Multicentre Study of Nomacopan (rVA576) in Paediatric Haematopoietic Stem-Cell Transplant Associated Thrombotic Microangiopathy
Phase: PHASE3
Conditions: Thrombotic Microangiopathies
Sponsor: AKARI Therapeutics

 
 
MULTICENTRE STUDY OF NOMACOPAN IN PAEDIATRIC HAEMATOPOIETIC 
STEM-CELL TRANSPLANT ASSOCIATED THROMBOTIC MICROANGIOPATHY 
 
 
PROTOCOL NUMBER: 
AK901 
 
DATE: 
10th November 2021 
 
Version: 
4.0 
 
SPONSOR: 
Akari Therapeutics Plc 
 
EudraCT NUMBER: 
2020-000086-17 
 
SPONSOR ADDRESS: 
Akari Therapeutics Plc. 
 
75-76 Wimpole Street, 
 
London, W1G 9RT, UK 
 
AUTHORISED SIGNATORIES:  
Dr Sanjeev K Khindri, MB, ChB, MRCP 
 
SPONSOR’S MEDICAL 
Dr Sanjeev K Khindri, MB, ChB, MRCP 
EXPERT: 
Senior Medical Director 
 
Akari Therapeutics Plc. 
  
 
London W1G 9RT, UK 
 
24 HOUR AKARI MEDICAL 
+44 1223 374220 
CONTACT:   
 
SAE REPORTING 
safety@akaritx.com 
 
 
MULTICENTRE: 
Yes 
 
 
 
 
This protocol is the property of Akari Therapeutics Plc.  It is provided subject to the recipient’s 
agreement to maintain it in confidence and is intended solely for the guidance of this clinical 
investigation.  This protocol may only be disclosed to those associated with the clinical 
investigation, who have a need to know and who have agreed in advance to maintain it in 
confidence.  It may not be disclosed to any third party or used other than for its intended 
purpose, unless approved in advance and in writing by Akari Therapeutics. 
 
 

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition/Term 
Abbreviation Definition/Term 
ADA 
Anti-drug Antibody 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
ADR 
Adverse Drug Reaction 
MIDD 
Model Informed Drug Development 
AE 
Adverse Event 
NIDDK 
National Institute of Diabetes and 
Digestive and Kidney Diseases 
AESI 
Adverse Event of Special 
Interest 
NOAEL 
No Observed Adverse Event Level 
aHUS 
atypical Haemolytic 
Uraemic Syndrome 
NONMEM 
Non-linear Mixed Effects Modelling 
AUC 
Area Under the Curve 
OmCI 
Ornithodoros moubata Complement 
Inhibitor 
CFHRs 
Complement Factor H-
Related Proteins 
PBS 
Phosphate Buffered Saline 
CRF 
Case Report Form 
PD 
Pharmacodynamics 
CRO 
Contract Research 
Organisation 
PI 
Principal Investigator 
ECG 
Electrocardiogram 
PIS 
Patient Information Sheet 
ELISA 
Enzyme-linked 
Immunosorbent Assay 
PK 
Pharmacokinetic 
eGFR 
estimated Glomerular 
Filtration Rate 
PNH 
Paroxysmal Nocturnal 
Haemoglobinuria 
FDA 
Food and Drug 
Administration 
PP 
Per Protocol 
GCP 
Good Clinical Practice 
PRBC 
Packed Red Blood Cells 
GI 
Gastrointestinal 
 
 
GVHD 
Graft versus Host Disease 
qd 
Every day 
HLA 
Human Leukocyte Antigen 
qs 
quantum satis (the amount which is 
enough) 
HSCT 
Haematopoietic Stem Cell 
Transplantation 
RBC 
Red Blood Cells 
HSCT-TMA 
Host Stem Cell Transplant 
Associated Thrombotic 
Microangiopathy 
SAE 
Serious Adverse Event 
ICF 
Informed Consent Form 
sc 
Subcutaneous 
ICH 
International Conference on 
Harmonisation 
SUSAR 
Suspected Unexpected Serious 
Adverse Reaction 
IEC 
Independent Ethics 
Committee 
TCA 
Terminal Complement Activation 
IMP 
Investigational Medicinal 
Product 
TEAE 
Treatment Emergent Adverse Event 
ITT 
Intention-to-Treat 
TMA 
Thrombotic Microangiopathy 
iv 
Intravenous 
TTP 
Thrombocytic Thrombocytopaenic 
Purpura 
kDa 
kiloDaltons 
ULN 
Upper Limit of Normal 
LDH 
Lactate Dehydrogenase 
UPCR 
Urine Protein Creatinine Ratio 
LLN 
Lower Limit of Normal 
WFI 
Water for Injection 
LLOQ 
Lower Limit of 
Quantification 
WHO 
World Health Organisation 
LTB4 
Leukotriene B4 
 
 
 
 
 
 
 
 

Protocol AK901 v4.0 
 
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11th November 2021 
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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title: 
Multicentre Study of nomacopan in Paediatric Haematopoietic 
Stem-Cell Transplant Associated Thrombotic Microangiopathy  
 
 
Protocol Number: 
AK901 
 
 
 
Authorised Sponsor Representative Signature: 
 
 
 
_______________________________________________  
_____________________ 
Signature: 
  
 
 
 
 
Date: 
Dr Sanjeev K Khindri, MB, ChB, MRCP 
75-76 Wimpole Street 
London 
W1G 9RT 
United Kingdom 
 
 
 
 
Principal Investigator’s Signature: 
I agree with the content of this protocol and the confidential nature of the documentation made as 
part of this study. I also acknowledge that the Sponsor of the study has the right to discontinue the 
study at any time. I have read the protocol and understand it and will work according to it, as well as 
according to the principles of Good Clinical Practice, applicable laws and regulations and the 
Declaration of Helsinki. 
 
 
 
_______________________________________________  
_____________________ 
Signature: 
  
 
 
 
 
Date: 
 
 
 

Protocol AK901 v4.0 
 
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11th November 2021 
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TABLE OF CONTENTS 
 
1 PROTOCOL SYNOPSIS ................................................................................................................... 8 
2 INTRODUCTION ............................................................................................................................ 14 
2.1 
OVERVIEW OF THE DISEASE:  BACKGROUND OF THROMBOTIC MICROANGIOPATHY, 
TREATMENT OPTIONS AND UNMET NEED ............................................................................. 14 
2.2 
NOMACOPAN IN THROMBOTIC MICROANGIOPATHY ............................................................. 15 
3 PRIOR EXPERIENCE WITH THE INVESTIGATIONAL PRODUCT ........................................ 17 
3.1 
INVESTIGATIONAL PRODUCT ................................................................................................. 17 
3.2 
SUMMARY OF RELEVANT NON-CLINICAL AND CLINICAL STUDIES ...................................... 18 
3.2.1 
Non-clinical ............................................................................................................................ 18 
3.2.2 
Clinical ................................................................................................................................... 19 
3.3 
PREVIOUS EXPERIENCE IN PATIENTS ..................................................................................... 19 
3.3.1 
Summary of Known and Potential Risks and Benefits to Human Patients ............................ 19 
3.3.2 
Summary of Experience with 8 Compassionate Use/Named Patient Paediatric 
HSCT/TMA Patients .............................................................................................................. 22 
3.3.3 
Anti-drug Antibodies ............................................................................................................. 22 
3.4 
DESCRIPTION OF AND JUSTIFICATION OF ROUTE OF ADMINISTRATION, DOSAGE 
REGIMEN AND TREATMENT PERIOD ...................................................................................... 23 
4 TRIAL OBJECTIVES AND ENDPOINTS ..................................................................................... 26 
4.1 
TRIAL OBJECTIVES ................................................................................................................. 26 
4.2 
ENDPOINTS (PARTS A AND B) ................................................................................................ 27 
4.2.1 
Composite Primary Endpoint ................................................................................................. 27 
4.2.2 
Secondary Endpoints (Efficacy)............................................................................................. 27 
4.2.3 
Safety Endpoints .................................................................................................................... 27 
4.2.4 
Exploratory Endpoints ........................................................................................................... 27 
5 TRIAL POPULATION .................................................................................................................... 28 
5.1 
INCLUSION CRITERIA ............................................................................................................. 28 
5.2 
EXCLUSION CRITERIA ............................................................................................................ 28 
5.3 
CONCOMITANT THERAPY....................................................................................................... 28 
5.3.1 
Prohibited Medications .......................................................................................................... 29 
5.4 
MENINGITIS PROPHYLAXIS .................................................................................................... 29 
5.5 
CONTRACEPTION .................................................................................................................... 29 
5.5.1 
Exposure of Partners During the Study .................................................................................. 30 
5.5.2 
Breast Feeding........................................................................................................................ 30 
6 TRIAL DESIGN AND PROCEDURES .......................................................................................... 30 
6.1 
TRIAL DESIGN ........................................................................................................................ 30 
6.2 
DOSING SCHEME .................................................................................................................... 31 
6.3 
BLOOD SAMPLE VOLUMES FOR PAEDIATRIC PATIENTS ........................................................ 32 
6.4 
TRIAL OVERVIEW, PROCEDURES AND PATIENT COMPLIANCE (PARTS A AND B) ................. 33 
6.4.1 
Screening (up to -14 days, Parts A and B) ............................................................................. 33 
6.4.2 
Part A ..................................................................................................................................... 34 
6.4.3 
Part B ..................................................................................................................................... 37 
6.4.4 
Dose Increase Part A – if required ......................................................................................... 39 
6.4.5 
Dose Increase Part B – if required ......................................................................................... 40 
6.5 
LOCAL LABORATORY TESTS .................................................................................................. 40 
6.5.1 
Clinical Chemistry Part A and Part B .................................................................................... 40 
6.5.2 
Haematology Part A and Part B ............................................................................................. 41 
6.5.3 
Urinalysis Part A and Part B .................................................................................................. 41 
6.6 
CENTRAL LABORATORY TESTS ............................................................................................. 41 
6.6.1 
Pharmacodynamics (PD) - CH50 ........................................................................................... 41 
6.6.2 
Pharmacokinetics (PK)........................................................................................................... 42 
6.6.3 
Total C5, sC5b-9 and C3b Assays ......................................................................................... 42 
6.6.4 
LTB4 (urinary) ....................................................................................................................... 42 
6.6.5 
Anti-drug Antibodies ............................................................................................................. 42 
6.7 
BLOOD TRANSFUSIONS .......................................................................................................... 42 
6.8 
OTHER ASSESSMENTS ............................................................................................................ 42 

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6.8.1 
Pregnancy Test ....................................................................................................................... 42 
6.9 
SAFETY ASSESSMENTS ........................................................................................................... 43 
6.9.1 
Adverse Events ...................................................................................................................... 43 
6.9.2 
Medical History and Present Conditions ................................................................................ 43 
6.9.3 
Physical Examination ............................................................................................................. 44 
6.9.4 
Vital Signs .............................................................................................................................. 44 
6.9.5 
Procedures for Clinical Laboratory Samples .......................................................................... 44 
6.10 MISSED DOSES ....................................................................................................................... 44 
7 REASON FOR WITHDRAWAL/EARLY DISCONTINUATION ................................................ 45 
7.1 
TERMINATION OR SUSPENSION OF THE STUDY ...................................................................... 45 
7.2 
WITHDRAWAL CRITERIA ........................................................................................................ 45 
8 SAFETY REPORTING ................................................................................................................... 46 
8.1 
DEFINITIONS ........................................................................................................................... 46 
8.1.1 
Adverse Event ........................................................................................................................ 46 
8.1.2 
Adverse Drug Reaction (ADR) .............................................................................................. 46 
8.1.3 
Unexpected Adverse Reaction ............................................................................................... 47 
8.1.4 
Serious Adverse Event or Serious Adverse Reaction ............................................................. 47 
8.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ................................................. 47 
8.1.6 
Treatment Emergent Adverse Events (TEAEs) ..................................................................... 47 
8.1.7 
Adverse Events of Special Interest (AESI) ............................................................................ 48 
8.2 
PROCEDURES FOR RECORDING OF SAFETY EVENTS .............................................................. 48 
8.2.1 
General ................................................................................................................................... 48 
8.2.2 
Pre-existing Conditions .......................................................................................................... 49 
8.2.3 
Overdose ................................................................................................................................ 50 
8.2.4 
Pregnancy ............................................................................................................................... 50 
8.2.5 
Transfusions ........................................................................................................................... 50 
8.3 
REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS .................................................. 51 
8.4 
EXPEDITED SAFETY REPORTING ............................................................................................ 51 
8.5 
DEVELOPMENT SAFETY UPDATE REPORTS ........................................................................... 51 
9 STATISTICS .................................................................................................................................... 52 
9.1 
STATISTICAL DESIGN ............................................................................................................. 52 
9.2 
SAMPLE SIZE CONSIDERATIONS ............................................................................................ 52 
9.3 
ANALYSIS SETS ...................................................................................................................... 52 
9.3.1 
Safety Analysis Set (SAS) ..................................................................................................... 52 
9.3.2 
Full Analysis Set (Intention-to-treat) ..................................................................................... 52 
9.3.3 
Per Protocol (PP) Analysis Sets ............................................................................................. 52 
9.4 
STATISTICAL ANALYSIS ......................................................................................................... 53 
9.4.1 
Overview ................................................................................................................................ 53 
9.4.2 
Disposition of Study Patients ................................................................................................. 53 
9.4.3 
Baseline .................................................................................................................................. 53 
9.4.4 
Primary Efficacy Endpoint Analysis ...................................................................................... 53 
9.4.5 
Secondary Endpoints Analysis ............................................................................................... 54 
9.4.6 
Exploratory Endpoints ........................................................................................................... 54 
9.4.7 
Subgroup Analysis ................................................................................................................. 54 
9.4.8 
Interim Analysis ..................................................................................................................... 55 
9.4.9 
Safety Analysis strategy for laboratory and clinical safety data ............................................ 55 
10 DATA HANDLING AND SOURCE DOCUMENTS .................................................................... 55 
10.1 INFORMED CONSENT PROCEDURES ....................................................................................... 56 
10.2 PROTOCOL DEVIATIONS ......................................................................................................... 56 
10.3 SUBJECT CONFIDENTIALITY ................................................................................................... 56 
11 DRUG ACCOUNTABILITY AND COMPLIANCE ...................................................................... 57 
11.1 ACCOUNTABILITY PROCEDURES ............................................................................................ 57 
11.2 COMPLIANCE .......................................................................................................................... 57 
12 QUALITY CONTROL AND ASSURANCE .................................................................................. 57 
13 ETHICAL CONDUCT OF THE STUDY ....................................................................................... 58 
14 FINANCING, INDEMNITY AND INSURANCE .......................................................................... 58 

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15 PUBLICATION POLICY ................................................................................................................ 58 
16 STUDY RECORD RETENTION .................................................................................................... 59 
16.1 CLINICAL STUDY REPORT ...................................................................................................... 59 
16.2 HANDLING AND RETENTION OF BLOOD AND PATHOLOGICAL SAMPLES .............................. 59 
17 REFERENCES ................................................................................................................................. 60 
18 APPENDICES .................................................................................................................................. 63 
18.1 SCHEDULE OF EVENTS PART A (FIRST 4 WEEKS) .................................................................. 63 
18.2 SCHEDULE OF EVENTS PART A (WEEK 8 ONWARDS) ............................................................ 65 
18.3 SCHEDULE OF EVENTS PART A (DOSE INCREASE) ................................................................ 67 
18.4 SCHEDULE OF EVENTS PART B (FIRST 12 WEEKS) ................................................................ 68 
18.5 SCHEDULE OF EVENTS PART B (WEEK 16 ONWARDS) .......................................................... 69 
18.6 SCHEDULE OF EVENTS PART B (DOSE INCREASE) ................................................................. 70 
18.7 SCHEDULE OF EVENTS PARTS A AND B (TREATMENT EXTENSION) ...................................... 71 
18.8 TOTAL BLOOD VOLUME CALCULATIONS .............................................................................. 72 
18.9 ACUTE GVHD GRADING ....................................................................................................... 75 
18.10 SUMMARY OF MAIN CHANGES AND JUSTIFICATION - VERSION 2.0 - VERSION 3.0 ............... 76 
 
 
 

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LIST OF TABLES 
 
Table 1 
Recombinant nomacopan Drug Product Formulated as a Lyophilized Powder 
for Reconstitution for Subcutaneous Injection ........................................................ 17 
Table 2 
Total Number of Subjects Exposed to Nomacopan in Clinical Trials & as 
Named Patients (07 Aug 2019) ................................................................................ 20 
Table 3 
Summary of Recommended Paediatric Dosing Regimens ...................................... 24 
Table 4 
Paediatric PKPD Exposure Metrics ......................................................................... 25 
Table 5 
Safety Factor Calculation - maintenance dosing ..................................................... 26 
Table 6 
Starting Dose for Patients in Part A ......................................................................... 31 
Table 7 
Initial Dose Increase for Part A ............................................................................... 32 
Table 8 
Second Dose Increase for Part A ............................................................................. 32 
Table 9 
Part A Dosing for youngest female patient –  maintenance dose agreed with 
the FDA as part of Model Informed Drug Development ........................................ 72 
Table 10 Part A Dose Increase 1 for youngest female patient  to maintenance dose of 
0.45 mg/kg/12 hours – if required ........................................................................... 73 
Table 11 Part A Dose Increase 2 for youngest female patient  to maintenance dose of 
0.60 mg/kg/12 hours – if required ........................................................................... 74 
 
 
LIST OF FIGURES 
 
Figure 1 HSCT-TMA Pathogenesis ....................................................................................... 16 
Figure 2 Nomacopan Amino Acid Sequence ......................................................................... 17 
 
 
 

Protocol AK901 v4.0 
 
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11th November 2021 
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1 
PROTOCOL SYNOPSIS 
 
Name of Sponsor/Company: 
Akari Therapeutics Plc 
 
Name of Investigational Product: 
nomacopan 
 
Name of Active Ingredient: 
nomacopan (rVA576) 
 
Title of Study: 
Multicentre Study of nomacopan in Paediatric Haematopoietic Stem-Cell Transplant 
Associated Thrombotic Microangiopathy 
 
Phase of Development: 
Pivotal Phase III 
 
Study Design: 
Open-label, multi-centre two-part study. 
 
Part A: dose algorithm, safety and efficacy 
To confirm the effective dosing and pharmacodynamic (PD) effect of nomacopan on 
terminal complement activity ablation in 7 paediatric patients with HSCT-TMA for 24 
weeks. 
 
Part B: safety and efficacy 
Following dose algorithm confirmation in Part A, up to 65 paediatric HSCT-TMA patients 
will be enrolled to evaluate the efficacy of nomacopan using a composite primary efficacy 
endpoint at 4, 8, 12, 16, 20 and 24 weeks (±5 days) to assess if TMA is resolved.  Treatment 
will be discontinued for patients who have achieved the primary endpoint at 4, 8, 12, 16, 20 
or 24 weeks (±5 days) but may continue for all patients for longer if requested by the 
investigator on clinical grounds. 
 
Objectives: 
 
Part A (7 patients aged ≥ 0.5 to < 18 years, in three age range cohorts) 
 
Dose algorithm confirmation: 
▪ To confirm the effective dose of nomacopan for the ablation of terminal complement 
activity.  The data derived from Part A of the trial will be used together with existing 
data for PK/PD simulation modelling to define an age-based dosing regimen to 
completely control terminal complement activity in paediatric patients treated with 
nomacopan in Part B. 
 
Efficacy and Safety Objectives: 
▪ Primary, secondary, safety and exploratory objectives as described under Part B. 
 

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Part B (up to 65 patients aged ≥ 0.5 to < 18 years) 
 
Objectives: 
 
Efficacy: 
To determine that the age-based dosing regimen defined in Part A can completely control 
complement activity in paediatric patients treated with nomacopan. 
 
Safety: 
To evaluate safety and tolerability of nomacopan 
 
Number of Patients (planned): 
7 patients in Part A. 
Up to 65 patients in Part B. 
 
Inclusion and Exclusion Criteria 
 
Inclusion: 
1. Aged ≥ 0.5 and < 18 years at the time of diagnosis of TMA. 
2. Undergone allogeneic or autologous HSCT. 
3. TMA diagnosis within a year of their allogeneic or autologous HSCT. 
4. Clinical diagnosis of TMA with all of the following diagnostic criteria: 
▪ elevated plasma sC5b-9 (80% or more of ULN) 
▪ Urine protein creatinine ratio > 2 mg/mg (demonstrated on two separate morning 
samples, at least one day apart) 
▪ elevated LDH (> ULN) 
▪ thrombocytopaenia (< 50,000 per mm3) 
▪ low haemoglobin concentration (< LLN) 
 
or 
 
Histological diagnosis of TMA with evidence of complement deposition: 
▪ Urine protein creatinine ratio > 2 mg/mg (demonstrated on two separate morning 
samples, at least one day apart), and 
▪ elevated plasma sC5b-9 (80% or more of ULN) 
5. Provision of written informed consent. 
6. Provision of informed assent (where appropriate)  
 
Exclusion: 
1. 
Patients weighing less than 5 kg. 
2. 
Patients with a positive direct Coombs’ test. 
3. 
Patients who do not receive nomacopan within 21 days of the initial diagnosis 
of TMA. 
4. 
Patients having an active systemic or organ system bacterial or fungal infection 
or progressive severe infection (including unresolved or untreated Neisseria 
meningitidis infection and E. coli Shiga toxin) at the time of diagnosis of the 
TMA.   
5. 
Grade 4 Acute GVHD (as per the Glucksberg grading system, see section 18.9). 
6. 
Received eculizumab or any other complement blocker therapy at any time. 
7. 
Known hypersensitivity to the active ingredient or excipients 
8. 
Patients who are pregnant and/or breastfeeding. All females of childbearing 
potential require a negative pregnancy test at screening.   
 

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Study Procedures: 
Part A 
 
The ablating dosing regimens (Day 1, two doses, 12 hours apart) will be 1.7 mg/kg/12 
hourly (aged ≥ 0.5 to < 2 years), 1.3 mg/kg/12 hourly (aged ≥ 2 to < 9 years) or 1.0 mg/kg/12 
hourly (aged ≥ 9 to < 18 years), and the maintenance dosing regimen (Days 2 to Week 24, 
12 hours apart) will be 0.30 mg/kg/12 hourly irrespective of age group. 
 
The patients will undergo PK/PD monitoring to assess whether terminal complement 
activity is fully controlled on the starting dose (ie CH50 is below the lower limit of 
quantification (LLOQ), and unbound nomacopan ≥ 55 ng/mL in serum).  If the CH50 is 
> 10 U Eq/mL and/or unbound nomacopan is < 55 ng/mL at any time from pre-dose on Day 
7 onwards once the CH50 results have been received, a single ablating dose (as per age 
group described above) will be administered followed by an increased maintenance dose of 
0.45 mg/kg/12 hourly from 12 hours after the ablating dose to the end of treatment. 
 
If 7 days or more after dose escalation to 0.45 mg/kg/12 hourly, CH50 > 10 U Eq/mL and/or 
unbound nomacopan is < 55 ng/mL, a final higher maintenance dose escalation is permitted 
with a single ablating dose (as described above), followed 12 hours later by 0.60 mg/kg 
every 12 hours until the end of treatment. 
 
The following PK/PD related measures will be assessed for up to 24 weeks (±5 days): 
▪ Terminal complement activity (measured by CH50). 
▪ Unbound nomacopan. 
▪ Soluble C5b9 (sC5b9). 
▪ Total C5. 
▪ C3b. 
▪ Anti-drug antibody (ADA). 
▪ LDH. 
▪ LTB4 (urine). 
 
Efficacy and safety will be assessed for up to 24 weeks at 4, 8, 12, 16, 20 and 24 weeks (± 
5 days). 
 
All patients will have a safety follow up 30 days (±5 days) after last dose of nomacopan. 
 
Except in exceptional circumstances, the treatment period with nomacopan within the study 
protocol will be for no longer than 24 weeks (± 5 days).  Patients may come off the drug 
sooner if the primary endpoint has been met (one or both components) and the treating 
clinician considers there is no longer a need for continued treatment with nomacopan.  
Patients who have achieved the primary endpoint and have stopped receiving nomacopan 
will have no further scheduled visits until their follow-up visit, which would be 30 days 
after their last dose of nomacopan.  All surviving patients who are no longer receiving 
nomacopan at 24 weeks will also attend the clinical visit at 24 weeks (± 5 days) for a 
physical examination and assessment of renal function. 
 
The PK/PD data from all 7 patients in Part A, together with existing adult and paediatric 
data from HSCT-TMA patients treated with nomacopan, will be used to undertake planned 
compartmental mechanistic simulation modelling, agreed in advance with the FDA, to 
select the optimal dose regimen for Part B. 
 
 
 

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Part B 
 
An age-based dosing regimen will be used, defined by analysis of Part A data.  It is planned 
that the starting dose will be effective in all patients, but a single higher dosing regimen (to 
be determined after Part A) will be available in the unexpected event that CH50 is not 
< LLOQ and/or free nomacopan is < 55ng/mL at any time from Day 7 onwards. 
 
All Part B patients will have the same efficacy and safety assessments and clinic visits as 
described above for Part A but with fewer PK/PD measures. 
 
Duration of Treatment: 
 
Part A 
 
A total of 7 patients (three patients in the ≥ 0.5 to < 2 category, and four other patients with 
at least one aged ≥ 2 to < 9 years, and at least one aged ≥ 9 to < 18 years) will be included 
in Part A of the trial. 
 
The treatment period for nomacopan will be for no longer than 24 weeks (± 5 days).  Patients 
may come off the drug sooner if the primary endpoint has been met (one or both 
components) and the treating clinician considers there is no longer a need for continued 
treatment with nomacopan.  All patients will have a safety follow-up 30 days (± 5 days) 
after the last dose of nomacopan.  All surviving patients who are no longer receiving 
nomacopan at week 24 will attend the clinic for a physical examination and assessment of 
renal function at 24 weeks (± 5 days).  The End of the Study will occur when all surviving 
patients have attended the long-term follow-up visit at two years after diagnosis of HSCT. 
 
In exceptional circumstances where the investigator requests continuation of nomacopan 
beyond 24 weeks for clinical reasons, the Sponsor may agree with the investigator to supply 
nomacopan for an additional 12 week period only.  Any patients on nomacopan after week 
24 will have safety assessed every 4 weeks while on the drug and will attend a safety follow-
up 30 days (± 5 days) after the last dose. 
 
Part B 
 
Following Part A, up to 65 HSCT-TMA paediatric patients (in any age category) will be 
enrolled in a 24-week study to evaluate efficacy and safety at 4, 8, 12, 16, 20 and 24 weeks 
(± 5 days). 
 
The treatment period for nomacopan will be for no longer than 24 weeks (± 5 days).  Patients 
may come off the drug sooner if the primary endpoint has been met (one or both 
components) and the treating clinician considers there is no longer a need for continued 
treatment with nomacopan.  All patients will have a safety follow-up 30 days (± 5 days) 
after the last dose of nomacopan.  All surviving patients who are no longer receiving 
nomacopan at Week 24 will attend the clinic for a physical examination and assessment of 
renal function at 24 weeks (± 5 days).  The End of the Study will occur when all surviving 
patients have attended the long-term follow-up visit at two years after diagnosis of HSCT. 
 
