Phase III, Single Arm, Open Label, International, Multi Centre Study to Evaluate the Efficacy and Safety of Lomitapide in Paediatric Patients With Homozygous Familial Hypercholesterolaemia (HoFH) on Stable Lipid Lowering Therapy
Phase: PHASE3
Conditions: Homozygous Familial Hypercholesterolaemia (HoFH)
Sponsor: Amryt Pharma

 
 
C O N F I D E N T I A L  
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of Amryt 
Pharmaceuticals DAC, and is therefore provided to you in confidence as an investigator, potential 
investigator, member of regulatory authorities or consultant, for review by you, your staff and an 
applicable Independent Ethics Committee. It is understood that this information will not be disclosed 
to others without written authorisation from Amryt Pharmaceuticals DAC, except to the extent 
necessary to obtain written informed consent from those persons to whom the drug may be 
administered. 
Study Protocol 
 
Phase III, Single-arm, Open-label, International, Multi-centre Study 
to Evaluate the Efficacy and Safety of Lomitapide in Paediatric 
Patients with Homozygous Familial Hypercholesterolaemia (HoFH) 
on Stable Lipid-lowering Therapy 
 
Investigational product 
Lomitapide 
Indication 
Homozygous Familial Hypercholesterolaemia (HoFH) 
Identifier 
EudraCT No. 2019-002278-30 
Study number 
APH-19 
Development phase 
Phase III 
Document 
Study Protocol APH-19 
Version number 
7.0 
Status 
Final 
Release date 
09 February 2023 
Revision chronology 
Version 1.0 
19 July 2019 
 
