Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 32
Healthy volunteers: no

Brief summary:
The goals of this clinical study were to assess the safety, tolerability, blood levels, and disease impact of UPB-101 when given to adults with mild asthma. Eligible participant were consecutively assigned to 1 of 3 to 5 planned treatment groups. Each treatment group consisted of 8 individuals, six of whom will received active drug (UPB-101) and 2 who received placebo. Neither the study doctors nor the participants knew which participants were assigned to active study drug and which were assigned to placebo. The study was performed at 4 experienced research sites in the United Kingdom.

Detailed description:
This was a two-part phase 1b, multi-center randomized, double-blind (Investigator and Subject blinded; Sponsor unblinded), placebo-controlled, multiple ascending-dose study to assess the safety, tolerability, immunogenicity, pharmacokinetics (PK), and pharmacodynamics (PD) of UPB-101 administered subcutaneously (SC) to adult subjects with asthma.

The study consists of Part A and Part B. Part A included 3 cohorts with pre-set dosing regimens. Part B (optional) included up to 2 additional cohorts whose doses and dosing intervals decided based upon the safety, PK, and PD results from Part A (i.e., an adaptive design), as applicable. The regimens selected for Part B did not exceed the exposures (i.e., doses and/or dosing intervals) included in Part A. Eight subjects were randomized per cohort (6 active, 2 placebo). Thus, a total of 32 subjects were enrolled in the study with 24 subjects in Part A and 8 in Part B.

Arms:
arm 1: UPB-101 Cohort 1 arm 2: UPB-101 Cohort 2 arm 3: UPB-101 Cohort 3 arm 4: UPB-101 Cohort 4

Interventions: intervention 1: UPB-101 intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous injection intervention 2: Subcutaneous injection

Protocol document:
Prot_000.pdf: 
UPB-101 
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CLINICAL STUDY PROTOCOL: UPB-CP-01 
Study Title: A Phase 1, Randomized, Double-blind, Placebo -Controlled, Multiple 
Ascending -Dose Study to Assess the Safety, Tolerability, Immunogenicity, 
Pharmacokinetics and Pharmacodynamics of UPB-101 in Subjects with Asthma 
Study Number:   
UPB-CP-01 
Study Phase:   
 
Phase 1 
Product Name:   
UPB-101 
 
IND Number:  
 
Not Applicable 
EudraCT Number:  2022-000132-36 
Indication:   
 
Asthma 
Lead Investigator:  Professor Dave Singh  
 
 
 
 
 
 
Medicines Evaluation Unit, Manchester, UK  
 
Sponsor:   
 
 
Upstream Bio 
Sponsor Contacts:  
 
 
 
 
 
 
 
Sponsor’s Unblinded Medical Monitor 
 
 
 
 
 
 
Upstream Bio 
460 Totten Pond Road, Suite 420 
Waltham, MA 02451, US 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor’s Blinded Medical Monitor 
tranScrip Ltd., 220 Wharfedale Road,  
Wokingham, RG41 5TP, UK  
 
 
 


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Version Number 
Date 
Original Protocol  
Version 1.0  
25 Feb 2022 
Updated protocol 
Version 2.0 
28 March 2022 
Updated protocol for submission 
Version 3.0 
01 April 2022 
Update protocol following MHRA/REC review 
Version 4.0 
19 May 2022 
Protocol Amendment 1 
Version 5.0 
18 August 2022 
Protocol Amendment 2 
Version 6.0 
14 September 2022 
Protocol Amendment 3 
Version 7.0 
27 October 2022 
Protocol Amendment 4 
Version 8.0 
17 January 2023 
Protocol Amendment 5 
Version 9.0 
31 March 2023 
 
 
Confidentiality Statement 
Property of the Sponsor 
This document is confidential and may not be used, divulged, published, or otherwise disclosed 
without consent of the Sponsor 


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PROTOCOL SYNOPSIS 
Sponsor: Upstream Bio 
Intervention Name: UPB-101  
Study Title: A Phase 1, Randomized, Double-blind, Placebo-controlled, Multiple 
Ascending-dose Study to Assess the Safety, Tolerability, Immunogenicity, 
Pharmacokinetics and Pharmacodynamics of UPB-101 in Subjects with Asthma  
Study Number: UPB-CP-01 
Study Phase: Phase 1 
Study Period: June 2022 – October 2023 
Study Sites: 3-5 sites in the United Kingdom 
Study Objectives and Endpoints: 
Primary Objective  
Primary Endpoints 
To assess the safety and tolerability of 
UPB-101 when administered as 
multiple ascending doses. 
• Adverse events (AEs), serious AEs (SAEs), 
physical examinations, clinical laboratory 
assessments, vital signs, and 
electrocardiograms (ECGs) from baseline 
through Week 24. 
• Subject withdrawals, early terminations, 
and dosing compliance from baseline 
through Week 24. 
Secondary Objectives 
Secondary Endpoints 
To assess the immunogenicity of 
UPB-101 when administered as 
multiple ascending doses. 
• UPB-101 anti-drug antibodies (ADA) from 
baseline through Week 24. 
To characterize the pharmacokinetics 
(PK) of multiple ascending doses of 
UPB-101. 
• Serum UPB-101 concentrations and 
analyses including maximum observed 
concentration (Cmax), time to maximum 
observed concentration (tmax), area under 
the concentration-time curve under one 
dosing interval (AUCtau) from baseline 
through Weeks 24. If appropriate, area 
under the concentration-time curve from 
the time of dosing extrapolated to time 
infinity (AUCinf), terminal elimination 
half-life (t1/2), apparent total body clearance 
after dosing (CL/F), and apparent volume 
of distribution during the terminal 


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elimination phase after dosing (Vz/F), all 
after the first dose, will be analysed as well. 
Exploratory Objectives 
Exploratory Endpoints 
To assess 32-week extended safety and 
tolerability of UPB-101 when 
administered as multiple ascending 
doses. 
• AEs, SAEs, pregnancy tests, physical 
examinations, clinical laboratory 
assessments, vital signs, and ECGs from 
baseline through Week 32. 
• Subject withdrawals, early terminations, 
and dosing compliance from baseline 
through Week 32. 
To assess 32-week extended 
immunogenicity of UPB-101 when 
administered as multiple ascending 
doses. 
• UPB-101 ADAs from baseline through 
Week 32. 
• Neutralizing antibodies )NAbs) from 
baseline through Week 32. 
To characterize 32-week extended PK 
of multiple ascending doses of UPB-
101. 
• Serum UPB-101 concentrations and 
analyses including Cmax, tmax, AUCtau from 
baseline through Week 32.  
To assess the pharmacodynamic (PD) 
effect of UPB-101 on biomarkers 
related to asthma and/or the thymic 
stromal lymphopoietin (TSLP) 
pathway. 
• Fractional exhaled nitric oxide (FeNO) and 
blood eosinophil numbers from baseline 
through Weeks 24 and 32. 
• Total immunoglobulin E (IgE), interleukins 
(IL)-5, IL-13, and IL-17A, interferon 
gamma (IFN λ), IFN λ-induced protein 10 
(IP-10), TSLP, eotaxin-3, tryptase, 
carboxypeptidase, thymus activation 
regulated chemokine (TARC), C-reactive 
protein (CRP), and flow cytometric 
assessment of phosphorylated signal 
transducer and activator of transcription 
(pSTAT) and receptor occupancy from 
baseline through Weeks 24 and 32. 
To assess the PD effect of UPB-101 on 
clinician and subject impression of 
overall asthma severity.  
• Clinician Global Impression of Change 
(CGI-C) from baseline through Weeks 24 
and 32. 
• Subject Asthma Control Questionnaire-7 
(ACQ-7) from baseline through Weeks 24 
and 32. 
To explore the PD effect of UPB-101 
on lung function. 
• Forced expiratory volume in 1 second 
(FEV1) from baseline through Weeks 24 
and 32. 


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Study Design 
This is a two-part Phase 1, multi-centre randomized, double-blind (Investigator and 
Subject blinded; Sponsor unblinded), placebo-controlled, multiple ascending dose study to 
assess the safety, tolerability, immunogenicity, PK, and PD of UPB-101 administered 
subcutaneous (SC) to adult subjects with asthma.  
The study consists of Part A and Part B. Part A includes 3 cohorts with pre-set dosing 
regimens. Part B includes up to 2 optional adaptive design cohorts whose doses and dosing 
intervals will be decided based upon the safety, PK, and PD results from Part A available 
to the unblinded Sponsor. The regimens selected for Part B will not exceed the exposures 
(i.e., doses and/or dosing intervals) included in Part A.  
The study will consist of 3 to 5 cohorts: 3 cohorts in Part A and up to 2 optional cohorts in 
Part B. Eight subjects will be randomized per cohort (6 active, 2 placebo). A total of 
approximately 24 to 40 subjects will be enrolled in the study with 24 subjects in Part A 
and up to 16 in Part B.  
The study includes 4 periods: Pre-Screening, Screening, Dosing, and Observation. 
Pre-screening Period: Sites may opt to utilize a Pre-screening Informed Consent Form 
(ICF) to enable performance of a complete blood count (for the absolute eosinophil 
numbers) in consenting subjects while subjects consider consent for the full study. Pre-
screening may not occur more than 90 days before Visit 1. 
Screening Period: Subjects will be evaluated for eligibility during the 21-day Screening 
Period before randomization and dosing. Eligible subjects will be allocated to cohorts and 
then be randomly allocated to treatment with UPB-101 or placebo in a 3:1 ratio, 
respectively.  
Dosing Period: Study drug will be administered SC as follows: 
Description of SC Dosing Regimens in Part A 
Cohort  
Treatment Arm and 
Dosage 
Number of Injections 
to Achieve Dose 
Frequency x Number of Doses 
Cohort 1 
UPB-101 
mg 
 
 
Placebo 
Cohort 2 
UPB-101 
 mg 
 
 
Placebo 
Cohort 3 
UPB-101 
 mg 
 
 
Placebo 
Description of SC Dosing Regimens in Part B (Adaptive Design) 
Cohort 4 
(optional) 
UPB-101 
mg 
 
 
Placebo 
Cohort 5 
(optional) 
UPB-101 
• 
  
 
 
 
Placebo 
 


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Subjects will be admitted to the inpatient area of their site the day before each dosing day. 
After each administration of the study drug, subjects will be monitored in the site for a 
minimum of 4 hours to assure their safety. 
Observation Period: Following their final dose administration, subjects will be followed 
for evaluation of safety, PD, PK, and immunogenicity monitoring. Subjects enrolled in 
cohorts with 
 or 
 dosing intervals will be observed for 6 months; subjects 
enrolled in cohort 3 (
 dosing intervals) will be observed for 5 months; subjects 
enrolled in cohort 4 (
) will be observed for 8 months. 
All Study Periods: All PD and PK assessments (with the exception of spirometry) will be 
conducted between 6 AM and 10 AM to minimize the impact of diurnal variations on 
biomarker assessments.  
Safety Review Committee 
Part A 
Subjects in Cohorts 1 and 2 will receive  doses of study drug. Before the first subject in 
each of those cohorts receives their 
 dose, the Safety Review Committee (SRC) will 
be convened. The committee will review at each of the meetings the safety data available 
at that point in time from all enrolling cohorts. 
Subjects enrolled in Cohort 3 will receive only  doses of the study drug. Therefore, no 
SRC meetings will be directly linked to the progress of that cohort.   
The blinded safety data reviewed will include AEs, vital signs, physical examinations, 
ECGs, haematology, biochemistry, urinalyses, as well as subject withdrawals and 
replacements. Eosinophil data will not be sent to sites or reviewed by the SRC. 
Following this data review, the SRC will report their safety findings and make a 
recommendation whether the third dosing in the current cohort should proceed as planned 
or be modified (e.g., repeated or reduced), paused, or halted. 
Part B 
If a 
 dosing regimen is selected for Cohorts 4 or Cohort 5 in Part B, an SRC meeting 
will be convened prior to the first subject in the relevant cohort(s) receiving their third 
dose. The data to be reviewed, and the process for the SRC to report their safety findings, 
will be as those detailed for Part A above. 
Study Population  
Approximately 24 to 40 subjects with mild-to-moderate asthma who meet the enrolment 
criteria will be enrolled/randomized in this study.  
Inclusion Criteria: 
1. 
Subject has signed, dated, and received a copy of the Independent Ethics 
Committee (IEC)-approved written ICF. 
2. 
Subject is aged 18 to 60 years. 
3. 
Subject has physician-diagnosed asthma. 
4. 
Subject has a body mass index between 18 and 35 kg/m2 at Visit 1. 


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5. 
Subject has either ≥200 eosinophils cells/µL OR FeNO >25 with ≥150 eosinophils 
cells/µL at Visit 1 or 2 AND ≥150 eosinophils cells/µL at the other visit. 
6. 
Subject is: 
a. a female subject with reproductive potential who has a negative serum 
pregnancy test (beta human chorionic gonadotropin) during the Screening 
Period, is not breastfeeding, does not plan to become pregnant during the study, 
and agrees to use a highly effective birth control method when engaging in 
sexual activity with a male partner from the first dose of study drug until 120 
days after the last dose of study drug or the Final Visit, whichever is later; OR 
b. a female subject either surgically sterile (i.e., post bilateral oophorectomy, 
hysterectomy, or tubal ligation) or naturally sterile (>12 consecutive months 
without menses with an elevated follicle stimulating hormone during the 
Screening Period); OR 
c. a male subject who is not sexually active; OR 
d. a male subject who is sexually active agrees to use a condom during the study 
from the first dose of study drug until 120 days after the last dose of study drug 
or the Final Visit, whichever is later. 
AND 
whose partner has childbearing potential must either be sterile (vasectomy with 
history of a negative sperm count at least 90 days following the procedure) or 
their partner must agree to use a highly effective birth control method from the 
first dose of study drug until 120 days after the last dose of study drug or the 
Final Visit, whichever is later. 
7. 
Female or male subject agrees not to donate eggs or sperm, respectively, for a 
period of 120 days after the last dose of study drug. 
8. 
Subject meets the Spirometry Performance Criteria: 
a. Pre-salbutamol/albuterol (hereafter referred to as salbutamol) FEV1 ≥65% 
predicted normal value at Visit 1. 
b. Perform acceptable spirometry (i.e., meet American Thoracic Society/European 
Respiratory Society acceptability criteria) at Visits 1 and 2. 
c. Perform technically acceptable spirometry meeting repeatability criteria for 
FEV1 during at least one (1) of the pre-bronchodilator assessments at Visits 1 
and 2. 
9. 
Medications: 
a. Subject is on stable, non-biologic asthma medication with no dose adjustments 
in the 8 weeks prior to Screening. 
b. Subject has not had an exacerbation of asthma (defined as an event requiring a 
change in asthma therapy) in the 8 weeks prior to Screening. 
c. Subject has not started any new prescribed drugs or had any dose adjustments in 
their prescribed drugs in the 8 weeks prior to Screening. 
Exclusion Criteria: 
1. 
Subject is an employee, consultant, and/or immediate family member (i.e., first 
degree relative, spouse, adoptee, or legal dependent) of the site or the Sponsor. 


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2. 
Subject is unreliable; incapable of adhering to the protocol and visit schedule 
according to the judgement of the Investigator; or has any disorder that may 
compromise their ability to give informed consent. 
3. 
Subject has previous exposure to the study drug or known allergy/sensitivity to any 
of its excipients. 
4. 
Female subject is pregnant or breastfeeding. 
5. 
Subject cannot fast and avoid strenuous exercise for 9 hours prior to each site visit 
which includes clinical chemistry testing. 
6. 
Subject has an abnormal medical history, physical finding or safety finding that in 
the opinion of the Investigator or Sponsor’s blinded Medical Monitor may obscure 
the study data. 
7. 
Subject has clinically significant history of a serious hypersensitivity reaction to 
any parenteral drug. 
8. 
Any clinical laboratory test result outside of the reference ranges considered by the 
Investigator as clinically significant. 
9. 
Subject has history or evidence of clinically significant pulmonary condition, 
including significant restrictive findings on pulmonary function testing, chronic 
bronchitis, emphysema, bronchiectasis, and pulmonary fibrosis, or any other 
related condition that in the opinion of the Investigator or Sponsor’s blinded 
Medical Monitor may obscure the study data (e.g., gastro-oesophageal reflux and 
vocal cord paralysis/dysfunction). 
10. Subject has donated blood (including blood products) or experienced loss of blood 
≥500 mL within 8 weeks of Screening. 
11. Screening supine blood pressure (BP) >150 mmHg (systolic) or >100 mmHg 
(diastolic), following at least 5 minutes of supine, semi supine or sitting rest. If BP 
is >150 mmHg (systolic) or >100 mmHg (diastolic), the BP should be repeated two 
more times and the average of the three BP values should be used to determine the 
subject’s eligibility. 
12. Subject has pacemaker; is not in sinus rhythm; has a resting heart rate <40 or 
>99 beats per minute; has a mean corrected QT interval (QTc; using Fridericia’s 
[QTcF] formula) of >450 ms in males or >470 ms in females during the Screening 
Period; or has a left bundle branch block or bi-fascicular block. 
13. Subject has a self-reported lower respiratory tract infection in the 8 weeks prior to 
Screening. 
14. Subject has evidence of active or suspected bacterial, viral, fungal or parasitic 
infections within the past 8 weeks prior to Screening (e.g., sinusitis, common cold, 
viral syndrome, flu-like symptoms). 
15. Subject has a history compatible with or diagnosis of a parasitic infection and has 
not been treated or has not responded to standard of care therapy. 
16. Subject has Type I or II diabetes under poor glucose control. 
17. Subject has an estimated glomerular filtration rate of <80 mL/min/1.73 m2 using 
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SC=subcutaneous 
Administration of the entire dose of study drug should not exceed 4 hours. Study drug may 
be administered in any extremity or in the abdominal wall. In exceptional cases where a 
subject cannot tolerate multiple SC injections, use of an infusion pump may be considered 
at the discretion of the Investigator. 
Study Duration:  
Approximately 9 months. All subjects will undergo Screening for a maximum of 3 weeks. 
Subjects assigned to a cohort with  doses administered 
 if such an 
interval is selected in Part B) will undergo 2 months of treatment followed by 6 months of 
observation. Subjects assigned to a 
 regimen will undergo 3 months of 
treatment followed by 5 months of observation. Subjects assigned to Cohort 4 will receive 
 dose followed by 8 months of observation. 
Safety Assessments:  
Safety and tolerability assessments will include AEs and SAEs, vital signs (BP, pulse, 
body temperature, and respiration rate), physical examinations, clinical laboratory 
parameters (haematology, clinical chemistry, coagulation, and urinalysis), ECGs, subject 
withdrawals, early terminations, and compliance.  
Immunogenicity Assessments: 
Serum samples will be collected for assessments of ADAs and Nabs. Samples from ADA-
positive subjects will be tested using a NAb assay. 
Pharmacokinetic Assessments:  
Timed blood samples will be collected for serum. The PK analyses will be based on the 
timed blood PK sampling of all enrolled subjects (PK Population). Serum UPB-101 
concentrations will be summarized using descriptive statistics. PK analyses will include 
maximum observed concentration (Cmax), time to maximum observed concentration (tmax) 
and area under the concentration-time curve under one dosing interval (AUCtau). A power 
model will be fitted using all doses and across all cohorts to assess dose proportionality for 
Cmax and AUCtau after the first dose. Within each dosing regimen, dose proportionality 
using a comparison of Cmax and AUCtau after the last dose will also be assessed using 
descriptive statistics. For each dosing regimen, accumulation of UPB-101 will be assessed 
by comparing the ratio of Cmax and AUCtau after the last dose and the first dose for each 
subject and summarized by dosing regimen. 
Exploratory Assessments: 
The PD effect of UPB-101 will be assessed by FeNO; blood eosinophil, total IgE 
concentrations, CRP, IL-5 and IL-13, IFN λ, IL-17A, IP-10, tryptase, carboxypeptidase, 
TARC, eotaxin-3, and TSLP levels; as well as flow cytometric assessment of pSTAT and 
receptor occupancy.  


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Additionally, a physician global impression of change will be assessed by the CGI-C 
questionnaire as well as by the ACQ-7 and pulmonary function testing will be conducted 
to assess FEV1. 
Statistical Methods:  
Continuous variables will be summarized by UPB-101 dose group and pooled placebo, 
and by dosing frequency with descriptive statistics (e.g., number of observations, mean, 
standard deviation, median, interquartile range, maximum, and minimum). Categorical 
variables will be tabulated by frequency and percent of subjects per UPB-101 dose group 
and pooled placebo, and by dosing frequency. Demographic data will be summarized by 
treatment, dose, and dose regimen. Analyses will be based on observed data only; no data 
will be imputed. 
Immunogenicity, PD biomarkers and clinical outcome measures such as FEV1, CGI-C and 
ACQ-7 will be explored across dose cohorts using dose and exposure-response modelling 
to assess for dose and/or exposure related trends. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities and 
summarized by system organ class, preferred term, and treatment group for the number 
and percent of subjects reporting AEs, the number of events, and the number of subjects 
with any AE. All AEs will be listed including onset and resolution dates, verbatim term, 
preferred term, treatment, severity, relationship to treatment, action taken, and outcome. 
Absolute values and change from baseline laboratory evaluations, physical examinations, 
vital signs assessments, and ECG parameters will be summarized by visit and by treatment 
group. The frequency of subjects with safety laboratory results outside of normal reference 
ranges will be tabulated by treatment and visit. No inferential statistical analyses are 
planned for safety parameters. 
Analysis of exploratory endpoints will be described in the Statistical Analysis Plan. 
Sample Size Considerations: 
The primary objective of the study is to assess the safety and tolerability of UPB-101 
when administered as multiple ascending doses. A sample size of 24-40 subjects with 
8 subjects per cohort (6 on active drug + 2 on placebo) is considered sufficient to meet this 
goal. The sample size is not based on formal statistical hypothesis testing. 
 Version 9.0, 31 March 2023 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ...................................................................................................... 3 
TABLE OF CONTENTS .................................................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 18 
1 
BACKGROUND AND RATIONALE ......................................................................... 22 
1.1 
Indication ........................................................................................................... 22 
1.2 
Asthma and TSLP .............................................................................................. 22 
1.3 
Unmet Medical Need ......................................................................................... 23 
1.4 
UPB-101 Clinical Summary ............................................................................... 25 
1.4.1 
Completed Clinical Studies ...................................................................... 25 
1.5 
Study Rationale .................................................................................................. 26 
1.6 
Rationale of Study Design .................................................................................. 26 
1.7 
Rationale of Dose Regimen and Duration of Treatment ...................................... 27 
1.8 
Benefits and Risks Assessment .......................................................................... 31 
1.8.1 
Patient Population .................................................................................... 31 
1.8.2 
Current Therapies ..................................................................................... 31 
1.8.3 
Brief Summary of Product Data ................................................................ 31 
1.8.4 
Study Rationale ........................................................................................ 32 
1.8.5 
Rationale for Dose Selection for Proposed Study ...................................... 32 
1.8.6 
Minimization of Risks in Study ................................................................ 32 
1.8.7 
Benefit/Risk Conclusion ........................................................................... 33 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 35 
3 
INVESTIGATIONAL PLAN ...................................................................................... 37 
3.1 
Overall Study Design and Plan ........................................................................... 37 
3.1.1 
Study Design: Cohorts .............................................................................. 37 
3.1.2 
Study Design: Periods .............................................................................. 37 
3.1.3 
General Considerations for Study Conduct ............................................... 39 
3.2 
Study Activities ................................................................................................. 40 
3.3 
Schedule of Events ............................................................................................. 40 
3.4 
Pre-Screening ..................................................................................................... 47 
3.5 
Screening Period ................................................................................................ 47 
3.6 
Dosing Period .................................................................................................... 47 
3.6.1 
Cohorts with 
 Dosing Intervals ......................................................... 48 
3.6.2 
Cohorts with 
 Dosing Intervals ......................................................... 48 
3.6.3 
Cohorts with 
 Dosing Intervals ....................................................... 48 
3.7 
Observation Period ............................................................................................. 48 
3.7.1 
Cohorts with 
 Dosing Intervals ......................................................... 48 


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3.7.2 
Cohorts with 
 Dosing Intervals ......................................................... 48 
3.7.3 
Cohorts with 
 Dosing Intervals ....................................................... 49 
3.8 
Unscheduled Visit and Early Termination Visit .................................................. 49 
3.9 
Procedures for Treatment Discontinuation and Study Withdrawal ...................... 49 
3.10 
Completion of Study .......................................................................................... 50 
4 
STUDY POPULATION SELECTION AND WITHDRAWAL CRITERIA ................ 51 
4.1 
Inclusion Criteria ............................................................................................... 51 
4.2 
Exclusion Criteria .............................................................................................. 52 
4.3 
Future Cohort Eligibility .................................................................................... 53 
4.4 
Re-screening Criteria ......................................................................................... 53 
4.5 
Randomization Criteria ...................................................................................... 54 
4.6 
Subject Identification ......................................................................................... 54 
4.7 
Prior, Concomitant, and Prohibited Medications ................................................ 54 
4.7.1 
Allowed Medications to Treat Asthma ...................................................... 54 
4.7.2 
Prohibited Medications ............................................................................. 54 
4.8 
Other Restrictions, Illicit Drugs, or Drugs of Abuse ........................................... 55 
4.8.1 
Illicit Drugs .............................................................................................. 55 
4.8.2 
Alcohol, Caffeine, and Tobacco Restrictions ............................................ 55 
4.8.3 
Dietary Restrictions .................................................................................. 55 
4.8.4 
Male and Female Contraception ............................................................... 55 
4.9 
Reasons for Treatment Discontinuation or Study Withdrawal ............................. 56 
4.9.1 
Duration of Study Participation ................................................................ 56 
4.9.2 
Reasons for Treatment Discontinuation .................................................... 56 
4.9.3 
Reasons for Subject Withdrawal ............................................................... 57 
4.10 
Replacement of Subjects .................................................................................... 58 
4.11 
Termination of the Study .................................................................................... 58 
4.12 
Day 225 / Final Visit .......................................................................................... 58 
5 
STUDY SAFETY ASSESSMENTS AND PROCEDURES ......................................... 59 
5.1 
Medical History ................................................................................................. 59 
5.2 
Prior Medication History .................................................................................... 59 
5.3 
Demographics .................................................................................................... 59 
5.4 
Safety Assessments ............................................................................................ 59 
5.4.1 
Adverse Events......................................................................................... 59 
5.4.2 
Vital Signs................................................................................................ 59 
5.4.3 
Weight, Height and Body Mass Index ...................................................... 60 
5.4.4 
Physical Examination ............................................................................... 60 
5.4.5 
Electrocardiogram .................................................................................... 60 
5.4.6 
Clinical Laboratory Assessments .............................................................. 61 


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5.4.7 
Pregnancy Test and FSH .......................................................................... 62 
5.4.8 
COVID-19 Testing ................................................................................... 62 
5.4.9 
Subject Compliance Assessment............................................................... 62 
5.5 
Immunogenicity Assessments ............................................................................ 62 
5.6 
Pharmacokinetic Assessments ............................................................................ 63 
5.7 
Study Oversight ................................................................................................. 63 
5.8 
Safety Review Committee .................................................................................. 64 
5.8.1 
General Safety Monitoring ....................................................................... 64 
5.8.2 
PK Safety Monitoring ............................................................................... 65 
5.9 
Stopping Criteria ................................................................................................ 65 
5.9.1 
Study Stopping Criteria ............................................................................ 65 
Dose Escalation Stopping Criteria ............................................................................ 66 
5.10 
Pharmacokinetic Stopping Limits ....................................................................... 66 
5.11 
Re-starting the Clinical Study Following a Clinical Stop Due to a Stopping 
Rule ................................................................................................................... 66 
6 
STUDY EFFICACY ASSESSMENTS AND PROCEDURES ..................................... 68 
6.1 
Pharmacodynamic Assessments ......................................................................... 68 
6.1.1 
Fractional Exhaled Nitric Oxide ............................................................... 68 
6.1.2 
Blood Eosinophils .................................................................................... 68 
6.1.3 
Total Immunoglobulin E........................................................................... 69 
6.1.4 
Flow Cytometry – pSTAT and Receptor Occupancy ................................ 69 
6.2 
Asthma Status Questionnaires ............................................................................ 69 
6.2.1 
Asthma Clinician Global Impression of Change ....................................... 69 
6.2.2 
Asthma Control Questionnaire.................................................................. 69 
6.3 
Pulmonary Function Tests (Spirometry) ............................................................. 70 
6.4 
Future Analysis of Additional Cytokines ............................................................ 71 
6.5 
Blood Sampling Volume per Subject.................................................................. 71 
7 
STUDY TREATMENT ............................................................................................... 72 
7.1 
Product Description............................................................................................ 72 
7.2 
Treatment Administration .................................................................................. 72 
7.2.1 
Dosing Instructions................................................................................... 72 
7.2.2 
Cohorts with
 Dosing Intervals ......................................................... 73 
7.2.3 
Cohorts with 
 Dosing Intervals ......................................................... 73 
7.2.4 
Cohorts with 
 Dosing Intervals ....................................................... 73 
7.2.5 
Rotation of Injection Sites ........................................................................ 74 
7.3 
Preparation/Handling/Storage/Accountability..................................................... 74 
7.3.1 
Acquisition and Accountability ................................................................ 74 
7.3.2 
Primary Packaging and Labelling Information .......................................... 75 


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7.3.3 
Secondary Packaging and Labelling Information (Bulk Packaging) .......... 76 
7.3.4 
Product Storage ........................................................................................ 76 
7.3.5 
Preparation ............................................................................................... 76 
7.4 
Treatment Assignment ....................................................................................... 76 
7.5 
Blinding ............................................................................................................. 76 
7.5.1 
Emergency Unblinding of Treatment Assignment..................................... 77 
8 
ADVERSE EVENTS................................................................................................... 79 
8.1 
Performing Adverse Event Assessments............................................................. 79 
8.2 
Adverse Event Definitions ................................................................................. 79 
8.3 
Pre-randomization Adverse Events..................................................................... 80 
8.4 
Severity.............................................................................................................. 80 
8.5 
Relationship ....................................................................................................... 80 
8.6 
Outcomes of Adverse Events ............................................................................. 81 
8.7 
Adverse Events of Special Interest ..................................................................... 81 
8.7.1 
Management of Injection Site Reactions ................................................... 81 
8.8 
Clinical Laboratory Adverse Events ................................................................... 82 
8.9 
Serious Adverse Events ...................................................................................... 82 
8.9.1 
Reporting of Serious Adverse Events........................................................ 83 
8.9.2 
Supplemental Investigations of Serious Adverse Events ........................... 84 
8.9.3 
Post-Study Follow-Up of Adverse Events ................................................. 84 
8.9.4 
Notification of Post-Study Serious Adverse Events .................................. 84 
8.9.5 
Independent Ethics Committee Notification of Serious Adverse Events .... 84 
8.9.6 
Health Authority Safety Reports ............................................................... 85 
8.9.7 
Overdose .................................................................................................. 85 
8.9.8 
Pregnancy................................................................................................. 85 
8.9.9 
Paternal Exposure ..................................................................................... 85 
8.9.10 
Hy’s Law ................................................................................................. 85 
9 
STATISTICAL CONSIDERATIONS ......................................................................... 86 
9.1 
Statistical Hypotheses ........................................................................................ 86 
9.2 
Sample Size Determination ................................................................................ 86 
9.3 
Populations for Analyses .................................................................................... 86 
9.4 
Statistical Analyses ............................................................................................ 86 
9.4.1 
General Considerations............................................................................. 86 
9.4.2 
Subject Disposition................................................................................... 87 
9.4.3 
Demographic and Baseline Characteristics ............................................... 87 
9.4.4 
Investigational Product Exposure.............................................................. 87 
9.4.5 
Prior and Concomitant Medications .......................................................... 87 
9.4.6 
Safety Analyses ........................................................................................ 87 


