report. 
AEs which meet all of the following criteria 
• Serious. 
• Unexpected (i.e., is not consistent with the applicable product information e.g., IB 
for an unapproved IMP or SmPC for an authorised product). 
• There is at least a reasonable possibility that there is a causal relationship between 
the event and the medicinal product.  
will be classified as suspected unexpected serious adverse reactions (SUSARs) and should be 
reported to the REC and to the MHRA in accordance with applicable regulatory requirements 
for expedited reporting. Simbec-Orion PV will report SUSARs to the REC and MHRA on 
behalf of the Sponsor as per the regulatory timeline / It is the Sponsor’s responsibility to report 
SUSARs to the REC and MHRA as per the regulatory timeline. 

 
 
 
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To ensure no confusion or misunderstanding of the difference between the terms “serious” and 
“severe,” which are not synonymous, the following note of clarification is provided: 
The term “severe” is often used to describe the severity of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This is not the same as “serious,” which 
is based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient’s life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
10.9.16 Monitoring of Participants with Adverse Events 
In the event of any abnormalities considered to be clinically significant by the investigating 
physician, participants will be followed up with appropriate medical management until: 
• It has resolved/returned to normal or baseline. 
• The event has stabilised at a level acceptable to the Investigator and is not considered 
to be clinically significant. 
10.9.17 Pregnancy 
Pregnancies of female partners of study participants must be reported within 24 h of first 
knowledge of the PI (or delegate) by submitting a pregnancy notification form via email or fax 
to Simbec-Orion PV following the same procedures described for SAEs reporting and should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or new-born complications.  
Once consent has been obtained, pregnancy outcomes must be collected for the female partners 
of males who received at least one dose of the IMP on the pregnancy outcome form and should 
be sent to Simbec-Orion PV within 24 hours of the time the information is known. Consent to 
report information regarding pregnancy outcomes should be obtained from the mother. 
Pregnancy is not regarded as an AE. 
 
If the pregnancy outcome meets the SAE definition also complete an SAE Form. It is important 
to monitor the outcome of any pregnancies of participants in order to provide SAE data on 
congenital anomalies, birth defects or spontaneous abortion. 
10.9.18 Laboratory Safety Assessments 
Laboratory Safety Screen 
Laboratory safety screen samples will be analysed by Simbec-Orion Laboratory Services. 
Printed laboratory test result reports will include normal reference ranges. A decision regarding 
whether the laboratory test result outside the normal reference range is of clinical significance 
or not shall be made by an Investigator/designee and the report will be annotated accordingly.  
Clinically significant laboratory test result abnormalities will be recorded on the AE page. The 
normal reference ranges for laboratory test parameters will be detailed in the SLPDoc0024 
Normal Reference Ranges and Alert Reference Values document.  

 
 
 
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Biochemistry Tests: Alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), 
aspartate transaminase (AST), bicarbonate, total bilirubin, direct bilirubin (if total bilirubin is 
raised), calcium (Ca), chloride (Cl) c-reactive protein (CRP), creatine kinase (CK), creatinine, 
glucose (fasting or random), gamma glutamyltransferase (GGT), potassium (K), total protein, 
sodium (Na), urea, total serum testosterone and luteinizing hormone (LH). 
Blood samples for biochemistry analyses for each time-point will be collected into an 
appropriately sized serum collection tube with or without a separator, and analysed by Simbec-
Orion Laboratory Services, or at an appropriate referral laboratory, using an appropriate 
analyser/method(s) of analyses. Assessments of blood sample quality (i.e., for sample 
verification) will be performed by measuring 3 indices [namely, Lipaemic (for Lipaemia), 
Haemolytic (for Haemolysis) and Icteric (for Icterus)] in serum. 
Haematology Tests: Haemoglobin (Hb), haematocrit, mean corpuscular volume (MCV), 
mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration 
(MCHC), platelet count, red blood cell count (RBC), red blood cell distribution width (RDW), 
white blood cell count (WBC), and WBC differential count (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils) (reported in absolute and percentage values). 
Blood samples for haematology analyses for each time-point will be collected into an 
appropriately sized blood collection tube containing ethylenediaminetetraacetic acid (EDTA) 
and analysed by Simbec-Orion Laboratory Services, or at an appropriate referral laboratory, 
using an appropriate analyser/method(s) of analyses. 
Coagulation Tests: Activated partial thromboplastin time (aPTT) and prothrombin time (PT)  
Blood samples for coagulation analyses for each time-point will be collected into an 
appropriately sized plasma collection tube containing buffered trisodium citrate solution (0.105 
M or 0.109 M, equivalent to 3.2% trisodium citrate) and analysed by Simbec-Orion Laboratory 
Services, or at an appropriate referral laboratory, using an appropriate analyser/method(s) of 
analyses. 
Urinalysis Tests: Bilirubin, blood, glucose, ketones [or ketone bodies], leucocytes, nitrite, pH, 
protein, specific gravity (SG), and urobilinogen. 
A mid-stream urine sample for each time-point will be collected into a 20 mL collection/storage 
container. Urinalysis will be performed by Simbec-Orion Laboratory Services, or at an 
appropriate referral laboratory, using an appropriate analyser/manual kit(s)/method(s) of 
analyses. 
In the event that the urinalysis ‘dipstick’ test result is positive for nitrite and/or 2+ or more 
reported for protein, blood, and/or leucocytes, then urine microscopy will be performed by 
reflex. The following test parameters will be reported: bacteria, casts (non-pathogenic), casts 
(pathogenic), crystals, epithelial cells, red blood cells and white blood cells. The urine 
microscopy will be performed by Simbec-Orion Laboratory Services, or at an appropriate 
referral laboratory, using an appropriate analyser/method(s) of analyses. 
10.9.19    Other Safety Assessments 
Vital signs: Systolic/diastolic blood pressure, heart rate, oral body temperature and respiration 
rate. 

 
 
 
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Measurements will be recorded in the supine position after 10 min supine. Blood pressure, 
heart rate and temperature will be measured by the DINAMAP* Compact Vital Signs Monitor 
(Model TS) or equivalent. Normal ranges for vital signs are presented in Appendix 13. 
Physical Examination 
A physical examination will be performed by an Investigator. The examination will include 
ear/nose/throat, 
ophthalmological, 
dermatological, 
cardiovascular, 
respiratory, 
gastrointestinal, central nervous system, lymph nodes and musculoskeletal. An Investigator can 
examine other body systems if required, at their discretion. 
12-lead ECG: Heart rate, PR interval, QRS width, RR interval, QT interval and QT interval 
corrected using Fredericia’s formula (QTcF).  
12-lead ECG recordings will be made using a Mortara ELI280 or equivalent. Each ECG trace 
should be labelled with the study number, participant number, age, gender, and ethnicity. An 
Investigator will provide an interpretation of each tracing. Clinically significant abnormalities 
will be recorded on the AE page. Normal ranges for 12-lead ECG parameters are presented in 
Appendix 13. 
Concomitant Medication 
All prior and concomitant medications taken during the study will be recorded in the 
participant’s eCRF (see Section 10.8.12). 
10.9.20 Appropriateness of Measurements 
All measurements performed in the study are standard measurements. 
The total volume of blood to be collected from each participant during each part of the study 
will not exceed 500 mL and is considered acceptable (Table 10.9.4, Table 10.9.5, Table 
10.9.6).   

