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Clinical Trial Protocol Trial No.: 9161.1 Title: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Doses of HBM9161(HL161BKN) in Healthy Chinese Volunteers (Randomized, Single-blinded, Placebo- controlled Trial) Clinical Phase: I Investigational HBM9161(HL161BKN) Product(s) Name:

Document History Document Version No. Date Summary of Changes and Rationale Protocol 1.0 28 Jan 2019 None Protocol 2.0 07 May 2019 See Section 12

Sponsor Information

Sponsor Harbour BioMed Therapeutics Limited Suite 2004, 20/F, Tower 5, China Hong Kong City, 33 Canton Road, Tsim Sha Tsui, Kowloon, Hong Kong

Confidentiality Statement Proprietary Confidential Information of Harbour BioMed (HBM). This document and accompanying materials are confidential information and may not be used, reproduced, published or otherwise disclosed without prior notification and written permission. Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019

SPONSOR SIGNATURE PAGE

Study Title: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Doses of HBM9161(HL161treBKN) in Healthy Chinese Volunteers (Randomized, Single-blinded, Placebo-e Trial)

Protocol Number: 9161.1

This protocol has been approved by sponsor’s representative. The following signatures document this approval.

Date:

[Name] Luyan Dai

Study Statistician, Harbour BioMed

Date:

[Name] Li Yue

Study Clinical Research Physician， Harbour BioMed

Date:

[Name] Yafeng He

Project Operation Lead, Harbour BioMed

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INVESTIGATOR STATEMENT PAGE

Study Title: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Doses of HBM9161(HL161BKN) in Healthy Chinese Volunteers (Randomized, Single-blinded, Placebo-controlled Trial)

Protocol Number: 9161.1

• I confirm agreement to conduct the study in compliance with the protocol.

• I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study.

• I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations and comply with the study protocol. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.

Signature: Date:

Name (print): Dr. Desmond Yat Hin YAP

Site: Phase 1 Clinical Trials Centre, The University of Hong Kong (“Phase 1 Centre”)

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CLINICAL TRIAL PROTOCOL SYNOPSIS

Company Name: Harbour BioMed Therapeutics Limited

Version: 2.0/07 May 2019 Trial No.: 9161.1 Title: Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single Ascending Doses of HBM9161(HL161BKN) in Healthy Chinese Volunteers (Randomized, Single-blinded, Placebo-controlled Trial)

Clinical Phase: I Rationale: The neonatal FcRn is a potential therapeutic target for many autoimmune diseases. This study will evaluate the safety, tolerability, PK, and PD of subcutaneous (SC) doses of HBM9161(HL161BKN) (abbreviated as HBM9161) in healthy Chinese subjects. This study will also provide guidance on doses to be used in future studies involving patients with autoimmune diseases. Trial Objective(s): To investigate the safety, tolerability, PK, and PD following single ascending doses of HBM9161 in healthy Chinese subjects.

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Trial Endpoints: Primary Endpoints:

• The number [N (%)] of subjects with drug-related AEs. Secondary Endpoints: Other variables for safety and tolerability assessments: the number [N (%)] of subjects with adverse events (AEs), abnormal 12-lead electrocardiogram (ECG), abnormal clinical laboratory tests, abnormal physical examination and change of vital signs (blood pressure, pulse rate) from baseline. PK parameters:

• Cmax (maximum measured concentration of the analyte in serum) AUC (area under the concentration-time curve of the analyte in serum • 0- over the time interval from 0 extrapolated to infinity)

• tmax (time from dosing to maximum measured concentration) • t1/2 (terminal half-life of the analyte in serum) • CL/F (total clearance of the analyte in serum after administration estimated using formula)

• Vz/F (apparent volume of distribution during the terminal phase z following administration estimated using formula) In addition, the following dose normalized parameters will be calculated for HBM9161: C , AUC • max, ,norm 0-∞,norm Other Endpoints: Pharmacodynamic parameters:

• Total serum IgG concentrations over time following subcutaneous (SC) administration of HBM9161

• Maximum change from baseline in total serum IgG concentrations • The AUC of total serum IgG concentrations (Days 1 to 29) • Maximum change from baseline in serum albumin • Immunogenicity after SC administration determined by change from pre- dose in anti-HBM9161 antibody

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Trial Design: A single site, randomized, single-blinded, placebo-controlled single ascending dose trial.

Trial Population:

Number of subjects: Up to 24 healthy Chinese subjects will be randomized into the study. For each dose group, 8 subjects will be randomized (6 subjects to HBM9161 group and 2 subjects to placebo group).

Main inclusion and exclusion criteria:

Main criteria for inclusion

Subjects must meet the following criteria to be entered in this trial:

1. Aged between 18 and 45 years, inclusive, at screening. 2. Han Chinese male or female subjects, and his/her biological parents and grandparents are of Han Chinese ethnicity.

2 3. Body weight50 kg with BMI ≥19.0 and 24.0 kg/m at screening and baseline visit. 4. Generally, in good health with no clinically significant abnormalities as determined by medical history, physical examination, 12-lead ECG and clinical laboratory tests. 5. Female subjects of childbearing potential (including female subjects who are within 12 months of menopause) and male subjects must agree to use at least one of the acceptable contraceptive method(s) from screening until 90 days after dosing of the study drug. Acceptable contraceptive methods include abstinence (for at least 1 month prior to screening), correct use of condom, spermicides, injectable or combined oral contraceptives, intrauterine device with or without local hormone release, cervical cap or diaphragm and vasectomy performed at least 1 year prior to screening. 6. Ability to understand the nature, scope and possible consequence of study participation. 7. Willing to give written informed consent in accordance with GCP and local legislation before any protocol-specific screening procedures. 8. Willing to comply with the study procedures and restrictions.

Main criteria for exclusion:

Subjects who meet any of the following criteria must be excluded.

1. Presence of any concomitant clinically significant diseases, including cardiovascular, gastrointestinal, endocrinological, hematological, hepatic, immunological,

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metabolism, urological, pulmonary, neurological, dermatological, psychiatric, renal, or other major disease or malignancy, as judged by the investigator. 2. Subject has a total IgG level of < 700mg/dL (test result from local laboratory) at screening. 3. Subject has an active infection (e.g. sepsis, pneumonia, and abscess) or has had a serious infection (resulting in hospitalization or requiring parenteral antibiotic treatment) within 6 weeks prior to Day -1 or infection requiring oral anti-infective agents within 2 weeks prior to Day-1, or subject had a febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to admission (Day -1). 4. History of relevant allergy/hypersensitivity (including allergy to study drug or its excipients). 5. Intake of prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) within 7 days or less than 5 half-lives (whichever is longer) of the respective drug prior to dosing of the study drug. Exceptions include topical medications or eye drops with no systemic action, and injectable or combined oral contraceptives. 6. Participation in another clinical trial and received investigational drug(s) (except this study) within 90 days prior to dosing of the study drug. 7. Subject has been a smoker or has used tobacco or nicotine-containing products within 3 months prior to screening. 8. Regular consumption of alcoholic beverages that exceeds 14 units per week (1 unit = 360ml of beer; 150ml of wine; 45ml of distilled spirits) within 3 months prior to screening. 9. Inability to refrain from smoking and alcohol consumption prior to dosing of the study drug. 10. History of substance (alcohol or illicit drugs) abuse/addiction in the past 5 years, or used illicit drugs 3 months prior to signing informed consent, or positive drug/alcohol screen at screening or Day -1. 11. Blood donation (more than 450 mL whole blood donation within 3 months, 50mLwhole blood donation within 1 month) prior to dosing of the study drug. 12. Subject has received a transfusion of blood or any blood products within 60 days prior to dosing of the study drug. 13. Subject has performed strenuous exercise within 7 days prior to dosing of the study drug. 14. Any laboratory values outside the reference range that are of clinical significance according to investigator’s clinical judgement. 15. Subject has estimated creatinine clearance ≤ 80 mL/min calculated by Cockcroft Gault formula at screening.

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16. Subject has any of the following ECG abnormality (a single repeat will be allowed for eligibility determination) at screening or Day -1: Resting heart rate <45 or >100 bpm PR interval <120 or >210 msec QRS duration <70 or >120 msec QTc interval F >450 msec

17. Positive HIV test result at screening. 18. Positive testing for HBs Antigen and/or a positive Hepatitis C antibody test result at screening.

19. Subject has a positive T-cell interferon-γ release assay (TIGRA) result i.e., QuantiFERON®-TB Gold Plus™ test at screening. A single repeat will be allowed for subjects with an indeterminate result of QuantiFERON®-TB Gold Plus™ test. 20. Inability to comply with the meal arrangement 21. Subjects who had immunization within 4 weeks before screening; or subjects who plan to have immunization during the study and within 12 weeks after dosing of the study drug. 22. For female subjects, positive pregnancy test at screening or Day -1, or planning to become pregnant from screening until 90 days after the dosing of the study drug. 23. Lactating female subjects.

Investigational Product(s) (IP): -Investigational Product: HBM9161(HL161BKN) -Dose: Cohort 1: 340mg; Cohort 2: 510mg; Cohort 3: 680mg Note: The Investigator and the Sponsor will review data from each cohort prior to advancing to the next dose escalation. Please see the detailed dose escalation and stopping rules in section 3.4 and section 4.4.2. -Method and route of administration: Subcutaneous injection Comparator Product(s): -Comparator product: Placebo -Dose: Matching placebo vial -Method and route of administration: Subcutaneous injection

Duration of Treatment: Single dose on Day 1

Statistical methods:

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Descriptive summaries for continuous variables will include n, mean, standard deviation (SD), median, first and third quartiles, minimum, and maximum. For categorical variables, n and percentage will be used as summary statistics.

Pharmacokinetic parameters will be listed by subject and summarized by dose groups. In addition, arithmetic means, geometric means and geometric coefficients of variation will be reported for all PK parameters.

Dose proportionality of HBM9161 will be assessed graphically and statistically as appropriate.

All observed pharmacodynamics and biomarker data will be descriptively summarized. All safety assessments will be summarized.

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TABLE OF CONTENTS

SPONSOR SIGNATURE PAGE ...... 2 INVESTIGATOR STATEMENT PAGE ...... 3 CLINICAL TRIAL PROTOCOL SYNOPSIS ...... 4 TABLE OF CONTENTS ...... 10 TIME AND EVENTS TABLE...... 13 TIME AND EVENTS TABLE...... 14 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...... 16 1 INTRODUCTION AND RATIONALE ...... 19 1.1 Background and Rationale...... 19 1.2 Profile of Investigational Product(s) ...... 20 1.2.1 Nonclinical Pharmacology ...... 20 1.2.2 Safety Pharmacology ...... 21 1.2.3 Toxicology ...... 21 1.2.4 Nonclinical Pharmacokinetics ...... 22 1.2.5 Clinical Experiences in Humans ...... 23 1.2.6 Rational for the Trial ...... 23 2 INVESTIGATIONAL PLAN ...... 25 2.1 Study Design and Plan ...... 25 2.2 Rationale of Study Design ...... 25 2.3 Rationale of Dose/Regimen and Duration of Treatment ...... 26 2.4 Dose Escalation and Data Review ...... 27 2.5 Benefit-Risk Assessment ...... 27 2.5.1 Risk Assessment ...... 27 3 SELECTION OF TRIAL POPULATION ...... 28 3.1 Inclusion Criteria ...... 28 3.2 Exclusion Criteria ...... 28 3.3 Lifestyle and/or Dietary Restrictions ...... 30 3.3.1 Meals and Dietary Restrictions ...... 30 3.3.2 Caffeine, Alcohol, and Tobacco ...... 30 3.3.3 Activity ...... 31 3.4 Withdrawal and Discontinuation of Subjects ...... 31 3.4.1 Subject Withdrawal Procedures ...... 31 3.4.2 Stopping Criteria ...... 32 3.4.3 Toxicity Management Criteria (Adverse Events, Cardiovascular, and Site Reactions) ...... 33 3.4.4 Subject and Study Completion ...... 35 4 CLINICAL SUPPLIES ...... 36

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4.1 Investigational Product(s) Descriptions ...... 36 4.2 Randomization / Treatment Assignment ...... 36 4.3 Blinding and Unblinding ...... 36 4.4 Packaging and Labelling Information ...... 37 4.5 Drug Preparation, Dispensing, Storage, Accountability and Destruction .... 37 4.6 Treatment After the End of the Study ...... 38 5 CONCOMITANT TREATMENT(S) AND PROHIBITED MEDICATION(S) ... 39 5.1 Permitted Medications and Non-Drug Therapies ...... 39 5.2 Prohibited Medications and Non-Drug Therapies ...... 39 6 STUDY PROCEDURES ...... 40 6.1 Screening and Critical Baseline Assessments ...... 40 6.2 Procedures by Study Period ...... 40 6.2.1 Physical Examinations ...... 40 6.2.2 Vital Signs ...... 41 6.2.3 Electrocardiogram ...... 41 6.2.4 Telemetry and Pulse Oximetry ...... 41 6.2.5 Clinical Safety Laboratory Assessments ...... 42 6.2.6 Pharmacokinetics ...... 43 6.2.7 Anti-Drug Antibody ...... 43 6.2.8 Pharmacodynamics ...... 44 6.2.9 Exploratory Biomarkers ...... 44 7 ADVERSE EVENTS ...... 45 7.1 Definitions of Adverse Events ...... 45 7.1.1 Abnormal Laboratory Values ...... 45 7.1.2 Abnormal Vital Sign Values ...... 45 7.2 Definition of Serious Adverse Event ...... 46 7.3 Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event ...... 47 7.4 Expedited Reporting to the Sponsor ...... 47 7.5 Method of Identifying Adverse Events and Serious Adverse Events ...... 47 7.6 Follow-up of Adverse Events and Serious Adverse Events ...... 47 7.7 Regulatory Reporting Requirements for Serious Adverse Events ...... 48 7.8 Pregnancy Reporting ...... 48 7.9 Overdose ...... 48 8 DATA ANALYSIS ...... 50 8.1 Hypotheses ...... 50 8.2 Sample Size Considerations ...... 50 8.3 Data Analysis Considerations ...... 50