Long-term follow-up visits will be performed at one and two years after the HSCT. 
 
In exceptional circumstances where the investigator requests continuation of nomacopan 
beyond 24 weeks for clinical reasons, the Sponsor may agree with the investigator to supply 
nomacopan for an additional 12 week period only.  Any patients on nomacopan after Week 

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24 will have safety assessed every 4 weeks while on the drug and will attend a safety follow-
up 30 days (± 5 days) after the last dose. 
 
Criteria for Evaluation (Parts A and B): 
 
Primary Endpoint 
 
This is a composite primary endpoint: 
▪ Independent of RBC transfusion† for ≥ 28 days immediately prior to any scheduled 
clinical visit up to Week 24 
or 
▪ Urine protein creatinine ratio ≤ 2 mg/mg maintained over ≥ 28 days immediately 
prior to any scheduled clinical visit up to Week 24 
 
Secondary Endpoints 
 
Efficacy: 
▪ Percentage of patients who achieve the primary endpoint of urine protein creatinine 
ratio ≤ 2 mg/mg (the nephrotic threshold) for ≥ 28 days 
▪ Platelet transfusion independence† for ≥ 28 days 
▪ Plasma sC5b-9 ≤ ULN 
▪ Lactate dehydrogenase (LDH) ≤ ULN 
▪ Normalization of haptoglobin 
 
sC5b-9, LDH and haptoglobin will be measured at the last efficacy assessment in the trial 
before nomacopan treatment is stopped. 
 
†Transfusion independence is defined as no RBC or platelet transfusion attributable to, or 
required to manage, TMA.  Transfusion required for causes other than TMA will not be 
considered within evaluation of endpoints. 
 
The Sponsor will not make this evaluation.  The investigator will decide if a transfusion is 
required for the management of TMA or is part of the management of other clinical events 
or part of a site clinical management policy (eg haemoglobin maintenance thresholds, 
infection management). 
 
Safety: 
▪ Safety and tolerability of nomacopan 
 
 
Statistical Methods & Data Analysis: 
Part A will recruit 7 patients, in three age range cohorts.  The purpose of Part A is to confirm 
the effective maintenance dose of nomacopan for ablation of terminal complement activity, 
which will then be used in Part B. 
 
For Part B it is assumed that the responder rate on nomacopan will be approximately 30% 
and the minimum acceptable responder rate is 15%.  Up to 65 patients will be recruited 
which gives 79% power to reject the null hypothesis proportion, π₀, of less than 0.15 when 
the alternative hypothesis proportion, π₁, is 0.3 using an exact binomial test with a 2.5% 
one-sided significance level. 
 
An interim analysis will be conducted when 40 patients have been recruited into Part B of 
the study and have either completed 24 weeks of the study or discontinued the study before 

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24 weeks.  In order to stop the study early for demonstration of efficacy, based on an 
O’Brien-Fleming stopping rule, at an information fraction of 0.62 (40 of 65 patients), the 
significance level at the interim analysis needs to be 0.0044 (1 sided).  To meet this 
significance level, at least 13 of the 40 patients (32.5%) will need to be responders.  If the 
study is not stopped early, recruitment will continue and the final significance level, after 
65 patients, will then need to be 0.024. 
 
Consideration will be given to including Part A patients in the primary overall analysis; 
this will be discussed with the FDA at the end of Part A. 
 
 
 
 

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2 
INTRODUCTION 
 
This study will be conducted and completed per study protocol and the guidelines of Good 
Clinical Practice (GCP).  Compliance with this standard provides public assurance that the 
rights, safety, and wellbeing of trial patients are protected, consistent with the principles that 
have their origin in the Declaration of Helsinki. 
 
 
2.1 
OVERVIEW OF THE DISEASE:  BACKGROUND OF THROMBOTIC MICROANGIOPATHY, 
TREATMENT OPTIONS AND UNMET NEED 
 
Thrombotic microangiopathy (TMA) is a pathology that can manifest in a range of conditions 
and presentations but is generally characterised by clinical presentation of thrombocytopaenia, 
microangiopathic haemolytic anaemia, and organ injury.  Haematopoietic stem cell 
transplantation (HSCT) is used as a therapy for various autoimmune diseases, inborn errors of 
metabolism and for some types of cancer.  TMA following HSCT is a rare disease with a 
mortality rate of 33-90% despite treatment1.  HSCT-TMA manifests with a variety of symptoms 
which may include thrombocytopaenia, haemolysis, schistocytes in peripheral blood, acute 
renal failure, mental status change, and involvement of other organs2.  The process of HSCT 
involves the intravenous (iv) infusion of autologous or allogeneic stem cells to re-establish 
haematopoietic function in patients whose bone marrow or immune system is damaged, 
defective, or has been therapeutically ablated. 
 
HSCT-TMA involves arteriolar thrombi associated with intimal swelling and fibrinoid necrosis 
of the vessel wall with thickening of arterioles and capillaries, endothelial swelling and 
detachment, and subendothelial accumulation of proteins and cell debris3.  This results from 
tissue injury that causes a release of cytokines that damage the microvascular epithelium.  
Activation and consumption of platelet and coagulation factors lead to thrombosis and fibrin 
deposition3.  Microangiopathic haemolytic anaemia and thrombocytopaenia result from damage 
to red blood cells caused by microthrombi or fibrin strands that obstruct the microcirculation3.  
The kidney is the most commonly affected organ due to the susceptibility of the glomerular 
circulation to endothelial damage and occlusion4, but HSCT-TMA can also affect the lung, 
bowel, heart, and brain5. 
 
Diagnosis is based on normal coagulation, negative direct Coombs’ test result on red blood cells 
(RBCs), presence of schistocytes, elevated serum lactate dehydrogenase (LDH) levels, 
concurrent renal or neurological dysfunction unexplained by other mechanisms, progressive 
anaemia, thrombocytopaenia, and decreased levels of serum haptoglobin2,5,6.  Jodele et al, in a 
study conducted in children and young adults in 2014, proposed a 2-pronged approach to 
diagnosis that includes diagnosis by direct renal tissue biopsy and a compilation of clinical and 
laboratory values including, elevated serum LDH, proteinuria, hypertension, de novo 
thrombocytopaenia, de novo anaemia, presence of schistocytes, and concentration of soluble 
terminal complement complex (sC5b-9)7.  Risk factors for HSCT-TMA include high-dose 
chemotherapy, radiation therapy during pre-conditioning, unrelated donor, human leukocyte 
antigen (HLA) mismatch, exposure to calcineurin inhibitors with or without concomitant 
exposure to sirolimus, graft-versus-host disease (GVHD), infections, and possibly complement 
protein polymorphisms2,3,8-10. 
 
HSCT-TMA is frequently, but not always, associated with terminal complement activation 
(TCA).  Involvement of TCA can be detected by measuring elevated circulating sC5b-9 levels 
and/or complement product deposition in tissues, including renal tissues, which may be 
detected by tissue biopsy and immunofluorescence staining.  It has been suggested that HSCT-
TMA with clear evidence of complement activation, may be effectively treated by complement 

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inhibition11.  Eculizumab, a complement component 5 (C5) blocking therapy, is being 
investigated as a treatment7,12,13. 
 
As reviewed by Choi et al, the prognosis of HSCT-TMA is currently very poor, with reported 
mortality rates as high as 90% in high-risk patients1.  There is no approved therapy for HSCT-
TMA, and despite current management of the disease which includes withdrawal of calcineurin 
inhibitors and/or co-therapy with sirolimus, and supportive care, such as dialysis, plasma 
exchange (PEX), transfusion of platelets and RBCs, and antihypertensive therapy2,3,5, the 
mortality rates remain very high.  The pathological process of microvascular thrombosis, 
consumptive thrombocytopaenia and microangiopathic haemolytic anaemia frequently lead to 
ischaemia and infarction in target organs, particularly the kidney and the brain although cardiac, 
gastrointestinal (GI), and other organ dysfunction can occur, all of which contribute to the high 
mortality rate.  Mortality estimates from more recent published clinical studies range from 
33%7,14,15 to 90%13 of patients treated for HSCT-TMA, suggesting that despite current treatment 
options, a novel therapy option is needed. 
 
Unlike the complement component C5 blocking therapy eculizumab, nomacopan binds to 
complement C5 at a different site, though like eculizumab it prevents cleavage of C5 and 
formation of the active terminal complement products (C5a and C5b9), but nomacopan also 
binds tightly (KD 0.2 nM) to the pro-inflammatory mediator leukotriene B4 (LTB4).  Further, 
nomacopan is a small recombinant protein (16.7 kDa) and can be given by low-volume 
subcutaneous (sc) injection instead of iv infusion.  As such, nomacopan may provide valuable 
therapy in the treatment of HSCT-TMA, a serious condition. 
 
 
2.2 
NOMACOPAN IN THROMBOTIC MICROANGIOPATHY 
 
Although the exact pathophysiology remains unclear, complement activation or defects in its 
regulation appear to play a role in TMA following haematopoietic stem cell transplantation 
since the regulation of complement activation is critical in maintaining endothelial cell 
integrity16.  Complement activation, including C4d deposition in tissues, has been demonstrated 
in the renal arterioles and other organs of patients with HSCT-TMA17.  Mutations in 
complement proteins including complement factor H-related proteins (CFHRs) 1 and 3 and 
auto-antibodies to CFHR that may predispose to development of HSCT-TMA have also been 
reported in patients8,9. 
 
The complement cascade has three activation pathways (classical, lectin, and alternative).  
Activated complement generates three major types of effectors: anaphylatoxins (C3a & C5a), 
opsonins (C3b, iC3b, & C3d), and the terminal complement complex (C5b-9).  There is strong 
evidence that C5b-9 formation is associated with TMA.  Elevated levels of C5a and soluble 
C5b-9 (sC5b9) have been reported in related TMAs, notably thrombotic thrombocytopaenic 
purpura (TTP) and atypical haemolytic uremic syndrome (aHUS)18,19.  Nomacopan inhibits all 
three complement activation pathways, as it acts after the convergence of the pathways after 
the formation of C3 convertase.  Nomacopan acts by preventing C5 activation thereby 
preventing formation of the terminal complement complex and the potent anaphylatoxin C5a 
while preserving the immune clearance and opsonization functions that depend on C3b.  
Nomacopan also exhibits very tight binding to LTB4 (KD 0.2 nM), a potent chemoattractant 
and activator of myeloid cells, particularly, neutrophils.  Nomacopan captures LTB4 within an 
internal binding cavity, which prevents binding of LTB4 to its two G protein-coupled receptors 
BLT1 and BLT2 and thereby prevents leukocyte activation and recruitment and inhibits 
inflammation. 
 

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Figure 1 
HSCT-TMA Pathogenesis 
 
Source:  Jodele 201820 
 
The development of HSCT-TMA and the chain of events in the disease pathology are described 
in Figure 1.  C5-inhibiting therapy with eculizumab may be effective in treating HSCT-
TMA7,12,13,21.  Jodele et al provide evidence of a role of complement activation in HSCT-TMA 
from a prospective study of subjects undergoing HSCT who had elevated sC5b-9 (evidence of 
complement activation) and proteinuria at the time of TMA diagnosis22.  These patients had a 
1-year survival of < 20%, whereas subjects with normal sC5b-9 and no proteinuria had a 
survival of 100%22.  Additionally, mutations in genes responsible for complement activation 
have been identified at a significantly higher rate in stem cell recipients with HSCT-TMA 
compared to those patients without HSCT-TMA10.  Because of the association found with 
complement activation, Jodele et al treated six children with severe HSCT-TMA with the 
complement inhibitor eculizumab and achieved TMA resolution in four patients; the other two 
critically ill patients were not able to reach therapeutic eculizumab levels and did not survive7. 
 
LTB4, which is also inhibited by nomacopan, is not known to play a role in the pathology of 
HSCT-TMA.  However, in the context of Figure 1, it is notable that LTB4 can induce 
expression of IL-823, can play a role in thrombus formation24, and has been shown by Akari to 
activate endothelial cells in vitro leading to deposition of C5b9 when cells are exposed to serum 
taken from patients with active aHUS (data on file, unpublished). 
 
As such, nomacopan is expected to be efficacious in the treatment of HSCT-TMA, a serious 
condition with a high mortality whose pathology is driven by complement activation. 
 
 

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3 
PRIOR EXPERIENCE WITH THE INVESTIGATIONAL PRODUCT 
 
3.1 
INVESTIGATIONAL PRODUCT 
 
Nomacopan is a small protein molecule derived from a native protein found in the saliva of the 
Ornithodoros moubata tick.  Profound complement component 5 (C5) inhibition occurs 
following nomacopan administration.  A surface-active site on the protein binds complement 
C5 with high affinity (KD 1.0 x 10−9 M by surface plasmon residence)25 preventing cleavage of 
C5 by C5 convertase to the active fragments C5a and C5b, and subsequent formation of the 
terminal complement complex26.  Nomacopan also exhibits very tight binding to LTB4 
(KD 0.2 nM by fluorescence titration), a potent chemoattractant and activator of myeloid cells, 
particularly, neutrophils.  Nomacopan captures LTB4 within an internal binding cavity, which 
prevents binding of LTB4 to its two G protein-coupled receptors BLT1 and BLT2 and thereby 
prevents leukocyte activation and recruitment and inhibits inflammation. 
 
The molecular mass of nomacopan, as predicted by molecular modelling and confirmed by 
mass spectrometry, is 16.786 kDa.  Nomacopan is not glycosylated.  The amino acid sequence 
showing disulphide bridges is shown in Figure 2.   
 
Figure 2 
Nomacopan Amino Acid Sequence 
 
 
Recombinant nomacopan drug product is formulated as a lyophilized powder for reconstitution 
for subcutaneous (sc) injection.  The lyophilised formulation is presented in 6 mL Type I glass 
vials containing lyophilized powder comprised of sodium phosphate buffered saline (PBS) and 
18 mg nomacopan per vial with no additional additives, preservatives, or stabilizers.  The vials 
are stored at 2-8ºC.  The drug product is reconstituted with 0.6 mL of sterile water for injection 
(WFI), to create a solution of 30 mg/mL nomacopan in PBS pH 7.2 (Table 1). 
 
Table 1 
Recombinant nomacopan Drug Product Formulated as a Lyophilized Powder for 
Reconstitution for Subcutaneous Injection 
Ingredient 
Amount per 
vial (mg) 
nomacopan 
18 
Disodium hydrogen orthophosphate dihydrate 
0.45 
Sodium dihydrogen orthophosphate dihydrate 
1.30 
NaCl 
4.34 
NaOH/HCL to adjust to pH 7.2 ± 0.2 
q.s. 
q.s. = quantum satis 
 

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After reconstitution, the drug will normally be injected immediately.  Only if absolutely 
needed the drawn-up syringe may be stored between 2-8ºC for up to 24 hours at pharmacy or 
in a secure environment and checked for clarity immediately prior to use.  The extractable 
volume from each vial using a standard syringe is ≥ 0.5 mL, permitting administration of 15 mg 
nomacopan per vial. 
 
 
3.2 
SUMMARY OF RELEVANT NON-CLINICAL AND CLINICAL STUDIES 
 
3.2.1 Non-clinical 
 
There is no animal model of HSCT-TMA in which to test the efficacy of nomacopan.  However, 
complement is believed to have a causative role in exacerbating the pathology of HSCT-TMA 
shown by means of an association between disease severity and sC5b9 levels7,11.  Since 
nomacopan has been shown to treat various diseases driven by complement in both nonclinical 
and clinical studies it may be an effective therapy for HSCT-TMA. 
 
Similar to eculizumab, nomacopan inhibits all three C activation pathways (classical, 
alternative, and lectin), as it acts after the convergence of these activation pathways.  
Nomacopan prevents the generation of C5 activation and formation of the terminal complement 
complex and the anaphylatoxin C5a while preserving the immune clearance and opsonization 
functions that depend on C3b.  As such it is expected to be efficacious in the treatment of HSCT-
TMA, a serious condition with a high mortality whose pathology may be driven by complement 
activation. 
 
The dose-response relationship of inhibition of TCA by nomacopan when administered to 
animals has been examined in 3 studies: 
 
1. 
Nomacopan was administered to C5 sufficient and C5 deficient mice by iv bolus and TCA 
measured by lytic assay27.  The data showed that in C5 sufficient mice, complement was 
fully ablated within minutes of iv administration and gradually returned to normal levels 
within 24 hours.  In C5 deficient mice, nomacopan is very rapidly cleared from 
circulation, whereas in the presence of C5, nomacopan has a prolonged half-life due to 
its tight binding to C5.  The half-life of nomacopan bound to C5 was estimated at 30 hours 
in rats. 
2. 
In a study to investigate complement C5 inhibition (VA002-REP-001), nomacopan was 
administered by slow iv infusion into the jugular vein of Sprague-Dawley rats (6 groups 
with 2 rats/group) over a 12-hour period at doses of 1, 5, 10, 50, and 500 µg/kg/hour, and 
serial blood samples were taken from the tail artery.  The study demonstrated a dose-
response relationship between concentration/kg/hour and inhibition of TCA measured by 
lytic assay.  Approximately 75% inhibition of activity was observed at 5 hours at a dose 
of 100 mg/kg/hour, and approximately 97% inhibition was observed at 2 hours at 500 
µg/kg/hour. 
3. 
In a 28-day toxicology study (S54790), nomacopan was administered to cynomolgus 
monkeys by daily sc injection.  The onset and offset of TCA was assessed by CH50 
ELISA.  The onset of inhibition of TCA was faster in cynomolgus monkeys than in 
humans where, in monkeys, nomacopan sc caused full complement blockade within 1 
hour of the first dose of 4.8 mg/kg.  The daily 4.8mg/kg dose sustained total complement 
blockade at trough for 28 days.  The lower 0.5 mg/kg dose produced approximately 90% 
blockade after 4 hours and about 80% inhibition at trough for 28 days. 
 

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While not specific to HSCT-TMA, these animal data provide support for the terminal 
complement inhibitory activity also observed in humans that is believed to be relevant to the 
pathology of HSCT-TMA. 
 
3.2.2 Clinical 
 
Nomacopan has not yet been studied in patients with HSCT-TMA in a clinical trial. 
 
 
3.3 
PREVIOUS EXPERIENCE IN PATIENTS 
 
Goodship et al reported on the first HSCT-TMA patient treated with nomacopan for HSCT-
TMA28.  The 3-year old boy underwent a HLA-matched unrelated HSCT and subsequently 
developed TMA with microangiopathic haemolytic anaemia and hypertension.  He was treated 
with eculizumab for 10 weekly infusions with no clinical improvement and was later found to 
be resistant to eculizumab due to an amino acid polymorphism in C5 that reduces eculizumab 
binding to the complement protein.  To determine whether C5 could be blocked by nomacopan, 
ascending doses of eculizumab and nomacopan were added to patient serum and pooled control 
serum and TCA was assessed.  Nomacopan at 15 μg/mL was found to completely block TCA 
in both patient and control serum, whereas eculizumab decreased complement activity by a 
maximum of approximately 75%.  Having shown that nomacopan but not eculizumab can fully 
inhibit C5 activation in vitro, the patient was then treated with nomacopan and showed some 
initial improvement including reduced gastrointestinal bleeding.  However, the patient’s 
condition worsened, and he died two weeks after he received his last daily dose of nomacopan.  
During the 58 days that the patient received nomacopan, there were no adverse events and no 
injection site reactions.  Low titre non-neutralizing anti-nomacopan antibodies were detected 
after 14 days of treatment. 
 
An additional seven “specials” patients who received nomacopan presented in extremis.  All 7 
of those treated in 2018/2019 had elevated sC5b9 and proteinuria (high risk group) and all 
presented with TMA more than six months after HSCT, whereas in work undertaken by Jodele 
et al it is evident that when patients are closely monitored for signs and symptoms of TMA the 
majority of patients (92%) develop TMA within 100 days of transplant, and early diagnosis and 
treatment of TMA is thought necessary to provide patients with the best chance of survival22.  
However, a small but important number of patients may develop TMA for up to year after 
HSCT and benefit from treatment.  Clinical performance of the first two paediatric HSCT-TMA 
patients treated with nomacopan was reported at a UK Bone Marrow Transplant meeting. Both 
patients received nomacopan for 56 days and showed a strong clinical response to treatment 
indicated by resolution of haemolytic anaemia, thrombocytopaenia, schistocytes and 
hypertension. One patient made a complete recovery and stopped receiving nomacopan the 
other died of lung complications considered unrelated to the drug. 
 
3.3.1 Summary of Known and Potential Risks and Benefits to Human Patients 
 
To date (August 2021), nomacopan has been administered by subcutaneous (sc) injection or 
ophthalmic (eye drops) routes to 97 subjects (32 healthy volunteers and 65 patients) - see Table 
2.  Fifty-six of the subjects are adults in clinical trials, and eight were children who received 
compassionate use nomacopan under a UK “specials licence”. 
 
Nomacopan was administered to 16 healthy male subjects in a Phase Ia single ascending dose 
study (VA576), 16 healthy male subjects in a Phase Ib 7-day repeat dose study (AK577), one 
eculizumab-resistant PNH patient in a Phase II study (AK578), eight PNH patients in the Phase 
II study (AK579), one eculizumab resistant PNH patient in AK585, nine PNH patients in 

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AK580, nine  bullous pemphigoid patients in AK801, and using ophthalmic eye drops six  
patients with atopic keratoconjunctivitis. 
 
Additionally, nine complex paediatric HSCT-TMA patients with advanced disease were treated 
with subcutaneous nomacopan using a compassionate use/ “specials” licence or on a named 
patient basis. 
 
In all these subjects, nomacopan has generally been found to be well tolerated. 
 
Table 2 
Total Number of Subjects Exposed to Nomacopan in Clinical Trials & as Named 
Patients (07 Aug 2021) 
Study 
Phase 
Number of 
Subjects 
Indication/route of admin 
sc = subcutaneous 
O = ophthalmic eye drops 
 
 
 
 
Healthy Volunteers 
VA576 
Ia 
16 
Healthy volunteer, sc 
VA577 
Ib 
16 
Healthy volunteer, sc 
Total Volunteers 
32 
 
Patients 
AK578 
II 
1 
PNH, sc 
AK579 
II 
8 
PNH, sc 
AK580 
III 
9 
PNH, sc 
AK585 
II 
1 
PNH (ongoing), sc 
AK801 
II 
9 
Bullous pemphigoid (ongoing), sc 
AK701 
II 
6 
Atopic keratoconjunctivitis 
(ongoing: LSLV complete: CSR 
being written), O 
Compassionate use/Specials 
licence named patients 
8 
HSCT-TMA pediatric, sc 
Compassionate use/Investigator-
initiated program  
23 
Covid-19 pneumonia, sc 
Total Patients 
65 
 
Overall Total 
97 
 
 
In the Phase Ia trial (VA576) four mild, non-serious AEs were reported in three subjects (two 
active and one placebo) but a causal relationship to the study drug was not established.  There 
was no dose relationship, and the AEs were mild and self-limiting. 
 
In the Phase Ib trial (VA577), an AE was reported which the investigator considered was not 
study drug related.  This patient was assessed by the investigator as having rhabdomyolysis and 
stopped treatment after the third dose of nomacopan.  The patient also experienced 
asymptomatic raised creatinine kinase and serum myoglobin levels which the investigator 
considered were related to the administration of ciprofloxacin as a prophylactic antibiotic 
during the trial.  Twenty-two other non-serious, mild/moderate AEs were reported in this trial 
in seven patients, all of which resolved without treatment. 
 
In the Phase II trial (AK578) the only PNH subject who was enrolled and completed the study 
benefited from nomacopan and currently continues therapy on nomacopan twice daily in Study 
AK581 (15 mg every 12 hours).  The drug was generally well-tolerated.  Overall, two SAEs 
occurred within this study.  The patient had breakthrough haemolysis (worsening of PNH 

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symptoms presenting with fatigue and dark urine) on Day 5 of treatment before full control of 
the disease had been achieved.  The investigators considered that this SAE was unrelated to 
nomacopan.  The second SAE was a lung infection in which the patient presented with fever 
and cough.  This SAE was assessed as not related to nomacopan.  No other significant findings 
arose from this study. 
 
Overall, nomacopan was well tolerated in the Phase II AK579 trial.  There were no drug related 
SAEs and few drug related AEs other than mild to moderate injection site reactions.  SAEs 
were reported in two patients.  One patient had an SAE of staphylococcal infection, and another 
patient had SAEs of angina pectoris, lethargy and dyspnoea.  All four SAEs resolved during the 
study and were considered to be not related to nomacopan.  The most frequently reported 
nomacopan-related AEs were injection site reactions (eg erythema, pruritis, bruising, pain, 
swelling, discharge, hypersensitivity, induration, or haematoma), which were reported in six 
out of the eight patients enrolled. 
 
In the Phase III trial (AK580) in PNH, three patients experienced four SAEs.  One patient had 
two SAEs of cholelithiasis and haemoglobinuria (associated with worsening of PNH).  A 
second patient had an episode of catheter site infection and a third had an episode of viral 
gastroenteritis.  These events were  assessed as not being related to nomacopan, and all  resolved.  
One patient had two SAEs of neutropenic sepsis and haemolysis during screening and were not 
randomised into the study.  This study has finished. 
 
Three SAEs were reported in Study AK585 in one patient (002-001) Grade 3 febrile neutropaenia, 
Grade 3 device-related infection and Grade 3 urinary tract infection.  None of these events was 
assessed as related to nomacopan.  All SAEs resolved.  The study is ongoing. 
 
In the Phase II trial (AK801) in BP, three patients each had one non-related SAE.  One patient 
had an episode of a localised (knee) infection that had not resolved by the end of study.  The 
other two patients had a single episode of condition (ie BP) aggravated with both resolving.  
This study has finished. 
 
In the Phase II, randomised and placebo controlled trial in SACK (AK701), six patients received 
nomacopan  whilst six received placebo.  There were no SAEs.  The study has finished. 
 
Patients in the PNH trials AK578, AK579, AK580 and AK585 were eligible to continue 
treatment with nomacopan within the long-term safety study (AK581).  Three of fifteen patients 
experienced a total of 13 SAEs during the study.  One patient experienced an episode of an E. 
coli UTI that was considered possibly related to nomacopan.  Based on a history of previous 
recurrent UTIs that usually resolved with oral antibiotics, the sponsor did not consider this a 
related event.  This patient also had three other SAEs.  One patient had two unrelated SAEs 
whilst the another had six unrelated SAEs.  Only one of these events (pulmonary hypertension 
had not resolved).  The study has finished. 
 
In all clinical trials to date nomacopan has been well tolerated and there have been no serious 
drug-related adverse events, no suspected unexpected serious adverse reactions (SUSARs) and 
no treatment emergent adverse events other than mild to moderate injection site reactions.  
These have been of a comparable type and severity to those seen with other subcutaneously 
administered drugs (eg insulin) and are not considered to be drug related. The most frequently 
reported TEAE is injection site discomfort, erythema, redness or pain. 
 