 
 
 
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Table 10.9.4 Part A (Single Ascending Dose) Summary of Blood Volume 
Procedure 
Visit 
Number of 
Samples 
Blood 
Volume per 
Sample (mL) 
No. 
Treatment 
Periods 
Blood Volume (mL) 
Biochemistry1  
Screening 
1 
4.5 
N/A 
4.5 
Treatment 
Period 
4 
4.5 
1 
18.0 
Haematology 
Screening 
1 
3.0 
N/A 
3.0 
Treatment 
Period 
4 
3.0 
1 
12.0 
Coagulation 
Screening 
1 
2.7 
N/A 
2.7 
Treatment 
Period 
4 
2.7 
1 
10.8 
PK Drug Conc. 
Measurement – 
AX-158 
Treatment 
Period 
14 
4.0 
1 
56.0 
Exploratory PD 
samples 
Treatment 
Period 
2 
2.7 
1 
5.4 
Total Blood Volume2 
112.4 
 
Footnotes: 
1 
The biochemistry blood sample collected at the Screening visit will also be used to complete the virology 
screen (HBsAg, HCV Ab, and HIV). 
2 
Please note: This total blood volume does not include any additional blood sample collection(s) for retest, 
unscheduled testing or additional tests required at the discretion of the Investigator/designee. The exact 
volumes of each sample may change but the total volume of blood drawn for any participant will not exceed 
500 mL. 
 
 
 
 
 

 
 
 
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Table 10.9.5 Part B (Food Effect) Summary of Blood Volume 
Procedure 
Visit 
Number of 
Samples 
Blood 
Volume per 
Sample (mL) 
No. 
Treatment 
Periods 
Blood Volume (mL) 
Biochemistry1  
Screening 
1 
4.5 
N/A 
4.5 
Treatment 
Period 
3 
4.5 
2 (+follow up) 
31.5 
Haematology 
Screening 
1 
3.0 
N/A 
3.0 
Treatment 
Period 
3 
3.0 
2(+follow up) 
21 
Coagulation 
Screening 
1 
2.7 
N/A 
2.7 
Treatment 
Period 
3 
2.7 
2(+follow up) 
18.9 
PK Drug Conc. 
Measurement – 
AX-158 
Treatment 
Period 
14 
4.0 
2 
112 
Total Blood Volume2 
193.6 
 
Footnotes: 
1 
The biochemistry blood sample collected at the Screening visit will also be used to complete the virology 
screen (HBsAg, HCV Ab, and HIV). 
2 
Please note: This total blood volume does not include any additional blood sample collection(s) for retest, 
unscheduled testing or additional tests required at the discretion of the Investigator/designee. The exact 
volumes of each sample may change but the total volume of blood drawn for any participant will not exceed 
500 mL. 
 
 
 
 
 

 
 
 
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Clinical Study Protocol General Template (Template SR-PMt057): Version 11.0, Final (10 August 2021) 
Table 10.9.6 Part C (Multiple Ascending Doses) Summary of Blood Volume 
Procedure 
Visit 
Number of 
Samples 
Blood 
Volume per 
Sample (mL) 
No. 
Treatment 
Periods 
Blood Volume (mL) 
Biochemistry1  
Screening 
1 
4.5 
N/A 
4.5 
Treatment 
Period 
7 
4.5 
1 
31.5 
Haematology 
Screening 
1 
3.0 
N/A 
3.0 
Treatment 
Period 
7 
3.0 
1 
21 
Coagulation 
Screening 
1 
2.7 
N/A 
2.7 
Treatment 
Period 
7 
2.7 
1 
18.9 
PK Drug Conc. 
Measurement – 
AX-158 
Treatment 
Period 
29 
4.0 
1 
116 
Exploratory PD 
Treatment 
Period 
2 
2.7 
1 
5.4 
Total Blood Volume2 
203 
 
Footnotes: 
1 
The biochemistry blood sample collected at the Screening visit will also be used to complete the virology 
screen (HBsAg, HCV Ab, and HIV). 
2 
Please note: This total blood volume does not include any additional blood sample collection(s) for retest, 
unscheduled testing or additional tests required at the discretion of the Investigator/designee. The exact 
volumes of each sample may change but the total volume of blood drawn for any participant will not exceed 
500 mL. 
10.9.21 Primary Efficacy Variable(s) 
 
Not applicable. 
10.9.22 Drug Concentration Measurements 
Plasma and urine samples for drug concentration measurements will be analysed at Simbec-
Orion Laboratory Services using a validated liquid chromatography tandem mass spectrometry 
(LC MS/MS) method, according to applicable local SOPs.  
10.9.23 Pharmacokinetic Blood Sampling 
Blood sample (4 mL) for the determination of plasma AX-158 levels will be collected per time-
point as specified in Table 10.9.1, Table 10.9.2 and Table 10.9.3. (please refer to the Sample 
Handling Manual [SHM] for processing instructions). 

 
 
 
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Immediately after sample collection, each sample collection tube will be identified with a 
barcoded label bearing details of the study number, participant number, sampling time-point, 
sample type (i.e., sample matrix, e.g., blood, etc.), and a unique 9-digit sample identification 
number. The date and time at which each PK sample are collected, received in the separating 
room, and subsequently placed in the appropriate freezer(s) will be recorded in the study 
documentation. 
Full details of sample handling and processing can be found in the SHM. 
Should a PK sample not be suitable for sample processing or analysis e.g., severely haemolysed 
sample, these can be repeated once only. 
10.9.24 Pharmacokinetic Urine Collection 
Urine samples will be collected in Part C for the determination of AX-158 level in urine at the 
time-points specified in Table 10.9.3. 
Each urine collection container will be identified with a barcoded label bearing details of the 
study number, participant number, sampling time-point, sample type (i.e., sample matrix, e.g., 
blood, etc), and a unique 9-digit identification number. 
The urine collection containers will be kept chilled (at approximately 4C) during the collection 
intervals. After the termination of each fractional urine collection interval, the urine volume 
excreted will be recorded and two 10 mL aliquots retained for the determination of AX-158 
level in urine. Each urine aliquot will be labelled similarly to the original collection container 
and will be stored at -20C pending analysis. 
Full details of sample handling and processing can be found in the SHM. 
10.9.25 Pharmacodynamic Assessments 
Not Applicable.  
10.9.26 Other Assessments 
Exploratory PD samples will be collected as specified in Table 10.9.1 and Table 10.9.3. 
Sample handling procedures will be documented in the relevant sample handling manuals. 
10.10 Data Quality Assurance 
At the time the study is initiated, a representative of Artax Biopharma Inc will thoroughly 
review the final protocol and eCRFs with the Principal Investigator and site staff. During the 
course of the study the Monitor will visit the Clinical Unit regularly to check the completeness 
of the participants’ records (including the volunteer (participant) master files, laboratory, and 
12-lead ECG print-outs), the accuracy of entries into the eCRFs, the adherence to the final 
protocol and to ICH GCP E6 (R2) guidelines[2], the progress of enrolment and also to ensure 
the storage, handling, and accountability of the IMP. The Principal Investigator and key study 
personnel will be available to assist the Monitor during these visits. 
The Principal Investigator will give the Monitor, Auditor(s), the REC, and the MHRA direct 
access to relevant clinical records to confirm their consistency with the CRF entries. No 
information in these records about the identity of the participants will leave Simbec-Orion. 