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8.3.1 Analysis Populations ...... 50 8.3.2 Interim Analysis ...... 50 8.4 Final Analysis ...... 51 8.4.1 Safety Analyses ...... 51 8.4.2 Pharmacokinetic Analyses ...... 52 8.4.3 Pharmacodynamic and Biomarker Analyses ...... 52 9 RESPONSIBILITIES ...... 53 9.1 Investigator Responsibilities ...... 53 9.1.1 Good Clinical Practice ...... 53 9.1.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Approval ...... 53 9.1.3 Informed Consent ...... 53 9.1.4 Confidentiality ...... 53 9.1.5 Study Files and Retention of Records ...... 54 9.1.6 Electronic Case Report Forms ...... 55 9.1.7 Drug Accountability ...... 55 9.1.8 Inspections ...... 55 9.1.9 Protocol Compliance ...... 56 9.2 Sponsor Responsibilities ...... 56 9.2.1 Protocol Modifications ...... 56 9.2.2 Study Report and Publications ...... 56 9.3 Joint Investigator/Sponsor Responsibilities ...... 56 9.3.1 Access to Information for Monitoring ...... 56 9.3.2 Access to Information for Auditing or Inspections ...... 56 9.3.3 Study Termination ...... 56 10 REFERENCES ...... 57 11 APPENDICES ...... 58 12 SUMMARY OF CHANGES ...... 60

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019

TIME AND EVENTS TABLE

Extended Follow- Screening Inpatient Phase Post-treatment Follow-up up Visit (if applicable)

85 /Early Termination 6, 9 and 12 months Study Timepoint (Day) Within 40 days -1 1 2 3 4 5 8 11 15 22 29 43 57 (End of post-dose Study Visit) Time Window (days) ±1 ±1 ±1 ±1 ±2 ±2 ±3 Informed consent X Inclusion/exclusion criteria X X Demographics and medical history X Height X Body weight X X Complete physical examination X X X X X X X Brief physical examination1 X X X X X X X X Viral serology X Drug and alcohol screen X X Vital signs2 X X X X X X X X X X X X X X X Telemetry/Pulse oximetry3 X 12-lead Electrocardiogram4 X X X X X X X X Pregnancy test (females)5 X X X X Urinalysis X X X X X X X X Serum complement (CH50, C3)* X X X Blood chemistry X X X X X X X X X X

Hematology and coagulation X X X X X X X X X X hs- C-reactive protein* X X X X X X

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019

TIME AND EVENTS TABLE

Extended Follow- Screening Inpatient Phase Post-treatment Follow-up up Visit(if applicable)

85 /Early Termination 6, 9 and 12 months Study Timepoint (Day) Within 40 days -1 1 2 3 4 5 8 11 15 22 29 43 57 (End of post-dose Study Visit)

Time Window (days) ±1 ±1 ±1 ±1 ±2 ±2 ±3 Drug administration6 X PK sampling7* X X X X X X X

8 Injection site reactions X Total IgG and albumin9^ X X X X X X X X X X X X X X X

10 QuantiFERON®-TB Gold Plus™ X Immunoglobulins (IgM, IgA, IgG X X X X X X 9 subclasses) * Anti- HBM9161antibody11* X X X X X X X

Anti-HBs* X X X X

Adverse events X12 X X X X X X X X X X X X X X X

Concomitant medication X X X X X X X X X X X X X X X X

Note: *Analysis will be performed at central lab. ^ Analysis will be performed at central lab and local lab. 1. Brief physical examination: Day 1 at 3 hours (±5 minutes) post dose and in the morning on other days. 2. Vital signs will be collected pre-dose (prior to breakfast) on Day 1 and at 10 (±2 minutes) , 60 (±5 minutes) , 120 (±5 minutes) minutes, 4 hours (±5 minutes) after subcutaneous injection and before dinner. Vital signs will be collected once on Day -1. On other non-dosing inpatient days, vital signs will be measured twice daily prior to breakfast and dinner.

3. Telemetry and Pulse Oximetry will begin 30 to 60 minutes prior to dosing and continue until 4 hours post-dose, then restart at 5 hours (±5 minutes) post-dose for at least 0.5 hour and then restart at 6 hours (±5 minutes) post-dose for at least 0.5 hour. 4. Electrocardiogram at screening, Day -1, at pre-dose on Day 1, at 6, 24, 48 and 72 hours (±15 minutes) post-dose, and on Day 8 and Day 85.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019

5. FSH as needed for confirmation of postmenopausal status at screening 6. Two SC injections will be administered to each subject at two separate injection sites (e.g. abdomen or upper thigh). 7. Pharmacokinetic timepoints will be: pre-dose and at 2, 4, 8, 12, 24, 36, and 48 hours after injection, and on Days 4, 5, 8, and 11. PK sample will be collected if early termination visit occurs before Day 11. If a subject prematurely withdraws/discontinues from the study, while the Early Termination falls on the planned pharmacokinetics sampling timepoint, collect the PK sample for the integrity of the PK data if the subject agrees such sample collection. Pharmacokinetic sampling time windows: pre-dose (up to 120 minutes pre-dose); 2 to 4 hours (±5 minutes) , 8 to 12 hours (±15 minutes) , 24 hours (±1 hour) , 36 to 48 hours and Days 4 to 8 (±3 hours), and Days 11 (±1 day) post-dose. 8. Local injection site reactions will be assessed at approximately 15 minutes post-dose, and at each brief physical examination.

9. Samples for total IgG，IgG subclasses, IgM, IgA and albumin will be collected pre-dose on Day 1. Samples for IgG subclasses, IgM, and IgA will be collected if early termination visit occurs before Day 57.

10. QuantiFERON®-TB Gold Plus™: A single repeat is allowed for the subject with an indeterminate result. 11. Subjects with positive Day 85 samples for anti- HBM9161 antibody will be requested to return at approximately 6, 9- and 12-months post-dose for additional sampling. However, the study database lock will be planned after last subject completes Day 85 visit. 12. At the screening stage, only SAEs and AEs related to study procedures will be collected.

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

ADA Anti-drug antibody AE Adverse event ADCC Antibody-dependent cell-mediated cytotoxicity ALP Alkaline phosphatase ALT Alanine aminotransferase Anti-HBs Hepatitis B surface antibody aPTT Activated partial thromboplastin time AST Aspartate aminotransferase AUC Area under the concentration curve AUC(0-inf) Area under the plasma concentration-time curve from time zero extrapolated to infinity AUC(0 inf)/D Dose normalized AUC(0 inf) BMI Body Mass Index BUN Blood urea nitrogen C Complement CFR Code of Federal Regulations CHO Chinese Hamster Ovary CI Confidence interval CIDP Chronic inflammatory demyelinating polyneuropathy CL/F Apparent Clearance Cmax Maximum concentration, obtained directly from the observed concentration versus time data Cmax/D Dose normalized Cmax

CO2 Carbon Dioxide CONSORT Consolidated Standards of Reporting Trials CPK Serum creatine phosphokinase CRF Case report form DAP Data analysis plan ECG Electrocardiogram eCRF Electronic case report form ED Effective dose EU European Union FcRn Neonatal Fc receptor FIH First-in-Human FSH Follicle stimulating hormone GCP Good clinical practice GGT Gamma glutamyl transferase GLP Good laboratory practice GMP Good manufacturing practice HBM9161 HBM9161(HL161BKN) HBsAg Hepatitis B surface antigen HCV Hepatitis C virus antibodies

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HED Human equivalent dose hFcRn Human neonatal Fc receptor HIPAA Health Insurance Portability and Accountability Act HIV Human immunodeficiency virus HRT Hormonal replacement therapy Hs-CRP High-sensitivity C-reactive protein IB Investigator’s brochure ICF Informed consent form ICH International Council for Harmonisation IEC Independent Ethics Committee IgA Immunoglobulin A IgG Immunoglobulin G IgG1 Immunoglobulin G1 IgM Immunoglobulin M INR International normalized ratio IP Investigational product IRB Institutional Review Board ISR Injection Site Reactions ITP Immune thrombocytopenia IUD Intrauterine device IV Intravenous IVIG Intravenous immunoglobulin K-PD Kinetic-pharmacodynamic LLOQ Lower limit of quantification MABEL Minimum anticipated biological effect level MAD Multiple ascending dose MDCK Madin-Darby Canine Kidney MedDRA Medical Dictionary for Regulatory Activities LDH Lactate dehydrogenase MCH Mean corpuscular hemoglobin MCHC Mean corpuscular hemoglobin concentration MCV Mean corpuscular volume MSDS Material safety data sheet NMOSD Neuromyelitis optica spectrum disorders NOAEL No observed adverse effect level PD Pharmacodynamics PK Pharmacokinetics PPD Purified protein derivative PT Prothrombin time RAUC Accumulation ratio of AUC RBC Red blood cell RCmax Accumulation ratio of Cmax SAD Single ascending dose SAE Serious adverse event SAP Statistical analysis plan

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SC Subcutaneous SIRS Systemic inflammatory response syndrome SUSAR Suspected unexpected serious adverse reactions TB Tuberculosis TIGRA T-cell interferon-γ release assay TMD Target-mediated disposition t½ Terminal half-life Tmax Time to Cmax ULN Upper limit of the normal reference range USA United States of America Vss Steady state volume of distribution Vss/F Volume of distribution Vz/F Volume of distribution of the terminal phase WOCBP Women of child bearing potential

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1 INTRODUCTION AND RATIONALE

1.1 Background and Rationale

HBM9161(HL161BKN) (abbreviated as HBM9161 afterwards) is a fully human monoclonal antibody, produced from recombinant CHO (Chinese Hamster Ovary) cells. HBM9161 targets the neonatal Fc receptor (FcRn) and is currently being developed for the treatment of autoimmune diseases. It is immunoglobulin G1 (IgG1) but has been Fc modified to decrease the potential for antibody-dependent cell- mediated cytotoxicity (ADCC). The FcRn mediates immunoglobulin G (IgG) recycling and endothelial transcytosis, which results in prolonged serum half-life for IgG and also mediates transendothelial transport of IgG allowing for extravascular distribution. FcRn is mainly localized on the vascular endothelial cells and cells of the reticulo-endothelial system, including monocytes and macrophages. Treatment with antibodies which block the binding of IgG to FcRn results in rapid depletion of blood levels of IgG, and also inhibits the transport of circulating IgG antibodies across the endothelium into tissue spaces. In this sense, like plasma exchange and plasmapheresis, it can lower the blood concentrations and tissue penetration of pathologic auto-antibodies. Because of this, anti- FcRn products are being considered as potential treatment strategies of diseases which involve the production of circulating pathogenic IgG autoantibodies such as immune thrombocytopenia (ITP), myasthenia gravis, and neuromyelitis optica spectrum disorders (NMOSD). FcRn also contains a separate binding site for human serum albumin and recycles albumin in a similar fashion. For the binding site on FcRn, HBM9161 preferentially binds Fc region of IgG more than albumin, and thus depletion of serum albumin is minimal by comparison to the effect on IgG of all sub-classes.

Anti-FcRn monoclonal antibodies have been administered safely to healthy volunteers by UCB, Argen-X, and other pharma companies (in single ascending dose (SAD) and multiple ascending dose (MAD) studies) [Kiessling, 2017; Ulrichts, 2016; Momenta, 2018]. Serial measurements of the concentrations of serum total IgG provide a primary pharmacodynamic (PD) read out of HBM9161 activity. The range of concentration of serum total IgG in humans is fairly broad (7 to 16 g/L). Experience with humoral immunodeficiency patients suggests little risk of short term (<1 month) levels of IgG as low as 1.5 g/L, since immunoglobulin M (IgM), immunoglobulin A (IgA), complement, cellular immunity, and innate immunity are all intact. Pharmacodynamic activity of anti-FcRn therapeutics is usually expressed in terms of the percent decrease in IgG from an individual’s baseline. Current therapies have reduced IgG in healthy volunteers and patient by 40-70% from baseline in clinical trials [Kiessling, 2017; Ulrichts, 2016; Momenta, 2018].

The first in human study of HBM9161 is ongoing in Canada. As of 15 Oct 2018, HBM9161 has been administered to overall 73 subjects at various dosages in both IV and SC, in both SAD and MAD. The drug has been well tolerated. Please see the details of Clinical Experiences in Humans in the section of 1.2.5.

