A Phase II, Double-blind, Placebo-controlled, Randomized, Cross-over, Dose-ranging Study of Oral PHA-022121 for Acute Treatment of Angioedema Attacks in Patients With Hereditary Angioedema Due to C1-inhibitor Deficiency Type I and II
Phase: PHASE2
Conditions: Hereditary Angioedema, Hereditary Angioedema Type I, Hereditary Angioedema Type II, Hereditary Angioedema Types I and II, Hereditary Angioedema Attack, Hereditary Angioedema With C1 Esterase Inhibitor Deficiency, Hereditary Angioedema - Type 1, Hereditary Angioedema - Type 2, C1 Esterase Inhibitor Deficiency, C1 Inhibitor Deficiency
Sponsor: Pharvaris Netherlands B.V.

 
Confidential 
The information contained in this document is the property of Pharvaris Netherlands BV and may not be 
reproduced, published or disclosed to others without written authorization from Pharvaris Netherlands BV. 
Clinical Study Protocol: PHA022121-C201 
 
Study Title: 
A Phase II, double-blind, placebo-controlled, Randomized, cross-
over, dose-ranging study of oral PHA-022121 for Acute treatment 
of angioedema attacks in Patients with hereditary angioedema due 
to C1-Inhibitor Deficiency type I and II 
Acronym: 
RAPIDe-1 
Study Number: 
PHA022121-C201 
Study Phase: 
Phase II 
Product Name: 
PHVS416 (PHA-022121 soft capsules) 
Indication: 
Hereditary angioedema 
EudraCT Number: 
2020-003445-11 
Investigators: 
Multicenter 
Sponsor: 
Pharvaris Netherlands BV (Leiden, The Netherlands) 
Sponsor Contact: 
clinical@pharvaris.com 
Sponsor 
Representatives: 
 
Chief Medical Officer 
 
Executive Director 
Clinical Development 
 
 
Date 
Protocol version 
Original Protocol: 
18 August 2020 
1.0 
Amendment 1 (UK only): 
22 December 2020 
1.1 
Amendment 2 (Germany only): 
27 January 2021 
1.2 
Amendment 3 (France only): 
08 March 2021 
1.3 
Amendment 4 (Czech Republic only): 
12 March 2021 
1.4 
Amendment 5 (global): 
08 April 2021 
2.0 
Amendment 6 (France only): 
28 June 2021 
2.1 
Amendment 7 (global): 
25 April 2022 
3.0 
 

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SYNOPSIS 
Sponsor: 
Pharvaris Netherlands BV (Leiden, The Netherlands) 
Name of Finished Product: 
PHVS416 (PHA-022121 soft capsules) 
Name of Active Ingredient: 
PHA-022121 
Study Title: 
A Phase II, double-blind, placebo-controlled, Randomized, cross-over, dose-ranging study 
of oral PHA-022121 for Acute treatment of angioedema attacks in Patients with hereditary 
angioedema due to C1-Inhibitor Deficiency type I and II 
Acronym: 
RAPIDe-1 
Study Number: 
PHA022121-C201 
Study Phase:  
Phase II 
Primary Objective: 
To evaluate the efficacy of three different single doses of PHA-022121 versus placebo in 
achieving angioedema symptom reduction, defined as change in the 3-symptom composite 
visual analogue scale (VAS-3) score during acute attacks in patients with hereditary 
angioedema (HAE) type I/II 
Secondary Objectives: 
The key secondary objectives of the study are: 
To evaluate the clinical efficacy of three different single doses of PHA-022121 versus 
placebo with regards to:  
• Time to onset of symptom relief by VAS-3, 
• Time to almost complete or complete symptom relief by VAS-3,  
• Change in mean symptom complex severity (MSCS) score at 4 h post-treatment, 
• Treatment outcome score (TOS) at 4 h post-treatment. 
 
Other secondary objectives of the study are: 
• To evaluate the clinical efficacy of three different single doses of PHA-022121 versus 
placebo with regards to: 
o Time to onset of primary symptom relief by visual analog scale (VAS) 
o Proportion of investigational medicinal product (IMP)-treated attacks requiring the 
use of HAE rescue medication 
o Time to the first use of HAE rescue medication 

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o Change in the individual VAS scores (skin pain, skin swelling, abdominal pain) 
from pre-treatment to 4 h post-treatment 
o Change in MSCS score at 24 h post-treatment 
o TOS at 24 h post-treatment 
• To evaluate the safety of three different single doses of PHA-022121 versus placebo 
• To evaluate the pharmacokinetics, dose-effect relationship, and concentration-effect 
relationship of PHA-022121 
• To evaluate the treatment satisfaction questionnaire for medication (TSQM) scores at 
48 h post-treatment 
 
Study Design: 
• After signing informed consent, patients will be screened for eligibility. Eligible 
patients will be enrolled in the study. 
• Enrolled patients will be randomized to one of the three dose levels (low, medium, 
high) first, then based on the assigned cohort randomized to one of nine treatment 
sequences comparing three single doses of PHA-022121 (low, medium, high) with 
placebo treatment. During Part I (at the study site), patients in quiescent state will 
receive the assigned active single dose of PHA-022121 (dose is blinded) to assess 
pharmacokinetics and safety.  
• In Part II of the study, patients will self-administer blinded study drug in the assigned 
treatment sequence at home to treat three qualifying HAE attacks, which should be 
consulted and confirmed by the investigator or designee via remote contact. The study 
drug should be taken when at least one attack symptom (skin pain, skin swelling, or 
abdominal pain) becomes of moderate intensity (VAS score ≥ 30). When the attack 
reaches this VAS intensity threshold, study drug should preferably be taken during the 
remote contact with the investigator or designee. If the patient cannot take the study 
drug within 3 h after reaching the VAS intensity threshold, the attack does not qualify 
for study drug treatment and should be treated with the patient’s standard HAE 
medication. In addition, treatment of the attack should happen within 6 h after onset of 
symptoms at any location. If the study drug cannot be administered within 6 h after 
onset of symptoms, the attack does not qualify for study drug treatment and should be 
treated with the patient’s standard HAE medication. Any symptoms involving the 
internal head and neck, regardless of intensity, also render an attack non-qualifying for 
treatment with study drug and should be treated with the patient’s standard HAE 
medication.  
At 4 h post study drug treatment, the patient will consult with the investigator or 
designee remotely again to assess symptom relief, safety, and any need for rescue 
medication.  
Patient-reported outcomes (PROs) are collected from study drug intake (including pre-
treatment) until 48 h post-treatment. After each attack treated with study drug, a safety 
follow-up visit will take place within 5 days post-treatment. Meanwhile, 
pharmacokinetic plasma samples are planned to be collected within 24 h post-treatment 
(preferably within 12 h) from a subset of patients for at least 50 attacks treated with 
PHA-022121 or placebo.  
In order to avoid carry-over effects of previous treatments, HAE attacks that occur 

PHVS416 (PHA-022121 soft capsules) 
 
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Clinical Study Protocol: PHA022121-C201 
 
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within 5 days of a previously treated attack (regardless of whether study drug or 
standard HAE medication was used) will not qualify for treatment with study drug. 
• The end-of-study visit will take place 10±5 days post-treatment of the last attack. This 
visit may be waived if patients continue in another clinical study with 
PHA-022121conducted by the Sponsor. 
 
 
 
Study Population:  
Approximately 72 male or female, adult patients with HAE due to C1-inhibitor deficiency 
(HAE type I/II) will be randomized in this study. For eligibility in the study, patients need 
to have experienced at least three HAE attacks in the last 4 months, or at least two HAE 
attacks in the last 2 months. The expected study duration per patient amounts to 
approximately 30 weeks, consisting of the Screening period of up to 4 weeks, the 
Non-attack visit (Part I), home treatment (Part II) of about 24 weeks (covering 3 qualifying 
attacks treated with study drug per patient), and up to 2 weeks until the end-of-study visit. 
In some cases, patients may need longer than 24 weeks to complete the assessments for 
3 qualifying attacks; therefore, the individual duration per patient may be longer. 
The study is planned to be conducted at approximately 35 study sites across 
12-15 countries. 

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Investigational Medicinal Product (IMP), Dose, and Mode of Administration:  
The IMP consists of 10 mg PHA-022121 soft capsules and matching placebo soft capsules 
for oral use:  
• Low dose (10 mg): one capsule of 10 mg PHA-022121 and two placebo capsules 
• Medium dose (20 mg): two capsules of 10 mg PHA-022121 and one placebo capsule 
• High dose (30 mg): three capsules of 10 mg PHA-022121 
• Placebo: three placebo capsules 
Duration of Treatment: 
In Part I, patients will receive one single dose of PHA-022121 (10, 20, or 30 mg). 
In Part II, patients will receive two single doses of PHA-022121 (10, 20, or 30 mg) and 
one single dose of placebo. 
Efficacy Assessments: 
Efficacy will be assessed during Part II with four PROs:  
• VAS scores of the three major HAE symptoms, including skin pain, skin swelling, and 
abdominal pain 
• MSCS score 
• TOS 
• TSQM scores 
Safety Assessments: 
• Physical examination 
• Vital signs 
• Digital 12-lead electrocardiogram (ECG) 
• Safety laboratory testing (blood chemistry, hematology, coagulation, urinalysis, 
pregnancy test) 
• Adverse events 
• HAE diary 

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Statistical Methods:  
All efficacy analyses will be performed on the Modified Intent-To-Treat (mITT) Analysis 
Set, defined as all randomized patients who had at least one HAE attack treated with study 
drug (PHA-022121 or placebo) and had non-missing VAS results at both pre-treatment and 
at least one post-treatment time point of that attack. All statistical tests are carried out 
2-sided. The primary endpoint, i.e., the change of the VAS-3 score from pre-treatment to 
4-h post-treatment, will be analyzed using a mixed model for repeated measures (MMRM) 
allowing within-patient and between-patient comparisons. The key secondary efficacy 
endpoints include time to onset of symptom relief assessed by ≥30% reduction in VAS-3 
score from pre-treatment, time to almost complete or complete symptom relief by VAS (all 
3 individual VAS scores reduced to ≤ 10 is considered almost complete, all scores reduced 
to 0 is complete symptom relief), time to ≥50% reduction in VAS-3 score from 
pre-treatment, change in MSCS score from pre-treatment to 4 h post-treatment, and TOS at 
4 h post-treatment. For these endpoints, marginal Cox proportional hazards models 
(CPHM) will be used for time-to-event endpoints, and MMRM will be used for continuous 
endpoints. For the analyses of primary and key secondary endpoints, multiplicity control 
procedure will be applied in testing the medium and high doses with the overall type 1 
error rate controlled at a 5% significance level for a 2-sided test. 
Date of Original Approved Protocol:  
18 August 2020 
Date of Most Recent Protocol Amendment:  
25 April 2022 (Amendment 7) 

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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF APPENDICES ..........................................................................................................10 
LIST OF TABLES ...................................................................................................................10 
LIST OF FIGURES .................................................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1 
INTRODUCTION ...........................................................................................................15 
1.1 
Study Rationale ......................................................................................................15 
1.2 
Background ............................................................................................................15 
1.2.1 
Hereditary Angioedema ...............................................................................15 
1.2.2 
Current Treatment of HAE ..........................................................................16 
1.2.3 
PHA-022121 ................................................................................................17 
1.2.3.1 
Relevant Non-clinical Findings .........................................................17 
1.2.3.2 
Clinical Research ...............................................................................18 
1.3 
Risk/Benefit Assessment .......................................................................................20 
1.3.1 
Known Potential Risks .................................................................................20 
1.3.2 
Known Potential Benefits ............................................................................22 
1.3.3 
Assessment of Potential Risks and Benefits ................................................22 
2 
STUDY OBJECTIVES ....................................................................................................23 
2.1 
Primary Objective ..................................................................................................23 
2.2 
Secondary Objectives.............................................................................................23 
3 
INVESTIGATIONAL PLAN ..........................................................................................24 
3.1 
Overall Study Design and Plan ..............................................................................24 
3.2 
Rationale for Study Design and Control Group .....................................................26 
3.3 
Study Duration and Dates ......................................................................................29 
4 
STUDY POPULATION SELECTION ...........................................................................30 
4.1 
Study Population ....................................................................................................30 
4.2 
Inclusion Criteria ...................................................................................................30 
4.3 
Exclusion Criteria ..................................................................................................31 
5 
STUDY TREATMENTS .................................................................................................33 
5.1 
Description of Investigational Medicinal Product (IMP) ......................................33 
5.1.1 
PHA-022121 ................................................................................................33 
5.1.2 
Placebo .........................................................................................................33 
5.2 
Treatments Administered .......................................................................................33 
5.3 
Selection and Timing of Dose for Each Patient .....................................................34 
5.4 
Method of Assigning Patients to Treatment Groups..............................................34 
5.5 
Blinding..................................................................................................................35 
5.6 
Concomitant Therapy.............................................................................................35 

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5.6.1 
Allowed HAE Rescue Medication ...............................................................35 
5.6.2 
Prohibited Concomitant Medications ..........................................................35 
5.6.3 
COVID-19 Vaccination ...............................................................................36 
5.7 
Restrictions ............................................................................................................36 
5.7.1 
Contraception ...............................................................................................36 
5.7.2 
Fluid and Food Intake ..................................................................................37 
5.8 
Treatment Compliance ...........................................................................................37 
5.9 
Packaging and Labeling .........................................................................................37 
5.10 
Storage and Accountability ....................................................................................37 
5.11 
Investigational Product Retention at Study Site ....................................................37 
6 
STUDY PROCEDURES .................................................................................................38 
6.1 
Informed Consent...................................................................................................38 
6.2 
Demographics and HAE Characteristics ...............................................................38 
6.3 
Medical History .....................................................................................................38 
6.4 
Weight and Height .................................................................................................38 
6.5 
Physical Examination.............................................................................................38 
6.6 
Vital Signs ..............................................................................................................38 
6.7 
Digital 12-Lead Electrocardiogram (ECG) ............................................................39 
6.8 
Clinical Laboratory Tests .......................................................................................39 
6.8.1 
Safety Laboratory Parameters ......................................................................39 
6.8.2 
Pharmacokinetic Plasma Sampling, Storage, and Shipping ........................40 
6.9 
Dispensing Study Drug ..........................................................................................41 
6.10 
Efficacy Assessments.............................................................................................41 
6.10.1 
VAS..............................................................................................................42 
6.10.2 
MSCS Score .................................................................................................42 
6.10.3 
TOS ..............................................................................................................43 
6.10.4 
TSQM Scores ...............................................................................................43 
6.11 
Adverse Events and Serious Adverse Events ........................................................44 
6.11.1 
Definitions....................................................................................................44 
6.11.2 
Adverse Event Assessments ........................................................................44 
6.11.3 
Classification of an Adverse Event ..............................................................45 
6.11.3.1 
Severity and Grade .............................................................................45 
6.11.3.2 
Relationship to IMP ...........................................................................46 
6.11.4 
Reporting Serious Adverse Events ..............................................................46 
6.11.5 
Events of Special Interest.............................................................................48 
6.11.6 
Reporting of Pregnancy ...............................................................................48 
6.12 
Concomitant Medication Assessments ..................................................................48 
6.13 
Removal of Patients from the Study or Study Drug ..............................................48 

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6.14 
Premature Study Termination ................................................................................49 
6.15 
Appropriateness of Measurements .........................................................................50 
7 
STUDY ACTIVITIES .....................................................................................................51 
7.1 
Screening................................................................................................................51 
7.2 
Part I: Non-Attack ..................................................................................................52 
7.3 
Part II Home Treatment: Attack 1, Attack 2, Attack 3 ..........................................52 
7.4 
Part II Home Treatment: Post-Attack 1, Post-Attack 2, Post-Attack 3 .................53 
7.5 
End of Study ..........................................................................................................54 
8 
QUALITY CONTROL AND ASSURANCE .................................................................55 
9 
PLANNED STATISTICAL METHODS ........................................................................56 
9.1 
General Considerations ..........................................................................................56 
9.2 
Determination of Sample Size ...............................................................................56 
9.3 
Analysis Sets ..........................................................................................................56 
9.4 
Demographics and Baseline Characteristics ..........................................................57 
9.5 
Primary Endpoint ...................................................................................................57 
9.6 
Secondary Endpoints .............................................................................................58 
9.6.1 
Secondary Efficacy Endpoints .....................................................................58 
9.6.2 
Safety Endpoints ..........................................................................................59 
9.6.3 
Pharmacokinetic Endpoints .........................................................................59 
9.7 
Interim Analysis .....................................................................................................60 
9.8 
Study Analyses.......................................................................................................61 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................62 
10.1 
Investigators and Study Administrative Structure .................................................62 
10.2 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
Approval ................................................................................................................62 
10.3 
Ethical Conduct of the Study .................................................................................63 
10.4 
Patient Information and Consent ...........................................................................63 
10.5 
Patient Confidentiality ...........................................................................................64 
10.6 
Study Monitoring ...................................................................................................64 
10.7 
Case Report Forms and Study Records .................................................................65 
10.8 
Data Monitoring Committee ..................................................................................65 
10.9 
Protocol Violations/Deviations ..............................................................................65 
10.10 Access to Source Documentation ..........................................................................66 
10.11 Data Generation and Analysis ...............................................................................66 
10.12 Retention of Data ...................................................................................................67 
10.13 Publication and Disclosure Policy .........................................................................67 
11 REFERENCE LIST .........................................................................................................68 
 

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LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...........................................................................................70 
Appendix 2 
Sponsor Signature ............................................................................................72 
Appendix 3 
Principal Investigator Signature .......................................................................73 
 
LIST OF TABLES 
Table 1 
Estimated EC50 and EC85 of PHA-022121 by PD parameter in the 
bradykinin challenge ........................................................................................28 
Table 2 
Estimated duration of effect of icatibant 30 mg and various doses of 
PHA-022121 ....................................................................................................28 
Table 3 
List of safety laboratory tests ...........................................................................40 
 
LIST OF FIGURES 
Figure 1 
Patient considerations for new HAE therapeutics (FDA) ................................15 
Figure 2 
Flowchart of study design ................................................................................25 
 
 

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LIST OF ABBREVIATIONS  
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
AUC 
area under plasma concentration-time curve 
AUC0-12h 
AUC from time 0 to 12 h post dosing (non-BQL) concentration, 
calculated by the linear-linear trapezoidal summation 
AUC0-24h 
AUC from time 0 to 24 h post dosing (non-BQL]) concentration, 
calculated by the linear-linear trapezoidal summation 
AUCinf 
AUC from time 0 to the time of the last measurable (non-BQL) 
concentration, calculated by the linear-linear trapezoidal summation 
AUClast 
AUC from time 0 to the time of the last measurable (non-BQL) 
concentration, calculated by the linear-linear trapezoidal summation 
BQL 
below quantification limit 
BUN 
blood urea nitrogen 
C1-INH 
C1-esterase inhibitor 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
total apparent systemic clearance of drug after extravascular 
administration, calculated as Dose/AUCinf 
Cmax 
maximum observed analyte concentration; 
COVID-19 
coronavirus disease 2019 
CPHM 
Cox proportional hazards model 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
deoxyribonucleic acid 
EC50 
estimated drug concentration for a 50% response 