 
 
 
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Artax Biopharma Inc will maintain the confidentiality of all participant records, in line with 
Section 6.10 of the ICH GCP E6 (R2) guidelines [2]. 
Study data will be fully documented in the eCRFs and study logbooks. Dated signatures will 
be given to account for all interventions in the study by research staff. 
Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data are contained in source documents 
(original records or certified copies). 
For the purposes of this study the source data will be recorded as detailed in Table 10.10.1. 

 
 
 
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Table 10.10.1 Summary of Source Documentation Location 
Data 
eCRF1* 
Paper Source File 
Volunteer 
Master File 
Clinic Source 
File 
Other Study 
Documentation 
Evidence of healthy participant 
status/primary disease 
condition for entry into clinical 
study 
 
X 
 
 
Demographic data (e.g., age, 
year of birth, gender) 
 
X 
 
 
Demographic data (e.g., race, 
ethnicity, height, weight, and 
BMI) 
X 
 
 
 
Medical history 
 
X 
 
 
Inclusion and exclusion criteria 
 
 
X 
 
Informed consents2 
 
 
 
X 
Participant involvement in the 
clinical study 
X 
 
 
 
Screening number 
 
 
 
X (screening log) 
Participant number  
 
 
 
X (enrolment log) 
AEs 
X 
 
 
 
SAEs 
 
 
 
X (SAE form) 
Pregnancies 
 
 
 
X (Pregnancy 
notification and outcome 
form) 
Previous and on-going therapy 
 
X 
 
 
Concomitant medication 
X 
 
 
 
Results of study examinations 
(e.g., 12-lead ECGs and 
laboratory safety tests)3 
 
 
X 
 
Vital Signs 
X 
 
 
 
Physical Examination4 
X 
 
 
 
Study visit dates 
X 
 
 
 
Administration of IMP 
X 
 
 
 
Blood PK sample collection 
times 
X 
 
 
 
Urine PK sample collection 
times  
 
 
 
X (log book) 
Blood safety sample collection 
times 
 
 
X (test request 
form) 
 
Urine safety sample collection 
times  
 
 
X (test request 
form) 
 
Blood PD sample collection 
times 
X 
 
 
 
1. 
In the event staff are unable to enter data directly into the eCRF (e.g., technical/internet issues), data will be entered directly 
into a back-up paper source workbook at the time of assessment, then transcribed and subsequently QC’d. 
2. 
The original informed consent forms will be maintained in the study officer file during the clinical phase and will then be 
transferred to the Project Manager for archiving with the Investigator Site File at the end of the study. 
3. 
The 12-lead ECG trace and laboratory safety test print-out including medical review will be stored in the paper source file. 
4. 
In the eCRF, the date and time of each physical examination will be recorded. Any abnormal findings will be captured on 
the Medical History form at Screening and as an Adverse Event during clinical conduct. 
 
AE = adverse event, CRF = case report form/eCRF = electronic case report form, ECG = electrocardiogram, IMP = investigational 
medicinal product, PK = pharmacokinetic, SAE = serious adverse event. 

 
 
 
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The above table indicates where source data will be recorded but for completeness the 
following information will also be recorded in the volunteer master file: 
• Clinical study code. 
• Study visit dates (pre-dose; post-dose). 
• IMP administration (date of last dose). 
• Results of any key safety and efficacy measures from the clinical study that, in the 
opinion of an Investigator, should be noted. 
• Any concomitant medications used to treat the participant during the study that, in 
the opinion of an Investigator, should be noted. 
The data collected in the eCRFs during the study will be subject to quality control checking by 
clinical staff prior to sign off. 
Designated investigator site staff will enter the data required by the protocol into the eCRFs 
using fully validated software that conforms to 21 CFR Part 11 requirements. Staff will not be 
given access to the eCRF until they have been trained. Automatic validation programs check 
for data discrepancies and, by generating appropriate error messages, allow the data to be 
confirmed or corrected before transfer of the data to the Biometrics group. The Investigator 
must certify that the data entered into the eCRF are complete and accurate.  
The study will be subject to an independent audit by the Simbec-Orion Quality Assurance Unit 
as outlined in Simbec-Orion SOP GRP-QA 002. 
Independent clinical quality assurance audits may be performed at any time during or following 
completion of the study by the Sponsor, or its authorised agents, and Regulatory Authorities 
and/or the REC. 
10.11 Statistical Methods and Determination of Sample Size 
10.11.1 Statistical and Analytical Plan 
A statistical analysis plan (SAP) will be written by Simbec-Orion and agreed by Artax 
Biopharma Inc prior to the locking of the database and subsequent reporting of the study data. 
10.11.2 Study Variables/Endpoints 
Part A (SAD):  
The following plasma PK endpoints will be derived: Cmax, Tmax, λz, t1/2, AUC0-24, AUC0-t, 
AUC0-inf, AUC%extrapolated, CL/F, Vz/F. 
Part B (Food Effect):  
The following plasma PK endpoints will be derived: Cmax, Tmax, Tlag, λz, t1/2, AUC0-24,AUC0-t, 
AUC0-inf, AUC%extrapolated, CL/F, Vz/F. 
Part C (MAD):  
The following plasma PK endpoints will be derived on Day 1: Cmax, Tmax and AUC0-24, (AUC0-τ 
will also be derived if dosing interval other than q.d).  