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1.2 Profile of Investigational Product(s)

1.2.1 Nonclinical Pharmacology

In vitro Pharmacology The FcRn is involved in pH-dependent regulation of IgG and albumin homeostasis [Montoyo, 2009]. The FcRn binds to IgG and albumin and regulates their degradation. The mechanism of action for HBM9161 is to inhibit immunoglobulin binding to the human FcRn, resulting in an increase in clearance and a reduction in the overall levels of circulating immunoglobulin.

HBM9161 has a strong binding affinity to the human FcRn target protein, with KD values of 0.78 nM and 2.6 nM at pH 6.0 and pH 7.4, respectively. HBM9161 also binds to human FcRn and monkey FcRn when expressed on the surface of HEK293 cells.

HBM9161 blocks the binding of human IgG (hIgG) to human FcRn when evaluated in an in vitro competitive binding assay at pH 6.0.

HBM9161 inhibits hIgG transcytosis by human FcRn when evaluated in human FcRn- expressing Madin-Darby Canine Kidney (MDCK) cells in vitro.

Intracellular trafficking studies conducted in human FcRn-expressing HEK cells showed that in the presence of HBM9161, hIgG moved into the lysosome quickly and was degraded; whereas, HBM9161 remained in the endosome for a long time and did not readily move into the lysosome.

In vivo Pharmacology Based on FcRn sequence homology (97%) and in vitro binding data, the cynomolgus monkey was selected as a relevant species for evaluation of the pharmacokinetic (PK), PD, and toxicity of HBM9161.

Once weekly intravenous (IV) administration of 5 or 20 mg/kg HBM9161 for 21 days significantly reduced (~80% decrease at 20 mg/kg) the levels of endogenous plasma IgG in cynomolgus monkeys but had no effect on endogenous plasma IgM or IgA levels.

Albumin levels were slightly decreased following once weekly IV administration of 20 mg/kg HBM9161 for 21 days in cynomolgus monkeys.

Both subcutaneous (SC) and IV administration of HBM9161 resulted in similar reductions in the endogenous plasma IgG levels in cynomolgus monkeys.

Following twice weekly IV administration of 0.5 to 5 mg/kg HBM9161in cynomolgus monkeys, endogenous plasma IgG levels were gradually reduced with 4 repeated administrations to about 50% of baseline at a dose of 0.5 mg/kg, but there was no effect on endogenous plasma IgM or IgA levels. As noted in monkeys administered higher doses of HBM9161, albumin levels were slightly decreased by administration of HBM9161.

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Pharmacologic activity, measured as a decrease in endogenous monkey immunoglobulin levels, was noted in all HBM9161-treated groups in the 1- and 6-week repeat-dose toxicity studies.

1.2.2 Safety Pharmacology

Adverse effects of HBM9161on the central nervous system, respiratory rate or cardiovascular parameters were not seen, evaluated in repeat-dose toxicity study in cynomolgus monkeys conducted following the Good Laboratory Practice (GLP) conditions.

1.2.3 Toxicology

Toxicology studies have been performed with HBM9161 treatment for 1-week and 6-week durations in cynomolgus monkeys.

There were no treatment-related changes observed in body weight, clinical signs, and clinical pathology in cynomolgus monkeys, after three doses of HBM9161 at 25 or 100 mg/kg/dose administered SC or 100 mg/kg/dose administered IV over a 1-week period. The no observed adverse effect level (NOAEL) for HBM9161 was 100 mg/kg, the highest dose tested. Pharmacologic activity, measured as a decrease in endogenous monkey immunoglobulin levels, was noted in all HBM9161-treated groups.

A GLP-compliant, 6-week, repeat-dose (twice weekly), IV and SC toxicology study in cynomolgus monkeys, was performed. After SC administration of 25, 50, or 100 mg/kg HBM9161 or IV administration of 25 or 100 mg/kg HBM9161 to the cynomolgus monkey twice weekly for 6 weeks there were no treatment-related adverse effects on immunophenotyping, cytokine levels, ophthalmic examination, cardiovascular safety parameters, respiratory rate or neurobehavioral observations. In the study, findings attributed to immune complexes were observed in individual animal in the HBM9161 groups of 50 mg/kg SC and 25 and 100 mg/kg IV. The study report noted that HBM9161 dose of 100 mg/kg, by SC or IV routes, was the NOAEL in the 6-week study as the findings have low relevance to human. When the data is interpreted within the confines of the 6-week study, the NOAEL could be justified as 25 mg/kg SC and below 25 mg/kg IV. Given the anti-drug antibody (ADA) response and abolition of the PD effect in the study, the immune complex in monkeys likely attributed to the immunogenic response of the systemic exposure of humanized monoclonal antibody. Immunogenicity in animals is generally not predictive for immunogenicity in humans, and the risk of severe adverse events (SAEs) due to anti- HBM9161 antibody production in humans is considered low. However, subjects in the clinical trials will be monitored carefully for any adverse events (AEs), and pertinent biomarkers (ADA, complement factors, and PD) and PK of HBM9161 will be measured in the clinical study (Investigational Brochure HBM9161). Pharmacologic activity, measured as a decrease in endogenous monkey immunoglobulin levels, was noted in all HBM9161- treated groups.

There were no HBM9161-related adverse effects on local tolerance at the IV or SC injection sites in the GLP-compliant, 6-week, repeat-dose (twice weekly), IV and SC toxicology study in cynomolgus monkeys. Findings recorded at the terminal sacrifice for the injection sites were consistent with a non-specific inflammatory reaction to injected protein with an

Confidential and Proprietary Page 21 of 69 Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 associated reaction in the local axillary and inguinal drainage lymph nodes. These findings were completely reversed after the 9-week recovery phase.

In the GLP-compliant human tissue cross-reactivity study, HBM9161-specific positive staining, predominantly membranous to cytoplasmic, was generally associated with mononuclear cells of indeterminate lineage potentially including lymphocytic subsets, cells of histiocytic origin, and cells with fibroblastic/reticular cell morphology. Some additional specific positive staining was observed in epithelial and endothelial components of a limited number of tissues. In some specific tissues, alveolar macrophage (lung), glial cells (brain), Hofbauer cells (placenta), and sinusoidal cells (liver) were also stained.

No reproductive studies have been performed with HBM9161 and effects of HBM9161 on conception, pregnancy, and lactation in humans are not known.

1.2.4 Nonclinical Pharmacokinetics

HBM9161 levels in plasma rapidly declined with a half-life (t½) of less than 24 hours following IV administration of 5 or 20 mg/kg in cynomolgus monkeys.

HBM9161 had a longer t½ at the high dose compared to the low dose, which is consistent with target-mediated elimination.

Lower maximum concentration (Cmax) and area under the concentration curve (AUC) values, and longer t½ values were observed following SC administration of HBM9161 in cynomolgus monkeys, compared to the values following IV administration.

The PK measurement of HBM9161 in the blood following IV administration of 0.5 to 5.0 mg/kg revealed a short t½ (less than 13 hours) which tended to increase in a dose-dependent manner.

In a 1-week, repeat-dose toxicity study in cynomolgus monkeys, the high SC dose of 100 mg/kg resulted in a mean Cmax and AUC levels of 2200 μg/mL and 145000 μg.h/mL, and the high IV dose of 100 mg/kg resulted in a mean Cmax and AUC levels of 4870 μg/mL and 203000 μg.h/mL, following the 3rd administration. In the 6-week GLP, repeat-dose toxicity study in cynomolgus monkeys, following the last (13th) dose administration, the SC dose of 100 mg/kg resulted in a mean Cmax and AUC(0- 168) levels of 2880 μg/mL and 362000 μg.h/mL in males and 2800 μg/mL and 272000 μg.h/mL in females. Following the last (13th) dose administration, the high IV dose of 100 mg/kg resulted in a mean Cmax and AUC(0-168) levels of 4760 μg/mL and 218000 μg.h/mL in males and 5330 μg/mL and 273000 μg.h/mL in females. From Day 22 onwards, all samples from HBM9161-treated animals were positive for ADA, except for 13 samples which were negative, possibly due to the drug intolerance of the assay. Although HBM9161-treated animals developed ADA, the toxicology and PD analyses showed that sufficient exposure and activity were maintained throughout the study.

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1.2.5 Clinical Experiences in Humans

The first in human study is ongoing in Canada. As of 15 Oct 2018, HBM9161 has been administered to 57 subjects at the following doses: 0.1 mg/kg as a 1-hour IV infusion (n=4); 100 mg as a 1-hour IV infusion (n=6); 340 mg as a 1-hour IV infusion (n=6); 0.5 mg/kg SC injection (n=3); 1.5 mg/kg SC injection (n=6); 5 mg/kg SC (n=6), 340 mg SC injection (n=6); 500 mg SC injection (n=6); and 765 mg SC injection (n=6). Eight subjects in the initial MAD cohort have received 340 mg SC injections weekly for 4 weeks.

Sixteen additional subjects have received a placebo IV infusion or SC injection. The drug has been well tolerated to date with no SAEs, no Grade 3 or 4 AEs, and no withdrawals due to AEs. All AEs have been reported as mild with the exception of one moderate gastroenteritis, one chest pain, five body aches and pain, one vomiting, one dizziness from catheter insertion, and six headaches (relatedness to drug not yet attributed). Other reported AEs were fatigue, sore throat, coughing, abdominal pain, nausea, somnolence, headache, itchy right arm, low back pain, nasal congestion and upper respiratory tract infection. Following the 5 mg/kg SC dose, 7 of 8 subjects developed mild erythema at the injection site that resolved within 3 hours after dose. Additionally, some subjects developed swelling near the injection site, which resolved within 30 minutes after dose and 4 days after dose for one subject. No clinically significant laboratory findings, ECGs, or vital signs have been observed.

Additional information is available in the Investigator’s Brochure (IB). The Sponsor will immediately notify the Investigator if any additional safety or toxicology information becomes available during the study.

1.2.6 Rational for the Trial

The FcRn is a potential therapeutic target for many autoimmune diseases.

Single ascending dose (SAD) will be used to further the understanding of the safety, PK and PD of HBM 9161 in healthy Chinese subjects, which, will then be able to compare the related data from Chinese with Caucasian subjects. The future use of HBM9161 would be for the treatment of autoimmune diseases. Therefore, characterization of PD effects on endogenous IgG, along with safety profile of HBM9161 is warranted. In addition, it will be important to identify the potential development of autoantibodies and their time course. These objectives are best studied in healthy volunteers to inform future dosing in patients.

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2 STUDY OBJECTIVES AND ENDPOINTS

Primary Objective: Primary Endpoints:

• The primary objective of this trial is to • The number [N (%)] of subjects with drug-related AEs. evaluate the safety, tolerability of HBM9161 following single SC dose in healthy subjects as assessed by drug- related AEs.

Secondary Objectives: Secondary Endpoints:

• The secondary objective of this trial is to • Other variables for safety and tolerability assessments: the evaluate the safety, tolerability of number [N (%)] of subjects with adverse events (AEs), HBM9161 following single SC dose in abnormal 12-lead ECG, abnormal clinical laboratory healthy subjects as assessed by other AE tests, abnormal physical examination and change of vital variables signs (blood pressure, pulse rate) from baseline.

PK parameters: • The secondary objective of this trial is also to evaluate the PK of HBM9161 • Cmax (maximum measured concentration of the analyte in following the SC dose in healthy subjects. serum) AUC (area under the concentration-time curve of the • 0- analyte in serum over the time interval from 0 extrapolated to infinity) • tmax (time from dosing to maximum measured concentration) • t1/2 (terminal half-life of the analyte in serum) • CL/F (total clearance of the analyte in serum after administration estimated using formula) • Vz/F (apparent volume of distribution during the terminal phase z following administration estimated using formula)

In addition, the following dose normalized parameters will be calculated for HBM9161:In addition, the following dose normalized parameters will be calculated for HBM9161: C , AUC • max, ,norm 0-∞,norm Other Objectives: Other Endpoints:

• This trial is also to evaluate the PD PD parameters: (change in serum concentrations of • Total serum IgG concentrations over time following immunoglobulin G [IgG] and albumin) of SC administration HBM9161. HBM9161 and measure anti-HBM9161 • Maximum change from baseline in total IgG antibodies following single SC dose in serum concentrations. healthy subjects. • PD AUC (Days 1 to 29): the AUC of total serum IgG concentrations

• Maximum change from baseline in serum albumin. • Immunogenicity after SC administration determined by change from pre-dose in anti--HBM9161 antibody.

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3 INVESTIGATIONAL PLAN

3.1 Study Design and Plan

This is a Phase I, randomized, single-blinded, placebo-controlled study to investigate the safety, tolerability, PK and PD of single ascending doses of HBM9161 in healthy Chinese subjects.

Each subject will only participate in one dosing cohort.

Table 1 illustrates the study design and planned escalation. Proposed doses may be adjusted during the study as soon as the preliminary results are made available.

Table 1: Study Design

Single Dose in Healthy Subjects Cohort N(Active/Placebo) Route Planned Dose (mg) 1 6/2 SC 340 2 6/2 SC 510 3 6/2 SC 680

Escalation to the next dose level will only occur if the previous dose level was deemed to be safe and well tolerated. PD (total IgG) data will be reviewed prior to next dose escalation.