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9.4.7 
Immunogenicity Analyses ........................................................................ 88 
9.4.8 
Pharmacokinetic Analyses ........................................................................ 88 
9.4.9 
Exploratory Analyses ............................................................................... 88 
9.4.10 
Administrative Interim Analysis ............................................................... 89 
10 ADMINISTRATIVE CONSIDERATIONS ................................................................. 90 
10.1 
Regulatory Authority Approval .......................................................................... 90 
10.2 
Ethical Conduct of the Study and Institutional Review Board or Independent 
Ethics Committee Approval ............................................................................... 90 
10.3 
Subject Information and Consent ....................................................................... 90 
10.4 
Laboratory Accreditation ................................................................................... 91 
10.5 
Confidentiality ................................................................................................... 91 
10.5.1 
Confidentiality of Data ............................................................................. 91 
10.5.2 
Confidentiality of Subject Records ........................................................... 91 
10.6 
Quality Control and Assurance ........................................................................... 91 
10.7 
Data Management .............................................................................................. 92 
10.8 
Study Monitoring ............................................................................................... 92 
10.9 
Retention of Data ............................................................................................... 93 
10.10 Financial Disclosure ........................................................................................... 93 
10.11 Publication Policy .............................................................................................. 93 
10.12 Annual Report .................................................................................................... 95 
10.13 End of Study Notification and Submission of Summary Report .......................... 95 
11 REFERENCE LIST ..................................................................................................... 96 
12 APPENDICES ........................................................................................................... 101 
Appendix 1 
Liver Safety Monitoring and Assessment ...................................... 101 
Appendix 2 
Spirometry Performance ............................................................... 104 
Appendix 3 
Sponsor Signature ......................................................................... 105 
Appendix 4 
Investigator’s Signature ................................................................ 106 
13 VERSION HISTORY ................................................................................................ 107 


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LIST OF TABLES 
Table 1 
Predicted Mean PK parameters After Single SC Administration UPB-101 
Compared to the Maximal IV Dose of Completed Study 7266-CL-0001 .............................. 28 
Table 2 
Predicted Serum PK Parameters After Repeated SC Administration of 
UPB-101 29 
Table 3 Risk Minimization Actions Based on Non-clinical Toxicology Studies ................... 33 
Table 4 
Schedule of Screening Assessments for All Cohorts ........................................... 41 
Table 5 
Schedule of Events Day 1 to Day 15 for All Cohorts .......................................... 42 
Table 6 
Schedule of Events - Cohorts with 
 Dosing Interval ................................... 43 
Table 7 
Schedule of Events - Cohorts with 
 Dosing Interval ................................... 44 
Table 8 
Schedule of Events - Cohorts with 
 Dosing Interval ................................. 45 
Table 9 
Timed Assessments at Each Dosing Visit ........................................................... 47 
Table 10 Clinical Laboratory Testsa .................................................................................. 61 
Table 11 Product Descriptions .......................................................................................... 72 
Table 12 Description of SC Dosing Regimens .................................................................. 73 
Table 13 Description of Boxes .......................................................................................... 76 
LIST OF FIGURES 
Figure 1 
Simulation of Repeated Administration of UPB-101 Given as a SC Injection ..... 30 
Figure 2 
Study Design...................................................................................................... 39 
Figure 3 
Rotation of Injection Sites .................................................................................. 74 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Ad 
admission 
ACQ 
Subject Asthma Control Questionnaire 
ACQ-7 
Subject Asthma Control Questionnaire-7 
ADA 
anti-drug antibody 
AE 
adverse event  
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
ATS 
American Thoracic Society 
AUCinf 
area under the concentration-time curve from the time of dosing extrapolated 
to time infinity 
AUCtau 
area under the concentration-time curve for one dosing interval 
BMI 
body mass index  
BP 
blood pressure 
CGI-C 
Clinician Global Impression of Change 
CL/F 
apparent total body clearance after dosing 
Cmax 
maximum observed concentration 
COVID-19 
Coronavirus disease 2019 
CPMP 
Committee for Proprietary Medicinal Products 
CRF 
case report form  
CRO 
contract research organisation 
CRP 
C-reactive protein 
D 
day  
Di 
discharge 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
ERS 
European Respiratory Society 


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EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FDA  
Food and Drug Administration  
FeNO 
fractional exhaled nitric oxide 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle stimulating hormone 
GCP  
Good Clinical Practice  
β-HCG 
beta human chorionic gonadotropin 
HDL 
high density lipoprotein 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH  
International Council on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
ID 
identification 
IEC  
Independent Ethics Committee  
IFN λ 
interferon gamma 
IgE 
immunoglobulin E 
IgG1 
immunoglobulin G1 
IL- 
interleukin- 
INR 
International Normalized Ratio 
IP-10 
interferon gamma-induced protein 10 
IV 
intravenous 
IXRS 
interactive response system 
LA-CRF 
liver abnormality case report form 
MedDRA 
Medical Dictionary for Regulatory Activities  
MHRA 
Medicines and Healthcare products Regulatory Agency 
Mon 
month 
NAb 
neutralizing antibodies 
NOAEL 
no observed adverse effect level 


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PD 
pharmacodynamic 
PIN 
personal identification number 
PK 
pharmacokinetic 
pSTAT 
phosphorylated signal transducer and activator of transcription  
PT 
prothrombin time 
PTT 
partial thromboplastin time 
 
 
 
 
 
 
QFT-G 
QuantiFERON®-tuberculosis Gold 
QTc 
QT interval corrected 
QTcF 
QT interval corrected using Fridericia’s formula 
SAD 
single ascending dose 
SAE  
serious adverse event  
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SGOT 
serum glutamic oxaloacetic transaminase   
SGPT 
serum glutamic pyruvic transaminase   
SOP 
standard operating procedure 
SRC 
Safety Review Committee 
t1/2 
terminal elimination half-life 
TARC 
thymus activation regulated chemokine 
TB 
tuberculosis 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
Th2 
T helper 2 
tmax 
time to maximum observed concentration 
TSLP 
thymic stromal lymphopoietin 
TSLPR 
thymic stromal lymphopoietin receptor 
ULN 
upper limit of normal 
US 
United States  


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Vz/F 
apparent volume of distribution during the terminal elimination phase after 
dosing 
W 
week 
WBC 
white blood cells 
WMA 
World Medical Association 
 
TRADEMARK INFORMATION 
Trademarks Not Owned by Upstream Bio: QuantiFERON®-tuberculosis Gold  


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1 
BACKGROUND AND RATIONALE 
Upstream Bio intends that this clinical protocol and the performance of the study prescribed 
herein will comply with Good Clinical Practice (GCP), local, and national regulations 
governing this clinical study.  
1.1 
Indication 
UPB-101 is a biologic under development for the treatment of subjects with asthma.  
1.2 
Asthma and TSLP 
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that is produced 
in response to pro-inflammatory stimuli and drives allergic inflammatory responses primarily 
through its activity on dendritic (Reche, Soumelis et al. 2001, Soumelis, Reche et al. 2002, 
Gilliet, Soumelis et al. 2003) and mast cells (Allakhverdi, Comeau et al. 2009). The 
production of TSLP by the epithelium or mast cells is induced by stimuli such as allergen 
exposure, viral infection, cigarette smoke, etc (Takai 2012). Thymic stromal lymphopoietin 
signals through a heterodimeric receptor consisting of the interleukin (IL)-7 receptor alpha 
(IL-7Rα) chain and a common γ chain-like receptor (thymic stromal lymphopoietin receptor; 
TSLPR) (Pandey, Ozaki et al. 2000, Park, Martin et al. 2000). UPB-101 is a novel 
recombinant fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting the 
TSLPR. Nonclinical pharmacology studies have demonstrated that UPB-101 binds to human 
and monkey TSLPRs and inhibits TSLPR-mediated signal transduction. Furthermore, UPB-
101 has been observed to inhibit TSLP-stimulated myeloid dendritic cell-mediated 
differentiation of CD4+ T cells into mature T cells in vitro. In sensitized monkeys, UPB-101 
suppressed ascaris extract-induced skin reactions, suggesting UPB-101 inhibits T helper 2 
(Th2) type allergic responses. 
Asthma is a chronic inflammatory disorder of the airways. In susceptible individuals, this 
inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and 
cough. The aetiology of asthma is thought to be multi-factorial, influenced by both genetic 
and environmental mechanisms. The majority of cases arise due to hypersensitivity to 
allergens (atopy). Approximately 300 million people suffer from asthma worldwide, and it is 
anticipated that this number will increase considerably over the next 2 decades (Murdoch and 
Lloyd 2010). The prevalence of asthma in developed countries is >10% of the individual 
populations (Bousquet, Bousquet et al. 2005, Braman 2006). 
Human TSLP expression is reported to be increased in asthmatic airways which correlates 
with disease severity; TSLP protein levels are detectable in the concentrated bronchoalveolar 
lavage fluid of subjects with asthma. A recent study demonstrated the association of a single 
nucleotide polymorphism in the human TSLP locus, 5.7 kB upstream of the transcriptional 
start site, with protection from asthma, atopic asthma and airway hyperresponsiveness. This 
suggested that differential regulation of expression of the TSLP gene might influence 
susceptibility to asthma (He, Hallstrand et al. 2009). Preclinical data additionally support a 
role of TSLP in asthma. These data suggest that targeting TSLP may serve to inhibit multiple 


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biological pathways involved in asthma, including but not limited to those involving IL-4 and 
IL-13. 
Thymic stromal lymphopoietin is considered to play a critical role in asthma (Ying, 
O'Connor et al. 2005, Ying, O'Connor et al. 2008). Levels of both TSLP messenger 
ribonucleic acid and protein were increased in the airways of subjects with asthma, as 
compared with healthy subjects. Further, levels of TSLP messenger ribonucleic acid were 
increased in subjects with severe asthma despite the use of high doses of inhaled or oral 
corticosteroids (Shikotra, Choy et al. 2012). In transgenic mice engineered to express 
increased TSLP in the lungs, the airway inflammatory response was accompanied by an 
increase of immunoglobulin E (IgE) and pulmonary Th2 cytokine levels and airway 
hyperreactivity (Zhou, Comeau et al. 2005). Conversely, the suppression of Th2 cytokines 
and IgE production in the blood and the improvement of respiratory function have been 
observed in TSLPR-knockout mice and in asthma-model mice to which an anti-TSLPR 
antibody was administered (Al-Shami, Spolski et al. 2005, Zhou, Comeau et al. 2005, Shi, 
Leu et al. 2008). Further, several studies have shown a genetic association between a single-
nucleotide polymorphism in the human TSLP gene locus and protection from asthma, atopic 
asthma and airway hyperresponsiveness, suggesting that differential regulation of TSLP 
expression might influence disease susceptibility (Hirota, Takahashi et al. 2011, Ferreira, 
Matheson et al. 2014, Eurostat). 
Tezepelumab is a fully human monoclonal antibody that targets and blocks TSLP. In Phase 2 
and Phase 3 clinical studies, long-term use of tezepelumab for up to 52 weeks significantly 
reduced rates of asthma exacerbations in subjects with uncontrolled asthma receiving 
standard of care treatment. This reduction was independent of baseline inflammatory 
biomarkers, including fractional exhaled nitric oxide (FeNO), blood eosinophil counts, and 
IgE, as well as being independent of allergic status (CPMP 1999, Corren, Parnes et al. 2017, 
Menzies-Gow, Corren et al. 2021). These results indicate that blocking TSLP activity is an 
effective treatment for subjects with asthma. 
While tezepelumab binds to the TSLP ligand, UPB-101, a novel recombinant fully human 
IgG1 monoclonal antibody, targets the TSLPR. Nonclinical pharmacology studies have 
demonstrated that UPB-101, formerly referred to as ASP7266, binds to human and monkey 
TSLPRs and inhibits TSLPR-mediated signal transduction. Furthermore, UPB-101 has been 
observed to inhibit TSLP-stimulated myeloid dendritic cell-mediated differentiation of naive 
CD4+ T cells into mature T cells in vitro. In sensitized monkeys, UPB-101 suppressed 
ascaris extract-induced skin reactions, suggesting UPB-101 inhibits Th2 type allergic 
responses. In multiple preclinical in vitro and in vivo studies, UPB-101 demonstrated 
between 4-fold to 5-fold better potency relative to tezepelumab, when tested side-by-side in 
the same assays. 
1.3 
Unmet Medical Need 
The prevalence of asthma in the general population ranges in the medical literature from 1 to 
18% (Bousquet, Bousquet et al. 2005). Data from the European Union (EU) support a 
prevalence of 8.2% of the adult population and 9.4% of children (Eurostat 2021). Knowledge 


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of the pathophysiological mechanisms, genotypes, and phenotypes as well as therapeutic 
options has significantly increased dramatically since the 1980s. More recently, the 
introduction of biologic drugs for severe asthma has paved the way to a true revolution in the 
field of asthma management, by allowing a precision medicine approach to this chronic 
disease (Menzies-Gow, Corren et al. 2021).  
Asthma affects an estimated 300 million individuals worldwide. It is a serious global health 
problem affecting all age groups, with increasing prevalence in many developing countries, 
rising treatment costs, and a rising burden for patients and the community. Asthma still 
imposes an unacceptable burden on health care systems, and on society through loss of 
productivity in the workplace and, especially for paediatric asthma, disruption to the family. 
Asthma still contributes to many deaths worldwide, including among young people (GINA 
2021a). 
Asthma management aims to achieve good control of symptoms, maintain normal activity 
levels, maintain lung function, and reduce the risk of flare-ups. Treatment generally involves 
inhaled corticosteroids, short-acting beta agonists, and long-acting beta agonists (GINA 
2021b). Inhaled corticosteroids are the most commonly used asthma treatment while short-
acting beta agonists are often used to treat mild intermittent asthma, and long-acting beta 
agonists and oral steroids are considered in more severe persistent asthma cases (Slater, 
Pavord et al. 2016, GINA 2021b). 
In 2003, Xolair (omalizumab) became the first biologic licensed for asthma. As an inhibitor 
of IgE, Xolair targets subjects with allergic asthma. With some overlap in this subject 
population, IL-5 pathway inhibitors Nucala (mepolizumab), Cinqair (reslizumab), and 
Fasenra (benralizumab) target eosinophilic asthma. These products came to market relatively 
recently, gaining United States Food and Drug Administration (US FDA) approvals in 2015, 
2016, and 2017, respectively. Dupixent (dupilumab) was approved in 2018 and is indicated 
to treat either subjects with an eosinophilic phenotype or those with oral corticosteroid-
dependent asthma and targets Il-13 and IL-4. However, these products target severe asthma 
subjects and adoption is limited by high cost and payer access. Finally, the first TSLP 
inhibitor, Tezspire (tezepelumab) gained approval in Dec 2021 for subjects with severe 
asthma.   
Despite the availability of several treatments that have been proven to be effective in most 
subjects, satisfactory asthma control remains an unmet need worldwide (Gruffydd-Jones 
2019, WHO 2021). The burden of poorly controlled asthma is relevant in terms of both direct 
(e.g., health care services, medications) and indirect costs including work absenteeism, 
disability, and psycho-social costs. There is a need not only for more effective therapeutics 
but also for medications with better safety, tolerability, and compliance profiles (Caminati 
and Senna 2019). Drugs that treat all asthmatics irrespective of their phenotype (i.e., high or 
low eosinophil numbers) are particularly in demand.  
Additional information can be found in the Investigator’s Brochure (IB). 


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1.4 
UPB-101 Clinical Summary 
1.4.1 
Completed Clinical Studies 
One clinical study (7266-CL-0001) has been conducted with UPB-101, a first-in-human 
Phase 1a single-dose study in healthy volunteers under an FDA Investigational New Drug 
application.  
Study 7266-CL-0001 was a randomized, subject- and Investigator-blinded, placebo-
controlled, single ascending-dose (SAD) study to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ASP7266 in healthy adult male and 
female subjects. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
1.5 
Study Rationale 
The findings cited in Section 1.2 suggest that targeting TSLP signalling may lead to a 
treatment that could inhibit multiple biologic pathways involved in asthma. One clinical 
study with UPB-101 has been completed in healthy subjects (Study 7266-CL-0001). Overall, 
SADs of UPB-101 from 
 (i.e., 
 
administered IV and SC were considered safe and well-tolerated in healthy male and female 
subjects.  
The current study will assess the safety, tolerability, immunogenicity, PK, and PD of 
UPB-101 in multiple ascending doses administered SC in subjects with asthma. Results will 
inform the future clinical development of UPB-101. 
1.6 
Rationale of Study Design 
The primary objective of this study is to evaluate the safety and tolerability of UPB-101 and 
thereby understand the clinical profile of UPB-101 to guide further clinical development as a 
treatment for asthma.  


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A placebo-controlled, double-blinded (Sponsor unblinded) design has been chosen to limit 
the occurrence of conscious and unconscious bias in the conduct and interpretation of the 
results of this clinical study. Knowledge of treatment assignment could influence recruitment 
and allocation of subjects as well as safety and efficacy assessments. It is considered the 
optimal approach according to International Council for Harmonisation (ICH) E9 “Statistical 
principles in clinical studies” (ICH E9 1998). 
Multiple dosing allows for assessment of UPB-101 at steady state, while the testing of 
ascending doses (
 mg) along with the option to assess multiple dosing intervals will 
help establish the optimal dose and dosing frequency (based on safety, tolerability, 
immunogenicity, PK, and PD) to use in Phase 2 studies.  
Safety, tolerability, immunogenicity, PK, and PD assessments will be conducted at specified 
intervals during the study keeping in mind t1/2 and time to maximum observed concentration 
(tmax). 
The use of placebo as control is considered the most reliable method to minimize subject and 
Investigator bias according to ICH E10 guidelines (ICH E10 2001) adopted by the 
Committee for Proprietary Medicinal Products (CPMP 1999) and the FDA. The use of 
placebo is recommended by the European Medicines Agency (EMA 2001) regulatory 
guidance in the design of dose-finding studies for moderate -to-severe asthma (EMA 2015) 
and this study will enrol only mild-to-moderate asthmatics. Additionally, during the study 
subjects are permitted to increase their asthma medication if their medical condition 
deteriorates.  
1.7 
Rationale of Dose Regimen and Duration of Treatment 
In the non-clinical 26-week repeat dose toxicity study in cynomolgus monkeys, the no 
observed adverse effect level (NOAEL) was determined as 
 mg/kg for both male and 
female monkeys. The human equivalent dose (HED) for this NOAEL level is 
 mg/kg or 
a dose of 
 mg, assuming a 70 kg human (HED calculation according to guideline (FDA 
2005)). The highest dose of 
mg to be used in this study is 
-fold lower than the HED 
NOAEL dose determined in non-clinical toxicity studies. 
UPB-101 has been administered as a single IV dose from  mg to 
 mg (
 
 mg/kg; assuming a 70 kg human) or a single SC dose of 
 mg (  mg/kg; assuming 
a 70 kg human) to healthy male and female subjects and is considered safe and well-tolerated 
(Study 7266-CL-0001). PK analysis found that area under the concentration-time curve from 
the time of dosing extrapolated to time infinity (AUCinf) and Cmax in that study increased 
dose proportionally. At the highest dose tested (
 mg/kg), Cmax and AUCinf after a single IV 
administration were 
 µg/mL and 
 days·µg/mL, respectively. Bioavailability after SC 
administration was 70%. SC dosing was chosen for further development since this has 
significant benefits including potential self-administration. 
PK modelling was performed based on the IV and SC data from Study 7266CL-0001. A 
two--compartment linear PK model was fitted to the mean data after single SC administration 


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of  mg/kg UPB-101 (Study 7266-CL-000). This PK model was subsequently used to predict 
exposure to UPB-101 after repeated SC administration at doses ranging from 
 mg and 
dosing intervals ranging from 
 to 
. Predictions for repeated administration of 
UPB-101 assume that the PK is both dose- and time-independent.  
Single Dose 
Part A of the proposed study will explore SC doses in the 
 mg range. Table 1 lists the 
model-projected exposures following a single 
 mg SC injection in comparison to the 
maximal exposure that was found safe and well-tolerated in the SAD study 
(Study 7266-CL-000). The predicted maximal Cmax and AUCinf for a single injection in this 
study (at the highest dose of 
mg SC) are 
-fold and 
-fold lower, respectively, when 
compared with the observed Cmax and AUCinf following administration of 
 mg/kg IV in 
Study 7266-CL-0001, a dose that was found to be safe and well-tolerated. 
These data provide the rationale for the parallel cohort design. For all cohorts, the projected 
single dose exposures are lower than the exposures that were found to be safe and well 
tolerated in Study 7266-CL-0001. 
Table 1 
Predicted Mean PK parameters After Single SC Administration UPB-101 
Compared to the Maximal IV Dose of Completed Study 7266-CL-0001 
 
Single Dose 
Fraction of Maximal 
SAD Exposure 
Route 
Dose 
(mg) 
Dose 
(mg/kg) 
Cmax 
(µg/mL) 
AUCinf 
(days·µg/
mL) 
Cmax IV/ 
Cmax SC 
 
AUCinf IV/ 
AUCinf SC 
 
SC 
 
 
 
 
  
  
SC 
 
 
 
 
  
  
SC 
 
 
 
 
 
 
SC 
 
 
 
 
 
  
IV 
 
 
 
 
 
 
AUCinf=area under the concentration-time curve from the time of dosing extrapolated to time infinity; 
Cmax=maximum observed concentration; IV=intravenous; PK=pharmacokinetic; SAD=single ascending dose; 
SC=subcutaneous. 
Local Tolerability 
All subjects enrolled in this study will receive 
 mg or 
 mg SC injections at each dosing 
visit depending upon to which cohort they are assigned. For example, subjects assigned to 
Cohort 1 (
 mg 
) will received two 
 mg SC injections at 2 separate injection sites at 
each dosing visit. The SC dose administered in the SAD study was  mg/kg (
 mg) and 
was well-tolerated; no injection site reactions were reported. Therefore, no significant local 
skin reactions are anticipated in the current study.  


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Multiple Dose 
The PK model described above was used to simulate multiple dose PK for the doses and 
dosing intervals to be administered in this study. Predicted PK parameters and predicted 
mean PK profiles after repeated SC administration of UPB-101 are shown in Table 2 and 
Figure 1, respectively. There is minimal accumulation after repeated administration, with 
close to steady state levels reached after 3 injection (for 
 regimen) or 2 injections (for 
 and 
 regimens). The predicted Cmax and area under the concentration-time curve 
for one dosing interval (AUCtau) in this study (at the highest dose of 
 mg SC) are 
-fold 
and 
-fold lower, respectively, when compared with the observed Cmax and AUCinf 
following administration of 
mg/kg IV in Study 7266-CL-0001, a dose that was found to 
be safe and well- tolerated. 
Table 2 
Predicted Serum PK Parameters After Repeated SC Administration of 
UPB-101 
  
Dose 
  
Frequency 
Number of 
doses 
Multiple SC dose  
Interval 
Cmax 
(µg/mL) 
AUCtau 
(days·µg/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
AUCtau=area under the concentration-time curve for one dosing interval; Cmax=maximum observed 
concentration; D=day; PK=pharmacokinetic; 
; 
; 
 
; SC=subcutaneous. 




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PK and PD data obtained from Part A, including the long Observation Period following the 
final dose, will supply the Sponsor with information required for modelling doses and dosing 
intervals in preparation for Phase 2 development of UPB-101.  
Part B, the optional adaptive design portion of the study, will afford the Sponsor an 
opportunity to fill any gaps in data that may remain following completion of Part A. For 
example, Part B will allow, as necessary, exploration of lower doses (e.g., 
 mg) and longer 
(e.g., 
 and/or 
) dose intervals, as well as possible repetition of cohorts already 
concluded in Part A in order to enhance existing data. Subjects enrolled in Part B may 
receive doses 
 mg at dosing intervals of 
 x 3 doses, 
 x 2 doses, 
 x 2 
doses, and/or 
 x 1 dose. Thus, the regimens selected for Part B will not exceed the 
exposures (i.e., doses and/or dosing intervals) included in Part A.  
Since the Sponsor will be unblinded to the available safety, PK, and PD data accumulated 
during the study, the decision regarding doses and dosing intervals for subjects enrolled in 
Part B will be made while Part A is still ongoing. Therefore, Cohort 4 of Part B may begin 
without delay.  
Each Dosing Period in Parts A and B is followed by an Observation Period to allow a full 
evaluation of safety, tolerability, immunogenicity, PK, PD, physician and subject global 
asthma status, and lung function.  
The doses and dose regimens to be assessed in this study will inform the development of 
UPB-101 in Phase 2 and beyond.  
1.8 
Benefits and Risks Assessment 
1.8.1 
Patient Population 
Asthma is characterized by a history of respiratory symptoms such as wheezing, shortness of 
breath, chest tightness, cough that can fluctuate in intensity over time and variable limitations 
in expiratory airflow. In 2019, asthma affected approximately 262 million people worldwide. 
1.8.2 
Current Therapies 
Five to 10% of patients with severe disease require high-dose inhaled corticosteroids and 
other medications to control their disease; others remain uncontrolled despite such therapies. 
In these patients, the inability to control their asthma, resulting in aggravated asthmatic 
symptoms, greatly reduces their quality of life, and increases healthcare costs. 
1.8.3 
Brief Summary of Product Data 
UPB-101 (formerly referred to as ASP7266) is a novel recombinant fully human IgG1 
monoclonal antibody targeting the TSLPR. 
Non-clinical pharmacology studies have demonstrated that UPB-101 binds to human and 
monkey TSLPRs and inhibits TSLPR-mediated signal transduction. UPB-101 has been 


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observed to inhibit TSLP-stimulated myeloid dendritic cell-mediated differentiation of naive 
CD4+ T cells into mature T cells in vitro. In sensitized monkeys, UPB-101 suppressed 
ascaris extract-induced skin reactions, suggesting that UPB-101 inhibits Th2 type allergic 
responses. 
The production of TSLP by the epithelium or mast cells is induced by stimuli such as 
allergens, bacteria, virus, chemical irritants, or physical trauma. TSLP is considered to be a 
“master switch” for allergy-induced inflammation. Targeting TSLP signalling may lead to a 
treatment that could inhibit multiple biologic pathways involved in asthma. Tezspire®, 
recently approved by the FDA for moderate-to-severe asthma, has a similar mechanism of 
action.  
1.8.4 
Study Rationale 
This study will assess the safety, tolerability, immunogenicity, PK, and PD of UPB-101 in 
multiple ascending doses administered subcutaneously in subjects with asthma. Results will 
inform the future clinical development of UPB-101. 
1.8.5 
Rationale for Dose Selection for Proposed Study 
In a non-clinical 26-week repeat dose toxicity study in cynomolgus monkeys, the NOAEL 
was determined as 
 mg/kg for both male and female monkeys. The HED for this NOAEL 
level is 
 mg/kg or a dose of 
 mg, assuming a 70 kg human (HED calculation 
according to guidelines guideline). The highest single dose of 
 mg that is to be used in 
this study is 
-fold lower than the HED NOAEL dose determined in non-clinical toxicity 
studies. 
1.8.6 
Minimization of Risks in Study 
Based on available non-clinical data, as well as known adverse effects of currently available 
biologic disease-modifying asthma agents, several potential risks have been identified for 
which mitigation actions have been developed to minimize the relevant risks in clinical 
studies of UPB-101. In addition, AE monitoring and other routine clinical and laboratory 
monitoring (including laboratory safety such as haematology and biochemistry, vital signs, 
physical examination, and ECGs) will be conducted. 
To ensure subjects’ safety, the protocol outlines the dose escalation process and dose 
stopping rules to be followed. Subjects will be followed for at least 12 weeks in consideration 
of the half-life of UPB-101 and to ensure adequate follow-up for immunogenicity 
monitoring. Subjects who have persistent anti-UPB-101 antibodies will continue to be 
evaluated until the level of these antibodies show evidence of declining, are no longer 
detectable, and/or are deemed to be of no clinical relevance. Based on the target organs of 
toxicity identified in the toxicology studies, the risk minimization actions that will be 
included in clinical studies are presented in Table 3. 


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Table 3 Risk Minimization Actions Based on Non-clinical Toxicology Studies 
Target Organs 
Theoretical/Potential Risks 
Risk Minimization Action 
Renal/Urinary 
System 
Occult blood observed in urine of 1 animal at 
mg/kg in the 4-week repeat dose toxicity study. 
Results were not reproduced in the 13- or 26-week 
repeat dose toxicity study at the same dose level. 
Measurement of standard blood 
biochemistry and urinalysis during 
the Screening Period to exclude 
subjects with abnormal renal 
function and during the Dosing and 
Observation Periods to assure 
subject safety. Positive results from 
urinalysis will be confirmed with a 
microscopic examination. 
Immunologic 
Response 
Perivascular inflammatory cell infiltration in several 
organs as well as inflammatory cell infiltration in the 
alveoli and bronchioles associated with changes in 
blood chemistry including high globulin and 
γ-globulin ratio. 
Immune complex deposition in tissues was not 
demonstrable. 
Standard safety monitoring and 
12 weeks of immunogenicity follow-
up. 
Immunologic 
Response 
Allergic reactions. 
Close monitoring for 4 h after the 
injection including assessment of 
vital signs (body temperature, pulse, 
respiratory rate, and blood pressure).  
Medical personnel and resuscitation 
equipment immediately available on 
site.  
Immunologic 
Response 
Immune complex disease. 
Assessments including medical 
history, physical examinations, and 
safety monitoring will be conducted. 
 