 
 
 
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The following plasma PK endpoints will be derived on Final Dosing Day : Cmax, Tmax, λz, t1/2, 
AUC0-24, (AUC0-τ will also be derived if dosing interval other than q.d)., AUC0-t, AUC0-inf, 
AUC%extrapolated, CL/F and Vz/F.  
The following urine PK parameters will be derived on Day 1 and Final Dosing Day: Ae, Ae%, 
CLR. 
Safety endpoints: 
• AEs.  
• Laboratory safety (biochemistry, haematology, coagulation, and urinalysis). 
• Vital signs (systolic/diastolic blood pressure, heart rate, oral body temperature and 
respiratory rate). 
• 12-lead ECG (Heart rate, PR interval, QRS width, RR interval, QT interval and QT 
interval corrected using Fredericia’s formula (QTcF). 
10.11.3Analysis Sets 
Safety Set: All randomised participants who receive at least 1 dose of IMP will be included in 
the safety analysis. 
PK Set: The PK set will include participants who receive IMP (one dose in Part A, both doses 
in Part B (fed/fasted), up to 10 doses in Part C), have sufficient plasma concentration-time 
profiles and comply with the following criteria: 
• 
Do not have an occurrence of vomiting (that occurs at or before 2 times median Tmax 
within the appropriate cohort or treatment) or diarrhoea which renders the concentration 
profile unreliable; For Part C this applies to PK sampling days only  
• Do not use a concomitant medication which renders the concentration profile 
unreliable;  
• Do not have a Day 1 pre-dose concentration that is greater than 5% of the corresponding 
Cmax; 
• Have at least one pharmacokinetic sample with concentration above the lower limit of 
quantitation (LLOQ); 
• Do not violate the protocol in such a way that may invalidate or bias the results (major 
protocol violators). 
10.11.4 Description of Statistical Methods 
All statistical analysis will be performed using SAS® (the most up to date version will be used 
and this will be documented in the SAP). 
10.11.5 Demographic and Background Data 
All demographic and background data will be listed, in addition: 
Disposition: Participant disposition will be listed with any withdrawals flagged.  Frequencies 
(number and %) of the total number of participants dosed, completed, and prematurely 

 
 
 
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discontinued (including reason for discontinuation) from the study will be summarised. 
Additionally, the frequency of participants within each analysis set will be summarised. 
Demographics: Demographic data will be listed. Descriptive statistics (number of participants 
in the analysis set (N), number of participants with non-missing observations (n), mean, 
standard deviation (SD), minimum, median, and maximum) will be tabulated for the 
continuous variables age, height, weight and BMI and frequencies (number and %) for the 
categorical variable race. 
10.11.6   Efficacy Data 
Not applicable. 
10.11.7   Safety Data 
All safety data will be listed, in addition: 
AEs: All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary (the most up to date version that is available at the time of database build will be 
used and will be listed in the Data Management Plan (DMP)). The MedDRA dictionary will 
not be updated during the course of the study.  
All AEs, including those which occurred prior to the first dose of IMP, will be listed. Only 
treatment emergent adverse events (TEAEs), i.e., existing conditions that worsen or events that 
occur during the course of the study after administration of IMP, will be included within the 
summary tables.   
An overall summary of AEs will be produced including the number of TEAEs; the number and 
% of participants reporting at least 1 TEAE, serious TEAE, TEAE leading to withdrawal from 
the study; the number and % of participants reporting TEAEs by severity and relationship to 
IMP.   
The number of TEAEs and the number and % of participants reporting at least 1 TEAE will be 
tabulated by system organ class (SOC) and preferred term. A participant reporting multiple 
episodes of a particular AE within a treatment period will only contribute 1 count towards the 
corresponding SOC and preferred term. 
The number of TEAEs and the number and % of participants reporting at least 1 TEAE will be 
tabulated by preferred term and sorted by descending frequency on the total number of 
participants with that AE. A participant reporting multiple episodes of a particular AE within 
a treatment period will only contribute 1 count towards the corresponding preferred term. 
In addition, the number and % of participants reporting TEAEs will be tabulated by maximum 
severity and strongest relationship to IMP.  For the summary of TEAEs by severity, if a 
participant has multiple events occurring within the same SOC or preferred term the event with 
the highest severity will be counted.  Similarly, for TEAEs by relationship to IMP, if a 
participant has multiple events occurring within the same SOC or preferred term, the event 
with the highest association to IMP will be counted. 
Laboratory Safety: Biochemistry, haematology, coagulation, and urinalysis parameters will 
be listed with any out of normal range values flagged.  Laboratory test results which are out of 
normal range will also be presented separately along with normal reference ranges. Descriptive 

 
 
 
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statistics (N, n, mean, SD, minimum, median, and maximum) of absolute and change from 
baseline (Day 1, pre-dose) values at each protocol-defined time point will be tabulated. 
Vital Signs: Vital signs parameters will be listed with any out of normal range values flagged.  
Descriptive statistics (N, n, mean, SD, minimum, median, and maximum) of absolute and 
change from baseline (Day 1, pre-dose) values at each time point will be tabulated.   
12-Lead ECG: 12-Lead ECG parameters will be listed with any out of normal range values 
flagged.  Descriptive statistics (N, n, mean, SD, minimum, median, and maximum) of absolute 
and change from baseline (Day 1, pre-dose) values at each time point will be tabulated.   
Additionally, the frequency (number and % of participants) for absolute and change from 
baseline QTcF values will be summarised according to the below categories: 
For absolute values 
• QTcF ≤ 450 msec  
• 450 < QTcF ≤ 480 msec 
• 480 < QTcF ≤ 500 msec 
• QTcF > 500 msec. 
For change from baseline 
• Decrease/no change 
• QTcF increase ≤ 30 msec  
• 30 < QTcF increase ≤ 60 msec  
• QTcF increase > 60 msec. 
10.11.8   PK Data 
Concentration-Time Data: Individual plasma and urine AX-158 concentration-time data will 
be listed.  Plasma and urine concentration-time data will also be summarised.  The descriptive 
statistics presented will be N, n, arithmetic mean, geometric mean, SD, coefficient of variation 
(CV%), minimum, median, and maximum. Individual and mean plasma concentration-time 
data will also be plotted on both linear and semi-logarithmic scales.  
For the purposes of summarising and plotting concentration-time data, concentration value(s) 
below the LLOQ will be assigned a value of zero if the timepoint is prior to treatment and 
LLOQ/2 otherwise. 
 
Derived PK Data: The following PK parameters will be derived from plasma and urine AX-
158 concentration-time data following administration of IMP using Phoenix WinNonlin (the 
most up to date version will be used and this will be documented in the SAP). Additional 
parameters may be reported as appropriate. 
 
For the purposes of calculating PK parameters, concentration value(s) below the LLOQ will 
be assigned a value of missing. 
 
 

 
 
 
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Plasma: 
• Cmax 
Maximum concentration.  
• Tmax 
The time to maximum observed concentration.  
• Tlag 
The delay in achieving Tmax 
• λz 
Elimination rate constant.  
• t1/2 
Terminal elimination half-life. 
• AUC0-24  
Area under the concentration-time curve (AUC) from 0 to 24 h 
post-dose. 
• AUC0-τ 
Area under the concentration-time curve (AUC) from 0 to τ, where 
τ is the dosing interval (planned, 0 - 24 h) (Part C only). 
• AUC0-t 
Area under the concentration-time curve (AUC) from the time of 
dosing to the time of the last measurable concentration. 
• AUC0-inf 
AUC extrapolated to infinity.  
• AUC% extrapolated 
Residual area. 
• CL/F 
Total apparent clearance following extravascular administration.  
• Vz/F 
Apparent volume of distribution following extravascular 
administration.  
Urine 
• Ae 
Amount and cumulative amount of dose excreted in urine over 
each collection interval. 
• Ae% 
% and cumulative % of dose excreted in urine over each collection 
interval. 
• CLR 
Renal clearance.  
 