Safety data from at least 6 subjects in the previous cohort must be reviewed before a decision to start next dose escalation. The Sponsor will decide on the dose escalation by considering recommendation of Investigator following the discussion with Investigator.

Subjects will be screened during up to 40 days prior to study drug administration. Eligible subjects will check in on Day -1 and remain confined to the Phase 1 Centre until Day 5. Subjects will return for follow-up visits and for an “End of Study Visit” (Day 85) per the Time and Events Table. Subjects who have persistent anti-HBM9161 antibodies after Day 85 will be requested to have blood samples drawn for anti-HBM9161 antibody test and be assessed for AEs at approximately 6, 9, and 12 months after dosing or until 2 consecutive samples have been confirmed to be negative for anti-HBM9161 antibody, whichever occurs earlier.

3.2 Rationale of Study Design

A standard sequential-group, single-blinded, placebo-controlled design will be used for this SAD study to evaluate the safety, tolerability, PK and PD of HBM9161 in healthy Chinese subjects. Subjects will be randomized to minimize bias. Placebo will be included to facilitate identification of effects due to HBM9161 from background noise (e.g., effects associated with residence in a drug research unit with a standard diet and restriction on exercise).

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The study will be conducted in healthy subjects to avoid interference from disease progression or other drugs. The selection criteria are defined so that the healthy subjects selected for participation this study will be known to be free from significant illness.

Serial measures of serum IgG will provide a rapid and convenient read-out of target engagement and PD activity in healthy subjects across varying exposures to HBM9161 and are ideal for identifying a therapeutic dose for studies in patients. Additionally, these measures will provide a direct read-out of drug PD effects to monitor safety.

Studies in nonhuman primates have suggested after biweekly repeated doses of HBM9161 5.0 mg/kg SC and IV, decreases in circulating IgG were cumulative, up to a maximum of 70% to 80% decrease. The normal range for total IgG in adults is broad, about 700 to 1600 mg/dL, and an IgG of 700 mg/dL or greater at baseline will be required for inclusion in this trial. Thus, an 80% post-treatment reduction could give an IgG level of 140 to 320 mg/dL, which would cause Grade 2 to Grade 3 hypogammaglobulinemia in such subjects. This reduction in circulating IgG will result in a slightly increased risk of bacterial infection, particularly sinus infection or pneumonia. As IgG levels are expected to return to normal soon after the last dose of study drug is given, preventative antibiotic use is not necessary. Since the B-cell and plasma cell compartment and “memory” B-cell response is unaffected by this treatment, antibody (both IgG and IgM) will be made in normal amounts in response to antigenic stimulus, but serum half-life of IgG will be greatly shortened while HBM9161 still has maximal PD effect. In addition, based on current available data, the treatment is not expected to affect the existing levels of IgM or IgA.

Exposure will not exceed a Cmax (2800 µg/mL) and/or AUC(0 -168) [272000 µg.h/mL] at the 100 mg/kg of NOAEL in the cynomolgus monkeys.

3.3 Rationale of Dose/Regimen and Duration of Treatment

The NOAEL level for both SC and IV doses of HBM9161 in cynomolgus monkeys dosed twice weekly every 3 days for 28 days was reported as 100 mg/kg. The human equivalent dose (HED) for this dose is 32 mg/kg. Using a 6-fold safety margin would result in a maximum safe starting dose of 5.0 mg/kg.

Data from ongoing Phase I study in non-Chinese healthy subjects indicate SC of 340mg, 500mg and 765 mg are safe and well tolerated. Based on pre-clinical and clinical data, 340mg is selected as the first dose level to be subcutaneously administered to evaluate safety and tolerability in Chinese healthy subjects.

Maximum exposure limits were set based on the steady-state max (2800 µg/mL) and AUC(0 - 168) (272000 µg .h/mL) which were observed in the 100mg/kg monkey SC dose group. The exposures of single dose from the ongoing phase I study in Canada are much lower than NOAEL from 6 weeks toxicity study, so the dosage to be investigated in this protocol will not approach that level. Additionally, the Cmax to be obtained in this protocol is estimated to be less than what has already been observed in humans thus far given the value observed following IV 340 mg, which was still 23-fold lower than NOAEL. For this protocol, PK data will not be reviewed before dose escalation. The safety profile, and extent and duration of

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IgG depletion will be considered when providing recommendations for dose escalation in the next cohort.

3.4 Dose Escalation and Data Review

The Investigator and the Sponsor will review data from each cohort prior to advancing to the next dose escalation. Escalation to the next dose level will only occur if the previous dose level was deemed to be safe and well tolerated following review of the safety, tolerability, and PD (total IgG) data from hospital admission to post-dose on Day 15. Specific parameters reviewed will be AEs, vital signs, 12-lead ECG, telemetry and clinical laboratory safety tests, and PD (total IgG).

For all cohorts, safety and PD (total IgG) data from 6 out of the 8 subjects in the previous cohort must be reviewed before a decision to advance to next dose escalation.

Subjects will be blinded to treatment assignment. Site investigator and other site staff will be unblinded to subject randomization.

3.5 Benefit-Risk Assessment

Summaries of findings from both clinical and non-clinical studies conducted with HBM9161 can be found in the IB. As a non-therapeutic trial in which there is no anticipated direct clinical benefit to the subject, subjects will be particularly closely monitored and should be withdrawn if they appear to be unduly distressed. The following section outlines the risk assessment and mitigation strategy for this study.

3.5.1 Risk Assessment

HBM9161 has been administered up to 765mg SC. No clinically significant AEs, laboratory findings, ECGs, or vital signs were observed. The safety, PK, and PD data support continued dose escalation in this study.

For suspected systemic inflammatory response syndrome (SIRS), (cytokine release syndrome) an unscheduled blood sample will be collected for measurement of mast-cell tryptase, complement (C)3a-des-Arg, C5a-des-Arg, and multiplexed serum cytokine profile.

Should any subject have severe hypogammaglobulinemia (<3g/L) and associated with an active bacterial infection, at the discretion of site investigator, consideration should be given to either:

• Treating with a replacement dose of IV Immunoglobulin (IVIG) [0.5 mg/kg], and/or • Coverage with appropriate oral broad-spectrum antibiotics.

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4 SELECTION OF TRIAL POPULATION

Deviations from inclusion and exclusion criteria will not be allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

To determine subject eligibility at screening, a single repeat of certain tests such as laboratory tests values, vital signs, or ECGs will be allowed at the discretion of the Investigator.

4.1 Inclusion Criteria

Subjects must meet the following criteria to be entered in this trial:

1. Aged between 18 and 45 years, inclusive, at screening. 2. Han Chinese male or female subjects, and his/her biological parents and grandparents are of Han Chinese ethnicity.

4.2 Exclusion Criteria

Subjects who meet any of the following criteria must be excluded. 1. Presence of any concomitant clinically significant diseases, including cardiovascular, gastrointestinal, endocrinological, hematological, hepatic, immunological, metabolism, urological, pulmonary, neurological, dermatological, psychiatric, renal, or other major disease or malignancy, as judged by the investigator. 2. Subject has a total IgG level of < 700mg/dL (test results from local laboratory) at screening. 3. Subject has an active infection (e.g. sepsis, pneumonia, and abscess) or has had a serious infection (resulting in hospitalization or requiring parenteral antibiotic treatment) within 6 weeks prior to Day -1 or infection requiring oral anti-infective agents within 2 weeks

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prior to Day-1, or subject had a febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to admission (Day -1). 4. History of relevant allergy/hypersensitivity (including allergy to study drug or its excipients). 5. Intake of prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) within 7 days or less than 5 half-lives (whichever is longer) of the respective drug prior to dosing of the study drug. Exceptions include topical medications or eye drops with no systemic action, and injectable or combined oral contraceptives. 6. Participation in another clinical trial and received investigational drug(s) (except this study) within 90 days prior to dosing of the study drug. 7. Subject has been a smoker or has used tobacco or nicotine-containing products within 3 months prior to screening. 8. Regular consumption of alcoholic beverages that exceeds 14 units per week (1 unit = 360ml of beer; 150ml of wine; 45ml of distilled spirits) within 3 months prior to screening. 9. Inability to refrain from smoking and alcohol consumption prior to dosing of the study drug. 10. History of substance (alcohol or illicit drugs) abuse/addiction in the past 5 years, or used illicit drugs 3 months prior to signing informed consent, or positive drug/alcohol screen at screening or Day -1. 11. Blood donation (more than 450 mL whole blood donation within 3 months, 50mLwhole blood donation within 1 month) prior to dosing of the study drug. 12. Subject has received a transfusion of any blood or blood products within 60 days prior to dosing of the study drug. 13. Subject has performed strenuous exercise within 7 days prior to dosing of the study drug; 14. Any laboratory values outside the reference range that are of clinical significance according to investigator’s clinical judgement. 15. Subject has estimated creatinine clearance ≤ 80 mL/min calculated by Cockcroft Gault formula at screening. 16. Subject has any of the following ECG abnormality (a single repeat is allowed for eligibility determination) at screening or Day -1: Resting heart rate <45 or >100 bpm PR interval <120 or >210 msec QRS duration <70 or >120 msec QTc interval F >450 msec

17. Positive HIV test result at screening.

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18. Positive testing for HBs Antigen and/or a positive Hepatitis C antibody test result at screening.

19. Subject has a positive T-cell interferon-γ release assay (TIGRA) result i.e., QuantiFERON®-TB Gold Plus™ test at screening. A single repeat is allowed for subjects with an indeterminate result of QuantiFERON®-TB Gold Plus™ test. 20. Inability to comply with the meal arrangement. 21. Subjects who had immunization within 4 weeks before screening; subjects who plan to have immunization during the study and within 12 weeks after dosing of the study drug. 22. For female subjects, positive pregnancy test at screening or Day -1, or planning to become pregnant from screening until 90 days after dosing of the study drug. 23. Lactating female subjects.

4.3 Lifestyle and/or Dietary Restrictions

Subjects should comply with the lifestyle and dietary restrictions from screening until End of Study Visit and Extended Follow-up Visit (if applicable). Site personnel will ensure that each subject can fully understand and be able to comply with the lifestyle and dietary restrictions during the study. Non-compliance with any of the lifestyle or dietary restrictions will be regarded as protocol deviation and shall be recorded accordingly. If the non- compliance may potentially compromise subject’s safety or jeopardize the scientific integrity of the study, it is subject to the discretion of Investigator whether to prematurely terminate or discontinue the subject from the study.

4.3.1 Meals and Dietary Restrictions

Subjects will be asked to abstain from consuming food containing poppy seeds from 72 hours prior to dosing until 7 days after dosing. There are no fasting requirements prior to dose administration. During admission periods subjects will receive a standard diet, which excludes caffeine and alcohol.

4.3.2 Caffeine, Alcohol, and Tobacco

Subjects will abstain from ingesting caffeine- or xanthine-containing products (e.g. coffee, tea, cola drinks, chocolate, and high energy drinks) within 24 hours prior to admission, during confinement period, and within 24 hours prior to each study visit.

Subjects will abstain from consuming alcohol throughout the study until End of Study Visit. Subjects must be advised to avoid excessive alcohol intake after End of Study Visit until their IgG levels return to within the local normal range, as confirmed by the Investigator, because of the increased risk of infection during the period of decreased IgG.

Subjects will abstain from the use of tobacco/nicotine/vaping/e-cig/ products throughout the study until End of Study Visit.

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4.3.3 Activity

Subjects will abstain from strenuous exercise within 7 days before dosing, within 7 days after dosing and within 72 hours prior to each blood collection for clinical laboratory tests. Subjects may participate in light recreational activities during studies (e.g. watch television, read). Subjects must be advised to avoid vigorous contact sports after this period until their IgG levels return to within the local normal range, as confirmed by the Investigator, because of the increased risk of infection during the period of decreased IgG.

Subjects must be advised to comply with the following restrictions:

• Any use of illicit drugs is prohibited throughout the study until End of Study Visit and Extended Follow-up Visit (if applicable).

• Avoid immunization throughout the study and within 12 weeks after dosing of the study drug.

• Avoid any blood donation (except for blood samplings in this study) throughout the study until End of Study Visit

• Female subjects of childbearing potential (including female subjects who are within 12 months of menopause) and male subjects must use at least one of the acceptable contraceptive method(s) throughout the study and within 90 days after dosing of the study drug. The acceptable contraceptive methods include abstinence (for at least 1 month prior to screening), correct use of condom, spermicides, injectable or combined oral contraceptives, intrauterine device with or without local hormone release, cervical cap or diaphragm and vasectomy performed at least 1 year prior to screening.

• Female subjects should avoid breastfeeding an infant or provide breast milk to other infant(s) throughout the study until End of Study Visit.

• Subjects should not participate in another clinical trials and receive investigational drug(s) (except this study) throughout the study until End of Study Visit and Extended Follow-up Visit (if applicable).

4.4 Withdrawal and Discontinuation of Subjects

4.4.1 Subject Withdrawal Procedures

If a subject is prematurely discontinued from the study, the Investigator must make every effort to perform an Early Termination Visit as per Time and Event Table and document the primary reason for discontinuation.