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EC85 
estimated drug concentration for a 85% response 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtrate rate 
EEG 
electroencephalogram 
EMA 
European Medicines Agency 
ePRO 
electronic patient-reported outcome 
EU 
European Union 
FA 
Full Analysis 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
GLP 
Good Laboratory Practice 
h 
hour(s) 
HAE 
hereditary angioedema 
HBsAg 
surface antigen of the hepatitis B virus 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCHF 
High-calorie high-fat 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HEENT 
head/eyes/ears/nose/throat 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HMWK 
high molecular weight kininogen 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  

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IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISF 
investigator site file 
iv 
intravenous(ly) 
KKS 
kallikrein-kinin system 
LC-MS 
liquid chromatography–mass spectrometry 
LDH 
lactate dehydrogenase 
MAD 
multiple ascending dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minute(s) 
mITT 
Modified Intent-To-Treat 
MMRM 
mixed model for repeated measures 
MS 
mass spectrometry 
MSCS 
mean symptom complex severity 
MTD/DRF 
Maximum tolerated dose/dose range finding 
NCI 
National Cancer Institute 
NOAEL 
no observed adverse effect level 
PA 
Primary Analysis 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic(s) 
po 
per os, oral 
PRO 
patient-reported outcome 

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QA 
quality assurance 
R2adj 
coefficient of determination 
RBC 
red blood cell  
RNA 
ribonucleic acid 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sc 
subcutaneous 
SD 
standard deviation 
SOC 
system organ class 
SOP  
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
apparent terminal elimination half-life, calculated as 0.693/λz 
TEAE 
treatment-related adverse event 
TESAE 
treatment-emergent serious adverse event 
tmax 
actual sampling time to reach the maximum observed analyte 
concentration 
TMF 
trial master file 
TOS 
treatment outcome score 
TSQM 
treatment satisfaction questionnaire for medication 
US 
United States 
VAS 
visual analogue scale 
VAS-3 
3-symptom composite visual analogue scale 
Vz/F 
apparent volume of distribution, based on terminal phase after a single 
dose 
WBC 
white blood cell  

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Three types of HAE have been characterized. Type I and II are defined by mutations in the 
C1-INH gene and result either in reduced levels of C1-INH (type I) or in reduced activity of 
C1-INH (type II). In both cases, decreased C1-INH protease activity results in increased 
activity of Factor XII and plasma kallikrein, resulting in an activated kallikrein-kinin system 
(KKS), i.e. excessive breakdown of high molecular weight kininogen (HMWK) and 
increased plasma levels of bradykinin. Type III HAE is characterized by mutations in other 
genes (e.g., FXII, PLG, and KNG-1) involved in the activation of the KKS and generation of 
bradykinin, accompanied by normal levels and activity of C1-INH.  
Bradykinin is the principal mediator of the signs and symptoms that represent acute attacks in 
HAE. Two bradykinin receptor types, B1 and B2, have been identified, cloned and 
characterized. Both are G protein-coupled receptors, seven transmembrane proteins. B1 
receptors are inducible, while B2 receptors are constitutively expressed. Bradykinin has a 
high affinity and high agonist potency at the B2 receptor, but a near 1000-fold lower affinity 
and potency at the B1 receptor, making it a selective B2 agonist. 
In humans, physiological responses to bradykinin include vasodilation through stimulation of 
endothelial B2 receptors, provoking synthesis and release of vasodilator agents such as 
endothelium-derived hyperpolarizing factor, prostacyclin, and nitric oxide. Bradykinin also 
regulates smooth muscle cell contraction. 
Excessive bradykinin generation, as in HAE, promotes vascular permeability, leading to 
plasma extravasation and subcutaneous or submucosal tissue swelling typical of an 
angioedema attack. Acute episodes of HAE often occur without warning and may be 
precipitated by triggers such as estrogens, dental procedures, infection, pregnancy, trauma, 
stress, etc. Disease severity and attack frequency vary significantly in the same patient over 
time. Angioedema attacks mainly affect gastrointestinal tract, extremities, trunk, face, throat 
and tongue. Abdominal attacks can be extremely painful, and cause nausea and vomiting. In 
rare cases it can lead to life-threatening complications including tetany, hemorrhagic stools 
and intussusception of the colon. Swelling of the throat can lead to dyspnea, loss of 
consciousness, and in some cases to asphyxiation and death. Frequent angioedema attacks are 
associated with lower quality of life and psychological burden.  
As the B2 receptor is the main target by which bradykinin elicits angioedema in HAE, the 
selective B2 receptor antagonist, icatibant, has proved to be efficacious, and is currently 
marketed and recommended as a first-line treatment option for acute attacks of HAE type I/II 
with C1-INH deficiency (for patients aged 2 years and older). However, this medication 
requires sc injections, and is associated with injection site pain (SPC 2013). 
1.2.2 
Current Treatment of HAE 
There are currently two treatment approaches to the management of HAE: acute (on-demand) 
treatment of attacks and prevention of attacks with short or long-term prophylactic therapy. 
The currently authorized medicinal products for treatment of acute attacks include C1-INH 
replacement products such as human plasma-derived C1-INH concentrates (Berinert®, 
Cinryze®, and Cetor®) or recombinant human C1-INH (Ruconest®), the B2 receptor 
antagonist icatibant (Firazyr®), and the plasma kallikrein inhibitor ecallantide (Kalbitor®). 

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Prophylactic therapies include the C1-INH replacement products such as iv Cinryze® and sc 
Haegarda®/Berinert® 2000/3000, and the monoclonal antibody and plasma kallikrein 
inhibitor lanadelumab-flyo (sc Takhzyro®).  
Subcutaneous icatibant is the only available B2 receptor antagonist indicated for acute attack 
treatment of HAE type I/II with C1-INH deficiency. In acute attacks icatibant provides a 
significantly faster onset of relief than placebo (2.0 h versus 19.8 h) (Lumry et al. 2011). 
Icatibant is recommended as a first-line treatment option for acute attack treatment in patients 
with HAE (Maurer et al. 2018) 
Current treatment guidelines recommend against the use of the traditionally used oral HAE 
medications, such as antifibrinolytics (tranexamic acid or epsilon aminocaproic acid) for 
HAE due to limited efficacy (Stoppa-Lyonnet et al. 1987). Attenuated androgens (e.g. 
danazol, stanozolol, and oxandrolone) are only recommended as second line treatment for 
prevention of HAE attacks, since there are numerous contraindications, therapeutic class 
adverse events (AEs) and overall suboptimal control of HAE in many patients. The use of 
attenuated androgens is limited by numerous safety issues, including seborrhea, altered 
libido, depression, fatigue, menstrual abnormalities, and masculinization. 
Currently, two other angioedema-specific oral medications for acute as well as prophylactic 
use are in clinical development. Both are kallikrein inhibitors (KVD824 and KVD900). In 
addition, the kallikrein inhibitor Orladeyo™ (berotralstat), recently approved in the United 
States, European Union, United Kingdom, and Japan, is a new oral HAE therapy, approved 
only for prevention of HAE attacks and it should not be used by patients for the treatment of 
acute attacks (Orladeyo 2020). 
1.2.3 
PHA-022121 
1.2.3.1 
Relevant Non-clinical Findings 
PHA-022121 has been extensively characterized in primary pharmacological studies as a 
potent, orally available B2 receptor antagonist. The main findings of results of non-clinical 
pharmacology and toxicology studies are described briefly below; more details can be found 
in the PHA-022121 Investigator’s Brochure.  
Primary Pharmacology 
In vitro and ex vivo assays demonstrated that PHA-022121 and its metabolite M2-D are 
competitive antagonists with high binding affinity (similar to icatibant) and high antagonist 
potency (about 20-fold higher than icatibant) at the human and monkey B2 receptor, without 
intrinsic agonist activity. 
Oral PHA-022121 showed efficacy in two animal models: the bradykinin challenge study in 
freely moving male Cynomolgus monkeys and the carrageenan-induced paw edema model in 
male and female humanized B2 Sprague Dawley rats. The duration of action was dose 
dependent. 
Safety Pharmacology 
The in vitro target profile of PHA-022121 showed a high degree of selectivity for the B2 
receptor. Following a single oral administration of up to 50 mg/kg in female and up to 

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100 mg/kg in male rats, PHA-022121 did not induce any adverse effects on behavioral and 
physiological parameters, covering the main central and peripheral nervous system functions 
(Irwin test). 
Adverse behavioral signs of PHA-022121 at 200 and 400 mg/kg po observed in maximum 
tolerated dose and dose range finding studies in Han-Wistar rats, associated with ictal 
discharges in video-electroencephalogram (EEG), were observed at time of Cmax of 
PHA-022121 and M2-D. No EEG signals were detected at 100 mg/kg po, corresponding to a 
no observed adverse effect level (NOAEL) of PHA-022121 of 100 mg/kg in male rats, the 
same as in the general toxicology studies. 
PHA-022121 and its metabolite M2-D induced a depression of the electrically evoked 
population spikes responses in a rat hippocampal slice model in vitro. The effects were 
reversible and partially reversible upon washout, respectively.  
PHA-022121 did not interact with eight human cardiac ion channels known to contribute to 
the cardiac action potential including hERG.  
In conscious male monkeys, PHA-022121 did not induce any relevant changes in heart rate, 
arterial blood pressure, body temperature, duration of PR, RR, QT and QTc intervals or QRS 
complex duration (monitored by telemetry) and did not affect ECG wave form or rhythm at 
oral doses up to 25 mg/kg, corresponding to a mean total Cmax of 2020 ng/mL. 
Respiratory function was assessed in conscious, freely moving female rats as measured by 
whole body plethysmography. The administration of PHA-022121 at 50 mg/kg was 
associated with moderate increases in respiratory rate, tidal volume and minute volume, 
returning towards vehicle values 4 h post-dose. The NOAEL in the plethysmographic 
environmental conditions was 15 mg/kg in the female rat. 
Toxicology 
Dose-limiting toxicity studies with PHA-022121 have been performed in rats and monkeys. 
In both species, non-tolerated doses were only observed at extremely high PHA-022121 
plasma concentrations. The dose limiting toxicity identified in these maximum tolerated 
dose/dose range finding (MTD/DRF) studies were central nervous system-related clinical 
signs, that included convulsive episodes and catalepsy (in rat) and imbalance (in monkey). 
These adverse observations are considered related to Cmax.  
General GLP toxicity studies of up to 6-month and 9-month duration have been completed in 
rats and monkeys, respectively. No adverse treatment-related effects were observed at any 
dose level, which included up to 2×100 mg/kg (po) in male rats, 2×50 mg/kg (po) in female 
rats, and 2×25 mg/kg (po) in male and female monkeys. 
PHA-022121 did not show a relevant genotoxic potential in vitro or in vivo. Neither did it 
show any potential for phototoxicity in the in vitro neutral red uptake phototoxicity assay. 
1.2.3.2 
Clinical Research 
PHA-022121 has been investigated in the Phase I study PHA022121-C001. This was a 
randomized, double-blind, placebo-controlled, single ascending dose and proof-of-
mechanism study to examine the safety, tolerability, pharmacokinetics and 
pharmacodynamics of orally administered PHA-022121 in healthy subjects. 

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In total, 52 subjects received single ascending oral doses of PHA-022121 up to 22 mg 
including bradykinin challenge pharmacodynamic assessments at doses of 12 and 22 mg. 
Preliminary results show that PHA-022121 at doses up to 22 mg was safe and well tolerated. 
The total incidence of adverse events was similar between active and placebo groups. For 
three subjects who received PHA-022121, treatment-related adverse events (AEs) were 
reported, all within the gastrointestinal disorders system organ class (SOC) and of mild 
severity: upper abdominal pain, vomiting, and nausea. 
A second Phase I single ascending dose study (PHA022121-C002) investigated single oral 
doses of 22, 33 and 50 mg of PHA-022121 after a standard caloric breakfast and 40 mg in 
fasting conditions. In this double-blind, placebo-controlled study, a total of 32 subjects 
received either PHA-022121 (n=24) or placebo (n=8). In general, all doses were well 
tolerated and no apparent new safety data emerged. There were no SAEs reported. The 
incidence of treatment-emergent adverse events (TEAEs) was not different between 
PHA-022121 and placebo. There were no clinically significant changes in laboratory or ECG 
parameters. 
A third Phase I placebo-controlled multiple ascending dose (MAD) study investigated 
PHA-022121 doses of 12, 22, 33 and 50 mg twice daily for 10 days. The proportion of 
subjects reporting at least one TEAE was 60.0% (18/30) for PHA-022121 compared with 
62.5% (5/8) for placebo. There were no clear differences between the different PHA-022121 
dose cohorts versus placebo with respect to the frequency and types of TEAEs reported 
across the different system organ classes. All reported TEAEs in the study were mild and 
resolved without treatment. 
Pharmacokinetics 
Dose proportional PK was observed after single oral administration under fasting condition 
of PHA-022121 in the dose range of 1 mg to 22 mg for Cmax, AUClast and AUCinf. Median 
tmax in the dose range of 1 mg to 22 mg was between 0.50 h and 1.00 h, with comparable 
ranges of individual values (ranging between 0.25 h and 1.02 h). Cmax ranged from 11.1 ± 
4.03 ng/mL at the 1 mg dose to 213 ± 49.5 ng/mL at the 22 mg dose. After the 22 mg dose, 
C12h was 8.34 ± 4.24 ng/mL and C24h was 1.12 ± 0.786 ng/mL. The apparent t1/2term ranged 
from 3.49 ± 1.32h for the 1 mg dose to 5.61 ± 0.707 h for the 22 mg dose. However, no clear 
relationship between the apparent t1/2 term and dose was observed. Mean values for apparent 
CL/F ranged from 31.5 L/h to 42.3 L/h. Mean values of apparent Vz/F ranged from 181 L to 
252 L. Less than 1% of the dose was excreted unchanged in urine within 72 h after 
administration. 
M2-D showed dose-proportional PK after single oral administration of PHA-022121 in the 
dose range 1 mg to 22 mg for Cmax, AUC0-24h, AUClast and AUCinf. The mean metabolite to 
parent ratios for Cmax and AUClast in the dose range from 1 mg to 22 mg were approximately 
0.15 and 0.20, respectively.  
After a 22 mg dose, mean Cmax of PHA-022121 was approximately 32% lower while AUCinf 
was approximately 42% higher when PHA-022121 was administered after a high-calorie-
high-fat (HCHF) breakfast compared to administration under fasted conditions. Median tmax 
of PHA-022121 was delayed by approximately 2 h after administration under fed conditions 
compared to the same dose under fasted conditions with median (range) of 3.00 h (2.00 h – 
3.00 h) and 0.75 h (0.25 h – 1.02 h), respectively. Mean (± SD) C12h was 8.34 ± 4.24 h and 

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19.6 ± 10.7 ng/mL under fasted and fed conditions, respectively. Mean C24h was 1.12 ± 0.786 
h to 5.39 ± 5.47 ng/mL under fasted and fed conditions, respectively. 
Mean Cmax of M2-D was approximately 34% lower while AUCinf was approximately 28% 
higher when PHA-022121 was given under fed conditions compared to administration under 
fasted conditions. Median tmax of M2-D was delayed by 2.5 h after administration under fed 
conditions compared to under fasted conditions with median (range) of 3.50 h (2.00 h – 
4.00 h) and 1.01 h (1.00 h – 2.00 h), respectively. 
Repeated bradykinin challenges after oral administration of 12 and 22 mg doses of 
PHA-022121 under fasting conditions did not lead to changes in PK parameters of 
PHA-022121 and its major metabolite M2-D. 
Pharmacodynamics 
PHA-022121 (12 and 22 mg) was administered orally to 16 healthy volunteers. Bradykinin 
injections were administered before and at 1, 4, 8, 12, and 24 h post PHA-022121 dosing to 
induce cardiovascular responses. All bradykinin-induced cardiovascular changes were 
significantly reduced with PHA-022121 treatment. The PK/PD analysis allowed quantitative 
modeling of these effects and direct comparison with those observed after sc administration 
of icatibant. Average composite potencies (EC50) were 2.4 ng/mL for PHA-022121 compared 
to 9.5 ng/mL for icatibant, closely matching respective in vitro potencies. 
1.3 
Risk/Benefit Assessment 
1.3.1 
Known Potential Risks 
Data generated in nonclinical pharmacokinetics, pharmacology, and toxicology studies, as 
well as the Phase I clinical studies in healthy subjects support the planned clinical study with 
the B2 receptor antagonist PHA-022121 in HAE patients. Based on the mode of action and 
on preclinical and clinical data, the following potential risks have been identified. 
Potential Risks Based on Toxicology Studies 
GLP toxicity studies of up to 6-month and 9-month duration have been completed in rats and 
monkeys, respectively. No adverse treatment-related effects were observed at any dose level, 
which included up to 2×100 mg/kg (po) in male rats, 2×50 mg/kg (po) in female rats, and 
2×25 mg/kg (po) in male and female monkeys. In dose-range finding toxicology studies in 
rats and monkeys, the dose-limiting toxicity identified in these studies were central nervous 
system-related clinical signs, that included convulsive episodes and catalepsy (in rat) and 
imbalance (in monkey). These adverse observations are considered related to Cmax. PHA-
022121 did not show a relevant genotoxic or phototoxic potential. 
Potential Risks to Fetus 
Reproductive and development toxicity studies are not available for PHA-022121 so far. For 
this reason, potential effects of PHA-022121 on the fetus are unknown. Therefore, there may 
be unknown risks of PHA-022121 which may be serious and unforeseen in case of 
pregnancy. Women of childbearing potential will only be enrolled if they agree to be 
abstinent (if that is their usual lifestyle), or use medically acceptable, highly effective forms 
of contraception during the study. Males with female partners of childbearing potential must 

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agree to be sexually abstinent or use a medically acceptable form of barrier contraception 
during the study and for 90 days after the last administration of study drug. In addition, they 
must agree to not donate sperm during study participation and within 90 days after the last 
study drug administration. Neither pregnant or breast-feeding women, nor children can be 
included in this clinical study. 
Theoretical Risks Based on the Mechanism of Action 
Physiological responses to bradykinin that are modulated by the B2 receptor include 
vasodilation, natriuresis, nitric oxide and prostaglandin release. B2 receptor blockade could 
therefore theoretically induce vasoconstriction, increase sodium retention, and reduce nitric 
oxide and prostaglandin release. Theoretically this could lead to increased blood pressure, 
reduced heart rate and worsening of ischemia. However, cardiac safety studies in the 
cynomolgus monkey did not show any of these effects up to the highest PHA-022121 dose 
tested (25 mg/kg). Preliminary data in healthy volunteers with single ascending doses up to 
50 mg did also not show any clinically relevant changes in heart rate, blood pressure or ECG 
parameters. 
Interactions 
Based on in vitro signals there might be a risk of changes of PHA-022121 exposure with 
concomitant use of drugs that are strong inhibitors/inducers of CYP3A4. A drug-drug 
interaction study was conducted to evaluate the effect of itraconazole 200 mg repeated 
dosing for 5 days on the PK of a single oral dose of 12 mg PHA-022121. The study showed 
that coadministration of PHA-022121 with the CYP3A4 inhibitor itraconazole to healthy 
subjects, led to a 2.2-fold increase in Cmax and an approximate 12-fold increase in AUClast. 
The clinical data are in line with in vitro findings showing that CYP3A4 plays an important 
role in the metabolism of PHA-022121.  
In vitro, PHA-022121 shows a weak inhibitory effect on CYP2C19, a weak to moderate 
inhibitory effect on CYP3A4 and a moderate inhibition of CYP1A1. In vitro induction 
studies indicate that there is potential of induction for CYP3A4 and to a lesser degree 
CYP2B6, CYP2C8, and possibly CYP1A2. PHA-022121 is not an inducer of CYP2C9 or 
CYP2C19. A human drug-drug interaction study indicated that at anticipated therapeutic 
doses, PHA-022121 does not inhibit or induce CYP1A2, CYP2C19, and CYP3A4. 
Therefore, medications that are metabolized by CYP1A2, CYP2C19, or CYP3A4 can be 
used with PHA-022121. 
Studies to evaluate whether PHA-022121 is a substrate of transporter(s) mediating drug 
efflux such as P-glycoprotein or organic anion transporting polypeptides in vitro (Caco-2 
assay) are currently ongoing. 
Potential Risks Based on Icatibant (Firazyr®) 
The B2 receptor antagonist icatibant (Firazyr®) has been approved for the symptomatic 
treatment of acute attacks of HAE in Europe in 2008 and in US in 2011. In contrast to 
PHA-022121, icatibant is intended for sc administration.  
During clinical trials with icatibant (Firazyr®), the most frequently reported AEs which can 
potentially also occur with PHA-022121 are: dizziness, headache, nausea, rash erythema, 
pruritus, pyrexia, and increased transaminases (SPC 2013). 