1.8.7 
Benefit/Risk Conclusion 
This study is primarily a patient safety and tolerability study to inform further clinical 
development, and whilst those asthma patients who receive UPB-101 could derive benefit, 
this is not the main objective of the study. Subjects will continue to administer their usual 
stable, non-biologic asthma medication regimen during participation in the study.  
The risks of participation are mainly those associated with possible side effects to UPB-101, 
although there may also be some discomfort from collection of blood samples and other 
study procedures. The study will be conducted at Medicines and Healthcare products 
Regulatory Agency (MHRA)-accredited Phase 1 facilities and procedures/interventions will 
be performed by qualified and trained professionals. Subjects will undergo Coronavirus 
disease 2019 (COVID-19) testing as per each site’s protocol. 
One previous human clinical study has been completed with UPB-101, in healthy volunteers, 
and in this study single increasing doses from 
 mg/kg body weight administered 
intravenously, or  mg/kg body weight administered subcutaneously, were considered safe 


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and well-tolerated. As detailed above, the Sponsor has identified risk minimization actions 
based upon non-clinical toxicology studies with UPB-101. 
The Sponsor believes that the potential risks to subjects are proportionate for the proposed 
study, and that these will be addressed through risk minimization activities and through the 
conduct of the study at three sites with significant Phase 1 asthma clinical trial experience. 
 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective 
The primary objective in this study is the assessment of the safety and tolerability of 
UPB-101 when administered as multiple ascending doses.  
Primary Endpoints 
The primary endpoints are AEs, SAEs, physical examinations, clinical laboratory 
assessments, vital signs, and electrocardiograms (ECGs). Subject withdrawals, early 
terminations, and dosing compliance are also assessed. Data collected from baseline through 
Week 24 are included. These endpoints are evaluated in the Safety Population (defined in 
Section 9.3).   
Secondary Objectives 
The secondary objectives are the assessment of the immunogenicity and PK of multiple 
ascending doses of UPB-101.  
Secondary Endpoints 
The secondary endpoints include UPB-101 anti-drug antibodies (ADAs) and serum UPB-101 
concentrations and analyses including Cmax, tmax, AUCtau. If appropriate, AUCinf, t1/2, apparent 
total body clearance after dosing (CL/F), and apparent volume of distribution during the 
terminal elimination phase after dosing (Vz/F), all after the first dose, will be analysed as 
well. These endpoints are assessed from baseline through Week 24 in the PK Population 
(defined in Section 9.3). 
Exploratory Objectives 
The exploratory objectives in this study include the assessments of the: 
1. Extended 32-week safety and tolerability of UPB-101 when administered in multiple 
ascending doses. 
2. Extended 32-week immunogenicity and PK of UPB-101 when administered in 
multiple ascending doses. 
3. Pharmacodynamic effect of UPB-101 on biomarkers related to asthma and/or TSLP-
related biomarkers. 
4. Pharmacodynamic effect of UPB-101 on clinician and subject impressions of overall 
asthma activity. 
5. Pharmacodynamic effect of UBP-101 on lung function 


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Exploratory Endpoints 
The exploratory endpoints include: 
1. AEs, SAEs, pregnancy tests, and changes from baseline in physical examinations, 
clinical laboratory assessments, vital signs, and ECGs. Subject withdrawals, early 
termination, and dosing compliance are also assessed. Data collected from baseline 
through Week 32 are included. These endpoints are evaluated in the Safety 
Population (defined in Section 9.3). 
2. UPB-101 ADAs, presence of neutralizing antibodies (NAbs) and serum UPB-101 
concentrations and analyses including Cmax, tmax, AUCtau. Data collected from 
baseline through Week 32 in the PK Population (defined in Section 9.3) are included. 
3. FeNO and blood eosinophil numbers from baseline through Weeks 24 and 32. Total 
IgE; IL-5, IL-13, IL-17A, interferon gamma (IFN λ), IFN λ-induced protein 10 
(IP-10), TSLP, eotaxin-3, tryptase, carboxypeptidase, thymus activation regulated 
chemokine (TARC), C-reactive protein (CRP) concentrations; and flow cytometric 
assessments of phosphorylated signal transducer and activator of transcription 
(pSTAT) and receptor occupancy will be evaluated from baseline through Weeks 24 
and 32. These PD markers are evaluated in the PD Population (defined in 
Section 9.3). 
4. Clinician Global Impression of Change (CGI-C) and Subject Asthma Control 
Questionnaire (ACQ-7) from baseline through Weeks 24 and 32. These PD markers 
are evaluated in the PD Population (defined in Section 9.3). 
5. Forced expiratory volume in 1 second (FEV1) from baseline through Weeks 24 and 
32. These PD markers are evaluated in the PD Population (defined in Section 9.3). 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a 2-part Phase 1, randomized, double-blind (Investigator and Subject blinded; 
Sponsor unblinded), placebo-controlled, multiple ascending -dose study to assess the safety, 
tolerability, immunogenicity, PK, and PD of UPB-101 administered SC to approximately 
40 subjects with asthma. The study is expected to last from June 2022 to October 2023. 
 
3.1.1 
Study Design: Cohorts 
The study will be conducted in 3-5 sites in the United Kingdom.  
The study consists of Part A and Part B. Part A includes 3 cohorts with pre-set dosing 
regimens. Part B includes up to 2 optional adaptive design cohorts whose doses and dosing 
intervals will be decided based upon the safety, PK, and PD results from Part A available to 
the unblinded Sponsor. The regimens selected for Part B will not exceed the exposures (i.e., 
doses and/or dosing intervals) included in Part A.  
The study will consist of 3 to 5 cohorts: 3 cohorts in Part A and up to 2 optional cohorts in 
Part B. Eight subjects will be randomized per cohort (6 active, 2 placebo). A total of 
approximately 24 to 40 subjects will be enrolled in the study with 24 subjects in Part A and 
up to 16 in Part B. 
Part A 
Subjects assigned to Part A will receive one of the following regimens: 
Cohort 1 – 3 SC doses of 
 mg at 
, 
Cohort 2 – 3 SC doses of 
 mg at 
, and 
Cohort 3 – 2 SC doses of 
 mg at 
. 
Part B 
Part B will consist of up to 2 treatment cohorts. The dose and dosing intervals to be 
administered to subjects enrolled in these cohorts will be determined by the Sponsor based 
upon the available unblinded safety, PK, and PD data acquired in Part A. The decision 
regarding doses and dosing intervals for subjects enrolled in Part B will be made while Part 
A is still ongoing to allow Cohort 4 in Part B to begin without delay.  
Safety Review Committee (SRC) meetings will be convened before administration of the 
third dose in Cohorts 1 and 2 and before the third dose in Cohorts 4 and/or 5 if a 
 
regimen is selected for those cohorts. Details regarding the SRC and their responsibilities are 
provided in Section 5.8. 
3.1.2 
Study Design: Periods 
The study will include 4 periods: Pre-screening, Screening, Dosing, and Observation.  


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Pre-screening 
Sites may opt to utilize a Pre-screening Informed Consent Form (ICF) to enable performance 
of a complete blood count (for the absolute eosinophil numbers) in consenting subjects while 
each subject considers consent for the full study. Pre-screening may occur within 90 days of 
Visit 1. 
Screening Period  
During the Screening Period (Day -21 to Day -1), subjects who have given written informed 
consent will be assigned a subject number, undergo Screening assessments which include, 
among other procedures, safety assessments. Eligible subjects will be allocated to cohorts 
and then be randomly allocated to treatment with UPB-101 or placebo in a 3:1 ratio, 
respectively. 
On the afternoon before the first dosing (Day -1), subjects will be admitted to the site for 
review of their Day -5 assessments and final Screening procedures. Subjects who continue to 
meet the study enrolment criteria will continue to the Day 1 Visit. 
Dosing Period 
On Day 1, the first day of the Dosing Period, subjects will remain housed at the site and will 
undergo baseline safety, PD, PK and antigenicity assessments. Following completion of 
those procedures, subjects who remain eligible for enrolment will be randomized and 
administered the first dose of the study drug. Dosed subjects will remain at the site for a 
minimum of 4 hours post-dose to assure subject safety. Study drug will be administered SC 
as outlined in Table 12. 
During the Dosing Period subjects will undergo frequent safety, PD, PK and antigenicity 
monitoring as well as study drug dosing according to the schedule listed in Table 4 through 
Table 9. 
Subjects will be re-admitted to the sites the afternoon before each dosing to better assure 
attendance, study rule compliance, and adherence to the dosing day timelines. Several 
procedures will be performed upon admission. Food and exercise restrictions begin the 
evening after admission in advance of the assessments planned for the following day. The 
following morning between 6 AM and 10 AM, prior to dosing, subjects will undergo safety, 
PD, PK and antigenicity assessments. Once these procedures have been completed, subjects 
will receive their assigned study drug dose. Dosed subjects will remain at the site for a 
minimum of 4 hours post-dose to assure subject safety. 
Observation Period 
The Observation Period begins after each subject has received their final study drug 
administration. During this period subjects will undergo periodic safety, PD, PK and 
antigenicity monitoring according to the schedule listed in Table 6 through Table 8. Subjects 
enrolled in cohorts with 
 dosing intervals will be observed for 6 months while 
subjects enrolled in cohorts with 
 dosing intervals will be observed for 5 months. 
Subjects enrolled in cohort 4 (and receiving 
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3.2 
Study Activities 
One day prior to visits that include a spirometric and/or clinical chemistry assessments, the 
site will contact the subject to remind them of the following study rules: 
• To withhold all asthma medications the day of the study visit, or for at least 6 hours 
prior to start of study assessments.  
• To fast (except for water) and refrain from vigorous exercise for at least 9 hours 
before a visit that includes a clinical chemistry assessment. 
• Refrain from ingestion of leafy vegetables such as lettuce, spinach, kale and beetroot 
for 9 hours before visits. 
At the start of each study visit, prior to any study procedures being performed, site personnel 
must confirm the subject withheld all asthma medications, including short-acting and -long-
acting bronchodilators, for at least 6 hours before coming into the site, by confirming the last 
time of dosing for all asthma medication. Subjects who inadvertently took asthma medication 
within 6 hours of the start of study procedures must have their clinic visit delayed to later in 
the 6 AM to 10 AM window or rescheduled within the specified visit window. 
The preferred order of assessments at all visits will be ECGs, vital signs, blood draws, 
FeNO, and lastly spirometry as appropriate for the study visit. Blood draws should 
ideally be performed in the morning to minimise diurnal variation in the level of 
eosinophils. 
For all study visits, all PK and PD assessments (with the exception of spirometry) will be 
conducted between 6 AM and 10 AM to minimize the impact of diurnal variations on 
biomarker assessments. The site should make every effort to assess subjects at approximately 
the same time of day throughout the study and to dose subjects during the morning hours.   
3.3 
Schedule of Events 
The Schedule of Screening Assessments for all cohorts is provided in Table 4. Assessments 
described in the Schedule of Events may be repeated during the study for safety reasons or if 
the assessment was deemed invalid (e.g., haemolysed blood sample). 
Pre-screening  
Sites may opt to utilize a pre-screening consent form to enable complete blood testing 
including eosinophil numbers, for consenting potential subjects, while they consider the ICF 
of the full study. Pre-screen may occur within 90 days of Screening Visit 1.  
Screening Period (Visits 1, 2, and 3) 
Screening Period consists of three visits. Prior to full execution of the ICF, no study-specific 
Screening procedures may be performed. However, once informed consent procedures have 
been completed, Visit 1 procedures may be initiated. Visit 1 will be performed no earlier than 












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The legend and footnotes for Table 4 through Table 8 are listed below.  
ACQ-7=Asthma Control Questionnaire; Ad=admission; ADA=anti-drug antibody; AE=adverse event; β-HCG=beta human chorionic gonadotrophin; BMI=body 
mass index; CGI-C=Clinician Global Impression of Change; COVID-19=Coronavirus disease 2019; D=day; Di=discharge; ECG=electrocardiogram; 
FeNO=fractional exhaled nitric oxide; FSH=follicle stimulating hormone; IFN λ=interferon gamma; IgE=immunoglobulin E; IL=interleukin; IP-10= interferon 
gamma-induced protein 10; NAbs=neutralizing antibodies; PK=pharmacokinetic; SOP=Standard Operating Procedures; TARC=thymus and activation-regulated 
chemokine; TB=tuberculosis; TSLP=thymic stromal lymphopoietin; 
; W=week. 
a 
In women of childbearing potential at Visit 2 and at the Final Visit a serum β-HCG pregnancy test will be performed. At other visits a urinary pregnancy test 
will be performed. Follicle stimulating hormone will be assayed in women who on Visit 1 fit the post-menopausal criterion included in Section 4.8.4. 
b 
A symptom-driven physical examination will be performed as needed based on reported signs and symptoms. 
c 
Vital signs will be body temperature, pulse, respiratory rate, and blood pressure. See Table 9 for timing of assessments on dosing days. 
d 
ECG assessments will be performed prior to any blood draws, FeNO measurements, and/or study drug administration. See Table 9 for timing of assessments 
on dosing days. All ECGs are performed in triplicate. 
e 
Spirometry on Screening Visits 1 and 2 will be conducted at 60 minutes and 30 minutes prior to bronchodilator administration and at 30 minutes post-
bronchodilator. At Visit 4 (Day 1) and at subsequent dosing visits, spirometry will be conducted approximately 60 minutes and 30 minutes prior to dosing (See 
Table 8). At non-dosing visits where spirometry is conducted, 2 assessments will be conducted 30 minutes apart; assessments should be conducted at 
approximately the same time as on dosing days. No post-bronchodilator spirometry will be performed.  
f 
Blood samples will be collected for assessment of haematology including eosinophils. On dosing days, samples will be collected pre-dose. Coagulation 
studies will be performed only at Visit 1 and the Final Visit.  
g 
On dosing visits, chemistry and urinalysis laboratory tests will be collected pre-dose. 
h 
On days where Spirometry is not performed, ACQ-7 question 7 will be answered based on the FEV1 value from the first measurement on the following 
morning 
i 
Blood sampling for PK on dosing days will be collected pre-dose.  
j 
Plasma levels of IL-5, IL-13, IFN λ, IL-17A, eotaxin-3, IP-10, and TSLP will be measured. Tryptase, carboxypeptidase, and TARC will also be measured.  
k 
Subjects will be contacted by site personnel the day before each visit that includes a spirometric assessment to remind subjects of their visit and study rules. 
Subjects will also be contacted the day before their admission to the site.  
l 
Flow cytometry samples will be collected and either analysed or frozen. The decision to assay the frozen samples will be based on previous results. 
m 
At Visit 5 (D2), Visit 6 (D4), Visit 16 (D86), Visit 17 (D88), Visit 18 (D92) and Visit 19 (D99) blood samples for haematology including eosinophils will 
only be collected for participants enrolled in Cohort 4.  
n 
At Visit 5 (D2), Visit 6 (D4), Visit 16 (D86), Visit 17 (D88), Visit 18 (D92) and Visit 19 (D99) FeNO will be performed only for participants enrolled in 
Cohort 4. 
o 
For subjects enrolled in Cohort 4, Visit 15 (WK12) will be handled as a non-dosing visit. All Visit 15 (WK 12) assessments/activities will be performed as 
they would on a non-dosing visit. Activities directly related to dose administration and post-dose observation (admission, study drug administration, 4-hour 
observation, assessment of injection site reactions and discharge) will NOT be performed.    
 
 


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The timing of vital sign, ECG, and spirometric assessments on dosing days is presented in 
Table 9. 
Table 9 
Timed Assessments at Each Dosing Visit 
Clinical Variable 
Pre-dose 
Post-dose 
-60 
minutes 
(±15 
minutes) 
-30 
minutes 
(±15 
minutes)  
30 
minutes 
(±15 
minutes) 
1 hour 
(±15 
minutes) 
2 hours 
(±30 
minutes) 
4 hours 
(±30 
minutes) 
Vital signs 
X  
 
X 
X 
 
X 
Electrocardiogram  
X  
 
 
 
X 
 
Spirometry 
X 
X 
X a 
 
 
 
a Spirometry will be obtained 30 minutes after the last injection is administered and may also be conducted at 
subsequent dosing visits if paradoxical bronchospasm is suspected. 
3.4 
Pre-Screening  
Sites are encouraged to pre-screen subjects prior to consenting. Sites may opt to utilize a 
pre-screening consent form to enable complete blood testing including eosinophil numbers, 
for consenting potential subjects while they consider the ICF for the full study. Pre-screening 
may occur within 90 days before Screening Visit 1. 
3.5 
Screening Period 
The goal of the Screening Period is to assess the eligibility of subjects, based on the criteria 
defined in Section 4. The assessments to be conducted on all cohorts during the Screening 
Period (Day -21 to Day -1) are found in Table 4. 
Procedures to be performed during Visit 1, the first visit in the Screening Period, must not 
begin until completion of all informed consent procedures and the subject has received a 
fully executed copy of the ICF.  
Subjects who continue to meet the enrolment criteria following review of all the results from 
Visit 1 will be invited to Visit 2. Visit 2 will take place on approximately Day -5 and is 
intended to assure that subjects deemed eligible after Visit 1 remain eligible and may be 
invited to continue to Visit 3 when limited safety assessments will be performed and subjects 
will be acclimated to the inpatient area.   
3.6 
Dosing Period 
Subjects who complete Screening Visits 1 through 3 and continue to meet the study 
enrolment criteria may proceed to Day 1. Table 5 During the Dosing Period, enrolled 
subjects will receive study drug according to the cohort to which they are assigned and 
undergo safety, immunogenicity, PK and PD assessments.  


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3.6.1 
Cohorts with 
 Dosing Intervals 
The Dosing Period of cohorts with
 dosing intervals (e.g., Cohorts 1 and 2 in Part A) 
will last  weeks (Days 
). Subjects assigned to this cohort will receive 3 doses of study 
drug at 
 intervals. The assessments to be conducted on subjects in these cohorts 
during the Dosing Period and their timing are listed in Table 5 and Table 6. 
3.6.2 
Cohorts with 
 Dosing Intervals 
While Part A does not include any cohorts with 
 dosing intervals, Part B might. The 
Dosing Period of cohorts with 
 dosing intervals will last  weeks (Days 
). Subjects 
assigned to such a cohort will receive 2 doses of study drug, -week apart. The assessments 
to be conducted on subjects in these cohorts during the Dosing Period and their timing are 
listed in Table 5 and Table 7. 
3.6.3 
Cohorts with 
 Dosing Intervals 
The Dosing Period for cohorts with 
(e.g., Cohort 3 in Part A) lasts 
 weeks (Days 
). Subjects assigned to this cohort will receive 2 doses of study drug, 
 weeks apart. The 
assessments to be conducted on subjects in these cohorts during the Dosing Period and their 
timing are listed in Table 5 and Table 8.  
The 
 cohorts may include either one or two dosing visits. In cohorts where only 1 dose 
is administered (such as cohort 4), the participants will undergo the same visits and 
procedures as those receiving 2 doses, but they will not be admitted to the unit on Day 
. 
The assessments to be conducted on subjects in these cohorts during the Dosing Period and 
their timing are listed in Table 5 and Table 8. 
3.7 
Observation Period 
Throughout the Observation Period, subjects will undergo safety, PD, PK, and 
immunogenicity assessments. No study drug will be administered during this period. 
Subjects assigned to cohorts receiving study drug 
 will be observed for 
6 months. Subjects assigned to cohort 3 (
 dosing intervals) will be observed for 
5 months. Subjects assigned to cohort 4 (
 dose) will be observed for 8 months.   
3.7.1 
Cohorts with 
 Dosing Intervals 
The Observation Period assessments to be conducted in cohorts with 
 dosing intervals 
(e.g., Cohorts1 and 2 in Part A) and their timing are depicted in Table 6. 
3.7.2 
Cohorts with 
 Dosing Intervals 
The Observation Period assessments to be conducted in cohorts with 
 dosing intervals 
and their timing are depicted in Table 7. 


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3.7.3 
Cohorts with 
 Dosing Intervals 
The Observation Period assessments to be conducted in cohorts with 
 dosing intervals 
(or receiving a single dose such as in cohort 4) and their timing are depicted in Table 8. 
3.8 
Unscheduled Visit and Early Termination Visit 
Repeat assessments, if needed, will be captured as unscheduled visits if repeated on a 
separate day. 
Early Termination Visits will be captured as unscheduled visits. The assessments conducted 
at the Early Termination Visit are the same as those conducted at the Final Visit of the 
Observation Period. 
3.9 
Procedures for Treatment Discontinuation and Study Withdrawal 
Subjects who decide to discontinue study drug treatment or whose study drug is stopped by 
an Investigator will be encouraged to continue in the study as usual, including completion of 
the Observation Period, in order to collect full safety, PK, immunogenicity, and PD data. The 
date and reason for discontinuation of the study drug should be recorded in the electronic 
case report form (eCRF). 
Subjects who received at least 1 dose of the study drug and withdraw at any point from the 
study completely should be asked to permit performance of an Early Termination Visit (see 
Section 3.8) in order to collect final safety, PK, immunogenicity and PD data. The date and 
reason for withdrawal from the study should be recorded in the eCRF. In addition, every 
effort should be made to obtain the subject’s permission for collection of samples for PK and 
immunogenicity assessment 12 weeks after the last dose of study drug. 
If a subject received all their expected study drug treatments but missed one or more 
Observation Period visits, the subject should resume study activities in the Observation 
Period based on the number of days that have elapsed following their last dose received. For 
example, if a subject is 14 days beyond their last dose, their next visit will be the first visit 
that occurs 14 days after their last dose.  
If a subject withdraws from the study after randomisation but before receiving the first dose 
of study drug, then additional subjects may be enrolled to provide a sufficient number of 
subjects per cohort to address the study objectives (Section 4.10).  
Subjects who contract COVID-19 after receiving the first dose of study drug should inform 
the study site and continue in the study as far as possible. When isolation or hospitalization is 
required and this coincides with a dosing visit, the Blinded Medical Monitor and the site 
Investigator will decide whether the dosing window should be extended or to stop future 
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3.10 Completion of Study 
The Investigator will document the completion or the reason for a subject’s early withdrawal 
from the study in the eCRF. The following categories should be used to describe these events 
in the eCRF: 
• Subject discretion (document reason). 
• Investigator considers it to be in the best interest of the subject. 
• AEs. 
• Administrative reasons (e.g., early termination of the study). 
• Subject lost-to-follow-up. 
• Major protocol deviation. 
• Death. 
• Completion of the study. 
• Protocol-specified criteria (Section 4.9). 


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4 
STUDY POPULATION SELECTION AND WITHDRAWAL 
CRITERIA 
Approximately 24 to 40 subjects with mild-to-moderate asthma will be randomized. Each 
subject must meet the following criteria to be enrolled in this study. 
4.1 
Inclusion Criteria 
1. Subject has signed, dated, and received a copy of the Independent Ethics Committee 
(IEC)-approved written ICF. 
2. Subject is aged 18 to 60 years. 
3. Subject has physician-diagnosed asthma. 
4. Subject has a body mass index (BMI) between 18 and 35 kg/m2 at Visit 1. 
5. Subject has ≥200 eosinophils cells/µL OR FeNO >25 with ≥150 eosinophils cells/µL 
at Visit 1 or 2 AND ≥150 eosinophils cells/µL at the other visit.  
6. Subject is: 
a. a female subject with reproductive potential who has a negative serum pregnancy 
test (β-HCG) during the Screening Period, is not breastfeeding, does not plan to 
become pregnant during the study, and agrees to use a highly effective birth 
control method when engaging in sexual activity with a male partner from the 
first dose of study drug until 120 days after the last dose of study drug or the Final 
Visit, whichever is later; OR 
b. a female subject either surgically sterile (i.e., post bilateral oophorectomy, 
hysterectomy, or tubal ligation) or naturally sterile (>12 consecutive months 
without menses with an elevated follicle stimulating hormone (FSH) during the 
Screening Period); OR 
c. a male subject who is not sexually active; OR 
d. a male subject who is sexually active agrees to use a condom during the study 
from the first dose of study drug until 120 days after the last dose of study drug or 
the Final Visit, whichever is later. 
AND 
whose partner has childbearing potential must either be sterile (vasectomy with 
history of a negative sperm count at least 90 days following the procedure) or 
their partner must agree to use a highly effective birth control method from the 
first dose of study drug until 120 days after the last dose of study drug or the Final 
Visit, whichever is later. 
7. Female or male subject agrees not to donate eggs or sperm, respectively, for a period 
of 120 days after the last dose of study drug. 
8. Subject meets the Spirometry Performance Criteria: 
a. Pre-salbutamol/albuterol (hereafter referred to as salbutamol) FEV1 ≥65% 
predicted normal value at Visit 1. 
b. Perform acceptable spirometry (i.e., meet American Thoracic Society/European 
Respiratory Society acceptability criteria) at Visits 1 and 2. 
c. Perform technically acceptable spirometry meeting repeatability criteria for FEV1 
during at least one (1) of the pre-bronchodilator assessments at Visits 1 and 2. 
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a. Subject is on stable, non-biologic asthma medication with no dose adjustments in 
the 8 weeks prior to Screening. 
b. Subject has not had an exacerbation of asthma (defined as an event requiring a 
change in asthma therapy) in the 8 weeks prior to Screening. 
c. Subject has not started any new prescribed drugs or had any dose adjustments in 
their prescribed drugs in the 8 weeks prior to Screening. 
4.2 
Exclusion Criteria 
1. Subject is an employee, consultant, and/or immediate family member (i.e., first 
degree relative, spouse, adoptee, or legal dependent) of the site or the Sponsor. 
2. Subject is unreliable; incapable of adhering to the protocol and visit schedule 
according to the judgement of the Investigator; or has any disorder that may 
compromise their ability to give informed consent. 
3. Subject has previous exposure to the study drug or known allergy/sensitivity to any of 
its excipients. 
4. Female subject is pregnant or breastfeeding. 
5. Subject cannot fast and avoid strenuous exercise for 9 hours prior to each site visit 
which includes clinical chemistry testing. 
6. Subject has an abnormal medical history, physical finding or safety finding that in the 
opinion of the Investigator or Sponsor’s blinded Medical Monitor may obscure the 
study data. 
7. Subject has clinically significant history of a serious hypersensitivity reaction to any 
parenteral drug. 
8. Any clinical laboratory test result outside of the reference ranges considered by the 
Investigator as clinically significant. 
9. Subject has history or evidence of clinically significant pulmonary condition, 
including significant restrictive findings on pulmonary function testing, chronic 
bronchitis, emphysema, bronchiectasis, and pulmonary fibrosis, or any other related 
condition that in the opinion of the Investigator or Sponsor’s blinded Medical 
Monitor may obscure the study data (e.g., gastro-oesophageal reflux and vocal cord 
paralysis/dysfunction). 
10. Subject has donated blood (including blood products) or experienced loss of blood 
≥500 mL within 8 weeks of Screening. 
11. Screening supine blood pressure (BP) >150 mmHg (systolic) or >100 mmHg 
(diastolic), following at least 5 minutes of supine, semi supine or sitting rest. If BP is 
>150 mmHg (systolic) or >100 mmHg (diastolic), the BP should be repeated two 
more times and the average of the three BP values should be used to determine the 
subject’s eligibility. 
12. Subject has pacemaker; is not in sinus rhythm; has a resting heart rate <40 or 
>99 beats per minute; has a mean corrected QT interval (QTc; using Fridericia’s 
[QTcF] formula) of >450 ms in males or >470 ms in females during the Screening 
Period; or has a left bundle branch block or bi-fascicular block. 
13. Subject has a self-reported lower respiratory tract infection in the 8 weeks prior to 
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14. Subject has evidence of active or suspected bacterial, viral, fungal or parasitic 
infections within the past 8 weeks prior to Screening (e.g., sinusitis, common cold, 
viral syndrome, flu-like symptoms). 
15. Subject has a history compatible with or diagnosis of a parasitic infection and has not 
been treated or has not responded to standard of care therapy. 
16. Subject has Type I or II diabetes under poor glucose control. 
17. Subject has an estimated glomerular filtration rate of <80 mL/min/1.73 m2 using the 
Chronic Kidney Disease Epidemiology Collaboration equation.  
18. Subject has a history of malignancy of any type, other than in situ cervical cancer or 
surgically excised non-melanomatous skin cancers, within 5 years before Screening. 
19. Subject has: (a) tested positive for illicit drugs, nicotine/cotinine, and/or alcohol at 
Screening; (b) consumed alcohol within 48 hours prior to Screening visits; and/or (c) 
refused to agree to consume <14 units per week (1 unit=½ pint beer, a 25 mL shot of 
40% spirit or a 125 mL glass of wine). 
20. Subject is positive for human immunodeficiency virus antibodies, hepatitis B surface 
antigen, or hepatitis C antibodies, or has a positive QuantiFERON®-tuberculosis Gold 
(QFT-G) test for tuberculosis at Screening. Subjects with an indeterminate QFT-G 
test may be re-tested; if a re-test remains indeterminant or is positive, the subject will 
be excluded. 
21. Subject has received a vaccine dose within 28 days prior to Day -1. 
22. Subject has received any immunosuppressant therapies including imatinib, 
ambrisentan, azathioprine, cyclophosphamide, bosentan, cyclosporine A, or 
methotrexate. 
23. Subject has received an antibody or therapeutic biologic product during the 6 months 
prior to Screening. 
24. Subject has received oral, IV, or intramuscular steroid within 8 weeks prior to 
Screening. Intrathecal or intra-articular steroids are permitted. 
25. Subject has participated in a clinical study or has been treated with an investigational 
drug within 28 days or 5 half-lives, whichever is longer, prior to Screening. 
26. Current tobacco smokers and those who have smoked within the last 12 months prior 
to Screening or prior to Day 1. 
27. Subject has a positive COVID-19 test within 28 days of Day -1. 
4.3 
Future Cohort Eligibility  
Subjects who are declared screen failures due to eosinophil numbers will be ineligible for 
enrolment at any time during the study unless the eosinophil number which resulted in their 
ineligibility is considered to be low due to diurnal variations.   
4.4 
Re-screening Criteria 
Subjects who following any Screening visit meet the enrolment criteria to proceed in the 
study but for some other reason (e.g., family emergency or coronavirus isolation) are not 
randomized may repeat the last visit performed provided Visit 3 will occur within the 
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Subjects who failed 1 or more criteria for reasons which in the opinion of the Investigator are 
likely to be remedied, may repeat the test(s) associated with those criteria (either at a 
subsequent Screening visit or at an unscheduled visit). In such situations the reasons for the 
repeat tests must be documented in the source notes and results which meet the criteria must 
be obtained prior to randomization. 
However, subjects unable to complete screening within the protocol-defined Screening 
Period, must be declared a screening failure. Such Subjects may be re-screened from scratch.    
4.5 
Randomization Criteria  
Subjects meeting all eligibility criteria (as defined in Section 4.1 and Section 4.2) at all three 
Screening visits are eligible for randomization on Day 1. 
4.6 
Subject Identification 
All subjects who undergo Screening will be assigned a unique subject number at Visit 1. 
Randomization will be centralized using an interactive response system (IXRS). 
4.7 
Prior, Concomitant, and Prohibited Medications 
All medications (prescription and over-the-counter), vitamin and/or mineral supplements, 
and herbal medicines or supplements taken at any time from Day 1 through the subject’s last 
visit will be documented on the concomitant medication eCRF. Those taken within 8 weeks 
of Day -1 will be recorded as recent prior medication history. Information recorded will 
include start and stop dates and times, dose, frequency, route of administration, and 
indication (i.e., medical diagnosis and/or AE).  
4.7.1 
Allowed Medications to Treat Asthma 
Subjects must be on a stable, non-biologic background asthma medication, including those 
used on an as-needed basis (e.g., single maintenance and reliever therapy), in the 8 weeks 
prior to Screening to be eligible for randomization. Background medications should remain 
stable for the duration of the study. However, background medication doses may be 
increased in response to worsening of asthma during the study.  
Subjects may not decrease their prescribed asthma medications if they feel their asthma 
control has improved.   
4.7.2 
Prohibited Medications  
No new concomitant medications (prescription or over-the-counter); no nutritional or dietary 
supplements, herbal preparations, or vitamins; and no concomitant procedures may be 
administered during the study, unless the Investigator (or designee) and/or Sponsor have 
given their prior consent. This prohibition does not apply to vaccinations. If new concomitant 
medications are initiated without the prior consent of the Investigator and Sponsor, the 
Investigator and Sponsor will review ongoing eligibility of the subject for the study. 