Should a subject fail to go to the clinic for a required study visit, the site should attempt to contact the subject and re-schedule the missed visit as soon as possible. The site should also counsel the subject on the importance of maintaining the assigned visit schedule and confirm whether the subject wants to continue to be in the study based on previous non-compliance. In cases where the subject does not return for the rescheduled visit or cannot be reached to

Confidential and Proprietary Page 31 of 69 Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 reschedule the missed visit, the site should make every effort to regain contact with the subject (3 documented telephone calls and if necessary a certified letter to the subject’s last known mailing address) so that they can appropriately be withdrawn from the study with a primary reason of “Lost to Follow-up”. 4.4.2 Stopping Criteria

Criteria for Stopping Dose Escalation

Dose escalation will be stopped if any of the following criteria are met and based on concurrence of the Investigator and the Sponsor. The Investigator and the Sponsor will thoroughly review available PD (total IgG) and safety and tolerability data before any further dose escalation. After the review, the Investigator and the Sponsor can agree to dose escalation if the overall data suggest that the dose escalation will be safe. Alternatively, they can determine to re-initiate the dose or proceed with an intermediate dose in a subsequent cohort:

• One or more HBM9161-treated subjects has a serious infective episode requiring hospitalization and IV antibiotic therapy (including bacteremia, meningitis, pneumonia, pyelonephritis, septic arthritis, or bacterial pneumonia) within 3 weeks of dosing during the period of hypo-gammaglobulinemia (at the discretion of site investigator) following dosing.

• Two or more HBM9161-treated subjects have a total IgG reduction of ≥80% for more than 7 days after the first occurrence.

• One or more HBM9161-treated subjects have total IgG reduced to a level of <300 mg/dL for more than 5 days after the first occurrence.

• Two or more HBM9161-treated subjects have an absolute lymphocyte count <0.5× 10 9/L.

9 • One HBM9161-treated subject has an absolute neutrophil count <1.0 × 10 /L, confirmed by a repeat CBC at least 8 hours later.

• Two or more HBM9161-treated subjects have an increase in ALT or AST >3 × the ULN, confirmed by a repeat evaluation at least 24 hours later.

• Two or more HBM9161-treated subjects have an increase in serum creatinine>1.5 × ULN, confirmed on a repeat evaluation at least 24 hours later.

• One HBM9161-treated subject has an injection reaction associated with angioedema, bronchospasm, or hypotension and requiring treatment with corticosteroids or epinephrine.

• Four or more HBM9161-treated subjects (cumulatively across cohorts), or 3 or more (within a cohort) experience the same or similar AE of Grade 3 (severe) severity considered by the Investigator to be drug-related. (except for Grade 3 erythema or swelling circumference at SC injection site).

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Criteria for Stopping the Study

If any of the following circumstances occur and with a reasonable possibility of a causal relationship with the study treatment, the study will be stopped, and based on concurrence of the Investigator and the Sponsor:

• If ≥1 HBM9161-treated subject experiences SAEs considered to have a reasonable possibility of relationship to HBM9161.

• If ≥1 HBM9161-treated subject fulfils Hy’s law defined as ALT or AST ≥3 × ULN and bilirubin ≥2 × ULN in the absence of significant increase in alkaline phosphatase (ALP) and in the absence of an alternative diagnosis that explains the increase in total bilirubin, to be assessed from the first administration of study treatment up to and including follow-up.

• If ≥2 HBM9161-treated subjects have a QTc prolongation defined as QTcF >500 ms, or an increase of QTcF >60 ms from baseline on the 12-lead ECG, confirmed (persistent for >5 minutes) by repeated 12-lead ECG. 4.4.3 Toxicity Management Criteria (Adverse Events, Cardiovascular, and Site Reactions)

For subjects who have developed a total IgG reduction of ≥80% OR had an IgG <300mg/dL, measurement of total IgG will be repeated daily until total IgG returns to the level which is acceptable to site investigator as per his/her judgment after discussion with sponsor.

For subjects who have severe hypogammaglobulinemia (<3g/L) and associated with an active bacterial infection, at the discretion of site investigator, consideration should be given to either:

• Treating with a replacement dose of IV Immunoglobulin (IVIG) [0.5 mg/kg], and/or

• Coverage with appropriate oral broad-spectrum antibiotics The severity of each AE (except injection site reactions) will be graded and managed according to the criteria in Table 2.

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Table 2 Criteria for Determining the Grade/Severity of Adverse Event Terms

Grade Criteria 1/Mild Asymptomatic or mild symptoms, clinical or diagnostic observations only; intervention not indicated

2/Moderate Limiting age-appropriate instrumental activities of daily living; minimal, local, or noninvasive intervention as indicated 3/Severe or medically Not immediately life-threatening; hospitalization or significant prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living, intervention as indicated 4/Life-threatening Life threatening consequences; urgent intervention indicated

5/Death Death related to adverse event

Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010)

Injection Site Reactions (ISR) Injection site evaluations will be made by the Investigator following SC administration of HBM9161 and placebo as described below. If an injection site reaction is observed, a physician will characterize and document the reaction as an AE. Observation of the injection site will continue until the AE is resolved.

Symptomatic treatment (e.g. antihistamines, NSAIDS, IV fluids) may be provided for any injection site reactions at the discretion of the Investigator.

The injection sites will be monitored for pain, tenderness, erythema and swelling.

Each injection site reaction will be recorded as an AE/SAE. The severity of injection site reactions should be graded using the severity grading scheme presented in Table 3 only, NOT the severity grading scheme of AE event terms in Table 2.

Table 3: Criteria for Determining the Grade/Severity of Injection Site Reactions

Grade Criteria 1/Mild Tenderness with or without associated symptoms (e.g., warmth, erythema, itching)

2/Moderate Pain; lipodystrophy; edema; phlebitis

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3/Severe or medically Ulceration or necrosis; severe tissue damage; significant operative intervention indicated

4/Life-threatening Life threatening consequences; urgent intervention indicated

5/Death Death

Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010).

4.4.4 Subject and Study Completion

A completed subject is one who has completed all phases of the study including the follow- up visit.

The end of the study is defined as the last visit of last subject.

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5 CLINICAL SUPPLIES

5.1 Investigational Product(s) Descriptions

The term study treatment is used throughout the protocol to describe HBM9161 or placebo.

Study Treatment Name: HBM9161 Placebo Supplier: Vetter Development Vetter Development Services USA, Inc Services USA, Inc Dosage Formulation: 170 mg/mL HBM9161 in 100 100 mM L- mM L- Histidine/Histidine HCl, Histidine/Histidine HCl, 100 mM L-Arginine HCl and 100 mM L-Arginine HCl 0.02% Polysorbate 20, pH 6.0 and 0.02% Polysorbate 20, pH 6.0 Dosage Level(s): The dose escalation plan is Not applicable. illustrated in Table 1 Route of Administration SC injection Dosing Instructions: The detailed methods are The detailed methods are indicated in the Pharmacy indicated in the Pharmacy Manual. Manual. Dose Preparation The dose solutions will be prepared at the Phase 1 Centre in two injections volume according to the following table:

Cohort Planned Total Volume of Number of Vials Dose Injection/Subject (ml) of IP /Placebo (mg) Required

1 340 2 ml (i.e. 1ml+1ml) 2 2 510 3 ml (i.e. 1.5ml+1.5ml) 3 3 680 4 ml (i.e. 2ml+2ml) 4

The preparation procedure and expiry details will be included in a Pharmacy Manual.

5.2 Randomization / Treatment Assignment

Subjects will be randomized in accordance with the randomization schedule, prepared prior to the start of the study.

5.3 Blinding and Unblinding

This will be a single-blinded study. The subjects will be blinded to treatment assignment. The Investigator and study site staff will be unblinded to treatment assignment for evaluating

Confidential and Proprietary Page 36 of 69 Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 the IgG and albumin data before initiating escalation to a higher dose. The PI’s awareness of the treatment should not influence the decision to enter any subjects or affect the order in which kind of subjects to be entered.

5.4 Packaging and Labelling Information

HBM9161 will be supplied to the study site as a sterile liquid formulation with a nominal fill of at least 1 mL in Nuova Ompi 2R clear glass vials with a flip-off cap. The solution is clear to slightly yellow, essentially free of visible particles, for SC administration. The formulation consists of 170 mg/mL HBM9161 in 100 mM L- Histidine/Histidine HCl, 100 mM L- Arginine HCl and 0.02% Polysorbate 20, pH 6.0.

Placebo will be provided as a sterile liquid formulation with a 1 mL fill in Nuova Ompi 2R clear glass vials with a flip-off cap. The solution is clear to colorless, essentially free of visible particles, for SC administration. The placebo formulation consists of 100 mM L- Histidine/Histidine HCl, 100 mM L-Arginine HCl and 0.02% Polysorbate 20, pH 6.0.

Doses will be prepared by the pharmacy with a label that includes at minimum the study number, subject number, and investigational drug name or placebo, and administered to subjects by study staff.

The interval between removing from refrigerated storage (2˚C to 8˚C) and completion of injection should not exceed 4 hrs. See Pharmacy Manual for exact instructions on dose preparation.

All labels will meet all local applicable requirements and Annex 13 of Good Manufacturing Practices (GMP): Manufacture of Investigational Medicinal Products (July 2010) and/or other local regulations as applicable.

5.5 Drug Preparation, Dispensing, Storage, Accountability and Destruction

A description of the methods and materials required for preparation will be detailed in a Pharmacy Manual.

• Only subjects entered in the study may receive study treatment and only authorized site staff may supply or administer study treatment. Two SC injections will be administered to each subject at two separate injection sites (e.g. abdomen or upper thigh). For dose volumes requiring greater than 2 mL, the dose should be divided approximately equally between 2 syringes. All study treatments must be stored in a secure environmentally controlled and monitored (manual or automated) area in accordance with the labelled storage conditions with access limited to the Investigator and authorized site staff.

• The Investigator will be responsible for study treatment accountability, reconciliation, and record maintenance (i.e. receipt, reconciliation and final disposition records).

• Under normal handling and administration conditions, study treatment is not expected to pose significant safety risks to site staff. In the case of

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unintentionally occupational exposure, the monitor and the Sponsor will be monitored. 5.6 Treatment after the End of the Study

Subjects will not receive any additional study treatment from the Sponsor after study completion because this study only includes healthy subjects.

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6 CONCOMITANT TREATMENT(S) AND PROHIBITED MEDICATION(S)

Subjects must abstain from taking prohibited medications (except permitted medications) unless it is prescribed by the Investigator as concomitant medication(s) for treatment of a medical need in consultation with the Sponsor. Otherwise, it is regarded as protocol deviation and shall be recorded accordingly. However, if the deviation(s) may potentially compromise subject’s safety or jeopardize the scientific integrity of the study, it is subject to the discretion of PI whether to prematurely terminate or discontinue the subject from the study.

6.1 Permitted Medications and Non-Drug Therapies

Acetaminophen, at doses of  4 grams/day will be allowed at the discretion of the Investigator after dosing. Topical medications or eye drops with no systemic action will be permitted for use at any time during the study. Injectable or combined oral contraceptives are allowed to be used as the contraceptive method in the study.

Other concomitant medication may be considered on a case by case basis by the Investigator for treatment of a medical need in consultation with the Sponsor. Any concomitant medication should be recorded in the study records, including the doses administered, the dates and time of administration and the reason for administration.

6.2 Prohibited Medications and Non-Drug Therapies

Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days or less than 5 half-lives (whichever is longer) of the respective drug prior to dosing and within 1 month after dosing, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study, and the medication is needed for proper medical management of the subject. Refer to section 6.1 for permitted medications.

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7 STUDY PROCEDURES

Protocol waivers or exemptions will not be allowed except for immediate safety concerns. Therefore, adherence to the study requirements, including those specified in the Time and Events Table, is mandatory.

This section lists the procedures and parameters for each planned study assessment. The exact timing of each assessment is listed in the Time and Events Table.

The following points must be noted:

• If assessments are scheduled for the same nominal time, THEN the assessments should occur in the following order: 1. 12-lead ECG 2. vital signs 3. blood draws Note: The timing of the assessments should allow the blood draw to occur at the exact nominal time.

• The IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the Informed Consent Form (ICF).

• The total blood volume collected will be specified in the ICF. 7.1 Screening and Critical Baseline Assessments

Screening assessments are outlined in the Time and Events Table. The following demographic parameters will be captured: year and month of birth, sex, race and ethnicity.

Medical/medication/family history will be assessed as related to the inclusion/exclusion criteria listed in Section 4.

7.2 Procedures by Study Period

7.2.1 Physical Examinations

A complete physical examination will include, at a minimum, assessment of the cardiovascular, respiratory, gastrointestinal, and neurological systems and skin. Height will be measured and recorded at screening only. Weight will be measured and recorded at screening and at check in (Day -1).

A brief physical examination will include at a minimum assessment of the skin (including any injection site reaction), respiratory, cardiovascular system, and abdomen (liver and spleen).

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7.2.2 Vital Signs

Vital signs will be assessed in supine or semi-reclining position after at least 5 minutes rest and will include body temperature, systolic and diastolic blood pressure, and pulse rate.

7.2.3 Electrocardiogram

Electrocardiogram will be measured in supine position after at least 5 minutes rest.

The 12-lead ECG will be obtained at each timepoint during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT intervals. QTcF interval will be calculated and collected.