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3.3.2 Summary of Experience with 9 Compassionate Use/Named Patient Paediatric 
HSCT/TMA Patients 
 
Despite the fact that nomacopan has not been studied to date in patients with HSCT-TMA in a 
clinical trial, it has been used to treat a paediatric patient in 201328 and seven paediatric HSCT-
TMA patients in 2018/2019 under a specials license in the United Kingdom. 
 
The ablating and maintenance dose regimens used for treatment of the 7 paediatric HSCT 
patients in 2018/2019 resulted in a reduction in TCA measured by enzyme-linked 
immunosorbent assay (ELISA) to < 8 CH50 U Eq/mL, corresponding to > 90% reduction in 
TCA compared to baseline.  The data demonstrate that TCA is quickly controlled by the 
ablating doses used (within 24 hours) and most patients remain fully controlled on the daily 
dosing regimen. 
 
Free nomacopan concentrations were also measured.  The data show that, with one exception, 
the ablating and maintenance doses used maintained free nomacopan levels above the 
calculated concentration required to ensure complete inhibition of TCA. 
 
The 8 “specials” patients who received nomacopan presented in extremis.  All 7 of those treated 
in 2018/2019 had elevated sC5b9 and proteinuria (high risk group) and all presented with TMA 
more than six months after HSCT, whereas in work undertaken by Jodele et al it is evident that 
when patients are closely monitored for signs and symptoms of TMA the majority of patients 
(92%) develop TMA within 100 days of transplant, and early diagnosis and treatment of TMA 
is thought necessary to provide patients with the best chance of survival22.  However, a small 
but important number of patients may develop TMA for up to year after HSCT and benefit from 
treatment. 
 
3.3.3 Anti-drug Antibodies 
 
Nomacopan is a xenologous protein with the recombinant protein originally derived from a 
cDNA encoding a tick salivary protein. In the AK577 healthy volunteer study, ADAs were 
detected in two of four subjects dosed with nomacopan for 21 days and in none of the subjects 
dosed with nomacopan for 7 days.  The antibodies were of low titre and did not neutralise the 
complement inhibitory activity of nomacopan.  The eculizumab resistant PNH patient who had 
been receiving nomacopan for more than 21 months in Study AK578 first had detectable ADA 
at Day 16, which peaked at Day 60 and declined thereafter.  All patients (n=8) in AK579 
developed detectable ADAs, which were first detectable between Day 14 to Day 90.  Again, 
the antibodies were of low titre and did not neutralise the complement inhibitory activity of 
nomacopan.   
 
The appearance of ADA does not appear to be associated with an increase in the rate or severity 
of injection site reactions.   
 
The most compelling data supporting that the human ADA are non-neutralising is that in PNH 
patients from trials AK578, AK579, AK581 and AK585, over a daily dosing period of years, 
TCA has been found to be below the lower limit of quantification at all time points after Day 1 
of nomacopan dosing.  Furthermore, ADA are not associated with a decrease in the 
concentration of unbound nomacopan in patients.   
 
Experience with nomacopan to date appears similar to patient experience with other parasite 
derived therapeutic molecules, such as the leech-derived anticoagulant hirudin, where the 
majority of patients develop detectable ADA which have no effect on the inhibitory function of 
the protein29. 

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3.4 
DESCRIPTION OF AND JUSTIFICATION OF ROUTE OF ADMINISTRATION, DOSAGE 
REGIMEN AND TREATMENT PERIOD 
 
Empirical data from the completed Phase 1 trials AK576 (MAD) and AK577 (SAD), and from 
the Phase 2/3 PNH trials AK579, AK580 and AK585 indicated that in 50-100 kg adults a fixed 
subcutaneous (sc) ablating dose of 60 mg followed by 30 mg 12 hours later and a fixed sc 
maintenance dose of 22.5 mg twice daily, 30 mg once daily, or 45 mg once daily inhibits 
systemic TCA measured by CH50 ELISA to less than the assays lower limit of quantification 
(LLOQ) which is 10 CH50 U Eq/mL. 
 
Pharmacokinetic and pharmacodynamic (PK/PD) data have also been obtained from 7 UK 
paediatric HSCT-TMA patients treated in 2018/2019 on a named patient basis with daily sc 
administration of nomacopan for durations of between one week to 56 days.  Intensive PK/PD 
measurements of free nomacopan and TCA were taken on Day 1 of dosing and at various 
intervals thereafter. 
 
Using this data AKARI has developed a mechanistic PK/PD model to describe and understand 
the dynamics of the nomacopan-complement C5 system following single and multiple sc doses 
in humans.  The model uses non-linear mixed effects modelling (NONMEM) methodology and 
describes the dynamics of free nomacopan concentrations and total TCA in plasma.  The model 
has been used to understand adult dosing in particular the proportion of patients who will have 
their TCA essentially fully inhibited by the ablating and fixed maintenance sc dosing regimens 
(this is described in the Investigator’s Brochure). 
 
Working with the FDA as part of their Model Informed Drug Development (MIDD) 
programme, the PK/PD model has been refined and extended to evaluate and select age based 
mg/kg dosing regimens to ablate complement.  With the three paediatric age categories defined 
as: Category 1, ≥ 0.5 to < 2 years; Category 2, ≥ 2 to < 12 years; and Category 3, ≥ 12 to < 18 
years.  The latest PK/PD model (Run6_023) utilizes data from 31 adults and 7 paediatric HSCT-
TMA patients dosed with nomacopan. 
 
The model includes inter-individual variability on clearance rate of nomacopan (CLnom), 
volume of intravascular compartment for C5 and nomacopan (Vint), rate constant for transfer of 
nomacopan from sc injection site to intravascular compartment (Ka), and concentration of free 
nomacopan in intravascular compartment at which CH50 is reduced to 50% of baseline value 
(EC50).  These are the 4 parameters where inter-individual variability was demonstrated to be 
the most significant and was quantified during the model-building process.  The model also 
includes a description of the influence of maturation of the estimated glomerular filtration rate 
(eGFR) on clearance of nomacopan. 
 
Based on the model’s outputs, paediatric ablation and maintenance dosing will use sc injections 
of nomacopan twice a day (12 hours apart) to ensure total inhibition of TCA, with the three age 
categories receiving ablating doses between 1.0 and 1.7 mg/kg, and an initial maintenance dose 
of 0.30 mg/kg (see Table 3 and text below for details). 
 
As described in more detail below, these dosing regimens are predicted to ablate TCA measured 
by CH50 ELISA within 18 hours of the first dose of nomacopan and maintain CH50 < 3% of 
baseline in approximately 99% of patients. 
 
To select age based dosing regimens for Part A of the trial the model was used to simulate a 
range of ablating doses and maintenance doses in 1000 virtual paediatric patients randomly 
sampled from the NHANESIII database30. 
 

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The ablating dose predicted to reduce TCA to 3% or less of baseline by 18h in 97.5% of the 
paediatric patients in each age category was determined (Table 3).  Similarly, the 12-hourly 
maintenance dose predicted to reduce TCA to 3% or less of baseline value in 99% of the 
paediatric patients at steady state in each age category was selected as the standard starting dose 
- this turned out to be 0.3 mg/kg in all three age categories (Table 3). 
 
Larger simulations (10000 virtual paediatric patients) were undertaken to identify those few 
patients whose TCA is not essentially fully inhibited on the starting dose.  Further maintenance 
dose simulations in this subset of patients were undertaken to identify two dose escalations for 
patients for whom the standard maintenance dosing regimen (0.3 mg/kg) fails to provide 
sufficient complement inhibition at steady state.  With failure to provide sufficent terminal 
complement inhibition defined as CH50 U Eq/mL ≥ 10 or concentration of free nomacopan 
< 55µg/L.  The simulations suggested maintenance dose escalations to either 0.45 mg/kg or 
0.6 mg/kg (the highest permitted 12-hourly dose) should provide near complete control of 
systemic TCA in almost all patients. 
 
Table 3 
Summary of Recommended Paediatric Dosing Regimens 
Age Range 
(Years) 
Recommended Ablation 
Dosing Regimen 
Recommended Maintenance Dosing 
Regimen 
 
 
 
≥ 0.5 to < 2 
1.7 mg/kg at 0 and 12 h 
0.30 mg/kg at 24 h, & every 12 h thereafter 
≥ 2 to < 12 
1.3 mg/kg at 0 and 12 h 
0.30 mg/kg at 24 h, & every 12 h thereafter 
≥ 12 to < 18 
1.0 mg/kg at 0 and 12 h 
0.30 mg/kg at 24 h, & every 12 h thereafter 
 
 
 
 
To simulate PK/PD exposure metrics during maintenance dosing at steady state, 1000 virtual 
paediatric patients were randomly sampled from the NHANESIII database30.  Simulations were 
executed using Run6_023 with inclusion of inter-individual variability for CLnom, Vint, Ka and 
EC50.  The Ka value used was that for diseased subjects, since during model refinement Ka 
was found to be significantly lower in diseased adult and paediatric subjects than in healthy 
subjects.  C5 concentration and CH50 at baseline in each virtual patient were sampled from log-
normal distributions with means and standard deviations estimated from the baseline C5 
concentration and CH50 from all subjects (n = 38) in the nomacopan PK/PD modelling data 
file.  Steady state values were assured by running the simulation through 21 days of dosing. 
 
All exposure metrics listed in Table 4 are quoted as geometric mean, with exception of Tmax 
which is given as median.  Values in parentheses give the range from the 5th to 95th percentile 
of the results from the 1000 virtual patients.  The median is preferred to the arithmetic mean 
because PK-related parameters except Tmax are log normally distributed. 
 
Table 4 shows that at steady state nomacopan administered subcutaneously enters paediatric 
patients circulation relatively rapidly with free nomacopan levels peaking (Tmax,ss) about 3.5 
hour after administration depending on the age category.  Once it has entered the circulation, 
free nomacopan has a short half-life when it is not bound to C5 (estimated at less than 30 
minutes in man), the level of free nomacopan then declines to Cmin immediately prior to the 
next dose.  The relatively prolonged action of the drug is due to the gradual entry of nomacopan 
from the sc site of administration into the circulation. 
 
When considering nomacopan dosing regimens, a critical value is the lowest concentration of 
free nomacopan that ensures that C5 that is essentially completely bound by nomacopan which 
therefore cannot be activated by the alternative and classical/lectin complement C5 convertases.  
This threshold concentration of free nomacopan that inhibits TCA by 95% is estimated at a 

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geometric mean of 12.1µg/L in both adults and pediatrics.  To maintain control of TCA by 95% 
or more (free C5 less than 5% of baseline at trough) this threshold value must be exceeded at 
Cmin ie immediately before receiving the next dose.  Table 4 (last row) shows that the majority 
(> 97.9%) of both adult and paediatric patients exceed the threshold. 
 
Thus at the recommended dosing for adult and paediatric patients, at steady state nomacopan 
0.3 mg/kg should provide full control of TCA in paediatric patients. 
 
A second consideration in selection of dose is to ensure that the concentration of nomacopan 
stays above the threshold that inhibits TCA by 95% even when the drug is not administered at 
exactly the same time each day.  As shown in Table 4 in paediatric patients at steady state the 
median time until free C5 exceeds 5% (equivalent to TCA of 5%) is between 51 and 57 hours 
(age dependent) in pediatrics with 5th to 95th centile range of 28 to 116 hours.  Thus, on the 
recommended doses most patients have a window of at least 3 hours each day in which to dose 
themselves to maintain essentially complete control of complement activity. 
 
Table 4 
Paediatric PKPD Exposure Metrics 
Paediatric PKPD exposure metrics, drug concentration thresholds for inhibition, duration of action and 
proportion of population expected to have TCA inhibited by more than 95% for three age cohorts 
dosed with age specific ablating doses and a fixed maintenance dose of 0.3mg/kg 
 
 
Age Category 1 
(≥ 0.5 to < 2 years) 
Ablating 1.7 mg/kg 
Age Category 2 
(≥ 2 to < 9 years) 
Ablating 1.3 mg/kg 
Age Category 3 
(≥ 9 to < 18 years) 
Ablating 1.0 mg/kg 
 
 
 
 
Free nomacopan Cmax,ss [µg/L] 
166.3 
(81.1 - 350.2) 
152.7 
(71.3 - 310.4) 
152.6 
(72.9 - 325.3) 
Free nomacopan Tmax,ss [h] 
3.4 
(3.2 - 3.7) 
3.3 
(3.1 - 3.6) 
3.3 
(3.1 - 3.5) 
Free nomacopan  Cmin,ss [µg/L] 
119.7 
(56.2 - 256.4) 
109.3 
(48.9 - 229.8) 
112.7 
(52.6 - 243.4) 
Threshold of free nomacopan that 
inhibits C5 by 95% (at steady state) 
[µg/L] 
12.11 
(12.00 - 12.22) 
12.12 
(12.01 - 12.20) 
12.13 
(12.03 - 12.21) 
Elapsed time after dose administration 
until free C5 concentration exceeds 5% 
of baseline value [h] 
51.3 
(28.9 - 98.5) 
51.6 
(27.6 - 97.3) 
57.3 
(31.4 - 115.6) 
Simulated percent of patient population 
with free C5 < 5% of baseline at steady 
state trough [%] 
100.0 
100.0 
100.0 
 
 
 
 
 
Once daily repeat dose toxicology studies in mice (1, 3 and 6 months) and NHP (1 month) have 
been performed using doses of up to 6.5 mg/kg (mouse, 6 months) and 4.8mg/kg (NHP, 1 
month).  On a weight basis, this is 22 times (mice) and 16 times (NHP) more nomacopan as a 
single dose than the starting paediatric maintenance dose of 0.3mg/kg.  To determine actual 
exposure to nomacopan, empirical data on free drug levels and TCA in the NHP dosed at 
4.8 mg/kg qd for 28 days was used re-parameterise the human PK/PD model for nomacopan 
permitting an estimate of free nomacopan Cmax, and Cmin.  Comparison of these values with the 
same values derived from paediatric patients under the dosing regimen proposed for AK580 
showed that Cmax of free nomacopan is similar (circa 1.6 times higher in NHP than paediatric 
patients), and thus the 1 month toxicology findings in non-human primates provide a valid 
reference for anticipated safety paediatric patients (Table 5). 

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Table 5 
Safety Factor Calculation - maintenance dosing 
PK Parameter 
Non-Human 
Primate* 
Paediatric  
Human 
Minimum Safety 
Factor 
 
 
 
 
Cmax,ss [µg/L] 
267.4 
(236.0 - 302.5) 
152.6 - 166.3 
(71.3 - 350.2) 
1.61 
 
Cmin, ss [µg/L] 
49.6 
(38.3 - 61.5) 
109.3 – 119.7 
(48.9 – 256.4) 
0.41 
 
 
 
 
 
*NHP predictions made with an earlier version of PKPD model 
 
It was not possible to derive exposure data from the long-term mouse toxicology studies 
because blood samples were not taken at sufficiently short intervals after dosing.  However, 
Akari recognise that this exposure data is important and have undertaken a study in the same 
strain of mice as used for the long-term mouse toxicology studies to evaluate PKPD.  The 
expectation from these studies is that mice dosed sc at 6.6 mg/kg will have a very high Cmax 
due to rapid absorption and relatively small AUC due to rapid elimination of unbound 
nomacopan by mice.  When they have been processed, these data will be presented in the 
Investigator’s Brochure.  
 
The duration of dosing with nomacopan in the paediatric HSCT-TMA study is expected to be 
no longer than the longest repeat dose toxicology study in mice (6 months).  In man, 9 PNH 
patients have been chronically dosed with nomacopan for more than 2 years each and the drug 
has been safe and well tolerated.  HSCT-TMA patients will be dosed with the drug until the 
treating clinician considers there is no further need for treatment with nomacopan or for up to 
a maximum 24 weeks.  In studies with eculizumab for treatment of HSCT-TMA, if patients 
resolve the clinical symptoms of TMA they usually do so within 2 - 4 months of starting 
treatment. 
 
 
4 
TRIAL OBJECTIVES AND ENDPOINTS 
 
4.1 
TRIAL OBJECTIVES 
 
Part A (7 patients aged ≥ 0.5 to < 18 years, in three age range cohorts) 
 
Dose algorithm confirmation:  
▪ 
To confirm the effective dose of nomacopan for ablation of TCA.  The data derived 
from Part A of the trial will be used together with existing data for PK/PD simulation 
modelling to define an age-based dosing regimen to completely control complement 
activity in paediatric patients treated with nomacopan in Part B. 
 
Efficacy: 
▪ 
 Primary, secondary, safety and exploratory objectives as described under Part B. 
 

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Part B (up to 65 patients aged ≥ 0.5 to < 18 years) 
 
Objectives: 
 
Efficacy: 
▪ 
To determine that the age-based dosing regimen defined in Part A can completely 
control complement activity in paediatric patients treated with nomacopan. 
 
Safety: 
▪ 
To evaluate safety and tolerability of nomacopan 
 
4.2 
ENDPOINTS (PARTS A AND B) 
 
4.2.1 Composite Primary Endpoint 
 
▪ 
RBC transfusion independence† for ≥ 28 days immediately prior to any scheduled 
clinical visit up to Week 24 
 
or 
▪ 
Urine protein creatinine ratio ≤ 2 mg/mg for ≥ 28 days immediately prior to any 
scheduled clinical visit up to Week 24 
 
 
4.2.2 Secondary Endpoints (Efficacy) 
 
▪ 
Percentage of patients who achieve the primary endpoint of urine protein creatinine ratio 
≤ 2 mg/mg (the nephrotic threshold) for ≥ 28 days  
▪ 
Platelet transfusion independence† for ≥ 28 days. 
▪ 
Plasma sC5b-9 ≤ ULN  
▪ 
Lactate dehydrogenase (LDH) ≤ULN  
▪ 
Normalization of haptoglobin  
 
The sC5b-9, LDH and haptoglobin will be measured at the last efficacy assessment in the trial 
before nomacopan treatment is stopped. 
 
†Transfusion independence is defined as no RBC or platelet transfusion attributable to, or 
required to manage, TMA.  Transfusion required for causes other than TMA will not be 
considered within evaluation of endpoints.  
 
4.2.3 Safety Endpoints 
 
▪ Safety and tolerability of nomacopan 
 
4.2.4 Exploratory Endpoints 
 
▪ 
Overall survival at Week 24 after the first dose of nomacopan, and at one year and two 
years after HSCT. 
▪ 
To evaluate the percentage of patients with urine protein creatinine ratio ≤ 1.5 mg/mg 
for ≥ 28 days. 
▪ 
To evaluate the percentage of patients with urine protein creatinine ratio ≤ 1 mg/mg for 
≥ 28 days. 

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▪ 
Renal function monitoring (urea, serum creatinine, urine protein creatinine ratio, 
proteinuria < 30 mg/dL, and eGFR) at baseline and at one year and two years after 
HSCT. 
 
 
5 
TRIAL POPULATION 
 
This is a study in paediatric patients who have undergone allogeneic or autologous HSCT and 
develop HSCT-TMA within 1 year of HSCT diagnosed using an adapted version of the 
diagnostic criteria of the Bone Marrow Transplant Clinical Trials Network and International 
Working Group6. 
 
 
5.1 
INCLUSION CRITERIA 
 
1. Aged ≥ 0.5 and < 18 years at the time of diagnosis of TMA. 
2. Undergone allogeneic or autologous HSCT. 
3. TMA diagnosis within a year  of their allogeneic or autologous HSCT. 
4. Clinical diagnosis of TMA with all of the following diagnostic criteria: 
▪ elevated plasma sC5b-9 (80% or more of ULN) 
▪ Urine protein creatinine ratio > 2 mg/mg (demonstrated on two separate morning 
samples, at least one day apart) 
▪ elevated LDH (> ULN) 
▪ thrombocytopaenia (< 50,000 per mm3) 
▪ low haemoglobin concentration (< LLN) 
 
or 
 
Histological diagnosis of TMA with evidence of complement deposition: 
▪ Urine protein creatinine ratio > 2 mg/mg (demonstrated on two separate morning 
samples, at least one day apart), and 
▪ elevated plasma sC5b-9 (80% or more of ULN) 
5. Provision of written informed consent. 
6. Provision of informed assent (where appropriate). 
 
 
5.2 
EXCLUSION CRITERIA 
 
1. Patients weighing less than 5 kg. 
2. Patients with a positive direct Coombs’ test. 
3. Patients who do not receive nomacopan within 21 days of the initial diagnosis of TMA. 
4. Patients having an active systemic or organ system bacterial or fungal infection or 
progressive severe infection (including unresolved or untreated Neisseria meningitidis 
infection and E. coli Shiga toxin) at the time of diagnosis of the TMA. 
5. Grade 4 Acute GVHD (as per the Glucksberg grading system, see section 18.9). 
6. Received eculizumab or any other complement blocker therapy at any time. 
7. Known hypersensitivity to the active ingredient or excipients. 
8. Patients who are pregnant and/or breastfeeding. All females of childbearing potential 
require a negative pregnancy test at screening.   
 
 
5.3 
CONCOMITANT THERAPY 
 
At screening, the PI will ask the patient about any medication that are currently ongoing.  
During the course of the study the PI should discuss medications at each visit.  All concomitant 

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medications, including herbal and vitamin supplements, must be recorded into the electronic 
case report form (eCRF).  Diary cards will be provided for patients on nomacopan not being 
treated in hospital. 
 
In addition, the use of immunosuppressant compounds administered since the diagnosis of 
TMA up to the baseline visit (even if they are not currently prescribed) will be recorded.  
 
5.3.1 Prohibited Medications 
 
The following medications are not allowed while the patient is taking part in this study.  The PI 
should discuss at each visit with the patient. 
 
▪ eculizumab (Soliris®), ravulizumab (Ultomiris®) or any other investigational drug 
that acts directly on the complement system  
▪ Chemotherapeutic agents (not including methotrexate – see permitted medicines 
below)  
▪ Therapeutic Plasma Exchange 
▪ rituximab or any other CD20 blocking agent 
Permitted medications: Prophylaxis for GVHD that is standard of care.  This includes: 
methotrexate, mycophenolate mofetil, corticosteroids and calcineurin inhibitors (ciclosporin, 
tacrolimus, sirolimus) 
 
If any patient has been found to have taken any of these prohibited medications during this trial, 
they should be withdrawn immediately, treatment with nomacopan stopped, and a follow-up 
visit performed 30 days after receiving the last dose of nomacopan.  Withdrawn patients will 
not be replaced. 
 
 
5.4 
MENINGITIS PROPHYLAXIS 
 
It is known that TCA is important in protection against infection by gram negative bacteria 
especially Neisseria31.  Patients taking part in previous trials (in adults) of complement C5 
inhibitors were found to be at greater risk of Neisseria infection, particularly meningococcal 
infection32, and prophylactic treatment is now usual when complement C5 inhibitors are used. 
 
All patients in the study must therefore receive antimicrobial therapy appropriate for N 
meningitidis prophylaxis. This should be commenced, at the latest, on the day of first study 
drug administration and be continued for 7 days after the last dose of nomacopan. 
 
In this study, patients will have received or be receiving immunosuppression therapy, and N. 
meningitidis immunisation should only be used when the investigator evaluates that immune 
function would be adequate for immunisation to be effective, with a positive risk benefit ratio. 
 
If required in the investigator’s judgement, it is suggested that an initial dose of a quadrivalent 
meningitis vaccine and/or Bexsero® vaccine may be given once the patient is fully stabilised 
on nomacopan therapy.  A second dose of Bexsero® meningitis B vaccine should then be given 
between 1 and 2 months later.  In countries in which Bexsero® meningitis B vaccine is not yet 
approved/available, it may be omitted. 
 
 
5.5 
CONTRACEPTION 
 

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There are no specific, identified risks to mother or foetus from nomacopan therapy.  A segment 
1 reproductive toxicology study has been undertaken in mice (YUU0001) to assess the effects 
of 0, 0.5, 5 and 10 mg/kg/day nomacopan on the fertility and early embryonic development of 
the mouse when administered for at least 14 days before and during pairing, and then to Day 6 
of gestation in females and until the day before necropsy for males.  The study reported no 
deaths or clinical signs considered to be associated with the doses of nomacopan test; the causes 
of death for 1 male and 1 female found dead during the study were considered to be unrelated 
to test item administration.  There was no effect of nomacopan on body weight, food intake, 
mating activity, fertility and mating, pregnancy or uterine implantation.  There were no findings 
at necropsy considered to be related to nomacopan and group mean ovary and testes weights 
for animals given the test item were similar to controls.  Until the reproductive toxicology 
studies are completed, patients being treated with nomacopan should be advised to use the 
following precautions against sexual exposure and pregnancy. 
 
Patients who are or become sexually active during the course of the study must use, with their 
partner, two approved methods of highly effective contraception from the time of signing the 
Informed Consent Form (ICF) until 90 days after the last dose of nomacopan.  Females of child-
bearing potential are considered those who have had menarche. 
Two or more of the following methods are acceptable and must include at least one barrier 
method: 
 
▪ 
Hormonal contraception associated with the inhibition of ovulation (implantable, patch, 
oral) 
▪ 
Barrier methods (for male patients, this must be a condom; for female patients, either their 
partner’s use of a condom or the patient’s use of an occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal foam/gel/film/cream/suppository).  Barrier methods 
must be used in conjunction with another method. 
 
Alternatively, true abstinence is acceptable when consistent with the patient’s preferred and 
usual lifestyle.  If a patient is usually not sexually active but becomes active during the course 
of the study, they and their partner should use two of the contraceptive methods listed above.  
Any female patient who becomes pregnant during the course of the trial will be withdrawn from 
the trial. 
 
 
5.5.1 Exposure of Partners During the Study 
 
There is a risk of drug exposure through ejaculate which might be harmful to the sexual 
partners, including pregnant partners of male patients.  Barrier contraception should be used 
throughout the study and for 90 days after the last day of nomacopan administration. 
 
 
5.5.2 Breast Feeding 
 
Female patients should not breast feed infants for the duration of the study and for at least 90 
days after the last day of nomacopan administration. 
 
 
6 
TRIAL DESIGN AND PROCEDURES 
 
6.1 
TRIAL DESIGN 
 
This is an open-label, multi-centre, two-part study. 

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Part A: dose algorithm, safety and efficacy 
To confirm the effective paediatric dosing, by measuring the pharmacokinetic (PK) and 
pharmacodynamic (PD) effect of nomacopan (drug levels, complete inhibition of TCA and 
control of sC5b-9 levels) and clinical safety in 7 paediatric patients with HSCT-TMA for 24 
weeks. 
 
Part B: safety and efficacy 
Following dose algorithm confirmation after Part A, up to 65 HSCT-TMA patients will be 
enrolled in a 24 weeks study to evaluate the efficacy and safety of nomacopan at 4, 8, 12, 16, 
20 and 24 weeks (± 5 days). 
 