Version 2.0 
18 August 2019 
 
Version 3.0 
04 December 2019 
 
Version 4.0 
14 February 2020 
 
Version 5.0 
04 September 2020 
 
Version 5.1 
Version 5.2 (Germany) 
21 September 2020 
17 November 2020 
 
Version 6.0 
05 May 2022 
Author(s) 
Dr Tracy Cunningham, LRCPI & SI, MB, BCh, BAO, FRCPI, AFPM 
Compliance 
The study will be conducted in accordance with standards of Good 
Clinical Practice, as defined by the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) and all applicable federal and local regulations. 
Sponsor 
Amryt Pharmaceuticals DAC 
45 Mespil Road, Dublin 4, Ireland 
Phone: +35-3-1-518-0200 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 4 of 111 
C O N F I D E N T I A L  
TABLE OF CONTENTS 
LIST OF TERMS AND ABBREVIATIONS ............................................................................. 9 
1 
SUMMARY OF CLINICAL STUDY ................................................................................ 12 
1.1 
Study Synopsis .................................................................................................. 12 
1.2 
Flow Chart of Study and Follow-up ..................................................................... 23 
2 
INTRODUCTION ............................................................................................................ 27 
2.1 
Background ........................................................................................................ 27 
2.1.1 
Homozygous Familial Hypercholesterolaemia ..................................... 27 
2.1.2 
Treatment Options and Medical Need ................................................. 27 
2.2 
Investigational Product ....................................................................................... 29 
2.3 
Summary of Non-clinical Studies with Lomitapide .............................................. 29 
2.4 
Summary of Clinical Studies with Lomitapide ..................................................... 29 
2.4.1 
Clinical Pharmacology and Pharmacokinetics ..................................... 29 
2.4.2 
Clinical Efficacy and Safety ................................................................. 29 
2.5 
Rationale for Dose Selection .............................................................................. 33 
2.6 
Known and Potential Benefits and Risks ............................................................ 34 
2.6.1 
Unmet Medical Need ........................................................................... 34 
2.6.2 
Known and Potential Benefits .............................................................. 35 
2.6.3 
Known and Potential Risks .................................................................. 36 
2.6.4 
Benefits and Risks Conclusions .......................................................... 38 
2.7 
Rationale of the Study and of the Study Design ................................................. 38 
3 
STUDY OBJECTIVES .................................................................................................... 39 
3.1 
Primary Objective ............................................................................................... 39 
3.2 
Secondary Objectives ........................................................................................ 39 
3.3 
Safety Objectives ............................................................................................... 39 
3.4 
Exploratory Objectives ....................................................................................... 40 
3.5 
Palatability Objective .......................................................................................... 40 
3.6 
Pharmacokinetic Objective ................................................................................. 40 
4 
INVESTIGATIONAL PLAN ............................................................................................ 41 
4.1 
Study Endpoints ................................................................................................. 41 
4.1.1 
Primary Endpoint ................................................................................. 41 
4.1.2 
Secondary Endpoints .......................................................................... 41 
4.1.3 
Safety Endpoints ................................................................................. 41 
4.1.4 
Exploratory Endpoints ......................................................................... 42 
4.1.5 
Palatability Endpoints .......................................................................... 42 
4.1.6 
Pharmacokinetic Endpoint ................................................................... 42 
4.2 
Overall Study Design .......................................................................................... 42 
4.2.1 
Study ................................................................................................... 43 
4.2.2 
End of Study ....................................................................................... 46 
4.3 
Data Safety Monitoring Board ............................................................................ 46 
5 
STUDY POPULATION ................................................................................................... 46 
5.1 
Inclusion Criteria ................................................................................................ 46 
5.2 
Exclusion Criteria ............................................................................................... 47 
6 
STUDY MEDICATION .................................................................................................... 48 
6.1 
Description of the Investigational Product ........................................................... 48 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 5 of 111 
C O N F I D E N T I A L  
6.1.1 
Formulation, Packaging and Labelling ................................................. 48 
6.1.2 
Storage and Stability ........................................................................... 48 
6.1.3 
Drug and Dietary Supplements Accountability ..................................... 48 
6.2 
Investigational Product Compliance ................................................................... 49 
6.3 
Dietary Supplements .......................................................................................... 49 
7 
STUDY TREATMENT .................................................................................................... 49 
7.1 
Treatment Assignment, Blinding Procedure ....................................................... 49 
7.2 
Treatment Schedule ........................................................................................... 49 
7.3 
Dose Modifications and Interruptions ................................................................. 50 
7.3.1 
Dose Escalation, Dose Reduction and Re-challenge .......................... 50 
7.3.2 
Dose Modification, Interruption or Discontinuation for Adverse 
Events ................................................................................................. 51 
7.3.3 
Dose Modification for Concomitant Medication .................................... 54 
7.4 
Patient Discontinuation Criteria .......................................................................... 55 
7.5 
Overdose ........................................................................................................... 56 
7.6 
Concomitant Medication ..................................................................................... 57 
7.6.1 
Concomitant Lipid-lowering Treatment ................................................ 57 
7.6.2 
Permitted Concomitant Medication ...................................................... 57 
7.6.3 
Non-permitted Concomitant Medication, Food or Substances ............. 58 
8 
ASSESSMENTS ............................................................................................................ 59 
8.1 
Eligibility and Safety Assessments ..................................................................... 59 
8.1.1 
Eligibility Assessments ........................................................................ 59 
8.1.2 
Safety Assessments ............................................................................ 60 
8.2 
Pharmacokinetics ............................................................................................... 63 
8.3 
Assessment of Efficacy ...................................................................................... 63 
8.3.1 
Fasting Lipid Panel .............................................................................. 63 
8.3.2 
LDL-C Treatment Criteria .................................................................... 64 
8.4 
Exploratory Assessments ................................................................................... 64 
8.4.1 
Regression or Resolution of Xanthomas ............................................. 64 
8.4.2 
Assessment of Carotid Intima-Media Thickness and Flow-mediated 
Dilation ................................................................................................ 64 
8.4.3 
Liposcale® Test ................................................................................... 64 
8.5 
Palatability .......................................................................................................... 65 
8.6 
Other Assessments ............................................................................................ 65 
8.6.1 
Diet Instructions and Diet Records ...................................................... 65 
9 
VISIT SCHEDULE .......................................................................................................... 66 
9.1 
Screening Period (Starting at Week -12, i.e., ≤12 Weeks Prior to Baseline for a 
Minimum of 6 Weeks), Visit 1 ............................................................................. 66 
9.1.1 
Visit 1 (Up to Week -12) ...................................................................... 67 
9.2 
Re-screening ...................................................................................................... 67 
9.3 
Stratified Enrolment and Start of Run-in Period (Starting at Minimum at 
Week -6, i.e., 6 Weeks Prior to Baseline for a Minimum of 6 Weeks, Visits 2 to 
3 ......................................................................................................................... 68 
9.3.1 
Visit 2 (Stratified Enrolment and Start of Run-in Period, at Minimum 
Week -6) ............................................................................................. 68 
9.3.2 
Visit 3 (Compliance, Week -3 to Week -2) ........................................... 68 
9.4 
Efficacy Phase (Baseline, D0 to Week 24±3 days), Visits 4 to 10 ....................... 68 
9.4.1 
Visit 4 (Baseline, D0) ........................................................................... 68 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 6 of 111 
C O N F I D E N T I A L  
9.4.2 
Visits 5, 6, 8, and 9 (Week 4±3 days, Week 8±3 days, 
Week 16±3 days, and Week 20±3 days) ............................................. 70 
9.4.3 
Visit 7 (Week 12±3 days) .................................................................... 71 
9.4.4 
Visit 10 (Week 24±3 days)................................................................... 72 
9.5 
Safety Phase (Week 28±3 Days to Week 92±1 Week), Visits 11 to 21 ............... 73 
9.5.1 
Visits 11 to 17 (Week 28±3 days, Week 32±3 days, 
Week 36±3 days, Week 40±3 days, Week 44±3 days, 
Week 48±3 days, and Week 52±3 days) ............................................. 73 
9.5.2 
Visit 18 (Week 56±3 days)................................................................... 73 
9.5.3 
Visits 19 to 21 (Week 68±1 week, Week 80±1 week, and 
Week 92±1 week) ............................................................................... 75 
9.6 
Unscheduled Visits ............................................................................................. 75 
9.7 
End of Treatment (Week 104±1 week), Visit 22 .................................................. 76 
9.8 
Follow-up (Week 108), Visit 23 ........................................................................... 77 
9.8.1 
Visit 23 (Week 108) ............................................................................. 77 
10 COLLECTION, STORAGE AND SHIPMENT OF LABORATORY SAMPLES ............... 78 
11 DRUG SAFETY .............................................................................................................. 79 
11.1 
Definitions .......................................................................................................... 79 
11.1.1 
Adverse Event ..................................................................................... 79 
11.1.2 
Adverse Drug Reaction ....................................................................... 79 
11.1.3 
Unexpected Adverse Drug Reaction ................................................... 79 
11.1.4 
Serious Adverse Event or Adverse Drug Reaction .............................. 79 
11.1.5 
Suspected Unexpected Serious Adverse Reaction ............................. 80 
11.1.6 
Adverse Events of Special Interest ...................................................... 80 
11.2 
Recording of Adverse Events and Serious Adverse Events................................ 81 
11.2.1 
Assessment of Seriousness ................................................................ 81 
11.2.2 
Assessment of Severity ....................................................................... 81 
11.2.3 
Assessment of Causality ..................................................................... 81 
11.3 
Monitoring Laboratory Assessments .................................................................. 82 
11.4 
Documenting of Adverse Events and Serious Adverse Events ........................... 82 
11.5 
Immediately Reportable Information ................................................................... 83 
11.5.1 
Reporting of Serious Adverse Events .................................................. 83 
11.5.2 
Reporting of Adverse Events of Special Interest.................................. 83 
11.5.3 
Reporting Safety Observations by the Investigator to the IEC/IRB ...... 84 
11.5.4 
Other Reportable Information: Pregnancy ........................................... 84 
12 STATISTICAL ANALYSIS ............................................................................................. 84 
12.1 
Statistical Methods ............................................................................................. 84 
12.1.1 
Tests of Hypotheses and Significance Levels ..................................... 84 
12.1.2 
Determination of Sample Size ............................................................. 85 
12.2 
Definition of Study Populations ........................................................................... 85 
12.3 
Planned Analysis ................................................................................................ 86 
12.3.1 
Disposition and Exposure .................................................................... 86 
12.3.2 
Demographic Data and other Baseline Characteristics ........................ 86 
12.3.3 
Interim Analysis ................................................................................... 86 
12.3.4 
Planned Analysis for Primary Endpoint ............................................... 86 
12.3.5 
Planned Analysis for Secondary Endpoints ......................................... 87 
12.3.6 
Planned Analysis for Safety Endpoints ................................................ 87 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 7 of 111 
C O N F I D E N T I A L  
12.3.7 
Planned Analysis for Exploratory Endpoints ........................................ 88 
12.3.8 
Planned Analysis for Palatability Endpoints ......................................... 88 
12.3.9 
Planned Analysis for Pharmacokinetic Endpoint .................................. 88 
12.4 
Statistical Criteria for Study Termination ............................................................. 88 
12.5 
Handling of Missing Data ................................................................................... 88 
12.6 
Time Windows .................................................................................................... 88 
13 QUALITY CONTROL AND QUALITY ASSURANCE ..................................................... 89 
13.1 
Pre-study Documentation ................................................................................... 89 
13.2 
Monitoring .......................................................................................................... 89 
13.3 
Data Management and Processing .................................................................... 89 
13.3.1 
Data Collection .................................................................................... 90 
13.3.2 
Data Management Procedures ............................................................ 90 
13.3.3 
Data Verification Procedures ............................................................... 90 
13.3.4 
Coding ................................................................................................ 90 
13.3.5 
Procedures for Analysis of Consistency and Medical Plausibility ......... 90 
13.3.6 
Data to be Recorded Directly into the Electronic Case Report Form ... 90 
13.4 
Study and Site Closure ....................................................................................... 90 
13.5 
Audits and Inspections ....................................................................................... 91 
14 LEGAL AND ETHICAL REQUIREMENTS ..................................................................... 91 
14.1 
Regulatory Authority Approval ............................................................................ 91 
14.2 
Independent Ethics Committee/Institutional Review Board ................................. 91 
14.3 
Patient and Parent/Legal Guardian Information and Informed Consent .............. 91 
14.4 
Data Protection .................................................................................................. 92 
14.5 
Notification of Primary Care Physician................................................................ 92 
14.6 
Investigator Reporting Requirements ................................................................. 92 
14.7 
Record Retention ............................................................................................... 92 
15 PROTOCOL AMENDMENTS ......................................................................................... 93 
16 DISCLOSURE OF INFORMATION ................................................................................ 93 
16.1 
Publication of Study Findings ............................................................................. 93 
17 COMPENSATION FOR INJURIES ................................................................................ 93 
18 REFERENCES ............................................................................................................... 94 
18.1 
Source Documents ............................................................................................. 94 
18.2 
Literature ............................................................................................................ 94 
19 APPENDICES ................................................................................................................ 98 
 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 8 of 111 
C O N F I D E N T I A L  
LIST OF TABLES 
Table 1 
Suggested 
Lomitapide 
Starting 
Doses 
by 
Age 
Group 
Based 
on 
Physiologically-based Pharmacokinetic Modelling and Allometric Scaling .......... 34 
Table 2 
Lomitapide Starting Dose and Dose Escalation by Age Group ........................... 49 
 
LIST OF FIGURES 
Figure 1 
Percentage of Patients Achieving EAS Treatment Goals with Lomitapide across 
Pivotal Studies and in Real-world Evidence ....................................................... 33 
Figure 2 
Proposed 
Mean 
Lomitapide 
Paediatric 
Starting 
Dose 
Based 
on 
Physiologically-based Pharmacokinetic Modelling and Allometric Scaling .......... 34 
Figure 3 
Design of Study .................................................................................................. 45 
Figure 4 
Example of a 5-Point Facial Hedonic Scale Used for Hedonic Ratings by 
Children (Guinard 2000) ..................................................................................... 65 
 