7.2.4 Telemetry and Pulse Oximetry

Continuous cardiac telemetry and pulse oximetry will be performed per the Time and Events Table. Full disclosures will be reviewed in detail and the review maintained as part of the subject’s source document.

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7.2.5 Clinical Safety Laboratory Assessments

All laboratory assessments required by the protocol must be conducted in accordance with the Study Reference Manual (SRM) or Laboratory Manual, and the Time and Events Table in the protocol.

Laboratory requisition forms must be completed, and samples must be clearly labelled with the subject number, protocol number, site/center number, and visit date. Details for the preparation and shipment of samples will be provided by the laboratory and will be detailed in the SRM or the laboratory manual. Reference ranges for all safety parameters will be provided to the site by the laboratory responsible for the assessments.

If additional laboratory assessments not specified in the protocol are performed at the institution’s local laboratory and result in a change to subject management or are considered clinically significant by the Investigator (e.g., SAE or AE or dose modification), the results must be recorded.

All subjects should fast for at least 8 hours prior to clinical safety laboratory tests (hematology and chemistry). If a subject does not fast for 8 hours, a minimum of 4-hours fast will be allowed prior to the tests for outpatient visits.

Hematology, clinical chemistry, urinalysis, and additional tests to be conducted are listed below:

Hematology Platelet Count RBC Indices: Automated WBC Differential: RBC Count MCV Neutrophils WBC Count (absolute) MCH Lymphocytes Hemoglobin MCHC Monocytes Hematocrit Eosinophils Basophils

Clinical Chemistry Urea Potassium AST (SGOT) Total and direct bilirubin Creatinine Chloride ALT (SGPT) Uric Acid Glucose, fasting Bicarbonate GGT Albumin Sodium Calcium Alkaline phosphatase Total Protein NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are given in Appendix 1: Liver Safety Required Actions and Follow up Assessments.

Coagulation INR aPTT PT

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Routine Urinalysis Specific gravity, pH glucose, protein, blood and ketones by dipstick Microscopic examination (if blood or protein is abnormal)

Other Screening Tests Total IgG Creatinine Clearance (Cockcroft-Gault equation) HIV1/HIV2 Hepatitis B (HBsAg), Hepatitis C (Hep C antibody) QuantiFERON®-TB Gold Plus™ FSH (as needed for confirmation of postmenopausal status) Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, marijuana, and opiates) Pregnancy Tests (serum or urine) *NOTE: Pharmacodynamic and exploratory laboratory tests will be performed per the Time and Events Table, PD and exploratory biomarker sections. All abnormal results of clinical significance in laboratory tests should be repeated until the values return to normal or baseline. If such values do not return to normal within a period judged reasonable by the Investigator, the etiology should be identified, and the Sponsor should be notified.

7.2.6 Pharmacokinetics

Blood samples for PK analysis of HBM9161 will be collected at the time points indicated in Time and Events Table. The actual date and time of each blood sample collection will be recorded. The timing of PK samples may be altered. The PK samples may also be obtained at additional time points to ensure thorough PK monitoring.

Processing, storage and shipping procedures are provided in the SRM or lab manual.

Serum analysis will be performed under the control of the Sponsor. Concentrations of HBM9161 will be determined in serum samples using the currently approved bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).

7.2.7 Anti-Drug Antibody

Blood samples for ADA analysis will be collected at the time points indicated in Time and Events Table. The actual date and time of each blood sample collection will be recorded.

Processing, storage and shipping procedures are provided in the SRM or laboratory manual.

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Serum analysis will be performed under the control of the Sponsor. Anti-HBM9161antibody titers will be determined in serum samples using the currently approved bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).

7.2.8 Pharmacodynamics

Blood samples for PD analysis will be collected for measurement of IgG and albumin at timepoints indicated in the Time and Events Table.

Pharmacodynamic Markers Total IgG, and differentiation by class: IgA, IgM, IgG subclasses (IgG1, 2, 3, and 4) Albumin The actual date and time of each blood sample collection will be recorded. The timing of PD samples may be altered and/or PD samples may be obtained at additional time points to ensure thorough PD assessment. These samples may be used for the analysis of exploratory biomarkers. Samples will be collected, labelled, stored, and shipped as detailed in the SRM or laboratory manual.

7.2.9 Exploratory Biomarkers

Blood samples for exploratory biomarker analysis will be collected at timepoints indicated in the Time and Events Table.

Exploratory Biomarkers C-reactive protein (hs-CRP), Serum complement (CH50, C3) Anti-HBs titre

The actual date and time of each blood sample collection will be recorded. The timing of samples may be altered and/or samples may be obtained at additional time points to ensure thorough biomarker assessment. These samples may be used for the analysis of additional exploratory biomarkers. Samples will be collected, labelled, stored, and shipped as detailed in the SRM or laboratory manual.

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8 ADVERSE EVENTS

The Investigator or site staff will be responsible for identifying, documenting and reporting events that meet the definition of an AE or SAE.

The Investigator will not be obligated to actively seek AEs or SAEs in former study participants. However, if the Investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he/she considers the event reasonably related to the study drug or study participation, the Investigator will promptly (within 24 hours of awareness of the event) notify the Sponsor.

8.1 Definitions of Adverse Events

An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

8.1.1 Abnormal Laboratory Values

Not every laboratory abnormality qualifies as an AE. An abnormal laboratory test result should be reported as an AE if it meets any of the following criteria:

• Accompanied by clinical symptoms • Results in a change in study treatment (e.g. dosage modification, treatment interruption, or treatment discontinuation)

• Results in a medical intervention (e.g. potassium supplementation for hypokalemia) or a change in concomitant therapy

• Clinically significant at the investigator’s judgment It is the investigator’s responsibility to review all laboratory findings. Medical and scientific judgment should be exercised in deciding whether an isolated laboratory abnormality should be classified as an AE.

8.1.2 Abnormal Vital Sign Values

Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported as an AE if it meets any of the following criteria:

• Accompanied by clinical symptoms • Results in a change in study treatment (e.g. dosage modification, treatment interruption, or treatment discontinuation)

• Results in a medical intervention or a change in concomitant therapy

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• Clinically significant at the investigator’s judgment It is the investigator’s responsibility to review all vital sign findings. Medical and scientific judgment should be exercised in deciding whether an isolated vital sign abnormality should be classified as an adverse event.

8.2 Definition of Serious Adverse Event

A SAE is any AE that meets any of the following criteria:

• Results in death • Is life-threatening NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject is at risk of death at the time of the event.

• Requires inpatient hospitalization or prolongation of existing hospitalization NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization will be considered as AEs. If a complication prolongs hospitalization or fulfills any SAE criteria, the event will be considered as a SAE. When in doubt as to whether “hospitalization” occurs or is necessary, the AE should be considered as a SAE.

• Results in persistent or significant disability/incapacity NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

• Is a congenital anomaly/birth defect • Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. Such events should also be considered as SAEs. Examples of such events include intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

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8.3 Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event

Investigators will seek AE information at each subject contact. All AEs, whether reported by the subject or noted by study personnel, will be recorded in the patient’s medical record and on the AE page in CRF.

• After informed consent has been obtained but prior to initiation of study drug, only SAEs and AEs related to interventions mandated by the protocol should be recorded on the AE page in CRF. Other medical occurrences will be recorded on the Medical History/Pre-existing Conditions page in CRF.

• After initiation of study drug, all AEs, regardless of relationship to study treatment, will be recorded until the last follow-up contact.

• From last follow-up contact to the end of the study, only AEs related to study drug will be recorded.

8.4 Expedited Reporting to the Sponsor

All SAEs will be reported to the Sponsor within 24 hours of awareness.

8.5 Method of Identifying Adverse Events and Serious Adverse Events

Care will be taken to prevent introducing bias when identifying AEs and SAEs. Open-ended and non-leading verbal questioning of the subject will be the preferred method. Appropriate questions include:

• “How are you feeling?” • “Have you had any (other) medical problems since your last visit/contact?” • “Have you taken any new medicines, other than those provided in this study, since your last visit/contact? 8.6 Follow-up of Adverse Events and Serious Adverse Events

After the initial AE/SAE report, the Investigator will be required to proactively follow up with each subject at subsequent visits/contacts. All SAEs, and non-serious AEs will be followed until resolution, or until the condition stabilizes, or until the event is otherwise explained, or the subject withdraws consent lost to follow-up. Ongoing AEs may not be followed up when study is completed after consultation between Investigator and Sponsor.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 8.7 Regulatory Reporting Requirements for Serious Adverse Events

The Investigator should notify the Sponsor of SAEs so that legal obligations and ethical responsibilities towards subject safety and the safety of an investigational product are met.

The Sponsor will be responsible for notifying both the local regulatory authorities and other regulatory agencies about the safety of an investigational product. The Sponsor will comply with country specific regulatory requirements relating to safety reporting to the regulatory authority, IRB/IEC, and the Investigator.

The Investigator safety reports will be prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and will be forwarded to Investigators as necessary.

The Investigator who receives an Investigator safety report from the Sponsor describing an SAE or other specific safety information (e.g., summary or listing of SAEs) will file it with the IB and will notify the IRB/IEC according to local requirements.

8.8 Pregnancy Reporting

All female subjects with childbearing potential will be tested for pregnancy prior to study drug dosing. Subjects with positive test results will be ineligible for study participation. Any pregnancy reported between the time of informed consent and study termination must be reported to the Sponsor within 24 hours of awareness. The Investigator should discontinue the study drug and counsel the subject, discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring of the patient should continue until the outcome of the pregnancy. Information on the status of the subject and newborn baby will be forwarded to the Sponsor. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

Male subjects will be instructed to immediately inform the Investigator if their partner becomes pregnant during the study. Pregnancy Reporting Form should be completed by the Investigator immediately (i.e. no more than 24 hours of awareness). Attempts should be made to collect and report details of the course and outcome of any pregnancy in the partner of a male subject exposed to study drug.

8.9 Overdose

Overdose is the accidental or intentional use of the study drug in an amount higher than the dose being studied. An overdose or incorrect administration of study drug will not be an AE unless it results in untoward medical effects.

Any overdose or incorrect administration of study drug should be noted on the Study Drug Administration page in CRF and recorded in Overdose Reporting Form. The Overdose Reporting Form should be sent to the Sponsor timely.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 All AEs associated with an overdose or incorrect administration of study drug should be recorded on the AE page in CRF. If the associated AE fulfils the criteria of a SAE, the event should be reported to the Sponsor immediately (i.e. no more than 24 hours of awareness).

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 9 DATA ANALYSIS

9.1 Hypotheses

No specific hypotheses will be tested. The safety, PK, and PD response of HBM9161 will be summarized descriptively.

9.2 Sample Size Considerations

Formal sample size estimation will be not conducted. The sample size of up to 24 subjects, 8 per cohort (HBM9161 vs placebo: 6:2) is considered sufficient for the summary of PK parameters in Chinese healthy subjects while exposing as few subjects as possible to the investigational product and study procedures.

9.3 Data Analysis Considerations

9.3.1 Analysis Populations

Randomized Population

The Randomized Population will consist of all subjects who are randomized to receive study medication. This population will be used primarily for subject accounting purposes and will not be used for summary or analysis.

Safety Population

All subjects who enter in the study and receive at least one dose of study treatment will be included in the Safety Population.

The safety population will be used for the safety analyses, as well as for summarization of baseline/demographic characteristics.

Pharmacokinetic Population The PK Population will include all subjects who undergo serum PK sampling and have at least one post-dose evaluable concentration-time data for analysis.

Pharmacodynamic Population The PD Population will include all subjects who undergo post-dose PD or exploratory biomarker sampling and have evaluable PD or biomarker data for analysis.

Subjects will be analyzed according to the treatment actually received, regardless of their randomized treatment assignment for all analysis populations.

9.3.2 Interim Analysis

At least one interim analysis is planned at 30 days after the dosing of last subject of cohort 2 and/or cohort 3.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 Besides interim analysis, a review of the safety, tolerability and PD (total IgG) will be conducted by investigators and sponsor study team after each cohort to decide on the dose to be administered in the next cohort.

The review of the PD data will include tabular summaries of maximum change from baseline of serum IgG and albumin concentrations for both subjects receiving study drug and placebo. Graphical summaries of change in serum IgG and albumin over time will also be reviewed prior to dose escalation, to ensure no subject has met predefined dose escalation stopping criteria.

9.4 Final Analysis

Final analysis will be performed after the completion of the study and when the database is locked.

Data will be listed and summarized. Treatment will be assigned based on the dosing schedule and included in the data listings.

Unless stated otherwise, descriptive summaries for continuous variables will include n, mean, SD, median, first and third quartiles, minimum, and maximum. The geometric mean with associated 95% CI and the between-subject CV (%CVb) for PK parameters only will also be included. For tmax, only median, minimum, and maximum will be provided. For categorical variables, n and percent will be used as summary statistics. Baseline is the last available assessment prior to time of the first dose unless it is specified otherwise. If there are multiple assessments collected on the same scheduled time, the average of these assessments will be used. For tabulated safety summaries, only the scheduled assessments will be included in the summary tables.

Any effect of administration of HBM9161 on inflammation markers will be explored, such as high-sensitivity C-reactive protein (hs-CRP), and on serum complement, albumin, IgA, and IgM concentrations over time following subcutaneous (SC) administration of HBM9161.