Derived PK parameters will be listed along with the points used to calculate kel (lower, upper, 
and number used) and coefficient of determination (R2) adjusted. The derived PK parameters 
will also be summarised. The descriptive statistics presented will be N, n, arithmetic mean, 
geometric mean (with the exception of Tmax), SD, coefficient of variation (CV%), minimum, 
median, and maximum.   
Part A (SAD): Dose Proportionality/Independence. Dose proportionality will be assessed by 
performing a regression analysis of the log-transformed Cmax, AUC0-t and AUC0-inf values 
versus the log-transformed dose using the power model with a fixed effect for log (dose). For 
each parameter, a point estimate and 95 % confidence interval (CI) will be calculated for the 
slope of the regression line.  
Dose independence will be assessed for t½ and CL/F by performing a regression analysis of 
the untransformed parameters versus dose with a fixed effect for dose. For each parameter, a 

 
 
 
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point estimate and corresponding 95 % CI will be calculated for the slope of the regression 
line. 
Part B (Food Effect): Following logarithmic transformation, Cmax, AUC0-t and AUC0-inf values 
will be subjected to an ANOVA including fixed effects for treatment and participant. Point 
estimates and 90% CI will be constructed for the contrasts between treatments using the 
residual mean square error obtained from the ANOVA. The point and interval estimates will 
be back-transformed to give estimates of the ratios of the geometric least squares means 
(LSmeans) and corresponding 90% CI. Estimated geometric means will also be presented for 
each treatment. 
 
Part C (MAD) 
Dose Proportionality/Independence: For Day 1 and Final Dosing Day (Day 10), dose 
proportionality will be assessed by performing a regression analysis of the log-transformed 
Cmax, AUC0-τ and AUC0-inf (Day 1 only) values versus the log-transformed dose using the power 
model with a fixed effect for log (dose). For each parameter, a point estimate and 95 % CI will 
be calculated for the slope of the regression line. 
For Final Dosing Day (Day 10), dose independence will be assessed for t½ and CL/F by 
performing a regression analysis of the untransformed parameters versus dose with a fixed 
effect for dose. For each parameter, a point estimate and corresponding 95 % CI will be 
calculated for the slope of the regression line. 
Steady-State: For each dose level, log-transformed trough concentration levels at pre-dose day 
5 will be subjected to a mixed effects ANOVA with study day as a fixed effect and participant 
as a random effect in order to establish whether and when steady-state has been attained for 
each dose level. Back-transformed ratios for the comparisons of each consecutive day (i.e., 
Day 3/Day 2) will be presented along with corresponding 90 % CI. 
Accumulation: For each dose level, log-transformed Cmax and AUC0-τ values on Day 1 and Final 
Dosing Day (Day 10) will be subjected to an ANOVA with study day as a fixed effect and 
participant as a random effect. For comparison, point estimates and 90 % CI for the difference 
between Final Dosing (Day10) and Day 1 will be constructed using the residual mean square 
error obtained from the ANOVA for each dose level. The point and interval estimates will then 
be back transformed to give estimates of the ratios of the geometric least squares means and 
corresponding 90 % CI. 
10.11.9 Other Data 
Not applicable. 
10.11.10  Sample Size Calculation 
The sample size chosen for this study is not based on a formal statistical estimation but is 
considered adequate to meet the objectives of the study. A sufficient number of participants 
will be initially screened for enrolment to ensure that the planned sample size is achieved.  

 
 
 
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11 PRACTICAL CONSIDERATIONS 
11.1 Storage of Data 
The Investigator site file and associated study documentation will be archived for at least 25 
years after the end of the study (last participant last visit) as per European Medicine Agency 
Guideline (EMA) INS/GCP/856758/2018 [4]. The study documentation may be transferred to 
an offsite storage facility during this period but will remain under the control of Simbec-Orion.   
The Sponsor has delegated the set up and maintenance of the Sponsor trial master file (TMF) 
to Simbec-Orion. The TMF will be returned to the Sponsor at the end of the study, who will 
archive it for at least 25 years after the end of the study. 
11.2 Protocol Amendments 
Changes in the study protocol must take the form of written protocol amendments and shall 
require the approval of all persons responsible for the study (see Section 1).  
A protocol amendment is deemed to constitute a substantial protocol amendment if it is 
considered to affect a significant degree either: 
a. The safety or physical or mental integrity of the participants of the study. 
b. The scientific value of the study. 
c. The conduct or management of the study. 
d. The quality or safety of any IMP used in the study. 
Such amendments must be submitted to the REC responsible for the study and the MHRA for 
approval prior to implementation. 
Protocol amendments required for urgent safety reasons may be implemented immediately. 
However, the REC and MHRA must be notified in writing within 3 days of the measures taken 
and the reasons for implementation. 
All other amendments shall be deemed to be non-substantial and as such do not need the prior 
approval of the REC and the MHRA. 
11.3 Confidentiality 
The confidentiality of the study must be maintained at all times, and the Principal Investigator 
must not reveal any information relating to the study without express permission from the study 
Sponsor. 
11.4 Study Report and Publication Policy 
The Principal Investigator will obtain the Sponsor’s written permission before any information 
concerning this study is submitted for publication. 
11.5 General Data Protection Regulation (GDPR) 
Personal data of the participant shall be processed in a manner that ensures it has appropriate 
security. This includes protection against unauthorised or unlawful processing and against 

 
 
 
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accidental loss, destruction, or damage and by using appropriate technical or organisational 
measures. One such measure is by the Investigator ensuring that the participants’ personally 
identifiable information should be replaced through the use of pseudonymisation. 
On the eCRFs or other documents submitted to Artax Biopharma Inc/Simbec-Orion 
participants will NOT be identified by their names but by the assigned participant number 
(panel/screening/participant number) to ensure confidentiality of the participants’ information 
and that data minimisation principles are maintained. If participant names are included in error 
on copies of documents submitted to Artax Biopharma Inc Simbec-Orion participants’, the 
names (except for initials) will be erased or securely destroyed and the assigned participant 
number added to the document. 