 
6.2 
DOSING SCHEME 
 
Nomacopan is provided as an 18 mg/vial powder for solution for injection.  The product will 
be administered sc twice daily.  Indwelling sc catheter systems may be used for administration 
if preferred to individual injections. 
 
The child’s weight taken at Day 1 will determine the dose calculations for the study. For 
children in the youngest two cohorts (≥ 0.5 to < 2 years, and ≥ 2 to < 9 years), the dose will be 
re-calculated at the week 8 and week 16 visits using the child’s new weight measured at that 
visit. 
 
Part A 
 
The following starting dosing regimens (Table 6) will be used for patients in Part A, dependent 
on age category:  
 
Table 6 
Starting Dose for Patients in Part A 
Age Category 
Ablating Dose 
Maintenance Dose 
 
Day 1; two doses 12 hours 
apart 
Day 2 to End of Treatment; 
12 hours apart 
≥ 0.5 to < 2 years 
1.7 mg/kg 
0.30 mg/kg 
≥ 2 to < 9 years 
1.3 mg/kg 
0.30 mg/kg 
≥ 9 to < 18 years 
1.0 mg/kg 
0.30 mg/kg 
 
The dosing regimens shown above are predicted to ablate TCA (measured by CH50 ELISA) 
within 18 hours of the first dose of nomacopan and maintain CH50 < 3% of baseline in 
approximately 99% of patients. 
 
The patients will undergo PK/PD monitoring to assess whether TCA is fully controlled on the 
starting dose (ie CH50 is below LLOQ, and unbound nomacopan ≥ 55 ng/mL in serum). 
 
The predicted maintenance dose for all three age groups is 0.30 mg/kg, and it is anticipated that 
this dose will normally fully inhibit TCA. 
 
Dose Escalation 
 
If required, the dose will be escalated if, at pre-dose on Day 7 or after, provided the CH50 
results have been received, CH50 > 10 U Eq/mL and/or unbound nomacopan in serum is 
< 55 ng/mL.  Dose escalation will consist of a single ablating dose, followed by a higher 0.45 

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mg/kg 12 hourly dose (for all age categories) starting from 12 hours after the ablating dose 
(Table 7). 
 
Table 7 
Initial Dose Increase for Part A 
Age Category 
Ablating Dose 
Maintenance Dose 
 
Day 1 of change to higher dosing; 
one dose then maintenance 
12 hours after ablating dose until 
End of Treatment; 12 hours apart 
≥ 0.5 to < 2 years 
1.7 mg/kg 
0.45 mg/kg 
≥ 2 to < 9 years 
1.3 mg/kg 
0.45 mg/kg 
≥ 9 to < 18 years 
1.0 mg/kg 
0.45 mg/kg 
 
If 7 days or more after dose escalation to 0.45 mg/kg, pre-dose CH50 > 10 U Eq/mL and/or 
unbound nomacopan in serum is < 55 ng/mL, a final higher dose escalation to 0.60 mg/kg is 
permitted (Table 8).  Dose escalation will consist of a single ablating dose, followed by a 
higher 0.6 mg/kg 12-hourly dose (for all age categories) starting from 12 hours after the 
ablating dose. 
 
Table 8 
Second Dose Increase for Part A 
Age Category 
Ablating Dose 
Maintenance Dose 
 
Day 1 of change to higher dosing; 
one dose then maintenance 
12 hours after ablating dose until 
End of Treatment; 12 hours apart 
≥ 0.5 to < 2 years 
1.7 mg/kg 
0.60 mg/kg 
≥ 2 to < 9 years 
1.3 mg/kg 
0.60 mg/kg 
≥ 9 to < 18 years 
1.0 mg/kg 
0.60 mg/kg 
 
In the exceptional situation that the unbound nomacopan in serum is < 30 ng/mL on the starting 
maintenance dose (0.3 mg/kg), the investigator and Sponsor may agree to escalation of the dose 
from 0.3 mg/kg straight to 0.6 mg/kg (bypassing the 0.45 mg/kg) which is the highest permitted 
maintenance dose. 
 
Dose assessments with changing weight measurements 
 
For children in the youngest two cohorts (≥ 0.5 to < 2 years, and ≥ 2 to < 9 years), the dose will 
be re-calculated at the week 8 and week 16 visits using the child’s new weight measured at that 
visit.  The new adjusted dose should be given after all study procedures have been performed. 
This new adjusted dose will not require an ablating dose.  
 
Part B 
 
All patients in Part B will receive an ablating dose of nomacopan on Day 1 and then receive the 
dosing regimen defined following Part A of the study.  It is planned that the starting dose will 
be effective in all patients, but a single higher dosing regimen (to be determined after Part A) 
will be available in the unexpected event that CH50 is not < LLOQ and/or free nomacopan is 
<55 ng/mL at any time from Day 7 onwards. 
 
 
6.3 
BLOOD SAMPLE VOLUMES FOR PAEDIATRIC PATIENTS 
 
The volume of blood taken from patients in this study will be monitored very carefully. 
 

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Calculations of blood volumes that may be taken from the youngest female patient permitted 
to enter the trial are provided in Section 18, Appendix 18.8.  The 6-month-old female would 
have an average weight of 7.3 kg and an average blood volume of 584 mL.  The greatest relative 
amount of blood would be taken in the unlikely event that the patient received two dose 
increases as permitted in Part A of the protocol. 
 
Older patients and Part B patients (who will have PKPD sampled less frequently) will have a 
smaller % of their blood sampled. 
 
To ensure compliance with guidelines, sites will monitor and record the total blood volume 
taken during this trial. 
 
 
6.4 
TRIAL OVERVIEW, PROCEDURES AND PATIENT COMPLIANCE (PARTS A AND B) 
 
Initiation of nomacopan treatment will be at the investigator’s clinic with nurses administering 
the sc injections initially.  Prior to discharge (if any), the nurses will train the patient (or the 
individual who will be administering the drug) on how to store, prepare and administer 
nomacopan, as well as guidance on what to do if a dose is missed. Patients will be provided 
with diary cards to complete when administering study drug at home. 
 
Study drug will be administered 12 hours apart, with a morning and an evening dose. 
 
The treatment period for nomacopan will be no longer than 24 weeks.  Patients may come off 
the drug sooner if one or both components of the primary endpoint have been met and the 
treating clinician considers there is no longer a need for continuing treatment with nomacopan.  
These patients who have stopped nomacopan will complete the end of study assessments and 
are then required to attend the 30-day follow-up visit, the 24-week visit (limited assessments) 
and the year 1 and 2 visit.   
 
Patients who have achieved one or both components of the primary endpoint prior to week 24 
but who remain treated with nomacopan will continue to receive 4-weekly assessments until 
Week 24 and are required to attend the 30-day follow up visits and attend the year 1 and 2 visits. 
 
In exceptional circumstances where the investigator requests continuation of nomacopan 
beyond 24 weeks for clinical reasons, the Sponsor may agree to supply nomacopan for an 
additional 12 week period. Any patients on nomacopan after week 24 will have safety assessed 
every 4 weeks while on the drug and will attend a safety follow-up 30 days (± 5 days) after the 
last dose (see SOEs in Appendix 18.7). 
 
6.4.1 Screening (up to 21 days, Parts A and B) 
 
The maximum period between the screening visit and starting study drug is 21 days.  However, 
the intent is to start study drug as soon as possible once diagnosis of HSCT-TMA has been 
confirmed. 
 
At the screening visit the following assessments will be performed: 
 
A record of all screened patients will be kept, with the date the screening assessment was 
performed, and whether or not the patient was eligible.  If the patient was not eligible for study 
entry, or did not wish to participate, the reason will be recorded.  Informed consent will be 
obtained and where appropriate, informed assent will be obtained. 
 

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Medical History & Prior Medication (including transfusions): any relevant medical history and 
prior medications along with start and stop dates (if appropriate) will be recorded. 
 
Details of all RBC or platelet transfusions given in the 30 days prior to enrolment should also 
be recorded. It should be determined whether these transfusions were TMA-related. 
 
Demography: date of birth, sex, race and ethnicity will be recorded. 
 
Physical Exam: a physical exam will be performed, and any abnormal results recorded along 
with an assessment of the clinical significance of any abnormality.  A complete physical 
examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, 
neurological system, lungs, cardiovascular system, abdomen (liver and spleen), lymph nodes, 
and extremities.  If clinically significant, further details should be provided.  An assessment of 
GVHD will also be performed. 
ECG: 12-lead ECG at screening only. Findings to be recorded as clinically significant or non-
clinically significant.  
 
Vital signs: weight, height, temperature, pulse rate, respiratory rate and systolic and diastolic 
blood pressures will be recorded.  Vital signs are to be taken while the subject is in a supine 
position, having rested in this position for at least five minutes.  Measurements are to be 
repeated if clinically significant changes are observed or a machine error occurs. 
 
Nasal and throat swabs:  nasal and throat swabs will be taken locally, and assays performed to 
identify any active infection.  Results from the swabs will not be used to confirm eligibility for 
study entry.   
 
Blood samples: blood samples for haematology and chemistry will be taken for assay at the 
local laboratory, and blood samples for direct Coombs’ Test, ADAMTS13, sC5b-9 and a serum 
pregnancy test for all females of childbearing potential will be taken for assay at the local or 
central laboratory. 
 
Urine samples: urine samples (morning urine) will be taken for urine protein creatinine ratio 
(UPCR) and protein. 
 
Adverse events: once the informed consent form is signed all adverse events beyond that point 
will be recorded. 
 
6.4.2 Part A 
 
Day 1 Pre-dose: Physical examination (including GVHD assessment) and vital sign assessment 
will be performed, and any adverse events and concomitant medications recorded.  Pre-dose 
samples for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, anti-drug 
antibodies (ADA), LTB4 (urine), sC5b-9, and C3b.  Urinalysis (morning urine), for UPCR and 
protein will also be performed. 
 
Additional blood samples for efficacy (CH50) and PK assessments will be taken at 3 and 6 
hours after the first ablating dose, and at 12 hours (immediately prior to the second ablating 
dose of nomacopan).  If the 12-hour samples cannot be taken for logistical reasons, then 9-hour 
samples can be taken.  Any AEs and concomitant medications will be recorded at these time 
points. 
 

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An additional vital sign assessment will be performed at 12 hours (immediately prior to the 
administration of the second ablating dose of nomacopan).  Any AEs and concomitant 
medications will be recorded. 
 
Day 2: Immediately prior to the morning study drug administration, vital signs (temperature, 
pulse rate, respiratory rate and systolic and diastolic blood pressures) will be recorded.  Pre-
dose samples for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5 and 
sC5b-9.  Urinalysis (morning urine), for UPCR and protein will also be performed.  Any AEs 
and concomitant medications will be recorded. 
 
Additional blood samples for efficacy (CH50) and free nomacopan levels (PK) assessments 
will be taken at 6 and 12 hours after the morning dose.  If the 12-hour samples cannot be taken 
for logistical reasons, then 9-hour samples can be taken.  Any AEs and concomitant medications 
will be recorded at these time points. 
 
Day 3: Immediately prior to the morning study drug administration, samples will be taken for 
CH50 and free nomacopan levels (PK).  These samples will NOT be taken for the youngest age 
cohort.  Any AEs and concomitant medications will be recorded. 
 
Day 4: Immediately prior to the morning study drug administration, pre-dose samples for 
haematology, chemistry, CH50, nomacopan drug levels (PK) and total C5, sC5b-9.  Urinalysis 
(morning urine), for UPCR and protein will also be performed.  Any AEs and concomitant 
medications will be recorded. 
 
Day 7 (± 1 day): Immediately prior to the morning study drug administration physical 
examination (including GVHD assessment) and vital sign assessment will be performed, and 
pre-dose samples for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, 
anti-drug antibodies (ADA), LTB4 (urine), sC5b-9, and C3b will be taken.  Urinalysis (morning 
urine), for UPCR and protein will also be performed.  Any AEs and concomitant medications 
will be recorded. 
 
Additional blood samples for efficacy (CH50) and PK assessments will be taken at 3, 6, 12 
hours after the morning dose, (immediately prior to the next dose of nomacopan).  In the 
youngest age cohort samples will be taken pre-dose at 3 and 12 hours only.  If the 12-hour 
samples cannot be taken for logistical reasons, then 9-hour samples can be taken.  Any AEs and 
concomitant medications will be recorded at these time points. 
 
Drug accountability to be undertaken. 
 
Day 11 (± 1 day): Immediately prior to the morning study drug administration a vital sign 
assessment and urinalysis (morning urine), for UPCR and protein will also be performed.  Any 
AEs and concomitant medications will be recorded. 
 
Day 14 (± 1 day): Immediately prior to the morning study drug administration, pre-dose 
samples for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, anti-drug 
antibodies (ADA), LTB4 (urine), sC5b-9, and C3b.  Urinalysis (morning urine), for UPCR and 
protein will also be performed.  AEs and concomitant medications will be recorded, and drug 
accountability undertaken. 
 
Week 4 (Day 28 (± 5 days)): Prior to the morning dose a physical examination (including 
GVHD assessment) and vital sign assessment will be performed.  Pre-dose samples for 
haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), 

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sC5b-9, and C3b.  Urinalysis (morning urine), for UPCR and protein will also be performed.  
A urine pregnancy test for females of childbearing potential will be taken. 
 
Any AEs and concomitant medications will be recorded, and drug accountability undertaken. 
 
Additional blood samples for CH50 and PK assessments will be taken at 3, 6 and 12 hours 
(immediately prior to the next dose of nomacopan) after the morning dose.  In the youngest age 
cohort samples will be taken pre-dose at 3 and 12 hours only.  If the 12-hour samples cannot be 
taken for logistical reasons, then 9-hour samples can be taken.  Any AEs and concomitant 
medications will be recorded at these time points.  
 
Week 8 (± 5 days): Prior to the morning dose a physical examination (including GVHD 
assessment) and vital sign assessment will be performed.  Pre-dose samples for haematology, 
chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), sC5b-9, and C3b.  
Urinalysis (morning urine), for UPCR and protein will also be performed.  A urine pregnancy 
test for females of childbearing potential will be taken. 
 
Any AEs and concomitant medications will be recorded, and a drug accountability undertaken. 
 
For children in the youngest two cohorts (≥ 0.5 to < 2 years, and ≥ 2 to < 9 years), the dose will 
be re-calculated using the child’s new weight measured at that visit. The new adjusted dose 
should be given after all study procedures have been performed. This new adjusted dose will 
not require an ablating dose. 
 
Week 12 (± 5 days): Prior to the morning dose a physical examination (including GVHD 
assessment) and vital sign assessment will be performed.  Pre-dose samples for haematology, 
chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), sC5b-9, and C3b.  
Urinalysis (morning urine), for UPCR and protein will also be performed.  A urine pregnancy 
test for females of childbearing potential will be taken. 
 
AEs and concomitant medications will be recorded, and a drug accountability undertaken. 
 
Week 16 (± 5 days): Prior to the morning dose a physical examination (including GVHD 
assessment) and vital sign assessment will be performed.  Pre-dose samples for haematology, 
chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), sC5b-9, and C3b.  
Urinalysis (morning urine), for UPCR and protein will also be performed.  A urine pregnancy 
test for females of childbearing potential will be taken. 
 
AEs and concomitant medications will be recorded, and drug accountability undertaken. 
 
For children in the youngest two cohorts (≥ 0.5 to < 2 years, and ≥ 2 to < 9 years), the dose will 
be re-calculated using the child’s new weight measured at that visit.  The new adjusted dose 
should be given after all study procedures have been performed.  This new adjusted dose will 
not require an ablating dose. 
 
Week 20 (± 5 days): Prior to the morning dose a physical examination (including GVHD 
assessment) and vital sign assessment will be performed.  Pre-dose samples for haematology, 
chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), sC5b-9, and C3b.  
Urinalysis (morning urine), for UPCR and protein will also be performed.  A urine pregnancy 
test for females of childbearing potential will be taken. 
 
AEs and concomitant medications will be recorded, and drug accountability undertaken. 
 

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Week 24 (± 5 days) - the last dosing day: Prior to the morning dose a physical examination 
(including GVHD assessment) and vital sign assessment will be performed.  Pre-dose samples 
for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), 
sC5b-9, and C3b.  Urinalysis (morning urine), for UPCR and protein will also be performed.  
A urine pregnancy test for females of childbearing potential will be taken. 
 
Any AEs and concomitant medications will be recorded, and drug accountability undertaken.   
 
Week 24 (± 5 days). Limited assessments – for all patients who completed dosing with 
nomacopan before 24 weeks and completed end of study procedures: A physical 
examination and vital sign assessment will be performed (including GVHD assessment), blood 
samples for haematology and chemistry, and urinalysis (morning urine) for UPCR and protein 
will also be performed.  AEs and concomitant medications will be recorded.  If the patient 
received study drug less than a week prior to this visit, then samples for CH50, nomacopan drug 
levels (PK), total C5, ADA, LTB4 (urine), sC5b-9, and C3b will also be taken. 
 
Safety Follow-up - 30 days (±5 days) after the last dose of nomacopan: The patient will 
attend the clinic for a physical examination (including GVHD assessment), assessment of vital 
signs, and blood samples will be taken for haematology, chemistry.  Urinalysis (morning urine), 
for UPCR and protein will also be performed.  A urine pregnancy test for females of 
childbearing potential will be performed.  AEs and concomitant medications will be recorded. 
 
One Year (post-HSCT) Follow-up (± 5 days): The patient will attend the clinic for a physical 
exam (including GVHD assessment), assessment of vital signs, and urinalysis (morning urine) 
for UPCR and protein will also be performed.  If the patient has died, the date and cause of 
death will be recorded. 
 
Two Year (post-HSCT) Follow-up (± 5 days): The patient will attend the clinic for a physical 
exam (including GVHD assessment), assessment of vital signs, and urinalysis (morning urine), 
for UPCR and protein will also be performed.  If the patient has died, the date and cause of 
death will be recorded. 
 
Unscheduled Visits: A physical exam (including GVHD assessment) and vital sign assessment 
will be performed, and urinalysis (morning urine) for UPCR and protein will also be performed.  
Any AEs and concomitant medications will be recorded.  Any other procedures are at the 
Investigators discretion. 
 
Early Withdrawal: Should a patient be withdrawn from the study, all end of study procedures 
should be performed. 
 
6.4.3 Part B 
 
Day 1 Pre-dose: A physical examination (including GVHD assessment) and vital sign 
assessment will be performed.  Pre-dose samples for haematology, chemistry, CH50, 
nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), sC5b-9, and C3b.  Urinalysis 
(morning urine) for UPCR and protein will also be performed.  AEs and concomitant 
medications will be recorded. 
 
An additional vital sign assessment will be performed at 12 hours (immediately prior to the 
administration of the second ablating dose of nomacopan).  Any AEs and concomitant 
medications will be recorded. 
 

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Day 2: Immediately prior to the morning study drug administration, vital signs (temperature, 
pulse rate, respiratory and systolic and diastolic blood pressures) will be recorded. Pre-dose 
samples for CH50, nomacopan drug levels (PK), total C5 and sC5b-9.  Urinalysis (morning 
urine) for UPCR and protein will also be performed.  AEs and concomitant medications will be 
recorded. 
 
Day 7 (± 1 day): Immediately prior to the morning study drug administration a physical exam 
(including GVHD assessment) and a vital sign assessment will be performed.  Pre-dose samples 
for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), 
sC5b-9, and C3b.  Urinalysis (morning urine) for UPCR and protein will also be performed.  
AEs and concomitant medications will be recorded, and drug accountability undertaken. 
 
Day 14 (± 1 day): Immediately prior to the morning study drug administration a physical exam 
(including GVHD assessment) and a vital sign assessment will be performed.  Pre-dose samples 
for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), 
sC5b-9, and C3b.  Urinalysis (morning urine) for UPCR and protein will also be performed.  
AEs and concomitant medications will be recorded, and drug accountability undertaken. 
 
Week 4 (± 5 days)): Immediately prior to the morning study drug administration a physical 
exam (including GVHD assessment) and a vital sign assessment will be performed.  Pre-dose 
samples for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, 
LTB4 (urine), sC5b-9, and C3b.  Urinalysis (morning urine) for UPCR and protein will also be 
performed.  AEs and concomitant medications will be recorded, and drug accountability 
undertaken.  A urine pregnancy test for females of childbearing potential will be taken. 
 
Week 8 (± 5 days): Immediately prior to the morning study drug administration a physical 
exam (including GVHD assessment) and a vital sign assessment will be performed.  Pre-dose 
samples for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, 
LTB4 (urine), sC5b-9, and C3b.  Urinalysis (morning urine) for UPCR and protein will also be 
performed.  AEs and concomitant medications will be recorded, and drug accountability 
undertaken.   A urine pregnancy test for females of childbearing potential will be taken. 
 
Week 12 (± 5 days): Immediately prior to the morning study drug administration a physical 
exam (including GVHD assessment) and a vital sign assessment will be performed.  Pre-dose 
samples for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, 
LTB4 (urine), sC5b-9, and C3b.  Urinalysis (morning urine) for UPCR and protein will also be 
performed. AEs and concomitant medications will be recorded, and drug accountability 
undertaken.   A urine pregnancy test for females of childbearing potential will be taken. 
 
Week 16 (± 5 days): Immediately prior to the morning study drug administration a physical 
exam (including GVHD assessment) and a vital sign assessment will be performed.  Pre-dose 
samples for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, 
LTB4 (urine), sC5b-9, and C3b.  Urinalysis (morning urine) for UPCR and protein will also be 
performed.  AEs and concomitant medications will be recorded, and drug accountability 
undertaken.  A urine pregnancy test for females of childbearing potential will be taken. 
 
Week 20 (± 5 days): Immediately prior to the morning study drug administration a physical 
exam (including GVHD assessment) and a vital sign assessment will be performed.  Pre-dose 
samples for haematology, chemistry, CH50, nomacopan drug levels (PK), total C5, ADA, 
LTB4 (urine), sC5b-9, and C3b.  Urinalysis (morning urine) for UPCR and protein will also be 
performed.  AEs and concomitant medications will be recorded, and drug accountability 
undertaken.  A urine pregnancy test for females of childbearing potential will be taken. 
 

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Week 24 (± 5 days) - the last dosing day: Immediately prior to the morning study drug 
administration a physical exam (including GVHD assessment) and a vital sign assessment will 
be performed.  Pre-dose samples for haematology, chemistry, CH50, nomacopan drug levels 
(PK), total C5, ADA, LTB4 (urine), sC5b-9, and C3b.  Urinalysis (morning urine) for UPCR 
and protein will also be performed.  AEs and concomitant medications will be recorded, and 
drug accountability undertaken.  A urine pregnancy test for females of childbearing potential 
will be taken.  
 
Week 24 (± 5 days), Limited assessments – for all patients who completed dosing with 
nomacopan before 24 weeks and completed all the final study procedures: A physical 
examination (including GVHD assessment) and a vital sign assessment will be performed.  
Blood samples for haematology and chemistry, and urinalysis (morning urine) for UPCR and 
protein will also be performed.  Any AEs and concomitant medications will be recorded.  If the 
patient received study drug less than a week prior to this visit, then samples for CH50, 
nomacopan drug levels (PK), total C5, ADA, LTB4 (urine), sC5b-9, and C3b) will also be 
taken. 
 
Safety Follow-up - 30 days (± 5 days) after the last dose of nomacopan: The patient will 
attend the clinic for a physical examination (including GVHD assessment), assessment of vital 
signs, and blood samples will be taken for haematology, chemistry, and urinalysis (morning 
urine) for UPCR and protein will also be performed.  A urine pregnancy test for females of 
childbearing potential will be performed.  Any AEs and concomitant medications will be 
recorded, and drug accountability undertaken. 
 
One Year (post-HSCT) Follow-up (± 5 days): The patient will attend the clinic for a physical 
exam (including GVHD assessment), assessment of vital signs, and urinalysis (morning urine) 
for UPCR and protein will also be performed.  If the patient has died, the date and cause of 
death will be recorded. 
 
Two Year (post-HSCT) Follow-up (± 5 days): The patient will attend the clinic for a physical 
exam, (including GVHD assessment) assessment of vital signs, and urinalysis (morning urine), 
for UPCR and protein will also be performed.  If the patient has died, the date and cause of 
death will be recorded. 
 
Unscheduled Visits: A physical examination (including GVHD assessment) and vital sign 
assessment will be performed, and urinalysis (morning urine), for UPCR and protein will also 
be performed.  Any AEs and concomitant medications will be recorded.  Any other procedures 
are at the Investigators discretion. 
 
Early Withdrawal: Should a patient be withdrawn from the study all end of study procedures 
should be performed. 
 
 
6.4.4 Dose Increase Part A – if required  
 
Day n:  Prior to the ablating dose, samples for CH50, nomacopan drug levels (PK) and 
urinalysis (morning urine) for UPCR and protein will also be performed.  AEs and concomitant 
medications will be recorded. 
 
Additional blood samples for CH50 and nomacopan drug levels (PK) will be taken at 3, 6 and 
12 hours (ie immediately prior to the second dose of nomacopan) after the first ablating dose.  
AEs and concomitant medications will be recorded. 
 

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Day n+1:  Prior to the maintenance dose, samples for CH50, nomacopan drug levels (PK) and 
urinalysis (morning urine) for UPCR and protein will also be performed. 
 
Additional blood samples for CH50 and nomacopan drug levels (PK) will be taken at 6 and 12 
hours after the first morning maintenance dose.  AEs and concomitant medications will be 
recorded. 
 
Day n+2:  Prior to the maintenance dose, samples for CH50, nomacopan drug levels (PK) and 
urinalysis (morning urine) for UPCR and protein will also be performed.  AEs and concomitant 
medications will be recorded. 
 
Day n+6 (± 1 day):  Prior to the maintenance dose, samples for haematology and chemistry, 
CH50, nomacopan drug levels (PK) and urinalysis (morning urine) for UPCR and protein will 
also be performed. 
 
Additional blood samples for CH50 and nomacopan drug levels (PK) will be taken at 3, 6 and 
12 hours (ie immediately prior to the second dose of nomacopan) after the first morning 
maintenance dose.  Drug accountability to be undertaken.  AEs and concomitant medications 
will be recorded. 
 
 
6.4.5 Dose Increase Part B – if required 
 
Day n:  Prior to the ablating dose, samples for CH50, nomacopan drug levels (PK) and 
urinalysis (morning urine) for UPCR and protein will also be performed.  AEs and concomitant 
medications will be recorded. 
 
Additional blood samples for CH50 and nomacopan drug levels (PK) will be taken at 12 hours 
prior to the administration of the maintenance dose.  AEs and concomitant medications will be 
recorded. 
 
Day n+1:  Prior to the maintenance dose, samples for CH50, nomacopan drug levels (PK) and 
urinalysis (morning urine), for UPCR and protein will also be performed.  AEs and concomitant 
medications will be recorded. 
 
Day n+6 (± 1 day):  Prior to the maintenance dose, samples for haematology and chemistry, 
CH50, nomacopan drug levels (PK) and urinalysis (morning urine) for UPCR and protein will 
also be performed.  Drug accountability to be undertaken.  Any AEs and concomitant 
medications will be recorded. 
 