Effects of HBM9161 on anti-HBs over time following subcutaneous (SC) administration of HBM9161 will also be explored.

Complete details of data handling and analysis procedures will be documented in the Statistical Analysis Plan (SAP).

9.4.1 Safety Analyses

Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital signs measurements, and ECG readings at various time points during the study, and by the documentation of AEs including severity of local reactions. Safety data from subjects who receive placebo will be pooled.

Adverse event verbatim text will be coded and classified by body system and preferred term using the MedDRA. All AEs, both serious and non-serious will be listed. The AE summaries

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 by treatment group including the number and percentage of subjects who report at least one event will be generated.

Clinical chemistry, hematology, and urinalysis values will be listed for each subject and flagged high or low relative to the normal range where appropriate. Descriptive summary statistics will be created by treatment, and assessment time.

Other safety data will be summarized descriptively by treatment and time. Details will be provided in the SAP.

9.4.2 Pharmacokinetic Analyses

Serum drug concentration-time data will be analyzed by non-compartmental methods with Phoenix WinNonlin or other PK software. Calculations will be based on the actual sampling times recorded during the study. From the serum concentration-time data, the following PK parameters will be determined: AUC(0-inf), Cmax, tmax, t1/2, CL/F, and Vz/F. Additional PK parameters may be calculated based on data. The PK data will be presented in graphical and tabular form and will be summarized descriptively. Dose proportionality of Cmax and AUC(0-inf) will be assessed graphically and statistically as appropriate using a power model. Complete details of the analysis will be provided in SAP.

9.4.3 Pharmacodynamic and Biomarker Analyses

Pharmacodynamic and biomarker analyses will be based on the PD population.

Pharmacodynamic data will include serum concentrations of IgG (total, and by class and subclass) and albumin.

Exploratory biomarker data will include serum concentrations of C-reactive protein (hs- CRP), and serum complement (CH50, C3).

Absolute concentrations and change from baseline will be summarized descriptively by treatment, dosing group, and assessment time.

Pharmacodynamic AUC (data from Days 1 to 29) of serum total IgG may be calculated based on % change from baseline and summarized descriptively by treatment, route of administration, and dosing group.

Complete details of the analysis will be provided in SAP.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 10 RESPONSIBILITIES

10.1 Investigator Responsibilities

10.1.1 Good Clinical Practice

The Investigator will ensure that this study will be conducted in accordance with the principles of the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South Africa), International Conference on Harmonization (ICH) guidelines, or with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the study subjects.

10.1.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Approval

This protocol and any accompanying material to be provided to the subject (such as advertisements, subject information sheets, or descriptions of the study used to obtain informed consent) will be submitted by the Investigator to an IRB or IEC. Approval from the IRB or IEC must be obtained before starting the study and should be documented in a letter to the Investigator specifying the protocol number, protocol version, protocol date, documents reviewed, and date on which the committee met and granted the approval.

Any protocol amendment after receipt of IRB or IEC approval must also be submitted to the IRB or IEC for approval before implementation.

10.1.3 Informed Consent

The Investigator or designee will be responsible for obtaining written informed consent from each subject participating in this study after adequate explanation of the aims, methods, objectives, and potential hazards of the study and before undertaking any study- related procedures. The Investigator must utilize an unconditional health authority and IRB/IEC- approved consent form for documenting written informed consent. Each informed consent will be appropriately signed and dated by the subject or the subject’s legally authorized representative and the person obtaining consent.

10.1.4 Confidentiality

The Investigator must assure that subjects’ anonymity will be strictly maintained and that their identities will be protected from unauthorized parties. Only subject number, date of birth, and an identification code (i.e., not names) should be recorded on any form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. The Investigator must keep a screening log showing codes, names, and addresses for all subjects screened and for all subjects entered in the trial.

The Investigator agrees that all information received from the Sponsor, including but not limited to the IB, this protocol, the investigational new drug, and any other study information, remain the sole and exclusive property of the Sponsor during the conduct of the study and thereafter. This information is not to be disclosed to any third party (except employees or

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 agents directly involved in the conduct of the study or as required by law) without prior written consent from the Sponsor. The Investigator further agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of the study site to any third party or otherwise into the public domain.

10.1.5 Study Files and Retention of Records

The Investigator must maintain adequate and accurate records to enable the conduct of the study to be fully documented and the study data to be subsequently verified. These documents should be classified into at least the following two categories: (1) Investigator’s study file, and (2) subject clinical source documents.

The Investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB or IEC and governmental approval with correspondence, informed consent, drug records, staff curriculum vitae and authorization forms, and other appropriate documents and correspondence.

The required source data should include the following for each subject:

• subject identification (name, date of birth, gender); • documentation that subject meets eligibility criteria, i.e., history, physical examination, and confirmation of diagnosis (to support inclusion and exclusion criteria);

• participation in trial (including trial number); • trial discussed and date of informed consent; • dates of all visits; • documentation that protocol specific procedures were performed; • results of efficacy parameters, as required by the protocol; • start and end date (including dose regimen) of trial medication (preferably drug dispensing and return should be documented as well);

• record of all adverse events and other safety parameters (start and end date, and preferably including causality and intensity);

• concomitant medication (including start and end date, dose if relevant; dose changes should be motivated); date of trial completion and reason for early discontinuation, if applicable. • The Investigator may be required to retain documents longer if required by applicable regulatory requirements, by local regulations, or by an agreement with the Sponsor. The Investigator must notify the Sponsor before destroying any clinical study records.

Should the Investigator wish to assign the study records to another party or move them to another location, the Sponsor must be notified in advance.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 If the Investigator cannot guarantee this archiving requirement at the study site for any or all of the documents, special arrangements must be made between the Investigator and the Sponsor to store these in sealed containers outside of the site so that they can be returned sealed to the Investigator in case of a regulatory audit. When source documents are required for the continued care of the subject, appropriate copies should be made for storage outside of the site.

Biological samples at the completion of this study may be retained in storage by the Sponsor for a period up to 10 years for purposes of this study.

10.1.6 Electronic Case Report Forms

For each subject screened, an eCRF must be completed and signed by the Investigator or sub- investigator (as appropriate) within a reasonable time period after data collection.

This also applies to records for those subjects who fail to complete the study (even during a pre-randomization screening period if an eCRF was initiated). If a subject withdraws from the study, the reason must be noted on the eCRF. If a subject is withdrawn from the study because of a treatment-limiting AE, thorough efforts should be made to clearly document the outcome.

10.1.7 Drug Accountability

The Investigator or designee (i.e., pharmacist) will be responsible for ensuring adequate accountability of all used and unused study drug, placebos. This includes acknowledgment of receipt of each shipment of study drug (quantity and condition), subject dispensing records, and unused or destroyed study drug. Dispensing records will document quantities received from the Sponsor and quantities dispensed to subjects, including lot number, date dispensed, subject identifier number, and the initials of the person dispensing the medication.

At study initiation, the monitor will evaluate the site’s standard operating procedure for study drug disposal/destruction in order to ensure that it complies with the Sponsor requirements. Drug may be returned or destroyed on an ongoing basis during the study if appropriate. At the end of the study, following final drug inventory reconciliation by the monitor, the study site will dispose of and/or destroy all unused study drug supplies, including empty containers, according to these procedures. If the site cannot meet the Sponsor’s requirements for disposal, arrangements will be made between the site and the Sponsor or its representative for destruction or return of unused study drug.

All drug supplies and associated documentation will be periodically reviewed and verified by the study monitor over the course of the study.

10.1.8 Inspections

The Investigator should understand that source documents for this trial must be made available to appropriately qualified personnel from the Sponsor or its representatives, to IRBs or IECs, or to regulatory authority or health authority inspectors.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 10.1.9 Protocol Compliance

The Investigator will be responsible for ensuring the study is conducted in accordance with the procedures and evaluations as described in this protocol.

10.2 Sponsor Responsibilities

10.2.1 Protocol Modifications

Protocol modifications, except for those intended to reduce immediate risk to study subjects, may be made only by the Sponsor.

10.2.2 Study Report and Publications

A clinical study report will be prepared and provided to the regulatory agency(ies). The Sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain cases.

10.3 Joint Investigator/Sponsor Responsibilities

10.3.1 Access to Information for Monitoring

In accordance with ICH Good Clinical Practice guidelines, the study monitor must have direct access to the Investigator’s source documentation in order to verify the data recorded in the CRFs for consistency.

The monitor will be responsible for routine review of the CRFs at regular intervals throughout the study to verify adherence to the protocol and the completeness, consistency, and accuracy of the data being entered on them. The monitor should have access to any subject records needed to verify the entries on the CRFs. The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the course of these monitoring visits are resolved.

10.3.2 Access to Information for Auditing or Inspections

Representatives of regulatory authorities or of the Sponsor may conduct inspections or audits of the clinical study. If the Investigator is notified of an inspection by a regulatory authority the Investigator must agree to notify the Sponsor immediately. The Investigator agrees to provide to representatives of a regulatory agency or the Sponsor access to records, facilities, and personnel for the effective conduct of any inspection or audit.

10.3.3 Study Termination

The Sponsor reserves the right to terminate the study at any time. Should this be necessary, the Sponsor will arrange discontinuation procedures and notify the appropriate regulatory authority (ies), IRBs, and IECs. In terminating the study, the Sponsor and the Investigator will assure that adequate consideration is given to the protection of the subjects’ interests.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 11 REFERENCES

Investigational Brochure HBM9161, Version 2.0, 7 February 2018.

Kiessling et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017; 9:1-12.

Momenta Pharmaceuticals Reports Positive Top-Line Phase 1 Data Showing Proof of Mechanism for M281, an Anti-FcRn Monoclonal Antibody, in Healthy Volunteers. 2018; press release, Momenta Pharmaceuticals, Jan 5, 2018.

Montoyo HP, Vaccaro C, Hafner M, Ober RJ, Mueller W, Ward ES. Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice.

Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2788-93.

Ulrichts P, et al. Argx-113, a Novel Fc-based approach for antibody-induced pathologies such as primary immune thrombocytopenia. Blood. 2016; 128:4919.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 12 APPENDICES

APPENDIX 1. LIVER SAFETY REQUIRED ACTIONS AND FOLLOW UP ASSESSMENTS

Phase I Liver chemistry stopping criteria have been designed to assure subject safety and to evaluate liver event etiology (in alignment with the FDA Drug-induced Liver Injury: Premarketing Clinical Evaluation). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance s/UCM174090.pdf.

Liver Safety Process

The procedures listed below are to be followed if a subject has ALT, bilirubin and/or INR elevations that meet the definition of a SAE (as defined in Section 8.2):

• Notify the sponsor within 24 hours of learning of the abnormality to confirm follow-up.

• Complete the liver event case report forms. • Upon completion of the safety follow-up, withdraw the subject from the study unless further safety follow-up is required.

• Make every reasonable attempt to have subjects return to the clinic within 24 hours for repeating liver chemistries, additional testing, and close monitoring (with specialist or hepatology consultation recommended).

• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to baseline values.

• Obtain viral hepatitis serology including: o Hepatitis A IgM antibody. o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). o Hepatitis C ribonucleic acid (RNA). o Cytomegalovirus IgM antibody. o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing).

o Hepatitis E IgM antibody. • Assess Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). • Assess eosinophilia

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• Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) on the AE page in CRF.

• Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins on the Concomitant Medications page in CRF.

• Record alcohol use on the Liver Events page in CRF. • Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma globulins).

• Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in subjects with definite or likely acetaminophen use in the preceding week [James,2009]. NOTE: not required in China Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease. The Liver Imaging and/or Liver Biopsy pages in CRF are also to be completed if these tests are performed.

James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 13 SUMMARY OF CHANGES

Change 1 Details of Update on the inclusion criteria changes Section 3.1 Inclusion Criteria #5 Female subjects of childbearing potential (including female subjects who are within 12 months of menopause) and male subjects must agree to use at least one of the acceptable contraceptive method(s) from first dose of the study screening till until 90 days after dosing the last dose of the study drug. (Acceptable contraceptive methods include abstinence (for at least 1 month prior to screening), correct use of condom, spermicides, and injectables, or combined oral contraceptives, intrauterine device with or without local hormone release, cervical cap or diaphragm and vasectomy performed at least 1 year prior to screening). #6 Male subjects must agree to use acceptable contraceptive methods from the screening visit, throughout the study and until 90 days after the last dose of study drug. Rationale • To remove duplicate information Section(s) Section 3.1 Inclusion Criteria involved Change 2 Details of Update on the exclusion criteria changes Section 3.2 Exclusion criteria

#2 Subject has a total IgG level of < 700mg/dL (test results from local laboratory) at screening. #5 Intake of prescription or non-prescription drugs (including vitamins and dietary or herbal supplements)drugs within 7 days or less than 5 half-lives (whichever is longer) of the respective drug prior to first dosing of the study drug. Exceptions include topical medications or eye drops with no systemic action, and injectable or combined oral contraceptives.

#6 Participation in another clinical trial and received an investigational drug(s) administration (except this study) within 90 days prior to first dosing of the study drug.