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A potential risk might be a deterioration of cardiac function and decrease in coronary blood 
flow under ischaemic conditions (e.g., during an acute myocardial infarction), due to a 
possible protective effect of bradykinin. Therefore, patients with cardiac risk factors were 
excluded from the clinical trials, and in the SPC a warning is included for patients with acute 
ischaemic heart disease and unstable angina pectoris and also stroke. 
Potential Risks Due to COVID-19 Pandemic 
Neither the HAE disease nor the study drug is expected to pose an extra risk on the patients 
to develop COVID-19 or to influence the course of the disease in a negative way. The 
number of planned hospital study visits has been minimized. In case of increased local 
regulations on social distancing, additional measures such as remote visits or home nursing 
visits may be implemented to further reduce patient risk. 
Potential Risks Based on Phase I Studies 
In two Phase I single ascending dose (SAD) studies, single oral doses of PHA-022121 
ranging from 1 to 50 mg were well tolerated and safe. The incidence of AEs was not different 
between active drug and placebo. AEs reported as possibly related to PHA-022121 or 
placebo were of mild (abdominal pain, nausea, vomiting and headache) or moderate 
(headache associated with vomiting) severity. 
1.3.2 
Known Potential Benefits 
PHA-022121 is a potent, orally available, highly selective B2 receptor antagonist. The 
compound was effective in blocking the pharmacodynamic effects of exogenous, iv 
administered bradykinin in a preclinical animal model and in healthy subjects. The effect in 
humans was demonstrated with single oral doses of 12 and 22 mg, which were safe and well 
tolerated. These data suggest that the compound can be expected to have a beneficial effect in 
the treatment and prevention of HAE attacks. 
1.3.3 
Assessment of Potential Risks and Benefits 
Available preclinical and human data indicate that PHA-022121 is a potent and highly 
selective B2 receptor antagonist with excellent oral bioavailability. The compound also 
effectively inhibits the pharmacodynamic effects of exogenously administered bradykinin in 
humans, which is predictive of efficacy in the treatment of HAE attacks. The efficacy in the 
bradykinin challenge in humans was obtained with doses that were well tolerated and safe 
and were within the range of the doses tested in the current study. The dose range tested 
(10-30 mg) in this study is well covered by the maximum dose of 50 mg tested in SAD and 
MAD studies, and maximum plasma concentrations of PHA-022121 after single dose 
administration (10-30 mg) are expected to remain well below the NOAEL in the most 
sensitive species in the toxicological studies. 

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2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of three different single doses 
of PHA-022121 versus placebo in achieving angioedema symptom reduction, defined as 
change in the 3-symptom composite visual analogue scale (VAS-3) score during acute 
attacks in patients with HAE type I/II. 
2.2 
Secondary Objectives 
The key secondary objectives of the study are: 
To evaluate the clinical efficacy of three different single doses of PHA-022121 versus 
placebo with regards to:  
• Time to onset of symptom relief by VAS-3, 
• Time to almost complete or complete symptom relief by VAS-3,  
• Change in mean symptom complex severity (MSCS) score at 4 h post-treatment, 
• Treatment outcome score (TOS) at 4 h post-treatment. 
 
Other secondary objectives of the study are: 
• To evaluate the clinical efficacy of three different single doses of PHA-022121 versus 
placebo with regards to: 
o Time to onset of primary symptom relief by visual analogue scale (VAS) 
o Proportion of investigational medicinal product (IMP)-treated attacks requiring the 
use of HAE rescue medication 
o Time to the first use of HAE rescue medication 
o Change in the individual VAS scores (skin pain, skin swelling, abdominal pain) from 
pre-treatment to 4 h post-treatment 
o Change in MSCS score at 24 h post-treatment 
o TOS at 24 h post-treatment 
• To evaluate the safety of three different single doses of PHA-022121 versus placebo 
• To evaluate the pharmacokinetics, dose-effect relationship, and concentration-effect 
relationship of PHA-022121 
• To evaluate the treatment satisfaction questionnaire for medication (TSQM) scores at 
48 h post-treatment 
 

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3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
In this study the efficacy of three oral doses (low: 10 mg, medium: 20 mg, and high: 30 mg) 
of PHA-022121 versus placebo to achieve angioedema symptom reduction will be assessed 
in adult patients with HAE type I/II.  
After signing informed consent, patients will be screened for eligibility. Eligible patients will 
be enrolled in the study.  
Enrolled patients will be randomized to one of the three dose levels (low, medium, high) 
first, then based on the assigned cohort, randomized to one of nine treatment sequences 
comparing three single doses of PHA-022121 (low, medium, high) with placebo treatment. 
Approximately 72 patients are planned to be randomized.  
During Part I (at the study site), patients in quiescent state receive the assigned active single 
dose of PHA-022121 (dose is blinded) to assess pharmacokinetics and safety.  
In Part II of the study, patients will self-administer blinded study drug in the assigned 
treatment sequence at home to treat three qualifying HAE attacks, which should be consulted 
and confirmed by the investigator or designee via remote contact. The study drug should be 
taken when at least one attack symptom (skin pain, skin swelling, or abdominal pain) 
becomes of moderate intensity (VAS score ≥ 30). When the attack reaches this VAS intensity 
threshold, study drug should preferably be taken during the remote contact with the 
investigator or designee. If the patient cannot take the study drug within 3 h after reaching 
the VAS intensity threshold, the attack does not qualify for study drug treatment and should 
be treated with the patient’s standard HAE medication. In addition, treatment of the attack 
should happen within 6 h after onset of symptoms at any location. If the study drug cannot be 
administered within 6 h after onset of symptoms, the attack does not qualify for study drug 
treatment and should be treated with the patient’s standard HAE medication. Any symptoms 
involving the internal head and neck, regardless of intensity, also render an attack non-
qualifying for treatment with study drug and should be treated with the patient’s standard 
HAE medication.  
At 4 h post study drug treatment, the patient will consult with the investigator or designee 
remotely again to assess symptom relief, safety, and any need for rescue medication.  
Patient-reported outcomes (PROs) are collected from study drug intake (including pre-
treatment) until 48 h post-treatment. After each attack treated with study drug, a safety 
follow-up visit will take place within 5 days post-treatment. Meanwhile, pharmacokinetic 
plasma samples are planned to be collected within 24 h post-treatment (preferably within 
12 h) from a subset of patients for at least 50 attacks treated with PHA-022121 or placebo.  
In order to avoid carry-over effects of previous treatments, HAE attacks that occur within 
5 days of a previously treated attack (regardless of whether study drug or standard HAE 
medication was used) will not qualify for treatment with study drug. The end-of-study visit 
will take place 10±5 days post-treatment of the last attack. This visit may be waived if 
patients continue in another clinical study with PHA-022121 conducted by the Sponsor. 

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A schematic flowchart of the study design is shown in Figure 2. For more details see the 
schedule of events in Appendix 1. 
 
 
Figure 2 
Flowchart of study design 
 
Efficacy will be assessed during Part II with four PROs:  
• VAS of the three major HAE symptoms, including skin pain, skin swelling, and 
abdominal pain 
• MSCS score 
• TOS 
• TSQM scores 
 
The primary endpoint is the change in the VAS-3 score from pre-treatment to 4 h 
post-treatment. 
The key secondary efficacy endpoints of the study are as follows:  
• Time to onset of symptom relief, assessed by a ≥30% reduction in VAS-3 score from the 
pre-treatment score. 
• Time to almost complete and complete symptom relief by VAS-3 score 
Almost complete symptom relief is defined as all 3 individual VAS scores of the VAS-3 
having a value ≤ 10. 
Complete symptom relief is defined as all 3 individual VAS scores of the VAS-3 having 
a value of 0. 
• Time to a ≥50% reduction in VAS-3 score from the pre-treatment score. 

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• Change in MSCS score from pre-treatment to 4 h post-treatment 
• TOS at 4 h post-treatment 
 
Other secondary efficacy endpoints of the study are as follows:  
• Time to onset of primary symptom relief assessed by a 30% reduction in the VAS for the 
primary symptom, and time to a 50% reduction in the VAS for the primary symptom. 
The symptom (skin swelling, skin pain, or abdominal pain) with the highest pre-treatment 
VAS score is considered the primary symptom.  
• Proportion of IMP-treated attacks requiring HAE rescue medication within 12 h, within 
24 h, and within 48 h post-treatment 
• Time to first HAE rescue medication use for IMP-treated attacks, if applicable. 
An IMP-treated attack refers to an attack treated with blinded IMP (study drug). 
• Change in the VAS score for individual symptoms (skin pain, skin swelling, abdominal 
pain) from pre-treatment to 4 h post-treatment 
• Change in MSCS score from pre-treatment to 24 h post-treatment 
• TOS at 24 h post-treatment 
• TSQM scores at 48 h post-treatment 
 
The safety endpoints of the study are: 
• Treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and treatment-
emergent serious adverse events (TESAEs), and treatment-related TESAEs 
• Clinical laboratory tests (chemistry, hematology, coagulation, and urinalysis) 
• Vital signs 
• Electrocardiograms (ECGs) 
 
The pharmacokinetic endpoints of the study are: 
• Pharmacokinetic parameters based on plasma profiles of PHA-022121 and metabolites: 
Cmax, tmax, AUC0-12h, AUC0-24h, AUClast, AUCinf, t1/2, Vz/F (PHA-022121 only) and CL/F 
(PHA-022121 only). 
 
3.2 
Rationale for Study Design and Control Group 
The study adopts a randomized double-blind controlled design in order to objectively 
quantify the efficacy of PHA-022121 at different doses. A placebo control is considered to be 
adequate in this study because the key feature of the drug is its potential for oral 
administration. All currently available on-demand drugs are injectables. An active control 
group would require a double dummy approach. This would not allow evaluation of an 
improved acceptance of oral treatment over injectable treatment. In addition, the most 
frequently used drug for on-demand treatment is icatibant. Injection site reactions are a very 
common adverse reaction of icatibant, which will lead to unblinding in a high proportion of 
patients. From a safety point of view, a placebo-controlled design does not put the patient at 
unnecessary risk because adequate rescue medication is available. All patients in the study 
will have approved treatment for HAE attacks available, which they can use for attacks that 

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do not qualify for study drug treatment (see Section 5.3) or attacks that do not respond within 
a reasonable time frame to study drug treatment. 
Patients will treat three qualifying attacks in a double-blind cross-over way. A cross-over 
design has the advantage that it can assess the within-patient efficacy in addition to the 
comparison between groups. A major condition is that treatments are sufficiently spaced in 
time to avoid treatment carry-over effects. In general, a period that covers five times the 
terminal half-life of the drug is considered sufficient. Given the terminal half-life of 
approximately 5 h, a period of 5 days after treatment of a single attack before a new attack 
can be treated is therefore considered sufficient to avoid potential carry-over effects. 
Dose Rationale 
PHA-022121 is an orally available B2 receptor antagonist. The doses of 10, 20 and 30 mg 
PHA-022121 selected for this study were supported collectively by the results of PHA-
022121 preclinical studies, and safety, PK and PD data from Phase I SAD studies 
(PHA022121-C001 and PHA022121-C002). Icatibant (Firazyr®), a synthetic decapeptide B2 
inhibitor, has been approved for the treatment of acute attacks of HAE, and has been used as 
a class reference for the dose selection of PHA-022121.  
The inhibition of bradykinin challenge model in healthy volunteers has been shown to 
correlate well with efficacy in the treatment of acute HAE attacks with a B2 receptor 
antagonist (FDA-CDER 2011). Intravenous administration of icatibant caused dose and time-
dependent inhibition of bradykinin-induced hypotension, vasodilation, and reflex tachycardia 
in healthy subjects. Based on the direct-response PK/PD analysis from the icatibant 
bradykinin challenge study, an approved sc dose of 30 mg icatibant was predicted to be 
effective in the treatment of acute attacks for at least 6 h. A single sc dose of 30 mg icatibant 
gives a 75% probability of having a plasma concentration above the EC50 at 6 h and a 50% 
probability of still being above the EC85 at that point in time. This was further demonstrated 
to correlate well with clinical response in Phase III clinical HAE trials (Cicardi et al. 2010). 
Recently, a 10-year outcome survey of icatibant clinical effectiveness and safety was 
published (Maurer et al. 2020). The data collected from 549 patients with a total of 5995 
HAE attacks indicated that one single injection of 30 mg icatibant was effective for 93% of 
attacks and the second injection was able to rescue an additional 6% of attacks. Therefore, 
approximately 99% of HAE attacks were successfully treated with one or two doses of 30 mg 
icatibant sc. All clinical and real-world observations match the prediction that was made 
based on the bradykinin challenge study and suggest that use of a bradykinin challenge for 
PD assessment is a suitable surrogate endpoint for the development of bradykinin-receptor 
antagonists such as PHA-022121. 
The inhibition of bradykinin challenge was assessed in study PHA022121-C001 with single 
doses of 12 and 22 mg PHA-022121. A PK/PD analysis using the same approach as in the 
icatibant evaluation was conducted and 
Table 1 lists the EC50 and EC85 values estimated for each PD response associated with the 
bradykinin challenge. The composite average shows an EC50 of 2.4 ng/mL and an EC85 of 
13.8 ng/mL for PHA-022121. The free plasma concentration associated with this EC50 value 
of 2.4 ng/mL (plasma protein binding 96.72%), is 170 pM, a potency that is in line with the 
potency of PHA-022121 for recombinant and endogenous human B2 receptor (150 and 350 
pM). 

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3.3 
Study Duration and Dates 
The expected study duration per patient amounts to approximately 30 weeks consisting of the 
Screening period of up to 4 weeks, the Non-attack visit (Part I), home treatment (Part II) of 
about 24 weeks (covering 3 qualifying attacks treated with study drug per patient), and up to 
2 weeks until the end-of-study visit. In some cases, patients may need longer than 24 weeks 
to complete the assessments for 3 qualifying attacks; therefore, the individual duration per 
patient may be longer. 
Patient recruitment is planned to be started in Q1 2021 and the study is planned to be 
completed in Q3 2022. Therefore, the expected overall duration of the study is approximately 
15-18 months. The overall study duration may be longer if some patients need longer than 
24 weeks to complete the assessments for 3 qualifying attacks. 
The end of the study is defined as the last visit of the last patient participating in the study. 

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4 STUDY POPULATION SELECTION 
4.1 
Study Population 
Approximately 72 male or female, adult patients with HAE due to C1-INH deficiency (HAE 
type I/II) will be randomized in this study. For eligibility in the study, patients need to have 
experienced at least three HAE attacks in the last 4 months, or at least two HAE attacks in 
the last 2 months. 
The anticipated number of study sites is approximately 35 across 12-15 countries. 
4.2 
Inclusion Criteria 
In order to be eligible to participate in this study, a patient must meet all of the following 
criteria: 
1. Provision of signed and dated informed consent form 
2. Male or female, aged ≥ 18 and ≤ 75 years at enrollment 
3. Diagnosis of HAE (type I or II) based upon all of the following: 
a. Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling without accompanying urticaria) 
b. At least one of the following: 
◦ 
Age at reported onset of first angioedema symptoms ≤ 40 years 
◦ 
Family history consistent with HAE type I or II 
◦ 
C1q within normal range 
c. Diagnostic testing results to confirm HAE type I or II:  
◦ 
C1-INH functional level < 50% of the normal level 
The diagnosis may be established by local laboratory values documented in the medical 
records or by genotyping of the C1-INH gene (SERPING1). Before entering Part II of the 
study (home treatment), the diagnosis needs to be confirmed by a central laboratory 
assessment or by genotyping of the C1-INH gene (SERPING1). 
4. Documented history of at least three HAE attacks in the last 4 months, or at least two 
HAE attacks in the last 2 months prior to screening 
5. Reliable access1 and experience to use standard of care treatment to effectively manage 
acute HAE attacks 
6. Capable to record PRO data using the ePRO device 
7. Female patients of childbearing potential2 must agree to be abstinent or to use highly 
effective forms of contraception methods from enrollment until 30 days after the last 
study drug administration. This includes progestin-only oral contraceptive associated 
with inhibition of ovulation (oral, injectable, or implantable), intrauterine device (IUD, 
all types) or intrauterine hormone releasing systems (IUS).3 A female of childbearing 
 
1 Reliable access of a drug is defined as being readily available on the market with guaranteed continuous 
supply. 
2 Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation) or post-menopausal (defined as no menses for at least 12 months 
without an alternative medical cause) do not require contraception during the study. 
3 Use of a male condom with or without spermicide or cervical cap, diaphragm or sponge with spermicide or a 
combination (double-barrier methods) is not considered highly effective 