 
6.5 
LOCAL LABORATORY TESTS 
 
Part A and Part B 
 
The specified times and measurements of clinical chemistry, haematology and urinalysis are 
the same in Part A and Part B of the trial. 
 
 
6.5.1 Clinical Chemistry Part A and Part B 
 
All samples will be taken as per the Schedule of Events in Section 18. 
 

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The clinical chemistry parameters to be assessed at each specified time point are sodium, 
potassium, calcium, phosphate, urea, creatinine (including eGFR calculation), ALT, AST, 
LDH, GGT, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, and c-reactive 
protein. 
 
All of the above parameters will be assessed by the local laboratory. 
 
eGFR will be calculated by sites using the NIDDK eGFR calculator for children which uses the 
Schwartz calculation33.  The calculation is different depending on the units used for reporting 
creatinine calculations at the local lab.  
 
For mg/dL, use: eGFR (mL/min/1.73 m²) = (0.41 × Height in cm) / Creatinine in mg/dL 
[https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-
evaluation/glomerular-filtration-rate-calculators/children-conventional-units]. 
 
For µmol/L, use: eGFR (mL/min/1.73 m²) = (36.2 × Height in cm) / Creatinine in µmol/L 
[https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-
evaluation/glomerular-filtration-rate-calculators/children-si-units]. 
 
 
6.5.2 Haematology Part A and Part B 
 
All samples will be taken as per the Schedule of Events in Section 18. 
 
The haematology parameters to be assessed at each specified time point are haemoglobin, 
haematocrit, total WBC, neutrophils, lymphocytes, monocytes, basophils, eosinophils, RBC, 
platelets, reticulocytes, haptoglobin and MCV. 
 
All of the above parameters will be assessed by the local laboratory. 
 
The Coombs’ test and ADAMTS13 test are required for screening.  
 
 
6.5.3 Urinalysis Part A and Part B 
 
All samples will be taken as per the Schedule of Events in Section 18. 
 
The urinalysis parameters to be assessed at each time point are UPCR and protein. 
 
The above parameters will be assessed by the local laboratory. 
 
 
6.6 
CENTRAL LABORATORY TESTS 
 
6.6.1 Pharmacodynamics (PD) - CH50 
 
TCA will be measured from serum by CH50 ELISA which measures formation of the terminal 
complement complex.  All samples will be taken as per the Schedule of Events in Section 18.   
 
 

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6.6.2 Pharmacokinetics (PK) 
 
Unbound nomacopan concentration will be measured from serum by ELISA.  All samples will 
be taken as per the Schedule of Events in Section 18. 
 
 
6.6.3 Total C5, sC5b-9 and C3b Assays 
 
All samples will be taken as per the Schedule of Events in Section 18.  All sC5b-9 samples will 
be analysed centrally and measured in plasma. 
 
 
6.6.4 LTB4 (urinary) 
 
All urine samples will be taken as per the Schedule of Events in Section 18. 
For determination of urinary LTB4, 24-hour urine samples will be collected.  Patients should 
NOT be catheterised specifically to allow for the collection of this urine sample.  For patients 
who are not catheterised (for other medical reasons), all urine samples should be collected over 
the defined 24-hour period.  In younger children, where possible, urine from diapers/nappies 
should be collected.   
 
 
6.6.5 Anti-drug Antibodies 
 
All samples will be taken as per the Schedule of Events in Section 18. 
 
6.7 
BLOOD TRANSFUSIONS 
 
Transfusion independence is defined as no RBC or platelet transfusion attributable to, or 
required to manage, TMA.  Transfusion required for causes other than TMA will not be 
considered within evaluation of endpoints.  
 
The Sponsor will not make this evaluation.  The investigator will decide if a transfusion is 
required for the management of TMA or is part of the management of other clinical events or 
part of a site clinical management policy (eg haemoglobin maintenance thresholds, infection 
management), and this assessment will be recorded on the CRF. 
 
Details of all RBC or platelet transfusions given in the 30 days prior to enrolment  
should also be recorded. It should be determined whether these transfusions were TMA-related.  
 
 
6.8 
OTHER ASSESSMENTS 
 
6.8.1 Pregnancy Test 
 
All females who are of childbearing potential must have a serum negative pregnancy test at 
screening.  Where a site is not able to perform a serum pregnancy, a urine pregnancy test will 
be acceptable.  This test will be performed at the local or central laboratory.  A urine pregnancy 
test will be performed every 4 weeks on all females of childbearing potential.  The patient will 
be discontinued from the study if she becomes pregnant during the study and will be followed 
up for health and condition of the baby for 1 year after the childbirth. 
 

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6.9 
SAFETY ASSESSMENTS 
 
6.9.1 Adverse Events 
 
All clinical AEs, defined in Section 8.1 occurring from when the patient has signed the ICF to 
the follow-up period (30 days after last dose of nomacopan), whether observed by the 
investigator or reported by the patient, will be recorded on the AE eCRF page.  Medical 
conditions (including laboratory values/vital signs that are out of range and found clinically 
significant) that exist prior to informed consent will be recorded as part of medical history, 
unless there is a deterioration of the pre-existing condition after baseline, in which case it would 
be an reported as an AE.  
 
All laboratory values and vital signs should be reviewed by the investigator to determine clinical 
significance.  Isolated abnormal laboratory results, vital sign findings, or ECG findings should 
be reported as AEs if they are symptomatic, lead to study drug discontinuation, require 
corrective treatment, or are clinically significant in the opinion of the investigator. 
 
All SAEs are to be reported according to the procedures in Section 8.  Always report the 
diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the primary signs or 
symptoms as the AE or SAE term with additional details included in the SAE narrative until 
the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest a 
common diagnosis, report as individual entries of AE or SAE.  For events that are serious due 
to hospitalisation, the reason for hospitalisation must be reported as the SAE (diagnosis or 
symptom requiring hospitalisation).  Pre-planned (prior to signing the ICF) procedures or 
hospitalisations for pre-existing conditions which do not worsen in severity should not be 
reported as SAEs (see Section 8 for Definitions).  For deaths, the underlying or immediate cause 
of death should always be reported as an SAE.  In addition, any serious, untoward event that 
may occur subsequent to the reporting period that the investigator assesses as related to study 
drug should also be reported and managed as an SAE. 
 
At each visit, the investigator should determine whether any AEs have occurred by evaluating 
the patient.  AEs may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit.  Patients should be questioned in a general way, 
without asking about the occurrence of any specific symptoms.  The investigator must assess 
all AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 8.  The investigator’s assessment must be clearly documented in the site’s source 
documentation with the investigator’s signature. 
 
Investigators should follow patients with AEs until the event has resolved or the condition has 
stabilized.  Unresolved drug related AEs, including significant abnormal laboratory values at 
the end of the study, should be followed until resolution or until no longer clinically relevant. 
 
6.9.2 Medical History and Present Conditions 
 
A complete medical history will include evaluation (past and present) of the following: 
 
General 
Heart/cardiovascular 
Chest/respiratory 
Dermatological/skin 
Past (or plans for future) surgeries Alcohol use or substance abuse 
Neurological/psychiatric 
Haematological/lymphatic 
Abdominal/urogenital 
Endocrine/metabolic 

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Medications 
Smoking 
Allergies/drug sensitivities 
Dialysis History 
 
Details of all RBC or platelet transfusions given in the 30 days prior to enrolment should be 
recorded.  It should be determined whether these transfusions were TMA-related. 
 
 
6.9.3 Physical Examination 
 
A complete physical examination will include assessments of the head, eyes, ears, nose, throat, 
skin, thyroid, neurological system, lungs, cardiovascular system, abdomen (liver and spleen), 
lymph nodes, and extremities.  A GVHD assessment will also be performed during the physical 
examination using the Glucksberg assessment (Appendix 18.9). 
 
 
6.9.4 Vital Signs 
 
Vital sign measurements will be recorded for pulse rate, systolic and diastolic blood pressure, 
respiratory rate, and body temperature.  Vital signs are to be taken while the subject is in a 
supine position, having rested in this position for at least five minutes.  Measurements are to be 
repeated if clinically significant changes are observed or a machine error occurs. 
 
 
6.9.5 Procedures for Clinical Laboratory Samples 
 
All samples will be collected in accordance with acceptable laboratory procedures at the 
timepoints specified in the schedule of events. 
 
Additional, non-genetic, testing may be conducted on retained samples if deemed appropriate 
by the investigator or Sponsor, should research suggest further investigation is required to 
improve disease evaluation and drug response.  Consent for additional, currently undetermined, 
exploratory analysis will be in place prior to further analysis.  The patient may refuse additional 
testing on their retained samples at any point and this will not influence their participation in 
the study. 
 
Additional and repeat blood draws considered necessary for safety and well-being of the patient 
may be performed at the discretion of the investigator. 
 
 
6.10 MISSED DOSES 
 
A missed dose is defined as a dose not taken either two hours before or after the time the patient 
would normally dose.  For example, for a dose scheduled at 07:00 am, the dose can be 
administered between 05:00 am and 09:00 am.  However, it is recommended that the patient is 
normally given their doses at the same time each day. 
 
▪ 
If a dose is missed between 2 and 6 hours after the time the patient should have had a 
scheduled dose, the missed dose should be given as soon as possible.  Subsequent doses 
should continue at the normal schedule. 
▪ 
If a dose is missed between 6 and 12 hours after the time the patient should have had a 
scheduled dose, the missed dose should not be given.  Instead the patient should be given 

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a single ablating dose.  The next scheduled dose should be missed, and then subsequent 
maintenance doses should continue at the normal scheduled times. 
▪ 
If two consecutive doses have been missed, the patient should receive a single ablating 
dose, and subsequent maintenance doses should continue at the normal schedule.  The 
reasons for the missed doses should be discussed, and consideration should be given to 
preventing any further missed doses and maintaining compliance with the protocol. 
 
 
7 
REASON FOR WITHDRAWAL/EARLY DISCONTINUATION 
 
7.1 
TERMINATION OR SUSPENSION OF THE STUDY 
 
The Sponsor may prematurely terminate or suspend the study at any time for the following 
reasons: 
 
▪ 
Safety concerns eg due to occurrence of many serious adverse drug reactions (ADRs) 
▪ 
Achieving the purpose of the study is considered impossible eg due to inadequate 
recruitment of patients 
▪ 
The planned interim analysis in Part B suggests lack of efficacy of the study drug 
 
The Sponsor may prematurely terminate or suspend the study as well at a particular medical 
institution at any time during the course of the study, if major violations/deviations of the 
protocol or other procedures have not been improved or International Committee on 
Harmonisation (ICH) GCP has not been followed. 
 
If the study is prematurely terminated or suspended, the Sponsor should promptly inform the 
Investigators.  The investigator should promptly inform the participating patients and change 
the study medication to other appropriate therapy(ies).  All supplies must be returned. 
 
The investigator may prematurely terminate or suspend the study at their medical institution 
with the agreement of the Sponsor.  This may be done at any time during the study if they 
consider that ensuring patient safety during the study is difficult due to safety concerns (eg 
occurrence of many SAEs). 
 
The party which terminates the study will provide a written statement as to the reason for the 
termination. 
 
The Sponsor will notify Regulatory Authorities, as appropriate of premature terminations.  The 
investigator should promptly inform the corresponding Ethics Committee. 
 
 
7.2 
WITHDRAWAL CRITERIA 
 
In accordance with applicable regulations, a patient has the right to withdraw from the study at 
any time and for any reason without prejudice to their future medical care by the physician or 
at the Institution.  Should a patient withdraw from the study, the patient will not undergo any 
further study-specific procedures or receive any treatment mandated by the protocol. 
 
If a patient fails to attend scheduled trial assessments, the investigator must determine the 
reasons and the circumstances as completely and accurately as possible. 
 

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If an enrolled patient has a positive ADAMTS13 test (< 10%) returned from their screening 
assessment, the patient should be withdrawn from the study and appropriate treatment for TTP 
should be commenced. 
 
In the event of the premature withdrawal of a patient from the trial, all end of study procedures 
should be performed.  In addition, the patient should return for a follow up safety assessment 
after 30 days. 
 
In the case of withdrawal due to the occurrence of unacceptable toxicity, the patient will be 
requested to remain under the supervision of the investigator until the toxicity has resolved or 
is no longer considered to be clinically significant by the investigator. 
 
If an AE classified as severe results in patient withdrawal from the study, the patient will be 
followed until the AE (or SAE) resolves or stabilises, and any interventions required to resolve 
or stabilise the event will be recorded in the eCRF. 
 
All withdrawals must be documented in the eCRF.  A patient may be withdrawn in any of the 
following circumstances: 
 
▪ 
Withdrawal of consent (mandatory withdrawal) 
▪ 
Intake of non-permitted concomitant medications (may be discussed with the Sponsor 
and dependent on the nature of the medication) 
▪ 
Patient is non-compliant with more than three consecutive missed doses and two missed 
clinic visits, in the opinion of the investigator (discretionary withdrawal) 
▪ 
If discontinuation is considered necessary by the investigator and/or Sponsor 
(mandatory withdrawal) 
▪ 
Request of Regulatory Agency (mandatory withdrawal) 
▪ 
Patient develops an illness that would compromise their participation in the study (may 
be discussed with Sponsor) 
▪ 
Patient is not achieving complete inhibition at the maximum assigned dose (inadequate 
response to nomacopan treatment)  
▪ 
Pregnancy. 
 
 
8 
SAFETY REPORTING 
 
8.1 
DEFINITIONS 
 
8.1.1 Adverse Event 
 
Any untoward medical occurrence in a patient or clinical trial patient administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of the study 
medication, whether or not considered related to the study medication. 
 
8.1.2 Adverse Drug Reaction (ADR) 
 
All untoward and unintended responses to an investigational medicinal product related to any 
dose administered.  All cases judged by either the reporting medically qualified professional or 
the Sponsor as having a reasonable suspected causal relationship to the study medication qualify 
as ADRs. 

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8.1.3 Unexpected Adverse Reaction 
 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information that is available (eg in the IB for an unauthorized investigational medicinal product 
or the Summary of Product Characteristics for an authorized product). 
 
 
8.1.4 Serious Adverse Event or Serious Adverse Reaction 
 
Any untoward medical occurrence or effect at any dose that: 
 
▪ 
Results in death, 
▪ 
Is life-threatening,  
▪ 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, 
▪ 
Results in persistent or significant disability/incapacity, or 
▪ 
Is a congenital abnormality / birth defect. 
 
NOTE: Other events that may not result in death, are not life threatening, or do not require 
hospitalisation, may be considered a serious adverse event when, based upon appropriate 
medical judgment, the event may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events include, but 
are not limited to, severe early onset reaction such as anaphylaxis, vasovagal episodes, 
episodes of hypotonia, hyporeactivity or hyperventilation, or convulsions. 
 
Note: Complications that occur during hospitalisation are AEs.  If a complication prolongs 
hospitalisation or fulfils any other seriousness criteria, the event is serious.  Hospitalisation for 
elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
 
All SAEs will be reported to the Sponsor (or designee) within 24 hours of notice of occurrence.  
The Sponsor (or designee) will be responsible for reporting the AE to the appropriate regulatory 
authorities and the ECs within the legally specified period.  It is important to distinguish 
between SAEs and severe AEs.  Severity is a measure of intensity whereas seriousness is 
defined by the criteria above.  An AE of severe intensity need not necessarily be considered 
serious.  For example, a migraine headache that incapacitates a patient for many hours may be 
considered a severe AE, whereas a stroke that results in a limited degree of disability may be 
considered mild but should be reported as an SAE. 
 
8.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 
A serious adverse reaction, the nature or severity of which is not consistent with the applicable 
product information that is available (eg in the IB for an unapproved investigational product or 
the Summary of Product Characteristics for an authorized product). 
 
8.1.6 Treatment Emergent Adverse Events (TEAEs) 
 
Treatment emergent adverse events (TEAEs) are undesirable events not present prior to medical 
treatment, or an already present event that worsens either in intensity or frequency following 
the treatment. 
 

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8.1.7 Adverse Events of Special Interest (AESI) 
 
An adverse event of special interest (AESI) is one of scientific and medical concern given the 
IMP’s mechanism of action and knowledge of similar products.  Ongoing or additional 
monitoring and immediate rapid communication by the Investigator to the Sponsor may be 
appropriate.  Such events may require further investigation in order to characterise and 
understand them.  Depending on the nature of the event, rapid communication by the trial 
Sponsor to other parties (eg regulators) might also be warranted. 
 
For this study, ‘serious gram-negative infections’ will be considered an AESI.  That is, any 
infection with a proven culture of a gram-negative organism that meets the SAE criteria. 
 
 
8.2 
PROCEDURES FOR RECORDING OF SAFETY EVENTS 
 
8.2.1 General 
 
All adverse events occurring during the study (from the time point of signing of the ICF until 
the patients’ 30-day follow up visit) observed by the investigator or reported by the patient, 
whether or not attributed to the IMP, shall be recorded in patient`s medical records and on the 
eCRF. 
 
The following information shall be recorded:  
 
▪ 
Description, 
▪ 
Date of onset and end date, 
▪ 
Severity/grading (by CTCAE criteria), 
▪ 
Assessment of relatedness to the IMP, 
▪ 
Seriousness, 
▪ 
Measures taken for management of the AE, 
▪ 
Outcome of the event. 
 
Follow-up information should be provided as necessary.  
 
AEs considered as being related to the IMP as judged by a medically qualified investigator, or 
the Sponsor, must be followed until their resolution or when patient`s status is considered as 
stable.  All related AEs that result in a patient’s withdrawal from the study or are present at the 
end of the study, should be re-evaluated and if needed followed until a satisfactory resolution 
occurs. 
 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require termination of IMP administration.  A patient may also voluntarily withdraw 
from IMP administration due to AEs perceived as intolerable.  If either of these occurs, the 
patient will be given appropriate care under medical supervision until symptoms cease or the 
condition becomes stable. 
 
The severity of reported events shall be assessed using the CTCAE criteria (version 5). 
General guidance of CTCAE severity assessment: 
 

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Grade 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living  
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self 
care activities of daily living  
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
 
Further guidance should be consulted on the below URL link: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_5x7.pdf 
 
The causal relationship of AEs to the IMP must be assessed by the investigator, or by a 
medically qualified designee, in accordance with the following criteria: 
 
Term 
Definition 
Unrelated 
Clinical event with an incompatible time relationship to administration of the IMP, 
and that could be explained by underlying disease or other drugs or chemicals or is 
incontrovertibly not related to the IMP 
Possibly Related 
Clinical event with a reasonable time relationship to IMP administration, and that 
is unlikely to be attributed to concurrent disease or other drugs or chemicals 
Related 
Clinical event with plausible time relationship to IMP administration and that 
cannot be explained by concurrent disease or other drugs or chemicals 
 
The degree of certainty with which an AE is attributed to IMP administration (or alternative 
causes, eg natural history of the underlying disease, concomitant therapy, etc.) will be 
determined by how well the experience can be understood in terms of one or more of the 
following: 
 
▪ 
Known pharmacology of the IMP, 
▪ 
Whether reactions of a similar nature have been previously observed with the IMP or 
this class of drug, 
▪ 
A temporal relationship to IMP administration, terminating with IMP withdrawal or 
recurring on re-challenge, 
▪ 
Alternative cause. 
 
At the last scheduled visit, the investigator shall instruct each patient to report any subsequent 
event(s) that the patient, or their personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the Sponsor (or designee) of any 
death or SAE occurring at any time after a patient has discontinued or terminated study 
participation that may reasonably be related to this study. 
 
8.2.2 Pre-existing Conditions 
 
For the purposes of this study a pre-existing condition means a diagnosed, clinically significant 
finding, symptom or laboratory abnormality present at screening.  Subsequently, during the 

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course of the study it shall be recorded as an AE/SAE if the frequency, intensity, or the character 
of the condition worsens during the study period. 
 
8.2.3 Overdose 
 
All overdoses with or without associated symptoms, should be reported as AEs on the 
appropriate eCRF page.  An overdose is defined as a dose greater than the total ablating dose 
that patients receive on Day 1 of the study in any 12-hour period.  If sequelae meeting the 
criteria for a SAE have occurred in association with the overdose, the case must be reported 
immediately, within 24 hours.   
 
Action to be taken, if any, in event of an overdose should be discussed with the Sponsor’s 
medical representative at the earliest opportunity.  However, in animal toxicology, no adverse 
events have been observed following single iv doses of approximately 50 times the human 
therapeutic dose, so no specific toxicity is anticipated.  There are no known antidotes to 
nomacopan, and observation and supportive treatment are the only recommended measures.  
An assessment of whether the overdose was accidental or intentional should be recorded.  If the 
overdose was a suicide attempt, this fact should be clearly stated.  The AEs and SAEs that occur 
as a result of an overdose should be recorded on the eCRF. 
 
8.2.4 Pregnancy 
 
Nomacopan is contraindicated during pregnancy.  If pregnancy is suspected, a blood sample 
for serum HCG examination must be sent to the sub-contracted laboratory within 48 hours.  As 
pregnancy tests may be negative during the first few weeks, pregnancy may later be confirmed 
by an ultrasound examination.  If at least one of the above-mentioned examinations is positive, 
administration of the IMP must be stopped, and the patient must be immediately withdrawn 
from the study.  All pregnancies (even if suspected) must be reported on the appropriate eCRF 
page and Pregnancy Form to the pharmacovigilance provider of the Sponsor within 24 hours of 
the investigator becoming aware of the pregnancy (or suspected pregnancy).  In any case each 
pregnancy must be followed until its resolution (either by birth of a child or abortion) and the 
eCRF page and Pregnancy Form has to be updated. 
 
Reporting to the pharmacovigilance provider of the Sponsor shall be done on the corresponding 
Pregnancy Form, provided to each centre during the initiation visit, and sent by fax or e-mail 
to: 
 
E-mail: safety@akaritx.com 
8.2.5 Transfusions 
 
Overnight stays for transfusion do not need to be reported as SAEs. 
 
As all patients are anticipated to be hospitalised at the start, and potentially for the duration of 
the study, existing hospitalisation will not automatically be regarded as an SAE.  Planned visits 
to hospital for routine follow up and planned medical care will not be regarded as an SAE.  
 
On the other hand, progression of the underlying disease (at investigator’s discretion) or 
potential complications have to be reported as AEs. 
 
 

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8.3 
REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS 
 
Any SAE occurring during the study has to be managed by established standard of care to 
protect life and health of participating patients.  If such treatment represents a significant 
deviation from the protocol, the investigator shall immediately notify the study monitor and/or 
the Sponsor to determine whether the patient should be withdrawn from the study, or not. 
 
All SAEs, irrespective of their causality, must be notified to the pharmacovigilance provider of 
the Sponsor, within 24 hours of investigator’s knowledge of the event.  Reporting shall be done 
on the corresponding SAE form, provided to each centre during the initiation visit, and sent by 
e-mail to: 
 
E-mail: safety@akaritx.com 
 
The provided information shall contain as much detail regarding the event as available.  
Investigators shall not wait to receive additional information to fully document the event, before 
notifying the SAE to Akari Therapeutics Plc.  The SAE reporting form should detail all relevant 
aspects of the AEs listed in Section 8.2.1.  Where applicable, information from relevant hospital 
records or autopsy reports should be obtained and provided to Akari Therapeutics Plc. 
 
 
8.4 
EXPEDITED SAFETY REPORTING 
 
Any SAE, which is unexpected and at least possibly related to the IMP, requiring expedited 
reporting to the respective regulatory authority, EudraVigilance and ECs / Institutional Review 
Boards (IRBs) of the sites participating in this study is subject to following timelines: 
 
▪ 
7 calendar days for SUSARs involving death and life-threatening events, 
▪ 
15 calendar days for SUSARs involving hospitalisation or prolongation of 
hospitalisation or persistent or significant disability/incapacity or congenital 
anomaly/birth defect or any other significant clinical/laboratory event of major concern 
in the opinion of the Investigator. 
 
Day zero (clock start) for expedited reporting purposes is the date of initial information or of 
the relevant follow-up information received in any form (in writing or verbal) by any personnel 
of the Sponsor or contracted parties including the Contract Research Organisation (CRO) and 
the Pharmacovigilance Provider. 
 
All SUSARs will be reported to the respective competent authorities, ECs (IRBs) and 
investigators within specified timelines in accordance with corresponding national legislation. 
 
8.5 
DEVELOPMENT SAFETY UPDATE REPORTS 
 
Development Safety Update Reports will be prepared by Akari Therapeutics Plc on an annual 
basis and distributed to all competent authorities and to relevant ECs in accordance with the 
corresponding national regulations. 
 
 

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9 
STATISTICS 
 
9.1 
STATISTICAL DESIGN 
 
The study is divided into two parts.  Both parts are single arm, and open-labelled.  The design 
of Part A is based on pragmatic considerations based on generating adequate data to confirm 
the paediatric dose algorithm; the design of Part B is based on determining if the responder rate 
obtained using the given dosing algorithm is at least 15%. Consideration will be given to 
including Part A patients in the primary overall analysis; this will be discussed with the FDA 
at the end of Part A. 
 
9.2 
SAMPLE SIZE CONSIDERATIONS 
 
Part A will recruit 7 patients, in three age range cohorts (≥ 0.5 to < 2 years, ≥ 2 to < 9 years, 
and ≥ 9 to < 18 years).  The purpose of Part A is to confirm the effective maintenance dose of 
nomacopan for ablation of TCA.  This dose will then be used in Part B. 
 
For Part B it is assumed that the responder rate on nomacopan will be approximately 30% and 
the minimum acceptable responder rate is 15%.  Up to 65 patients will be recruited which gives 
79% power to reject the null hypothesis proportion, π₀, of less than 0.15 when the alternative 
hypothesis proportion, π₁, is 0.3 using an exact binomial test with a 2.5% one-sided significance 
level. 
 
An interim analysis will be conducted when 40 patients have been recruited into Part B of the 
study and have either completed 24 weeks of the study or discontinued the study before 24 
weeks.  In order to stop the study early for demonstration of efficacy, based on an O’Brien-
Fleming stopping rule, at an information fraction of 0.62 (40 of 65 patients), the significance 
level at the interim analysis needs to be 0.0044 (1 sided).  To meet this significance level, at 
least 13 of the 40 patients (32.5%) will need to be responders.  If the study is not stopped early, 
recruitment will continue and the final significance level, after 65 patients, will then need to be 
0.024. 
 
 
9.3 
ANALYSIS SETS 
 
9.3.1 Safety Analysis Set (SAS) 
 
All patients in Part A and in Part B who receive any dose of nomacopan.  The data from patients 
in both parts of the study will be combined together for summaries of safety. 
 
9.3.2 Full Analysis Set (Intention-to-treat) 
 
All patients in Part B who receive any dose of nomacopan.  The primary efficacy analyses will 
be based on only the Part B patients although additional summary results will be included that 
also combine Part A and Part B together. 
9.3.3 Per Protocol (PP) Analysis Sets 
 
All patients in Part B who do not have major protocol deviations, die of causes that are 
considered not to be related to TMA (as determined by the review committee) or who on later 
analysis were considered not to have had TMA at the time that treatment with nomacopan was 
initiated.  
 