 
 
 
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12 REFERENCES  
[1] 
Current version of AX-158 Investigator’s Brochure (IB).  
[2] 
ICH (International Council on Harmonisation). Guideline for Good Clinical 
Practice (GCP) E6 (R2) (CPMP/ICH/135/95) 2016. 
[3]  
 
Current version of AX-158 Investigational Medicinal Product Dossier (IMPD). 
[4]  
EMA (European Medicine Agency). Guideline on the Content, Management and 
Archiving of the Clinical Trial Master File (paper and/or electronic) 
INS/GCP/856758/2018.  
[5] 
FDA. 2002. Guidance for Industry Food-Effect Bioavailability and Fed 
Bioequivalence 
Studies. 
Available 
at: 
https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/food-effect-bioavailability-and-fed-
bioequivalence-studies 
[6] 
Ec.europa.eu. 2015. EudraLex - Volume 4 Good Manufacturing Practice (GMP) 
Guidelines. 
- 
European 
Commission. 
[online] 
Available 
at: 
https://ec.europa.eu/health/documents/eudralex/vol-4_en  
 
 
 
 
 

 
 
 
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13 APPENDIX 1: NORMAL RANGES FOR VITAL SIGNS AND ECG 
PARAMETERS 
 
Vital Sign Parameters  
Parameter 
Normal Range 
Units 
Heart Rate 
40-100  
beat(s) per minute (bpm) 
Systolic Blood pressure 
90-140  
millimetre(s) of mercury (mmHg) 
Diastolic Blood pressure 
50-90  
millimetre(s) of mercury (mmHg) 
Respiratory Rate 
12-18 
breath(s) per minute 
Oral Temperature 
35.0-37.5  
degrees Celsius (ºC) 
 
ECG Parameters  
Parameter 
Normal Range 
Units 
Heart Rate  
40-100  
beat(s) per minute (bpm) 
PR Interval  
120-220  
millisecond(s) (ms) 
QRS Width 
70-120  
millisecond(s) (ms) 
QT Interval  
N/A 
N/A 
QTc Interval (Fridericia’s 
Formula) 
Male: 350-450  
 
millisecond(s) (ms)  
 
 
 

 
 
 
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14 APPENDIX 2: DECLARATION OF HELSINKI (BRAZIL, 2013) 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-
medical-research-involving-human-subjects/ 

 
Amendment Assessment Form: SA01 
Study Code: RD 675.34625 (AX-158-101) 
Version and Date: v1.0 (14 January 2022) 
 
 
Rat005 Amendment Assessment Form: Version Final 
(30 July 2019) 
 
Page 1 of 8 
 
AMENDMENT ASSESSMENT FORM 
 
This form serves to document the decision on whether the amendment is considered substantial or 
non-substantial. It is the responsibility of the sponsor to determine whether an amendment is 
substantial.  
 
If the sponsor is satisfied that an amendment is not substantial, there is no requirement to notify the 
Competent Authority or Ethics Committee.  Although non-substantial amendments may be notified 
to the Competent Authority or Ethics Committee for information only based on local requirements.  
 
Substantial Amendment  
 
In accordance with EC guidance 2010/C 82/01 (CT-1), amendments to the trial are regarded as 
‘substantial’ where they are likely to have a significant impact on: 
• The safety or physical or mental integrity of the clinical trial participants or  
• The scientific value of the trial 
 
 
Non-substantial Amendment 
 
A Non-substantial amendment does not meet the criteria listed above.  
 
 
Further Guidance 
 
Please see the following for more guidance: 
• 
EC guidance 2010/C 82/01 (CT-1) 
• 
Local regulations for EU and non-EU member states (for example US 21 CFR for US FDA) 
• 
CHMP/QWP/185401/2004 for IMPs 
 

 
Amendment Assessment Form: SA01 
Study Code: RD 675.34625 (AX-158-101) 
Version and Date: v1.0 (14 January 2022) 
 
 
Rat005 Amendment Assessment Form: Version Final 
(30 July 2019) 
 
Page 2 of 8 
 
Sponsor name 
 
Artax Biopharma Inc. 
 
EudraCT Number (if applicable): 
 
2021-002541-16 
Simbec-Orion Clinical Pharmacology  
RD number (Phase I HV studies) /  
Simbec-Orion Clinical Development internal 
number 
RD 675.34625 
Protocol Number: 
 
AX-158-101 
 
Amendment Code:  
(This is not the same as the protocol amendment 
code) 
SA01 
 
List of the regulatory documents impacted by this amendment: 
 
Document Title 
Version & Date 
Previous Version & Date 
Study Protocol 
 
V4.0 Dated 14 January 2022 
V3.0 Dated 22 October 2021 
Participant Information Sheet 
& Consent Form – Part A 
MASTER 
 
V3.0 Dated 14 January 2022 
V2.0 Dated 22 October 2021 
Participant Information Sheet 
& Consent Form – Part B 
MASTER 
 
V3.0 Dated 14 January 2022 
V2.0 Dated 22 October 2021 
Participant Information Sheet 
& Consent Form – Part C 
MASTER 
 
V3.0 Dated 14 January 2022 
V2.0 Dated 22 October 2021 
Details of the amendment are described below:  
The Sponsor wishes to proceed with this amendment in order to implement changes to the study 
protocol, and participant information sheet and consent form (PIS) for each respective study part (Part 
A, Part B & Part C). This amendment affects the study protocol and PIS only; no other subject facing 
or regulatory documentation is impacted as a result of these changes.  
The purpose of the protocol amendment is to introduce a number of changes within the protocol in 
relation to COVID-19 risk mitigation strategies in response to the evolution of the COVID-19 
pandemic in the UK and to introduce blood sampling for the measurement of exploratory 
pharmacodynamics (PD) within Part A of the study.  
With respect to the changes implemented in response to the COVID-19 pandemic, the Sponsor wishes 
to implement the following revisions. In recognition of the MHRA requirement to conduct ongoing 
COVID-19 risk/benefit assessments to support the continued conduct of clinical trials in the context of 
the COVID-19 pandemic, the Sponsor has determined at this stage that it is appropriate to implement 
new measures in line with the current status of the pandemic within the UK. The risk assessment within 

 
Amendment Assessment Form: SA01 
Study Code: RD 675.34625 (AX-158-101) 
Version and Date: v1.0 (14 January 2022) 
 
 
Rat005 Amendment Assessment Form: Version Final 
(30 July 2019) 
 