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4.8 
Other Restrictions, Illicit Drugs, or Drugs of Abuse 
4.8.1 
Illicit Drugs 
Illicit drugs or drugs of abuse, including methamphetamine and marijuana, will not be 
allowed from the start of Screening to the end of the Observation Period or Early 
Termination Visit. If any illicit drugs or drugs of abuse are used by the subject during the 
study, the dates of use and the amount will be documented, and the subject may be 
discontinued from study drug at the discretion of the Investigator. Subjects who are positive 
on drug Screening for a drug prescribed to that subject may be enrolled following approval 
by both the Principal Investigator and the Sponsor’s blinded Medical Monitor. 
4.8.2 
Alcohol, Caffeine, and Tobacco Restrictions 
Regular alcohol consumption will be limited in males and females <14 units per week 
(1 unit=½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine). Subjects must 
refrain from alcohol consumption for the 48-hour periods prior to Screening and site visits. 
The use of nicotine or tobacco containing products (including but not limited to snuff, 
chewing tobacco, cigars, cigarettes, pipes, vaping, or nicotine patches) will not be permitted 
for the duration of the study. Subjects will be tested for nicotine/cotinine during the 
Screening Period.  
Subjects must refrain from caffeinated products (including caffeinated teas, coffees, cola and 
other beverages), chocolate-containing products, including drinks, and vigorous exercise for 
9 hours before all study visits.  
4.8.3 
Dietary Restrictions 
A diet rich in nitrate-containing food may increase FeNO (ATS 2005, Kerley, Kilbride et al. 
2016, Kroll, Werchan et al. 2018). Therefore, subjects will avoid nitrate-rich foods, 
especially leafy vegetables such as lettuce, spinach, and kale, but also beetroot, for 9 hours 
before all study visits so as avoid complexity and potential errors.  
Subjects will be fasting a minimum of 9 hours before visits that include clinical chemistry 
testing to afford accurate morning glucose and lipid testing. 
4.8.4 
Male and Female Contraception 
Subjects must abstain from unprotected sex from the first dose of study drug until 120 days 
after the final dose of study drug or the Final Visit, whichever is later.  
As per the Clinical Trial Facilitation Group guidance (CTFG 2020), female subjects of 
childbearing potential must use a highly effective method of birth control (i.e., failure rate 
<1% per year when used consistently and correctly) when engaging in sexual activity with a 
male partner from the first dose of study drug until 120 days after the final dose of study drug 
or the Final Visit, whichever is later. Highly effective methods of birth control are: 


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• Combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: oral, intravaginal, transdermal. 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, 
injectable, implantable. 
• Intrauterine device or intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Vasectomized partner provided that the male partner is the sole sexual partner of the 
study participant, and that the vasectomized partner has received medical assessment of 
the surgical process. 
Post-menopausal (naturally sterile) is defined as amenorrhea ≥1 year and a serum FSH 
concentration within the post-menopausal range.  
Male subjects must use a condom with all partners through the study, from the time of the 
first dose of study drug until 120 days after the final dose of study drug or the Final Visit, 
whichever is later. Partners of male subjects who are not vasectomized and who are women 
of childbearing potential should use highly effective methods of birth control from the first 
dose of study drug until 120 days after the final dose of study drug or the Final Visit, 
whichever is later. 
Subjects must refrain from gamete (i.e., sperm or egg) donation from the first dose of study 
drug until 120 days after the final dose of study drug. 
4.9 
Reasons for Treatment Discontinuation or Study Withdrawal 
4.9.1 
Duration of Study Participation 
Subjects will remain in the study for approximately 9 months. All subjects will undergo 
Screening for a maximum of 3 weeks. Subjects assigned to a cohort with 3 doses 
administered 
 (or 2 doses 
 if such an interval is selected in Part B) will undergo 
2 months of treatment followed by 6 months of observation. Subjects assigned to a 2-dose 
 regimen will undergo 3 months of treatment followed by 5 months of observation. 
Subjects assigned to a 
 regimen (ohort 4) will receive 
 dose followed by 
8 months of observation.  
A subject is considered to have completed study treatment if they completed the Dosing 
Period. A subject is considered to have completed the study if they completed the Dosing and 
the Observation Periods. 
4.9.2 
Reasons for Treatment Discontinuation 
The subject may voluntarily discontinue study drug at any time without prejudice to further 
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Study drug treatment of individual subject may be discontinued at the discretion of the 
Investigator and/or the Sponsor due to clinically significant findings including but not limited 
to AEs, clinical laboratory abnormalities, or physical examination findings. See Section 5.9 
for specific subject stopping rules. Subjects may also be discontinued from treatment for 
noncompliance, including starting a new concomitant medication (see Section 4.7.2).  
If study drug is discontinued, the Investigator will report the discontinuation to the Sponsor’s 
blinded Medical Monitor and document the date and reason for study drug discontinuation on 
the appropriate eCRF. Subjects who discontinue treatment will be encouraged to continue in 
the study and complete the remaining study visits, otherwise they will be asked to attend an 
Early Termination Visit (see Section 3.9). In addition, every effort should be made to obtain 
the subject’s permission for collection of samples for PK and immunogenicity assessment 
12 weeks after the last dose of study drug. 
4.9.3 
Reasons for Subject Withdrawal 
Subjects may be withdrawn from the study at any time at their own request, upon request of 
the Investigator, or by Sponsor at any time or for any reason. A subject who withdraws 
consent will always be asked about the reasons and the presence of any AE.  
Subjects will be withdrawn from the study by the Investigator and/or Sponsor for either of 
the following: 
• If a female subject becomes pregnant during the study, the subject will be withdrawn 
from the study and the pregnancy will be followed through delivery or final outcome (see 
Section 8.9.8). 
• If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the 
subject. 
A subject may also be withdrawn from the study by the Investigator and/or Sponsor at any 
time for other safety, behavioural, compliance, or administrative reasons such as the 
following: 
• Significant noncompliance with study procedures/restrictions. 
• If the subject no longer meets eligibility criteria. 
• Study termination by the Sponsor. 
Any subject who received at least one dose of the study drug and is about to be withdrawn 
from the study should be asked to undergo an Early Termination Visit (see Schedule of 
Events in Section 3.3) before subject withdrawal.  
The Investigator must document the date and primary reason for the withdrawal on the 
appropriate eCRF. Subjects who withdraw prematurely may be replaced at the discretion of 
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4.10 Replacement of Subjects 
Subjects who prematurely discontinue from the study before receipt of their first dose may be 
replaced as per Section 3.9. The IXRS will be programmed for the replacement subject to 
receive the same blinded treatment assignment as the subject who discontinued. The decision 
whether to replace the subject will be a joint decision between the Principal Investigator and 
the Sponsor.  
4.11 Termination of the Study 
An Investigator may choose to discontinue study participation at any time with sufficient 
notice by the Investigator for any reason as per the terms of the contract with the Sponsor. 
The Sponsor reserves the right to discontinue the study at any time for clinical or 
administrative reasons. Such a termination must be implemented by the Investigator, if 
instructed to do so by the Sponsor, in a time frame that is compatible with the subjects’ 
wellbeing. 
4.12 Day 225 / Final Visit 
The site visit on Day 225 is also referred to as the Final Visit in this document. This visit 
marks the last Observation Period visit.  


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5 
STUDY SAFETY ASSESSMENTS AND PROCEDURES 
The timing of study assessments and procedures for each part of the study is provided in the 
Schedule of Events in Section 3.3.  
Assessments conducted during the Screening Period only are described in Section 3.5. 
5.1 
Medical History 
Medical history, including any diseases, all past surgeries including skin procedures, and 
psychiatric illnesses will be documented. 
Each subject will be questioned regarding any planned elective procedures that may occur 
during or following completion of the study, and these must be documented in the subject’s 
medical record and the medical history section of the eCRF.   
5.2 
Prior Medication History 
All medications or medical products taken by the subject within 8 weeks prior to Screening, 
whether the subject has stopped the medication or whether the subject has continued taking 
the medication, will be recorded as a Prior Medication History. This also includes 
medications taken as needed.  
5.3 
Demographics 
The subject’s gender, age, race, and ethnicity will be recorded.  
5.4 
Safety Assessments 
Safety assessments will include AEs and SAEs, vital signs (BP, pulse, body temperature, and 
respiration rate), physical examinations, clinical laboratory parameters (haematology, clinical 
chemistry, coagulation, and urinalysis), ECGs, pregnancy tests, subject withdrawals, early 
terminations, and compliance.   
5.4.1 
Adverse Events 
AE procedures are described in Section 8. 
5.4.2 
Vital Signs 
Body temperature, pulse, respiratory rate, and BP will be collected. Assessments may be 
obtained while the subject is resting for 5 minutes in either the supine, semi-supine or seated 
position.  
Heart rates are best obtained electronically, if available. If heart rate data are obtained 
electronically, the results may not be obtained from an ECG scheduled at the same time. If 
these data are obtained manually, a minimum observation period of 30 sec is required.   


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Respiratory rate will be determined following a minimum observation of 30 sec.  
Assessment of vital signs will be conducted on visit days detailed in Table 4 to Table 9 in 
Section 3.3. 
On dosing days, vital signs will be measured within 60 minutes pre-dose, 30-minutes, 1 hour, 
and 4 hours post-dose (see Table 9). 
5.4.3 
Weight, Height and Body Mass Index 
Height for all subjects will only be collected at Screening Visit 1. Weight will be collected 
for each subject at Screening Visit 1 and at the Final/Early Termination Visit. BMI will be 
calculated at Screening Visit 1 to determine eligibility. 
5.4.4 
Physical Examination 
The physical examination at Screening (Visit 1) and the Final/Early Termination Visit 
includes an assessment of general appearance, skin, eyes, ears, nose, throat, neck (including 
thyroid), lymph nodes, chest (lungs), cardiovascular, abdominal, extremities, and 
musculoskeletal.  
The Investigator will also be asked to assess whether the following neurologic functions are 
normal / abnormal.  
• Mentation: appropriate behaviour; logical thought processes. 
• Motor: use of all 4 extremities. 
• Cerebellar: gait; balance standing and sitting. 
• Cranial nerves: speech, facial symmetry, and hearing. 
• A symptom-driven physical examination will be conducted in any other visits as needed 
based on reported signs and symptoms. If any physical examinations change from 
baseline, the Investigator will be asked to describe the new findings. Otherwise, except 
for at the time of the Final Visit, the physical examination will not have to be repeated.   
5.4.5 
Electrocardiogram  
Electrocardiograms will be conducted on visit days detailed in Table 4 through Table 9 in 
Section 3.3. A standard 12-lead ECG will be recorded after the subject has been supine for at 
least 5 minutes. All ECGs will be acquired in triplicate with a maximum of 5 minutes 
between the first and the third recordings. All recordings will be transmitted to the central 
ECG laboratory for interval calculations and interpretation.  
The Investigator or designated physician will review all ECGs and opine regarding the 
tracings. A paper printout of every ECG will be stored at the site.  


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All ECG will include at a minimum the subject’s study number as well as the time and date 
of each recording. On dosing days, ECGs will be conducted within 60 minutes pre-dose and 
approximately 2 hours post-dose (see Table 9). ECG assessments will be performed prior to 
any scheduled blood tests, FeNO measurements, and/or study drug administration.   
5.4.6 
Clinical Laboratory Assessments 
Clinical laboratory assessments include haematology, blood chemistry, and urinalysis as 
listed in Table 10. Subjects will have fasted (except for water) for a minimum of 9 hours 
prior to these assessments. On dosing days, samples will be collected pre-dose. All laboratory 
test results must be reviewed by the Investigator or qualified designee. 
Table 10 Clinical Laboratory Testsa 
Haematology 
Chemistry 
Urinalysis 
Infectious Disease 
Complete Blood Count 
Sodium 
Specific gravity 
HIV 
Automated differentialb 
Potassium 
pH 
Hepatitis B 
PT, aPTT, and INRc 
Chloride 
Blood 
Hepatitis C 
 
Bicarbonate 
Protein  
QuantiFERON®-TB Gold 
 
Urea 
Glucose 
 
 
Creatinine 
Bilirubin 
 
 
Total protein 
WBC 
 
 
Albumin 
Ketones 
 
 
Calcium 
Nitrites 
 
 
Phosphorus 
Microscopic 
examinationd 
 
 
Glucose 
Drug, nicotine, 
cotinine 
Miscellaneous 
 
Total creatinine kinase 
 
FSHe 
 
AST (SGOT) 
 
Total IgE 
 
ALT (SGPT) 
 
Pregnancy test 
(Section 5.4.7) 
 
Alkaline phosphatase 
 
C-reactive protein 
 
Total bilirubin 
 
Alcohol breath or urine test 
 
Direct bilirubin 
 
 
 
HDL 
 
 
 
Total cholesterol 
 
 
 
Triglycerides 
 
 
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase; 
FSH=follicle stimulating hormone, HDL=high density lipoprotein; HIV=human immunodeficiency virus; 
IgE=immunoglobulin E, INR=international normalized ratio, PT=prothrombin time, SGOT=serum glutamic 
oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; TB=tuberculosis; WBC=white blood 
cell. 
a 
Chemistry and urinalysis panels may be changed depending upon the clinical laboratory’s standard panels. 
b 
Eosinophil number from the complete blood count differential will be used for the eosinophil endpoint.  
c 
Coagulation will only be performed at Visit 1 and at the Final visit.  
d 
Microscopic examination will only be triggered if urine result is abnormal for blood, WBC, nitrites and/or 
protein.   
e 
All females who are eligible based upon post-menopausal criteria as per Section 4.8.4. 
Clinical laboratory assessments will be conducted on visit days detailed Table 4 through 
Table 9 in Section 3.3. 


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Results from the haematology test will be used to generate the eosinophil number. Note: No 
eosinophil data collected after screening will be accessible to the site personnel 
(including the Investigators) to avoid unblinding them to the randomization 
assignment. To remove the possibility of eosinophil data being calculated from the 
remaining haematology parameters, data relating to monoctyes and basophils collected 
after screening will also not be provided to site personnel. 
5.4.7 
Pregnancy Test and FSH 
A β-HCG pregnancy test will be conducted for all female subjects with childbearing potential 
(as defined in Section 4.8.4) on visit days detailed Table 4 through Table 9 in Section 3.3. A 
urine pregnancy test will be performed at all visits noted in those tables except on Visit 2 and 
at the Final Visit when serum pregnancy tests will be performed. Subjects with a positive test 
result at any Screening visit will be ineligible for enrolment in the study.  
In the event a female subject or the female partner of a male subject becomes pregnant during 
the study, the process described in Section 8.9.8 will be followed. Pregnant female subjects 
will be withdrawn immediately from the study (as described in Section 4.9.3) and followed 
as described in Section 8.9.8.  
FSH will be assayed in women who on Visit 1 fit the post-menopausal criterion included in 
Section 4.8.4. 
5.4.8 
COVID-19 Testing 
Subjects will undergo COVID-19 testing as per each site’s protocol. 
5.4.9 
Subject Compliance Assessment 
Subject compliance will be assessed by comparing the number of study drug doses the 
subject received to the number of doses the subject was scheduled to receive as per the 
protocol.  
5.5 
Immunogenicity Assessments 
Serum samples for the assessment of UPB-101 ADAs and NAbs will be collected as detailed 
in Table 4 through Table 9 in Section 3.3. 
Immunogenicity testing will follow a 3-tiered approach of screening, confirmation, and 
titration. Any sample screened as positive should be confirmed. Any confirmed positive 
sample should be titrated and tested for NAb activity and may be further characterized for 
quantity/titre, isotype, and affinity. Screening, confirmation, and titration assessments should 
be performed when samples are available; the NAb assay may be conducted later on frozen 
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5.6 
Pharmacokinetic Assessments 
Timed serum samples will be collected to determine the concentration of UPB-101 and will 
be collected as detailed in Table 4 through Table 9 in Section 3.3. Pharmacokinetic serum 
samples will be collected pre-dose on dosing days. 
When the PK sampling coincides with the ECG and/or vital sign recordings, priority should 
be given to the ECGs and vital signs. The actual date and time of each PK sample collection 
will be recorded in the eCRF. 
Blood sample collection, handling, and storage will be described in the laboratory manual. 
The PK analyses will be based on the timed blood PK sampling of all enrolled subjects (PK 
Population). Serum UPB-101 concentrations will be summarized using descriptive statistics 
and used for PK analyses including the following endpoints if appropriate: 
• Cmax.  
• tmax. 
• AUCtau. 
• AUCinf after the first dose, if appropriate. 
• t1/2, if appropriate. 
• CL/F, if appropriate. 
• Vz/F, if appropriate. 
A power model will be fitted using all doses and across all cohorts to assess dose 
proportionality for Cmax and AUCtau after the first dose. Within each dosing regimen, dose 
proportionality using a comparison of Cmax and AUCtau after the last dose will also be 
assessed using descriptive statistics. For each dosing regimen, accumulation of UPB-101 will 
be assessed by comparing the ratio of Cmax and AUCtau after the last dose and the first dose 
for each subject and summarized by dosing regimen. 
Analysis of UPB-101 will be performed using a validated method at a bioanalytical 
laboratory specified by the Sponsor.  
5.7 
Study Oversight 
Primary oversight during the conduct of the study will be the responsibility of the Principal 
Investigators at each Study Site. The Principal Investigators are responsible for 
communicating any issues that may compromise subject safety to the Sponsor’s blinded 
Medical Monitor.  


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5.8 
Safety Review Committee 
5.8.1 
General Safety Monitoring 
Results of the SAD study performed with UPB-101 were reported in Section 1.4.1. In that 
clinical study, UPB-101 was safe and well-tolerated. Since the highest dose administered in 
the completed single-dose Phase 1 was 
 mg/kg (the equivalent of approximately 
 mg), 
all 3 doses proposed for Cohort 1 (
 and Cohort 2 (
 as 
well as the 2 doses of Cohort 3 (
) in the current study are supported by 
those data. However, the SRC will meet before the first subject in any cohort with 
 
dosing receives their third dose as an extra precaution so as to assure that formal reviews of 
all the available safety data occur at specific timepoints in the study.  
Part A: Subjects in Cohorts 1 and 2 will receive 3 doses of study drug. Before the first 
subject in each of those cohorts receives their third dose, the SRC will be convened. The 
committee will review at each of the 3 meetings the safety data available at that point in time 
from all enrolling cohorts. Subjects enrolled in Cohort 3 will receive 2 doses of the study 
drug. Therefore, no SRC meetings will be directly linked to the progress of those cohorts. 
The blinded safety data reviewed will include AEs, vital signs, physical examinations, ECGs, 
haematology, biochemistry, urinalyses, as well as subject withdrawals and replacements. 
Eosinophil data will not be sent to sites or reviewed by the SRC. Following this data review, 
the SRC will report their safety findings and make a recommendation whether the third 
dosing in the current cohort should proceed as planned or be modified (e.g., repeated or 
reduced), paused, or halted (Section 5.9 and Section 4.11). 
Part B: Study drug exposures in Cohorts 4 and 5 will not exceed the exposure of any of the 
cohorts in Part A.  If a 
 dosing regimen is selected for Cohorts 4 or Cohort 5 an SRC 
meeting will be convened prior to the first subject in the relevant cohort(s) receiving their 
third dose. The data to be reviewed, and the process for the SRC to report their safety 
findings, will be as those detailed for Part A above. 
The data will be blinded for review; however, if considered necessary, the SRC can request 
that data be unblinded for either individual subjects or the entire dose cohort. The 
randomization code will be broken following tranScrip’s standard procedures. 
The SRC will be comprised of individuals with expertise in internal medicine, clinical 
development, allergy and clinical immunology, clinical pharmacology, safety risk 
management, and clinical operations. The SRC will include Sponsor (Upstream Bio) 
personnel, the Principal Investigators (their designees), and external experts. 
The SRC will consist of voting members (the chairperson and additional members) and 
non-voting members. Blinded voting members will be the following: 
• Principal Investigators (or their designates) from each of the Study Sites. 
• tranScrip’s (the study clinical contract research organisation [CRO]) Head of 
Translational Medicine/Clinical Pharmacology. 
• tranScrip’s Clinical Development Team Lead – Chairperson. 


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The following non-voting members will support the SRC voting members in their role: 
• Sponsor’s unblinded Medical Monitor. 
• tranScrip study statistician (blinded). 
Other non-voting members may be added as needed to support the SRC. 
All voting members will constitute a quorum. Any SRC recommendation will be made by a 
unanimous quorum vote at a meeting. Non-voting members cannot vote for cohort 
progression, study termination, or study enrolment halt. In an exceptional circumstance (e.g., 
illness or sudden unavailability), the Chairperson will have the discretion, in consultation 
with the SRC, to have a SRC recommendation made in the absence of a maximum of 
1 voting member.  
5.8.2 
PK Safety Monitoring 
When subjects enrolled in each cohort have completed their respective Day 22 procedures, 
serum PK samples collected following the first dosing will be assessed in a timely fashion for 
UPB-101 concentrations (PK). The PK results will be analysed, and a summary report will be 
written by the Sponsor’s PK consultant with particular attention to Cmax and AUCtau, with a 
comparison to the pre-study PK modelling as described in Section 5.10. The report will be 
distributed to all members of the SRC. Unblinding individual subject PK data will not be 
included in this report so as not to unblind the blinded members of the SRC. After reviewing 
the summary safety, any member of the SRC may request a formal meeting of that committee 
to discuss the results.    
5.9 
Stopping Criteria 
5.9.1 
Study Stopping Criteria 
If any of the following events develop during the study, at any dose of UPB-101, and these 
events are considered by the Investigator and/or Sponsor to be at least probably related to the 
administration of UPB-101, an ad hoc SRC meeting will be called immediately to investigate 
the event and to provide a recommendation for stopping or continuing the study or modifying 
the protocol: 
• One or more subjects develop an SAE. 
• Two or more subjects in the same cohort develop severe non-serious AEs, independent of 
within or not within the same system-organ-class. 
• One or more subjects develop elevated plasma concentrations of ALT or AST ≥3-fold the 
ULN and elevated plasma concentrations of total bilirubin (TBL) ≥2-fold the ULN which 
is confirmed by repeat testing at least 48 to 72 hours after the initial test. 
If the SRC recommends modifying the protocol as a condition for restarting the study, a 
protocol amendment will be submitted to the relevant regulatory authorities and IEC.  


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Procedures required prior to restarting a halted study are listed in Section 5.11. 
Dose Escalation Stopping Criteria 
If any of the following events develop during the study, dose escalation will be halted and the 
SRC will review the event and make a recommendation to stop dose escalation and/or 
continue dosing with modifications: 
• Two or more subjects administered UPB-101 have an elevated plasma concentration of 
ALT or AST ≥3 × ULN that is considered by the Investigator and/or Sponsor related to 
the investigational product and is confirmed by repeat testing 48 to 72 hours after the 
initial test. 
• Two or more subjects administered UPB-101 have an elevated plasma concentration of 
TBL ≥2 × ULN that is considered by the Investigator and/or Sponsor related to the 
investigational product and is confirmed by repeat testing 48 to 72 hours after the initial 
test. 
• For additional information on hepatic parameter abnormalities, refer to Appendix 1, Liver 
Safety Monitoring and Assessment. 
• One or more subjects administered UPB-101 has prolongation of QTcF, defined as QTcF 
>500 ms or >60 ms change from Baseline, that, on multiple ECGs, persists for at least 
30 minutes and is considered by the Investigator and/or Sponsor related to the 
investigational product. 
• Pharmacokinetic Stopping Rules – see Section 5.10. 
• One or more subjects administered UPB-101 develop any other event that poses an 
unacceptable risk to other subjects in the study. 
Procedures required prior to restarting a halted study are listed in Section 5.11. 
5.10 Pharmacokinetic Stopping Limits 
UPB-101 exposure at the NOAEL dose (
 mg/kg IV) in the 26-week cynomolgus monkey 
study gave a Cmax 
 µg/mL and AUCtau 
 µg.day/mL, which are 
-fold and 
-fold higher than the predicted Cmax and AUCtau at the maximum dose (
mg SC) in the 
current study, which are 
 ug/mL and 
 day.ug/mL, respectively (see Section 1.7). 
Despite the very large margins, if the following events develop during the study, the SRC 
will review the data and make a recommendation to stop dosing, continue dosing, or continue 
dosing with modifications: One or more subjects administered UPB-101 have Cmax
 of 
the preclinical NOAEL level, i.e., Cmax 
 µg/mL.  
Procedures required prior to restarting a halted study are listed in Section 5.11. 
5.11 Re-starting the Clinical Study Following a Clinical Stop Due to a Stopping 
Rule 
Should the clinical study be halted because of any stopping rule listed in Section 5.9 or 5.10 
was triggered, the study restart will only be possible after receipt of written regulatory 


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authority approval via a substantial Clinical Trial Application amendment (with or without a 
protocol modification required by the SRC or Sponsor etc.).  
 


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6 
STUDY EFFICACY ASSESSMENTS AND PROCEDURES 
6.1 
Pharmacodynamic Assessments 
The assessments described in this section will be conducted to assess asthma-related PD 
biomarkers. Samples will be collected as indicated in Section 3.3; the actual date and time of 
each sample collection will be recorded in the eCRF. Blood sample collection, handling, and 
storage will be described in the specimen collection and processing instructions. Blood 
samples for biomarker analysis will be taken and frozen. The decision to assay the frozen 
samples will be based on results from earlier sample analyses. 
On dosing days, all PD assessments must be completed prior to initiation of the study drug 
administration.  
Numerous cytokines are involved in the pathogenesis of asthma and several additional 
biomarkers have been associated with asthma activity (Custovic, Siddiqui et al. 2022). 
Several approved or in development asthma medications target cytokines (Lambrecht, 
Hammad et al. 2019).  
Plasma levels of IL-5, IL-13, IFN λ, IL-17A, eotaxin-3, IP-10 (C-X-C motif chemokine 
ligand 10), and TSLP will be measured using ultrasensitive assays. Tryptase, 
carboxypeptidase, and TARC will also be measured. CRP, and total IgE will be assayed by 
the central clinical laboratory.  
Initially, select samples from those collected will be analysed and the resulting data assessed. 
Following this, should analysis of the remaining samples be deemed informative, they too 
will be analysed.  
6.1.1 
Fractional Exhaled Nitric Oxide 
Measuring the FeNO level in asthmatic subjects is used as a surrogate marker for the 
presence and degree of airway inflammation. The FeNO levels will be measured via exhaled 
breath. 
Subjects should refrain from eating nitrate-rich foods for at least 9 hours prior to FeNO 
measurements (see Section 4.8.3). 
Assessment of FeNO will be conducted as detailed in Table 4 through Table 9 in Section 3.3.  
6.1.2 
Blood Eosinophils 
Increased eosinophils are associated with increased severity, exacerbations, decreased lung 
function, and mortality in subjects with asthma (Hospers, Schouten et al. 2000, Garcia, Taille 
et al. 2013, Talini, Novelli et al. 2015, Price, Wilson et al. 2016). Blood eosinophils have 
become an established biomarker in inflammatory airway disease (Kostikas, Brindicci et al. 
2018). 


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Absolute numbers of blood eosinophils will be measured using blood collected as part of the 
automated complete blood count clinical laboratory test which includes a differential count of 
white blood cells. Results will be reported at the highest precision (level of significant 
figures) offered by the clinical laboratory. Assessment of blood eosinophils will be 
conducted at the visits reflected in Section 3.3. The sites will be blinded to eosinophil count. 
6.1.3 
Total Immunoglobulin E 
Total IgE is a well-established biomarker for severe asthma whose levels have been shown to 
be targeted and/or reduced by current biologic therapies (Lambrecht, Hammad et al. 2019). 
Total IgE levels will be measured as detailed in Table 4 through Table 9 in Section 3.3.  
6.1.4 
Flow Cytometry – pSTAT and Receptor Occupancy 
Phosphorylated signal transducer and activator of transcription and receptor occupancy will 
be assayed via flow cytometry. Blood samples obtained from subjects will be analysed fresh 
or frozen. The decision to assay the frozen samples will be based on the results from the fresh 
samples. Analysis of blood samples (whether fresh or frozen) for pSTAT may be 
discontinued, based on assay status. 
6.2 
Asthma Status Questionnaires 
6.2.1 
Asthma Clinician Global Impression of Change 
The CGI-C instrument is used to evaluate the overall response to treatment. The Investigator 
(clinician) will be asked to rate the degree to which the overall asthma status may have 
changed when compared to baseline (Day -1). It is recommended that the same clinician 
completes the CGI-C at all applicable visits for an individual subject.  
Before making the assessment, the clinician will need to access and review the results from 
all relevant assessments, including pulmonary function tests performed before the visit. The 
assessment uses a 7-point rating scale: 1=Very Much Improved; 2=Much Improved; 
3=Minimally Improved; 4=No Change; 5=Minimally Worse; 6=Much Worse; and 7=Very 
Much Worse.  
Assessment of CGI-C will be conducted as detailed in Table 5 through Table 9 in 
Section 3.3. 
6.2.2 
Asthma Control Questionnaire 
The Subject ACQ has 7 questions: the top scoring 5 symptoms, FEV1% predicted, and daily 
rescue bronchodilator use. Subjects will be asked to recall how their asthma has been during 
the previous week and to respond to the symptom and bronchodilator use questions on a 7-
point scale (0=no impairment; 6=maximum impairment). The Investigator will also score the 
FEV1% predicted on a 7-point scale (0=no impairment; 6=maximum impairment). If the 
ACQ is completed on a visit where FEV1% predicted is not measured, this question will be 
answered using the FEV1% predicted from the first reading taken on the following morning. 


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The questions are equally weighted and the ACQ score is the mean of the questions and, 
consequently, ranges from 0 (totally controlled) to 6 (severely uncontrolled). The scale has 
been validated for use in both the clinical setting and in clinical studies. 
The ACQ has strong measurement properties and has been fully validated for use in both 
clinical practice and clinical studies (Juniper, Bousquet et al. 2006). For clinical practice, 
clinical studies and epidemiological studies, the ACQ has strong discriminative and 
evaluative properties which means that it can detect small differences between subjects with 
different levels of asthma control and it is very sensitive to within-subject change in asthma 
control over time. 
The ACQ can identify the adequacy of asthma control in individual subjects. In general, 
subjects with a score below 1.0 will have adequately controlled asthma and above 1.0 their 
asthma will not be well controlled. However, there is a very grey area between 0.75 and 1.25 
where subjects are on the borderline of adequate control. On the 7-point scale of the ACQ, a 
change or difference in score of 0.5 is the smallest that can be considered clinically 
important.   
Assessment of ACQ-7 will be conducted as detailed in Table 4 through Table 9 in 
Section 3.3. 
6.3 
Pulmonary Function Tests (Spirometry) 
Spirometry will be conducted both to ensure no worsening of asthma during the study and as 
an exploratory PD endpoint. The spirometric exploratory analyses will be addressed in the 
Statistical Analysis Plan (SAP). 
The site will be provided with a spirometry system with customized, study specific software. 
The volume accuracy of the spirometer across different flow ranges is to be checked with 
appropriate documentation via a printed calibration check report, prior to the conduct of 
spirometry on each test day. See Appendix 2 for spirometry performance criteria. 
All study staff responsible for performing spirometry testing will receive training on the 
provide spirometry system and study specific software. All spirometry technicians are 
required to demonstrate proficiency in the use of the equipment and the ability to perform 
technically acceptable and repeatable spirometry sessions prior to performing testing on 
study subjects (see Appendix 2).  
After completion of subject spirometry testing, the study staff will electronically transmit the 
spirometric measurements for centralized quality assurance review. Feedback on the quality 
of the spirometry data will be provided to the site and to the Sponsor or designee for central 
data management.  
Spirometry on Screening Visits 1 and 2 will be conducted at 60 minutes and 30 minutes prior 
to bronchodilator administration and at 30 minutes post-bronchodilator (after 4 puffs of 
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At Visit 4 (Day 1) and at subsequent dosing visits, spirometry will be conducted 
approximately 60 minutes and 30 minutes prior to dosing.  
At non-dosing visits where spirometry is conducted, 2 assessments will be conducted 
30 minutes apart; assessments should be conducted at approximately the same time as on 
dosing days. No post-bronchodilator spirometry will be performed after Visit 2.  
Subjects must withhold all asthma medications, including short-acting bronchodilators, for at 
least 6 hours before coming into the clinic on all scheduled spirometry visits. Subjects who 
inadvertently take asthma medication within 6 hours of the start of study procedures must 
have their clinic visit delayed (but not exceed study drug dosing by 10 AM) or rescheduled 
within the specified visit window. 
Spirometry will be conducted as detailed in Table 4 through Table 9 in Section 3.3.  
6.4 
Future Analysis of Additional Cytokines 
Additional blood samples will be collected as detailed in the Schedule of Events (Table 5 
through Table 8 in Section 3.3) and the plasma stored for future analysis of asthma 
biomarkers not included in this study that would enhance the interpretation of the data 
generated. Examples of such biomarkers include cytokines (e.g., macrophage inhibitory 
proteins and IL-1β) and proteins (e.g., periostin) involved in inflammation, fibrosis, and/or 
re-modelling. No genetic testing will be performed on these samples.  
6.5 
Blood Sampling Volume per Subject  
The total blood sampling volume for individual subjects in this study will not exceed 800 mL 
during the course of the study (32 weeks). The actual collection times of blood sampling may 
change, but the total blood volume collected will not increase. Additional blood samples may 
be taken for safety assessments at times specified by the Sponsor, provided the total volume 
taken during the study does not exceed 550 mL during any period of 90 consecutive days. 