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9.4 
STATISTICAL ANALYSIS 
 
9.4.1 Overview 
 
A detailed statistical analysis plan (SAP) will be written before any patients are recruited into 
Part B of the trial (but may be written whilst Part A is ongoing).  The protocol explains the key 
elements of data presentation and analysis. 
 
Part A patients will have their data summarised separately to Part B patients – although for key 
endpoints, summary Tables combining data from Parts A and B will also be included. 
 
At a minimum, analyses of all 7 patients until week 12 of dosing will be completed before Part 
B starts. 
 
9.4.2 Disposition of Study Patients 
 
Summaries showing the number of patients recruited into Parts A and B separately, the number 
and percentage of patients discontinuing Part A or Part B and the reasons for discontinuation 
(as collected on the eCRF) will be produced.  
 
The number and percentage of patients included in each analysis set will be summarized by 
Parts A and B and overall for all recruited patients. 
 
A listing of patients excluded from the PP set and the reason for exclusion will be provided. 
 
9.4.3 Baseline 
 
Demographic and baseline characteristics will be listed for Part A patients (sub-identified by 
age cohort) and Part B patients separately.  Summary Tables will be produced for Part B 
patients. 
 
The following demographic and baseline characteristics will be summarized: 
 
age, gender, race, ethnicity, weight, temperature, pulse rate, systolic and diastolic blood 
pressures, transfusion history (number of units of PRBCs and platelets transfused, along with 
corresponding Hb concentration and platelet count) and sC5b-9 concentration. 
 
9.4.4 Primary Efficacy Endpoint Analysis 
 
The primary efficacy endpoint for Part B is: 
 
independence of RBC transfusion† for ≥ 28 days immediately prior to any scheduled 
clinical visit up to Week 24 
or 
urine protein creatinine ratio ≤ 2 mg/mg, maintained over a ≥ 28-day period 
immediately prior to any scheduled clinical visit up to Week 24 
 
†Transfusion independence is defined as no RBC or platelet transfusion attributable to, or 
required to manage, TMA.  Transfusions required for causes other than TMA will not be 
considered within the evaluation of the primary efficacy endpoints. 
 

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The number and proportion of patients fulfilling this composite endpoint will be reported, along 
with a 95% confidence interval for the proportion and an exact binomial test of the null 
hypothesis that the responder rate is 0.15 vs. alternative hypothesis that the responder rate is 
0.15 or above. 
 
Supporting analyses will be performed on the individual components of the composite 
endpoint: 95% confidence intervals for each of the rates of RBC infusion independence and 
urine protein creatinine ratio ≤ 2 mg/mg will be reported.  In addition, 95% confidence intervals 
will be given for the responder rate based on pooling Part A and Part B patients together.  
 
9.4.5 Secondary Endpoints Analysis 
 
The proportions of patients meeting each of the following criteria will be reported, along with 
a 95% confidence interval for the proportions: 
 
▪ Percentage of patients who achieve the primary endpoint of urine protein creatinine ratio 
≤ 2 mg/mg (the nephrotic threshold) for ≥ 28 days,  
▪ platelet transfusion† independence for ≥ 28 days, 
▪ sC5b-9 ≤ ULN, 
▪ lactate dehydrogenase (LDH) ≤ ULN and 
▪ normalization of haptoglobin - (only in a subset of patients where haptoglobin was 
abnormal at baseline. 
 
The sC5b9, LDH and haptoglobin secondary endpoints will be measured at the last efficacy 
assessment in the trial before nomacopan treatment is stopped. 
 
These results will be reported for patients in Part B of the study, and for the combined Part A 
and Part B patient group. 
 
9.4.6 Exploratory Endpoints 
 
▪ Overall survival at Week 24 after the first dose of nomacopan, and at 1 year and 2 years 
after HSCT will be analysed by - Kaplan Meier survival curves. Overall survival is 
calculated as the time from first dose of nomacopan to death. Overall survival as time from 
HSCT to death will also be analysed by Kaplan Meier methods.  From these survival curves, 
the respective 24-week, 1-year and 2-year survival rates will be reported. 
 
For the following exploratory endpoints, 95% confidence intervals for rates (percentages) will 
be reported. 
 
▪ Percentage of patients with urine protein creatinine ratio ≤ 1.5 mg/mg for ≥ 28 days.  
▪ Percentage of patients with urine protein creatinine ratio ≤ 1 mg/mg for ≥ 28 days.  
▪ To evaluate renal function (urea, serum creatinine, urine protein creatinine ratio, proteinuria 
< 30 mg/dL and eGFR) at baseline and at 1 year and 2 years after HSCT. 
 
These results for all exploratory endpoints will be reported for patients in Part B of the study, 
and for the combined Part A and Part B patient group. 
 
9.4.7 Subgroup Analysis 
 
The primary and secondary endpoints will also be reported in subgroups based on degree of 
elevation of sC5b-9 categorised as below or above the median. 

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9.4.8 Interim Analysis 
 
One interim analysis will take place when 40 Part B patients have been recruited into the study 
and have either completed 24 weeks of the study or discontinued the study before 24 weeks.  
This analysis will only include Part B patients.  An O’Brien-Fleming stopping rule, at an 
information fraction of 0.62 (40 of 65 patients), will be used.  At the time of the interim analysis, 
to stop the study early, the 1-sided P-value needs to be less than 0.0044.  To meet this 
significance level, at least 13 of the 40 patients (32.5%) will need to be responders. Methods of 
primary efficacy analysis endpoint (see Section 9.4.4) will be used for the interim analysis on 
40 patients. 
 
If the study does not meet statistical significance at this time, the one-sided P-value needed at 
the final analysis with all 65 patients will be 0.024. 
 
9.4.9 Safety Analysis strategy for laboratory and clinical safety data 
 
Analysis of all safety data will be performed on the Safety Analysis Set.  Adverse events (AEs) 
and medical history will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  New or worsening AEs after dosing of investigational 
product will be summarized by system organ class, preferred term, and treatment.  Listings of 
subjects who have an SAE or who discontinue from the study due to an AE will be provided.  
AEs leading to withdrawal will be summarized for Part A and Part B. 
 
Summary statistics for laboratory values will be provided at baseline, post-baseline visits, and 
for changes from baseline to post-baseline for Part A and Part B.  Vital signs parameters will 
be summarized similarly.  Occurrence of significant laboratory abnormalities will be 
summarized for Part A and Part B.  Physical examination and urine pregnancy tests data will 
be listed. 
 
 
10 DATA HANDLING AND SOURCE DOCUMENTS 
 
Patient data will be collected on eCRFs and will be substantiated by source documents at the 
clinical site.  The eCRFs will be completed according to guidelines provided by the CRO and 
their SOPs.  Source documentation supporting the eCRF data should indicate the patient’s 
participation in the study and should document the dates and details of all study procedures, 
AEs and patient status. 
 
The investigator must maintain source documents, such as laboratory reports, complete medical 
history, and physical examination reports.  All source documents should be accessible for 
verification by the site monitor, auditor, the EC, or for inspections by the regulatory authorities.  
In addition, the site will allow the Sponsor and assigned CRO direct access to all source 
documents and will permit trial-related auditing of clinical, pharmacy and laboratory facilities. 
 
Direct access to these documents must be guaranteed by the investigator or their designee, or 
the study coordinator, who must provide support at all times for these activities. 
The nature and location of all sources of original data required to complete the eCRF will be 
identified by the CRO and the site staff. 
 
The Study Monitor will perform 100% source data verification to ensure adequate quality 
control (QC) and assurance of patient data.  An explanation of missing data must be given.  All 
data entered into the eCRF will be saved directly into the study database.  This data will be 
validated both manually and programmatically.  Clarification of data will be requested from the 

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study site as necessary.  The database will be quality assured and will be available for analysis 
according to the Statistical Analysis Plan. 
 
Patient data will be reviewed for major protocol deviations by the Study Monitor during site 
visits and the entire team will review the database at timed intervals prior to the database lock. 
 
 
10.1 INFORMED CONSENT PROCEDURES 
 
Written informed consent expresses the understanding and agreement of fully informed 
parent(s) or legal guardian(s) to permit the child to enter into this study.  In addition, it also 
means the assent (the affirmative agreement) of the child to participate in this study, where the 
child is able (old enough) to provide assent.  Lack or absence of agreement or disagreement 
must not be interpreted as assent. 
 
For the sake of simplicity in this protocol, references to the patient can also mean references to 
the legal guardian where appropriate. 
 
 
10.2 PROTOCOL DEVIATIONS 
 
The investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the regulatory authority(ies), and which was given approval/favourable 
opinion by the independent ethics committee (IEC). 
 
A protocol deviation to eliminate any apparent immediate hazard to a patient(s) may be 
implemented immediately.  The Sponsor, Competent Authorities and the IEC must be notified 
of the deviation and reason.  The Sponsor must be notified of all intended or unintended 
deviations to the protocol (eg inclusion/exclusion criteria, dosing, missed study visits) on an 
expedited basis. 
 
The investigator, or person designated by the investigator, should document and explain any 
deviation from the approved protocol. 
 
If a patient received at least one dose of study medication but was subsequently determined to 
be ineligible or to have received the wrong dose or investigational treatment, all appropriate 
safety and early termination procedures should be performed, with data collected for inclusion 
in the safety and efficacy analysis, as appropriate.  The protocol deviation should be 
appropriately documented. 
 
The investigator should notify the IEC of deviations from the protocol in accordance with local 
procedures.  The Competent Authorities should also be notified of any protocol deviation 
performed to protect the patients against any immediate hazard which meets the definition of 
an urgent safety measure. 
 
 
10.3 SUBJECT CONFIDENTIALITY 
 
The investigators and the Sponsor will preserve the confidentiality of all patients taking part in 
the study, in accordance with GCP and local regulations. 
 
The investigator must ensure that the patient’s anonymity is maintained.  On the eCRFs or other 
documents submitted to the Sponsor or designee, subjects should be identified by a unique 

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subject identifier as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or designee (eg signed ICF) should be kept in strict confidence by the investigator. 
 
In compliance with applicable regulations and ICH GCP guidelines, it is required that the 
investigator and institution permit authorised representatives of the company, of the regulatory 
agency(s), and the IEC direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  The investigator is obligated to inform the 
subject that his/her study-related records will be reviewed by the above-named representatives 
without violating the confidentiality of the patient. 
 
 
11 DRUG ACCOUNTABILITY AND COMPLIANCE 
 
11.1 ACCOUNTABILITY PROCEDURES 
 
In accordance with GCP, the clinical unit will account for all study medication.  The clinical 
unit are responsible for study medication accountability, reconciliation, and record 
maintenance. 
 
Drug accountability records will be maintained during the study as follows:  
 
▪ 
Amount of study medication received from the Sponsor 
▪ 
Amount distributed to each patient and returned by them 
▪ 
Amount of unused drug returned to the Sponsor or destroyed at the Sponsors request  
 
In addition, in the event of necessary disposal of opened but wasted medication, the disposal 
should be documented appropriately (ie witnessed), in accordance with applicable local 
regulations, and GCP procedures. 
 
Patients are required to return used and unused vials to the clinical unit if at some point during 
the study they are discharged from hospital.  Storage bags will be provided to each patient.  For 
all unused study medication, the patient should adhere to the storage instructions until the study 
medication is returned to the clinical unit. 
 
 
11.2 COMPLIANCE 
 
Reasonable levels of compliance are assumed as a condition of entry to the study.  For each 
patient, a reconciliation will be made between the number of vials recorded to have been used, 
the number of vials actually used (number of vials returned empty), and the number of vials 
that should have been used according to the dosing record.  As an additional measure of 
compliance, all empty nomacopan vials will be returned to the clinical unit.  At the end of the 
study, all unused vials may be returned to the Sponsor or representative. 
 
 
12 QUALITY CONTROL AND ASSURANCE 
 
The hospitals/departments taking part in the trial are responsible for maintaining their own 
SOPs and QA/QC procedures.  The Sponsor or their delegate will also implement and maintain 
QC and quality assurance (QA) procedures with written standard operating procedures (SOPs) 
to ensure that the study is conducted, and data are generated, documented and reported in 
compliance with the protocol and ICH GCP and all applicable regulatory requirements.  The 

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Sponsor or delegate will be responsible for monitoring the trial and carrying out 100% source 
data verification. 
 
The study will be in accordance with the provisions of the Declaration of Helsinki and all 
revisions thereof, in accordance with ICH GCP and as required by applicable regulatory 
requirements. 
 
Any necessary training for the study will be provided to investigators and study personnel by 
the Sponsor or their designee prior to study initiation. 
 
 
13 ETHICAL CONDUCT OF THE STUDY 
 
The study will be conducted in accordance with all appropriate regulatory requirements and 
under an approved protocol.  The study will be conducted in accordance with current ICH GCP, 
all appropriate patient privacy requirements and the ethical principles outlined in the 
Declaration of Helsinki. 
 
 
14 FINANCING, INDEMNITY AND INSURANCE 
 
The Sponsor will have a commercial contract in place with the CRO and the 
hospitals/universities will be responsible for any payments to patients for payment of travel and 
other expenses reimbursable by the Sponsor on delivery of receipts. 
 
The Sponsor has a clinical trials insurance policy in place, underwritten by AON Limited.  A 
copy of the policy/certificate of insurance will be supplied separately.  Provision is made for 
(1) The indemnity or compensation in the event of injury or death attributable to the clinical 
trial and (2) Insurance or indemnity to cover the liability of the investigator or Sponsor. 
 
Akari Therapeutics Plc will indemnify the investigators from all or any claims arising out of 
this study except for their negligence or malpractice and providing that the study is conducted 
according to the standards established by the protocol. 
 
In the event that it can be demonstrated that a patient suffers any significant deterioration in 
health or well-being or any harmful susceptibility or toxicity as a direct result of their 
participation in this study, then Akari Therapeutics Plc will agree to abide by the current 
Association of the British Pharmaceutical Industry Guidelines with regard to compensation 
payable to the patient residing in the UK.  The amount of compensation will be calculated by 
reference to the level of damages commonly awarded according to local law for similar injuries 
occurring in patients residing outside the UK. 
 
 
15 PUBLICATION POLICY 
 
The key design elements of this protocol will be posted in a publicly accessible database.  The 
CRO has no independent publication rights. 
 
Akari Therapeutics Plc actively encourages publication of clinical trial data in reputable peer 
reviewed journals.  Authorship will be discussed and agreed in advance.  If the investigator 
drafts a publication, he/she agrees to send it to Akari Therapeutics Plc for review and comment 
before its submission to the journal.  In cases where Akari Therapeutics Plc considers that the 
proposed publication contains information which should be protected as valuable confidential 

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information or is out of compliance with applicable laws and regulations, Akari Therapeutics 
Plc reserves the right to delay submission to the journal, until the required deletion or 
amendment of the confidential information from the proposed publication has been done. 
 
 
16 STUDY RECORD RETENTION 
 
The investigators shall ensure that the documents contained in the Investigator Site File are 
retained for 15 years after the conclusion of the trial.  The Sponsor shall ensure that the 
documents contained in the Trial Master File are retained for 25 years after the conclusion of 
the trial.  The Sponsor and investigators will ensure that during this period the files are 
complete, legible and readily available to the licensing authority on request. 
 
All data derived from the study will remain the property of Akari Therapeutics Plc. 
 
All correspondence (eg with the Sponsor, or designee, EC) relating to this study should be kept 
in the appropriate files.  Records of patient’s source documents, eCRF’s, IMP inventory 
pertaining to the study must be kept on file. 
 
If the investigator moves, withdraws from the study, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept responsibility.  
Notice of transfer must be made to and agreed by the Sponsor. 
 
 
16.1 CLINICAL STUDY REPORT 
 
The results of this clinical study must be summarised by the Sponsor (or designee) and a final 
audited report must be retained on file.  This report will include discussions on the study 
objectives, methodology, findings and conclusions.  The PI(s) will be asked to review and 
comment on the draft report and the Chief Investigator will be required to sign the final version.  
All Investigators will be provided with a final copy of the CSR.  The report must be archived 
with all other study documents. 
 
 
16.2 HANDLING AND RETENTION OF BLOOD AND PATHOLOGICAL SAMPLES 
 
Samples should be handled according to the instructions provided in the Laboratory Manual.  
The duration of retention of blood and pathological samples will be in accordance with details 
provided in the patient information leaflet and agreed to by signing the ICF. 
 
 
 
 

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17 REFERENCES 
 
1. 
Choi CM, Schmaier AH, Snell MR, Lazarus HM. 
 
Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and 
treatment. 
 
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2. 
Elsallabi O, Bhatt VR, Dhakal P, Foster KW, Tendulkar KK. 
 
Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy. 
 
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Academy of Clinical and Applied Thrombosis/Hemostasis 2016;22:12-20. 
3. 
Rosenthal J. 
 
Hematopoietic cell transplantation-associated thrombotic microangiopathy: a review of 
pathophysiology, diagnosis, and treatment. 
 
Journal of blood medicine 2016;7:181-6. 
4. 
Kerr H, Richards A. 
 
Complement-mediated injury and protection of endothelium: lessons from atypical 
haemolytic uraemic syndrome. 
 
Immunobiology 2012;217:195-203. 
5. 
Seaby EG, Gilbert RD. 
 
Thrombotic microangiopathy following haematopoietic stem cell transplant. 
 
Pediatric nephrology (Berlin, Germany) 2018;33:1489-500. 
6. 
Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim 
DW, Lee JW, Min WS, Park CW. 
 
Validation of recently proposed consensus criteria for thrombotic microangiopathy after 
allogeneic hematopoietic stem-cell transplantation. 
 
Transplantation 2010;90:918-26. 
7. 
Jodele S, Fukuda T, Vinks A, Mizuno K, Laskin BL, Goebel J, Dixon BP, Teusink A, 
Pluthero FG, Lu L, Licht C, Davies SM. 
 
Eculizumab therapy in children with severe hematopoietic stem cell transplantation-
associated thrombotic microangiopathy. 
 
Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation 2014;20:518-25. 
8. 
Ardissino G, Salardi S, Berra S, Colussi G, Cugno M, Zecca M, Giglio F, Peccatori J, 
Diral E, Tel F, Clivio A, Tedeschi S. 
 
Acquired Complement Regulatory Gene Mutations and Hematopoietic Stem Cell 
Transplant-Related Thrombotic Microangiopathy. 
 
Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation 2017;23:1580-2. 
9. 
Jodele S, Licht C, Goebel J, Dixon BP, Zhang K, Sivakumaran TA, Davies SM, Pluthero 
FG, Lu L, Laskin BL. 
 
Abnormalities in the alternative pathway of complement in children with hematopoietic 
stem cell transplant-associated thrombotic microangiopathy. 
 
Blood 2013;122:2003-7. 
10. 
Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, Lane A, Meller J, 
Medvedovic M, Chen J, Davies SM. 
 
The genetic fingerprint of susceptibility for transplant-associated thrombotic 
microangiopathy. 
 
Blood 2016;127:989-96. 
11. 
Jodele S, Dandoy CE, Myers KC, El-Bietar J, Nelson A, Wallace G, Laskin BL. 
 
New approaches in the diagnosis, pathophysiology, and treatment of pediatric 
hematopoietic stem cell transplantation-associated thrombotic microangiopathy. 
 
Transfusion and apheresis science : official journal of the World Apheresis Association 
: official journal of the European Society for Haemapheresis 2016;54:181-90. 

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12. 
de Fontbrune FS, Galambrun C, Sirvent A, Huynh A, Faguer S, Nguyen S, Bay JO, 
Neven B, Moussi J, Simon L, Xhaard A, Resche-Riggon M, O'Meara A, Fremeaux-
Bacchi V, Veyradier A, Socie G, Coppo P, de Latour RP. 
 
Use of Eculizumab in Patients With Allogeneic Stem Cell Transplant-Associated 
Thrombotic Microangiopathy: A Study From the SFGM-TC. 
 
Transplantation 2015;99:1953-9. 
13. 
Jodele S, Fukuda T, Mizuno K, Vinks AA, Laskin BL, Goebel J, Dixon BP, Chima RS, 
Hirsch R, Teusink A, Lazear D, Lane A, Myers KC, Dandoy CE, Davies SM. 
 
Variable Eculizumab Clearance Requires Pharmacodynamic Monitoring to Optimize 
Therapy for Thrombotic Microangiopathy after Hematopoietic Stem Cell 
Transplantation. 
 
Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation 2016;22:307-15. 
14. 
Sakellari I, Gavriilaki E, Boussiou Z, Batsis I, Mallouri D, Constantinou V, 
Kaloyannidis K, Yannaki E, Bamihas G, Anagnostopoulos A. 
 
Transplant-associated thrombotic microangiopathy: an unresolved complication of 
unrelated allogeneic transplant for hematologic diseases. 
 
Hematological oncology 2017;35:932-4. 
15. 
Shayani S, Palmer J, Stiller T, Liu X, Thomas SH, Khuu T, Parker PM, Khaled SK, 
Forman SJ, Nakamura R. 
 
Thrombotic microangiopathy associated with sirolimus level after allogeneic 
hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host 
disease prophylaxis. 
 
Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation 2013;19:298-304. 
16. 
Riedl M, Fakhouri F, Le Quintrec M, Noone DG, Jungraithmayr TC, Fremeaux-Bacchi 
V, Licht C. 
 
Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic 
insights identifying novel treatment approaches. 
 
Seminars in thrombosis and hemostasis 2014;40:444-64. 
17. 
Laskin BL, Maisel J, Goebel J, Yin HJ, Luo G, Khoury JC, Davies SM, Jodele S. 
 
Renal arteriolar C4d deposition: a novel characteristic of hematopoietic stem cell 
transplantation-associated thrombotic microangiopathy. 
 
Transplantation 2013;96:217-23. 
18. 
Cataland SR, Holers VM, Geyer S, Yang S, Wu HM. 
 
Biomarkers of terminal complement activation confirm the diagnosis of aHUS and 
differentiate aHUS from TTP. 
 
Blood 2014;123:3733-8. 
19. 
Chapin J, Shore T, Forsberg P, Desman G, Van Besien K, Laurence J. 
 
Hematopoietic transplant-associated thrombotic microangiopathy: case report and 
review of diagnosis and treatments. 
 
Clinical advances in hematology & oncology : H&O 2014;12:565-73. 
20. 
Jodele S. 
 
Complement in Pathophysiology and Treatment of Transplant-Associated Thrombotic 
Microangiopathies. 
 
Seminars in hematology 2018;55:159-66. 
21. 
Brocklebank V, Kavanagh D. 
 
Complement C5-inhibiting therapy for the thrombotic microangiopathies: accumulating 
evidence, but not a panacea. 
 
Clinical kidney journal 2017;10:600-24. 
22. 
Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, Myers K, Grimley M, 
Bleesing J, El-Bietar J, Wallace G, Chima RS, Paff Z, Laskin BL. 

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Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study 
in children and young adults. 
 
Blood 2014;124:645-53. 
23. 
McCain RW, Holden EP, Blackwell TR, Christman JW. 
 
Leukotriene B4 stimulates human polymorphonuclear leukocytes to synthesize and 
release interleukin-8 in vitro. 
 
American journal of respiratory cell and molecular biology 1994;10:651-7. 
24. 
Schaub RG, Yamashita A. 
 
Leukocyte mediated vein injury and thrombosis is reduced by a lipoxygenase inhibitor. 
 
Experimental and molecular pathology 1986;45:343-53. 
25. 
Roversi P, Ryffel B, Togbe D, Maillet I, Teixeira M, Ahmat N, Paesen GC, Lissina O, 
Boland W, Ploss K, Caesar JJ, Leonhartsberger S, Lea SM, Nunn MA. 
 
Bifunctional lipocalin ameliorates murine immune complex-induced acute lung injury. 
 
The Journal of biological chemistry 2013;288:18789-802. 
26. 
Nunn MA, Sharma A, Paesen GC, Adamson S, Lissina O, Willis AC, Nuttall PA. 
 
Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata. 
 
Journal of immunology (Baltimore, Md : 1950) 2005;174:2084-91. 
27. 
Hepburn NJ, Williams AS, Nunn MA, Chamberlain-Banoub JC, Hamer J, Morgan BP, 
Harris CL. 
 
In vivo characterization and therapeutic efficacy of a C5-specific inhibitor from the soft 
tick Ornithodoros moubata. 
 
The Journal of biological chemistry 2007;282:8292-9. 
28. 
Goodship THJ, Pinto F, Weston-Davies WH, Silva J, Nishimura JI, Nunn MA, Mackie 
I, Machin SJ, Palm L, Pryce JW, Chiesa R, Amrolia P, Veys P. 
 
Use of the complement inhibitor Coversin to treat HSCT-associated TMA. 
 
Blood advances 2017;1:1254-8. 
29. 
Greinacher A, Warkentin TE. 
 
The direct thrombin inhibitor hirudin. 
 
Thrombosis and haemostasis 2008;99:819-29. 
30. 
NHANESIII. 
 
National Health and Nutrition Examination Survey (NHANES) III. 
 
[http://wwwcdcgov/nchs/nhanes/nh3datahtm]. 
31. 
Ram S, Lewis LA, Rice PA. 
 
Infections of people with complement deficiencies and patients who have undergone 
splenectomy. 
 
Clinical microbiology reviews 2010;23:740-80. 
32. 
Dmytrijuk A, Robie-Suh K, Cohen MH, Rieves D, Weiss K, Pazdur R. 
 
FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal 
nocturnal hemoglobinuria. 
 
The oncologist 2008;13:993-1000. 
33. 
NIDDK. 
 