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potential whose male partner has had a vasectomy must agree to use one additional form 
of medically acceptable contraception. 
Male patients, including males who are surgically sterile (post vasectomy), who have a 
female partner of childbearing potential must agree to be sexually abstinent or use a 
medically acceptable form of barrier contraception during the study and for 90 days after 
the last administration of study drug. In addition, they must agree to not donate sperm 
during study participation and within 90 days after the last study drug administration. 
4.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Pregnant or breast-feeding 
2. Clinically significant abnormal ECG, most notably a QTcF > 470 ms (for females) or 
> 450 ms (for males) 
3. Any clinically significant history of angina, myocardial infarction, syncope, stroke, left 
ventricular hypertrophy or cardiomyopathy, uncontrolled arterial hypertension (systolic 
blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg), bradycardia 
(< 50 bpm), or any other cardiovascular abnormality within the previous year 
4. Any other systemic disease (e.g., gastrointestinal, renal, respiratory, neurological) or 
significant disease or disorder that would interfere with the patient’s safety or ability to 
participate in the study  
5. Use of: 
a. long-term prophylactic therapy for HAE (C1-INH, oral kallikrein inhibitors, 
attenuated androgens, or anti-fibrinolytics) within 2 weeks prior to enrollment 
b. long-term prophylactic monoclonal therapy for HAE (e.g., lanadelumab) within 
12 weeks prior to enrollment 
c. acute C1-INH treatment or short-term prophylaxis for HAE within 7 days prior to 
screening 
Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics 
to avoid angioedema complications from medically indicated procedures. 
Patients who receive long-term prophylactic treatment for HAE are not eligible for the 
study. Patients who have previously stopped long-term prophylactic HAE treatment 
because of intolerance or lack of efficacy can enter the study with a sufficiently long 
wash-out period as defined above for the different drugs. 
6. Positive serology for human immunodeficiency virus (HIV) or active infection with 
hepatitis C virus (HCV), or active infection with hepatitis B virus (HBV) associated with 
signs of active liver disease 
7. Abnormal hepatic function (AST > 2×ULN, ALT > 2×ULN, or total bilirubin 
> 1.5×ULN), with the exception of patients with Gilbert’s syndrome 
8. Abnormal renal function (eGFR CKD-EPI < 60 mL/min/1.73 m2) 
9. History of alcohol or drug abuse within the previous year, or current evidence of 
substance dependence or abuse (self-reported alcoholic intake > 3 drinks/day) 
10. History of documented severe hypersensitivity to any medicinal product 
11. Participation in any other investigational drug study currently, within the last 30 days or 
within 5 half-lives of study drug at enrollment (whichever was longer) 

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12. Regular use of corticosteroids, antihistamines, narcotics, and other pain relief 
medications for acute HAE attack treatment 
13. Use of concomitant medication that are moderate or potent inhibitors/inducers of 
CYP3A4, such as clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, 
ritonavir, verapamil, goldenseal and grapefruit, as well as phenobarbital, phenytoin, 
rifampicin, St. John's Wort, and glucocorticoids (not for topical use or inhalation) 

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5 STUDY TREATMENTS 
5.1 
Description of Investigational Medicinal Product (IMP) 
Note: Blinded PHA-022121 and Placebo are considered as the IMP and may both be referred 
to as study drug. 
5.1.1 
PHA-022121 
The active study drug consists of 10 mg PHA-022121 soft capsules for oral use with a 
concentration of the fill of 50 mg/g PHA-022121 in a 40:50:10 (w/w/w) mixture of 
Kolliphor RH 40, Capryol 90 and propylene glycol. 
5.1.2 
Placebo 
Placebo treatment consists of matching placebo soft capsules for oral use. 
5.2 
Treatments Administered 
The treatments to be administered in the study consist of 10 mg PHA-022121 soft capsules 
and matching placebo soft capsules for oral use:  
• Low dose (10 mg): one capsule of 10 mg PHA-022121 and two placebo capsules 
• Medium dose (20 mg): two capsules of 10 mg PHA-022121 and one placebo capsule 
• High dose (30 mg): three capsules of 10 mg PHA-022121 
• Placebo: three placebo capsules 
 
The treatment will consist of three soft capsules (each containing 10 mg PHA-022121 or 
placebo) that must be ingested at the same time. The capsules are to be swallowed with a cup 
of water of at least 200 mL. 
In Part I of the study, each patient receives a single dose of PHA-022121 (10, 20, or 30 mg). 
In Part II, patients will receive two single doses of PHA-022121 (10, 20, or 30 mg) and one 
single dose of placebo. 
In Part II of the study, each patient self-administers two single doses of PHA-022121 (10, 20, 
or 30 mg) and one single dose of placebo for each of the three qualifying HAE attacks 
according to one of the following sequences (cross-over design): 
1. Low dose - Low dose - Placebo 
2. Low dose - Placebo - Low dose 
3. Placebo - Low dose - Low dose 
4. Medium dose – Medium dose – Placebo 
5. Medium dose – Placebo – Medium dose 
6. Placebo – Medium dose – Medium dose 
7. High dose – High dose – Placebo 
8. High dose – Placebo – High dose 
9. Placebo – High dose – High dose 
 

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5.3 
Selection and Timing of Dose for Each Patient 
In Part I of the study, patients in quiescent state receive the dose of PHA-022121 under 
fasting conditions (fasting from midnight or for at least 8 h) according to their randomized 
treatment assignment.  
In Part II of the study, patients will self-administer blinded study drug in the assigned 
treatment sequence at home to treat three qualifying HAE attacks, which should be consulted 
and confirmed by the investigator or designee via remote contact. The study drug should be 
taken when at least one attack symptom (skin pain, skin swelling, or abdominal pain) 
becomes of moderate intensity (VAS score ≥ 30). When the attack reaches this VAS intensity 
threshold, study drug should preferably be taken during the remote contact with the 
investigator or designee. If the patient cannot take the study drug within 3 h after reaching 
the VAS intensity threshold, the attack does not qualify for study drug treatment and should 
be treated with the patient’s standard HAE medication. In addition, treatment of the attack 
should happen within 6 h after onset of symptoms at any location. If the study drug cannot be 
administered within 6 h after onset of symptoms, the attack does not qualify for study drug 
treatment and should be treated with the patient’s standard HAE medication.  
Study drug should not be taken for laryngeal and pharyngeal attacks (because of risk of 
airway involvement) or attacks associated with vomiting, swallowing difficulty, or 
intolerable pain. These attacks should be treated with the patient’s standard HAE medication 
(if possible in consultation with the investigator) or the investigator may hospitalize the 
patient. 
At 4 h post study drug treatment, the patient will consult with the investigator or designee 
remotely again to assess symptom relief, safety, and any need for rescue medication.  
In order to avoid carry-over effects of previous treatments, attacks that occur within 5 days of 
a previously treated attack (regardless of whether study drug or standard HAE medication 
was used) will not qualify for treatment with study drug. 
5.4 
Method of Assigning Patients to Treatment Groups 
The patients will be randomized to one of the three dose levels (low, medium, high) first, 
then randomized to one of the nine treatment sequences to be received in Part II of the study 
(see Section 5.2). The randomization will be stratified by whether the patient is willing to 
participate in full PK sampling in Part I (Yes, No), which will be done in approximately four 
patients from each dose cohort (see Section 6.8.2). The stratification factor will not be used 
for analysis. Then the patients will be further randomized to one of the three treatment 
sequences with the given dose level. Patients who are initially willing to participate in the full 
PK sampling but withdraw their consent for this PK sampling before the sampling starts, can 
continue study participation without full PK sampling. Their full PK sampling slot may be 
fulfilled by another study patient at the discretion of the Sponsor. 
Each treatment sequence is planned to be assigned to eight patients. In Part I of the study, 
patients in quiescent state will receive the PHA-022121 dose from their randomized 
treatment assignment. 

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Randomization will be performed by an interactive response technology (IRT) system. All 
drug supplies will be handled in a double-blinded manner. 
5.5 
Blinding 
Blinding is achieved because PHA-022121 capsules and placebo capsules have an identical 
appearance and each single dose consists of a combination of three capsules of 10 mg 
PHA-022121 and/or placebo as described in Section 5.2. 
The labels are blinded and contain a unique code. Assignment of study drug in accordance 
with their randomized treatment assignment is managed by the IRT system. 
Access to study drug assignment will be available if the investigator deems it necessary to 
break the study blind in the interest of a patient’s medical safety, in case of a medical 
emergency, to meet regulatory reporting obligations, or if warranted during scheduled safety 
reviews. Where medically appropriate, the investigator will contact the Medical Monitor to 
discuss the situation which has arisen and resulted in the need for unblinding of the patient. 
The Medical Monitor will not be involved in the decision to unblind. 
5.6 
Concomitant Therapy 
Concomitant medications will be recorded in the eCRF from the time patients give informed 
consent until the end of study visit. 
5.6.1 
Allowed HAE Rescue Medication 
If in Part II of the study, patients do not experience symptom relief within 4 h post-study 
drug, they are allowed to use any approved and prescribed acute HAE rescue medication, 
such as icatibant, ecallantide, or C1-INH. 
The patient’s standard HAE medication should be used for the treatment of any laryngeal and 
pharyngeal attacks (because of risk of airway involvement), or attacks associated with 
vomiting, swallowing difficulty, or intolerable pain (if possible in consultation with the 
investigator; see Section 5.3). Use of standard HAE treatment should not be delayed for such 
attacks.  
5.6.2 
Prohibited Concomitant Medications 
The following medications are not allowed to be used during the study: 
• Kallikrein inhibitors for prophylactic use, antifibrinolytics (tranexamic acid or epsilon-
aminocaproic acid), attenuated androgens (e.g., danazol, stanozolol, and oxandrolone), or 
C1-INH for prophylactic use. These medications are prohibited during the study. 
• Corticosteroids, antihistamines, narcotics, and other pain relief medications are prohibited 
for treatment of acute HAE attacks (can be used to treat intercurrent illnesses between 
HAE attacks if needed). These medications are prohibited during the HAE attack period 
(Part II). If needed, each patient will have reliable access to use standard of care 
treatment for acute HAE attacks. 

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• Moderate or potent inhibitors/inducers of CYP3A4, such as clarithromycin, 
erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and 
grapefruit as well as phenobarbital, phenytoin, rifampicin, St. John's Wort, and 
glucocorticoids (not for topical use or inhalation). 
Concomitant use of these medications with the study drug is prohibited throughout the 
study. If one of these drugs would be prescribed for chronic use (e.g. diltiazem, 
phenytoin) the subject will be withdrawn from the study. If a patient requires a short-term 
treatment for an intercurrent illness (e.g. erythromycin for bronchial infection) treatment 
with study drug should be suspended for the duration of treatment and an appropriate 
wash out period. The duration of suspension will be defined in agreement with the 
medical monitor. Any HAE attack during this period will be considered as a non-
qualifying attack and should be treated with patient’s usual HAE acute attack medication. 
5.6.3 
COVID-19 Vaccination 
The IMP is not known to be an immunomodulator, therefore COVID-19 vaccination for 
study patients is not prohibited during the study. However, patients who have received the 
COVID-19 vaccination should not treat an attack with IMP within 48 hours of receiving the 
vaccine as a precaution (any attack within this timeframe should be treated with their 
standard HAE medication). If the COVID-19 vaccine is administered while a patient is 
participating in the study, the details must be documented in the eCRF. The COVID-19 
vaccine should be administered in compliance with local guidelines. 
5.7 
Restrictions 
5.7.1 
Contraception 
In the absence of a completed non-clinical data package on teratogenicity/fetotoxicity, 
PHA-022121 is considered a study drug with possible human teratogenicity/fetotoxicity in 
early pregnancy according to the CTFG recommendations(CTFG 2020). Therefore, the 
inclusion of females of childbearing potential requires the use of medically accepted, highly 
effective contraceptive measures from enrollment until 30 days after the last study drug 
administration. 
The following birth control methods are considered highly effective: 
• Combined (estrogen and progestogen containing) hormonal contraception methods 
associated with inhibition of ovulation: oral, intravaginal, or transdermal 
Birth control methods containing estrogen such as ethinyl estradiol (EE) can be a trigger 
for HAE attacks in some females. Although females using EE methods on a stable dose 
without safety issues may be enrolled on this study, females should not be recommended 
to use EE methods if they did not use them prior to enrollment in the study. 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, 
injectable, or implantable 
• Intrauterine device (IUD, all types) 
• Intrauterine hormone-releasing system (IUS) 
• Sexual abstinence, where it is the anticipated usual lifestyle of the patient 
 

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A female patient of childbearing potential whose male partner has had a vasectomy must 
agree to use one additional form of medically acceptable contraception. 
Male patients, including males who are surgically sterile (post vasectomy), who have a 
female partner of childbearing potential must agree to be sexually abstinent or use a 
medically acceptable form of barrier contraception during the study and for 90 days after the 
last administration of study drug. In addition, they must agree to not donate sperm during 
study participation and within 90 days after the last study drug administration. 
5.7.2 
Fluid and Food Intake  
In Part I of the study, the assigned single dose of PHA-022121 will be given at the study site 
under fasting conditions (fasting from midnight or for at least 8 h). No other restrictions for 
fluid and food intake apply during the study. 
5.8 
Treatment Compliance 
Treatment compliance in Part I will be ensured by intake of study drug under supervision of 
study personnel. Treatment compliance in Part II will be assessed by documenting drug 
accountability, including review of returned blisters. 
The protocol does not allow for dose adjustment. Any deviation from taking the defined 
number of capsules will be a deviation of treatment compliance. Treatment compliance will 
be verified by review of patient diaries and returned blisters. The number of capsules taken 
by the patient will be entered in the clinical database. Non-compliance will be flagged in the 
clinical database, and taken into account for the analysis of the efficacy and safety profile. 
5.9 
Packaging and Labeling 
The IMPs (study drug or placebo) are packaged and labelled according to current Good 
Manufacturing Practice. 
The IMPs are packaged in aluminium/aluminium (alu/alu) blisters. Each blister will be sealed 
into a wallet. The wallet will be labelled with a booklet label and rendered tamper evident. 
Each wallet will contain one single dose, which consists of a combination of three capsules 
of 10 mg PHA-022121 and/or placebo. 
5.10 Storage and Accountability 
The IMPs should not be stored above 25 ºC. 
Access to the IMPs should be restricted to designated study personnel. 
5.11 Investigational Product Retention at Study Site 
Not applicable. 

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6 STUDY PROCEDURES 
6.1 
Informed Consent 
At the Screening visit, a signed informed consent form (ICF) must be obtained from each 
patient prior to performing any study-related procedures. Each patient should be given both 
verbal and written information describing the nature and duration of the clinical study. More 
details on the informed consent are given in Section 10.4. 
6.2 
Demographics and HAE Characteristics 
At Screening, demographic information, including year of birth, gender, race, and ethnicity 
will be captured in the eCRF for each patient. 
In addition, HAE characteristics, including the year of diagnosis, family history, the type of 
HAE, and the number of attacks in the last 2 and 4 months, and the last year will be 
collected. 
To confirm the HAE diagnosis, results of C1-INH functional level, C1q level, and C4 level 
must be obtained from a Screening plasma sample by a central laboratory assessment. Only 
patients with a confirmed HAE Type I/II diagnosis based upon a central laboratory 
assessment or by genotyping of the C1-INH gene (SERPING1) may continue into Part II of 
the study. 
6.3 
Medical History 
At Screening, existing general medical history (current or resolved) will be recorded for the 
following body systems: head/eyes/ears/nose/throat (HEENT), respiratory, cardiovascular, 
gastrointestinal, genitourinary, musculoskeletal, neurological, endocrine/metabolic, 
blood/lymphatic, dermatologic, psychiatric, allergy, and other. 
6.4 
Weight and Height 
Height will be measured at the Screening visit. Weight will be measured at Screening and at 
the Non-attack visit. 
6.5 
Physical Examination 
A physical examination will be conducted at Screening. At minimum, the following body 
systems will be examined: gastrointestinal system; head/eyes/ears/nose/throat (HEENT); 
endocrine (including thyroid); respiratory system; cardiovascular system; integumentary 
system (skin); and nervous system (central and peripheral). Abnormalities will be reported in 
the eCRF. 
6.6 
Vital Signs 
Vital signs include blood pressure, heart rate, body temperature, and respiratory rate. Blood 
pressure (systolic and diastolic) and heart rate will be taken after the patient has rested in 

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supine position for at least 5 min, at Screening, at the Non-attack visit (pre-dose, and 1 and 
4 h post-dose), and at the Post-attack visits. Blood pressure measurements must be obtained 
with an appropriate cuff size and with the patient’s arm supported at the level of the heart. It 
is acceptable to obtain a pulse rate from the blood pressure or ECG machine. 
6.7 
Digital 12-Lead Electrocardiogram (ECG) 
A 12-lead ECG (digital triplicate) will be recorded after the patient has rested in supine 
position for at least 10 min at Screening and at the Non-attack visit (pre-dose, and 1 and 4 h 
post-dose). ECGs will be evaluated by the investigator and any abnormalities will be reported 
in the eCRF. Central reading of all recorded ECGs will be performed by the ECG vendor. 
6.8 
Clinical Laboratory Tests 
6.8.1 
Safety Laboratory Parameters 
Patients will be in a seated or supine position during blood collection. Safety laboratory tests 
are listed in Table 3. Blood and/or urine sampling for blood chemistry, hematology, 
urinalysis, and pregnancy test will be done at the Screening visit, the Non-attack visit 
(pre-dose), and the Post-attack visits. Blood sampling for viral testing will be done at 
Screening only. 
Blood and urine samples will be processed by a central laboratory. The investigator will 
classify all laboratory values outside the normal range of the central laboratory as “Clinically 
significant” or “Not clinically significant”. 
The estimated glomerular filtration rate (eGFR) at Screening will be calculated with the 
CKD-EPI creatinine equation based on serum creatinine and patient characteristics (Levey et 
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Table 3 
List of safety laboratory tests 
Hematology: 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood cell (RBC) count 
• 
White blood cell (WBC) count with 
percent and absolute differential counts 
(neutrophils, bands, lymphocytes, 
eosinophils, monocytes, and basophils) 
Coagulation: 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 
 
Urinalysis:  
• 
Macroscopic analysis: 
• 
Bilirubin 
• 
Blood 
• 
Glucose 
• 
Ketones  
• 
Leukocyte esterase 
• 
Nitrite 
• 
pH 
• 
Protein 
• 
Specific gravity  
• 
Urobilinogen 
• 
Microscopic analysis: 
• 
Bacteria  
• 
Casts  
• 
Crystals  
• 
Epithelial cells  
• 
RBCs 
• 
WBCs 
• 
Yeast 
• 
Urine drug test * 
 
Blood chemistry: 
• 
Albumin 
• 
Alkaline phosphatase (AP) 
• 
Alanine aminotransferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
Blood urea nitrogen (BUN) 
• 
Bicarbonate 
• 
Calcium 
• 
Chloride 
• 
Creatinine 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Magnesium 
• 
Phosphate 
• 
Potassium 
• 
Sodium 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total protein 
• 
Uric acid 
• 
eGFR CKD-EPI (calculated) 
 
Pregnancy test (for women of childbearing 
potential and surgically sterile women): 
• 
Serum human chorionic gonadotropin 
(hCG) 
 
Testing to confirm post-menopausal status of 
women**: 
• 
Serum follicle-stimulating hormone 
(FSH) 
 
Viral testing **: 
• 
HBV (HBsAg) 
• 
HCV (antibodies, if positive followed by 
HCV-RNA) 
• 
HIV1/2 (antibodies) 
 
* Non-attack visit only 
** At Screening only 
 
6.8.2 
Pharmacokinetic Plasma Sampling, Storage, and Shipping 
In Part I of the study, in approximately four patients from each dose cohort (~12 patients in 
total), plasma samples will be collected at pre-dose, 15±5 and 30±5 min post-dose, and 
1h±10min, 2h±10min, 4h±15min, 8h±15min, and 10h±15min post-dose (full PK profile). 
From all other patients in Part I, plasma samples will only be collected pre-dose, and at 
1h±10min and 4h±15min post-dose.  