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7 
STUDY TREATMENT 
7.1 
Product Description 
UPB-101 injection 
 mg/mL is a sterile, colourless to pale yellow, clear to slightly 
opalescent liquid solution supplied in a single-use vial with a coated rubber stopper and an 
aluminium cap. The description of UPB-101 and placebo are presented in Table 11. 
Table 11 Product Descriptions 
Product Description 
Product Name & 
Potency 
Dosing 
Strength 
Dosage Form/ Fill 
Count 
Administration 
UPB-101 
 mg/mL 
mg 
 solution for 
injection 
Delivered as 
 mL of the 
formulated solution per SC injection 
(containing 
 mg UPB-101) 
UPB-101 
 mg/mL 
mg 
 solution for 
injection 
Delivered as 
 mL of the 
formulated solution per SC injection 
(containing 
 mg UPB-101) 
Placebo 
mg 
matching 
Placebo 
As supplied by site 
Delivered as 
 mL of normal saline 
per SC injection. 
Placebo 
 mg 
matching 
Placebo 
As supplied by site 
Delivered as 
mL of normal 
saline per SC injection. 
SC=subcutaneous. 
7.2 
Treatment Administration 
UPB-101 or matching placebo will be administered SC at the sites. All study drug dosing 
should be complete by 12 noon. 
A description of the dosing regimens for the study is presented in Table 11 and described in 
further detail in Section 7.2.1.  
Criteria for study drug discontinuation are provided in Section 4.9.1. 
7.2.1 
Dosing Instructions  
Each vial is filled with an overfill sufficient to deliver 
 mL of the formulated solution 
(containing 
 mg UPB-101) or placebo.  
Site personnel will administer 
 mL of formulated solution SC to deliver 
 mg of 
UPB-101, 
 mL to deliver 
 mg, or placebo per SC injection. 


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Table 12 Description of SC Dosing Regimens 
Description of SC Dosing Regimens in Part A 
Cohort  
Treatment Arm and 
Dosage 
Number of Injections 
to Achieve Dose 
Frequency x Number of Doses 
Cohort 1 
UPB-101 
 mg 
 
 
Placebo 
Cohort 2 
UPB-101 
 mg 
 
 
Placebo 
Cohort 3 
UPB-101 
 mg 
 
 
Placebo 
Description of SC Dosing Regimens in Part B (Adaptive Design) 
Cohort 4 
(optional) 
UPB-101 
 mg 
 
 
Placebo 
Cohort 5 
(optional) 
UPB-101 
• 
  
 
 
 
Placebo 
; SC=subcutaneous. 
In exceptional cases where a subject cannot tolerate multiple SC injections, use of an 
infusion pump may be considered at the discretion of the Investigator. Administration of the 
entire dose of study drug via an infusion pump should not exceed 4 hours.  
7.2.2 
Cohorts with 
 Dosing Intervals 
In cohorts with 
 dosing intervals, the study drug will be administered on Days 
 
 for an -week Dosing Period. Dosing will begin at 
 mg (Cohort 1). Once all 8 subjects 
have been enrolled in Cohort 1, Cohort 2 (
 mg) will enrol the next 8 eligible subjects.  
Prior to the administration of the third dose to subjects enrolled in Cohort 1, the SRC will 
meet as per Section 5.8. The same process will be repeated prior to the third dosing in 
Cohort 2. 
7.2.3 
Cohorts with 
 Dosing Intervals 
In cohorts with 
 dosing intervals, study drug will be administered on Days 
 for 
an -week Dosing Period. 
7.2.4 
Cohorts with 
 Dosing Intervals 
In cohorts with 
 dosing intervals, study drug will be administered on Days 
 for 
a 
-week Dosing Period, except for Cohort 4 where study drug will be administered on Day 
1 ONLY. None of the cohorts with 
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Under no circumstances will the Investigators allow the study drug to be used other than as 
directed by this protocol. 
The study drug must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secure location to which only the Investigator and 
designated assistants have access. Storage conditions for the study drug should be observed, 
monitored, and documented. Study drug is to be dispensed only in accordance with this 
protocol. The Investigator or designee is responsible for keeping accurate records of the 
study received, the amount dispensed, and the amount remaining at the conclusion of the 
study. Study drug should be handled in accordance with Good Pharmacy Practices (i.e., 
gloves should always be worn by study personnel if directly handling any investigational 
medicinal drug). The Sponsor’s blinded Medical Monitor should be contacted with any 
questions concerning investigational products where special or protective handling is 
indicated. At the end of the study, study drug should be accounted for and destroyed under 
local handling procedures and permission from the Sponsor. 
Sites should discuss with the Sponsor representative for appropriate documentation that 
needs to be completed for drug accountability and destruction. 
The Investigator or designated assistant should not open individual study drug until all 
pre-dose assessments have been completed and the subject has been approved by the 
Investigator to be randomized and enrolled into the study. Any deviation from this must be 
discussed with the Sponsor’s blinded Medical Monitor. 
All product complaints must be reported to the Sponsor. The Sponsor will contact the site to 
evaluate the nature of the complaint and determine what further action is needed, if 
applicable. 
7.3.2 
Primary Packaging and Labelling Information 
 
Investigational materials will be packaged by the Sponsor.  
Labels will be printed with black ink and may include the following text: 
Lot # (Packaging Lot Trace ID)  
Kit # 
Expiration date 
Subject # 
Investigator 
Space for subject #  
Contents 
Visit #   
Product identifiers (name and strength) 
Storage conditions  
Protocol #  
Country regulatory requirements  
Sponsor name, address, and telephone number 
Route of administration 
Directions for use 
Caution statement (to be used by qualified 
Investigators only) 
ID=identification; #=number 
Each vial will be labelled with a single label to enable blinding of the subjects and all site 
personnel (except for the designated unblinded dispensing pharmacist). 


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7.3.3 
Secondary Packaging and Labelling Information (Bulk Packaging) 
Table 13 Description of Boxes 
Drug Supplies  
Individual Box Contents  
Blinded 
 per box  
Each shipping package will be labelled with a single label printed with black ink and may 
include the following text: 
Protocol #  
Kit # 
Lot # (Packaging Lot Trace ID) 
Visit # 
Expiration date  
Kit contents  
Product identifiers (name and strength) 
Route of administration 
Directions for use 
Caution statement (to be used by qualified 
Investigators only) 
Storage conditions  
Sponsor name, address, and telephone number 
Country regulatory requirements  
ID=identification; #=number. 
7.3.4 
Product Storage 
UPB-101 should be stored at -20°C ±5°C. The stability of the UPB-101 has been evaluated at 
-20°C ±5°C (for 36 months) and at 5°C ±3°C (for 6 months) and the product was found to be 
stable under these conditions.  
7.3.5 
Preparation 
UPB-101 vials should be placed at room temperature until fully thawed upon visual 
inspection. Once transferred to a syringe for SC injection, the syringe should be allowed to 
reach room temperature for approximately 1 hour prior to administration.  
7.4 
Treatment Assignment 
Subjects will be randomized by IXRS in a double-blind fashion to either UPB-101 or 
matching placebo in a 3:1 ratio. Each subject will be assigned a randomization number by 
IXRS which will correspond to the treatment and cohort allocation. 
7.5 
Blinding 
Subjects, Investigators, all site personnel (except for the designated unblinded dispensing 
pharmacist and flow cytometry laboratory personnel) and the blinded CRO team will be 
blinded to study drug.  
The following procedures have been instituted to mitigate the risk of unblinding of the 
enrolled subjects and blinded site personnel during the study drug administration: 
• Qualified study personnel situated in the isolated site pharmacy will prepare the 
solutions for injection based upon the randomization allocation; 


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• 
The study drug and matching placebo will be identical (or nearly identical) in 
appearance once drawn into the syringe for injection; 
• 
All the prepared syringes will be covered with blinding labels; 
• Subjects will be dosed by site personnel trained in blinding techniques and instructed 
not to discuss the subjects’ study drug assignments with blinded site personnel; 
• Subjects will be dosed in a cordoned area out of the view of other study subjects (note: 
site personnel performing dosing may be blinded site personnel, provided all conditions 
within this section are met).  
• The IXRS will be used to control all drug distribution and inventory for this study.  
The Sponsor will be unblinded throughout this exploratory study but will not be involved in 
the treatment or clinical evaluation of the subjects.  
All potentially unblinded roles and unblinding parameters within the study will be 
documented separately and a risk assessment performed to ensure appropriate processes are 
in place to maintain the blind throughout the blinded period of the study. 
Since PK data and PD assessments from individual subjects may be unblinding, such data 
will be available to the unblinded Sponsor but not to any of the blinded parties. Therefore, 
until the entire study (i.e., Parts A and B) has been concluded and the database locked, results 
of eosinophil numbers, FeNO, total IgE, CRP, cytokines, and TSLP will be accessible only to 
unblinded parties. Summary analyses of the overall PK data will be reported to the SRC 
(Section 5.8.2). These reports will not contain any unblinded individual PK results. In 
addition, summary data that might bias blinded personnel will also be inaccessible to blinded 
parties. 
A blinded Medical Monitor will be assigned to support site communications regarding 
specific subjects and adverse events, assignment of Sponsor causalities and other activities 
that will be described in the medical monitoring plan. 
7.5.1 
Emergency Unblinding of Treatment Assignment 
The IXRS will be programmed to allow an Investigator to unblind subjects and to unmask 
drug identity. When the Investigator contacts the system to unblind a subject, he/she must 
provide the requested subject identifying information and confirm the necessity to unblind 
the subject. The Sponsor will not provide a disclosure envelope with the clinical supplies. 
The Investigator may unblind a subject’s treatment assignment only in the case of an 
emergency when immediate knowledge of the study treatment is essential for the appropriate 
clinical management or welfare of the subject. 
The decision to unblind must be that of the Investigator or delegated treating physician. 
Authorization from the Sponsor (or designee) is not required. Whenever possible, the 


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Investigator is encouraged to discuss options with the Sponsor’s blinded Medical Monitor or 
appropriate study personnel before unblinding the subject’s treatment assignment so long as 
this incurs no delay. If this is impractical, the Investigator must notify the Sponsor and/or 
Sponsor’s blinded Medical Monitor as soon as possible, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the safety of 
subjects currently in the study. The date and reason for the unblinding must be recorded in 
the appropriate data collection tool. 


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8 
ADVERSE EVENTS 
8.1 
Performing Adverse Event Assessments 
The Investigator is responsible for promptly documenting and reporting all AEs observed 
during the study in the subject’s eCRF. If the AE is “unexpected,” the Investigator must 
report the AE immediately to Sponsor or its designee. In addition, certain AEs (as described 
in Section 8.9) are classified as “serious” and must be reported no later than 24 hours after 
the Investigator recognizes/classifies the event as an SAE to the Sponsor or its designee. 
In the case of SAEs, the Investigator may discontinue the subject from treatment prematurely 
but should discuss with the blinded Medical Monitor beforehand where possible. 
8.2 
Adverse Event Definitions 
The following definitions of terms are guided by the ICH, the US Code of Federal 
Regulations (21 Code of Federal Regulations 312.32) and EU Directive 2001/83/EC and are 
included herein. 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE (also referred to as an adverse experience) 
can be any unfavourable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment 
about causality. An AE can arise from any use of the drug (e.g., off-label use, use in 
combination with another drug) and from any route of administration, formulation, or dose, 
including an overdose. 
Adverse events include, but are not limited to: 
• Any symptom or condition not previously reported by the subject (medical history). 
• An exacerbation of a pre-existing symptom or condition. 
• A significant increase in frequency or intensity of a pre-existing episodic event or 
condition. 
• A drug interaction. 
• A condition first detected or diagnosed after study drug administration even though it 
may have been present prior to the start of the study. 
An AE does not include: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, blood 
transfusion); the condition that leads to the procedure is an AE (e.g., bleeding 
oesophageal varices, dental caries). 
• Overdose of either study drug or concurrent medication without any clinical signs or 
symptoms. 


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• Non-clinically significant abnormal laboratory values. (If accompanied by 
signs/symptoms, the signs or symptoms are considered an AE). 
8.3 
Pre-randomization Adverse Events 
Adverse events that occur between the time subject signs the ICF for the study and the time 
when that subject is randomized will be summarized as medical history and not as an AE 
unless the event meets the definition of an SAE as defined in Section 8.9. 
8.4 
Severity 
The Investigator must categorize the severity of each AE according to the following 
guidelines: 
Mild: Associated with no limitation of usual activities or only slight discomfort; generally, 
not requiring alteration or cessation of study drug administration; and/or not needing 
therapeutic intervention. 
Moderate: Associated with limitation of usual activities or significant discomfort; generally 
requiring alteration or cessation of study drug administration; and/or requiring therapeutic 
intervention. 
Severe: Associated with inability of subject to carry out usual activities or very marked 
discomfort; considered to be life-threatening; resulting in significant disability or incapacity; 
and requiring therapeutic intervention. 
8.5 
Relationship 
The relationship of each AE to the study drug administration will be assessed by the Investigator 
after careful consideration, and according to the following guidelines:  
Definitely: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; it disappears 
or decreases on cessation or reduction in study drug dose; and/or it reappears or worsens 
when the study drug is administered.  
Probably: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; and/or that 
could not be reasonably explained by other factors such as underlying disease, complications, 
concomitant drugs, or concurrent treatments.  
Possibly: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug, but that 
could reasonably have been produced by a number of other factors including underlying 
disease, complications, concomitant drugs, or concurrent treatments.  


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Not Related: A reaction for which sufficient data exist to indicate that the aetiology is 
unrelated to the study drug. 
8.6 
Outcomes of Adverse Events 
Outcome data will be collected for each AE. Options for terms to be applied will include 
resolved, recovered with minor sequelae, recovered with major sequelae, or unresolved.  
8.7 
Adverse Events of Special Interest 
Certain AEs have been identified as AEs of special interest (AESIs) due to the class of drugs 
being studied. These AEs will be captured through spontaneous reporting in the eCRF and 
the reporting of these AESIs will be described in the SAP. An AESI may be serious or 
non-serious. For this study, AESIs based on the class of drugs include: 
• Allergic reactions. 
• Immune complex disease. 
• Severe infections which are defined as: 
o Life threatening or, 
o Requiring hospitalization or, 
o Requiring treatment with antiviral medications, IV antibiotics or medications 
for helminth parasitic infection or, 
o Requiring a permanent discontinuation of study drug. 
• Injection site reactions. 
8.7.1 
Management of Injection Site Reactions 
Subjects will be monitored for unusual signs and symptoms of injection site reactions such as 
pain, localized swelling, tenderness, or erythema. 
If a subject experiences an injection site reaction, pre-medication including acetaminophen 
and/or antihistamine, may be administered per institutional standard at the discretion of the 
Investigator.  
Use of an infusion pump may also be considered to reduce a subject’s injection site reactions 
at the discretion of the Investigator. 


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8.8 
Clinical Laboratory Adverse Events 
Laboratory abnormalities observed during the study that are associated with a medical 
condition will be reported under the AE for that condition. For example, significantly 
elevated creatinine may be included under renal failure. Isolated laboratory abnormalities 
should be reported as AEs if they are deemed clinically significant by the Investigator. 
Criteria for a “clinically significant” laboratory abnormality are: 
• A laboratory abnormality that leads to a dose-limiting toxicity (e.g., an abnormality 
that results in study drug dose reduction, suspension, or discontinuation). 
• A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy). 
• Other laboratory abnormality judged by the Investigator to be of clinical concern 
(e.g., significant fall in haemoglobin not requiring transfusion). 
For laboratory abnormalities that do not meet the above criteria but are outside of normal 
reference range, the Investigator should indicate whether the value is clinically significant or 
not clinically significant for the subject. 
8.9 
Serious Adverse Events 
An AE is considered “serious” if, in the view of the Investigator or Sponsor, it results in any 
of the following outcomes:  
• Death. 
• A life-threatening AE. 
• Inpatient hospitalization or prolongation of existing hospitalization.  
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.  
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate judgment, they may 
jeopardize the subject or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of 
drug dependency or drug abuse.  
Hospitalization for a pre-existing condition, including elective procedures, which has not 
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• Medical history of the subject and concomitant medications. 
• Details of any laboratory tests. 
• Intensity of the event (refer to Section 8.4 for definitions).  
• Relationship of the event to study treatment (refer to Section 8.5 for definitions).  
• Action taken: none; change in the study drug administration (e.g., temporary interruption 
in dosing); drug treatment required; nondrug treatment required; hospitalization or 
prolongation of hospitalization required (complete SAE page); diagnostic procedure 
performed; subject discontinued from treatment (complete End-of-Treatment visit).  
• Outcome: Recovered/Resolved, Recovering/Resolving, Not Recovered/Not 
Resolved/Ongoing, Recovered/Resolved with Sequelae, Fatal, Unknown (notify the 
Medical Monitor immediately and complete the SAE report form). 
8.9.2 
Supplemental Investigations of Serious Adverse Events  
The Investigator and supporting personnel responsible for subject care should discuss with 
the Sponsor’s Medical Monitor any need for supplemental investigations of SAEs. The 
results of these additional assessments conducted must be reported to the Sponsor. If a 
subject dies during participation in the study and a post-mortem examination is performed, a 
copy of the autopsy report must be submitted to the Sponsor. 
8.9.3 
Post-Study Follow-Up of Adverse Events 
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
eCRF. The Sponsor retains the right to request additional information for any subject with 
ongoing AEs/SAEs at the end of the study, if judged necessary. 
8.9.4 
Notification of Post-Study Serious Adverse Events 
Investigators are not obligated to actively follow subjects after the completion of the study. 
SAEs after the Final Visit of the Observation Period do not need to be reported unless 
considered related to the study drug by the investigator, in which case the SAE should be 
reported to the Sponsor. All SAEs must be reported to the Sponsor no later than 24 hours 
after the Investigator recognizes/classifies the event as an SAE, as described in Section 8.9.1. 
8.9.5 
Independent Ethics Committee Notification of Serious Adverse Events 
The Investigator is responsible for promptly notifying their IEC of all SAEs, including any 
follow-up information, occurring at their site and any SAE regulatory report, including any 
follow-up reports that he/she receives from the Sponsor. Documentation of the submission to 
the IEC must be retained for each safety report. As with all IEC communications, the 
Investigator must copy the Sponsor and is also responsible for notifying the Sponsor if their 
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8.9.6 
Health Authority Safety Reports 
The Sponsor or its representatives will submit a safety report to appropriate regulatory 
agencies of any suspected adverse reaction that is both serious and unexpected within the 
appropriate timeframe. 
The Sponsor or its representatives will send the Investigator copies of each safety report 
submitted to regulatory agencies. Safety reports must be submitted to the appropriate IEC as 
per their requirements.  
Documentation of all communications with the IEC and regulatory authorities must be 
retained for each safety report. 
8.9.7 
Overdose 
An overdose is defined as a dose greater than the intended dose level assigned to the cohort. 
In the event of an overdose of study drug, the Investigator should use clinical judgment in 
treating the overdose and contact the Sponsor’s Medical Monitor. The Investigator should 
refer to the relevant documents for detailed information regarding warnings, precautions, 
contraindications, AEs, and other significant data pertaining to the study drug being used in 
this study. Such documents may include, but not be limited to, the IB for study drug. 
8.9.8 
Pregnancy 
To ensure subject safety, each pregnancy in a female subject from Screening until study 
completion must be reported to the Sponsor within 24 hours of learning of its occurrence. 
The pregnancy 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 newborn complications. Pregnancy should be 
recorded on a Paper Pregnancy Report Form and reported by the Investigator to the 
Sponsor’s Clinical Safety Management or designee. Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the 
Sponsor study drug of any pregnancy outcome. Any SAE experienced during pregnancy 
must be reported in the eCRF as per Section 8.9.1. 
8.9.9 
Paternal Exposure 
If a male subject’s partner becomes pregnant during the course of the study, it must be 
reported to the Sponsor within 24 hours of the Investigator learning of its occurrence. 
8.9.10 
Hy’s Law 
Cases where a subject shows an AST or ALT ≥3x ULN and TBL ≥2x ULN may need to be 
reported as SAEs. Please refer to Appendix 1 for further instructions in cases of combined 
increase of aminotransferase and TBL. 


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9 
STATISTICAL CONSIDERATIONS 
An outline of the key statistical methods follows; full details will be described in in the SAP. 
9.1 
Statistical Hypotheses 
No formal statistical hypotheses will be tested in this safety study.  
9.2 
Sample Size Determination 
The primary objective of the study is to assess the safety and tolerability of UPB-101 when 
administered as multiple ascending doses. A sample size of 40 subjects with 8 subjects per 
cohort (6 on active drug + 2 on placebo) is considered sufficient to meet this goal. The 
sample size is not based on formal statistical hypothesis testing. 
9.3 
Populations for Analyses 
The following analysis sets will be used for the planned analyses. 
• Safety Population: Subjects who receive at least 1 dose of study drug. 
• Pharmacokinetic Population: Subjects who receive at least 1 complete dose of study drug 
and for whom at least 1 PK parameter can be estimated. 
• Pharmacodynamic Population: Subjects who receive at least 1 dose of study drug and 
have at least 1 post-baseline blood sample measured for biomarkers.  
9.4 
Statistical Analyses 
9.4.1 
General Considerations 
All safety, immunogenicity, PK, and PD data will be listed by subject. Unless otherwise 
specified, baseline is defined as the last observed measurement, whether scheduled or 
unscheduled, prior to the first dose of study drug.  
UPB-101 treatment groups will be defined based on the cohort and dose assignment (e.g., 
). The placebo treatment 
group will include all subjects assigned to placebo and will be pooled according to dosing 
regimen (e.g., Placebo 
, Placebo 
) or, where appropriate, across all study parts. 
No analysis windows will be defined. Data for repeatedly measured endpoints will be 
analysed according to the nominal visit. Summaries will be grouped by study part to maintain 
visit alignment across treatment groups. 
Continuous variables will be summarized by UPB-101 dose group and pooled placebo, and 
by dosing frequency with descriptive statistics (e.g., number of observations, mean, standard 
deviation, median, interquartile range, maximum, and minimum). Categorical variables will 
be tabulated by frequency and percent of subjects per UPB-101 dose group and pooled 


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placebo, and by dosing frequency. Demographic data will be summarized by treatment, dose, 
and dose regimen. Analyses will be based on observed data only; no data will be imputed. 
9.4.2 
Subject Disposition 
The number of subjects who are randomized, treated, and complete the study will be 
tabulated by treatment group. The data on subject disposition and informed consent will be 
listed.  
9.4.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics and 
listed. Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and listed. 
9.4.4 
Investigational Product Exposure 
Number of injections and total dose received will be tabulated by treatment group. Reasons 
for incomplete and interrupted injections will be listed. 
9.4.5 
Prior and Concomitant Medications 
All medications will be coded using WHODrug. 
Background asthma medications are defined as medications taken for asthma at a stable dose 
during at least 3 months prior to randomization. Background asthma medications will be 
tabulated, and their duration summarized. Changes from the stable dose during the study will 
be listed. 
Medication history, Screening concomitant medications, and post-dose concomitant 
medications will be tabulated by Anatomical Therapeutic Chemical class and preferred term. 
9.4.6 
Safety Analyses  
All safety analyses will be conducted using the Safety Population.  
MedDRA will be used to code verbatim terms of AEs. Adverse events will be summarized 
by system organ class, preferred term, and treatment group for the number and percent of 
subjects reporting AEs, the number of events, and the number of subjects with any AE. All 
AEs will be listed, including onset and resolution dates, verbatim term, preferred term, 
treatment, severity, relationship to treatment, action taken, and outcome. The pooled placebo 
group will be used in these summaries. 
Absolute values and change from baseline physical examinations, clinical laboratory 
evaluations vital signs assessments, and ECG parameters will be summarized by visit and by 
treatment group. The frequency of subjects with safety laboratory results outside of normal 
reference ranges will be tabulated by treatment and visit. No inferential statistical analyses 
are planned for safety parameters. Placebo groups will not be pooled in these summaries. 


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9.4.7 
Immunogenicity Analyses 
Immunogenicity analyses will be conducted on the Safety Population. 
Anti-drug antibody data will be listed for each subject. A selected ADA-positive sample for 
each subject who has ADA-positive results will undergo a confirmatory assay (NAb) to 
assess their neutralizing potential. Summaries of positive ADA test results over time and 
NAb test results may be provided. 
9.4.8 
Pharmacokinetic Analyses 
All PK analyses will be conducted using the PK Population. Actual blood sampling time 
points will be used to evaluate the PK parameters. 
Individual concentrations of UPB-101 will be displayed graphically and listed by treatment 
group. They will be summarized using the number of available observations, the number of 
values below the lower limit of quantification, mean, median, standard deviation, minimum, 
maximum, geometric mean, and geometric coefficient of variation (assuming log-normally 
distributed data). Descriptive statistics of concentrations will be calculated if at least one 
third of the individual data points are quantifiable (≥lower limit of quantification). 
Dose proportionality information will be obtained by comparing PK parameters of UPB-101 
across applicable dose levels. A model will be fitted using all doses and across all cohorts to 
assess dose proportionality for Cmax, tmax, and AUCtau after the first dose. Within each dosing 
regimen, dose proportionality using a comparison of Cmax and AUCtau after the last dose will 
also be assessed using descriptive statistics. 
Immunogenicity, PD biomarkers and clinical outcome measures such as FEV1, CGI-C and 
ACQ-7 will be explored across dose cohorts using dose and exposure-response modelling to 
assess for dose and/or exposure related trends. 
9.4.9 
Exploratory Analyses 
Analysis of all exploratory PD endpoints (biomarkers, flow cytometry assays, CGI-C, 
ACQ-7, and FEV1) will be fully described in the SAP.  
9.4.9.1 
Pulmonary Function Tests 
Analysis of the spirometric data will be fully described in the SAP. 
Baseline for spirometry will be defined as the mean of the 60-minute and 30-minute pre-dose 
values at Visit 4. On dosing days after Visit 4, these are the 60-minute and 30-minute 
pre-dose values. At subsequent (non-dosing) visits, morning trough FEV1 will be defined as 
the mean of 2 measurements performed approximately 30 minutes apart. If one of the 
measurements is not available or conducted post-dose, the other value will be used as the 
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Change from baseline in morning trough FEV1 will be summarized descriptively by visit and 
by treatment group. 
9.4.10 
Administrative Interim Analysis 
An administrative interim analysis will be conducted when, at a minimum, Cohorts 1 and 2 
are expected to have completed dosing. This interim is solely for internal decision-making 
pertaining to matters unrelated to the current study, UPB-CP-01, and so will have no bearing 
on the continued conduct and/or analysis of the study.  


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Regulatory Authority Approval 
The Sponsor will obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements prior to a 
site initiating the study in that country. 
10.2 Ethical Conduct of the Study and Institutional Review Board or 
Independent Ethics Committee Approval 
The study will be conducted in accordance with GCP. These standards respect the following 
guidelines: 
• ICH (ICH E6 (R1) 1996). 
• US Code of Federal Regulations dealing with clinical studies (21 Code of Federal 
Regulations Parts 50, 54, 56, and 312). 
• World Medical Association Declaration of Helsinki (WMA). 
• Any additional regulatory requirements. 
The Investigator (or Sponsor, where applicable) is responsible for ensuring that this protocol, 
the site’s ICF, and any other information that will be presented to potential subjects 
(e.g., advertisements or information that supports or supplements the ICF) are reviewed and 
approved by the appropriate IEC. The Investigator agrees to allow the IEC direct access to all 
relevant documents. The IEC must be constituted in accordance with all applicable 
regulatory requirements. 
The Sponsor will provide the Investigator with relevant documents/data that are needed for 
IEC review and approval of the study. If the protocol, the ICF, or any other information that 
the IEC has approved for presentation to potential subjects is amended during the study, the 
Investigator is responsible for ensuring the IEC reviews and approves, where applicable, 
these amended documents. The Investigator must follow all applicable regulatory 
requirements pertaining to the use of an amended ICF including obtaining IEC approval of 
the amended form before new subjects’ consent to take part in the study using this version of 
the form. The IEC approval of the amended ICF/other information and the approved 
amended ICF/other information must be forwarded to the Sponsor promptly. 
10.3 Subject Information and Consent 
The study will be conducted in accordance with applicable subject privacy requirements. The 
proposed ICF, which will comply with applicable regulations, must be reviewed and 
approved by the IEC and the Sponsor prior to initiation of the study. 


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The Investigator or designee will be responsible for obtaining written informed consent from 
potential subjects prior to any study-specific Screening and entry into the study. A copy of 
the signed ICF will be provided to the subject. The original will be retained by the 
Investigator. 
Sites may opt to utilize a pre-screening consent form to enable complete blood count testing 
which includes the absolute eosinophil number, for consenting potential subjects while they 
consider the ICF for the full study. This pre-screening ICF will also be reviewed and 
approved by the IEC and Sponsor prior to use. The execution, dating, signing, copying, 
distribution, and filing of this ICF will be identical to the ICF of the main study. 
Pre-screening may occur no longer than 90 days prior to Screening Visit 1. 
10.4 Laboratory Accreditation 
Any laboratory facility intended to be used for analysis of clinical laboratory samples 
required by this protocol must provide evidence of adequate licensure or accreditation 
according to the prevailing regulations in that state and/or country. Reference values and/or 
normal ranges for the test results must be provided to the Sponsor. The Sponsor must be 
notified promptly in writing of any changes occurring in reference values during the study. 
10.5 Confidentiality 
10.5.1 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to the Sponsor that information furnished to 
the Investigator by the Sponsor will be maintained in confidence and such information will 
be divulged to the IEC, or similar or expert committee; affiliated institution; and employees 
only under an appropriate understanding of confidentiality with such board or committee, 
affiliated institution, and employees. Data generated by this study will be considered 
confidential by the Investigator, except to the extent that it is included in a publication 
consistent with relevant clauses in Section 10.11. 
10.5.2 
Confidentiality of Subject Records 
By signing this protocol, the Investigator agrees that the Sponsor (or representative), IEC, or 
Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/CRF data. By signing the ICF, the Subject also agrees to this process. If 
study documents will be photocopied during the process of verifying worksheet/CRF 
information, the Subject will be identified by unique code only; full names/initials will be 
masked prior to transmission to Sponsor. In addition, the Investigator agrees to treat all 
subject data used and disclosed in connection with this study in accordance with all 
applicable laws, rules and regulations. 
10.6 Quality Control and Assurance 
The Sponsor or their designee is responsible for implementing and maintaining quality 
control and quality assurance systems with written standard operating procedures to ensure 


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that studies are conducted properly; data are generated, documented, and reported in 
compliance with the protocol, accepted standards of GCP; and all applicable laws, rules, and 
regulations relating to the conduct of the clinical study. 
10.7 Data Management 
Data management procedures and information for this protocol will be provided by the 
Sponsor or their designee. 
10.8 Study Monitoring 
In accordance with applicable regulations, GCP, and the Sponsor (or its designee) 
procedures, the tranScrip’s monitor (or designee) will contact the site prior to subject 
enrolment to review the protocol and data collection procedures with site staff. In addition, 
the monitor will periodically contact the site, including conducting on-site visits. The extent, 
nature, and frequency of on-site visits will be based on such considerations as the study 
objective and/or endpoints, the purpose of the study, study design complexity, and enrolment 
rate. 
During these contacts, the monitor will: 
• Check the progress of the study. 
• Review study data collected. 
• Conduct source document verification. 
• Identify any issues and address their resolution. 
This will be to verify that the: 
• Data are authentic, accurate, and complete. 
• Safety and rights of subjects are being protected. 
• Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues. 
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the Investigator or site staff, as appropriate: 
• Return of all study data to the Sponsor. 
• Resolution of all data queries. 