National Institute of Diabetes and Digestive and Kidney Diseases. 
https://www.niddk.nih.gov/health-information/communication-
programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators 
 
 

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18 APPENDICES 
 
18.1 SCHEDULE OF EVENTS PART A (FIRST 4 WEEKS) 
Evaluation & 
Procedures 
Screening 
Day 1 
Intense Monitoring 
Day 2 
Intense 
Monitoring 
Day 
3 
Day 4 
Day 7 
Intense Monitoring 
(± 1 day) 
Day 11 
(± 1 
day) 
Day 14 
(± 1 
day) 
Week 4 
Intense Monitoring 
(± 5 days) 
 
Up to -21 
days 
Pre-
dose 
3 
hrs 
6 
hrs 
12 hrs 
Predose 
Pre-
dose 
6 
hrs 
12 
hrs 
Pre-
dose 
Pre-
dose 
Pre-
dose 
3 
hrs 
6 
hrs 
12 hrs 
Predose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
3 
hrs 
6 
hrs 
12 hrs 
Predose 
Eligibility & ICF 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam1 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
ADAMTS132 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coombs’ Test2 & ECG3 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal & Throat Swabs4 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs5 
x 
x 
 
 
x 
x 
 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
CH506 
 
x 
x 
x 
x 
x 
x 
x 
X15 
x 
x14 
x14 
x14, 
15 
x14 
 
x 
x 
x 
X15 
x 
PK6 
 
x 
x 
x 
x 
x 
x 
x 
X15 
x 
x14 
x14 
x14, 
15 
x14 
 
x 
x 
x 
X15 
x 
Total C56 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
 
 
 
x 
x 
 
 
 
Antibodies6 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
 
 
 
Urinary LTB46 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
 
 
 
sC5b-96,7 
x7 
x 
 
 
 
x 
 
 
 
x 
x 
 
 
 
 
x 
x 
 
 
 
C3b6 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
 
 
 
Chemistry2,8 
x 
x 
 
 
 
x 
 
 
 
x 
x 
 
 
 
 
x 
x 
 
 
 
Haematology2,9 
x 
x 
 
 
 
x 
 
 
 
x 
x 
 
 
 
 
x 
x 
 
 
 
Urinalysis2,10 
x 
x 
 
 
 
x 
 
 
 
x 
x 
 
 
 
x 
x 
x 
 
 
 
Pregnancy test11 
x12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x13 
 
 
 
Drug Accountability 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
 
 
 
AEs & Con Meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
1A physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological & cardiovascular systems, lungs, abdomen (liver & spleen), lymph nodes & extremities. A 
GVHD assessment will also be performed. 
2 Local laboratory. 
3 12-lead ECG. 
4 Nasal & throat swab results prior to first dose is not an entry requirement.  Meningitis prophylaxis with vaccines will be in accordance with the investigator’s judgement & local guidelines. 
5 Vital signs: pulse rate, systolic & diastolic blood pressure, respiratory rate, & body temperature.  Vital signs are to be taken after the subject has been supine for at least 5 minutes.  Measurements 
should be repeated if clinically significant changes are observed or a machine error occurs.  In addition, weight should be measured every 4 weeks, and height at screening and Week 24. 
6 Central laboratory. For the 24 hours urine (LTB4) - in non-catheterised patients all urine samples over the period should be collected, as completely as possible. For younger children, urine from 
diapers/nappies should be collected if feasible. 
7 Plasma sC5b-9 is mandatory before study entry and may be performed more frequently than shown at the investigator’s discretion. 
8 Liver function, Renal function including eGFR Calculation & LDH. 
9 Including haptoglobin. 
10 Urinalysis: UPCR &Protein. 
11For females of childbearing potential. 

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12 Serum pregnancy test. 
 
13 Urine pregnancy test. 
14A dose increase CANNOT be given until Day 7 PK/PD results are available. 
15 These samples will NOT be taken in the youngest age cohort. 
 
 

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18.2 SCHEDULE OF EVENTS PART A (WEEK 8 ONWARDS) 
Evaluation & Procedures 
Week 814 
(± 5 days) 
Week 12 
(± 5 days) 
Week 1614 
(± 5 days) 
Week 20 
(± 5 days) 
End of 
Treatment 
Week 2411, 
(± 5 days) 
Safety 
Follow-up 
(30 days after 
last dose) 
1 Year 
Post HSCT 
follow-up 
(± 5 days) 
2 Years Post 
HSCT follow-
up12 
(± 5 days) 
Early 
Withdrawal 
Unscheduled 
Visit 
 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
(± 5 days) 
 
 
 
Pre-dose 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
Physical Exam1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coombs’ Test & ECG16 
 
 
 
 
 
 
 
 
 
 
Nasal & Throat Swabs 
 
 
 
 
 
 
 
 
 
 
Vital signs3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CH504 
x 
x 
x 
x 
x13 
 
 
 
x 
 
PK4 
x 
x 
x 
x 
x13 
 
 
 
x 
 
Total C54 
x 
x 
x 
x 
x13 
 
 
 
x 
 
Antibodies4 
x 
x 
x 
x 
x 
 
 
 
x 
 
Urinary LTB44 
x 
x 
x 
x 
x13 
 
 
 
x 
 
sC5b-94,5 
x 
x 
x 
x 
x13 
 
 
 
x 
 
C3b4 
x 
x 
x 
x 
x13 
 
 
 
x 
 
Chemistry2,6 
x 
x 
x 
x 
x 
x 
 
 
x 
 
Haematology2,7 
x 
x 
x 
x 
x 
x 
 
 
x 
 
Urinalysis2,8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x13 
Pregnancy test9 
x10 
x10 
x10 
x10 
x10 
x10 
 
 
x10 
 
Drug Accountability 
x 
x 
x 
x 
x 
 
 
 
x 
 
AEs & Con Meds 
x 
x 
x 
x 
x 
x 
x15 
x15 
x 
x 
Overall survival status 
 
 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 A physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological & cardiovascular systems, lungs, abdomen (liver & spleen), lymph nodes & extremities. 
A GVHD assessment will also be performed. 
2 Local laboratory. 
3 Vital signs: pulse rate, systolic & diastolic blood pressure, respiratory rate, & body temperature.  Vital signs are to be taken after the subject has been supine for at least 5 minutes.  Measurements 
should be repeated if clinically significant changes are observed or a machine error occurs.  In addition, weight should be measured every 4 weeks, and height at screening and Week 24. 
4 Central laboratory. For the24 hours urine (LTB4)- in non-catheterised patients all urine samples over the period should be collected, as completely as possible. For younger children, urine from 
diapers/nappies should be collected if feasible.  
5 Plasma sC5b-9 is mandatory before study entry and may be performed more frequently than shown at the investigator’s discretion.  
6 Liver function, Renal function including eGFR calculation & LDH. 
7 Including haptoglobin. 
8 Urinalysis: UPCR & Protein. 
9 For females of childbearing potential. 
10 Urine pregnancy test. 
11 Patients who meet the primary endpoint before week 24 and who stop drug must attend the Week 24 visit and 30 day safety visit after last dose.   
12 End of Study is two years after of HSCT. 
13 Samples for PK and efficacy measurements (free nomacopan, CH50, total C5, LTB4(urine), sC5b-9, and C3b) will only be taken if patient received study drug < 1 week prior to this visit. 
14 For children in the youngest two cohorts (≥ 0.5 to < 2 years, and ≥ 2 to < 9 years), the dose will be re-calculated at the week 8 and week 16 visits using the child’s new weight measured at that visit. 
The new adjusted dose should be given after all study procedures have been performed. This new adjusted dose will not require an ablating dose. 

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
CONFIDENTIAL 
Page 66 of 85 
15 Only SAEs considered possibly related or related to nomacopan to be reported at these visits. 
16 12-lead ECG 
 
 

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
CONFIDENTIAL 
Page 67 of 85 
 
18.3 SCHEDULE OF EVENTS PART A (DOSE INCREASE)  
 
Evaluation & Procedures 
Day n Dose Increase7 
Intense Monitoring. 
(single ablation dose 
followed by increased 
maintenance dose 12 hrs 
later) 
Day n+1 
Intense Monitoring 
Day n+2 
Day n+6 
Intense Monitoring 
(± 1 day) 
Proceed to Next 
Scheduled Visit 
 
Pre-
dose 
3 
hrs 
6 
hrs 
12 
hrs 
Pre-
dose 
Pre-
dose 
6 
hrs 
12 
hrs 
Pre-dose 
Pre-
dose 
3 
hrs 
6 
hrs 
12 
hrs 
Pre-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility & ICF 
 
 
 
 
 
 
 
 
 
 
 
 
Scheduled visits 
according to 18.1 and 
18.2 will continue as 
scheduled.  If a 
PKPD visit that is 
scheduled due to a 
dose increase 
coincides with 18.1 
or 18.2 scheduled 
visit the visits will be 
combined. 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam1 
 
 
 
 
 
 
 
 
 
 
 
 
Coombs’ Test & ECG8 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal & Throat Swabs 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
CH503 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PK3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry2,4 
 
 
 
 
 
 
 
 
x 
 
 
 
Haematology2,5 
 
 
 
 
 
 
 
 
x 
 
 
 
Urinalysis2,6 
x 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
 
 
 
 
 
 
x 
AEs & Con Meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Overall survival status 
 
 
 
 
 
 
 
 
 
 
 
 
Long term follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 A physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological & cardiovascular systems, lungs, abdomen (liver & spleen), lymph nodes & extremities. 
A GVHD assessment will also be performed. 
2 Local laboratory. 
3 Central laboratory. 
4 Liver function, Renal function including eGFR calculation & LDH. 
5 Including haptoglobin. 
6 Urinalysis: UPCR & Protein  
7 Dose Increase 1 is a maintenance dose of 0.45 mg/kg and Dose Increase 2 is a maintenance dose of 0.60 mg/kg. 
8 12-lead ECG 
 
 
 
 

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
CONFIDENTIAL 
Page 68 of 85 
18.4 SCHEDULE OF EVENTS PART B (FIRST 12 WEEKS) 
Evaluation & Procedures 
Screening 
Day 1 (ablation dose followed 
by maintenance dose 12 hours 
later) 
Day 2 
Day 7 
(± 1 day) 
Day 14 
(± 1 day) 
Week 4 
(± 5 days) 
Week 8 
(± 5 days) 
Week 12 
(± 5 days) 
 
Up to -21 days 
Pre-dose 
12 hrs Pre-
dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Eligibility & ICF 
x 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Physical Exam1 
x 
x 
 
 
x 
x 
x 
x 
x 
ADAMTS13 
x 
 
 
 
 
 
 
 
 
Coombs’ Test2 & ECG13 
x 
 
 
 
 
 
 
 
 
Nasal & Throat Swabs3 
x 
 
 
 
 
 
 
 
 
Vital signs4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CH505 
 
x 
 
x 
x 
x 
x 
x 
x 
PK5 
 
x 
 
x 
x 
x 
x 
x 
x 
Total C55 
 
x 
 
x 
x 
x 
x 
x 
x 
Antibodies5 
 
x 
 
 
x 
x 
x 
x 
x 
Urinary LTB45 
 
x 
 
 
x 
x 
x 
x 
x 
sC5b-95,6 
x 
x 
 
x 
x 
x 
x 
x 
x 
C3b5 
 
x 
 
 
x 
x 
x 
x 
x 
Chemistry2,7 
x 
x 
 
 
x 
x 
x 
x 
x 
Haematology2,8 
x 
x 
 
 
x 
x 
x 
x 
x 
Urinalysis2,9 
x 
x 
 
x 
x 
x 
x 
x 
x 
Pregnancy test10 
x11 
 
 
 
 
 
x12 
x12 
x12 
Drug Accountability 
 
 
 
 
x 
x 
x 
x 
x 
AEs & Con Meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Overall survival status 
 
 
 
 
 
 
 
 
 
Long term follow-up 
 
 
 
 
 
 
 
 
 
1 A physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological & cardiovascular systems, lungs, abdomen (liver & spleen), lymph nodes & extremities. 
A GVHD assessment will also be performed. 
2 Local laboratory. 
3 Nasal & throat swab results prior to first dose is not an entry requirement.  Meningitis prophylaxis with vaccines will be in accordance with the investigator’s judgement & local guidelines. 
4 Vital signs: pulse rate, systolic & diastolic blood pressure, respiratory rate, & body temperature.  Vital signs are to be taken after the subject has been supine for at least 5 minutes.  Measurements 
should be repeated if clinically significant changes are observed or a machine error occurs.  In addition, weight should be measured every 4 weeks, and height at screening and Week 24. 
5 Central laboratory. For the 24 hours urine (LTB4) - in non-catheterised patients all urine samples over the period should be collected, as completely as possible. For younger children, urine from 
diapers/nappies should be collected if feasible. 
6 Plasma sC5b-9 is mandatory before study entry and may be performed more frequently than shown at the investigator’s discretion.  
7 Liver function, Renal function including eGFR calculation & LDH. 
8 Including haptoglobin. 
9 Urinalysis: UPCR & Protein.  
10 For females of childbearing potential. 
11 Serum pregnancy test, where available. 
12 Urine pregnancy test. 
13 12-lead ECG. 

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
CONFIDENTIAL 
Page 69 of 85 
18.5 SCHEDULE OF EVENTS PART B (WEEK 16 ONWARDS) 
 
Evaluation & Procedures 
 
Week 16 
(± 5 days) 
Week 20 
(± 5 days) 
End of 
Treatment 
Week 2411 
(± 5 days) 
Safety 
Follow-up 
(30 days 
after last 
dose) 
1 Year 
Post HSCT 
follow-up 
(± 5 days) 
2 Years 
Post HSCT 
follow-up 
(± 5 days) 
Early  
Withdrawal 
 
Unscheduled 
Visit 
 
Pre-dose 
Pre-dose 
Pre-dose 
(± 5 days) 
 
 
 
 
Eligibility & ICF 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
Physical Exam1 
x 
x 
x 
x 
x 
x 
x 
x 
Coombs’ Test & ECG 
 
 
 
 
 
 
 
 
Nasal & Throat Swabs 
 
 
 
 
 
 
 
 
Vital signs2 
x 
x 
x 
x 
x 
x 
x 
x 
CH503 
x 
x 
x12 
 
 
 
x 
 
PK3 
x 
x 
x12 
 
 
 
x 
 
Total C53 
x 
x 
x12 
 
 
 
x 
 
Antibodies3 
x 
x 
x12 
 
 
 
x 
 
Urinary LTB43 
x 
x 
x12 
 
 
 
x 
 
sC5b-93,4 
x 
x 
x12 
 
 
 
x 
 
C3b3 
x 
x 
x12 
 
 
 
x 
 
Chemistry5,6 
x 
x 
x 
x 
 
 
x 
 
Haematology5,7 
x 
x 
x 
x 
 
 
x 
 
Urinalysis5,8 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test9 
x10 
x10 
x10 
x10 
 
 
x10 
 
Drug Accountability 
x 
x 
x 
x 
 
 
x 
 
AEs & Con Meds 
x 
x 
x 
x 
X13 
X13 
x 
x 
Overall survival status 
 
 
 
 
x 
x 
 
 
Long term follow-up11 
 
 
 
 
x 
x 
 
 
1 A physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological & cardiovascular systems, lungs, abdomen (liver & spleen), lymph nodes & extremities. 
A GVHD assessment will also be performed. 
2 Vital signs: pulse rate, systolic & diastolic blood pressure, respiratory rate, & body temperature.  Vital signs are to be taken after the subject has been supine for at least 5 minutes.  Measurements 
should be repeated if clinically significant changes are observed or a machine error occurs.  In addition, weight should be measured every 4 weeks, and height at screening and Week 24. 
3 Central laboratory. For the 24 hours urine (LTB4) -in non-catheterised patients all urine samples over the period should be collected, as completely as possible. For younger children, urine from 
diapers/nappies should be collected if feasible. 
4 Plasma sC5b-9 is mandatory before study entry and may be performed more frequently than shown at the investigator’s discretion. 
5 Local laboratory. 
6 Liver function, Renal function including eGFR calculation & LDH. 
7 Including haptoglobin. 
8 Urinalysis: UPCR & Protein.  
9 For females of childbearing potential. 
1  Urine pregnancy test. 
11 Patients who meet the primary endpoint before week 24 and who stop drug must attend the Week 24 visit and the 30 day safety visit after last dose.   
12 Samples for PK and efficacy measurements (free nomacopan, CH50, total C5, ADA, LTB4(urine), sC5b-9, and C3b) will only be taken if patient received study drug < 1 week prior to this visit. 
13 Only SAEs considered possibly related or related to nomacopan to be reported at these visits.   
 

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
CONFIDENTIAL 
Page 70 of 85 
18.6 SCHEDULE OF EVENTS PART B (DOSE INCREASE) 
 
Evaluation & Procedures 
Day n Dose Increase7 (single ablation 
dose followed by increased maintenance 
dose 12 hrs later) 
Day n+1 
Day n+6 
(± 1 day) 
Proceed to Next 
Scheduled Visit 
 
Pre-dose 
12 hrs pre-dose 
Pre-dose 
Pre-dose 
 
 
 
 
 
 
 
Eligibility & ICF 
 
 
 
 
Scheduled visits 
according to 18.4 and 
18.5 will continue as 
scheduled.  If a 
PKPD visit that is 
scheduled due to a 
dose increase 
coincides with 18.4 
or 18.5 scheduled 
visit the visits will be 
combined. 
Medical History 
 
 
 
 
Demographics 
 
 
 
 
Physical Exam1 
 
 
 
 
Coombs’ Test & ECG8 
 
 
 
 
Nasal & Throat Swabs 
 
 
 
 
Vital signs 
 
 
 
 
CH503 
x 
x 
x 
x 
PK3 
x 
x 
x 
x 
Chemistry2,4 
 
 
 
x 
Haematology2,5 
 
 
 
x 
Urinalysis2,6 
x 
 
x 
x 
Urine pregnancy test 
 
 
 
 
Drug Accountability 
 
 
 
x 
AEs & Con Meds 
x 
x 
x 
x 
 
 
 
 
 
 
 
1 A physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological & cardiovascular systems, lungs, abdomen (liver & spleen), lymph nodes & extremities. 
A GVHD assessment will also be performed. 
2 Local laboratory. 
3 Central laboratory. 
4 Liver function, Renal function including eGFR calculation & LDH. 
5 Including haptoglobin. 
6 Urinalysis: UPCR & Protein. 
7 Dose increase 1 is a maintenance dose of 0.45 mg/kg and Dose increase 2 is a maintenance dose of 0.60 mg/kg. 
8 12-lead ECG. 
 
 
 
 

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
CONFIDENTIAL 
Page 71 of 85 
18.7 SCHEDULE OF EVENTS PARTS A AND B (TREATMENT EXTENSION) 
 
Evaluation & Procedures 
Week 24 
Week 28 
Week 32 
End of Study 
Treatment 
(Extension Period) 
Safety Follow-up, 
1 Year and 2 Years 
 
 
Pre-dose 
Pre-dose 
Pre-dose 
 
 
As per Week 24 Visit 
in 18.2 or 18.5 
 
 
 
As per 18.2 or 18.5 
Eligibility & ICF 
 
 
 
Medical History 
 
 
 
Demographics 
 
 
 
Physical Exam1 
x 
x 
x 
Coombs’ Test & ECG10 
 
 
 
Nasal & Throat Swabs 
 
 
 
Vital signs2 
x 
x 
x 
CH503 
x 
x 
x 
PK3 
x 
x 
x 
Total C53 
x 
x 
x 
Antibodies3 
x 
x 
x 
Urinary LTB43 
x 
x 
x 
sC5b-93,4 
x 
x 
x 
C3b3 
x 
x 
x 
Chemistry5,6 
x 
x 
x 
Haematology5,7 
x 
x 
x 
Urinalysis5,8 
x 
x 
x 
Urine pregnancy test9 
x 
x 
x 
Drug Accountability 
x 
x 
x 
AEs & Con Meds 
x 
x 
x 
 
 
 
 
 
1 A physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological & cardiovascular systems, lungs, abdomen (liver & spleen), lymph nodes & extremities. 
A GVHD assessment will also be performed. 
2 Vital signs: pulse rate, systolic & diastolic blood pressure, respiratory rate, & body temperature.  Vital signs are to be taken after the subject has been supine for at least 5 minutes.  Measurements 
should be repeated if clinically significant changes are observed or a machine error occurs.  In addition, weight should be measured every 4 weeks, and height at screening and Week 24. 
3 Central laboratory. For the 24 hours urine (LTB4) - in non-catheterised patients all urine samples over the period should be collected, as completely as possible. For younger children, urine from 
diapers/nappies should be collected if feasible. 
4 plasma sC5b-9 is mandatory before study entry and may be performed more frequently than shown at the investigator’s discretion. 
5 Local laboratory. 
6 Liver function, renal function including eGFR calculation & LDH. 
7 Including haptoglobin. 
8 Urinalysis: UPCR & Protein. 
9 For females of childbearing potential. 
10 12-lead ECG.

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
CONFIDENTIAL 
Page 72 of 85 
18.8 TOTAL BLOOD VOLUME CALCULATIONS 
 
In the tables that follow we present data on the % of blood sampled at each time point in Part A of the 
trial for the youngest female patient (average weight of 7.3 kg and an average blood volume of 584 mL) 
permitted to enter the trial.  Older patients and the Part B patients (who will have PKPD sampled less 
frequently) will have a smaller % of their blood sampled. 
Table 9 
Part A Dosing for youngest female patient –  
maintenance dose agreed with the FDA as part of Model Informed Drug Development 
6-month-old Female 
Average Weight (WHO) - 
7.3 kg 
 
Average Blood Volume - 
584 mL 
Volume of Blood Parameter (mL) 
Total 
Blood 
Volume 
(mL) 
Total 
Blood 
Volume 
in 24 
hours 
(mL) 
% of Average 
Blood Volume 
for 6-month-
old Female in 
24-hour period 
Hem/Chem 
Coombs’  
Pregnancy 
ADAMTS13 
sC5b-9 
CH50 + PK + ADA + C5 
C3b 
Study Visit 
Study 
Day 
Hour 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
-21 
- 
2 
1 
2 
1.8 
1 
 
 
7.8 
7.8 
1.3 
Day 1 
Intensive 
1 
0 
3 
6 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
2.5 
16.0 
2.7 
Day 2 
2 
0 
6 
12 
2 
 
 
 
1 
2.5 
2.5 
2.5 
 
5.5 
2.5 
2.5 
10.5 
1.8 
Day 4 
4 
0 
2 
 
 
 
1 
2.5 
 
5.5 
5.5 
0.9 
Day 7 
Intensive 
7 
0 
3 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
13.5 
2.3 
Day 14 
14 
0 
2 
 
 
 
1 
3.5 
2 
8.5 
8.5 
1.5 
Week 4 
Intensive 
28 
0 
3 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
13.5 
2.3 
Week 8 
56 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 12 
84 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 16 
112 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 20 
140 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 24 
168 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
30 Day F-U 
198 
0 
2 
 
 
 
 
 
 
2.0 
2.0 
0.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
CONFIDENTIAL 
Page 73 of 85 
Table 10 
Part A Dose Increase 1 for youngest female patient  
to maintenance dose of 0.45 mg/kg/12 hours – if required 
6-month-old Female 
Average Weight (WHO) - 
7.3 kg 
 
Average Blood Volume - 
584 mL 
Volume of Blood Parameter (mL) 
Total 
Blood 
Volume 
(mL) 
Total 
Blood 
Volume 
in 24 
hours 
(mL) 
% of Average 
Blood Volume 
for 6-month-
old Female in 
24-hour period 
Hem/Chem 
Coombs’  
Pregnancy 
ADAMTS13 
sC5b-9 
CH50 + PK + ADA + C5 
C3b 
Study Visit 
Study 
Day 
Hour 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
-21 
- 
2 
1 
2 
1.8 
1 
 
 
7.8 
7.8 
1.3 
Day 1 
Intensive 
1 
0 
3 
6 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
2.5 
16.0 
2.7 
Day 2 
2 
0 
6 
12 
2 
 
 
 
1 
2.5 
2.5 
2.5 
 
5.5 
2.5 
2.5 
10.5 
1.8 
Day 4 
4 
0 
2 
 
 
 
1 
2.5 
 
5.5 
5.5 
0.9 
Day n Dose 
Increase 
7 
0 
3 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
13.5 
2.3 
Day n+1 
8 
0 
6 
12 
 
 
 
 
 
2.5 
2.5 
2.5 
 
2.5 
2.5 
2.5 
7.5 
1.2 
Day n+2 
9 
0 
 
 
 
 
 
2.5 
 
2.5 
2.5 
0.4 
Day n+6 
13 
0 
3 
6 
12 
2 
 
 
 
 
2.5 
2.5 
2.5 
2.5 
 
4.5 
2.5 
2.5 
2.5 
12.0 
2.1 
Day 14 
14 
0 
2 
 
 
 
1 
3.5 
2 
8.5 
8.5 
1.5 
Week 4 
Intensive 
28 
0 
3 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
13.5 
2.3 
Week 8 
56 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 12 
84 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 16 
112 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 20 
140 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 24 
168 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
30 Day F-U 
198 
0 
2 
 
 
 
 
 
 
2.0 
2.0 
0.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol AK901 v4.0 
 
©Akari Therapeutics Plc 
11th November 2021 
CONFIDENTIAL 
Page 74 of 85 
Table 11 
Part A Dose Increase 2 for youngest female patient  
to maintenance dose of 0.60 mg/kg/12 hours – if required 
6-month-old Female 
Average Weight (WHO) - 
7.3 kg 
 
Average Blood Volume - 
584 mL 
Volume of Blood Parameter (mL) 
Total 
Blood 
Volume 
(mL) 
Total 
Blood 
Volume 
in 24 
hours 
(mL) 
% of Average 
Blood Volume 
for 6-month-
old Female in 
24-hour period 
Hem/Chem 
Coombs’  
Pregnancy 
ADAMTS13 
sC5b-9 
CH50 + PK + ADA + C5 
C3b 
Study Visit 
Study 
Day 
Hour 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
-21 
- 
2 
1 
2 
1.8 
1 
 
 
7.8 
7.8 
1.3 
Day 1 
Intensive 
1 
0 
3 
6 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
2.5 
16.0 
2.7 
Day 2 
2 
0 
6 
12 
2 
 
 
 
1 
2.5 
2.5 
2.5 
 
5.5 
2.5 
2.5 
10.5 
1.8 
Day 4 
4 
0 
2 
 
 
 
1 
2.5 
 
5.5 
5.5 
0.9 
Day n Dose 
Increase 1 
7 
0 
3 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
13.5 
2.3 
Day n+1 
8 
0 
6 
12 
 
 
 
 
 
2.5 
2.5 
2.5 
 
2.5 
2.5 
2.5 
7.5 
1.3 
Day n+2 
9 
0 
 
 
 
 
 
2.5 
 
2.5 
2.5 
0.4 
Day n+6 
13 
0 
3 
6 
12 
2 
 
 
 
 
2.5 
2.5 
2.5 
2.5 
 
4.5 
2.5 
2.5 
2.5 
12.0 
2.1 
Day n Dose 
Increase 2 
14 
0 
3 
6 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
2.5 
16.0 
2.7 
Day n+1 
15 
0 
6 
12 
 
 
 
 
 
2.5 
2.5 
2.5 
 
2.5 
2.5 
2.5 
7.5 
1.3 
Day n+2 
16 
0 
 
 
 
 
 
2.5 
 
2.5 
2.5 
0.4 
Day n+6 
20 
0 
3 
6 
12 
2 
 
 
 
 
2.5 
2.5 
2.5 
2.5 
 
4.5 
2.5 
2.5 
2.5 
12 
2.1 
Week 4 
Intensive 
28 
0 
3 
12 
2 
 
 
 
1 
3.5 
2.5 
2.5 
2 
8.5 
2.5 
2.5 
13.5 
2.3 
Week 8 
56 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 12 
84 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 16 
112 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 20 
140 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
Week 24 
168 
0 
2 
 
 
 
1 
3.5 
 
6.5 
6.5 
1.1 
30 Day F-U 
198 
0 
2 
 
 
 
 
 
 
2.0 
2.0 
0.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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18.9 ACUTE GVHD GRADING  
 
(Glucksberg-Seattle, adapted from: Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus 
conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–828) 
 