LIST OF APPENDICES 
Appendix 1 Child-Pugh Score ............................................................................................... 98 
Appendix 2 Schwartz Formula .............................................................................................. 99 
Appendix 3 Common Terminology Criteria for Adverse Events (CTCAE), Hepatobiliary 
Disorders .......................................................................................................... 100 
Appendix 4 WHO Growth Charts for Boys and Girls 5 to 19 Years of Age .......................... 102 
Appendix 5 Tanner Staging ................................................................................................. 104 
Appendix 6 Laboratory Tests .............................................................................................. 105 
Appendix 7 Declaration of Helsinki ...................................................................................... 107 
 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 9 of 111 
C O N F I D E N T I A L  
LIST OF TERMS AND ABBREVIATIONS 
Term or Abbreviation 
Description 
AA 
Arachidonic acid 
ACTH 
Adrenocorticotrophic hormone 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALA 
Alpha-linolenic acid 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
AP 
Alkaline phosphatase 
apo A-I 
Apolipoprotein A-I 
apo B 
Apolipoprotein B 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical 
BG 
Blood glucose 
BMI 
Body mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CAS 
Completer analysis set 
CBC 
Complete blood count 
c-het 
compound heterozygous 
CIMT 
Carotid intima-media thickness 
CK 
Creatinine kinase 
Cl 
Chloride 
Cmax 
Maximum concentration 
C-R 
Concentration-Response 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P 450 
D 
Day(s) 
DHA 
Docosahexaenoic acid 
DSMB 
Data Safety Monitoring Board 
EAP 
Expanded Access Programme 
EAS 
European Atherosclerosis Society 
EASL 
European Association for the Study of the Liver 
EC 
European Commission 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EEA 
European Economic Area 
EFA 
Essential fatty acids 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 10 of 111 
C O N F I D E N T I A L  
Term or Abbreviation 
Description 
EMA 
European Medicines Agency 
EoT 
End of Treatment 
EPA 
Eicosapentaenoic acid 
EPAR 
European Public Assessment Report 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FH 
Familial Hypercholesterolaemia 
FMD 
Flow-mediated dilatation 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
HDL-C 
High-density lipoprotein cholesterol 
HMG-CoA 
3-hydroxy-3-methylglutaryl coenzyme A 
HoFH 
Homozygous familial hypercholesterolaemia 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
INR 
International normalised ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat (analysis set) 
IU 
International units 
IV 
Intravenous 
K 
Potassium 
LA 
Lipoprotein apheresis 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol (conventional mg/dL units 
can be converted to SI [mmol/L] units using the factor 0.0259) 
LDLR 
LDL receptor 
LDLRAP1 
LDL-receptor adapter protein 1 
LFT 
Liver function test 
LH 
Luteinising hormone 
LLT 
Lipid-lowering therapy (including LA, where applicable) 
LOCF 
Last observation carried forward 
LOWER 
Lomitapide Observational Worldwide Evaluation Registry 
Lp(a) 
Lipoprotein a 
MACE 
Major adverse cardiac event(s) 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 11 of 111 
C O N F I D E N T I A L  
Term or Abbreviation 
Description 
MTD 
Maximum tolerated dose 
MTP 
Microsomal triglyceride transfer protein 
Na 
Sodium 
NASH 
Non-alcoholic steatohepatitis 
NMR 
Nuclear magnetic resonance 
Non-HDL-C 
Non-high-density lipoprotein cholesterol 
NYHA 
New York Heart Association 
PBPK 
Physiologically based pharmacokinetic modelling 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PFT 
Pulmonary function test 
PK 
Pharmacokinetics 
PP 
Per-protocol (analysis set) 
RMP 
Risk Management Plan 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SD 
Standard deviation 
SOC 
Standard of care 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TC 
Total cholesterol 
TG 
Triglycerides 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
V 
Visit 
VLDL-C 
Very low-density lipoprotein cholesterol 
W 
Week(s) 
WHO 
World Health Organization 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 12 of 111 
C O N F I D E N T I A L  
1 
SUMMARY OF CLINICAL STUDY 
1.1 
Study Synopsis 
 