Page 3 of 8 
 
the current approved version of the study protocol (v3.0, Dated 22 October 2021) outlines that 
participants may be enrolled into the study provided that they have not received a COVID-19 vaccine 
within the 28 days prior to the first dose of the IMP until the completion of the post-study follow up 
procedures. The current protocol does not require participants to be vaccinated against COVID-19. 
The rationale for this assessment is based on the potential for interaction between the IMP and the 
vaccine, the immunomodulatory nature of the drug and the basis that this is a first-in-human (FiH) study 
and therefore, the action of the drug is not known in humans as of yet. 
However, given the current status of the pandemic within the UK with the evolution of new variants 
etc., the Sponsor has determined that the protocol, specifically the inclusion criteria for the study should 
be updated in order to mandate that any participants who are enrolled within the study must have 
received their full doses of the COVID-19 vaccine as per the current Welsh/UK Government guidelines 
and that these doses should have been received outside of the defined restriction window defined 
above. As the definition of ‘full’ doses is likely to evolve with the continued rollout of the vaccination 
programme and requirement for follow up booster doses, the language in the protocol will be presented 
flexibly such that the ‘full’ dose definition for determining participant eligibility will be reflective of the 
latest definition at the time of enrolment. 
In addition, the Sponsor wishes to update the protocol to include flexibility for the nature and type of 
COVID-19 testing which may be conducted during the study. As part of the study protocol and in 
alignment with the COVID-19 risk mitigation strategies implemented at Simbec-Orion in order to 
support the continued conduct of clinical trials in the context of the ongoing pandemic, COVID-19 PCR 
antigen testing is a mandatory requirement for all participants undertaking a clinical trial involving 
overnight stays at the clinical unit. In the context of this study, COVID-19 PCR antigen testing is 
conducted on Day -1 of each treatment period across all parts of the study. 
To date, Simbec-Orion have utilised the Menarini Diagnostics VitaPCR Point of Care analyser to 
perform Real-Time Polymerase Chain Reaction testing (RT-PCR) using a SARS-CoV-2 assay. This test 
equipment is CE IVD marked and provides 95% sensitivity and 100% specificity.  
However, as of October 2021, it has been highlighted by the manufacturer that as part of a revised UK 
government approach (COVID Testing Devices Authorisation CDTA), it is a requirement that clinical 
data should be submitted for review to enable the manufacturer to be included on the list of government 
approved COVID-19 testing suppliers. At this stage, the manufacturer (Menarini) have advised that until 
approved they are unable to distribute any further COVID-19 testing kits and as such, in order to 
mitigate against any potential testing kit shortage, Simbec-Orion proposes to implement an alternative 
method of COVID-19 testing in the interim period whilst the Menarini kits are pending approval and 
to provide ongoing flexibility for testing methods as the pandemic evolves further.  
Therefore, it is proposed that the protocol will be updated in order to include flexibility for the conduct 
of Lateral Flow Testing (LFT) as standard routine testing in the first instance, in addition to PCR Antigen 
Testing as required in order to ensure that there is continuity of testing throughout the study and 
sufficient measures in place in order to mitigate against the spread of the COVID-19 virus. A risk 
assessment has been conducted for this approach and confirmed as appropriate as this aligns with the 
current strategy being implemented across a number of Phase 1 Clinical Trials Units across the UK. It 
is intended that LFT testing will be the routine method of testing utilised during the ongoing conduct 
of the study based on kit availability and if necessary, PCR Antigen Testing may be performed as a 
confirmatory evaluation of a positive LFT test if needed and at the Principal Investigator’s discretion. In 
the circumstances where PCR antigen kit availability stabilises, the testing regime outlined within the 
study protocol will revert back to PCR testing instead of LFT. 
Further to this, the Sponsor wishes to implement a COVID-19 test on Day 8 and prior to discharge on 
the last day of the treatment period (currently defined as Day 13) of the study for participants who are 
enrolled to Part C of the study which is the Multiple Ascending Dose (MAD) part of the study. Given 
the length of the in-house treatment period for Part C whereby participants are resident within the 

 
Amendment Assessment Form: SA01 
Study Code: RD 675.34625 (AX-158-101) 
Version and Date: v1.0 (14 January 2022) 
 
 
Rat005 Amendment Assessment Form: Version Final 
(30 July 2019) 
 
Page 4 of 8 
 
clinical unit for a minimum period of 14 days (from Day -1 to Day 13), the Sponsor has determined that 
in order to best mitigate against the potential for development of a COVID-19 positive scenario whilst 
participants are in-house during this treatment period, the inclusion of  additional COVID-19 testing at 
the half-way point and last day of the treatment period prior to discharge from the clinical unit is 
appropriate. As the study protocol includes flexibility such that the length of the in-house treatment 
period may be extended to permit dosing up to 14 days, if this change is implemented based on dose 
escalation data review, then the timepoints of the COVID-19 testing will be adjusted accordingly such 
that the testing falls at the half-way point of the treatment period and on the last day of the treatment 
period prior to discharge from the clinical unit (defined as 72 hours post-last dose of AX-158). 
With respect to the other aspects of this protocol amendment, the Sponsor wishes to introduce blood 
sampling for the measurement of exploratory pharmacodynamics (PD) within Part A of the study. 
Within the current approved version of the study protocol (v3.0, Dated 22 October 2021), an adaptive 
design element has been included such that exploratory PD samples may be taken at selected timepoints 
within Part C (MAD) of the study based on emerging data from Part A (SAD) and Part B (Food Effect). 
At present, these timepoints are not defined due to the fact that Part A of the study is ongoing. 
Therefore, timepoints for exploratory PD sampling within Part C of the study will be defined following 
dose escalation data review of Part A and Part B data as indicated. However, following evaluation of 
the study protocol, the Sponsor now wishes to include the performance of exploratory PD sampling 
within Part A of the study (to be implemented from Cohort 3 onwards and for all subsequent Part A 
cohorts). Therefore, the protocol will be updated in order to include reference to this sampling. The 
intention is that two exploratory PD samples will be taken: one at pre-dose on Day 1 in Part A and 
Part C (serving as the baseline control) and a second sample at a defined timepoint. At present, the 
timing of the second exploratory PD sample within Part A and Part C is to be defined and will be 
confirmed following dose escalation data review of Cohort 2 PK data from Part A for the timepoint in 
Part A of the study and following dose escalation data review of Part A and Part B data for the timepoint 
with respect to the Part C of the study. These measures are exploratory in nature and do not contribute 
to the overall evaluation of the study objectives and will apply to all cohorts within Part A from Cohort 
3 onwards and all Part C cohorts. 
Therefore, this amendment serves to implement the changes as described above. 
Substantial Amendment – Study Protocol v4.0 (14 January 2022)  
 
As described above, the scope of the substantial amendment impacts the study protocol. 
 
The scope of the protocol changes in protocol v4.0 (14 January 2022) are as follows: 
 
Protocol Section 
Section Change 
Protocol Section 3 - Synopsis 
- Updated to align with changes in main body text 
 
Protocol Section 5 - Abbreviations 
– Minor updates to abbreviations list to include 
Lateral Flow Test (LFT) 
 
Protocol Section 8.8 - Coronavirus Disease 2019 
(COVID-19) Risk/Benefit Assessment 
 
- Risk/benefit assessment updated to reflect the 
requirement for all participants enrolled into the 
study to be fully vaccinated against COVID-19 as 
per 
the 
current 
Welsh/UK 
Government 
guidelines 
 
 
Protocol Section 10.2 – Adaptive Elements 
- Adaptive design elements updated to indicate 
that the timing of exploratory PD samples in both 

 
Amendment Assessment Form: SA01 
Study Code: RD 675.34625 (AX-158-101) 
Version and Date: v1.0 (14 January 2022) 
 
 
Rat005 Amendment Assessment Form: Version Final 
(30 July 2019) 
 
Page 5 of 8 
 
 
Part A and Part C of the study will be taken at 
pre-dose on Day 1 in both parts and at an 
additional timepoint to be determined based on 
emerging data generated during the study. 
 