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In Part II of the study, sparse blood sampling within 24 h post-dose (preferably within 12 h 
post-dose) will be applied for PK purposes. The goal is to collect blood samples from a 
subset of patients for at least 50 attacks treated with PHA-022121 or placebo. 
Collected plasma samples will be stored at -80±16°C. Plasma samples will be transferred 
frozen to the bioanalytical laboratory contracted by the sponsor. 
To allow selection of samples, the bioanalytical laboratory will receive randomization lists 
per treatment sequence. Unblinding of the treatment code will be performed at the 
bioanalytical laboratory only, and will be subjected to a procedure that will ensure that codes 
will not be revealed to anyone involved in the execution of the study. 
Plasma will be analyzed to determine concentrations of PHA-022121 and metabolites using 
validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) 
methods under the supervision of the sponsor. 
6.9 
Dispensing Study Drug 
The study drug must be dispensed under the supervision of the investigator using the IRT 
system for assigning treatments, allocating drug supplies, minimizing drug wastage, and 
assisting with reordering supplies. The investigator or designee pharmacist will maintain 
complete and current accountability records recording receipt, dispensing, return and 
destruction of all clinical study supplies. Local regulations should be adhered to. 
Any damaged or unusable study drug in a given shipment will be documented in the study 
files and recorded in IRT. The investigator must notify study sponsor of any damaged or 
unusable study drugs that were supplied to the investigator’s site. 
All used and unused study drug will either be returned to Pharvaris (or nominated facility) or 
following written agreement with Pharvaris can be destroyed on site (according to local 
regulations) or by an authorized destruction unit. All correspondence related to study drug 
destruction must be filed with the study accountability records.  
Any medication errors, including incorrect dosage, using expired drug, storage requirement 
excursions, administration errors etc., should be recorded as protocol deviation and Pharvaris 
should be immediately informed. 
6.10 Efficacy Assessments 
Patients will complete electronic diaries at home in real-time to collect information on attack 
locations and attack severity as assessed by four patient-reported outcomes (PROs): a visual 
analogue scale (VAS), the mean symptom complex severity (MSCS) score, the treatment 
outcome score (TOS), the treatment outcome score (TOS), and the satisfaction questionnaire 
for medication (TSQM) scores. For this purpose an ePRO device will be applied, which 
throughout Part II of the study needs to be checked daily by the patient and also contains an 
HAE diary in which the patient will record on a daily basis potentially relevant HAE events 
not treated with IMP.  
Patients will be trained in the use of the ePRO device at Screening and at the Non-attack visit 
according to the ePRO device training instructions. 

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6.10.1 
VAS 
The VAS scores of the three major HAE symptoms (skin swelling, skin pain, and abdominal 
pain) range between 0 (No swelling/No pain) and 100 (Extreme swelling/Excruciating pain) 
(Lumry et al. 2011; Kusuma et al. 2012). They must be reported pre-treatment at the time the 
investigator is consulted to confirm eligibility of the attack for study drug treatment. 
Thereafter the VAS scores have to be reported every 30±10 min from 0 to 4 h post-treatment, 
and at 5±0.5, 6±0.5, 8±1, 24±4 and 48±6 h post-treatment. If the 5 h and/or 6 h timepoints 
fall during the overnight/sleeping hours, these timepoints are optional to report. All other 
time points are required.  
A symptom is considered to be severe when the patient has scored the severity as ≥ 50 on the 
VAS, moderate when the score is between 30 and 50, and mild when a patient has scored the 
symptom as < 30 on the VAS. 
The primary endpoint of the study is the change of the 3-symptom composite visual analogue 
scale (VAS-3) score from pre-treatment to 4 h post-treatment. This endpoint is the mean of 
the VAS scores of the three major HAE symptoms: skin swelling, skin pain, and abdominal 
pain. 
The VAS is a validated tool for assessing a patient’s perception of symptom severity, which 
has been widely used in clinical studies in diseases other than hereditary angioedema but 
with similar symptoms, to assess abdominal pain, cutaneous pain, and swelling (Cicardi et al. 
2010). 
6.10.2 
MSCS Score 
The MSCS score evaluates global symptom severity at a point in time. The MSCS score is 
made up of two components: (1) symptom complex identification (patients identify where on 
the body symptoms are occurring); and (2) severity assessment of each symptom complex 
(Vernon et al. 2009). 
Patients are asked to identify where on the body they are experiencing symptoms. Symptoms 
that may be occurring within a symptom complex site include pain, swelling, rash, etc. 
Patients do not identify specific symptoms (i.e., rash), but rather identify symptom 
complexes (body areas) where symptoms are occurring. There are five symptom complexes 
in total: internal head/neck, stomach/gastrointestinal, genital/buttocks, external head/neck, 
and cutaneous. After affected body sites are identified, the patient is asked to rate the severity 
of symptoms within each symptom complex. For example, if patients indicate that they are 
experiencing symptoms in the stomach/gastrointestinal (abdominal) area, they are asked to 
rate the severity of the symptoms within that area. Severity options include normal=0, 
mild=1, moderate=2, severe=3. 
Pre-treatment and at 1±0.25, 2±0.25, 4±0.25, 6±1, 8±1, 24±4, and 48±6 h post-treatment 
(Attack 1, 2, and 3), patients will report the symptom complexes within which they are 
experiencing symptoms and the severity of symptoms within each affected symptom 
complex (called the severity assessment). If the 6h timepoint falls during the 
overnight/sleeping hours, this timepoint is optional to report. All other time points are 
required. 

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The MSCS score is calculated by taking the arithmetic mean of the individual symptom 
complex severity assessments. Please note that no zeros are included in the pre-treatment 
scoring, but zeros can be included in the post-treatment scoring if they refer to symptom 
complexes experienced pre-treatment. 
6.10.3 
TOS 
The TOS is a composite measure that evaluates patient’s recollection of symptom change in 
response to treatment, taking into account symptom severity. The TOS is made up of three 
components: (1) symptom complex identification pre-treatment (patients identify where on 
the body symptoms are occurring); (2) severity assessment of each symptom complex pre-
treatment; and (3) response assessment post-treatment (Vernon et al. 2009).  
Pre-treatment (Attack 1, 2, and 3), patients are asked to identify where on the body they are 
experiencing symptoms. Symptoms that may be occurring within a symptom complex site 
include pain, swelling, rash, etc. Patients do not identify specific symptoms (i.e., rash), but 
rather identify symptom complexes (body areas) where symptoms are occurring. There are 
five symptom complexes in total: internal head/neck, stomach/gastrointestinal, 
genital/buttocks, external head/neck, and cutaneous. After affected body sites are identified, 
the patient is asked to rate the severity of symptoms within each symptom complex. For 
example, if patients indicate that they are experiencing symptoms in the 
stomach/gastrointestinal (abdominal) area, they are asked to rate the severity of the 
symptoms within that area. Severity options include severe=3, moderate=2, or mild=1. 
At 1±0.25, 2±0.25, 4±0.25, 6±1, 8±1, 24±4, and 48±6 h post-treatment (Attack 1, 2, and 3), 
patients are asked to rate change in the affected symptom complexes they identified pre-
treatment (called the response assessment). The response assessment includes the following 
options: significant improvement=100, improvement=50, the same=0, worsening=-50, or 
significant worsening = -100. If the 6h timepoint falls during the overnight/sleeping hours, 
this timepoint is optional to report. All other time points are required. 
The TOS is calculated as the sum of individual symptom complex response assessments 
multiplied by the symptom complex severity assessment at pre-treatment, divided by the sum 
of all individual symptom complex severity assessments at pre-treatment. 
6.10.4 
TSQM Scores 
The 11-item treatment satisfaction questionnaire for medication (TSQM version II) evaluates 
patient treatment satisfaction with the medication for the following scales: effectiveness, side 
effects, convenience, and overall satisfaction (Atkinson et al. 2005). Scale scores are 
transformed into scores ranging from 0 to 100 and can be used to calculate a total composite 
score. 
Patients are requested to rate the 11 items of the TSQM at 48±6 h post-treatment (Attack 1, 
2, and 3). 

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6.11 Adverse Events and Serious Adverse Events 
6.11.1 
Definitions 
An adverse event (AE) as is as any untoward medical occurrence in a clinical investigation 
patient administered study drug (i.e., IMP) and which does not necessarily have a causal 
relationship with this study drug. An AE can therefore be any unfavorable and unintended 
sign, symptom, or disease temporally associated with the use of study drug, whether or not 
related to the study drug. 
Pre-existing diseases, symptoms, or abnormal diagnostic/laboratory values are not considered 
as an AE, and should be recorded in the eCRF as medical history. However, worsening in 
severity or increase in frequency of a pre-existing medical condition or value is considered to 
be an AE. 
An adverse drug reaction (ADR) is defined as a noxious and unintended response to a study 
drug related to any dose. This means that a causal relationship between the study drug and an 
adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out 
(ICH E2A). 
A serious adverse event (SAE) is any untoward medical occurrence (AE) that at any dose:  
• results in death; 
• is life-threatening (at the time of the event); 
• requires inpatient hospitalization or prolongation of an existing hospitalization; 
• results in persistent or significant disability/incapacity; 
• is a congenital anomaly/birth defect; or 
• is an important medical event that may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed above. 
 
For the purpose of this protocol, HAE attacks and their associated symptoms will not be 
defined as AEs, unless they meet the criteria for an SAE. HAE attacks and associated 
symptoms will be recorded in the patient’s diary (ePRO). The events that may trigger a HAE 
attack such as an infection or trauma are considered AEs and should be reported per the usual 
AE reporting process. 
6.11.2 
Adverse Event Assessments 
The investigator or qualified designee will be responsible for assessing AEs. Reporting of 
AEs may result from spontaneous reports by the patient, general questioning by the 
investigator or designee, clinically significant abnormalities found during physical 
examination, or clinically significant findings from vital signs ECGs, or diagnostic test 
results, including laboratory tests. Clinically significant abnormalities are defined as 
abnormalities that require investigation and/or treatment. Simply repeating an abnormal test 
is not considered sufficient for clinical significance. 
The investigator is responsible for monitoring the safety of patients who participate in the 
study and for providing appropriate medical care. In addition, the investigator is responsible 
for alerting the sponsor or its designee to any AE or finding that seems unusual, whether or 

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not that finding is considered related to study drug, and even if it may be considered to be an 
unanticipated beneficial effect. 
All AEs (including SAEs) are to be recorded on the eCRF from the time of signing informed 
consent until the end-of-study visit. AEs should be described in acceptable medical 
terminology using a single reached diagnosis (versus signs and symptoms of the reached 
diagnosis). Abnormal diagnostic test results that support the reached diagnosis should not be 
recorded. However, if the diagnosis is initially unknown or uncertain, signs and symptoms 
must be recorded. As soon as the diagnosis causing the signs and symptoms is known, the 
event terms must be adjusted to the final reached diagnosis.  
Other event information to be collected includes (but is not limited to): onset date, 
assessment of severity (CTCAE grading), relationship to the IMP (i.e., causality assessment), 
action taken, outcome, and date of resolution/stabilization of the event.  
AEs are to be followed up until the event resolves (or resolves with sequelae/stabilizes) or 
the patient is lost to follow-up. If a Grade 1 or 2 event (see Section 6.11.3.1 for AE grading) 
is ongoing at the end-of-study visit, it does not need to be followed if it has been assessed as 
unrelated to the IMP. If possible, for all Grade 3-5 events and events assessed as related to 
the IMP, the event should be followed until the AE is resolved, the patient is in a clinically 
stable condition in regard to the AE, the patient withdraws from the study, the patient is lost 
to follow-up, or the patient has died. 
The sponsor/designee retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
If a patient dies during participation in the study or during a recognized follow-up period 
(and only if allowed by local legislation), the investigator should attempt to provide the 
sponsor/designee with relevant information regarding the death (e.g., a redacted copy of 
relevant post-mortem findings, autopsy report, death certificate, pathology findings, etc.). 
6.11.3 
Classification of an Adverse Event 
6.11.3.1 
Severity and Grade 
The severity of an AE provides a qualitative assessment of the extent or intensity of an AE, 
as determined by the investigator. The severity does not always reflect the clinical 
seriousness of the event, only the degree or extent of the affliction or occurrence (e.g. severe 
nausea, mild seizure).  
The severity grade should be evaluated and recorded on the eCRF according to the grading 
described in the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 
5.0 (NCI 2017). The severity grade refers to the severity of the AE. The CTCAE displays 
Grades 1 through 5 with unique clinical descriptions of severity for each AE based on the 
following general guideline: 
• 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 

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• 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 
6.11.3.2 
Relationship to IMP 
All AEs will be examined to determine their relationship to the IMP (causality). The 
investigator will assess the causality as “Related” or “Unrelated”. AEs should be considered 
“Related” only if there is a reasonable possibility of a causal relationship to the IMP. 
Rationales for an Unrelated assessment may include: 
• Event attributed to concomitant medication or disease 
• Event not reasonably temporally associated with IMP administration 
• Negative dechallenge and/or negative rechallenge 
 
Rationales for a Related assessment may include: 
• Temporal relationship of event to IMP exposure 
• Event is known to be associated with the IMP or drug class  
• Event improved on discontinuation or dose reduction of IMP 
• Event reoccurred on rechallenge with study drug  
• Biological plausibility 
6.11.4 
Reporting Serious Adverse Events 
All SAEs after signing of the informed consent through the end-of-study visit must be 
reported by the investigator, within 24 h of knowledge of their occurrence to the sponsor or 
its designee, independent of the circumstances or suspected cause.  

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The report must be completed via Electronic Data Capture (EDC) in English and must 
include a causality assessment (relationship to IMP). Simultaneously, information about 
every SAE should be recorded on the applicable eCRF pages, including information on AEs 
and concomitant medications. If the electronic data capture (EDC) system is unable to be 
accessed, a back-up paper SAE Report Form should be completed in the interim. The paper 
SAE report form should be sent by e-mail or fax to: 
Medpace Clinical Safety 
SAE Reporting Phone Line: 
+1-800-730-5779, dial 3 or 
+1-513-579-9911, dial 3 (US) 
+49 89 89 55 718 44 (EU) 
Safety Fax: 
+1-866-336-5320 or 
 +1-513-570-5196 (US) 
+49 89 89 55 718 104 (EU) 
E-mail: 
medpace-safetynotification@medpace.com 
 
If a paper SAE Report Form was utilized, the original SAE report form, together with the fax 
confirmation sheet (if applicable), must be kept at the study site. If the initial report is made 
verbally or by telephone, a written confirmation via e-mail or fax must follow within 24 h. 
The investigator will be requested to supply detailed information regarding the event at the 
time of the initial report. 
Each SAE should be recorded as a single reached diagnosis on the SAE report form. 
Accompanying signs (including abnormal diagnostics tests, laboratory values and ECG 
findings) or symptoms should not be reported as additional SAEs. However, if initially the 
diagnosis is unknown, the signs and symptoms should be reported. As soon as the reached 
diagnosis causing the signs and symptoms is known, the event terms will be adjusted to the 
final reached diagnosis. 
For all SAEs occurring during the study, the investigator must submit follow-up reports to 
the sponsor or its designee regarding the patient’s subsequent course until the SAE has 
resolved, or until the condition stabilizes (in the case of persistent impairment), or the patient 
dies.  
The Medical Monitor will be responsible for determining whether an SAE is expected or 
unexpected. An SAE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the list of expected adverse reactions (Reference Safety 
Information) included in the Investigator’s Brochure version in place at the time of the 
assessment. 
All suspected unexpected serious adverse reactions (SUSARs) will be subject to expedited 
reporting to the regulatory authorities by the sponsor or designee, per recognized regulatory 
timelines. The timelines and procedure for follow-up reports are the same as those for the 
initial report (unless the initial SAE report meets 7-day reporting rules). 

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6.11.5 
Events of Special Interest 
Not applicable. At the time of this protocol version, no events of special interest have been 
identified for PHA-022121. 
6.11.6 
Reporting of Pregnancy 
Any female patient who becomes pregnant during the course of the study should have study 
drug discontinued immediately and must be followed to the end of the pregnancy (i.e. 
pregnancy outcome). While pregnancy is not considered an SAE per se, pregnancies must be 
reported immediately to the sponsor or designee using the pregnancy report form and 
following SAE reporting timelines. 
A pregnancy in a patient exposed to the study drug should be followed to term to assess for 
any potential occurrence of congenital anomalies or birth defects. All pregnancies must be 
followed to outcome, which will be reported on the pregnancy outcome report form. 
Pregnancy outcomes include: live birth (full term or pre-term); stillbirth; spontaneous 
abortion; and induced abortion (therapeutic or by choice). 
If a spontaneous abortion occurs or a congenital abnormality/birth defect is observed, such 
events will be reported immediately to the sponsor or designee. 
6.12 Concomitant Medication Assessments 
The investigator or designee is responsible for assessing and reviewing the use of 
concomitant medication from the Screening visit. Details of concomitant medication use 
(generic name, dose, administration route, indication) are recorded on the eCRF. 
All patients in the study must refrain from taking prohibited concomitant medications as 
outlined in Section 5.6.2. 
The use of rescue medication for HAE attacks will be recorded separately. 
6.13 Removal of Patients from the Study or Study Drug 
Patients are free to withdraw from participation in the study at any time upon their request. 
An investigator should discontinue or withdraw a patient from the study for the following 
reasons: 
• Pregnancy 
• Significant study drug non-compliance 
• If any clinical (S)AE, laboratory abnormality, or other medical condition or situation 
occurs that negatively impacts the benefit-risk assessment in such way that continued 
participation in the study would not be in the best interest of the patient, e.g., worsening 
of HAE or disease progression requiring initiation of standard of care treatment 
prohibited in Section 5.6.2, based on the patient’s treating physician criteria and as per 
local guidelines. 
The following stopping criteria for individual patients will be applied for Part I and 
Part II of the study: 

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- 
Any patient that develops an SAE within 48 h after study drug administration that is 
considered to have a reasonable possibility of a causal relationship with the study 
drug, will be discontinued from the study and provided treatment and follow up as 
appropriate. 
- 
Any patient that develops an AE with a CTCAE grading of 3 and above within 48 h 
after drug administration that is considered to have a reasonable possibility of a 
causal relationship with the study drug, will be discontinued from the study and 
provided treatment and follow-up as appropriate. 
- 
Any other AE that, in the opinion of the investigator, would substantially increase the 
risk for the patient during the treatment of an acute attack at home will be 
discontinued from the study. 
• If the patient meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation.  
• Patients without a confirmed HAE Type I/II diagnosis based upon a central laboratory 
assessment or by genotyping of the C1-INH gene (SERPING1) should not enter Part II of 
the study and must be withdrawn. 
• If the patient is unable to complete the assessments for three qualified attacks within a 
reasonable treatment period. 
 
A patient will be considered lost to follow-up if he or she fails to return for a scheduled visit 
and is unable to be contacted by the study site staff.  
The reason for patient discontinuation or withdrawal from the study will be recorded on the 
electronic case report form (eCRF).  
Withdrawn patients will be requested to be available for the end-of-study visit. Patients 
withdrawn during Part II of the study will be requested to attend the post-attack visit after 
their last HAE attack that was treated with IMP (if applicable). 
Randomized patients who subsequently withdraw, or are withdrawn or discontinued from the 
study, will not be replaced. 
6.14 Premature Study Termination 
This study will be prematurely terminated or suspended if there is sufficient reasonable 
cause. Patients in the study will be contacted, as applicable, and be informed of changes to 
the study visit schedule. Circumstances that warrant termination or suspension include, but 
are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients, e.g. new and 
unjustifiable risk and/or toxicity in risk-benefit analysis, such as occurrence of new 
severe or serious adverse events that have a reasonable possibility of a causal relationship 
with the IMP and were previously unknown in respect of their nature, severity, duration 
or frequency in relation to the current established safety profile; new preclinical or 
clinical scientific evidence becoming available during the study that could affect the 
patient’s safety. 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 

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• Data that are not sufficiently complete and/or evaluable 
• Determination of futility 
6.15 Appropriateness of Measurements 
All efficacy, safety, and pharmacokinetic measurements in the study are widely used and 
generally recognized as reliable, accurate, and relevant. 