Title of study 
Phase III, single-arm, open-label, international, multi-centre study to evaluate the efficacy and safety of 
lomitapide in paediatric patients with Homozygous Familial Hypercholesterolaemia (HoFH) on stable 
lipid-lowering therapy 
Sponsor 
Amryt Pharmaceuticals DAC, 45 Mespil Road, Dublin 4, Ireland 
Coordinating investigator 
Prof. Luis Masana, Director of Vascular Medicine and Metabolism Unit, Research Unit on Lipids and 
Atherosclerosis, "Sant Joan" University Hospital, Universitat Rovira I Virgili, IISPV, 43201 Reus, Spain.  
Study centres 
International multi-centre study with approximately 15 study sites 
Countries 
Germany, Israel, Italy, Saudi Arabia, Spain, and Tunisia with potential for others as needed 
Phase of development 
Phase III 
Number of patients 
Approximately 45 patients to achieve 30 evaluable patients at Week 24±3 days 
Study objectives 
Primary objective 
To evaluate the efficacy of lomitapide, as defined by the percent change in low-density lipoprotein 
cholesterol (LDL-C) at the maximum tolerated dose (MTD) at Week 24±3 days compared to Baseline, 
when added to stable lipid-lowering therapy (LLT, including lipoprotein apheresis [LA] where applicable) 
in paediatric patients (5 to ≤17 years of age) with HoFH. 
Secondary objectives 
To evaluate the efficacy of lomitapide in paediatric HoFH patients as assessed by: 
• Percent change from Baseline at Week 24±3 days in lipid parameters, including total cholesterol 
(TC), non high-density lipoprotein cholesterol (Non-HDL-C), very low-density lipoprotein cholesterol 
(VLDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)], and apolipoprotein B (apo B). 
• Percent change from Baseline in TC, non-HDL-C, LDL-C, TG, VLDL-C, Lp(a), and apo B at all other 
time-points through Week 104±1 week. 
• Change in LLT and LA from Week 24±3 days through Week 104±1 week. 
• Number (percent) of paediatric HoFH patients achieving the European Atherosclerosis Society 
(EAS) recommended target LDL-C of <135 mg/dL (3.5 mmol/L) at Week 24±3 days and at any time 
on study. 
Safety objectives 
To evaluate the long-term safety and tolerability of lomitapide in paediatric HoFH patients as assessed 
by: 
• Incidence in reported adverse events (AEs) and in clinically significant abnormal findings of physical 
examinations including weight and body mass index (BMI), electrocardiogram (ECG), standard of 
care echocardiography (if available), vital signs, pulmonary function tests (PFT), and laboratory 
parameters including hepatic and renal function tests. 
 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 13 of 111 
C O N F I D E N T I A L  
Safety objectives (continued) 
• Effects on growth, bone health and bone age will be assessed using both measurements of 
children’s height and growth charts to track age-appropriate progress at Screening and from 
Baseline at every visit through Week 104±1 week and/or at EoT, together with analysis of Vitamin D 
and K levels at Screening, Baseline, Week 24±3 days, Week 56±3 days, Week 80±1 week, 
Week 104±1 week and/or at EoT (and at Week 108 for patients who opt not to participate in or are 
unsuitable for the Expanded Access Programme [EAP; <18 years of age]/opt not to transition to 
commercial product [≥18 years of age]). 
• Potential effects on maturation, reproductive development, gonadotropins, and variables of the 
pituitary-adrenal axis at Screening, Baseline, Week 56±3 days, Week 104±1 week and/or at EoT will 
be analysed; potential effects on the levels of sex steroids will be analysed for patients assessed as 
Tanner Stage ≥2. 
• Lipid accumulation in the liver as measured by nuclear magnetic resonance (NMR) imaging or 
echography (i.e., ultrasound scan) at Baseline and at Week 24±3 days, Week 56±3 days, and at 
Week 104±1 week (for patients who opt not to participate in or are unsuitable for the EAP [<18 years 
of age]/opt not to transition to commercial product [≥18 years of age], lipid accumulation in the liver 
will be measured at Baseline, at Week 24±3 days, Week 56±3 days, and at Week 108). All patients 
will undergo NMR imaging unless it is contraindicated or not feasible (e.g., due to the need for 
sedation or general anaesthesia in very young or anxious patients). In this case, ultrasound scans 
will be used at the discretion of the investigator. 
Exploratory objectives 
To evaluate the exploratory assessments of: 
• Change from Baseline at Week 56±3 days and Week 104±1 week in mean carotid intima-media 
thickness (CIMT, mandatory) and flow-mediated dilatation (FMD, whenever possible). 
• Resolution 
and/or 
regression 
of 
pre-existing 
xanthomas 
at 
Week 56±3 days 
and 
at 
Week 104±1 week. 
• Changes from Baseline through Week 24±3 days in cholesterol and triglyceride content of VLDL, 
intermediate density lipoprotein (IDL), LDL and HDL, particle number and size of VLDL, LDL, and 
HDL as well as particle number of their respective lipoprotein subclasses (large, medium, and small) 
as assessed based on 2D NMR (Liposcale® Test) of pharmacokinetics (PK) samples. 
Palatability objective 
• Assess the palatability of the study medication using a 5-point facial hedonic scale, anchored with 
descriptors, to record the children’s assessment of palatability in terms of overall liking.  
• The parent(s)/legal guardian(s) interpretation of the child’s reaction/facial expression will be used to 
determine whether they find lomitapide “pleasant”, “unpleasant” or are “not sure”.  
• Ease of administration of the study medication and dietary supplements by the parent(s)/legal 
guardian(s) will be assessed using the following question at each visit during the treatment phase: 
“Do you sometimes have problems in giving the medication to your child because he/she refuses to 
take it or throws it up immediately after taking it? (Yes/No).” 
Pharmacokinetics objective 
• To evaluate the pharmacokinetics (PK) of lomitapide in paediatric HoFH patients through sparse 
blood sampling. 
Study endpoints 
Primary endpoint 
Percent change from Baseline in LDL-C at Week 24±3 days. 
Secondary endpoints 
• Percent change from Baseline at Week 24±3 days for the following lipid parameters: TC, 
Non-HDL-C, VLDL-C, TG, Lp(a), and apo B. 
• Percent change from Baseline at all other time points through Week 104±1 week for the following 
lipid parameters: LDL-C, TC, Non-HDL-C, VLDL-C, TG, Lp(a), and apo B. 
• Total number and percent of patients with a change from Baseline in LLT and LA from 
Week 24±3 days through Week 104±1 week. 
• Total number and percent of patients achieving the EAS recommended target LDL-C of <135 mg/dL 
(3.5 mmol/L) in paediatric HoFH patients at Week 24±3 days and at any time on study. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 14 of 111 
C O N F I D E N T I A L  
Safety endpoints 
Safety evaluations and endpoints from Baseline through Week 104±1 week include: 
• Incidence of AEs overall and by severity and relatedness. 
• Physical examinations including regular measurements of height, weight, and BMI. 
• Sexual maturation (Tanner staging):  
− In patients with Tanner Stage ≥2: Changes from Baseline in sex hormones (serum testosterone 
and serum oestradiol). 
• 12-Lead safety ECG (read locally), standard of care echocardiography (if available), vital signs and 
blood pressure. 
• PFT. 
• Laboratory tests:  
− Standard haematology (complete blood count [CBC]) and clinical chemistry panels. 
− Liver 
function 
tests: 
Alanine 
transaminase 
(ALT), 
aspartate 
transaminase 
(AST), 
gamma-glutamyl transferase (GGT), alkaline phosphatase (AP), total bilirubin, and serum 
albumin. 
− High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I). 
− Creatinine kinase (CK). 
− Serum lipase. 
− Serum levels of essential fatty acids (EFA): Linoleic acid, alpha linoleic acid (ALA), 
eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and 
eicosatrienoic acid. 
− Serum concentrations of fat-soluble vitamins: Vitamin A (retinol), vitamin E (alpha tocopherol), 
ratio of vitamin E to total lipids (total cholesterol plus fasting triglycerides), and vitamin D 
(25-hydroxy-D). Levels of vitamin K will be assessed indirectly by measuring total and 
uncarboxylated levels of serum osteocalcin. (Bone health will be assessed indirectly using growth 
to track age-appropriate progress, and measurement of 25-hydroxy-D as well as total and 
uncarboxylated osteocalcin levels.). 
− Pituitary-adrenal hormone levels (thyroid stimulating hormone [TSH], follicle stimulating hormone 
[FSH], luteinising hormone [LH], adrenocorticotrophic hormone [ACTH], and morning serum 
cortisol). 
− Urinalysis. 
• Lipid accumulation in the liver as measured by NMR imaging or echography (i.e., ultrasound scan) 
at Baseline and at Week 24±3 days, Week 56±3 days, and at Week 104±1 week (Week 108 for 
patients who opt not to participate in or are unsuitable for the EAP [<18 years of age]/opt not to 
transition to commercial product [≥18 years of age]). All patients will undergo NMR imaging unless 
it is contraindicated or not feasible (e.g., due to the need for sedation or general anaesthesia in very 
young or anxious patients). In this case, ultrasound scans will be used at the discretion of the 
investigator. 
Exploratory endpoints 
• Percent change from Baseline at Week 56±3 days and Week 104±1 week in CIMT and FMD. 
• Total number and percent of patients with resolution and/or regression of pre-existing xanthomas at 
Week 56±3 days and at Week 104±1 week. 
• Changes from Baseline through Week 24±3 days in cholesterol and triglyceride content of VLDL, 
IDL, LDL and HDL, particle number and size of VLDL, LDL, and HDL as well as particle number of 
their respective lipoprotein subclasses (large, medium, and small) as assessed based on 2D NMR 
(Liposcale® Test) of PK samples at Week 4±3 days, Week 8±3 days, Week 12±3 days, 
Week 16±3 days, Week 20±3 days and at Week 24±3 days. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 15 of 111 
C O N F I D E N T I A L  
Palatability endpoints 
• 
Total number and percent of patients for each response of palatability: 
− Able to swallow capsule (including food media responses if used). 
− Palatability rating (using a 5-point facial hedonic scale). 
− Parent/guardian interpretation of child’s reaction/facial expression (using a 3-point scale). 
− Parent/guardian experience problems in giving medication to child because they refuse to take 
or throw up immediately after taking. 