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• Accountability, reconciliation, and arrangements for all investigational products. 
• Review of site study records for completeness. 
After the final review of the study files, the files should be secured for the appropriate time 
period as specified in Section 10.9. The Investigator will also permit inspection of the study 
files by the Sponsor’s Quality Assurance auditors, and authorized representatives of the FDA 
or other applicable regulatory agencies. 
In exceptional circumstances, related to restrictions due to COVID-19, the Sponsor, in 
agreement with the Principal Investigator and the hospital, may implement monitoring 
activities that may include, among others, remote source data verification. Remote source 
data verification involves sharing of study-related medical records/documents with the 
monitor electronically using a suitably controlled remote access method. 
If remote monitoring is required, no copy of any source records will be collected by the 
monitor and no images will be recorded during the review. 
10.9 Retention of Data 
Documents that individually and collectively permit evaluation of the conduct of the study 
and the quality of the data produced must be maintained for review by the Sponsor’s quality 
assurance auditors and by all applicable regulatory authorities. The period of time these 
documents must be maintained is governed by applicable regulations. The Sponsor or its 
designee will inform the Investigator when these documents may be destroyed. The Sponsor 
or its designee must be notified in writing at least 6 months prior to the intended date of 
disposal of any study record related to this protocol to allow the Sponsor to make alternate 
storage arrangements. 
10.10 Financial Disclosure 
The Principal Investigator or sub-Investigators named on the FDA Form 1572 or the locally 
accepted alternate Investigator Statement form, will need to complete a financial disclosure 
form prior to study initiation, at any time during the study execution if new information 
needs to be disclosed, and for 1 year after study completion. Investigators should make the 
IEC aware of any financial interests that the Investigator has in the investigational product. 
10.11 Publication Policy 
The Sponsor intends to publish the results of all clinical studies it sponsors in compliance 
with the Declaration of Helsinki (http://www.wma.net/en/10home/index.html). Consistent 
with the recommendations of the editors of several leading medical journals, the International 
Committee of Medical Journal Editors (ICMJE), authorship of publications resulting from 
Sponsor-sponsored studies should fairly recognize the activities of those that have made a 
significant contribution to the study. Thus, it is anticipated that authorship will reflect the 
contribution made by Sponsor personnel, the Investigators and others involved, such as 
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In recent years, issues about conflicts of interest and accuracy of the study data have been 
raised in the medical press. Accordingly, the Sponsor has developed publication guidelines as 
described below: 
1. Responsibility: Each Principal Investigator is responsible for the accuracy and 
completeness of all data from their site. The Sponsor (or its representatives) is 
responsible for the accuracy of the data entered into the study databases and for the 
accuracy of the analyses conducted. 
2. Authorship and Publication Committee: The Sponsor, in collaboration with the 
Investigators, will establish the appropriate authorship and responsibility for drafting 
study documents in accordance with the principles of the ICMJE and the International 
Society for Medical Publication Professionals. It is anticipated that a publication 
committee will be formed to assume oversight of these activities. All manuscripts will 
be reviewed and agreed upon before submission for publication by all authors. 
3. Sponsor Review of External Manuscripts: Consistent with the previous bullet 
point, drafts of any and all publications or presentations that may arise from this study 
must be submitted at least 30 days prior to submission for publication or presentation 
to the Sponsor for review, approval, and to ensure consistency with the policy in this 
protocol. The Sponsor will have the right to request appropriate modification to 
correct facts and to represent its opinions, or the opinions of the publication 
committee, if these differ with the proposed publication. Investigators will delete any 
Sponsor confidential information from the publication or presentation upon Sponsor’s 
request. 
4. Confidentiality: Investigators will conduct all interactions with the Sponsor and with 
third parties consistent with the executed confidentiality agreements. While 
publication, by intention, presents the critical scientific data in a public forum, some 
information (such as future plans, results of non-clinical studies, or chemical 
formulae) may still need to remain confidential. 
5. Medical Journal Review: Consistent with the intention of the Sponsor to publish the 
study in a fair and accurate manner, the Sponsor supports diligence in the publication 
review process of medical journals. Accordingly, upon request, all pertinent study 
data and information will be made available as supplemental information for journal 
editors and reviewers to evaluate and audit, e.g., protocol and amendments, data 
tabulations. The journal and reviewers will need to make arrangements to maintain 
the confidentiality of such supplemental information, where relevant, and the Sponsor 
will make suitable arrangements to ensure that the identity of journal reviewers is 
kept confidential. Records will be maintained of reviewers and the respective 
documents and datasets that were reviewed by each of them. 
6. Reporting of Clinical Study Results: To provide transparency in the conduct and 
reporting of randomized clinical studies, the Sponsor reports clinical findings based 
on the guidance of The Consolidated Standards of Reporting Trials Statement 
(Schulz, Altman et al. 2010) and a 25-item checklist which is intended to improve the 


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reporting of a randomized controlled study, and to facilitate reader understanding of 
the study design, conduct, analysis and interpretation, and to support their ability to 
assess the validity of its results. 
7. Internet Clinical Study Listing: In addition, also consistent with the 
recommendations of the ICMJE, the Sponsor will make available appropriate 
information regarding the study via the internet. This will include registration and 
listing of the study on www.clinicaltrials.gov, the US National Institutes of Health 
listing of clinical studies, and other clinical study listings as appropriate (e.g., 
European Union Drug Regulating Authorities Clinical Trials Database; 
https://eudract.ema.europa.eu).  
10.12 Annual Report  
Upstream Bio will be responsible for preparing the Annual Report of the study status and 
submitting the Annual Report to the Regulatory Authorities in each country in which the 
study is conducted as well as to each of the IECs. 
10.13 End of Study Notification and Submission of Summary Report  
Upstream Bio is responsible for preparing and submitting the end of study notification to the 
Ethics Committees and Regulatory Authorities in the EU Member States in which the study 
has been conducted. This must be submitted within 90 days of the end of the study (15 days 
if the study is terminated early).   
For this purpose, the end of the study (study completion) is defined as the Last Patient Last 
Visit. Any change to this definition is considered a significant amendment and MUST be 
notified to (and approval sought from) the Ethics Committees and the Regulatory Authorities 
concerned.  
Upstream Bio will be responsible for preparing and submitting a summary of the Clinical 
Study Report to the regulatory authorities in each member state in which the study was 
conducted within 12 months of the end of the study. This report must follow the ICH E6 (R2) 
guideline (ICH E6(R2) 2016). 


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EMA (2001). "Note for guidance on choice of control group in clinical trials 
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GINA (2021a). "Pocket Guide for Asthma Management and Prevention Based on the Global 
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Gruffydd-Jones, K. (2019). "Unmet needs in asthma." Ther Clin Risk Manag 15: 409-421. 
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Hirota, T., A. Takahashi, M. Kubo, T. Tsunoda, K. Tomita, S. Doi, K. Fujita, A. Miyatake, T. 
Enomoto, T. Miyagawa, M. Adachi, H. Tanaka, A. Niimi, H. Matsumoto, I. Ito, H. Masuko, 
T. Sakamoto, N. Hizawa, M. Taniguchi, J. J. Lima, C. G. Irvin, S. P. Peters, B. E. Himes, A. 
A. Litonjua, K. G. Tantisira, S. T. Weiss, N. Kamatani, Y. Nakamura and M. Tamari (2011). 
"Genome-wide association study identifies three new susceptibility loci for adult asthma in 
the Japanese population." Nat Genet 43(9): 893-896. 
Hospers, J. J., J. P. Schouten, S. T. Weiss, D. S. Postma and B. Rijcken (2000). "Eosinophilia 
is associated with increased all-cause mortality after a follow-up of 30 years in a general 
population sample." Epidemiology 11(3): 261-268. 
ICH E6 (R1) (1996). "Guideline for Good Clinical Practice." 
ICH E6(R2) (2016). "Integrated Addendum to ICH E6(R1): Guideline for Good Clinical 
Practice." 
ICH E9 (1998). "Statistical Principles for Clinical Trials." 
ICH E10 (2001). "Choice of Control Group in Clinical Trials "  CPMP/ICH/364/96. 


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Juniper, E. F., J. Bousquet, L. Abetz and E. D. Bateman (2006). "Identifying 'well-controlled' 
and 'not well-controlled' asthma using the Asthma Control Questionnaire." Respir Med 
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Kerley, C. P., E. Kilbride, P. Greally and B. Elnazir (2016). "Dietary Nitrate Acutely and 
Markedly Increased Exhaled Nitric Oxide in a Cystic Fibrosis Case." Clin Med Res 14(3-4): 
151-155. 
Kostikas, K., C. Brindicci and F. Patalano (2018). "Blood Eosinophils as Biomarkers to 
Drive Treatment Choices in Asthma and COPD." Curr Drug Targets 19(16): 1882-1896. 
Kroll, J. L., C. A. Werchan, D. Rosenfield and T. Ritz (2018). "Acute ingestion of beetroot 
juice increases exhaled nitric oxide in healthy individuals." PLoS One 13(1): e0191030. 
Lambrecht, B. N., H. Hammad and J. V. Fahy (2019). "The Cytokines of Asthma." Immunity 
50(4): 975-991. 
Menzies-Gow, A., J. Corren, A. Bourdin, G. Chupp, E. Israel, M. E. Wechsler, C. E. 
Brightling, J. M. Griffiths, A. Hellqvist, K. Bowen, P. Kaur, G. Almqvist, S. Ponnarambil 
and G. Colice (2021). "Tezepelumab in Adults and Adolescents with Severe, Uncontrolled 
Asthma." N Engl J Med 384(19): 1800-1809. 
Murdoch, J. R. and C. M. Lloyd (2010). "Chronic inflammation and asthma." Mutat Res 
690(1-2): 24-39. 
Pandey, A., K. Ozaki, H. Baumann, S. D. Levin, A. Puel, A. G. Farr, S. F. Ziegler, W. J. 
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Park, L. S., U. Martin, K. Garka, B. Gliniak, J. P. Di Santo, W. Muller, D. A. Largaespada, 
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Sims (2000). "Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: 
Formation of a functional heteromeric complex requires interleukin 7 receptor." J Exp Med 
192(5): 659-670. 
Price, D., A. M. Wilson, A. Chisholm, A. Rigazio, A. Burden, M. Thomas and C. King 
(2016). "Predicting frequent asthma exacerbations using blood eosinophil count and other 
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Reche, P. A., V. Soumelis, D. M. Gorman, T. Clifford, M. Liu, M. Travis, S. M. Zurawski, J. 
Johnston, Y. J. Liu, H. Spits, R. de Waal Malefyt, R. A. Kastelein and J. F. Bazan (2001). 
"Human thymic stromal lymphopoietin preferentially stimulates myeloid cells." J Immunol 
167(1): 336-343. 
Schulz, K. F., D. G. Altman, D. Moher and C. Group (2010). "CONSORT 2010 Statement: 
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Shi, L., S. W. Leu, F. Xu, X. Zhou, H. Yin, L. Cai and L. Zhang (2008). "Local blockade of 
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Shikotra, A., D. F. Choy, C. M. Ohri, E. Doran, C. Butler, B. Hargadon, M. Shelley, A. R. 
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(2012). "Increased expression of immunoreactive thymic stromal lymphopoietin in patients 
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Shamji, M. J. Edwards, T. H. Lee and C. J. Corrigan (2008). "Expression and cellular 
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Zhou, B., M. R. Comeau, T. De Smedt, H. D. Liggitt, M. E. Dahl, D. B. Lewis, D. Gyarmati, 
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12  APPENDICES 
Appendix 1 
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy that reveals an increase of 
serum aminotransferases ≥3 × ULN or bilirubin ≥2 × ULN should undergo detailed testing 
for liver enzymes using the study Chemistry panel defined in Table 10 which includes ALT, 
AST, alkaline phosphatase (ALP) and TBL. Testing should be repeated within 48 to 72 hours 
of notification of the test results. For studies for which a central laboratory is used, alerts will 
be generated by the central laboratory to inform the Investigator, Sponsor’s Medical Monitor, 
and study team when ALT, AST or TBL exceed the thresholds above. Subjects should be 
asked if they have any symptoms suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate or severe by the Investigator 
where ULN: 
ALT or AST   
 
 
 
TBL 
Moderate  
>3 × ULN  
or  
>2 × ULN 
Severe† 
 
>3 × ULN  
and 
>2× ULN 
† Hy’s Law Definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% 
mortality (or transplant). The 2 “requirements” for Hy’s Law are:  
• Evidence that a drug can cause hepatocellular-type injury, generally shown by an 
increase in transaminase elevations higher than 3 ×ULN (“2 × ULN elevations are too 
common in treated and untreated subjects to be discriminating”).  
• Cases of increased bilirubin (at least 2 × ULN) with concurrent transaminase 
elevations at least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin 
obstruction (elevated ALP) or Gilbert’s syndrome (Temple 2006). 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
• ALT or AST >8 × ULN. 
• ALT or AST >5 × ULN for more than 2 weeks. 
• ALT or AST >3 × ULN and International Normalized Ratio (INR) >1.5 (If INR 
testing is applicable/evaluated). 


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• ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
The Investigator may determine that abnormal liver test results, other than as described 
above, may qualify as moderate or severe abnormalities, and require additional monitoring 
and follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The Investigator or designee should complete the 
liver abnormality case report form (LA-CRF) that has been developed globally and can be 
activated for any study or another appropriate document (e.g., liver abnormality source 
consistent with the LA-CRF content). Subjects with confirmed abnormal liver test results 
should be followed up as described below. 
Confirmed moderately abnormal liver tests should be repeated 2 to 3 times weekly then 
weekly or less if abnormalities stabilize or the study drug has been discontinued and the 
subject is asymptomatic. 
Severe hepatic function abnormalities as defined above, in the absence of another aetiology, 
may be considered an important medical event and may be reported as an SAE. The Sponsor 
should be contacted and informed of all subjects for whom severe hepatic liver function 
abnormalities possibly attributable to study drug are observed. 
To further assess abnormal hepatic laboratory findings, the Investigator is expected to: 
• Obtain a more detailed history of symptoms and prior or concurrent diseases. 
Symptoms and new-onset diseases should be recorded as “AEs” on the AE page. 
Illnesses and conditions such as hypotensive events and decompensated cardiac 
disease that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis is seen in obese hyperlipoproteinemic and/or diabetic subjects, and 
may be associated with fluctuating aminotransferase levels. The Investigator should 
ensure that the medical history documentation captures any illness that predates 
clinical study enrolment that may be relevant in assessing hepatic function. 
• Obtain a history of concomitant drug use (including non-prescription medications, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page. Information on alcohol, other substance use, and diet should be 
entered on the LA-CRF or an appropriate document (e.g., liver abnormality page 
from the source). 
• Obtain a history of exposure to environmental chemical agents. 
• Based on the subject’s history, other testing may be appropriate including: 


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o Acute viral hepatitis (A, B, C, D, E or other infectious agents). 
o Ultrasound or other imaging to assess biliary tract disease. 
o Other clinical laboratory tests including INR, direct bilirubin. 
• Consider gastroenterology or hepatology consultations. 
• Submit results for any additional testing and possible aetiology on the LA-CRF or an 
appropriate document (e.g., liver abnormality page from the source). 
Study Discontinuation 
In the absence of an explanation for increased liver tests, such as viral hepatitis, pre-existing 
or acute liver disease or exposure to other agents associated with liver injury, the subject may 
be discontinued from the clinical study. The Investigator may determine that it is not in the 
subject’s best interest to continue clinical study enrolment. Discontinuation of treatment 
should be considered if: 
• ALT or AST >8 × ULN. 
• ALT or AST >5 × ULN for more than 2 weeks. 
• ALT or AST >3 × ULN and TBL >2 × ULN or INR >1.5) (If INR testing is 
applicable/evaluated). 
• ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
In addition, if close monitoring of a subject with moderate or severe hepatic laboratory tests 
is not possible, clinical study drug should be discontinued. 
References 
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
April;15(Suppl 4):241-3 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009. 
 


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Appendix 2 
Spirometry Performance 
Spirometry data of the highest quality must be obtained for proper interpretation of the 
results of this protocol. To these ends, a standard spirometer will be used (provided by the 
Sponsor), central training provided, qualification will be required, and specific operating 
instruction will also be provided. 
Methods for spirometry performance will be included in the spirometry laboratory manual.  




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Appendix 4 
Investigator’s Signature 
Study Title: A Phase 1, Randomized, Double-blind, Placebo-controlled, Multiple 
Ascending -Dose Study to Assess the Safety, Tolerability, Immunogenicity, Pharmacokinetics 
and Pharmacodynamics of UPB-101 in Subjects with Asthma 
Study Number: UPB-CP-01 
Protocol Version: 9.0 Final Date: 31 March 2023 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with the protocol and with any other study conduct 
procedures provided by the Sponsor. 
• 
Not to implement any changes to the protocol without agreement from the Sponsor and 
prior review and written approval from the Institutional Review Board/ Independent 
Ethics Committee (IEC), except where necessary to eliminate an immediate hazard to the 
subjects, or for administrative aspects of the study (where permitted by all applicable 
regulatory requirements). 
• 
That I am aware of, and will comply with, Good Clinical Practices and all applicable 
regulatory requirements. 
• 
That I am thoroughly familiar with the appropriate use of the investigational product, and 
other information provided by the Sponsor including, but not limited to, the following: 
the protocol and the current Investigator’s Brochure (IB). 
• 
To ensure that all persons assisting me with the study are qualified, adequately informed 
about the investigational product and of their study-related duties and functions. 
• 
To supply the Sponsor with any necessary information regarding ownership interest and 
financial ties; to promptly update this information if any relevant changes occur during 
the course of the study and for 1 year following completion of the study; and agree that 
the Sponsor may disclose any information it has about such ownership interests and 
financial ties to regulatory authorities. 
• 
To report all information or data in accordance with the protocol and any other study 
conduct procedures provided by the Sponsor. 
• 
That since the information in this protocol and IB is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or 
conduct of the study is prohibited. 
• 
To accurately transfer all required data from each subject’s source document to the 
electronic case report forms (eCRFs). The eCRFs will be provided to the Sponsor in a 
timely manner at the completion of the study, or as otherwise specified by the Sponsor. 
• 
To allow authorized representatives of the Sponsor or regulatory authority representatives 
to conduct on-site visits to review, audit, and copy study documents. I will personally 
meet with these representatives to answer any study-related questions. 
Signature:                                                                                              Date:            
 
 
Name:           
 
 
 
 
 
 
 
 Site Name:            
 
 
 
 
 
  
  
Site number:   0__         


UPB-101 
Upstream Bio  
Clinical Study Protocol: UPB-CP-01 
Version 9.00, 31 March 2023
 
 
 
 
Confidential and Proprietary 
Page 107 of 111 
 
13 VERSION HISTORY 
Version 4.0 of the protocol was the initial version approved by the MHRA/REC, changes to 
prior versions are not detailed below as they were not implemented at the study sites. 
 
Version 9.0; 31 March 2023 
Change 
Reason for Change 
Protocol synopsis, Section 1.7 Study Posology, Section 3.1.1 Study Design: 
Cohorts, Section 7.2.1 Dosing Instructions Table 12 
 
Clarification that Part B cohorts are adaptive and optional in nature and may 
not all be implemented.  
Clarification 
Protocol synopsis, Section 3.1.1 Study Design: Cohorts, Section 4 Study 
Population Selection and Withdrawal Criteria 
 
Approximate number of subjects update to 24 to 40 to reflect adaptive and 
optional nature of Part B cohorts. 
Clarification 
Protocol synopsis, Section 1.7 Study Posology, Section 7.2.1 Dosing 
Instructions Table 12, Figure 2: Study Design, Section 3.6.3 Cohorts with 
 Dosing Intervals, Section 7.2.4 Cohorts with 
 Dosing Intervals, 
Section 9.4.1 General Considerations 
 
Removal of the 
 dose for subjects in Cohort 4. Regimen changed from 
 
Change 
Protocol synopsis, Section 3.1.2 Study Design: Periods, Section 3.7 
Observation Period, Section 3.7.3 Cohorts with 
 Dosing Interval, 
Section 4.9.1 Duration of Study Participation 
 
Observation period for Cohort 4 amendment to 8 months following 
 
dose. 
Change 
Protocol synopsis, Section 9.4.6 Safety Analyses 
 
Removal of detail relating to version of MedDRA to be used for the study 
This detail will be captured in the Data Management Plan. 
Clarification 
 
Table 8: Schedule of Events – Cohorts with 
 Dosing Interval 
 
Removal of the 
 dose for subjects in Cohort 4. Overnight admission 
and post-dose procedures will not be performed for this cohort. 
Change 
Section 6.1.4 Flow Cytometry 
Addition of statement that analysis of blood samples for pSTAT may be 
discontinued, based on assay status. 
Addition 
Section 9.4.11 Weeks 24 and 32 Analyses 
 
Removal of section related to monitoring and data management details 
related to Week 24 and Week 32 analysis. Monitoring and data management 
expectations are described in separate Monitoring and Data Management 
Plans, and analysis will be performed per standard practice. 
Change 
 


UPB-101 
Upstream Bio  
Clinical Study Protocol: UPB-CP-01 
Version 9.00, 31 March 2023
 
 
 
 
Confidential and Proprietary 
Page 108 of 111 
 
Version 8.0; 17 January 2023 
Change 
Reason for Change 
Protocol Synopsis, Section 3.1: Overall Study Design and Plan 
Extension of study period end date from May 2023 to October 2023. 
Clarification/Correction 
Protocol Synopsis, Section 7.2.1: Dosing Instructions, Table 12 
Specification of dose level, frequency of administration and 
number of injections to achieve the dose for Cohort 4 
Addition 
Protocol Synopsis, Section 7.2.1: Dosing Instructions, Table 12 
Addition of FeNO and blood samples for haematology including eosinophils 
to Visit 5 (D2), Visit 6 (D4), Visit 16 (D86), Visit 17 (D88), Visit 18 (D92) 
and Visit 19 (D99) for participants enrolled in Cohort 4.  
Addition 
Section 1.7: Rationale of Dose Regimen and Duration of Treatment – Local 
Tolerability 
Include injection information specific to the 
mg dose  
Addition 
Section 1.7: Rationale of Dose Regiment and Duration of Treatment – Study 
Posology, and Section 3.1.1: Study Design: Cohorts 
Clarification to the timing of transition to Part B 
Clarification/Correction 
Section 3.1.3: General Considerations for Study Conduct 
Update to Cohort 4 portion of the study design figure to replace the generic 
Adaptive Design notation with the specific dose to be administered to 
participants in Cohort 4 
Addition 
Section 3.3: Schedule of Events, Table 5 
Addition of FeNO and haematology with Eosinophils to visits 5 and 6 for 
participants in Cohort 4 
Addition 
Section 3.3: Schedule of Events, Table 8 
Addition of FeNO and haematology with Eosinophils to visits 16, 17, 18, 
and 19 for participants in Cohort 4 
Addition 
Legend and footnotes for Table 4 through Table 8 
Addition of footnotes m and n which provide instruction that FeNO ad 
haematology with Eosinophils performed at Visit 5, 6, 16, 17, 18 and 19 
apply only to participants enrolled in Cohort 4 
Addition 
Section 7.2.1: Dosing Instructions 
Dose level of 
mL to deliver 
 mg of UPB-101 added to clarify the 
volume of drug product to be administered at that dose.  Information also 
added to specify the volume of placebo to be delivered for participants in the 
 mg cohort. 
Addition 
 
Version 7.0; 27 October 2022 
Change 
Reason for Change 
Synopsis, Section 1.6 Rationale of Study Design, Section 3.1 
Overall Study Design and Plan, and Section 5.8 Safety Review 
Committee 
Removal of language related to parallel-sequential cohort 
approach, which enables subjects to be enrolled in cohort 3 prior to 
completion of cohort 2.  Updates to language related to meetings 
for Safety Review Committee.  
Clarification/Correction 
 


UPB-101 
Upstream Bio  
Clinical Study Protocol: UPB-CP-01 
Version 9.00, 31 March 2023
 
 
 
 
Confidential and Proprietary 
Page 109 of 111 
 
Version 6.0; 14 September 2022 
Change 
Reason for Change 
Section 4.1 Inclusion Criterion 2: 
Upper age range limited changed from 55 to 60 years of age 
Expand inclusion criteria 
Section 4.1 Inclusion Criterion 5: 
Adjustment to the eosinophils criterion to allow subjects with 
150 to 199 eosinophils cells/µL to be considered when FeNO is 
greater than 25 ppb at the same visit. 
Expand inclusion criteria  
Section 4.1 Inclusion Criterion 10: 
Requirement for participants to be fully vaccinated against Covid-
19 removed.  
No longer valid 
Section 3.3 Schedule of events, Table 8: 
Visit window changed from ±3 days to ±5 days for later visits 
Allow more flexibility 
Protocol cover page: 
The blinded medical monitors contact telephone number replaced 
with a 24/7 cascade telephone number 
Addition 
 
Version 5.0; 18 August 2022 
Change 
Reason for Change 
Secondary Endpoints, Exploratory Endpoints: 
All references to Plasma UPB-101 concentrations corrected to 
Serum UPB-101 concentrations 
Correction 
Timing of PD and PK assessments (All Study Periods): 
Correction that requirements for all PD and PK assessments to be 
conducted between 6 AM and 10 AM does not apply to spirometry 
assessments. This allows the spirometry measurements to be 
collected at appropriate times relating to other assessments/dosing. 
Removal of duplicate wording where appropriate to improve 
clarity. 
Correction/Clarification 
Inclusion criteria: 
Clarification that requirement for contraception for female subjects 
only applies when engaging in sexual activity with a male partner 
Clarification that males who have a partner of CBP must either be 
sterile or their partner must use contraception  
Clarification 
Exploratory assessments; section 6.1.3: 
Remove serum when referring to total IgE measurements 
Correction 
Section 3.2, description of Screening Period 
Clarification 


UPB-101 
Upstream Bio  
Clinical Study Protocol: UPB-CP-01 
Version 9.00, 31 March 2023
 
 
 
 
Confidential and Proprietary 
Page 110 of 111 
 
Clarification that the Screening Period is defined as Day -21 to 
Day -1. 
Section 3.2 Study Activities 
Order of assessments updated to allow blood draws to occur earlier 
in the visit to minimise diurnal variations in the level of 
eosinophils. 
Correction 
Section 3.3 Schedule of events: 
Addition of explicit statement to allow procedures for Visit 1 to be 
conducted across multiple days. 
Clarification 
Section 3.3 Schedule of events, Table 4 
Removal of requirement to perform CGI-C assessment prior to 
dosing. This assessment records the change in the asthmatic’s 
status since the baseline and is therefore not appropriate prior to 
dosing. 
Correction 
Section 3.3 Schedule of events, Table 6, Table 7 and Table 8 
COVID testing added for Day 
 for 
 and 
 cohorts and 
for Days 
 and 
 for 
 cohorts. 
Correction 
Section 3.3 Schedule of events Table 7: 
Samples for future analysis of additional cytokines added for 
 
cohorts, Day 10 
Correction 
Section 3.3 Schedule of events Table 8: 
Visit window of ±3 days added for D127 and D155 for 
 
cohorts 
Correction 
Section 3.3 Schedule of events Table 4 to Table 8 
Addition of footnote h to ACQ-7 assessments 
On days where Spirometry is not performed, ACQ-7 question 7 
will be completed by the investigator based on the FEV1 value 
from the first measurement on the following morning. 
Note: footnote letters are reassigned as needed to accommodate the 
new footnote h. 
Addition 
Section 4.3 Future Cohort Eligibility 
12. Clarification for Future Cohort Eligibility allowing rescreening 
of subjects who failed eligibility due to potential diurnal variations 
in eosinophil levels drawn after 11 am. 
Clarification 
Section 4.4 Re-screening Criteria 
Clarification to process for repeating of tests that may be remedied 
with time when enrolment criteria are initially failed. 
Clarification 
Section 5.4.6 Clinical Laboratory Assessments 
Clarification that eosinophil data will be provided to sites during 
screening but not afterwards. 
Clarification/Addition 


UPB-101 
Upstream Bio  
Clinical Study Protocol: UPB-CP-01 
Version 9.00, 31 March 2023
 
 
 
 
Confidential and Proprietary 
Page 111 of 111 
 
Addition of requirements for monocytes and basophils data 
obtained after screening to not be provided to any blinded parties 
including site personnel in order to remove the possibility of 
eosinophil data being calculated. 
Section 6.2.1 Asthma Clinical Global Impression of Change 
Clarification that baseline for assessment is Day -1. 
CGI-C is an assessment of the change vs. that baseline and is 
therefore not required on or prior to Day -1. 
Clarification/Correction 
Section 6.2.2 Asthma Control Questionnaire 
Addition that if the ACQ is to be performed on a day without 
FEV1 predicted assessment, question 7 will be completed by the 
investigator based on FEV1 value from the first measurement on 
the following morning. 
Addition 
Section 7.5 Blinding 
Clarification that blinded site personnel may dose subjects 
provided all of the blinding conditions are met 
Clarification 
Section 7.5.1 Emergency Unblinding of Treatment Assignment 
Clarification that the Investigator is encouraged to discuss options 
with the blinded Medical Monitor and to notify the blinded 
Medical Monitor as soon as possible. 
Clarification 
Appendix 1: Liver Safety Monitoring and Assessment: 
Clarification to process of delivery of liver safety monitoring alerts 
from central laboratory and assessment of the parameters by the 
Investigator 
Clarification 
 

SAP_001.pdf: 
Upstream Bio/UPB-CP-01 
CONFIDENTIAL 
S-cubed Biometrics Ltd. Statistical Analysis Plan Page 1 of 115
Final Version 03-00 17Nov2023
 
 
 
 
STATISTICAL ANALYSIS PLAN 
FINAL VERSION 03.00, 17 NOVEMBER 2023 
 
 
A Phase 1, Randomized, Double-blind, Placebo-controlled, Multiple Ascending 
Dose Study to Assess the Safety, Tolerability, Immunogenicity, 
Pharmacokinetics and Pharmacodynamics of UPB-101 in Subjects with 
Asthma 
 
UPB-CP-01 
 
Prepared by: S-cubed Biometrics Ltd. 
For: Upstream Bio 
 
 
 
 
 
 