#9 Inability to refrain from smoking and alcohol consumption prior to dosing of the study drug.from screening until the end of the study. #10 History of substance (alcohol or illicit drugs) abuse/addiction in the past 5 years, or used illicit drugs 3 months prior to signing informed consent, or The subject has a positive drug/alcohol screen at screening and/or Day -1.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 #11 Blood donation (more than 450 mL whole blood donation within 3 months, 50mLwhole blood donation within 1 month) prior to first dosing of the study drug.

#12 Subject has received a transfusion of blood or any blood products within 60 days prior to Day -1 dosing of the study drug. #13 Subject has performed Excessive physical activities strenuous exercise (within 1 week7 days prior to first dosing of the study drug, of current study).

#15 Subject has estimated creatinine clearance ≤ 80 mL/min calculated by Cockcroft Gault formula prior to first dosing of the study drug at screening. #16 Subject has any of the following ECG abnormality (a single repeat will be allowed for eligibility determination) at screening or Day -1:

#19 Subject has a positive T-cell interferon-γ release assay (TIGRA) result i.e., QuantiFERON®-TB Gold Plus™ test at screening. A single repeat will be allowed for subjects with an indeterminate result of QuantiFERON®-TB Gold Plus™ test. #21 Subjects who had immunization within 4 weeks before screening; or subjects who plan to have immunization during the study anduntil within 12 weeks after the last doseing of the study drug. #22 For female subjects, positive pregnancy test at screening or and Day -1, or planning to become pregnant from screening during the study until 90 days after the last dosedosing of the study drug. Rationale • To update the information in the exclusion criteria • To specify in exclusion #5 that the intake of prescription and non- prescription drugs are not allowed with a few exceptions.

Section(s) Section 3.2 Exclusion Criteria involved Change 3 Details of Update on the lifestyle and/or dietary restrictions changes Section 4.3 Lifestyle and/or Dietary Restrictions

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 Section 4.3.1 Meals and Dietary Restrictions

Subjects will be asked to abstain from consuming food containing poppy seeds within from 72 hours prior to dosing and until 7 days after dosing. There are no fasting requirements prior to dose administration. During admission periods subjects will receive a standard diet, which excludes caffeine and alcohol.

Section 4.3.2 Caffeine, Alcohol, and Tobacco

Subjects will abstain from ingesting caffeine- or xanthine-containing products (e.g. coffee, tea, cola drinks, and chocolate, and high energy drinks) for within 24 hours prior to admission, during confinement for the duration of the in-house period, and within 24 hours prior to each study center visit.

Subjects will abstain from consuming alcohol throughout the study until End of Study Visitand extended follow-up visit (if applicable) and high energy drinks for 72 hours prior to the start of dosing and 7 days after dosing. Subjects must be advised to avoid excessive alcohol intake after this period End of Study Visit until their IgG levels return to within the local normal range, as confirmed by the Investigator, because of the increased risk of infection during the period of decreased IgG.

Subjects will abstain from the use of tobacco/nicotine/vaping/e-cig/ products within 3 months prior to screening and throughout the study until End of Study Visit.

Section 4.3.3 Activity

Subjects will abstain from strenuous exercise within 7 days before dosing, during confinement periods within 7 days after dosing and forwithin 72 hours prior to each blood collection for clinical laboratory tests. and for 1 week after dosing. Subjects may participate in light recreational activities during studies (e.g., watch television, read). Subjects must be advised to avoid vigorous contact sports after this period until their IgG levels return to within the local normal range, as confirmed by the Investigator, because of the increased risk of infection during the period of decreased IgG.

Subjects must be advised to comply with the following restrictions:

• Any use of illicit drugs is prohibited throughout the study until End of Study Visit and Extended Follow-up Visit (if applicable).

• Avoid immunization throughout the study and within 12 weeks after dosing of the study drug.

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019

• Avoid any blood donation (except for blood samplings in this study) throughout the study until End of Study Visit

• Female subjects should avoid breastfeeding an infant or provide breast milk to other infant(s) throughout the study until End of Study Visit.

Rationale • To state that any non-compliance with the lifestyle and dietary restriction(s) will be regarded as protocol deviation but it is subject to the discretion of Investigator whether to prematurely terminate or discontinue the subject from the study • To update the specific time/period of each restriction • To integrate the inclusion/exclusion criteria into the lifestyle and dietary restrictions during the study Section(s) Section 3.3 Lifestyle and/or dietary restrictions involved Change 4 Details of Deletion of Table 3 Cardiovascular Grading Criteria changes Table 3 Grades Cardiovascula Origin r Grading 1 2 3 CriteriaParameter 40 if ＜ Clinical lack decrease of Not CPI from tolerability Heart rate – applicable baseline and /or ECG bradycardia (beats exceeding 1 – abnormalities min– ) * 20 FDA 54 to 50 49 to 45 ＜45 NIH No data No data No data

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019

＞131 or CPI 100 to 115 116 to 130 ventricular Heart rate – tachycardia (beats dysrhythmias min) * FDA 100 to 115 116 to 130 ＞130 NIH No data No data No data 160 or ULNR to ＞ CPI 150 to 160 Supine systolic 150 headache or blood pressure clinical signs increase (mmHg) * FDA 141 to 150 151 to 155 ＞155 NIH 140 to 159 160 to 179 ＞180 95 to 99 and ＞110 or Supine diastolic CPI increase 100 to 110 headache or blood pressure exceeding clinical signs increase (mmHg) * 10 FDA 91 to 95 96 to 100 ＞100 NIH 90 to 99 100 to 109 ＞110 LNNR to 80 and 70 or Supine systolic CPI decrease 80 to 70 ＜ symptomatic blood pressure exceeding decrease (mmHg) * –25 FDA No data No data No data NIH No data No data No data Decrease Syncope or exceeding prevents 20 and Cannot stay CPI – daily activity Postural association standing or requires hypotension to reflex – treatment systolic blood tachycardia pressure 2 to 3 min Not FDA No data No data after standing applicable (mmHg)* Symptomatic Symptomatic corrected by NIH NA i.v. fluid oral fluid indicated replacement *Assuming supine position, 10 min at rest conditions, not sleeping subjects, measurements on the same arm and several concordant results. ULNR, Upper limit of normal range; LLNR, Lower limit of normal range; CPI, Club phase I task force.

Rationale • All cardiovascular AE will be graded using the “Criteria for Determining the Grade/Severity of Adverse Event Terms” in table 2

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 Section(s) Section 4.4.3 Toxicity Management Criteria (Adverse Events, Cardiovascular, involved and Site Reactions)

Change 5 Details of Additional information on Injection Site Reactions (ISR) changes Injection Site Reactions (ISR) Injection site evaluations will be made by the Investigator following SC administration of HBM9161 and placebo as described below. If an injection site reaction is observed, a physician will characterize and document the reaction as an AE. Observation of the injection site will continue until the AE is resolved.

Symptomatic treatment (e.g. antihistamines, NSAIDS, IV fluids) may be provided for any injection site reactions at the discretion of the Investigator.

The injection sites will be monitored for pain, tenderness, erythema and swelling.

Each injection site reaction will be recorded as an AE/SAE. The severity of injection site reactions should be categorized graded using the intensity severity grading scheme presented in Table 3 only, NOT the severity grading scheme of AE event terms in Table 2.

Table 3: Criteria for Determining the Grade/Severity of Injection Site Reactions

Grade Criteria

1/Mild Tenderness with or without associated symptoms (e.g., warmth, erythema, itching)

2/Moderate Pain; lipodystrophy; edema; phlebitis

3/Severe or medically Ulceration or necrosis; severe tissue significant damage; operative intervention indicated

4/Life-threatening Life threatening consequences; urgent intervention indicated

5/Death Death

Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010).

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 Rationale • Any event of the Injection Site Reactions (ISR) will be graded using the severity grading specifically for ISR in table 3

Section(s) Section 4.4.3 Toxicity Management Criteria (Adverse Events, Cardiovascular, involved and Site Reactions)

Change 6 Details of Update on time and events table changes • To clarify that vital signs will be collected once on Day -1 and before breakfast at pre-dose on Day 1 • Restart the telemetry and pulse oximetry at 5 hours and at 6 hours for at least 0.5 hour post-dose. • Removed hs-C-reactive protein test on screening • Removed PK sampling time points: Day 15, 22, 29, 57 and 85 • To clarify that if a subject prematurely withdraws/discontinues from the study, while the Early Termination falls on the planned pharmacokinetics sampling timepoint, collect the PK sample for the integrity of the PK data if the subject agrees such sample collection. • Removed Immunoglobulins (IgM, IgA, IgG subclasses) test on Day-1, 22 and 85 • Immunoglobulins (IgM, IgA, IgG subclasses) will be collected pre- dose on Day 1. • Removed quantitative anti- tetanus and anti-diphtheria • Update 6, 9, and 12 months post-dose as Extended Follow-up Visit • Addition on information that some tests will be analyzed in both central and local laboratories. Rationale • hs-C-reactive protein (exploratory biomarker) test is not necessary on screening • The PK sampling time points for single dose administration of HBM9161in first-in-human study in Canada were collected until Day 11 post-dose. • To ensure subject’s safety Section(s) Time and Events Table involved Change 7 Details of Deletion of 2nd paragraph in section 3.5.1 changes Section 3.5.1 Risk Assessment

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 As reproductive toxicology studies are currently ongoing with HBM9161, women of childbearing potential will be excluded from participating in this study.

For suspected systemic infusion reactions or systemic inflammatory response syndrome (SIRS), (cytokine release syndrome) an unscheduled blood sample will be collected for measurement of mast-cell tryptase, complement (C)3a- des-Aarg, C5a-des-Aarg, and multiplexed serum cytokine profile.

Should any subject have severe hypogammaglobulinemia (<3g/L) and associated with an active bacterial infection, at the discretion of site investigator, consideration should be given to either:

• Treating with a replacement dose of IV Immunoglobulin (IVIG) [0.5 mg/kg], and/or • Coverage with appropriate oral broad-spectrum antibiotics.

Rationale • The information contradicts with subject inclusion #5 that female subjects of childbearing potential (including female subjects who are within 12 months of menopause) will be recruited into the study, with a condition that at least one of the acceptable contraceptive methods should be used during the study. Section(s) Section 3.5.1 Risk Assessment involved Change 8 Details of 14 Update on Concomitant Treatment(s) and Prohibited Medication(s) changes 15 Section 6 Concomitant Treatment(s) and Prohibited Medication(s)

Section 6.1 Permitted Medications and Non-Drug Therapies

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Harbour BioMed 9161.1 HBM9161(HL161BKN) V2.0 07 May 2019 Other concomitant medication may be considered on a case by case basis by the Investigator for treatment of a medical need in consultation with the Sponsor. Any concomitant medication should be recorded in the study records, including the doses administered, the dates and time of administration and the reason for administration.

Section 6.2 Prohibited Medications and Non-Drug Therapies

Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 14 7 days or less than 5 half-lives (whichever is longer) of the respective drug prior to admission on Day-1dosing and until within 1 month after dosing, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study, and the medication is needed for proper medical management of the subject.Refer to section 6.1 for permitted medications.

Rationale • To synchronize the information in exclusion criteria #5 with Section 6 • To state that any intake of prohibited medications will be regarded as protocol deviation but it is subject to the discretion of PI whether to prematurely terminate or discontinue the subject from the study. Section(s) Section 6 Concomitant Treatment(s) and Prohibited Medication(s) involved

Change 9 Details of Removal of PK parameters: CL and Vz changes Section 2 Study objectives and endpoints PK parameters:

• Cmax (maximum measured concentration of the analyte in serum) AUC (area under the concentration-time curve of the analyte in • 0- serum over the time interval from 0 extrapolated to infinity)

• tmax (time from dosing to maximum measured concentration) • t1/2 (terminal half-life of the analyte in serum) • CL (total clearance of the analyte in serum after administration) • CL/F (total clearance of the analyte in serum after administration estimated using formula)

• Vz (apparent volume of distribution during the terminal phase z following administration)

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• Vz/F (apparent volume of distribution during the terminal phase z following administration estimated using formula) Section 9.4.2 Pharmacokinetic Analyses Serum drug concentration-time data will be analyzed by non-compartmental methods with Phoenix WinNonlin or other PK software. Calculations will be based on the actual sampling times recorded during the study. From the serum concentration-time data, the following PK parameters will be determined: AUC(0-inf), Cmax, tmax, t1/2, CL, CL/F, Vz and Vz/F.

Rationale • CL and Vz are not applicable to subcutaneous administration of HBM9161 Section(s) Section 2 Study objectives and endpoints involved Section 9.4.2 Pharmacokinetic Analyses Change 10 Details of Update on the fasting requirement prior to clinical safety laboratory tests changes All subjects should fast for at least 8 hours prior to clinical safety laboratory tests (hematology and chemistry). If a subject does not fast for 8 hours, a minimum of 4-hours fast will be allowed prior to the tests for outpatient visits A minimum of 4-hour fast will be allowed for outpatient visits and on admission to the clinical research unit.

Rationale • To further clarify that a minimum of 4-hours fast will be allowed prior to the tests for outpatient visits if a subject does not fast for 8 hours. Section(s) Section 7.2.5 Clinical Safety Laboratory Assessments involved

Administrative Changes Change 1 Change of PI from Dr. Tommy Tsang CHEUNG to Dr. Desmond Yat Hin YAP Change 2 Update on table of contents Change 3 Update on list of abbreviations and definitions of terms

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