Protocol Section 10.5.1 – Inclusion Criteria 
- Criterion #16 updated to remove reference to 
the specific type of COVID-19 testing with text 
updated to reflect the requirement for a negative 
COVID-19 test at admission 
 
- New criterion #17 added to reflect the 
requirement for all participants enrolled into the 
study to be fully vaccinated against COVID-19 as 
per 
the 
current 
Welsh/UK 
Government 
guidelines 
 
Table 10.9.1 – Study Flow Chart Part A Single 
Ascending Dose 
- Flow chart updated to remove reference to the 
specific type of COVID-19 testing on Day -1 of 
the treatment period 
 
- Flow chart updated to include timepoints for 
exploratory PD sampling 
 
Table 10.9.2 – Study Flow Chart Part B Food 
Effect 
- Flow chart updated to remove reference to the 
specific type of COVID-19 testing on Day -1 of 
each treatment period 
 
 
Table 10.9.3 – Study Flow Chart Part C Multiple 
Ascending Dose 
- Flow chart updated to remove reference to the 
specific type of COVID-19 testing on Day -1, Day 
8 and the last day of the treatment period (i.e., 
discharge from the clinical unit 72 hours post-last 
dose of AX-158) 
 
- Flow chart updated to include COVID-19 
testing on Day 8 and on the last day of the in-
house treatment period (i.e., discharge from the 
clinical unit 72 hours post-last dose of AX-158) 
 
 
- Flow chart updated to include timepoints for 
exploratory PD sampling 
 
Protocol Section 10.9.6 – COVID-19 Testing 
- 
Section 
updated to 
reference 
routine 
performance of  Lateral Flow Testing in each 
respective study part with the option to perform 
COVID-19 PCR Antigen testing at the Principal 
Investigators’ discretion 
 
Table 10.9.4 - Part A (Single Ascending Dose) 
Summary of Blood Volume 
- Blood volume updated to reflect addition of 
exploratory PD samples 

 
Amendment Assessment Form: SA01 
Study Code: RD 675.34625 (AX-158-101) 
Version and Date: v1.0 (14 January 2022) 
 
 
Rat005 Amendment Assessment Form: Version Final 
(30 July 2019) 
 
Page 6 of 8 
 
 
Table 10.9.6 - Part C (Multiple Ascending Dose) 
Summary of Blood Volume 
- Blood volume updated to reflect addition of 
exploratory PD samples 
 
Protocol Section 10.9.26 – Other Assessments 
- New section added to describe the procedures 
for collection of exploratory PD samples 
 
Protocol Section 10.10.1 – Summary of Source 
Documentation Location 
 
- Addition of reference to PD sample collection 
Protocol 
Section 
10.11.2 
– 
Study 
Variables/Endpoints 
 
- Endpoints for derived plasma PK for all study 
parts updated to include AUC0-24 
Protocol Section 10.11.8 – PK Data 
 
- Text updated to include AUC0-24 
 
As a result of the protocol changes described above, the participant information sheet and consent 
form for each respective study part will be updated. No other subject facing or regulatory 
documentation is impacted as a result of these changes.  
On the basis of the changes and in consideration of the relevant guidance, the Sponsor has determined 
that the changes detailed above are considered substantial in nature and therefore the updated study 
protocol and associated participant facing documents will require review and approval by the ethics 
committee and MHRA.  
 
In addition, as per standard practice, this amendment will notify all previous non-substantial 
amendments which have been implemented since the point of the last approval issued by the ethics 
committee and MHRA. 
 
In the context of this study, this will incorporate the notification of the following amendment: 
• 
Non-Substantial Amendment 01 (NSA01) – Affecting the protocol, IMPD and other 
associated participant facing documents. Details of this amendment may be found in NSA01 
amendment assessment form v1.0 (22 October 2021). 
 
The sponsor considers this amendment to be: 
Note: The categories listed below are extracted from the Annex 2 form (Notification of Substantial Amendment Form). 
 
Please confirm appropriate option 
Substantial   
 
Category#: D 
 
 
Non-Substantial  
 
 
 
 
A 
Changes in safety or integrity of trial subjects 
 
B 
Changes in interpretation of scientific documents/value of the trial  
 
 

 
Amendment Assessment Form: SA01 
Study Code: RD 675.34625 (AX-158-101) 
Version and Date: v1.0 (14 January 2022) 
 
 
Rat005 Amendment Assessment Form: Version Final 
(30 July 2019) 
 
Page 7 of 8 
 
C 
Changes in quality of IMP(s)   
 
D 
Changes in conduct or management of the trial 
 
E 
Change or addition of principal investigator(s), coordinating investigator 
 
 
F 
Change/addition of site(s) 
 
G 
Other change  - Please specify: 
 
 
Type of Notification (Approval or Notification Only) 
 
Competent Authority approval required: 
 
 
 
 
Ethics Committee(s) approval required:  
 
 
 
 
Other approval (e.g. HRA, ARSAC etc) required:  
 
Please specify: 
 
Competent Authority approval not required (No 
notification):  
                         
 
 
 
 
Ethics Committee approval not required  
(No notification):  
 
 
 
 
 
 
 
 
COMPLETED BY REGULATORY LEAD: 
Gabrielle Brill 
Senior Regulatory Affairs Associate 
 
Signature: 
Date: 
 
PROJECT MANAGER: 
Adam Chessun 
Senior Project Manager 
 
Signature: 
Date: 
 

 
Amendment Assessment Form: SA01 
Study Code: RD 675.34625 (AX-158-101) 
Version and Date: v1.0 (14 January 2022) 
 
 
Rat005 Amendment Assessment Form: Version Final 
(30 July 2019) 
 
Page 8 of 8 
 
STUDY SPONSOR: 
Andres Gagete 
Chief Operating Officer 
 
Signature: 
Date: 
 

Certificado de finalización
Identificador del sobre: B8130938F88648A9A0D702D44B11CA17
Estado: Completado
Asunto: Please DocuSign: RD675.34625 (AX-158-101) Clinical Study Protocol v4.0 14 Jan 2022 CLEAN.pdf, R...
Sobre de origen: 
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Gabrielle Brill
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Zona horaria: (UTC) Dublín, Edimburgo, Lisboa, Londres
Unit 29 Simbec Research Ltd
Merthyr Tydfil Industrial Park, Pentrebach 
Merthyr Tydfil , Merthyr Tydfil  CF464DR
gabrielle.brill@simbecorion.com
Dirección IP: 81.154.157.127 
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             14-ene.-2022 | 20:56
Titular: Gabrielle Brill
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Simbec Orion
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Andres Gagete
agagete@artaxbiopharma.com
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      Aceptado: 20-may.-2021 | 18:22
      ID: e39e11f4-8ca3-49e0-a566-b657402801d4

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Annelize Koch
annelize.koch@simbecorion.com
Medical Director - Clinical Pharmacology
Orion Clinical Services Limited (acting for itself and 
on behalf of its Affiliates) - Part 11
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gabrielle.brill@simbecorion.com
Simbec Orion
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Información sobre confidencialidad de registros y firmas electrónicos: 
      Aceptado: 14-ene.-2022 | 22:27
      ID: a3463661-14c2-43e2-8f6f-2a3588081a71
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Información sobre confidencialidad de registros y firmas electrónicos

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Divulgación sobre los registros electrónicos y las firmas electrónicas creada el: 23-ago.-2020 | 21:55
Las partes acuerdan: Andres Gagete, Richard Polisson

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