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CONFIDENTIAL 
 
S-cubed Biometrics Ltd. Statistical Analysis Plan Page 2 of 115 
Final Version 03-00, 17Nov2023 
CONTENTS 
1. 
STATISTICAL ANALYSIS PLAN APPROVAL FORM............................................................................ 4 
2. 
STATISTICAL ANALYSIS PLAN AUTHORS........................................................................................ 5 
3. 
LIST OF ABBREVIATIONS .............................................................................................................. 6 
4. 
INTRODUCTION ........................................................................................................................... 8 
5. 
STUDY OBJECTIVES .................................................................................................................... 11 
5.1. Primary Objective(s) .......................................................................................................... 11 
5.2 Secondary Objective(s) ........................................................................................................ 11 
5.3 Exploratory Objective(s) ...................................................................................................... 11 
6. 
STUDY DESIGN ........................................................................................................................... 12 
6.1. Summary of Study Design .................................................................................................. 12 
6.1.1. Safety Review Committee ...................................................................................... 13 
6.2. Randomisation and Blinding .............................................................................................. 13 
6.3. Time and Events Schedule ................................................................................................. 15 
6.4. Interim Analysis / Data Monitoring .................................................................................... 23 
7. 
STUDY ENDPOINTS .................................................................................................................... 24 
7.1. Primary Endpoint ............................................................................................................... 24 
7.2. Secondary Endpoints ......................................................................................................... 24 
7.3. Exploratory Endpoints ....................................................................................................... 24 
8. 
SAMPLE SIZE .............................................................................................................................. 25 
9. 
STUDY ANALYSIS SETS ............................................................................................................... 26 
10. PLANNED STATISTICAL METHODS .............................................................................................. 27 
10.1. Statistical Considerations ................................................................................................... 27 
10.1.1. General definitions ................................................................................................. 27 
10.1.2. Administrative Interim Analysis .............................................................................. 27 
10.1.3. Data Presentation .................................................................................................. 27 
10.1.4. Statistical Testing and Estimation .......................................................................... 29 
10.1.5. Handling of Dropouts or Missing Data ................................................................... 29 
10.1.6. Multiple Comparison/Multiplicity ........................................................................... 29 
10.1.7. Examination of Subgroups ..................................................................................... 29 
10.1.8. Model checking ...................................................................................................... 29 
10.1.9. Software ................................................................................................................ 29 


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10.1.10. Data Conversion (CDISC) .................................................................................... 30 
10.2. Participant Disposition ....................................................................................................... 30 
10.3. Protocol Deviations ........................................................................................................... 30 
10.4. Demographic and other Baseline Characteristics ............................................................... 30 
10.4.1. Demographics ........................................................................................................ 30 
10.4.2. Other Baseline Characteristics ................................................................................ 30 
10.4.3. Medical History ...................................................................................................... 30 
10.5. Prior and Concomitant Medications................................................................................... 30 
10.6. Pregnancy.......................................................................................................................... 31 
10.7. Other Baseline/Screening Tests ......................................................................................... 31 
10.8. Investigational Product Exposure ....................................................................................... 31 
10.9. Pharmacokinetic Analysis .................................................................................................. 31 
10.10. 
Immunogenicity Analysis ........................................................................................... 32 
10.11. 
Pharmacodynamic Analysis ........................................................................................ 32 
10.11.1. Biomarkers ........................................................................................................ 32 
10.11.2. Spirometry ......................................................................................................... 32 
10.11.3. CGI-C ................................................................................................................. 33 
10.11.4. ACQ-7 ................................................................................................................ 33 
10.12. 
Safety Analysis ........................................................................................................... 34 
10.12.1. Injection Site Reactions ...................................................................................... 34 
10.12.2. Adverse Events .................................................................................................. 34 
10.12.3. Laboratory Variables ......................................................................................... 35 
10.12.4. Vital Signs .......................................................................................................... 36 
10.12.5. Physical Examination ......................................................................................... 36 
10.12.6. 12-Lead ECG ...................................................................................................... 36 
11. CHANGES TO THE PROTOCOL SPECIFIED ANALYSIS DETAILED IN THE STATISTICAL ANALYSIS PLAN
 
38 
12. REFERENCES .............................................................................................................................. 39 
13. TABLES, FIGURES AND LISTINGS................................................................................................. 40 
13.1. Specific Presentation Details .............................................................................................. 40 
13.2. List of Tables...................................................................................................................... 41 
13.3. List of Figures .................................................................................................................... 45 
13.4. List of Listings .................................................................................................................... 46 
14. TABLE AND LISTING SHELLS ....................................................................................................... 49 
 






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3. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ACQ-7 
Asthma Control Questionnaire-7 
ADA 
Anti-Drug Antibody 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BDRM 
Blinded data review meeting  
ɴ-HCG 
Beta human chorionic gonadotropin 
BLQ 
Below level of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
Bpm 
Beats per minute 
CGI-C 
Clinicians Global Impression of Change 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
FeNO 
Fractional exhaled nitrous oxide 
FEV1 
Forced expiratory volume in 1 second  
FSH 
Follicle stimulating hormone 
FVC 
Forced vital capacity  
GM 
Geometric Mean 
GSD 
Geometric Standard Deviation 
HbsAg 
Hepatitis B surface antigen 
HCAb 
Hepatitis C antibodies 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
HR 
Heart Rate 
ICF 
Informed Consent Form 
IFN 
Interferon 
IgE 
Immunoglobulin E 
IL- 
Interleukin- 
INR 
International Normalized Ratio 
IP-10 
Interferon gamma-induced protein 10 
IV 
Intravenous 
IMP 
Investigational medicinal product 


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Abbreviation 
Definition 
LLOQ 
Lower Limit of Quantification 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralising Antibody 
PD 
Pharmacodynamic 
PEF 
Peak Expiratory Flow 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
pSTAT 
Phosphorylated signal transducer and activator of transcription  
PT 
Prothrombin time 
PT 
Preferred Term 
Q1 
Lower Quartile 
 
every 
weeks 
 
every weeks 
 
every  weeks 
QTc 
QT interval corrected 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
Q3 
Upper Quartile 
RR 
Respiratory rate 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard Deviation 
SE 
Standard Error  
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TARC 
thymus activation regulated chemokine 
TB 
Tuberculosis 
TEAE 
Treatment emergent adverse event 
TFL 
Tables, Figures and Listings 
TSLP 
thymic stromal lymphopoietin 
ULN 
upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organisation 
 


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4. INTRODUCTION 
This statistical analysis plan (SAP) explains in detail the statistical analyses that will be performed for 
the Upstream Bio UPB-CP-01 study. The study is sponsored by Upstream Bio and being conducted in 
partnership with tranScrip. The analysis is outlined within the study protocol V8.0, dated 17 Jan 2023, 
and this SAP contains a more technical and detailed description of those analyses outlined in the 
protocol. In particular, information is provided on the definitions of the study populations, and it also 
details the list of Tables, Figures and Listings (TFL) that will be produced by S-cubed Biometrics for use 
and inclusion with the Clinical Study Report (CSR). 
This SAP provides a detailed description of the analyses that will be undertaken at the time of each 
analysis and has been written and finalised before the statistical and programming teams are 
unblinded for the Primary (Week 24) Analysis. The Sponsor personnel are unblinded throughout the 
study and so their involvement in any changes to the statistical analysis specified in the SAP beyond 
the first draft will be documented in an appendix to the final SAP. 
A Blinded Data Review Meeting (BDRM) will be conducted when the study is complete (all subjects 
have completed Week 32 visit) and data is cleaned, prior to final database lock. 
Additionally, an unblinded administrative interim analysis will take place prior to the Primary Analysis. 
The outputs and analyses required for the administrative interim analysis are described in this SAP 
also. 
Any deviations from the protocol specified analyses will be listed in Section 11, and any deviations 
from the analyses stated within this SAP, will be described within the CSR. 
Below is a summary of the protocol updates, any changes required to the statistical analysis plan (SAP) 
as a result of these changes have been incorporated as appropriate. 
Following MHRA/REC review, Version 4.0 was created which updated the inclusion criteria and 
restrictions related to pregnancy and contraception, increased the frequency of symptom driven 
physical examinations and amended the wording around stopping criteria and restarting the trial. 
Version 5.0 made a number of non-substantial changes to the protocol: 
x 
Correction to order of assessments to allow blood draws to occur earlier in the visit to minimise 
diurnal variations in the level of eosinophils.  
x 
Corrections/clarifications to timing of PK/PD assessments to be conducted between 6 AM and 
10 AM. Spirometry assessments are excluded from the 6 – 10 AM time window to allow them 
to be collected at appropriate times relating to other assessments/dosing.  
x 
Clarification that requirement for contraception for female subjects only applies when 
engaging in sexual activity with a male partner. Clarification that males who have a partner of 
child-bearing potential must either be sterile or their partner must use contraception.  
x 
Clarification that the Screening Period is defined as Day -21 to Day -1.  
x 
Addition of explicit statement to allow procedures for Visit 1 to be conducted across multiple 
days.  
x 
Correction to Schedule of Events Table 6, Table 7 and Table 8. COVID testing added for Day 78 
for 
 and 
 cohorts and for Days 127 and 155 for 
 cohorts.  
x 
Correction to Schedule of Events, Table 7. Samples for future analysis of additional cytokines 
added for 
 cohorts, Day 10.  
x 
Correction to Schedule of Events, Table 8. Visit window of ±3 days added for D127 and D155 
for 
 cohorts.  


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x 
Clarification that on days where Spirometry is not performed, ACQ-7 question 7 will be 
completed by the investigator based on the FEV1 value from the first measurement on the 
following morning.  
x 
Clarification/Correction to assessment of Asthma Clinical Global Impression of Change (CGI-C). 
CGI-C is an assessment of the change vs. baseline (Day -1) and is therefore not required on or 
prior to Day -1.  
x 
Clarification for repeating of tests that may be remedied with time when enrolment criteria 
are initially failed.  
x 
Clarification for Future Cohort Eligibility allowing rescreening of subjects who failed eligibility 
due to potential diurnal variations in eosinophil levels drawn after 11 am.  
x 
Clarification to Clinical Laboratory Assessments stating that eosinophil data will be provided 
to sites during screening but not afterwards. Addition of requirements for monocytes and 
basophils data obtained after screening to not be provided to any blinded parties including 
site personnel in order to remove the possibility of eosinophil data being calculated.  
x 
Clarification that blinded site personnel may dose subjects provided all of the blinding 
conditions are met.  
x 
Clarification to management of Emergency Unblinding of Treatment Assignment. The 
Investigator is encouraged to discuss options with the blinded Medical Monitor and to notify 
the blinded Medical Monitor as soon as possible.  
x 
Clarification for process of delivery of liver safety monitoring alerts from central laboratory 
and assessment of the parameters by the Investigator (Appendix 1).   
x 
Correction of all references to Plasma UPB-101 concentrations to Serum UPB-101 
concentrations.  
x 
Correction to remove “serum” in all instances of total IgE measurements.  
Version 6.0 was another non-substantial amendment which updated the following: 
x 
Adjustment to the acceptable upper age limit from 55 to 60 years.  
x 
Modification to the eosinophils requirement during the Screening Period, allowing for 
participants with eosinophil count ш150 and ф200 cells/μL to be considered in instances where 
their fractional exhaled nitric oxide (FeNO) is greater than 25 parts per billion (ppb) at either 
Visit 1 or Visit 2.  
x 
Removal of the requirement for participants to be fully vaccinated against SARSCoV-2 
(Coronavirus disease 2019 [COVID19]).  
x 
Expansion of the window for later visits from +/- 3 to +/- 5 day.  
x 
Replacement of the blinded medical monitor’s contact telephone number with a 24/7 
telephone call cascade number.  
Version 7.0 was a substantial protocol amendment and updated: 
x 
Removal of language specifying cohort enrolment as parallel-sequential in nature. This change 
enables enrolment into Cohort 3 following partial enrolment into Cohort 2 due to the 
temporary halt to dosing.  
x 
Updates to language related to Safety Review Committee which according to the original 
protocol would have been convened only between the second and third doses of Cohorts 1 
and 2. 
Version 8.0 was a non-substantial amendment and updated: 
x 
Addition of timepoints for evaluation of the pharmacodynamic (PD) effect of UPB-101 
biomarkers, specficially, the fractional exhaled nitric oxide (FeNO) and blood eosinophil 
numbers to participants enrolled in Cohort 4.   
x 
Specification of the dose level and regimen to be administered to participants enrolled in 
Cohort 4.  


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x 
Extension of the estimated study end date to October 2023.  
 


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5. STUDY OBJECTIVES 
5.1. Primary Objective(s) 
To assess the safety and tolerability of UPB-101 when administered as multiple ascending doses. 
5.2 Secondary Objective(s) 
To assess the immunogenicity of UPB-101 when administered as multiple ascending doses.  
To characterize the pharmacokinetics (PK) of multiple ascending doses of UPB-101. 
5.3 Exploratory Objective(s) 
To assess 32-week extended safety and tolerability of UPB-101 when administered as multiple 
ascending doses. 
To assess 32-week extended immunogenicity of UPB-101 when administered as multiple ascending 
doses. 
To characterize 32-week extended PK of multiple ascending doses of UPB-101. 
To assess the pharmacodynamic (PD) effect of UPB-101 on biomarkers related to asthma and/or the 
thymic stromal lymphopoietin (TSLP) pathway. 
To assess the PD effect of UPB-101 on clinician and subject impression of overall asthma severity. 
To explore the PD effect of UPB-101 on lung function. 
 
 
  
 


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6. STUDY DESIGN 
6.1. Summary of Study Design 
This is a two-part Phase 1, multi-centre randomized, double-blind (Investigator and Subject blinded; 
Sponsor unblinded), placebo-controlled, multiple ascending dose study to assess the safety, 
tolerability, immunogenicity, PK, and PD of UPB-101 administered subcutaneous (SC) to adult subjects 
with asthma.  
The study consists of Part A and Part B. Part A includes 3 cohorts with pre-set dosing regimens. Part B 
includes 2 adaptive design cohorts whose doses and dosing intervals will be decided based upon the 
safety, PK, and PD results from Part A available to the unblinded Sponsor. The regimens selected for 
Part B will not exceed the exposures (i.e., doses and/or dosing intervals) included in Part A.  
The study will consist of 5 parallel-sequential cohorts: 3 cohorts in Part A and 2 cohorts in Part B. Eight 
subjects will be randomized per cohort (6 active, 2 placebo). The term ‘parallel-sequential cohorts’ 
means that the first 8 subjects will be randomized to Cohort 1. As soon as quota for Cohort 1 has been 
filled, Cohort 2 will be open to enrolment and so forth. A total of approximately 40 subjects will be 
enrolled in the study with 24 subjects in Part A and 16 in Part B.  
The study includes 4 periods: Pre-Screening, Screening, Dosing, and Observation. 
Pre-screening Period: Sites may opt to utilize a Pre-screening Informed Consent Form (ICF) to enable 
performance of a complete blood count (for the absolute eosinophil numbers) in consenting subjects 
while subjects consider consent for the full study. Pre-screening may not occur more than 90 days 
before Visit 1. 
Screening Period: Subjects will be evaluated for eligibility during the 21-day Screening Period before 
randomization and dosing. Eligible subjects will be allocated to cohorts sequentially and then be 
randomly allocated to treatment with UPB-101 or placebo in a 3:1 ratio, respectively.  
Dosing Period: Study drug will be administered SC as follows: 
Description of SC Dosing Regimens in Part A 
Cohort 
Treatment Arm and Dosage 
Number of Injections to 
Achieve Dose 
Frequency x Number of Doses 
Cohort 1 
UPB-101 
mg 
 
 
Placebo 
Cohort 2 
UPB-101 
mg 
 
 
Place
Cohort 3 
UPB-101 
mg 
 
 
Place
Description of SC Dosing Regimens in Part B (Adaptive Design) 
Cohort 4 
UPB-101 
 mg 
 
 
Placebo 
Cohort 5 
UPB-101 
mg
, or
 
OR 
mg 
 (repeated) 
Placebo 
 = every  weeks; 
 = every  weeks; 
 = every 
weeks; SC = subcutaneous 
 
Subjects will be admitted to the inpatient area of their site the day before each dosing day. After 
each administration of the study drug, subjects will be monitored in the site for a minimum of 
4 hours to assure their safety. 
Observation Period: Following their final dose administration, subjects will be followed for evaluation 
of safety, PD, PK, and immunogenicity monitoring. Subjects enrolled in cohorts with 
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dosing intervals will be observed for 6 months; subjects enrolled in any cohorts with 
 dosing 
intervals will be observed for 5 months. 
All PD and PK assessments will be conducted between 6 AM and 10 AM to minimize the impact of 
diurnal variations on biomarker assessments.  
6.1.1. Safety Review Committee 
Part A 
Subjects in Cohorts 1 and 2 will receive 3 doses of study drug. Before the first subject in each of those 
cohorts receives their third dose, the Safety Review Committee (SRC) will be convened. The committee 
will review at each of the meetings the safety data available at that point in time from all enrolling 
cohorts. 
Subjects enrolled in Cohort 3 will receive only 2 doses of the study drug. Therefore, no SRC meetings 
will be directly linked to the progress of that cohort.   
The blinded safety data reviewed will include AEs, vital signs, physical examinations, ECGs, 
haematology, biochemistry, urinalyses, as well as subject withdrawals and replacements. Eosinophil 
data will not be sent to sites or reviewed by the SRC. 
Following this data review, the SRC will report their safety findings and make a recommendation 
whether the third dosing in the current cohort should proceed as planned or be modified (e.g., 
repeated or reduced), paused, or halted. 
Part B 
Study drug exposures in Cohorts 4 and 5 will not exceed the exposure of any of the cohorts in Part A. 
Therefore, no SRC meetings are scheduled for Part B.   
Administrative Interim Analysis 
An administrative interim analysis will be conducted during Q4 of 2022. This will be unblinded and will 
be undertaken by a team who will have no other involvement in the study until after unblinding. The 
data and results will be kept in a restricted area which will only be accessible by this unblinded team. 
The results will be made available to the sponsor via a secure transfer service. 
This interim is solely for internal decision-making pertaining to matters unrelated to the current study, 
UPB-CP-01, and so will have no bearing on the continued conduct and/or analysis of the study.  
6.2. Randomisation and Blinding 
Subjects will be randomized by IXRS in a double-blind fashion to either UPB-101 or matching placebo 
in a 3:1 ratio. Each subject will be assigned a randomization number by IXRS which will correspond to 
the treatment and cohort allocation. Subjects, Investigators, all site personnel (except for the 
designated unblinded dispensing pharmacist and flow cytometry laboratory personnel) and the 
tranScrip team will be blinded to the subjects’ allocations.  
The following procedures have been instituted to mitigate the risk of unbinding of the enrolled 
subjects and blinded site personnel during the study drug administration:  
 
Qualified study personnel situated in the isolated site pharmacy will prepare the solutions for 
injection based upon the randomization allocation; 


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The study drug and matching placebo will be identical (or nearly identical) in appearance once 
drawn into the syringe for injection; 
 
All the prepared syringes will be covered with blinding labels; 
 
Subjects will be dosed by site personnel trained in blinding techniques and instructed not to 
discuss the subjects’ study drug assignments with blinded site personnel; 
 
Subjects will be dosed in a cordoned area out of the view of the blinded site personnel and of 
other study subjects. 
The Sponsor will be unblinded throughout this exploratory study but will not be involved directly in 
the treatment or clinical evaluation of the subjects. 
All potentially unblinded roles and unblinding parameters within the study will be documented 
separately and a risk assessment performed to ensure appropriate processes are in place to maintain 
the blind throughout the blinded period of the study. 
Since PK data and some PD assessments from individual subjects may be unblinding, such data will 
be available to the unblinded Sponsor but not to any of the blinded parties. Therefore, until the 
entire study (i.e., Parts A and B) has been concluded and the database locked, results of eosinophil 
numbers, FeNO, total IgE, CRP, cytokines, and TSLP will be accessible only to unblinded parties. 
Summary analyses of the overall PK data will be reported to the SRC. These reports will not contain 
any unblinded individual PK results.  
A blinded Medical Monitor will be assigned to support site communications regarding specific 
subjects and adverse events, assignment of Sponsor causalities and other activities that will be 
described in the medical monitoring plan. 
 
 
















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The legend and footnotes for Table 1 through Table 5 are listed below.  
ACQ-7=Asthma Control Questionnaire; Ad=admission; ADA=anti-drug antibody; AE=adverse event; ȕ-HCG=beta human chorionic gonadotrophin; BMI=body 
mass index; CGI-C=Clinician Global Impression of Change; COVID-19=Coronavirus disease 2019; D=day; Di=discharge; ECG=electrocardiogram; 
FeNO=fractional exhaled nitric oxide; FSH=follicle stimulating hormone; IFN Ȝ=interferon gamma; IgE=immunoglobulin E; I/=interleuNin; I3-10= interferon 
gamma-induced protein 10; NAbs=neutralizing antibodies; 3.=pharmacoNinetic; SO3=Standard Operating 3rocedures; 7A5C=thymus and activation-regulated 
chemoNine; 7B=tuberculosis; 7S/3=thymic stromal lymphopoietin
=every
ZeeNs;
=every
ZeeNs;
=every
 ZeeNs; :=ZeeN 
 
a 
In Zomen of childbearing potential at Visit 2 and at the Final Visit a serum ȕ-HCG pregnancy test Zill be performed At other visits a urinary pregnancy
test Zill be performed Follicle stimulating hormone Zill be assayed in Zomen Zho on Visit 1 fit the post-menopausal criterion included in Section  
b 
A symptom-driven physical examination Zill be performed as needed based on reported signs and symptoms 
c 
Vital signs Zill be body temperature pulse respiratory rate and blood pressure See 7able 9 for timing of assessments on dosing days 
d 
ECG assessments Zill be performed prior to any blood draZs FeNO measurements andor study drug administration See 7able 9 for timing of 
assessments on dosing days All ECGs are performed in triplicate 
e 
Spirometry on Screening Visits 1 and 2 Zill be conducted at 0 minutes and 30 minutes prior to bronchodilator administration and at 30 minutes post-
bronchodilator At Visit  Day 1 and at subseTuent dosing visits spirometry Zill be conducted approximately 0 minutes and 30 minutes prior to dosing See
7able  At non-dosing visits Zhere spirometry is conducted 2 assessments Zill be conducted 30 minutes apart; assessments should be conducted at 
approximately the same time as on dosing days No post-bronchodilator spirometry Zill be performed  
f 
Blood samples Zill be collected for assessment of haematology including eosinophils On dosing days samples Zill be collected pre-dose Coagulation
studies Zill be performed only at Visit 1 and the Final Visit  
g 
On dosing visits chemistry and urinalysis laboratory tests Zill be collected pre-dose 
h 
On days Zhere Spirometry is not performed ACQ-7 Tuestion 7 Zill be ansZered based on the FEV1 value from the first measurement on the folloZing
morning 
i 
Blood sampling for 3. on dosing days Zill be collected pre-dose  
j 
3lasma levels of I/- I/-13 IFN Ȝ I/-17A eotaxin-3 I3-10 and 7S/3 Zill be measured 7ryptase carboxypeptidase and 7A5C Zill also be measured  
N 
Subjects Zill be contacted by site personnel the day before each visit that includes a spirometric assessment to remind subjects of their visit and study 
rules Subjects Zill also be contacted the day before their admission to the site  
l 
FloZ cytometry samples Zill be collected and either analyzed or frozen 7he decision to assay the frozen samples Zill be based on previous results 
m 
At Visit  D2 Visit  D Visit 1 D Visit 17 D Visit 1 D92 and Visit 19 D99 blood samples for haematology including eosinophils Zill
only be collected for participants enrolled in Cohort   
n 
At Visit  D2 Visit  D Visit 1 D Visit 17 D Visit 1 D92 and Visit 19 D99 FeNO Zill be performed only for participants enrolled in 
Cohort  


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6.4. Interim Analysis / Data Monitoring 
An administrative interim analysis is planned for this study prior to the Primary Analysis. The results of 
the administrative interim analysis will have no impact on the trial design or analysis. A separate team 
will produce the results for this analysis and will have no further involvement in the study until after 
the study has been unblinded, see Section 10.1.3. 
A Safety Review Committee will take place before the first subject in each of Cohorts 1 and 2 receive 
their third dose. All safety data available at that point will be reviewed by the SRC. The outputs that 
will be produced for the SRC and the remit of the SRC will be defined outside of the SAP as part of the 
SRC charter. 


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7. STUDY ENDPOINTS 
7.1. Primary Endpoint 
The primary endpoints are AEs, SAEs, physical examinations, clinical laboratory assessments, vital 
signs, and electrocardiograms (ECGs). Subject withdrawals, early terminations, and dosing compliance 
are also assessed. These endpoints are evaluated in the Safety Population. 
7.2. Secondary Endpoints 
The secondary endpoints include UPB-101 anti-drug antibodies (ADAs) and serum UPB-101 
concentrations and analyses including Cmax, tmax, AUCtau. If appropriate, AUCinf, t1/2, apparent total body 
clearance after dosing (CL/F), and apparent volume of distribution during the terminal elimination 
phase after dosing (Vz/F), all after the first dose, will be analyzed as well. These endpoints are assessed 
from baseline through Week 24 in the PK Population. 
7.3. Exploratory Endpoints 
The exploratory endpoints include: 
AEs, SAEs, pregnancy tests, and changes from baseline in physical examinations, clinical laboratory 
assessments, vital signs, and ECGs. Subject withdrawals, early termination, and dosing compliance are 
also assessed. Data collected from Baseline through Week 32 are included (data up to Week 24 are 
examined as part of the primary endpoints analysis). These endpoints are evaluated in the Safety 
Population. 
UPB-101 ADAs, presence of neutralizing antibodies (Nabs) and serum UPB-101 concentrations and 
analyses including Cmax, tmax, AUCtau. Data collected from Baseline through Week 32 in the PK 
Population are included (data up to Week 24 are examined as part of the secondary endpoints 
analysis). 
FeNO and blood eosinophil numbers from Baseline through Weeks 24 and 32. Total IgE; IL-5, IL-13, IL-
17A, interferon gamma (IFN ʄ), IFN ʄ-induced protein 10 (IP-10), TSLP, eotaxin-3, tryptase, 
carboxypeptidase, thymus activation regulated chemokine (TARC), C-reactive protein (CRP) 
concentrations; and flow cytometric assessments of phosphorylated signal transducer and activator of 
transcription (pSTAT) and receptor occupancy will be evaluated from Baseline through Weeks 24 and 
32. These PD markers are evaluated in the PD Population. 
Clinician Global Impression of Change (CGI-C) and Subject Asthma Control Questionnaire (ACQ-7) from 
Baseline through Weeks 24 and 32. These PD markers are evaluated in the PD Population. 
Forced expiratory volume in 1 second (FEV1) from Baseline through Weeks 24 and 32. These PD 
markers are evaluated in the PD Population. 
 


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8. SAMPLE SIZE 
The primary objective of the study is to assess the safety and tolerability of UPB-101 when 
administered as multiple ascending doses. A sample size of 40 subjects with 8 subjects per cohort (6 
on active drug + 2 on placebo) is considered sufficient to meet this goal. The sample size is not based 
on formal statistical hypothesis testing. 
 
 




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10.PLANNED STATISTICAL METHODS 
10.1. Statistical Considerations 
10.1.1. General definitions 
In all applicable summary/analysis presentations of safety endpoints, Baseline is defined as the last 
non-missing assessment value for a subject, for that particular parameter, that is prior to dosing with 
UPB-101 or placebo on Day 1 (including unscheduled assessments), unless over-ruled after review of 
data at the BDRM or otherwise stated in the appropriate endpoint sections below.  
For efficacy endpoints, the baseline definition is as per the appropriate endpoint sections below. For 
the derivation of most efficacy endpoints, the first assessment to be used should be the first 
assessment that was taken after the first dose of study treatment.  
A subject will be considered to have completed the study after his/her attendance at the last planned 
study visit (i.e., Week 32 visit), or the last unscheduled visit after the Week 32 visit (if any occur), as 
applicable. 
Within summary presentations/analyses it is envisaged that only scheduled protocol visit values will 
be used for post-baseline time points. In the clinical database a number of data points have been 
labelled as unscheduled/additional recordings of data. These data points will be included within 
subject listings only. However, at the BDRM the occurrence of such unscheduled data will be reviewed 
for each subject to decide if (and how) any such data point(s) should be included within summary 
presentations/analyses. Any such decisions will be documented in the BDRM minutes. 
10.1.2. Administrative Interim Analysis 
An administrative interim analysis will be conducted prior to the Final analysis. This analysis is solely 
for internal decision-making pertaining to matters unrelated to the current study, UPB-CP-01, and so 
will have no bearing on the continued conduct and/or analysis of the study. 
The administrative interim analysis will consist of a selected subset of the TFLs that will be produced 
for the final study reporting, identified in Section 13. 
A separate unblinded team comprising of a statistician and programmers will produce the outputs for 
the administrative interim analysis. All data and outputs will be kept in a secure folder which is only 
accessible by the unblinded team for the administrative interim analysis.  Since the Sponsor is 
unblinded, the results may be made available to all Sponsor personnel but not to any CRO or site 
personnel.  
10.1.3. Data Presentation 
The full list of TFLs to be produced for the final study analysis are shown in Section 13, and the specific 
format and content of each data Table/Listing presentation is shown in Section 14. 
Summary Tables and Figures will be presented by treatment group (and also for an Overall column 
including all subjects, for selected data presentations). Within all Tables and Figures values for the 
treatment groups will be labelled as follows: 
x 
 mg 
 
x 
mg 
 


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x 
mg 
 
x 
mg 
 
x 
Placebo and/or 
x 
Screen Failures 
An Overall column may be included in the disposition, and selected safety outputs which will include 
all treatment groups (Active and Placebo). Generally, the placebo groups will be pooled across all 
cohorts however, for some summaries placebo may be summarized according to dosing regimen (e.g. 
Placebo 
, Placebo 
) or treatment group (e.g. Placebo 
).  
For screen failures, data is only expected in a selection of datasets. The data collected within these 
datasets will be included in the relevant listings only. Additional data that may have been collected for 
screen failures, in error, will not be displayed in the participants listings. They will not be included in 
any summary tables.  
For selected outputs the dosing regimen may be used in the summaries where cohorts of the same 
dosing regimen (i.e. 
, 
) will be grouped together, similarly cohorts may be grouped together 
by treatment group if there are multiple cohorts with the treatment group (e.g. 
 