− Parent/guardian experience problems in giving dietary supplement to child because they refuse 
to take or throw up immediately after taking. 
Pharmacokinetic endpoints 
• 
The PK data from this study will be incorporated into an existing population PK model in adult 
HoFH patients. 
Study design 
This is a single-arm, open-label, multi-centre phase III study to evaluate the efficacy and long-term 
safety of lomitapide in paediatric patients with HoFH receiving stable LLT (including LA, when 
applicable) comprising the following phases: 
• Screening Period (starting at Week -12, i.e., ≤12 weeks prior to Baseline for up to 6 weeks). 
• Stratified Enrolment and Start of Run-in Period (starting at minimum at Week -6, i.e., 6 weeks prior 
to Baseline for a minimum of 6 weeks): 
− Enrolment will be stratified to ensure approximately equal numbers of patients in the following 
age groups: 5 to 10 years, 11 to 15 years, and 16 to ≤17 years (with ≥8 patients in any individual 
age group). 
− Patients must be stabilised on current LLT (including LA, when applicable) and established on a 
diet supplying <20% of energy (calories) from fat or <30 g fat, whichever is the lesser amount. 
− Daily supplementation with vitamin E (200 international units [IU] for patients 5 to 8 years of age, 
400 IU for patients 9 to ≤17 years of age) and an EFA supplement containing approximately 
200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA starting at Week -2. 
• Efficacy Phase (starting at Baseline, i.e., Day [D] 0 for 24 weeks±3 days): 
− Approximately 45 paediatric patients with HoFH will be treated with lomitapide given orally, added 
to their current, stable LLT (including LA, when applicable) established during the Run-in Period. 
− Assuming a withdrawal rate of approximately 33% by Week 24±3 days, this would result in 
30 evaluable patients at Week 24±3 days (with ≥8 patients in any individual age group). 
− After stabilisation of the patient on his/her current MTD of LLT (including LA, when applicable) 
during the 6-week Run-in Period, treatment with lomitapide will be started as an add-on therapy 
on D0 of the Efficacy Phase. 
− Dosing will be initiated at the recommended starting dose and escalated to the maximum dose 
as applicable to the age groups based upon safety and tolerability in addition to LDL-C values. 
− The first dose of study medication will be administered at the study site on D0. 
− During the 24-week Efficacy Phase, patients will be required to remain on the stable LLT regimen 
(including LA, when applicable) established during the 6-week Run-in Period. 
• Safety Phase (starting at Week 24±3 days for 80±1 weeks): 
− Patients will enter the 80-week Safety Phase after the Week 24±3 days assessments have been 
completed. Each patient will continue receiving the MTD of lomitapide he/she achieved during 
the Efficacy Phase (unless criteria is met for reducing or increasing the dose) for an additional 
80±1 weeks in the Safety Phase. 
− If after Week 24±3 days both the investigator and the sponsor consider a patient 5 to 15 years of 
age to be eligible for further escalation of the lomitapide dose beyond the maximum 
recommended dose by the respective age group, the lomitapide dose can be increased to an 
extent defined by the investigator after consultation with the sponsor based on individual safety, 
efficacy, and concomitant LLT criteria. If the patient tolerates this new dose for ≥4 weeks, then 
this will be considered the new MTD. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 16 of 111 
C O N F I D E N T I A L  
Study design (continued) 
− If after Week 24±3 days, a patient has crossed over into the next age category, the study drug 
can be escalated to the maximum dose applicable for the new age category. If the patient 
tolerates this new dose for ≥4 weeks, then this will be considered the new MTD. 
− During the 80-week Safety Phase, the lomitapide dose can be reduced from the MTD due to 
tolerability or safety issues, and the patient can be re-challenged after a minimum period of 
4 weeks following dose reduction with a higher dose of lomitapide once these issues resolve, but 
the dose during the Safety Phase cannot exceed the MTD established during the Efficacy Phase 
unless eligibility for exceptional dose escalation described above is met. 
− Adjustments to background LLT (including LA, when applicable) will be allowed at the discretion 
of the investigator. 
• Follow-up (starting at Week 104±1 week for 4 weeks): 
− At Week 104±1 week, eligible patients who complete the study per protocol and are <18 years 
of age may choose to enter the EAP. Patients ≥18 years of age may opt to transition to 
commercial product under the approved product label for adults. For both these patient groups, 
a follow-up phone call will be conducted at Week 108±1 week to monitor safety including AE and 
concomitant medication reporting. 
− Patients who opt not to participate in or are unsuitable for the EAP (<18 years of age), or patients 
≥18 years of age who opt not to transition to commercial product will discontinue lomitapide 
treatment at Week 104±1 week and enter a 4-week Follow-up period during which they will 
remain on concomitant LLT (including LA, when applicable). These patients will then attend in 
person for a Week 108±1 week visit. 
Study population 
Paediatric population of male and female patients aged 5 to ≤17 years with HoFH who are receiving 
optimal, stable LLT (including LA, when applicable), and who meet the definition of functional HoFH as 
defined in the Inclusion Criteria below. 
Inclusion criteria 
A patient will be eligible for study participation only, if all of the following criteria apply: 
1. Male and female patients aged 5 to ≤17 years with HoFH as defined by any of the following criteria 
recommended by the Consensus Panel on Familial Hypercholesterolaemia of the EAS (Cuchel, 
Bruckert et al. 2014): 
a. Genetic confirmation of 2 mutant alleles at the LDL receptor (LDLR), apo B, Proprotein 
convertase subtilisin/kexin type 9 (PCSK9), or LDL-receptor adapter protein 1 (LDLRAP1) gene 
locus OR 
b. An untreated LDL-C >500 mg/dL (13 mmol/L) or treated LDL-C ≥300 mg/dL (8 mmol/L) 
together with either 
− Cutaneous or tendon xanthoma before age 10 years or  
− Untreated LDL-C levels consistent with heterozygous FH in both parents. 
2. Baseline LDL-C on LLT (maximum concentration [Cmax] immediately prior to LA, if applicable) of 
either: 
a. >160 mg/dL (4.1 mmol/L, no documented cardiovascular disease [CVD]) or 
b. >130 mg/dL (3.4 mmol/L, established CVD defined as aortic valve disease and/or coronary 
atherosclerosis). 
3. Body weight ≥15 kg or BMI and height both >10th percentile according to World Health Organization 
(WHO) Growth Charts for Boys and Girls 5 to 19 Years of Age. 
4. Patient and/or his/her legal representative has/have been informed, has/have read and understood 
the patient information/informed consent form, and has/have given written informed 
assent/consent. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 17 of 111 
C O N F I D E N T I A L  
Inclusion criteria (continued) 
5. Patient and/or his/her legal representative must be able and willing to follow study procedures and 
instructions, particularly that: 
a. LLT (including LA, when applicable) must be stable for at least 6 weeks prior to Baseline (Run in 
Period) and remain stable through Week 24±3 days (end of Efficacy Phase). 
b. The patient must be compliant with both the low fat diet supplying <20% of energy (calories) from 
fat or <30 g fat, whichever is the lesser amount starting at the beginning of the Run in Period and 
the dietary supplement regimen starting at Week -2 of the Run in Period, both continuing until 
completion of the study (and during the EAP/administration of commercial product, when 
applicable). 
6. Postmenarchal female adolescents must be willing to use an effective form of birth control with 
failure rates <1% per year (e.g., implant, injectable, combined oral contraceptive, intrauterine 
contraceptive device, sexual abstinence, vasectomy or vasectomised partner) during participation 
in the study (and at least 4 weeks thereafter). Patients taking oestrogen-based oral contraceptives 
should be advised about possible loss of effectiveness due to diarrhoea and/or vomiting. Additional 
contraceptive measures should be used for 7 days after resolution of symptoms. 
7. Patient must be in stable physical and mental health at Screening. 
Exclusion criteria 
A patient will not be eligible to participate in this study, if any of the following criteria apply: 
1. Other forms of primary hyperlipoproteinaemia and secondary causes of hypercholesterolaemia 
(e.g., nephrotic syndrome, hypothyroidism). 
2. Contraindications for the use of lomitapide according to section 4.3 of the Summary of Product 
Characteristics (SPC; included in the Lojuxta® SPC in lieu of an Investigator’s Brochure [IB]), such 
as hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 of the 
SPC, known significant or chronic inflammatory bowel disease or malabsorption. 
3. Moderate (Child-Pugh B) or severe hepatic impairment (Child-Pugh C), active liver disease and/or 
abnormal liver function tests at Screening (AST or ALT >1.5 x upper limit of normal (ULN) and/or 
total bilirubin >1.5 x ULN in the absence of Gilbert’s syndrome or AP >1.5 x ULN [based on 
appropriate age and gender normal values]).  
4. Serum CK >2 x ULN. 
5. Chronic renal insufficiency with glomerular filtration rate (GFR) <70 mL/min/1.73 m2 calculated using 
the Schwartz formula. 
6. Uncontrolled hypertension (defined as mean systolic and/or diastolic blood pressure ≥95% of normal 
for age and sex) despite medical therapy. 
7. New York Heart Association (NYHA) Class III or IV congestive heart failure. 
8. Precocious/delayed puberty or endocrine disorder affecting growth (e.g., hypothyroidism, premature 
adrenarche). 
9. History of drug abuse within the last 3 years or habitual alcohol consumption (defined as >1 ounce 
[28 g] of liquor or 4-ounce glass [113 g] of wine, or the equivalent, ≥3 times per week). 
10. Life expectancy predicted to be <5 years. 
11. History of a non-skin malignancy (with the exception of cervical cancer in situ) within 3 years prior 
to enrolment. 
12. Treatment with any Investigational Medicinal Product (IMP) within 6 months or 5 times the terminal 