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7 STUDY ACTIVITIES 
In the following sections all study procedures to be performed are listed by visit/period. 
A concise schedule of study events is provided in Appendix 1. 
Since the study will be conducted during the COVID-19 pandemic it is foreseen that some of 
the planned visits and assessments will be done remotely or by a visiting home nurse where 
feasible. However, the Screening visit and the Non-attack visit (Part I) have to be performed 
at the study sites. 
7.1 
Screening 
The Screening period may take up to 28 days. It consists of an on-site visit and a remote visit. 
At the latter visit the investigator may confirm that the patient is eligible for the study after 
the results of all safety laboratory tests have become available. 
The following assessments will take place at the on-site visit: 
• Informed consent: the informed consent form must be signed by the patient before any 
study-specific procedures are performed. 
• Demographics and HAE characteristics including plasma sampling for laboratory 
assessment of C1-INH functional level, C1q level, and C4 level 
• Medical history 
• Weight and height 
• Physical examination 
• Vital signs: blood pressure, heart rate, body temperature, and respiratory rate 
• Digital 12-lead ECG 
• Blood chemistry: sampling 
• Pregnancy test: for women of childbearing potential and surgically sterile women, 
sampling for a serum pregnancy test must be performed. 
• Menopause test: for post-menopausal women, serum sampling for FSH test 
• Hematology: sampling 
• Coagulation: sampling 
• Urinalysis: sampling 
• Concomitant medications: all concomitant medications used during the study are to be 
recorded. 
• Initial ePRO device training: patient is introduced in the use of the ePRO device and 
capability to complete ePROs as requested is confirmed. 
• Enrollment (within 28 days of informed consent): 
After written informed consent has been obtained and preliminary eligibility according to 
the inclusion and exclusion criteria has been established, the study site will submit 
documentation supporting eligibility to the sponsor or designee and obtain the sponsor’s 
approval to enroll the patient into Part I of the study.  
 
 

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7.2 
Part I: Non-Attack 
If a patient experiences HAE attack symptoms after enrollment, but before the non-attack 
visit, the non-attack visit should be postponed until symptoms have resolved. 
If a patient is treated with acute C1-INH treatment after screening but prior to non-attack 
visit, the patient can continue with the non-attack visit as long as symptoms of the HAE 
attack have resolved at the time of the visit. 
The Non-attack visit takes place at the study site. 
• Randomization: the investigator requests randomization of the patient by the IRT system. 
Randomization may be done at the day of the onsite visit or one day before. 
• Study drug administration: the patient (in quiescent state) receives a single dose of the 
study drug (PHA-022121) under fasting conditions, according to their randomized 
treatment assignment. 
• Weight: at pre-dose 
• Vital signs (blood pressure, heart rate, body temperature, and respiratory rate): at 
pre-dose, and 1 and 4 h post-dose 
• Digital 12-lead ECG (digital triplicate): at pre-dose, and 1 and 4 h post-dose 
• Blood chemistry: sampling at pre-dose 
• Pregnancy test: for women of childbearing potential, sampling for a serum pregnancy test 
must be performed at pre-dose. 
• Hematology: sampling at pre-dose 
• Coagulation: sampling at pre-dose 
• Urinalysis: sampling at pre-dose 
• Urine drug test: pre-dose 
• PK plasma sampling: In approximately four patients from each dose cohort (~12 patients 
in total), plasma samples will be collected at pre-dose, 15 and 30 min post-dose, and 1, 2, 
4, 8, and 10 h post-dose.  
From all other patients, plasma samples will only be collected pre-dose, and at 1 and 4 h 
post-dose. 
• Continued ePRO device training: patient is fully trained in the use of the ePRO device 
and how to consult with the investigator or designee remotely. 
• Adverse events: all AEs with onset after signing informed consent (including SAEs) are 
to be recorded. 
• Concomitant medications: all concomitant medications used during the study are to be 
recorded. 
 
7.3 
Part II Home Treatment: Attack 1, Attack 2, Attack 3 
Only patients with a confirmed HAE Type I/II diagnosis based upon a central laboratory 
assessment or by genotyping of the C1-INH gene (SERPING1) may continue into Part II of 
the study. 
In Part II of the study, the patient self-administers blinded study drug according to the 
randomly assigned treatment sequence at home to treat three qualifying HAE attacks, 

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remotely guided by the investigator. Part II is expected to take approximately 24 weeks, but 
may take longer. 
• Immediate study drug treatment should be taken (within 3 h) after at least one attack 
symptom (skin pain, skin swelling, or abdominal pain) becomes of moderate intensity 
(VAS score ≥ 30), and within 6 h after attack onset at any location. The investigator or 
designee needs to be consulted via remote contact in order to confirm the attack and 
exclude any contraindications for administering study drug (e.g. prohibited medication, 
prior HAE attack treated within the past 5 days). 
Study drug should not be taken for laryngeal and pharyngeal attacks (because of risk of 
airway involvement) or attacks associated with vomiting, swallowing difficulty, or 
intolerable pain. These attacks should be treated with the patient’s standard medication (if 
possible in consultation with the investigator) or the investigator may hospitalize the 
patient. 
• At 4 h post-treatment, the patient consults the investigator or designee remotely to assess 
symptom relief, safety, and any need for rescue medication. If no symptom relief within 
4 h has been experienced, the patient is allowed to use any approved and prescribed acute 
HAE medication. 
• Adverse events: all AEs with onset after signing informed consent (including SAEs) are 
to be recorded. 
• Concomitant medications: all concomitant medications used during the study are to be 
recorded. 
• ePRO device - daily device check and recording of HAE attacks 
• ePRO device - VAS scores: pre-treatment, every 30±10 min from 0 to 4 h post-treatment, 
and at 5±0.5, 6±0.5, 8±1, 24±4 and 48±6 h post-treatment 
• ePRO device - MSCS scores: pre-treatment, at 1±0.25, 2±0.25, 4±0.25, 6±1, 8±1, 24±4, 
and 48±6 h post-treatment 
• ePRO device - TOS: pre-treatment, at 1±0.25, 2±0.25, 4±0.25, 6±1, 8±1, 24±4, and 
48±6 h post-treatment 
• ePRO device – TSQM scores: at 48±6 h post-treatment 
 
7.4 
Part II Home Treatment: Post-Attack 1, Post-Attack 2, Post-Attack 3 
After each HAE attack treated with study drug, an on-site Post-attack visit will take place 
within 5 days post-treatment. Visits may be performed remotely if required, and only if in 
compliance with the protocol and local regulations. 
• Vital signs: blood pressure, heart rate, body temperature, and respiratory rate 
• Blood chemistry: sampling 
• Pregnancy test: for women of childbearing potential, sampling for a serum pregnancy test 
must be performed. 
• Hematology: sampling 
• Coagulation: sampling 
• Urinalysis: sampling 

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• PK plasma sampling: pharmacokinetic plasma samples are planned to be collected within 
24 h post-treatment (preferably within 12 h) from a subset of patients for at least 
50 attacks. 
• Adverse events: all AEs with onset after signing informed consent (including SAEs) are 
to be recorded. 
• Concomitant medications: all concomitant medications used during the study are to be 
recorded. 
• HAE diary: daily device check and recording of potentially relevant HAE events not 
treated with IMP (throughout Part II of the study; starting after the Non-attack visit) 
 
7.5 
End of Study 
The end-of-study visit will take place remotely 10±5 days post-treatment of the last attack 
and if possible in case of withdrawal from the study. 
• Adverse events: all AEs with onset after signing informed consent (including SAEs) are 
to be recorded. 
• Concomitant medications: all concomitant medications used during the study are to be 
recorded. 
This visit may be waived if patients continue in another clinical study with PHA-022121 
conducted by the Sponsor. 

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8 QUALITY CONTROL AND ASSURANCE 
Procedures relevant to the clinical management of this study are either described in the 
applicable standard operating procedures (SOPs) of Pharvaris or their representatives. In 
accordance with Pharvaris SOPs, this study may be subject to independent QA GCP audits at 
the study sites. 
Pharvaris will not allow any waivers to the applicable protocol throughout the conduct of the 
study. An unplanned excursion from the protocol not implemented or intended as a 
systematic change, which could not be justified as necessary to protect the safety, rights, or 
welfare of the patients, will be reported and followed up according to the local IEC/IRB 
requirements.  
Investigators and other study personnel will be appropriately trained by the sponsor or its 
designee. The study will be monitored by sponsor-independent clinical monitors (see also 
Section 10.6). 
To ensure the collection of accurate, consistent, and reliable data, laboratory tests will be 
done at central laboratories, and ECG-reading will be centralized. 

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9 PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The planned analyses are summarized below. Any deviations from these analyses will be 
justified in the clinical study report (CSR). Details of the planned analyses will be described 
in the statistical analysis plan (SAP). All analyses will be carried out using SAS® software 
version 9.4 or higher. 
Unless otherwise specified, all analyses for efficacy endpoints will be based on assessment 
results of HAE attacks that are treated with IMP. For efficacy analyses described in this 
section, post-treatment results refer to the assessment results collected from HAE attacks 
after they are treated with IMP.  
For the analyses of primary and key secondary endpoints for the medium and high doses, 
multiplicity control procedure will be applied to control the overall type 1 error rate at a 5% 
significance level for a 2-sided test. The low dose will be included in the analysis for 
evaluating dose response but will not spend α in the multiplicity control procedure; the 
nominal p values for testing the 10-mg dose will be provided. A graphical multiple testing 
procedure (Bretz et al. 2011) will be used to control the overall type 1 error rate in testing in 
the primary and key secondary endpoints for the medium and high doses. Details on the 
multiplicity control procedure, including the ordering of the key secondary endpoints and the 
selection of weight that determines the fraction of local α from a rejected hypothesis to 
subsequent hypotheses will be specified in the SAP. 
9.2 
Determination of Sample Size 
The study is powered for the expected treatment effect on the VAS-3 score at 4 h post-
treatment, assuming a treatment difference between PHA-022121 and placebo of 10 in VAS-
3 score change from pre-treatment at 4 h post-treatment with a standard deviation of 11, 
based on the previous HAE studies with oral on-demand (Longhurst et al. 2019) and with 
icatibant treatment (Lumry et al. 2011). With the cross-over design, there are nine different 
treatment sequences comparing twice the same active dose and placebo within the same 
patient. Assuming a very low correlation of 0.2 between the within-patient measurements on 
the different attacks, a total of 72 randomized patients, i.e. 8 patients per sequence 
randomized to the nine sequences, will provide approximately 90% power to detect a 
difference of 10 in VAS-3 score change from pre-treatment at 4 h post-treatment between a 
PHA-022121 treatment group (medium dose or high dose) and the placebo group at a 
conservative significance level of 2.5% for a 2-sided test, and the power will reach 94% for a 
significance level of 5% for a 2-sided test. This sample size is adjusted to take into account a 
20% attrition rate for evaluable attacks and 5% of attacks that will be treated with rescue 
medication within 4 h post-treatment.  
The study is planned to be conducted at approximately 35 study sites across 12-15 countries. 
On average, two patients per study site are projected to be enrolled. 
9.3 
Analysis Sets  
The following analysis sets will be analyzed in the study: 

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• Full Analysis Set, defined as all patients enrolled and randomized in the study 
• Modified Intent-To-Treat (mITT) Analysis Set, defined as all randomized patients who 
had at least one IMP-treated (blinded PHA-022121 or placebo) HAE attack and who had 
non-missing VAS results at both pre-treatment and at least one post-treatment time point 
of that attack. 
• Safety Analysis Set, defined as all randomized patients who received any dose of study 
drug 
• Pharmacokinetic Analysis Set, defined as all patients for whom PK parameters can be 
estimated 
9.4 
Demographics and Baseline Characteristics 
The three doses will be compared on demographics and baseline characteristics, using 
descriptive statistics. 
Descriptive statistics will be tabulated as follows:  
• Categorical data will be summarized in frequencies and percentages. 
• Continuous data will be summarized using number of non-missing values (n), mean, 
standard deviation, median (25th, 75th), minimum, and maximum values. 
9.5 
Primary Endpoint 
The primary endpoint of the study is the change in the 3-symptom composite visual analogue 
scale (VAS-3) score from pre-treatment to 4 h post-treatment. The VAS-3 score is the mean 
of the patient-reported VAS scores of the three major HAE symptoms: skin swelling, skin 
pain, and abdominal pain. It was applied earlier in a large Phase III study investigating the 
efficacy of icatibant in patients with acute HAE attacks (Lumry et al. 2011). 
All efficacy analyses will be performed on the mITT Analysis Set. All statistical tests are 
carried out 2-sided. The primary endpoint will be analyzed using a mixed model for repeated 
measures (MMRM) allowing within-patient and between-patient comparisons. All available 
composite VAS-3 score data measured on the different time points before intake of rescue 
medication (if applicable), will be used to estimate the least squares mean difference for 
VAS-3 change at 4 h between PHA-022121 and placebo. The MMRM includes the fixed 
effects of treatment, time, treatment-by-time interaction, period, and pre-treatment VAS-3 
score. No carry-over effect is assumed. The MMRM assumes Missing at Random. This 
hypothetical strategy for handling the intercurrent event “rescue medication intake” would 
estimate the treatment effect of PHA-022121 in change in VAS-3 score at 4 h post-treatment, 
as if all patients had remained on planned treatment regimen throughout each period and had 
not taken rescue medication before 4 h post-treatment. Other sensitivity analyses, including 
an alternative imputation method and another intercurrent event handling strategy, may be 
employed. Details will be included in the SAP. 
The testing procedure for the primary endpoint and key secondary endpoints with 
multiplicity control is described in Section 9.1.  

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In addition, summary statistics of the changes from pre-treatment at the different post-
treatment time points will be provided, for the different periods and for the different doses of 
PHA-022121. 
9.6 
Secondary Endpoints 
9.6.1 
Secondary Efficacy Endpoints 
The key secondary efficacy endpoints of the study are as follows:  
• Time to onset of symptom relief assessed by a ≥30% reduction in VAS-3 score from the 
pre-treatment score. 
• Time to almost complete or complete symptom relief by VAS-3 score. 
Almost complete symptom relief is defined as all 3 individual VAS scores of the VAS-3 
having a value ≤ 10. 
Complete symptom relief is defined as all 3 individual VAS scores of the VAS-3 having 
a value of 0. 
• Time to a ≥50% reduction in VAS-3 score from the pre-treatment score. 
• Change in MSCS score from pre-treatment to 4 h post-treatment 
• TOS at 4 h post-treatment 
 
Other secondary efficacy endpoints of the study are as follows:  
• Time to onset of primary symptom relief assessed by a 30% reduction in the VAS for the 
primary symptom, and time to 50% reduction in the VAS for the primary symptom.  
The primary symptom is determined as follows. The symptom with the highest 
pre-treatment VAS score is considered the primary symptom. If skin pain and abdominal 
pain tie at pre-treatment, abdominal pain is taken forward as primary. If skin pain and 
skin swelling tie, then skin pain is taken forward as primary. If all are tied, abdominal 
pain would be taken forward as primary. 
• Proportion of IMP-treated attacks requiring HAE rescue medication within 12 h, within 
24 h, and within 48 h post-treatment 
• Time to first HAE rescue medication use for IMP-treated attacks, if applicable.  
An IMP-treated attack refers to an attack treated with blinded IMP (study drug). 
• Change in the VAS score for individual symptoms (skin pain, skin swelling, abdominal 
pain) from pre-treatment to 4 h post-treatment 
• Change in MSCS score from pre-treatment to 24 h post-treatment 
• TOS at 24 h post-treatment 
• TSQM scores at 48 h post-treatment 
 
All secondary efficacy endpoints will be analyzed on the mITT Analysis Set. Only 
IMP-treated HAE attacks are considered for these endpoints. For key secondary efficacy 
endpoints, multiplicity control procedure will be applied as described in Section 9.1. For 
other secondary efficacy endpoints, analyses are descriptive in nature and nominal p-values 
will be provided as applicable. 
Each of the time-to-event endpoints will be modeled using a marginal Cox proportional 
hazards model (CPHM) with a robust variance-covariance estimator to account for the 

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within-patient correlation. Patients who have not had the event of interest at the time of the 
analysis (i.e. 48 h time period) will be censored. Patients will also be censored at the time of 
intake of rescue medication (except for the endpoint Time to first HAE rescue medication). 
Estimated hazard ratio of each PHA-022121 dose versus placebo with 95% CI and p-value 
will be provided from the CPHM.  
For the endpoint of proportion of study drug treated attacks requiring HAE rescue 
medication, which is based on binary outcome data, the generalized estimating equation 
(GEE) with a logit link (Jones and Kenward 2014) will be used to analyze the proportion of 
IMP treated attacks requiring HAE rescue mediation. The model will include treatment, 
period, and pre-treatment VAS-3 score as fixed effects. The estimated odds ratio of each 
PHA-022121 dose versus placebo will be provided with 95% CI and p-value. 
For continuous endpoints including change in MSCS score, TOS, change of individual VAS 
score at 4 h, and TSQM score, analyses based on MMRM will be carried out similarly to the 
analysis for the primary endpoint. 
In addition, descriptive summary statistics of the secondary endpoints will also be provided. 
9.6.2 
Safety Endpoints 
The safety endpoints of the study are: 
• Treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and treatment-
emergent serious adverse events (TESAEs), and treatment-related TESAEs  
• Clinical laboratory tests 
• Vital signs 
• ECGs 
 
AEs will be coded with MedDRA. 
Safety endpoints will be summarized by actual treatment received using the Safety Analysis 
Set. Frequencies and percentages will be provided. 
If applicable, descriptive statistics of safety related baseline assessments will be tabulated 
combined with those of their repeat assessments during the study (e.g., safety laboratory, 
vital signs, ECG), by visit/time point. 
9.6.3 
Pharmacokinetic Endpoints 
The pharmacokinetic endpoints of the study are: 
• Pharmacokinetic parameters based on plasma profiles of PHA-022121 and metabolites 
 
Based on the individual concentration-time data, using the actual sampling times, the 
following PK parameters will be derived for PHA-022121 and its metabolites (only for those 
patients from whom a complete PK profile is obtained in Part I) using non-compartmental 
analysis: 

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Cmax, tmax, AUC0-12h, AUC0-24h, AUClast, AUCinf, t1/2, Vz/F (PHA-022121 only) and CL/F 
(PHA-022121 only). Other PK parameters may be estimated as appropriate for exploration of 
the data.  
For the PK parameters, definitions and methods of calculations are:  
Cmax 
The maximum observed analyte concentration; 
tmax 
The actual sampling time to reach the maximum observed analyte 
concentration; 
AUC0-12h 
AUC from time 0 to 12 h post dosing (non-below quantification limit [BQL]) 
concentration, calculated by the linear-linear trapezoidal summation; 
AUC0-24h 
AUC from time 0 to 24 h post dosing (non-below quantification limit [BQL]) 
concentration, calculated by the linear-linear trapezoidal summation; 
AUClast 
AUC from time 0 to the time of the last measurable (non-below quantification 
limit [BQL]) concentration, calculated by the linear-linear trapezoidal 
summation; 
AUCinf 
AUC from time 0 to infinite time, calculated as AUClast + Clast/λz, where Clast 
is the last observed measurable (non-BQL) concentration; extrapolations of 
more than 20 % of the total AUC are reported as approximations;  
t1/2 
Apparent terminal elimination half-life, calculated as 0.693/λz; 
Vz/F 
Apparent volume of distribution, based on terminal phase after a single dose; 
CL/F 
Total apparent systemic clearance of drug after extravascular administration, 
calculated as Dose/AUCinf; 
 
The following requirements should be met for an acceptable calculation of t1/2, λz and AUCinf 
(and related parameters): 
a. At least 3 data points used in the calculation (not including tmax), otherwise t1/2 and 
AUCinf (and related parameters) will be reported as not assessable.  
b. Coefficient of determination (R2adj) is at least 0.90. 
 