), or summaries may be produced combining all of the active groups 
together. The ordering of treatment groups shown here represents the order in which they will appear 
in outputs.  
The scheduled protocol visits will be labelled in (applicable) report presentations as follows: 
x 
Screening: Visit 1 
x 
Screening: Visit 2 
x 
Screening: Visit 3 
x 
Day 1 
x 
Day X (where X is the protocol specified Day, to be included within summary Table) 
x 
Week X (where X is the protocol specified study Week, to be included within summary Table) 
Generally, the summaries will be produced by Day, although in some cases it may be preferable to 
summarize by Week. This will be specified within each of the shells, as appropriate.  
Note that the Baseline label will be used in some summaries, where Baseline will consist of data 
collected at the screening visits, on Day 1 pre-dosing or unscheduled assessments prior to dosing (if 
they are the last non-missing assessment). The actual Baseline definition will be provided in the section 
relevant for each endpoint.  
Unscheduled visit data will be labelled as “Unscheduled” together with a date in data Listings. 
Unscheduled data will not be used in the summary tables unless otherwise agreed at the BDRM. 
Where duplicate information is collected in both the database and in the vendor data transfer(s) (e.g., 
sampling date and time) this information will be reconciled by data management and then the 
information from the database will be included in subject Listings. 
All variables will be listed to the same number of decimal places as reported.  Descriptive statistics for 
all endpoints that are continuous data will have the following summary statistics presented in the 
following order:  n, (arithmetic) mean (rounded to one more decimal place than recorded), geometric 
mean (for pre-specified endpoints only; rounded to one more decimal place than recorded), standard 


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deviation (rounded to two more decimal places than recorded), geometric standard deviation (for pre-
specified endpoints only; rounded to two more decimal places than recorded), standard error (for pre-
specified endpoints only; rounded to two more decimal places than recorded), median (rounded to 
one more decimal place than recorded), lower and upper quartiles (rounded to one more decimal 
place than recorded), minimum (as recorded), and maximum (as recorded). 
Note: for endpoint(s) that require a geometric mean to be produced, and those endpoint(s) can have 
raw values of 0 (zero), the geometric mean calculation will add an appropriate constant value to all 
raw values prior to logging and will subtract that constant value from the final calculated anti-logged 
mean. The constant value used will be documented in the footnote of the tables. An example of such 
a calculation is shown below: 
Geometric Mean = anti-log {mean (logged (base 10) endpoint values + 1)} - 1  
Categorical variables will be summarized using proportions (counts and percentages). The specific 
approach to calculating percentages (relevant denominator) is detailed within each (relevant) Table 
template (Section 14). 
Unless otherwise stated in the appropriate endpoint section(s) below, laboratory/efficacy parameter 
values that are below the level of quantification (BLQ), or less than the lower limit of quantification 
(фLLOQ) will be set to zero in computations for summary presentations and analysis but will be noted 
as below the limit of quantification in subject Listings.  
10.1.4. Statistical Testing and Estimation 
No formal statistical analysis will be performed within the SAP specified analysis. 
10.1.5. Handling of Dropouts or Missing Data 
In general, missing data will not be imputed and all summary statistics will be reported based upon 
observed data. For a limited number of summary presentations, missing data rules may be introduced. 
In particular, methods of handling incomplete dates for adverse events (Section 10.8.2) and 
incomplete dates for concomitant medications (Section 10.5) are presented. For any other data which 
has partial dates, which are required for use in time related calculations, these dates will be completed 
using a suitably conservative approach. Dates will be shown in subject Listings as they have been 
recorded. 
10.1.6. Multiple Comparison/Multiplicity 
As no formal hypothesis testing is taking place, no alpha adjustments will be made to handle 
multiplicity. 
10.1.7. Examination of Subgroups 
No subgroup analyses will be undertaken. 
10.1.8. Model checking  
As no formal hypothesis testing is taking place no formal model checking will be required. 
10.1.9. Software 
Data will be reported using SAS (version 9.4 or later). 


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10.1.10. 
Data Conversion (CDISC) 
For the reporting of this study both CDISC SDTM (SDTM version 1.7 and SDTM Implementation Guide 
version 3.3) and ADaM (ADaM version 2.1 and ADaM Implementation Guide version 1.1) standards will 
be applied.  
10.2. Participant Disposition 
The number of subjects randomized, treated, received all doses as planned, received all doses 
expected, completed the Week 24 visit, and completed the study will be tabulated by treatment 
group, as well as the number who withdrew from the study and/or discontinue treatment early. The 
data on subject disposition and informed consent will be listed.  
Note it was possible for participants to be rescreened. In order to maintain the link between screen 
failures and their subsequent rescreen records these will be displayed as XXXX/YYYY in all relevant 
listings (where screen failure data are displayed), where XXXX is the final screening number given to 
the subject and YYYY is the screening number under which the data being displayed was collected. 
10.3. Protocol Deviations  
Subject data will be reviewed for major protocol deviations by a qualified clinical reviewer prior to 
database lock and unblinding, at the BDRM at the time of the Final Analysis. All protocol deviations will 
be listed.  
10.4. Demographic and other Baseline Characteristics 
The Safety Population will be used in all presentations of demographic and baseline data. No statistical 
testing will be used to compare treatments for different baseline characteristics. 
10.4.1. Demographics 
Demographic variables at screening (sex, age, ethnicity, race, height (cm), weight (kg), and body mass 
index (BMI [g/m2]), will be summarized by treatment group and across all subjects.  
10.4.2. Other Baseline Characteristics 
Smoking history, alcohol consumption and drugs of abuse information will all be listed 
10.4.3. Medical History 
All medical history will be coded using MedDRA, Version 25.0 (March 2022), summarized by treatment 
group and listed.  
Asthma medical history will also be listed, as will allergy history and past and planned surgical 
procedures 
10.5. Prior and Concomitant Medications 
All medication terms will be coded using the World Health Organisation (WHO) Drug Dictionary 
Enhanced (WHO Drug Global, version March 1, 2022).  


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Background asthma medications are defined as medications taken for asthma at a stable dose during 
at least 3 months prior to randomization.  
Other medications will be assigned as being prior to or concomitant with the treatment, based on the 
start and stop dates of the medication and the date of first dose of study treatment. If the medication 
stop date is before the date of first dose of study treatment, the medication will be assigned as being 
prior to study treatment. In all other situations, the medication will be assigned as being concomitant 
with study treatment.  
Note: Start and Stop times will not be used for determining if a medication is concomitant or not. 
All background asthma medications will be summarized, including the duration of exposure. 
Background asthma medications will also be listed, along with any changes from the stable dose that 
occur during the study. 
All concomitant medications will be summarized by ATC class (Level 2) and preferred base name (WHO 
Code 01001). All medications will be listed. 
10.6. Pregnancy 
The results of pregnancy tests, both urine and serum, carried out throughout the study will be listed 
for all females. The results of the follicle stimulating hormone test will also be listed for the females 
who meet the post-menopausal criteria.  
10.7. Other Baseline/Screening Tests 
Drugs of abuse screening results will be listed, as will the results of any alcohol breath tests and urine 
cotinine tests. 
10.8. Investigational Product Exposure  
For each cohort the number and percentage of participants receiving each possible number of doses 
and injections will be tabulated.  The details of each injection, including location and the reasons for 
incomplete and interrupted injections will be listed. 
Planned Compliance will be calculated as: (the actual number of injections received / the number of 
injections planned given the assigned dosing regimen) * 100. 
Expected Compliance will be calculated as: (the actual number of injections received / the expected 
number of injections given the assigned dosing regimen and the conduct of the trial) * 100. 
The expected compliance accounts for the hold on dosing that occurred during the running of the trial 
during which subjects were not expected to have received any doses of study treatment, both will be 
listed. 
10.9. Pharmacokinetic Analysis 
The pharmacokinetic analysis will be reported separately, the specifications will be outlined within the 
PK analysis plan. This will include the identification of the PK population, the summary of the PK 
concentrations and PK parameters as well as the investigation of dose proportionality. 


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10.10. Immunogenicity Analysis 
The immunogenicity analysis of neutralising antibodies and anti-drug antibodies will be reported 
separately, the specifications will be outlined within the PK analysis plan.  
10.11. Pharmacodynamic Analysis 
All Pharmacodynamic analysis will use the Pharmacodynamic population. 
10.11.1. 
Biomarkers 
The biomarkers collected in the study include cytokines (IL-5,IFN ʄ, IP-10, TSLP, eotaxin-3, TARC and 
lab parameters (Eosinophils, Total IgE and C-reactive protein). Receptor occupancy evaluated by flow 
cytometry, considered as a biomarker for target engagement, is also included. 
All biomarkers, with the exception of the flow cytometry biomarker, will be summarized by visit as 
absolute values, change from baseline and percentage change from baseline, by treatment group. Any 
scheduled pre-baseline data will also be summarized by visit and treatment group. 
Flow cytometry based evaluation of receptor occupancy (free receptors) will be calculated as the 
difference between the signal intensity (measured as % of TSLPR+ CD14+ cells) of the test sample and 
an aliquot of the same sample incubated ex vivo with saturating levels of UPB-101 prior to adding the 
detection antibody.  The receptor occupancy will then be summarized at each visit, along with the 
percentage of free receptors, where; 
% free receptors at any timepoint (t) = (difference between signal intensity at timepoint (t) / difference 
between signal intensity at baseline )* 100. 
For negative % Free Receptors, set the value to 0.  For % Free Receptors greater than 100%, set the 
value to 100%. 
For all biomarkers the baseline will be the last non-missing result prior to first dose. 
Any data that is below the limit of quantification will be replaced with zero before summarising but 
will be listed as ‘фBLQ’.  
A mean plot of the biomarker results over time will be displayed, where the plots will display the mean 
at each visit +/- the standard error, with a line per treatment group. 
10.11.2. 
Spirometry 
FeNO and other spirometry parameters (FEV1, FEV1%, FVC and PEF) will be summarized by visit as 
absolute values, change from baseline and percentage change from baseline, by treatment group. Any 
scheduled pre-baseline data will also be summarized by visit and treatment group. 
Plots of the mean over time will be displayed for each of the spirometry parameters listed above and 
all spirometry parameters collected will be included within subject listings.  
Baseline for spirometry will be defined as the 60-minutepre-dose values at Visit 4. On all other dosing 
days the values recorded at 60 minutes pre-dose will be summarized. In case of multiple 
measurements at 60 minutes pre-dose (unexpected), the average of these will be used for baseline 
and the best (maximum) of these values will be used at the post-baseline timepoints. On all non-dosing 
post-baseline days the best (maximum) of the 2 measurements performed will be summarized.  


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10.11.3. 
CGI-C 
The asthma clinician global impression of change (CGI-C) is a 7-point rating scale instrument used to 
assess the investigators evaluation of the change in asthma since baseline.  
The rating scale uses the following categories: 
1: Marked Improvement 
2: Moderate Improvement 
3: Minimal Improvement 
4: No change 
5: Minimal Worsening 
6: Moderate Worsening 
7: Marked Worsening 
This assessment will be summarized as the number and proportion of subjects with each rating by 
treatment group at each visit this is collected. 
A summary of the numerical score by treatment group and visit will also be displayed. 
10.11.4. 
ACQ-7 
The Asthma Control Questionnaire (ACQ-7) score is derived as an average of the responses to the 7 
questions in the questionnaire. A subject is required to recall their asthma symptoms over the previous 
7 days and respond, using a 7-point rating scale, to each question. The mean score is then categorised 
from 0 to 6, where 0 is totally controlled and 6 is severely uncontrolled. 
This score will be summarized at each visit, by treatment group, along with the change from baseline 
in the mean ACQ-7 score. 
 
 


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10.12. Safety Analysis 
The Primary endpoints for the study are safety related. All analyses of safety endpoints will be 
descriptive and will use the safety population. No statistical analysis of safety data will be performed. 
10.12.1. 
Injection Site Reactions 
For each injection site, information will be collected on whether any reactions are experienced by the 
subject.  The number of subjects that ever experienced each of the reactions (pain, localised swelling, 
tenderness and erythema) will be summarized by treatment group, as well as the maximum severity 
experienced for each of the symptoms. Additionally, the number of subjects experiencing injection site 
reactions will be summarized by location and treatment group. 
Erythema and swelling are recorded as size (in mm). The severity of these will be derived using the FDA 
guidance as below: 
Erythema and Swelling Severity:  
ф2.5 cm
= None 
2.5 to 5 cm   = Mild  
5.1 to 10 cm = Moderate  
>10cm           = Severe. 
The proportion of injections that resulted in reactions will also be summarized, by treatment group 
and  all injection site reactions will be listed. 
Any injection site reaction is also considered an adverse event of special interest and so the summaries 
of injection site reactions will be considered as part of the AESIs for the study. 
10.12.2. 
Adverse Events 
Adverse event (AE) data presentations will be produced for unsolicited adverse events that occur 
during the study. 
All adverse events will be coded using MedDRA, Version 25.0. 
Treatment emergent adverse events will be summarized over 2 distinct time periods within the study, 
from first dose of study treatment to Week 24, as well as from first dose of study treatment to Week 
32 (i.e. over the entire study period).  
Adverse events will be assigned to time periods according to the AE start and stop dates and times and 
dates/times of first dose of study treatment. Any adverse event with an onset date/time earlier than 
the date/time of first dose of study treatment will be classified as a pre-treatment adverse event. Any 
adverse event worsening in severity will be considered as a separate event, starting from the date/time 
of the updated severity.    
Should any onset date for an adverse event be missing or only a partial date recorded (such that it 
cannot be determined if the event onset was prior to first dose of study treatment or not) then it will 
be assumed that the event is following first dose of study treatment, unless the adverse event stop 
date indicates otherwise.  
If a subject experiences more than one adverse event with the same preferred term, that preferred 
term will be counted only once in summary presentations. It will be assigned the worst observed 


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severity and the strongest relationship to IMP among those events for the summaries in which those 
characteristics are considered.   
Adverse Events of Special Interest (AESI) will be identified within the database as such. Additionally 
injection site reactions will be considered as AESIs. 
An overall summary of adverse events will present the number of subjects with events and serious 
adverse events (also split by severity), number of subjects with adverse events and serious adverse 
events related to study treatment, the number of subjects with adverse events leading to 
discontinuation from study treatment or withdrawal from the study. This summary will be produced 
for adverse events occurring from first dose of study treatment to Week 24, and over the entire study 
period. 
Additionally, each of the summaries below will be presented for the entire study period: 
x 
Adverse Events by treatment group, System Organ Class (SOC) and Preferred Term (PT).  
x 
Serious Adverse Events by treatment group, SOC and PT.  
x 
Adverse Events by treatment group, SOC, PT and severity.  
x 
Adverse Events related to study treatment by treatment group, SOC and PT.  
x 
Adverse Events of Special Interest by treatment group, SOC and PT.  
Listings will be provided for AEs, serious adverse events (SAEs), adverse events directly resulting in 
discontinuation of study treatment or withdrawal from study. 
In all adverse event summary tables results will be displayed in descending order of the number of AEs 
across all active treatment groups by SOC and also preferred term within SOC.  
10.12.3. 
Laboratory Variables 
The following haematology, biochemistry, coagulation, viral serology and urinalysis parameters (as 
shown within the protocol) will be included within subject listings (and presented in the units as shown) 
and summary tables where relevant: 
x 
Haematology: platelet count (x10^9/L), white blood cell (WBC) count (absolute) (x10^9/L), 
neutrophils (absolute) (x10^9/L), lymphocytes (absolute) (x10^9/L), monocytes (absolute) 
(x10^9/L), eosinophils (absolute) (x10^9/L), basophils (absolute) (x10^9/L), red blood cell 
(RBC) count (x10^12/L), haemoglobin (g/L).  
o Note: Complete blood count differentials are collected for this study but will only be 
listed and not included in any summaries, with the exception of the eosinophils 
differential which will be summarised as a biomarker (see Section 10.11.1). 
x 
Biochemistry: sodium (mmol/L), potassium (mmol/L), glucose (mmol/L), albumin (g/L), 
chloride (mmol/L), bicarbonate (mmol/L), calcium (mmol/L), total protein (g/L), creatinine 
(umol/L), total bilirubin (umol/L), direct bilirubin (umol/L), phosphorus (mmol/L), alkaline 
phosphatase (ALP) (IU/L), alanine transaminase (ALT) (IU/L), aspartate transaminase (AST) 
(IU/L), urea (mmol/L), Total creatinine kinase (IU/L), HDL (mmol/L), Total Cholesterol 
(mmol/L), Triglycerides (mmol/L), C-reactive protein (mg/L). 
x 
Coagulation: prothrombin time (PT) (secs), activated partial thromboplastin time (APTT) (secs), 
International normalised ratio. 


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x 
Other: HIV-1 and HIV-2 antibodies, hepatitis B surface antigen (HbsAg), hepatitis C antibodies 
(HCAb), FSH (IU/L), beta HCG (qualitative), QuantiFERON-TB Gold/Tuberculosis.  
x 
Urinalysis: Specific gravity, pH, blood, protein, glucose, bilirubin, white blood cells, ketones, 
nitrites. 
x 
Urinalysis (microscopy): Urine RBC (/HPF), Urine WBC (/HPF), Hyaline Casts, Cellular Casts, 
Granular Casts, Urine Culture. 
Laboratory data collected in different units to that shown will be converted to the above specified units 
(if possible) for presentation in subject Listings. 
Summary statistics for absolute and changes from baseline by timepoint, including pre-baseline 
timepoints, will be tabulated, by treatment group, for haematology, biochemistry and coagulation). 
Baseline here will be the last non-missing measurements taken prior to the first dose of study 
treatment. Shift tables will also be presented for the shift from baseline to above, below, or within 
normal range at each visit. Any scheduled pre-baseline data will also be summarized by visit and 
treatment group. 
Categorical urinalysis parameter (not including microscopy, specific gravity or pH) will be summarized 
at each visit by the number and percentage of subjects having results in each category. 
Laboratory parameters (Haematology, Biochemistry, Coagulation, Human Immunodeficiency Virus, 
Hepatitis A, B and C, Urinalysis and Urinalysis (microscopy) where done) will be included in subject 
listings. Laboratory values outside the normal range will be identified in subject listings as above or 
below the normal range.  
Unscheduled visit assessments will be included within subject listings. 
10.12.4. 
Vital Signs 
Summary statistics for absolute and changes from baseline will be tabulated, by timepoint, including 
pre-baseline timepoints, and by treatment group, for vital signs parameters (systolic blood pressure 
(SBP) (mmHg), diastolic blood pressure (DBP) (mmHg), pulse (beats/min), respiratory rate (RR) (breaths 
per minute), and temperature) and will be included within subject listings. Baseline vital signs are the 
last non-missing values taken prior to first dose of study treatment. Body measurements, height, 
weight and BMI will be listed separately. 
10.12.5. 
Physical Examination 
Physical examination findings will be listed, including the initial screening visit physical, the physical at 
Week 32 and any additional physicals carried out throughout the study. The listing will display the 
assessment (normal, abnormal not clinically significant, abnormal clinically significant) for each of the 
body systems assessed at each visit the physical examinations were performed. 
10.12.6. 
12-Lead ECG 
ECGs will be carried out in triplicate at each visit and the mean of these three (or more) results will be 
used in any summaries.  
Summary statistics for absolute values and change from baseline by time point, including pre-baseline 
timepoints,  will be tabulated, by treatment group and for all subjects, for ECG parameters (Respiratory 
Rate (RR), Heart Rate (HR), Pulse Rate (PR), QRS duration (sec), QT interval (sec), QTcB interval (sec) 
and QTcF interval (sec)) and will also be included within subject listings, along with the overall 


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interpretation of the ECG. Baseline will be the last non-missing ECG results prior to the first dose of 
study treatment.  
The shift in overall interpretation of the ECG from baseline, as defined by Clario,  will also be presented 
at each scheduled visit. 
Additionally, a table of the number and percentage of subjects with QTc in the ranges below will be 
presented by visit and treatment group: QTc interval > 450, QTc interval > 480, QTc interval > 500, QTc 
interval between 450 and 480 and QTc interval between 480 and 500 as well as change from baseline 
in QTc interval > 30, change from baseline in QTc interval > 60 and change from baseline between 30 
and 60. The tables will display both QTcF and QTcB. 
All ECG results will be listed, one for all Clario reported results, and another with the site interpretation 
as captured in the database. 


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11.CHANGES TO THE PROTOCOL SPECIFIED ANALYSIS DETAILED IN THE 
STATISTICAL ANALYSIS PLAN 
The PK and PD Populations have been refined to clarify the need for baseline and post-baseline results 
for subjects to be included in either of these populations. The updates have been implemented to align 
the populations in terms of their requirement for post-baseline results.  
It was initially planned to carry out analyses at 4 timepoints during the study: Part A – Week 24, Part A 
– Week 32, Part B – Week 24 and Part B – Week 32. It has since been agreed that only one formal 
analysis will take place, at Week 32, when all subjects (Part A and Part B) have completed the study. 
During the study it was decided not to proceed with some of the exploratory cytokines. The cytokines 
that are available will be summarised as described in Section 10.11.1. 
 
 


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12.REFERENCES 


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13.TABLES, FIGURES AND LISTINGS 
13.1. Specific Presentation Details 
Tables, Listings and Figures will be provided in pdf and WORD format. All summary Tables and Figures 
will have source data footnotes that refer to the relevant Listings. Dates will appear as ddmmmyyyy 
and times as hh:mm (24-hour clock times). All Listings will be ordered by treatment group, subject 
number and scheduled visit. Any unscheduled visit information will also be included within the Listings, 
identified as unscheduled. 
For the presentation of summary data, values will be aligned based on the unit column, and not 
left/right justified. For example: 
 
 
Parameter 
 
 
n 
 
XX 
 
XX 
 
 
 
 
 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
 
 
 
 
 
Median 
 
XX.X 
 
XX.X 
 
 
 
 
[optional] 
GM (GSD)  
XX.X 
 
XX.X 
 
 
 
 
 
 
Q1, Q3 
 
XX.X, XX.X 
XX.X, XX.X 
 
 
 
 
 
Min, Max  
XX, XX 
 
XX, XX 
 
 
 
All Tables, Listings and Figures will have the SAS program name, output filename and date of 
production in the footnote. 
 
All Tables, Listings and Figures will include the following study header and footer: 
 
CONFIDENTIAL 
 
 
 
      Upstream Bio 
 
 
 
Page x of y 
UPB-CP-01 
 
Table X.X 
Title 
Population 
 
 
 
 
 
 
 
 
 
 
Source Data: Listing 16.2.X {Source data footnote only appears for tables, where x references relevant listing 
number} 
 
Program: XXXXXXXX 
 
 
Output: XXXXXXX  
 
Date: XXXXXXXXX 


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13.2. List of Tables 
The columns Final and Admin Analysis identify the tables that will be produced for each of the Final 
Analysis and Administrative Interim Analysis, respectively.  
 
Table 
Number 
Table Title 
Final 
Admin 
Analysis 
14.1.1 
Subject Disposition – All Subjects 
X 
X 
14.1.2 
Demography and Baseline Characteristics – Safety 
Population 
X 
X 
14.1.3 
Medical History – Safety Population 
X 
 
14.1.4.1 
Concomitant Medications – Safety Population 
X 
 
14.1.4.2 
Background Asthma Medications – Safety Population 
X 
 
14.1.5 
Investigational Product Exposure – Safety Population 
X 
X 
14.2.3.1.1 
Biomarkers: Cytokines Change from Baseline Summary – 
Pharmacodynamic Population 
X 
X 
14.2.3.1.2 
Biomarkers: Cytokines Percentage Change from Baseline 
Summary – Pharmacodynamic Population 
X 
X 
14.2.3.2.1.1 
Biomarkers: Eosinophils Change from Baseline Summary 
– Pharmacodynamic Population 
X 
X 
14.2.3.2.1.2 
Biomarkers: Eosinophils Percentage Change from 
Baseline Summary – Pharmacodynamic Population 
X 
X 
14.2.3.2.2.1 
Biomarkers: Other Labs Change from Baseline Summary 
– Pharmacodynamic Population 
X 
X (IgE 
only) 
14.2.3.2.2.2 
Biomarkers: Other Labs Percentage Change from 
Baseline Summary – Pharmacodynamic Population 
X 
X (IgE 
only) 
14.2.3.3.1 
Biomarkers: Flow Cytometry Change from Baseline 
Summary – Pharmacodynamic Population 
X 
X 
14.2.3.3.2 
Biomarkers: Flow Cytometry Percentage of Baseline 
Summary – Pharmacodynamic Population 
X 
X 
14.2.3.4.1.1 
Biomarkers:  FeNO Change from Baseline Summary – 
Pharmacodynamic Population 
X 
X 
14.2.3.4.1.2 
Biomarkers:  FeNO Percentage Change from Baseline 
Summary – Pharmacodynamic Population 
X 
X 


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Table 
Number 
Table Title 
Final 
Admin 
Analysis 
14.2.3.4.2.1 
Biomarkers: Other Spirometry Change from Baseline 
Summary – Pharmacodynamic Population 
X 
X (FEV1 
only) 
14.2.3.4.2.1 
Biomarkers: Other Spirometry Percentage Change from 
Baseline Summary – Pharmacodynamic Population 
X 
X (FEV1 
only) 
14.2.4.1.1 
CGI-C Summary – Safety Population 
X 
 
14.2.4.1.2 
CGI-C Categorical Summary – Safety Population 
X 
X 
14.2.4.2.1 
ACQ-7 Summary – Safety Population 
X 
X 
 
Safety 
 
 
14.3.1.1 
Injection Site Reactions Summary – Safety Population 
X 
X 
14.3.1.2 
Injection Site Reactions by Location – Safety Population 
X 
 
14.3.1.3 
Injection Site Reactions -  Proportion with Reactions – 
Safety Population 
X 
 
14.3.2.1.1 
Overall Summary of Treatment Emergent Adverse Events 
up to Week 24 – Safety Population 
X 
 
14.3.2.1.2 
Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term up to Week 24 – Safety 
Population 
X 
 
14.3.2.1.3 
Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and Severity up to Week 24 – 
Safety Population 
X 
 
14.3.2.1.4 
Treatment Emergent Adverse Events Related to IMP by 
System Organ Class and Preferred Term up to Week 24 – 
Safety Population 
X 
 
14.3.2.1.5 
Treatment Emergent Adverse Events of Special Interest 
by System Organ Class and Preferred Term up to Week 
24 – Safety Population 
X 
 
14.3.2.1.6 
Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term up to Week 24 – Safety 
Population 
X 
X 
14.3.2.1.7 
Treatment Emergent Adverse Events Leading to 
Discontinuation of Investigational Product by System 
Organ Class and Preferred Term up to Week 24 – Safety 
Population 
X 
 


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Table 
Number 
Table Title 
Final 
Admin 
Analysis 
14.3.2.1.8 
Treatment Emergent Adverse Events Leading to 
Withdrawal from the Study by System Organ Class and 
Preferred Term up to Week 24 – Safety Population 
X 
X 
14.3.2.2.1 
Overall Summary of Treatment Emergent Adverse Events 
Over Entire Study Period – Safety Population 
X 
 
14.3.2.2.2 
Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term Over Entire Study Period – 
Safety Population 
X 
 
14.3.2.2.3 
Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and Severity Over Entire Study 
Period – Safety Population 
X 
 
14.3.2.2.4 
Treatment Emergent Adverse Events Related to IMP by 
System Organ Class and Preferred Term Over Entire 
Study Period – Safety Population 
X 
 
14.3.2.2.5 
Treatment Emergent Adverse Events of Special Interest 
by System Organ Class and Preferred Term Over Entire 
Study Period – Safety Population 
X 
 
14.3.2.2.6 
Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term Over Entire Study Period 
– Safety Population 
X 
 
14.3.3.1 
Haematology Parameters Summary – Safety Population 
X 
 
14.3.3.2 
Haematology Parameters: Shift of Normal Range – Safety 
Population 
X 
 
14.3.4.1 
Biochemistry Parameters Summary – Safety Population 
X 
 
14.3.4.2 
Biochemistry Parameters: Shift of Normal Range – Safety 
Population 
X 
 
14.3.5.1 
Coagulation Parameters Summary – Safety Population 
X 
 
14.3.5.2 
Coagulation Parameters: Shift of Normal Range – Safety 
Population 
X 
 
14.3.6 
Urinalysis Parameters: Summary – Safety Population 
X 
 
14.3.7 
Vital Signs Parameters Summary – Safety Population 
X 
 
14.3.8.1 
Electrocardiogram Parameters Summary – Safety 
Population 
X 
 


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Table 
Number 
Table Title 
Final 
Admin 
Analysis 
14.3.8.2 
Electrocardiogram Interpretation Shift Summary– Safety 
Population 
X 
 
14.3.8.3 
Electrocardiogram 
Category 
Summary 
– 
Safety 
Population  
X 
 


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13.3. List of Figures 
The columns Final and Admin Analysis identify the figures that will be produced for each of the Final 
and Administrative Interim Analysis, respectively.  
 
Figure 
Number 
Figure Title 
Final 
Admin 
Analysis 
14.2.1 
Mean Plot of Biomarkers: Cytokines– 
Pharmacodynamic Population 
X 
X 
14.2.2 
Mean Plot of Biomarkers: Labs – 
Pharmacodynamic Population 
X 
X 
14.2.3 
Mean 
Plot 
of 
Biomarkers: 
Flow 
Cytometry 
– 
Pharmacodynamic 
Population 
X 
 
14.2.4.1 
Mean Plot of Biomarkers: Spirometry– 
Pharmacodynamic Population 
X 
X 
 
 


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13.4. List of Listings 
The columns Final and Admin Analysis identify the tables that will be produced for each of the Final 
and Administrative Interim Analysis, respectively.  
Listing 
Number 
Listing Title 
Final 
Admin 
Analysis 
16.2.1.1 
Subject Disposition 
X 
X 
16.2.1.2 
Failed Inclusion and Exclusion Criteria for 
Screen Failures 
X 
 
16.2.2 
Protocol Deviations 
X 
X 
16.2.3 
Subject Populations  
X 
 
16.2.4.1 
Demographic and Baseline 
Characteristics 
X 
 
16.2.4.2 
Smoking History 
X 
 
16.2.4.3 
Alcohol Consumption History 
X 
 
16.2.4.4 
Reproductive Status and Contraception 
Use 
X 
 
16.2.4.5.1 
Medical and Surgery History  
X 
 
16.2.4.5.2 
Asthma Medical History 
X 
 
16.2.4.5.3 
Allergy History 
X 
 
16.2.4.5.4 
Past and Planned Surgical Procedures 
X 
 
16.2.4.6.1 
Prior Medications  
X 
 
16.2.4.6.2 
Concomitant Medications  
X 
 
16.2.4.6.3 
Asthma Medication 
X 
 
16.2.5.1 
Investigational Product Accountability 
X 
 
16.2.5.2 
Investigational Product Exposure 
X 
 
16.2.6.1 
Biomarkers: Cytokines 
X 
 
16.2.6.2 
Biomarkers: Labs 
X 
 


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Listing 
Number 
Listing Title 
Final 
Admin 
Analysis 
16.2.6.3 
Biomarkers: Flow Cytometry 
X 
 
16.2.6.4 
Spirometry 
X 
 
16.2.6.5.1 
ACQ-7 
X 
 
16.2.6.5.2 
CGI-C 
X 
 
16.2.7.1 
Injection Site Reactions  
X 
 
16.2.7.2 
Adverse Events 
X 
X 
16.2.8.1 
Blood Sample Collection 
X 
 
16.2.8.2.1 
Haematology 
X 
 
16.2.8.2.2 
Chemistry 
X 
 
16.2.8.2.3 
Coagulation 
X 
 
16.2.8.2.4 
Urinalysis 
X 
 
16.2.9.1 
Other Laboratory Tests: Pregnancy  
X 
 
16.2.9.2 
Other Laboratory Tests: Drugs of Abuse 
Screen  
X 
 
16.2.9.3 
Other Laboratory Tests: Urine Cotinine 
X 
 
16.2.9.4 
Other Laboratory Tests: Alcohol 
Breath/Urine Test 
X 
 
16.2.9.5 
Other Laboratory Tests: Viral Serology 
X 
 
16.2.9.6 
Other Laboratory Tests: Other Tests 
X 
 
16.2.10.1 
Vital Signs  
X 
 
16.2.10.2 
Body Measurements 
X 
 
16.2.11.1 
Electrocardiogram – Clario 
X 
 
16.2.11.2 
Electrocardiogram - Site 
X 
 
16.2.12 
Physical Examination  
X 
 


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Listing 
Number 
Listing Title 
Final 
Admin 
Analysis 
16.2.13 
Neurological Examination 
X 
 
16.2.14 
Visit Dates 
X 
 
 
 


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14.TABLE AND LISTING SHELLS