half-life of the corresponding IMP, whichever is longer, before Screening (Visit 1). 
13. Patient is a dependent of the sponsor, of the investigational team or his/her immediate family. 
14. Pregnant or nursing women. 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 18 of 111 
C O N F I D E N T I A L  
Treatment plan 
Investigational product 
Lomitapide is a first in class oral, selective inhibitor of microsomal transfer protein (MTP), an intracellular 
lipid-transfer protein that is found in the lumen of the endoplasmic reticulum and is responsible for 
binding and shuttling individual lipid molecules between membranes. MTP plays a key role in the 
assembly of apo B containing lipoproteins in the liver and intestines. Inhibition of MTP reduces 
lipoprotein secretion and circulating concentrations of lipoprotein-borne lipids including cholesterol, 
LDL-C and triglycerides. 
The European Commission (EC) granted authorisation for lomitapide under the trade name ‘Lojuxta®’ 
in July 2013. Lomitapide is indicated as an adjunct to a low-fat diet and other lipid-lowering medicinal 
products with or without LA in adult patients with HoFH. Genetic confirmation of HoFH should be 
obtained whenever possible. Other forms of primary hyperlipoproteinaemia and secondary causes of 
hypercholesterolaemia (e.g., nephrotic syndrome, hypothyroidism) must be excluded. 
Dosage and mode of administration 
• Run-in Period (starting at minimum at Week -6, i.e., 6 weeks prior to Baseline for a minimum of 
6 weeks):  
− Patients must be stabilised on current LLT (including LA, when applicable) and established on a 
diet supplying <20% of energy (calories) from fat or <30 g fat, whichever is the lesser amount. 
− Week -2: Start of daily supplementation with vitamin E (200 IU for patients 5 to 8 years of age, 
400 IU for patients 9 to ≤17 years of age) and an EFA supplement containing approximately 
200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA. 
• Efficacy Phase (Baseline, D0 for 24 weeks±3 days): 
− During the 24-week Efficacy Phase, patients will be required to remain on the stable LLT 
(including LA, when applicable) regimen established during the 6-week Run-in Period. 
− Lomitapide capsules will be provided in 4 dose strengths: 2, 5, 10 and 20 mg. Each patient will 
take 1 to 3 capsule(s) once daily with a glass of water, without food, at least 2 hours after their 
evening meal to achieve the doses specified in the titration scheme. 
− Oral administration: Patients who are unable to swallow intact capsules may open the capsule 
and sprinkle the capsule content on 1 tablespoon of apple sauce or mashed banana. 
− Titration from 2 mg lomitapide (in 5 to 15 year old patients) or 5 mg lomitapide (in 16 to ≤17 year 
old patients) at D0 to the maximum recommended dose by age group based upon safety and 
tolerability in addition to LDL-C values according to the table below: 
Dose escalation by age group 
Age Group (years) 
Lomitapide Dose (mg) 
D0 
Week 4 
Week 8 
Week 12 
Week 16 
Maximum 
5 to 10 
2 
2 
5 
10 
20 
20 (10, in Child-Pugh A) 
11 to 15 
2 
5 
10 
20 
40 
40 (20, in Child-Pugh A) 
16 to ≤17 
5 
10 
20 
40 
60 
60 (40, in Child-Pugh A) 
− Lomitapide will not be escalated, if LDL-C is less than the target threshold: 
o 
LDL-C is <100 mg/dL (<2.5 mmol/L, in patients without CVD at Baseline) 
o 
LDL-C is <70 mg/dL (<1.8 mmol/L, in patients with CVD at Baseline) 
− Dose must be tolerated for ≥4 consecutive weeks before escalation to the next higher dose. 
− If a dose reduction is required, dosage will either be reduced to the previous tolerated dose or to 
an intermediate dose. Please note that only down-titrations to intermediate doses are allowed, 
dose escalations need to follow the guidance provided in the table above. After resolution of the 
cause for dose reduction, patients may be re-challenged after a minimum period of 4 weeks 
following dose reduction with prior doses in stepwise increments based on dose escalation 
guidelines, but may not exceed the MTD established during the Efficacy Phase until 
Week 24±3 days, after which further increase is only possible if patients have crossed into the 
next age category or if both the investigator and the sponsor consider a patient 5 to 15 years of 
age to be eligible for further escalation of the lomitapide dose beyond the maximum 
recommended dose by the respective age group based on individual safety, efficacy, and 
concomitant LLT criteria. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 19 of 111 
C O N F I D E N T I A L  
Dosage and mode of administration (continued) 
− If the investigator determines that a patient is not tolerating any particular dose (per specified 
criterion), the investigator may request a dose reduction or a hold on the current dose until the 
next scheduled visit. Once the patient has stabilised on the reduced dose, the dose can be 
increased back to the next step again, and the patient may progress through subsequent dose 
increases. If the patient does not tolerate the re-challenge dose, then the MTD is considered the 
reduced dose and will be the highest dose allowed for the remainder of the study. 
− The MTD is defined as the highest dose of lomitapide that does not result in tolerability or safety 
concerns. 
• Efficacy Phase (Baseline, D0 for 24 weeks±3 days): 
− Week 0 through Week 24±3 days establish the MTD; Week 20±3 days is the last visit that the 
lomitapide dose can be increased, except when there has been a down-titration at/or after 
Week 16±3 days. Re-challenging will depend on the assessment of safety and tolerability criteria 
and the LDL-C value relative to the LDL-C goal of <135 mg/dL (3.5 mmol/L), and is at the 
discretion of the investigator except for Hy’s law cases or comparable signs of liver toxicity, 
irrespective of origin, in which no re-challenge will be allowed. The study drug can be escalated 
as a re-challenge dose during the next scheduled visit after a minimum period of 4 weeks 
following dose reduction. In addition, a re-challenge with lomitapide will not be performed, if the 
LDL-C is below the target threshold while the patient was receiving the reduced dose.  
− The dose of lomitapide will be reduced with the addition of a concomitant Cytochrome P 450 
(CYP) 3A4 inhibitor during the Safety Phase; in patients with hepatic or renal impairment; and in 
patients who experience liver enzyme elevations above prespecified thresholds. 
• Safety Phase (Week 24±3 days for 80±1 weeks): 
− 
Adjustments to background LLT (including LA, when applicable) will be allowed at the discretion 
of the investigator. 
− 
If after Week 24±3 days both the investigator and the sponsor consider a patient 5 to 15 years 
of age to be eligible for further escalation of the lomitapide dose beyond the maximum 
recommended dose by the respective age group, the lomitapide dose can be increased to an 
extent defined by the investigator after consultation with the sponsor based on individual safety, 
efficacy, and concomitant LLT criteria. If the patient tolerates this new dose for ≥4 weeks, then 
this will be considered the new MTD. 
• 
Follow-up (Week 104±1 week for 4 weeks): 
− 
At Week 104±1 week, eligible patients who complete the study per protocol and are <18 years 
of age may choose to enter the EAP. Patients ≥18 years of age may opt to transition to 
commercial product under the approved product label for adults. For both these patient groups, 
a follow-up phone call will be conducted at Week 108±1 week to monitor safety including AE 
and concomitant medication reporting. 
− 
Patients who opt not to participate in or are unsuitable for the EAP (<18 years of age), or 
patients ≥18 years of age who opt not to transition to commercial product will discontinue 
lomitapide at Week 104±1 week and enter a 4-week Follow-up period during which they will 
remain on concomitant LLT (including LA, when applicable). These patients will then attend in 
person for a Week 108±1 week visit. 
Concomitant treatment/medication 
Permitted concomitant treatment/medication 
The following medication will be permitted during study and follow-up: 
• Lipid-lowering medicinal products including statins, fibrates, bile acid sequestrants, and 
PCSK9 inhibitors 
Please note: Patients who receive atorvastatin, should separate the dose of the medicinal products 
by 12 hours, e.g., by taking atorvastatin in the morning and lomitapide in the evening. Patients who 
receive bile acid sequestrants, should separate the dose of the medicinal products by 4 hours. 
Concomitant administration of >40 mg simvastatin is not permitted. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 20 of 111 
C O N F I D E N T I A L  
Concomitant treatment/medication (continued) 
• Oestrogen-based oral contraceptives 
Please note: Postmenarchal female adolescent patients taking oestrogen-based oral contraceptives 
should be advised that diarrhoea and/or vomiting may reduce hormone absorption. In case of 
protracted or severe diarrhoea and/or vomiting lasting more than 2 days, the investigator should 
advise according to national practice, which additional contraceptive measures (such as sexual 
abstinence, barrier methods) should be used for 7 days after resolution of symptoms. 
• Supportive therapy upon the investigators’ discretion 
The following medication will be permitted during the Safety Phase of the study: 
• If a weak CYP 3A4 inhibitor, e.g., aminoglutethimide, nafcillin, non-nucleoside reverse transcriptase 
inhibitors, phenobarbital, rifampicin, carbamazepine, pioglitazone, glucocorticoids, modafinil and 
phenytoin inhibitor is required during the Safety Phase, the dose of lomitapide should be reduced. 
Please note: Patients who receive weak CYP 3A4 inhibitors, should separate the dose of the 
medicinal products by 12 hours. 
If atorvastatin is given concomitantly, it should be administered in the morning to separate it from 
lomitapide dosing by 12 hours. In case it is not possible to administer atorvastatin and lomitapide 
12 hours apart, the lomitapide dose should be reduced by half. 
Non-permitted concomitant treatment/medication 
The following medication will not be permitted during the study: 
• Contraindications for the use of lomitapide according to Section 4.3 of the SPC (included in the 
Lojuxta® SPC in lieu of an IB), such as  
− Concomitant administration of >40 mg simvastatin. 
− Concomitant use of strong or moderate CYP 3A4 inhibitors, e.g., antifungal azoles such as 