 
Skin 
Gastrointestinal 
(output/day) 
Liver 
Grade 0 
No Rash 
Child:  
<10 mL/kg/day 
 
Adult (if over 50kg): 
<500 mL/day 
Bilirubin <2 mg/dL 
Or 
Bilirubin <34 µmol/L 
Grade 1 
Rash <25% Body Surface 
Area 
 
Child:  
10-19.9 mL/kg/day 
Or  
persistent nausea/vomiting 
 
Adult (if over 50kg): 
500-1000 mL/day 
Or  
persistent nausea/vomiting 
Bilirubin 2-3 mg/dL 
Or 
Bilirubin 34-51 µmol/L 
Grade 2 
Rash 25-50% Body 
Surface Area 
 
Child:  
20–30 mL/kg/day 
 
Adult (if over 50kg): 
1001-1500 mL/day 
Bilirubin 3.1-6 mg/dL 
Or 
Bilirubin 52-102 µmol/L 
Grade 3 
Rash >50% Body Surface 
Area 
 
Child:  
>30 mL/kg/day 
 
Adult (if over 50kg): 
>1500 mL/day 
Bilirubin 6.1-15 mg/dL 
Or 
Bilirubin 103-255 µmol/L 
Grade 4 
Generalised erythroderma 
and bullae formation 
 
Severe abdominal pain 
with or without ileus 
Or 
Grossly bloody diarrhoea 
Bilirubin >15 mg/dL 
Or 
Bilirubin >255 µmol/L 
 
 
Skin 
Gastro-intestinal 
Liver 
Grade 1 
1-2 
0 
0 
Grade 2 
3 
1 
1 
Grade 3 
0-3 
2-3 
2-4 
Grade 4 
4 
4 
0-4 
 
 
 

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18.10 SUMMARY OF MAIN CHANGES AND JUSTIFICATION - VERSION 2.0 - VERSION 3.0 
 
• Change 1: Title Page and Protocol Signature page– Authorised Signatories and Sponsor’s 
Medical Expert  
 
Previous text: 
 
AUTHORISED SIGNATORIES:  Dr James Fettiplace MBBS 
 
SPONSOR’S MEDICAL 
Dr James Fettiplace MBBS 
EXPERT 
 
Updated text: 
 
AUTHORISED SIGNATORIES:  Dr Sanjeev K Khindri, MB, ChB, MRCP  
 
 
SPONSOR’S MEDICAL 
Dr Sanjeev K Khindri, MB, ChB, MRCP  
EXPERT 
Senior Medical Director  
 
Justification:  
Change in the sponsor’s medical expert and authorised signatory 
 
 
• Change 2: Inclusion Criterion #4, Secondary Endpoint, Central Laboratory Tests:  
 
Previous text (Synopsis, Section 5.1): 
 
4. Clinical diagnosis of TMA with all of the following diagnostic criteria: 
▪ elevated serum C5b-9 (80% or more of ULN for age) 
▪ Urine protein creatinine ratio > 2 mg/mg (demonstrated on two separate morning samples, at 
least one day apart) 
▪ elevated LDH (> ULN) 
▪ thrombocytopaenia (< 50,000 per mm3) 
▪ low haemoglobin concentration (< LLN) 
 
or 
 
Histological diagnosis of TMA with evidence of complement deposition: 
▪ Urine protein creatinine ratio > 2 mg/mg (demonstrated on two separate morning samples, at 
least one day apart), and 
elevated serum C5b-9 (80% or more of ULN for age) 
 
Updated text (Synopsis, Section 5.1): 
 
4. Clinical diagnosis of TMA with all of the following diagnostic criteria: 
▪ elevated plasma serum sC5b-9 (80% or more of ULN for age) 
▪ Urine protein creatinine ratio > 2 mg/mg (demonstrated on two separate morning samples, at 
least one day apart) 
▪ elevated LDH (> ULN) 
▪ thrombocytopaenia (< 50,000 per mm3) 
▪ low haemoglobin concentration (< LLN) 
 
or 
 
Histological diagnosis of TMA with evidence of complement deposition: 

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▪ Urine protein creatinine ratio > 2 mg/mg (demonstrated on two separate morning samples, at 
least one day apart), and 
elevated serum plasma sC5b-9 (80% or more of ULN for age) 
 
Previous text (Secondary Endpoints – Synopsis, Section 4.2.2): 
 
▪ Percentage of patients who achieve the primary endpoint of urine protein creatinine ratio 
≤ 2 mg/mg (the nephrotic threshold) for ≥ 28 days 
▪ Platelet transfusion independence† for ≥ 28 days 
▪ Serum sC5b-9 ≤ ULN 
▪ Lactate dehydrogenase (LDH) ≤ ULN 
▪ Normalization of haptoglobin 
 
Updated text (Secondary Endpoints– Synopsis, Section 4.2.2): 
 
▪ Percentage of patients who achieve the primary endpoint of urine protein creatinine ratio 
≤ 2 mg/mg (the nephrotic threshold) for ≥ 28 days 
▪ Platelet transfusion independence† for ≥ 28 days 
▪ Plasma Serum sC5b-9 ≤ ULN 
▪ Lactate dehydrogenase (LDH) ≤ ULN 
▪ Normalization of haptoglobin 
 
Previous text (Section 6.6.3 – Total C5, sC5b-9 and C3b assay): 
 
All samples will be taken as per the Schedule of Events in Section 18.  The screening sC5b-9 sample 
can be analysed locally or centrally for a quicker turnaround.    All sC5b-9 samples that follow will 
be sent to a central laboratory. 
 
Updated text (Section 6.6.3 – Total C5, sC5b-9 and C3b assay): 
 
All samples will be taken as per the Schedule of Events in Section 18. The screening sC5b-9 sample 
can be analysed locally or centrally for a quicker turnaround.    All sC5b-9 samples that follow will 
be sent to a central laboratory. All sC5b-9 samples will be analysed centrally and measured in 
plasma.  
 
Justification:  
To ensure a comparable assessment of soluble C5b9 (sC5b9) from clinical sites in both the USA 
and Europe we are now planning to use a single lab (Cincinnati Children’s Hospital, CCH) for 
measurement of sC5b9 from all sites. CCH requires plasma rather than serum for use in their 
validated sC5b9 assay.  The change from collecting serum to collecting plasma from patients does 
not present any safety issues as the mode (IV draw) and frequency is not changed by collecting 
plasma-EDTA rather than serum.  The change to measurement of sC5b9 from plasma-EDTA rather 
than serum also has no impact on assessment of the secondary endpoint of “Serum sC5b9 < ULN” 
as the endpoint is a relative one.  Thus it does not make a difference whether sC5b9 is measured 
from serum or plasma as if the sC5b9 is normalised at the end of nomacopan treatment patients 
achieve the endpoint ie patients join the trial with sC5b9 >ULN and to achieve the secondary 
endpoint must have sC5b9 < ULN at the last efficacy assessment in the trial before nomacopan 
treatment is stopped. 
 
C5b-9 is a cell surface protein/biomarker and as we are measuring the circulating ie soluble C5b-9 
in plasma, we have added sC5b-9 to provide clarity.  We have made this change consistently 
throughout the protocol.  

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We are not aware of any age-specific reference ranges for sC5b-9 and therefore have modified the 
inclusion criterion to >80% of ULN without adjusting for age.  Furthermore, as all samples are being 
analysed at a single central laboratory in a Children’s Hospital, the laboratory’s reference range will 
be applied across the overall study population.  
 
 
• Change 3: Inclusion Criterion #6  
 
Previous text (Synopsis, Section 5.1): 
6. Provision of informed assent  
 
Updated text (Synopsis, Section 5.1): 
6. Provision of informed assent (where appropriate) 
 
Justification:  
To clarify that informed assent will not be taken from all participants but only where appropriate.  
 
 
• Change 4: Other Assessments - Pregnancy Test– Screening  
 
Previous text (Section 6.4.1 & 6.8.1): 
 
Blood samples: blood samples for haematology and chemistry will be taken for assay at the local 
laboratory, and blood samples for direct Coomb’s Test, ADAMTS13, sC5b-9 and a serum 
pregnancy test for all females of childbearing potential will be taken for assay at the local or central 
laboratory. 
 
New text (Section 6.4.1 & 6.8.1): 
 
Blood samples: blood samples for haematology, chemistry and direct Coombs’ Test will be taken 
at the local laboratory. ADAMTS13 and sC5b-9 will be performed at a central laboratory. All 
females who are of childbearing potential must have a serum negative pregnancy test at screening.  
Where a site is not able to perform a serum pregnancy, a urine pregnancy test will be acceptable. 
This test will be performed at the local or central laboratory. 
 
Justification:  
Based on the outcome of ongoing feasibility and conduct of pre-study site selection visits, it has 
come to light that some sites will not be able to perform a serum pregnancy test, therefore, at these 
sites a urine pregnancy test will be acceptable.   
 
 
• Change 5: Section 6.4.2 Part A - Day 1, Day 2, Day 7, Week 4, Dose Increase (n, n+1, n+6) Pre-
dose  
 
New text: 
 
If the 12-hour samples cannot be taken for logistical reasons, then 9-hour samples can be taken.   
 
Justification:  
Based on the outcome of ongoing feasibility and conduct of pre-study site selection visits, it is come 
to light that many sites may not be able to perform the 12-hour blood draw as stipulated in the 
protocol.  The issue has arisen from the opening times of laboratories and resourcing of site staff to 

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centrifuge and prepare the tubes for storage. Therefore, in these circumstances, a 9-hour sample is 
acceptable. The site should note and specify where this occurs. 
 
 
• Change 6: Section 6.4.2 Part A - Day 3 
 
New text: 
 
These samples will NOT be taken for the youngest age cohort. 
 
Justification:  
In order to minimise the volume of blood drawn over any given 24-hour period and across the entire 
study, a trough sample will not be taken on Day 3.  Trough samples are taken at other timepoints 
over the course of the study; therefore, the overall assessment of PK/PD will not be negatively 
impacted.  
 
 
• Change 7: Section 6.4.2 Part A - Day 7 (+/- 1 day), Week 4 (Day 28 (+/- 5 days) 
 
Previous text: 
 
Additional blood samples for CH50 and PK assessments will be taken at 3, 6 and 12 hours 
(immediately prior to the next dose of nomacopan) after the morning dose.  Any AEs and 
concomitant medications will be recorded at these time points.  
 
New text: 
 
Additional blood samples for CH50 and PK assessments will be taken at 3, 6 and 12 hours 
(immediately prior to the next dose of nomacopan) after the morning dose.  In the youngest age 
cohort, samples will be taken pre-dose at 3 and 12 hours only.  If the-12 hour samples cannot, be 
taken for logistical reasons, then 9-hour samples can be taken. 
 
Justification:  
In order to minimise the volume of blood drawn over any given 24-hour period and across the entire 
study, a 6-hour sample will not be taken on Day 7 and Week 4. With the evaluation of PK/PD at 3 
and 12 hours the overall assessment of PK/PD will not be negatively impacted.  
 
 
• Change 8: Section 6.5.2 Haematology for Part A and Part B   
 
Previous text: 
 
The haematology parameters to be assessed at each specified time point are haemoglobin, 
haematocrit, total WBC, neutrophils, RBC, platelets, reticulocytes, haptoglobin and MCV. 
 
Updated text:  
 
The haematology parameters to be assessed at each specified time point are haemoglobin, 
haematocrit, total WBC, neutrophils, lymphocytes, monocytes, basophils, eosinophils, RBC, 
platelets, reticulocytes, haptoglobin and MCV. 
 

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Justification:  
A full white blood cell panel was missing and therefore has been added.  
 
 
• Change 9: Section 6.6.2 Pharmacokinetics (PK)  
 
Previous text: 
 
Unbound nomacopan concentration will be measured from plasma-EDTA by ELISA.  All samples 
will be taken as per the Schedule of Events in Section 18. 
 
Updated text:  
 
Unbound nomacopan concentration will be measured from serum plasma-EDTA by ELISA.  All 
samples will be taken as per the Schedule of Events in Section 18. 
 
Justification:  
Plasma-EDTA sample for measurement of unbound nomacopan is incorrect. Our validated assay 
for measurement of unbound nomacopan requires a serum sample. 
 
 
• Change 10: Section 6.6.4 LTB4 (urinary)  
 
New text: 
 
For determination of urinary LTB4, 24-hour urine samples will be collected.  Patients should NOT 
be catheterised specifically to allow for the collection of this urine sample.  For patients who are not 
catheterised (for other medical reasons), all urine samples should be collected over the defined 24-
hour period. In younger children, where possible, urine from diapers/nappies should be collected.   
 
 
Justification:  
New text added to clarify that LTB4 will measured in a 24-hour urine sample and that patients 
should NOT be catheterised specifically to collect this sample. In addition, guidance has been 
provided on collecting urine from diapers/nappies in the youngest patients (where possible).  
 
 
• Change 11:– ALL Schedule of events Part A and Part B and Dose Calculation Tables 
 
The schedule of events and dose calculation tables have been updated to reflect the above changes. 
 
 
 

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18.11 SUMMARY OF MAIN CHANGES AND JUSTIFICATION – VERSION 3.0 - VERSION 4.0 
 
• Change 1:– Inclusion Criterion #3  
 
Previous text (Synopsis, Section 5.1): 
 
3. TMA diagnosis within 100 days of their first allogeneic or autologous HSCT. 
 
Updated text:  
 
3. TMA diagnosis within 100 days a year of their first allogeneic or autologous HSCT. 
 
Justification:  
In paediatric patients, whilst transplant associated TMA (TA-TMA) typically occurs early after 
allogenic HSCT with a median diagnosis of between 35 and 47 days and approximately 90 % occur 
within 100 days, a small but important number of patients develop TMA up to a year after HSCT.  
In addition, TMA can develop after any HSCT, whether this is the first or subsequent/sequential 
transplant, indeed may be more common after second or subsequent transplants.  Based on this data 
and taking into account advise received from our investigators, we have revised the eligibility 
criteria to allow the recruitment of patients with TA-TMA that occurs within a year of any HSCT 
and not limited only to that occurring after the first transplant. 
 
• Change 2:– Exclusion Criterion #3  
 
Previous text (Synopsis, Section 5.2, 18-Schedule of Events, Blood Volume Tables): 
 
3. Patients who do not receive nomacopan within 14 days of the initial diagnosis of TMA. 
 
Updated text:  
 
3. Patients who do not receive nomacopan within 14 21 days of the initial diagnosis of TMA. 
 
Justification: 
Whilst it is important to identify and initiate treatment with nomacopan for TMA as soon as possible, 
given diagnostic and logistical challenges to complete all diagnostic tests and those to establish 
eligibility, we have, considered advice from our investigators and propose to allow for a screening 
window of up to 21 days, although a concerted effort to randomise eligible patients as soon as 
possible will be made. 
 
• Change 3:– Summary of known and potential risks and benefits to human patients  
 
Previous text (Section 3.3.1): 
 
To date (August 2019), nomacopan has been administered by subcutaneous (sc) injection or 
ophthalmic (eye drops) routes to 64 subjects (32 healthy volunteers and 32 patients) - see Table 2.  
Fifty-six of the subjects are adults in clinical trials, and eight were children who received 
compassionate use nomacopan under a UK “specials licence”. 
 
Nomacopan was administered to 16 healthy male subjects in a Phase Ia single ascending dose study 
(VA576), 16 healthy male subjects in a Phase Ib 7-day repeat dose study (AK577), one eculizumab-
resistant PNH patient in a Phase II study (AK578), eight PNH patients in the Phase II study 

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(AK579), one eculizumab resistant PNH patient in AK585, five PNH patients in AK580, six bullous 
pemphigoid patients in AK801, and using ophthalmic eye drops three patients with atopic 
keratoconjunctivitis. 
 
 
Additionally, eight complex paediatric HSCT-TMA patients with advanced disease were treated 
with subcutaneous nomacopan using a compassionate use/ “specials” licence.  
 
In all of these subjects, nomacopan has generally been found to be well tolerated. 
 
Table 12 
Total Number of Subjects Exposed to Nomacopan in Clinical Trials & as Named Patients (07 
Aug 2019) 
Study 
Phase 
Number of 
Subjects 
Indication/route of admin 
sc = subcutaneous 
O = ophthalmic eye drops 
 
 
 
 
Healthy Volunteers 
VA576 
Ia 
16 
Healthy volunteer, sc 
VA577 
Ib 
16 
Healthy volunteer, sc 
Total Volunteers 
32 
 
 
 
 
 
Patients 
AK578 
II 
1 
PNH, sc 
AK579 
II 
8 
PNH, sc 
AK580 
III 
5 
PNH (ongoing), sc 
AK585 
II 
1 
PNH, sc 
AK801 
II 
6 
Bullous pemphigoid (ongoing), sc 
AK701 
II 
3 
Atopic keratoconjunctivitis 
(ongoing), O 
Compassionate use/Specials 
licence named patients 
8 
HSCT-TMA Pediatric, sc 
Total Patients 
32 
 
 
 
 
Overall Total 
64 
 
 
 
 
 
 
In the Phase Ia trial (VA576) four mild, non-serious AEs were reported in three subjects (two active 
and one placebo) but a causal relationship to the study drug was not established.  There was no dose 
relationship and the AEs were mild and self-limiting. 
 
In the Phase Ib trial (VA577), an AE was reported which the investigator considered was not study 
drug related.  This patient was assessed by the investigator as having rhabdomyolysis and stopped 
treatment after the third dose of nomacopan.  The patient also experienced asymptomatic raised 
creatinine kinase and serum myoglobin levels which the investigator considered were related to the 
administration of ciprofloxacin as a prophylactic antibiotic during the trial.  Twenty-two other non-
serious, mild/moderate AEs were reported in this trial in seven patients, all of which resolved 
without treatment. 
 
In the Phase II trial (AK578) the only PNH subject who was enrolled and completed the study 
benefited from nomacopan and currently continues therapy on nomacopan twice daily in Study 
AK581 (15 mg every 12 hours).  The drug was generally well-tolerated.  Overall, two SAEs 
occurred within this study.  The patient had breakthrough haemolysis (worsening of PNH symptoms 
presenting with fatigue and dark urine) on Day 5 of treatment before full control of the disease had 

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been achieved.  The investigators considered that this SAE was unrelated to nomacopan.  The 
second SAE was a lung infection in which the patient presented with fever and cough.  This SAE 
was assessed as not related to nomacopan.  No other significant findings arose from this study. 
 
Overall, nomacopan was well tolerated in the Phase II AK579 trial.  There were no drug related 
SAEs and few drug related AEs other than mild to moderate injection site reactions.  SAEs were 
reported in two patients.  One patient had an SAE of staphylococcal infection, and another patient 
had SAEs of angina pectoris, lethargy and dyspnoea.  All four SAEs resolved during the study and 
were considered to be not related to nomacopan.  The most frequently reported nomacopan-related 
AEs were injection site reactions (eg erythema, pruritis, bruising, pain, swelling, discharge, 
hypersensitivity, induration, or haematoma), which were reported in six out of the eight patients 
enrolled. 
 
Two SAEs have been reported in Study AK580, neutropenic sepsis and haemolysis.  Neither of 
these events was assessed as related to nomacopan, and they have both resolved.  This study is 
ongoing. 
 
Three SAEs were reported in Study AK585 in one patient (002-001) Grade 3 febrile neutropaenia, Grade 
3 device-related infection and Grade 3 urinary tract infection.  None of these events was assessed as 
related to nomacopan.  All SAEs resolved.  The study has finished. 
 
One non-related SAE has been reported in Study AK801 (condition aggravated).  The SAE resolved.  
This study is ongoing. 
 
Patients in the PNH trials AK578, AK579, AK580 and AK585 are eligible to continue treatment 
with nomacopan within the long-term safety study (AK581).  To date (August 2019) 10 patients 
have entered the AK581 study only four of whom have experienced treatment related AEs to date.  
These were mostly injection site reactions which have all resolved. 
 
In all clinical trials to date nomacopan has been well tolerated and there have been no serious drug-
related adverse events, no suspected unexpected serious adverse reactions (SUSARs) and no 
treatment emergent adverse events other than mild to moderate injection site reactions.  These have 
been of a comparable type and severity to those seen with other subcutaneously administered drugs 
(eg insulin) and are not considered to be drug related. The most frequently reported TEAE is 
injection site discomfort, erythema, redness or pain. 
 
 
Updated text:  
 
To date (August 2021), nomacopan has been administered by subcutaneous (sc) injection or 
ophthalmic (eye drops) routes to 97 subjects (32 healthy volunteers and 65 patients) - see Table 2.  
Fifty-six of the subjects are adults in clinical trials, and eight were children who received 
compassionate use nomacopan under a UK “specials licence” 
 
Nomacopan was administered to 16 healthy male subjects in a Phase Ia single ascending dose study 
(VA576), 16 healthy male subjects in a Phase Ib 7-day repeat dose study (AK577), one eculizumab-
resistant PNH patient in a Phase II study (AK578), eight PNH patients in the Phase II study 
(AK579), one eculizumab resistant PNH patient in AK585, nine PNH patients in AK580, nine 
bullous pemphigoid patients in AK801, and using ophthalmic eye drops six patients with atopic 
keratoconjunctivitis. 
 
 
Commented [RV1]: Hard to see what the changes are, 
perhaps we can bold the text in the updated text? 

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Additionally, nine complex paediatric HSCT-TMA patients with advanced disease were treated 
with subcutaneous nomacopan using a compassionate use/ “specials” licence or on a named 
patient basis. 
 
In all of these subjects, nomacopan has generally been found to be well tolerated. 
 
Table 13 
Total Number of Subjects Exposed to Nomacopan in Clinical Trials & as Named Patients (07 
Aug 2021) 
Study 
Phase 
Number of 
Subjects 
Indication/route of admin 
sc = subcutaneous 
O = ophthalmic eye drops 
 
 
 
 
Healthy Volunteers 
VA576 
Ia 
16 
Healthy volunteer, sc 
VA577 
Ib 
16 
Healthy volunteer, sc 
Total Volunteers 
32 
 
 
 
 
 
Patients 
AK578 
II 
1 
PNH, sc 
AK579 
II 
8 
PNH, sc 
AK580 
III 
9 
PNH, (ongoing), sc 
AK585 
II 
1 
PNH (ongoing), sc 
AK801 
II 
9 
Bullous pemphigoid (ongoing), sc 
AK701 
II 
6 
Atopic keratoconjunctivitis 
(ongoing: LSLV complete: CSR 
being written), O 
Compassionate use/ /Specials 
licence named patients 
8 
HSCT-TMA Pediatric, sc 
Compassionate use/Investigator-
initiated program  
23 
Covid-19 pneumonia, sc 
Total Patients 
 65 
 
 
 
 
Overall Total 
97 
 
 
 
 
 
 
In the Phase Ia trial (VA576) four mild, non-serious AEs were reported in three subjects (two active 
and one placebo) but a causal relationship to the study drug was not established.  There was no dose 
relationship, and the AEs were mild and self-limiting. 
 
In the Phase Ib trial (VA577), an AE was reported which the investigator considered was not study 
drug related.  This patient was assessed by the investigator as having rhabdomyolysis and stopped 
treatment after the third dose of nomacopan.  The patient also experienced asymptomatic raised 
creatinine kinase and serum myoglobin levels which the investigator considered were related to the 
administration of ciprofloxacin as a prophylactic antibiotic during the trial.  Twenty-two other non-
serious, mild/moderate AEs were reported in this trial in seven patients, all of which resolved 
without treatment. 
 
In the Phase II trial (AK578) the only PNH subject who was enrolled and completed the study 
benefited from nomacopan and currently continues therapy on nomacopan twice daily in Study 
AK581 (15 mg every 12 hours).  The drug was generally well-tolerated.  Overall, two SAEs 
occurred within this study.  The patient had breakthrough haemolysis (worsening of PNH symptoms 
presenting with fatigue and dark urine) on Day 5 of treatment before full control of the disease had 
been achieved.  The investigators considered that this SAE was unrelated to nomacopan.  The 

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second SAE was a lung infection in which the patient presented with fever and cough.  This SAE 
was assessed as not related to nomacopan.  No other significant findings arose from this study. 
 
Overall, nomacopan was well tolerated in the Phase II AK579 trial.  There were no drug related 
SAEs and few drug related AEs other than mild to moderate injection site reactions.  SAEs were 
reported in two patients.  One patient had an SAE of staphylococcal infection, and another patient 
had SAEs of angina pectoris, lethargy and dyspnoea.  All four SAEs resolved during the study and 
were considered to be not related to nomacopan.  The most frequently reported nomacopan-related 
AEs were injection site reactions (eg erythema, pruritis, bruising, pain, swelling, discharge, 
hypersensitivity, induration, or haematoma), which were reported in six out of the eight patients 
enrolled. 
 
In the Phase III trial (AK580) in PNH, three patients experienced four SAEs.  One patient had 
two SAEs of cholelithiasis and haemoglobinuria (associated with worsening of PNH).  A 
second patient had an episode of catheter site infection and a third had an episode of viral 
gastroenteritis.  These events were assessed as not being related to nomacopan, and all  
resolved. One patient had two SAEs of neutropenic sepsis and haemolysis during screening 
and were not randomised into the study.  This study has finished. 
 
Three SAEs were reported in Study AK585 in one patient (002-001) Grade 3 febrile neutropaenia, Grade 
3 device-related infection and Grade 3 urinary tract infection.  None of these events was assessed as 
related to nomacopan.  All SAEs resolved.  The study is ongoing. 
 
In the Phase II trial (AK801) in BP, three patients each had one non-related SAE.  One patient 
had an episode of a localised (knee) infection that had not resolved by the end of study.  The 
other two patients had a single episode of condition (ie BP) aggravated with both resolving.  
This study has finished. 
 
In the Phase II, randomised and placebo controlled trial in SACK (AK701), six patients 
received nomacopan  whilst six received placebo.  There were no SAEs.  The study has 
finished. 
 
Patients in the PNH trials AK578, AK579, AK580 and AK585 were eligible to continue treatment 
with nomacopan within the long-term safety study (AK581).  Three of fifteen patients 
experienced a total of 13 SAEs during the study.  One patient experienced an episode of an 
E. coli UTI that was considered possibly related to nomacopan.  Based on a history of 
previous recurrent UTIs that usually resolved with oral antibiotics, the sponsor did not 
consider this a related event.  This patient also had three other SAEs.  One patient had two 
unrelated SAE whilst the another had six unrelated SAEs.  Only one of these events 
(pulmonary hypertension had not resolved).  The study has finished.  
 
In all clinical trials to date nomacopan has been well tolerated and there have been no serious drug-
related adverse events, no suspected unexpected serious adverse reactions (SUSARs) and no 
treatment emergent adverse events other than mild to moderate injection site reactions.  These have 
been of a comparable type and severity to those seen with other subcutaneously administered drugs 
(eg insulin) and are not considered to be drug related. The most frequently reported TEAE is 
injection site discomfort, erythema, redness or pain. 
 
Justification:  
Updated safety information on completed and ongoing studies in line the most recent DSUR 07 Aug 
2021