If requirement b. is not met, t1/2, λz and AUCinf (and related parameters) will be reported as 
approximations. 
Dose normalization will be done by dividing the relevant PK parameters by the dose. 
Actual sampling times will be checked for major aberrations. In case a major aberration 
occurs for an actual sampling time of > 20% deviation from scheduled time, this plasma 
concentration will be excluded from descriptive statistics in the plasma concentration-time 
table.  
Other PK parameters may be estimated as appropriate for exploration of the data. 
For those patients from whom only sparse samples have been obtained, the PK parameters 
will be determined using the existing population PK model for PHA-022121. 
9.7 
Interim Analysis 
No interim analyses are planned. 

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9.8 
Study Analyses 
A Primary Analysis (PA) may be performed before all enrolled patients have experienced 
3 qualified attacks, because some patients may be unable to complete the assessments for 
3 qualified attacks within a reasonable treatment period. 
If a PA is conducted, all the formal statistical tests for the efficacy endpoints as specified in 
Section3.1 9.5 and Section 9.6 will be performed for the PA. Following the PA, a Final 
Analysis (FA) will be conducted at the very end of the study once most patients have 
completed the assessments for 3 qualified attacks or have been discontinued from the study. 
The FA will include all data accumulated from the beginning of the study through the end of 
the entire study. All statistical analyses at the FA will be regarded as descriptive in nature. 

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substantial amendments, e.g., containing administrative changes, will only be submitted to 
the IEC/IRB for notification. All changes to the consent form must be IEC/IRB approved. 
10.3 Ethical Conduct of the Study 
The study will be conducted in accordance with this study protocol, the International Council 
for Harmonisation GCP (ICH GCP E6[R2]), and applicable local laws and regulations. 
Compliance with ICH-GCP provides public assurance that the rights, safety and well-being 
of study patients are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical trial data are credible. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will 
take place without prior agreement from the sponsor and documented approval from the 
IEC/IRB, except where necessary to eliminate an immediate hazard to the patients. All 
relevant personnel involved in the conduct of this study have completed ICH GCP training. 
10.4 Patient Information and Consent 
At the Screening visit, a signed informed consent form (ICF) must be obtained from each 
patient prior to performing any study-related procedures. Each patient should be given both 
verbal and written information describing the nature and duration of the clinical study.  
The ICF must describe in detail the study drug treatment, study procedures, and risks of 
study participation. The ICF and any other written study material provided to the patient has 
to be approved by an IEC/IRB before patient enrollment. 
The investigator or designee is responsible for explaining the nature and purpose of the study 
as well as other study-related matters to patients, using the written information, and for 
obtaining their full understanding and written consent to participate in the study at their own 
free will. No patient may be subjected to undue influence, such as compulsory enrollment 
into a study. The investigator or designee who provided explanations to the patient should 
sign and date the ICF as well as the patient. The patient should receive a copy of the signed 
ICF and the original must be filed by the investigator. The process and communication of the 
consent should be documented on medical records of the patient. The signed ICFs will be 
retained by the investigator and made available upon request (for review only) to the study 
monitor and auditor. 
The language and expressions used in the written information should be as plain and 
understandable as possible. Patients should be given the opportunity to ask questions and 
receive satisfactory answers to the inquiry and should have adequate time to decide whether 
or not to participate in the study. Written information should not contain any language or 
content that causes the patient to waive or appears to waive any legal rights, or that 
releases/mitigates or appears to release/mitigate the study site, the investigator, other study 
personnel, collaborators, or the sponsor from liability for negligence. 
If an ICF is updated as a result of a substantial protocol amendment, the new IEC/IRB-
approved version will be used to re-consent currently enrolled patients and must be provided 
to newly enrolled patients prior to their entry into the study. 

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10.5 Patient Confidentiality 
The information to be obtained during the conduct of this clinical study is confidential, and 
disclosure to third parties other than those noted below is strictly prohibited. Upon the 
patient’s permission, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her medical welfare.  
Pharvaris will use the information obtained during the conduct of this study for the 
development of PHA-022121. The investigator is obliged to provide Pharvaris or its 
designees with complete test results and all data collected in this study, as described in this 
protocol. 
Access to stored samples will be limited. Samples and data will be stored using codes 
assigned by the sponsor. The code key linking the patient name to the research records will 
be kept by the investigator and may not be released outside the study site. The coded data 
does not include any identifying information of the patient, such as name or address. Data 
will be kept in password-protected computers. Only investigators, the sponsor and affiliates 
or contracted parties will have access to the coded samples and data. 
Data generated by this study must be available for inspection by representatives of the 
European Medicines Agency (EMA), the Food and Drug Administration (FDA), Health 
Canada, and any other competent authority. Even though individuals involved in the study, 
such as study monitors and auditors, may get to know matters related to patients’ privacy due 
to direct access to source documents, or from other sources, they may not disclose these 
contents to third parties.  
10.6 Study Monitoring 
Pharvaris is responsible for monitoring the clinical study to ensure that patients’ human 
rights, safety, and well-being are protected, that the study is properly conducted in adherence 
to the current protocol and any study-specific documents (e.g., CRF completion guidelines), 
to GCP ICH E6(R2), and to applicable regulatory requirements, and that study data reported 
by the investigator are accurate and complete and that they are verifiable with study-related 
records such as source documents. The sponsor or designee will determine the extent and 
nature of the monitoring and assign sponsor-independent clinical monitors who are GCP-
trained. The sponsor will provide the monitors with adequate training on the study protocol. 
The study will be monitored in accordance with the clinical study monitoring plan, which 
specifies the monitoring tasks. 
Monitoring visits or remote monitoring will be conducted to confirm that e.g.:  
• The investigational team is adhering to the study protocol. 
• Informed consent has been obtained from all patients. 
• AEs/SAEs are being reported as required. 
• Data are being accurately recorded in the CRFs. 
• Study drug is being stored correctly and drug accountability is being performed on an on-
going basis. 
• Facilities are, and remain, acceptable throughout the study. 

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• The investigator and site are receiving sufficient information and support throughout the 
study. 
10.7 Case Report Forms and Study Records 
A validated EDC system will be used for entry of the data by the investigator into study-
specific eCRFs designed by the Sponsor or its designee. All information recorded on eCRFs 
for this study must be consistent with the patient's source documentation. The investigator 
will attempt to obtain specific source documents for all data recorded in the eCRF (e.g. 
eligibility criteria, medical history). Where there is no specific source available in the 
medical records, the investigator will attempt to obtain specific, written source documents 
from previous treating physicians. Only when no written source is available, may the 
investigator obtain responses from the patient him/herself during the intake interview(s), 
record these into the source documents and enter the data into the eCRF. 
Initial data entry and any changes to the data will be made only by authorized users, and data 
entries and changes will be captured in an electronic audit trail. An explanation of any data 
change should be recorded. 
A validated ePRO system including ePRO device will be used for entry of the patient 
reported outcome data by the patient into a study-specific patient diary designed by the 
Sponsor or its designee. ePRO data will be considered source data. 
10.8 Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be assembled prior to the study to 
review accumulating safety data on a regular basis (and ad-hoc in case of unexpected safety 
issues) throughout the study. The review of safety data will be performed according to an 
IDMC charter, which will be prepared before data collection starts. All relevant data 
available from this study will be provided for these reviews. The IDMC will consist of 
independent experts external to the study. 
The responsibilities of the IDMC include: 
• to minimize the exposure of patients to an unsafe therapy or dose 
• to make recommendations for changes in study processes where appropriate 
• to advise on the need for dose adjustments because of safety issues 
• to endorse continuation of the study if warranted 
 
Further details on the membership, responsibilities and working procedures of the IDMC are 
described in the IDMC charter, provided as a separate document in the study file. 
10.9 Protocol Violations/Deviations 
The following deviations from the protocol will be considered protocol violations: 
• Deviations from the inclusion and exclusion criteria 
• Deviations from concomitant medication restrictions 

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• Deviations from any other protocol requirements that result in a significant added risk to 
the patient or their rights, or have an impact on the quality of the data collected or the 
outcome of the study. 
 
Protocol violations will be reported in the final clinical study report. 
10.10 Access to Source Documentation 
The investigator and the study site must accept monitoring and auditing by Pharvaris or their 
representatives as well as inspections from the IEC/IRB and relevant regulatory authorities. 
Source documents may be reviewed remotely during monitoring, using regulatory-compliant 
and documented computerized systems, when agreed upon with the investigator study site 
(and study patients), as applicable by local regulations. In these instances, the site must 
provide all study-related records, such as source documents when they are requested by the 
monitors and auditors, the IEC/IRB, or regulatory authorities. The confidentiality of the 
patients’ identities shall be well protected consistent with local and national regulations when 
the source documents are subject to direct access. In accordance with Pharvaris procedures, 
this study may be subject to an independent QA GCP audit at the study sites. 
For France only:   
If remote source data verification is needed in France, the study site will provide the Clinical 
Research Associate, under the responsibility of the Principal Investigator, with access to the 
source documentation through a secure video conference platform. The remote source data 
verification will be conducted using a validated and encrypted videoconference system 
(including, but not limited to, WebEx, Zoom, Microsoft Teams, etc.), as well as a Webcam 
that will allow for the Clinical Research Associate to view the source documents in real-time 
only (i.e., no file sharing will take place). To ensure the privacy and rights of the study 
subject are maintained, the Clinical Research Associate will ensure that no other individuals 
have a view of their screen or access to their laptop while the remote source data verification 
is ongoing and will only be provided with source data from subjects participating in the 
clinical study. 
10.11 Data Generation and Analysis 
The investigator or designee must enter all protocol-required data in the available electronic 
case report form (eCRF), which is a validated system. In the interest of collecting data in the 
most efficient manner, the investigator or designee should enter data into the eCRF as soon 
as possible after the patient’s visit. Laboratory results from the central laboratory will be 
electronically integrated with the EDC data. The eCRFs and any supporting documents 
should be available for retrieval at any given time. The monitor should verify the data in the 
eCRFs with source documents and confirm that there are no inconsistencies between them. If 
any inconsistency is detected on the eCRFs, the monitor must query the investigator and the 
investigator should make corrections/additions in the eCRF or provide an explanation within 
the eCRF system. The monitor should verify the corrected data with source documents to 
confirm that there are no inconsistencies between them, and also check that appropriate 
records on the corrections/additions of data are maintained. 

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Patients will be provided with electronic diaries (ePRO) to carry with them at all times in 
order to collect information on attack locations and severity in real time. The ePRO device is 
a validated “21 CFR Part 11 compliant” electronic data capture tool. 
For screening failures, defined as patients who signed informed consent but were not eligible 
for study participation, relevant data will be collected in the eCRF. 
The investigator is responsible to ensure that all data in the eCRFs are accurate and complete, 
and that all entries are verifiable with source documents. Source data must be available at the 
site to document the existence of the study patients, and to substantiate the integrity of study 
data collected (see also Section 10.7). In case a patient is prematurely discontinued, the 
reason for discontinuation must be documented in the source documents. Study data 
collected from a patient before study discontinuation will still be used in the overall data 
analysis. 
Data management will be coordinated by a delegated CRO, in accordance with their SOPs 
for data management. All study specific processes and definitions will be described in the 
data management plan. Coding of medical terms will be performed using the Medical 
Dictionary for Regulatory Activities (MedDRA) and medications will be coded with the 
WHO Drug Dictionary (WHO-DD). 
10.12 Retention of Data 
All records (data and documents) relating to the study that are generated by or collected by 
the CRO will be filed in a trial master file (TMF) according to ICH-GCP. The TMF will be 
transferred to Pharvaris after the study and will be archived for at least 25 years. Also, all 
records relating to the study that are generated by or collected by the investigators will be 
filed in an investigator site file (ISF) according to ICH GCP. Investigators will retain the ISF 
for at least 25 years. The investigators will also retain source documents that are under their 
control for at least 25 years. All medical records will be retained by the medical center 
according to their own internal procedures. 
10.13 Publication and Disclosure Policy 
All data generated from this study are the property of Pharvaris and shall be held in strict 
confidence along with all information provided by Pharvaris. Except as provided through 
written agreement between Pharvaris, independent analysis and/or publication of these data 
by the investigator or any member of his/her staff is not permitted without prior written 
consent of Pharvaris. Such consent will not be withheld unreasonably. Pharvaris is in 
agreement with the principle of full disclosure of clinical trial results. 

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Page 68 of 73 
11 REFERENCE LIST 
 
Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical Construct Validity of the 
Treatment Satisfaction Questionnaire for Medication (TSQM Version II) among 
Outpatient Pharmacy Consumers. Value Health. 2005;8(s1):S9–24.  
Aygören-Pürsün E, Magerl M, Maetzel A, Maurer M. Epidemiology of Bradykinin-mediated 
angioedema: a systematic investigation of epidemiological studies. Orphanet J Rare Dis. 
2018;13(1):73.  
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical 
approaches for multiple comparison procedures using weighted Bonferroni, Simes, or 
parametric tests. Biometrical J. 2011;53(6):894–913.  
Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a New 
Bradykinin-Receptor Antagonist, in Hereditary Angioedema. New Engl J Medicine. 
2010;363(6):532–41.  
CTFG. Clinical Trial Facilitation and Coordination Group: Recommendations related to 
contraception and pregnancy testing in clinical trials [Internet]. 2020 [cited 2021 Jan 7]. 
Available from: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
about_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_
Version_1.1_updated.pdf 
FDA. The-Voice-of-the-Patient. Hereditary Angioedema. Food and Drug Administration’s 
Patient-Focused Drug Development Initiative [Internet]. 2018 [cited 2020 Dec 17]. 
Available from: https://www.fda.gov/media/113509/download 
FDA-CDER. Medical Review(s) NDA 22-150 (Icatibant) accessed at 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022150Orig1s000MedR.pdf. 
2011.  
Jones B, Kenward MG. Design and analysis of cross-over trials. 3rd ed. Boca Raton: CRC 
Press, Taylor & Francis Group; 2014.  
Kusuma A, Relan A, Knulst AC, Moldovan D, Zuraw B, Cicardi M, et al. Clinical Impact of 
Peripheral Attacks in Hereditary Angioedema Patients. Am J Medicine. 
2012;125(9):937.e17-937.e24.  
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. 
www.ncbi.nlm.nih.gov 5/12/2020, 8:12:24 PM.pdf. Ann Intern Med. 2009;150(9):604.  
Longhurst H, Moldovan D, Bygum A, Cicardi M, Huissoon A, Aygoren-Pursun E, et al. Oral 
Plasma Kallikrein Inhibitor BCX7353 is Safe and Effective as an On-Demand Treatment 

PHVS416 (PHA-022121 soft capsules) 
 
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Page 69 of 73 
of Angioedema Attacks in Hereditary Angioedema (HAE) Patients: Results of the 
ZENITH-1 Trial. J Allergy Clin Immun. 2019;143(2):AB36.  
Lumry WR, Li HH, Levy RJ, Potter PC, Farkas H, Moldovan D, et al. Randomized placebo-
controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of 
acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol. 
2011;107(6):529-537.e2.  
Maurer M, Longhurst HJ, Bouillet L, Caballero T, Grumach SS, Botha J, et al. Long-term 
effectiveness and safety of icatibant for the on-demand treatment of hereditary 
angioedema attacks: 10 years of the Icatibant Outcome Survey (EAACI abstract #1118). 
Allergy. 2020;75(S109):59–60.  
Maurer M, Magerl M, Ansotegui I, Aygören‐Pürsün E, Betschel S, Bork K, et al. The 
international WAO/EAACI guideline for the management of hereditary angioedema—
The 2017 revision and update. Allergy. 2018;73(8):1575–96.  
NCI. NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 
[Internet]. 2017 [cited 2020 May 10]. Available from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
Orladeyo. US Prescribing Information [Internet]. 2020 [cited 2021 Jan 27]. Available from: 
https://biocryst.com/wp-content/uploads/2020/12/ORLADEYO_PI_V1_2020.pdf 
SPC. Summary of Product Characteristics Firazyr [Internet]. 2013. Available from: 
https://www.ema.europa.eu/en/documents/product-information/firazyr-epar-product-
information_en.pdf 
Stoppa-Lyonnet D, Tosi M, Laurent J, Sobel A, Lagrue G, Meo T. Altered C1 Inhibitor 
Genes in Type I Hereditary Angioedema. New Engl J Med. 1987;317(1):1–6.  
Vernon MK, Rentz AM, Wyrwich KW, White MV, Grienenberger A. Psychometric 
validation of two patient-reported outcome measures to assess symptom severity and 
changes in symptoms in hereditary angioedema. Qual Life Res. 2009;18(7):929–39.  
Zanichelli A, Arcoleo F, Barca MP, Borrelli P, Bova M, Cancian M, et al. A nationwide 
survey of hereditary angioedema due to C1 inhibitor deficiency in Italy. Orphanet J Rare 
Dis. 2015;10(1):11.  
Zuraw BL. Hereditary Angioedema. New Engl J Medicine. 2008;359(10):1027–36.  
 