itraconazole, fluconazole, ketoconazole, voriconazole, posaconazole; macrolide antibiotics such 
as erythromycin or clarithromycin; ketolide antibiotics such as telithromycin; HIV protease 
inhibitors; the calcium channel blockers diltiazem and verapamil, and the anti-arrhythmic 
dronedarone. 
The following medication will not be permitted during the Efficacy Phase of the study: 
Weak CYP 3A4 inhibitors, e.g., aminoglutethimide, nafcillin, non-nucleoside reverse transcriptase 
inhibitors, phenobarbital, rifampicin, carbamazepine, pioglitazone, glucocorticoids, modafinil and 
phenytoin. If a weak cytochrome CYP 3A4 inhibitor is required during the Safety Phase, the dose of 
lomitapide should be reduced and the doses of medicinal products should be separated by 12 hours. 
The use of the following food or substances should be avoided with lomitapide: 
• Alcohol: Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. 
• Grapefruit juice: Grapefruit juice is a moderate inhibitor of CYP 3A4 and is expected to substantially 
increase exposure to lomitapide. 
• Peppermint oil or Seville oranges. 
• St. John’s Wort (i.e., Hypericum perforatum). 
Duration of patient participation in the study 
Each patient will participate for up to 120 weeks (about 2.5 years) in the study: 
• Screening Period: starting at Week -12, i.e., ≤12 weeks prior to Baseline for up to 6 weeks. 
• Stratified Enrolment and Start of Run-in Period: ≥6 and ≤12 weeks starting at minimum at Week -6, 
i.e., 6 weeks prior to Baseline for a minimum of 6 and a maximum of 12 weeks. 
• Efficacy Phase: 24 weeks±3 days. 
• Safety Phase: 80 weeks±1 week. 
• Follow-up Period: 4 weeks.  
Timelines of study 
• Estimated Date of First Patient Screened: Quarter 4 2020 
• Estimated Date of Last Patient Screened: Quarter 1 2022 
• Estimated Date of Last Patient Last Visit: Quarter 4 2023 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 21 of 111 
C O N F I D E N T I A L  
Number of visits (study) 
There will be 23 visits from Screening through Follow-up: 
• Screening: n = 1. 
• Run-in Period: n = 2. 
• Efficacy Phase: n = 7, every 4 weeks±3 days. 
• Safety Phase including End of Treatment (EoT): 
− After Week 24±3 days through Week 52±3 days: n = 8, every 4 weeks±3 days. 
− After Week 56±3 days through Week 104±1 week: n = 4, every 12 weeks±1 week. 
• Follow-up: n = 1. 
Patient discontinuation criteria 
Patients and/or their parents/legal guardians will have the right to withdraw from the study at any time 
for any reason without prejudice to their future medical care. A patient may be withdrawn from the study 
at any time at either the investigator’s, sponsor’s, or Data Safety Monitoring Boards discretion.  
A patient must be discontinued from the study for any of the following reasons: 
• The patient matches the criteria referred to as “Hy’s law case” according to the European Association 
for the Study of the Liver (EASL) Clinical Practice Guidelines on Drug-induced Liver Injury (EASL 
2019) and the FDA Guidance for Industry Drug-Induced Liver Injury Premarketing Clinical Evaluation 
(FDA 2009). Any Hy's law case or comparable signs of liver toxicity, irrespective of origin, must lead 
to permanent treatment discontinuation of the individual patient (no re-challenge allowed). 
• The patient and/or his/her parent/legal guardian withdraws assent/consent. 
• Pregnancy as evidenced by a positive pregnancy test. 
• If a patient becomes pregnant during the study, during the follow up, or 30 days within the last 
application of study medication, the sponsor will have to be informed within 24 hours. The 
investigator will be asked to complete a pregnancy report provided by the sponsor. He/she will be 
asked to obtain data on the course of the pregnancy, including perinatal and neonatal outcome. 
• Any AE which, in the opinion of the investigator, places the patient at unacceptable risk, including 
intolerable AE(s) after attempted dose reduction. 
The investigator will be able to withdraw patients from the study for the following reasons: 
• Hepatobiliary criteria for discontinuation 
• Hepatobiliary AE Common Terminology Criteria for Adverse Events (CTCAE) Grade 4, regardless 
of relationship to study drug  
• Biochemical hepatobiliary guideline Level 4 Hepatotoxicity or Level 3 Hepatotoxicity that persists 
despite interruption of study drug 
• Histopathological diagnosis of Type 3 or Type 4 non-alcoholic steatohepatitis (NASH) 
• Patient is noncompliant with the study procedures or medications in the opinion of the investigator 
• Progression of a medical condition, which in the opinion of the investigator should preclude further 
participation of the patient in the study (e.g., excessive weight loss) 
• Administration of non-permitted concomitant medication(s), substances, foods, or supplements 
• Investigators’ decision that a change of therapy is in the patients’ best interest 
• Occurrence of an AE (including abnormal laboratory findings), which makes discontinuation 
desirable or necessary in the investigators’ and/or the patients’ and/or parents/legal guardians 
opinion 
If a patient discontinues the study or the follow-up prematurely due to an AE/serious adverse event 
(SAE), he/she will be followed up until the resolution or stabilisation of the AE/SAE. 
If a patient discontinues the study prematurely, the assessment of the EoT visit should be made.  
All data collected before premature discontinuation of the study will be used for analysis. Patients who 
drop out will not be replaced unless the assumptions for drop-out have been exceeded 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 22 of 111 
C O N F I D E N T I A L  
Data Safety Monitoring Board 
Periodic safety analyses will be performed by an independent Data Safety Monitoring Board (DSMB). 
The DSMB will have an initial organizational meeting at which time the composition, activities, and 
responsibilities of the DSMB will be detailed in a Charter as agreed upon by the sponsor and the DSMB 
members. The DSMB will be comprised of at least 3 members who are not otherwise involved in the 
conduct of the study; at least 1 of whom will be a statistician. The DSMB will meet at least 3 times during 
the conduct of the study. The DSMB in consultation with the sponsor will have the authority to stop the 
study for any reason including, but not limited to, unacceptable safety risks. Interim safety analyses 
may be performed by the DSMB at their discretion, at any time, on an ‘as needed’ basis according to 
ongoing study results. If a patient discontinues treatment permanently due to a Hy’s law case or 
comparable signs of liver toxicity irrespective of origin, the DSMB will initiate an immediate recruitment 
stop as an urgent safety measure and will assess individual benefits and risks for the patients being 
treated with study medication regarding further therapy. 
Statistical methods 
The primary efficacy analysis will be conducted once all patients have completed (or withdrawn prior 
to) Visit 10 at Week 24±3 days (End of the Efficacy Phase). The primary efficacy analysis will include 
the key primary/secondary efficacy data, all safety data available up to the data cut-off date of the last 
patient reaching Week 24±3 days, and PK parameter analysis. The reporting of Week 24±3 days data 
will allow for an early submission of an application for regulatory approval of Lojuxta® in the paediatric 
indication. The final statistical analysis will be performed when all patients have completed the 
Follow-up Visit (Visit 23) at Week 108±7 days. Efficacy, safety, and exploratory data collected during 
the Safety Phase and follow-up will be included. 
Tests of hypotheses and significance levels 
The primary and secondary efficacy parameters collected during the Efficacy Phase of the study will be 
statistically tested using a 2-sided test at the 5% significance level. 
To address the efficacy objectives, the efficacy parameters will be tested sequentially in a step-wise 
fashion, thereby controlling the overall type I error. First, the primary testing for percent change from 
Baseline in LDL-C at Week 24±3 days will be performed. If this test is statistically significant with a 
2-sided α = 0.05 and is statistically significant in a positive direction, then the tests of the secondary 
hypotheses will be performed in the following specified order at Week 24±3 days: (1) Non-HDL-C, (2) 
TC, (3) VLDL-C, (4) apo B, (5) TG, (6) Lp(a). 
If at any step of the testing procedure a non-significant p-value is reached, further tests in the sequence 
will be performed and p-values will be reported as a measure of the strength of effect without declaring 
statistical significance. 
Analysis of other secondary endpoints collected during the Efficacy Phase and of endpoints collected 
during the Safety Phase will be analysed without adjustment for multiplicity. 
Sample size of the study 
The study will have 92% power to declare a treatment effect (α = 0.05, 2-sided) in the reduction of 
LDL-C at Week 24±3 days compared to Baseline. The study sample size is based on the assumption 
that the true percent reduction from Baseline in LDL-C at Week 24±3 days would be 25%, with a 
standard deviation of 40%. As a conservative assumption, this estimated 25% reduction represents 
approximately 60% (relatively) of the 41% reduction from Baseline to Week 26 (End of Efficacy Phase) 
seen in the adult study UP1002/733-005, Intent-to-treat (ITT) population. This is the same assumption 
used for the sample size in the adult study. Further, the standard deviation (SD) represents an 
approximate 1/3 increase from the corresponding 31% SD seen in the adult study. This increase in SD 
was used to account for potentially increased variability across the 3 age groups.  
A total of 30 evaluable patients will be required; to allow for up to a 33% drop-out rate during the Efficacy 
Phase (prior to Week 24±3 days), approximately 45 patients will be enrolled. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 23 of 111 
C O N F I D E N T I A L  
1.2 
Flow Chart of Study and Follow-up 
Examination 
Screening 
Run-in Period 
Efficacy Phase 
Safety Phase 
EoTB 
Follow-upC 
Enrolment 
Compliance 
Baseline 
Efficacy 
Safety/Tolerability 
Visit 
1A 
2A 
3 
4 
5 to 10 
11 to 18 
19 to 21 
22 
23 
Week(s) 
Up to -12 
Minimum -6 
-2 
0 
(Day 0) 
4/8/12/16/ 
20/24 
28/32/36/40/ 
44/48/52/56 
68/80/92 
104 
108 
Window Procedure 
 