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1  
Screening period may take up to 28 days from ICF signature until enrolment. 
2  
Within 5 days post treatment. Visits may be performed remotely if required, and only if in compliance with 
the protocol and local regulations. 
3  
10±5 days post-treatment of the last attack 
4  
Informed consent form must be signed by the patient before any study-specific procedures are performed. 
5  
After preliminary eligibility according to the inclusion and exclusion criteria has been established, the study 
site will submit documentation supporting eligibility to the sponsor or designee and obtain the sponsor’s 
approval to enroll the patient. The patient will be informed that he/she is eligible for participation and an 
appointment for the Non-attack visit will be made. 
6  
Including plasma sampling for laboratory assessment of C1-INH functional level, C1q level, and C4 level 
7  
Height is only measured at Screening. 
8  
Blood pressure, heart rate, body temperature, and respiratory rate 
9  
Pre-dose, and 1 and 4 h post-dose 
10  For details see Table 3 in section 6.8.1. 
11  Pre-dose; urinalysis including urine drug test 
12  For women of childbearing potential and surgically sterile women, a serum pregnancy test must be 
performed. 
13  For postmenopausal women, serum sampling for a FSH test must be performed. 
14  In approximately four patients from each dose cohort, plasma samples will be collected at pre-dose, 15±5 
and 30±5 min post-dose, and 1h±10min, 2h±10min, 4h±15min, 8h±15min, and 10h±15min post-dose (full PK 
profile). From all other patients, plasma samples will only be collected pre-dose, and at 1h±10min and 
4h±15min post-dose. 
15  PK plasma samples are planned to be collected within 24 h post-treatment (preferably within 12 h) from a 
subset of patients for at least 50 attacks. 
16  The patient (in quiescent state) receives a single dose of the randomized study drug (PHA-022121) at the 
study site under fasting conditions. 
17  Attack treatment: Before administration of study drug the investigator or designee must confirm eligibility 
of the attack for study drug treatment via a remote consultation. The study drug should be taken when at least 
one attack symptom (skin pain, skin swelling, or abdominal pain) becomes of moderate intensity (VAS score 
≥ 30). When the attack reaches this VAS intensity threshold, study drug should preferably be taken during the 
remote contact with the investigator or designee. If the patient cannot take the study drug within 3 h after 
reaching the VAS intensity threshold, the attack does not qualify for study drug treatment and should be treated 
with the patient’s standard HAE medication. In addition, treatment of the attack should happen within 6 h after 
onset of symptoms at any location. If the study drug cannot be administered within 6 h after onset of symptoms, 
the attack does not qualify for study drug treatment and should be treated with the patient’s standard HAE 
medication. Any symptoms involving the internal head and neck, regardless of intensity, also render an attack 
non-qualifying for treatment with study drug and should be treated with the patient’s standard HAE medication.  
At 4 h post study drug treatment, the patient will consult with the investigator or designee remotely again to 
assess symptom relief, safety, and any need for rescue medication. 
18  All AEs with onset after signing informed consent (including SAEs) are to be recorded. Last follow-up for 
AEs will occur 10±5 days after the last attack treatment. 
19  Daily device check and recording of potentially relevant HAE events not treated with IMP (throughout 
Part II of the study; starting after the Non-attack visit) 
20  VAS score: pre-treatment, every 30±10 min from 0 to 4 h post-treatment, and at 5±0.5, 6±0.5, 8±1, 24±4 
and 48±6 h post-treatment 
21  MSCS score: pre-treatment, and at 1±0.25, 2±0.25, 4±0.25, 6±1, 8±1, 24±4, and 48±6 h post-treatment 
22  TOS: pre-treatment, and at 1±0.25, 2±0.25, 4±0.25, 6±1, 8±1, 24±4, and 48±6 h post-treatment 
23  TSQM scores: at 48±6 h post-treatment 
 
 
 
 

 
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Appendix 2 
Sponsor Signature 
Study Title: 
A Phase II, double-blind, placebo-controlled, Randomized, 
cross-over, dose-ranging study of oral PHA-022121 for Acute 
treatment of angioedema attacks in Patients with hereditary 
angioedema due to C1-Inhibitor Deficiency type I and II 
Acronym: 
RAPIDe-1 
Study Number: 
PHA022121-C201 
Original Protocol: 
Version 1.0 (18 August 2020) 
Amendment 7: 
Version 3.0 (25 April 2022) 
 
 
 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor. 
 
 
 
Signed: 
 
 
Date:  
 
 
Executive Director 
Clinical Development 
Pharvaris Netherlands BV 

 
Confidential 
 
Page 73 of 73 
Appendix 3 
Principal Investigator Signature 
Study Title: 
A Phase II, double-blind, placebo-controlled, Randomized, 
cross-over, dose-ranging study of oral PHA-022121 for Acute 
treatment of angioedema attacks in Patients with hereditary 
angioedema due to C1-Inhibitor Deficiency type I and II 
Acronym: 
RAPIDe-1 
Study Number: 
PHA022121-C201 
Original Protocol: 
Version 1.0 (18 August 2020) 
Amendment 7: 
Version 3.0 (25 April 2022) 
I have read all pages of this clinical study protocol for which Pharvaris Netherlands BV is the 
sponsor. I agree that it contains all the information required to conduct this study. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions 
set out therein. I confirm that I will conduct the study in accordance with the ICH GCP 
guidelines (ICH E6[R2]) and the provisions of the Helsinki Declaration. I will also ensure 
that all relevant members of my staff have access to copies of this protocol, the ICH GCP 
guidelines and the Helsinki Declaration to enable them to work in accordance with the 
provisions of these documents.” 
 
 
 
 
Signed: 
 
 
Date:  
 
 
 
Printed name: ………………………………………………………………………. 
Affiliation: …………………………………………………………………………. 
……………………………………………………………………………………… 
……………………………………………………………………………………… 
 
 

 
Confidential 
The information contained in this document is the property of Pharvaris Netherlands BV and may not be 
reproduced, published or disclosed to others without written authorization from Pharvaris Netherlands BV. 
Protocol Amendment 7: PHA022121-C201 
 
Study Title: 
A Phase II, double-blind, placebo-controlled, Randomized, cross-
over, dose-ranging study of oral PHA-022121 for Acute treatment 
of angioedema attacks in Patients with hereditary angioedema due 
to C1-Inhibitor Deficiency type I and II 
Acronym: 
RAPIDe-1 
Study Number: 
PHA022121-C201 
Study Phase: 
Phase II 
Product Name: 
PHA-022121 soft capsules (PHVS416) 
Indication: 
Hereditary Angioedema 
EudraCT Number: 
2020-003445-11 
Investigators: 
Multicenter 
Sponsor: 
Pharvaris Netherlands B.V. 
J.H. Oortweg 21  
2333 CH Leiden  
The Netherlands 
Sponsor Contact: 
clinical@pharvaris.com 
Sponsor 
Representative(s): 
 
Chief Medical Officer 
 
Executive Director 
Clinical Development 
 
 
Date 
Protocol version 
Original Protocol: 
18 August 2020 
1.0 
Amendment 1 (UK only): 
22 December 2020 
1.1 
Amendment 2 (Germany only): 
27 January 2021 
1.2 
Amendment 3 (France only): 
08 March 2021 
1.3 
Amendment 4 (Czech Republic only): 
12 March 2021 
1.4 
Amendment 5 (global): 
08 April 2021 
2.0 
Amendment 6 (France only): 
28 June 2021 
2.1 
Amendment 7 (global): 
25 April 2022 
3.0 

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TABLE OF CONTENTS 
1 
SUMMARY AND JUSTICATION OF CHANGES .........................................................3 
SPONSOR SIGNATURE ..........................................................................................................8 
PRINCIPAL INVESTIGATOR SIGNATURE .........................................................................9 
 

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1 SUMMARY AND JUSTICATION OF CHANGES 
The protocol was amended to include brief results from the most recent non-clinical and 
clinical studies, to modify the secondary efficacy endpoints, to update the statistical methods, 
to make a change to the AE causality text per a request by a regulatory authority, and to 
incorporate changes from a previous amendment prepared for sites in France (Amendment 6, 
version 2.1). 
Other changes made pertain to: 
• Waiving the end-of-study visit if patients continue in another clinical study with 
PHA-022121 conducted by the Sponsor 
• Extending the duration of participation and overall study if some patients need longer 
than 24 weeks to complete assessments for 3 qualifying HAE attacks 
• Allowing inclusion of patients with positive hepatitis B serology if they have normal liver 
function tests and no signs of active liver disease 
• Allowing bilirubin elevation at screening if elevation is due to Gilbert’s syndrome 
• Removing the prohibition on concomitant medications that are metabolized by CYP3A4  
• Defining clinically significant as it pertains to abnormal findings from safety assessments 
• Indicating that Part II is subject to the same stopping rules as Part I 
• Clarified the use of the ePRO device for recording HAE attacks 
• Adding a new section for “Study Analyses” to describe the circumstance under which the 
Sponsor may elect to perform a Primary Analysis and a Final Analysis 
 
Material changes are summarized in the table below. Administrative changes, editorial 
changes, and those made to correct formatting, grammatical, or typographical errors are not 
itemized. 
None of the revisions are judged to have a clinically significant impact on the safety of 
patients or the integrity of the study. 
 
Protocol Amendment 
Summary of Changes from Protocol Version 2.0 (08 April 2021) 
Amendment Number: 
7 
Amendment Date: 
25 April 2022 
Scope: 
Global 
Change 
Rationale 
Location(s) 
Affected 
Removed the following from the key 
secondary efficacy 
objectives/endpoints: 
• 
The proportion of attacks 
requiring the use of HAE rescue 
medication. 
To focus the key secondary 
objectives/endpoints on the assessment 
of symptom improvement for HAE 
attacks; however, the proportion of 
attacks requiring rescue medication use 
is being retained as a secondary efficacy 
endpoint 
Synopsis, 
Section 2.2, 
Section 3.1, 
Section 9.6.1 

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Protocol Amendment 
Summary of Changes from Protocol Version 2.0 (08 April 2021) 
Amendment Number: 
7 
Amendment Date: 
25 April 2022 
Scope: 
Global 
Change 
Rationale 
Location(s) 
Affected 
Added a statement that the end-of-
study visit may be waived if patients 
continue in another clinical study with 
PHA-022121 conducted by the 
Sponsor. 
To avoid an unnecessary delay in 
treatment should the patient qualify for 
another PHA-022121 study 
Synopsis, 
Section 3.1, 
Section 7.5 
Added text to indicate that individual 
patient participation and overall study 
duration may be longer than 
previously specified 
To allow for some patients who need 
longer than 24 weeks to complete 
assessments for 3 qualifying HAE 
attacks 
Synopsis, 
Section 3.3, 
Section 7.3 
To specify that for inclusion in the 
Modified Intent-to-Treat Analysis 
Set, the patient must have a pre-
treatment VAS assessment and at 
least one post-treatment assessment 
for the qualifying HAE attack. 
Changes in VAS scores cannot be 
analyzed if the pre-treatment assessment 
and/or all post-treatment assessments are 
missing. 
Synopsis, 
Section 9.3 
Added the following as a key 
secondary efficacy endpoint: 
• 
Time to onset of symptom relief 
assessed by a ≥30% reduction in 
VAS-3 score from the pre-
treatment score 
 
Added/further defined the following 
as other secondary efficacy endpoints: 
• 
Time to onset of primary 
symptom relief assessed by a 30% 
reduction in the VAS for the 
primary symptom, and time to a 
50% reduction in the VAS for the 
primary symptom 
• 
Proportion of IMP-treated attacks 
requiring HAE rescue medication 
within 12 h, within 24 h, and 
within 48 h post-treatment 
 
Since patients treat HAE attacks early 
and in the home setting, baseline HAE 
attack severity is relatively moderate; 
thus, for some attacks a 50% reduction in 
VAS-3 would achieve almost complete 
symptom resolution. Therefore, based on 
the feedback from a recent advisory 
board meeting, the key opinion leaders 
believe that the onset of symptom relief 
should be defined as a reduction of at 
least 30% in VAS-3. The definition for 
onset of symptom relief is being updated 
to a reduction of ≥30% in VAS-3, and 
time to 50% reduction in VAS-3 is being 
retained as one of the key secondary 
efficacy endpoints. 
Synopsis, 
Section 3.1, 
Section 9.6.1 
 
 
 
 
 
Section 3.1, 
Section 9.6.1 

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Protocol Amendment 
Summary of Changes from Protocol Version 2.0 (08 April 2021) 
Amendment Number: 
7 
Amendment Date: 
25 April 2022 
Scope: 
Global 
Change 
Rationale 
Location(s) 
Affected 
Multiplicity control procedure will be 
applied only to the medium and high 
dose groups 
The three dose levels used in this study 
were chosen based on the data from the 
bradykinin challenge in healthy 
individuals performed in the Phase 1 
study PHA022121-C001 (see Section 3.2 
Rationale for Study Design and Control 
Group of the protocol for details). All 
three dose levels used in this study are 
expected to be as effective as one or two 
30-mg doses of icatibant, which is the 
approved dose of icatibant. The 20- and 
30-mg dose levels of PHA-022121 were 
projected to provide a duration of 
efficacy comparable to that of two 
injections of icatibant.  At this point in 
the study with 57 patients having 
received at least one dose of 
PHA-022121 and ~110 attacks having 
been treated with blinded study treatment 
(PHA-022121 or placebo), PHA-022121 
appears to be well tolerated and no 
significant safety issue has been 
observed. Therefore, the Sponsor 
proposes not to spend α in the 
multiplicity control procedure for the 
10-mg dose to maximize the chance of 
meeting the primary endpoint and all the 
key secondary endpoints with the 20- 
and 30-mg doses. The nominal p-values 
for testing the 10-mg dose will be 
provided. 
Synopsis, 
Section 9.1 
Updated the text pertaining to the 
approval status of berotralstat with 
recent marketing authorization 
approvals in the European Union and 
the United Kingdom 
Incorporated this change from a prior 
protocol amendment prepared for sites in 
France (Amendment 6, version 2.1). 
Section 1.2.2 
Updated the nonclinical toxicology 
and potential risk sections with 
information from the completed 6- 
and 9-month GLP studies  
To provide the most recently available 
nonclinical safety data to the 
investigators 
Section 1.2.3.1, 
Section 1.3.1 

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Protocol Amendment 
Summary of Changes from Protocol Version 2.0 (08 April 2021) 
Amendment Number: 
7 
Amendment Date: 
25 April 2022 
Scope: 
Global 
Change 
Rationale 
Location(s) 
Affected 
Updated the clinical research section 
with the most recent information from 
completed Phase 1 studies 
To provide the most recently available 
nonclinical and clinical safety data to the 
investigators 
Section 1.2.3.2 
Updated the potential risk section 
with brief results from the drug-drug-
interaction study in humans 
To provide the most recently available 
clinical safety data to the investigators 
Section 1.3.1 
Modified exclusion criterion #6 to 
indicate that patients who test positive 
for HBsAg and who have normal 
liver function tests with no clinical 
sign of liver disease are not excluded 
from the study. 
Patients who test positive for HBsAg and 
who have normal liver function tests 
with no clinical sign of liver disease 
should undergo testing to quantify 
HBsAg or HBV DNA, and detection of 
HBeAg. Patients who test negative for 
HBeAg and have low or intermediate 
level of HBV DNA and normal ALT, 
formerly called “inactive carriers” are 
considered at low risk of progression to 
cirrhosis and liver carcinoma, according 
to the European Association for the 
Study of the Liver (EASL) 2017 Clinical 
Practice Guidelines on the management 
of hepatitis B virus infection, as 
published in Journal of Hepatology, 
2017, vol. 67, pp 370–398. Therefore, 
such patients are not excluded from the 
study. 
Section 4.3, 
Section 6.8.1 
(Table 3) 
Modified exclusion criterion #7 such 
that a bilirubin level >1.5 × the upper 
limit of normal is not exclusionary if 
consistent with a diagnosis of 
Gilbert’s syndrome 
In such patients, the increased bilirubin 
is not indicative of liver injury, thus there 
is no increased risk for these patients to 
participate in the study. 
Section 4.3 
Medications metabolized by CYP3A4 
are no longer prohibited concomitant 
medications and are no longer 
exclusionary. 
The recently completed human 
drug-drug interaction study 
(PHA022121-C004) indicates that at 
anticipated therapeutics doses, 
PHA-022121 does not inhibit or induce 
CYP3A4; therefore, medications that are 
metabolized by CYP3A4 are no longer 
prohibited or exclusionary. 
Section 4.3, 
Section 5.6.2 

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Protocol Amendment 
Summary of Changes from Protocol Version 2.0 (08 April 2021) 
Amendment Number: 
7 
Amendment Date: 
25 April 2022 
Scope: 
Global 
Change 
Rationale 
Location(s) 
Affected 
Added a standard definition of 
clinically significant as it pertains to 
abnormal findings from safety 
assessments. 
To guide assessments made by the 
investigator 
Section 6.11.2 
Deleted “Event is expected in the 
targeted disease and/or population” 
from the list of rationales for the 
investigator to assess an event as 
unrelated to study treatment 
Per feedback from regulatory authority 
on the AE causality text and for 
compliance with International Council 
for Harmonisation E2A section 2A2 
Section 6.11.3.2 
Clarified that the stopping criteria for 
individual patients applies to both 
Part I and Part II 
To avoid misunderstanding 
Section 6.13 
Modified the procedural text 
pertaining to use of the ePRO device 
All HAE attacks are to be recorded in the 
HAE diary, whether treated with IMP or 
not 
Section 7.3 
Revised the significance level, power, 
and attrition rate in the sample size 
calculation 
To reflect testing for the medium and 
high dose levels, without the low dose 
level 
Section 9.2 
Added a new section entitled “Study 
Analyses” to describe the 
circumstance under which the 
Sponsor may elect to perform a 
Primary Analysis and a Final 
Analysis  
A Primary Analysis may be performed 
before all enrolled patients have 
experienced all 3 qualified attacks, 
because some patients may take longer 
than 24 weeks to complete assessments 
for all 3 attacks 
Section 9.8 
For France only:   
Added text to describe the process 
and method of remote source data 
verification for study sites located in 
France, for situations where on-site 
monitoring would not be possible 
Incorporated this change from a prior 
protocol amendment prepared for sites in 
France (Amendment 6, version 2.1) 
Section 10.10 

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SPONSOR SIGNATURE 
Study Title: 
A Phase II, double-blind, placebo-controlled, Randomized, 
cross-over, dose-ranging study of oral PHA-022121 for Acute 
treatment of angioedema attacks in Patients with hereditary 
angioedema due to C1-Inhibitor Deficiency type I and II 
Acronym: 
RAPIDe-1 
Study Number: 
PHA022121-C201 
Original Protocol: 
18 August 2020, Version 1.0 
Amendment 7: 
25 April 2022, Version 3.0 
 
 
 
This protocol amendment was subject to critical review and has been approved by the 
sponsor. 
 
 
 
 
 
Signed: 
 
 
Date:  
 
 
Executive Director 
Clinical Development 
Pharvaris Netherlands BV 
 

PHA-022121 soft capsules (PHVS416) 
 
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PRINCIPAL INVESTIGATOR SIGNATURE 
Study Title: 
A Phase II, double-blind, placebo-controlled, Randomized, 
cross-over, dose-ranging study of oral PHA-022121 for Acute 
treatment of angioedema attacks in Patients with hereditary 
angioedema due to C1-Inhibitor Deficiency type I and II 
Acronym: 
RAPIDe-1 
Study Number: 
PHA022121-C201 
Original Protocol: 
18 August 2020, Version 1.0 
Amendment 7: 
25 April 2022, Version 3.0 
 
I have read all pages of this protocol amendment for which Pharvaris Netherlands BV is the 
sponsor. I agree that it contains all the information required to conduct this study. I agree to 
conduct the study as outlined in the protocol and amendments and to comply with all the 
terms and conditions set out therein. I confirm that I will conduct the study in accordance 
with the ICH GCP guidelines (ICH E6[R2]) and the provisions of the Helsinki Declaration. I 
will also ensure that all relevant members of my staff have access to copies of this protocol 
amendment, the ICH GCP guidelines and the Helsinki Declaration to enable them to work in 
accordance with the provisions of these documents.” 
 
 
 
 
Signed: 
 
 
Date:  
 
 
 
Printed name: ………………………………………………………………………. 
Affiliation: …………………………………………………………………………. 
……………………………………………………………………………………… 
………………………………………………………………………………………