 
-1 week 
 
±3 days 
±3 days 
±1 week 
±1 week 
- 
Window Procedure for LA 
 
 
 
 
±3 days 
±3 days 
±3 days 
 
 
Eligibility & Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed consent & assent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical exam (incl. xanthomas, height, weight, BMI, BSA)D 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Tanner stagingD 
X 
 
 
X 
XD 
Week 56 
 
X 
 
 
12-Lead safety ECG (read locally) 
 
 
 
X 
Week 24 
Week 56 
Week 80 
X 
 
 
Most recent standard of care echocardiography on fileE (if available) 
 
 
 
X 
Week 24 
Week 56 
 
X 
 
 
Vital signs and blood pressure 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Pulmonary function testF 
 
 
 
X 
Week 24 
Week 56 
 
X 
 
 
Lipid accumulation in liver (NMR or echography)G,H 
 
 
 
X 
Week 24 
Week 56 
 
XH 
XH 
 
Genetic testingI 
X 
 
 
 
 
 
 
 
 
Dietary CounsellingJ 
 
X 
X 
X 
Week 4 
 
 
 
 
 
2-Day Diet record 
 
XK 
X 
X 
X 
X 
X 
X 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
CIMT (mandatory) and FMD (whenever possible) 
 
 
 
X 
 
Week 56 
 
X 
 
Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
 
 
X 
 
Week 56 
 
X 
X 
 
Metabolic panel (albumin, BG, BUN, Ca, carbon dioxide, Cl, 
creatinine, CRP, K, Na, total protein), CKL 
X 
 
 
X 
X 
X 
X 
X 
X 
 
LFTs: ALT, AST, GGT, AP, total bilirubin, (in)direct bilirubin 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Fasting lipid panel: LDL-C, TC, HDL-C, Non-HDL-C, VLDL-C, TG, 
Lp(a), apo A-I, apo BM 
X 
 
X 
XN 
X 
X 
X 
X 
X 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
 
Version: 7.0 / Final / 09 February 2023 
Page 24 of 111 
C O N F I D E N T I A L  
Examination 
Screening 
Run-in Period 
Efficacy Phase 
Safety Phase 
EoTB 
Follow-upC 
Enrolment 
Compliance 
Baseline 
Efficacy 
Safety/Tolerability 
Visit 
1A 
2A 
3 
4 
5 to 10 
11 to 18 
19 to 21 
22 
23 
Week(s) 
Up to -12 
Minimum -6 
-2 
0 
(Day 0) 
4/8/12/16/ 
20/24 
28/32/36/40/ 
44/48/52/56 
68/80/92 
104 
108 
Window Procedure 
 
 
-1 week 
 
±3 days 
±3 days 
±1 week 
±1 week 
- 
Window Procedure for LA 
 
 
 
 
±3 days 
±3 days 
±3 days 
 
 
Laboratory Tests (Continued) 
 
 
 
 
 
 
 
 
 
 
Serum levels of EFA: Linoleic acid, ALA, EPA, DHA, AA, and 
eicosatrienoic acid 
X 
 
 
X 
Week 24 
Week 56 
Week 80 
X 
X 
 
Serum lipase 
 
 
 
X 
Week 24 
Week 56 
 
X 
 
 
Fat-soluble vitamin levelsO (retinol, 25-hydroxy-D, alpha tocopherol, 
ratio alpha tocopherol/total lipids, ratio uncarboxylated 
osteocalcin/total osteocalcin) 
X 
 
 
X 
Week 24 
Week 56 
Week 80 
X 
X 
 
TSH, FSH, LH, ACTH, serum cortisol (between 6:00 and 08:00 a.m.)P 
X 
 
 
X 
 
Week 56 
 
X 
 
 
In patients who are Tanner Stage ≥2: Serum testosterone (males), 
serum oestradiol (females) 
X 
 
 
X 
 
Week 56 
 
X 
 
 
PharmacokineticsQ 
 
 
 
X 
X 
 
 
 
 
 
Urinalysis (bilirubin, blood, colour, glucose, ketones, pH, protein, 
turbidity, white blood cells) 
X 
 
 
X 
 
Week 56 
 
X 
X 
 
Urine pregnancy testR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Medicinal Product 
 
 
 
 
 
 
 
 
 
 
AdministrationS, compliance checkS & palatability assessmentT 
 
 
 
X 
X 
X 
X 
 
 
Dietary SupplementsU 
 
 
X 
X 
X 
X 
X 
 
 
Adverse Events & Concomitant Medication 
 
 
 
Incidence, severity, and relatedness of AEs/SAEs 
 
Continuously throughout the study until resolution or stabilisation of the AE/SAE 
 
Review of concomitant medication 
Continuously throughout the study with date of onset until Follow-up Visit 23 
Withdrawal from Study 
End of Treatment Visit 22 Assessments (Week 104±1 week) should be conducted. 
 
Abbreviations 
AA 
Arachidonic acid 
ACTH 
Adrenocorticotrophic hormone 
AE 
Adverse event 
ALA 
Alpha linoleic acid 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase  
apo A-I  
apolipoprotein A-I  
apo B  
apolipoprotein B  
AST 
Aspartate aminotransferase 
BG 
Blood glucose 
BMI 
Body mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen  
Ca 
Calcium 
CBC 
Complete blood count 
CIMT 
Carotid intima-media thickness 
CK 
Creatinine kinase 
Cl 
Chloride 
CRP 
C-reactive protein 
DHA 
Docosahexaenoic acid 
ECG 
Electrocardiogram 
EFA 
Essential fatty acids 
EoT 
End of Treatment 
EPA 
Eicosapentaenoic acid 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
 
Version: 7.0 / Final / 09 February 2023 
Page 25 of 111 
C O N F I D E N T I A L  
Abbreviations (continued) 
FMD 
Flow-mediated dilatation 
FSH 
Follicle stimulating hormone 
GGT 
Gamma-glutamyl transferase 
HDL-C 
High-density lipoprotein cholesterol 
K 
Potassium 
LA 
Lipoprotein apheresis 
LDL-C 
Low-density lipoprotein cholesterol 
LFTs 
Liver function tests 
LH 
Luteinising hormone 
Lp(a) 
Lipoprotein(a) 
Na 
Sodium 
NMR 
Nuclear Magnetic Resonance 
Non-HDL-C 
Non high-density lipoprotein 
cholesterol 
PK 
Pharmacokinetic 
SAE 
Serious adverse event 
TC 
Total cholesterol 
TG 
Triglycerides 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 
 
A. There is no minimum timeframe between Screening, Enrolment and Start of the Run-in Period, as long as all results of diagnostic tests determining eligibility are available. 
B. In the event of early termination, EoT assessments should be performed. If a patient discontinues the study or the follow-up prematurely due to an AE/SAE, he/she will be followed up until the resolution 
or stabilisation of the AE/SAE.  
C. Patients entering the Expanded Access Programme (<18 years of age)/transitioning to commercial product (≥18 years of age) will have a follow-up phone call at Week 108±1 week to monitor safety 
including AE and concomitant medication reporting. Patients who have opted not to participate in or are unsuitable for the Expanded Access Programme (<18 years of age)/opted not to transition to 
commercial product (≥18 years of age) will return for an in person safety Follow-up Visit. 
D. A full physical exam, including growth and sexual maturation assessments, a genitourinary exam per the Principal Investigator’s judgment, but not rectal exam, will be performed at Screening, Baseline, 
Week 12±3 days, Week 24±3 days, Week 56±3 days, Week 104±1 week and/or at EoT. At all other time points shown, an abbreviated physical exam including measurement of height, weight, BMI 
and BSA may be performed. Please note that weight will be measured using a consistent approach at Screening and at each visit after the Run-in Period (i.e., child/adolescent always weighed in same 
amount of clothing, either in underwear, hospital gowns or by subtracting the weight of clothes). Xanthomas will be evaluated at every physical exam. 
E. It is anticipated that echocardiography will be performed annually as standard of care in this patient population. For this study, echocardiography is not mandated but data/results will be included as 
part of the study safety data. Information in relation to the most recent echocardiography on file (if available) will be documented in the electronic Case Report Form at the following visits: Baseline, 
Week 24±3 days; Week 56±3 days, and Week 104±1 week. 
F. Spirometry with DL,CO (diffusion capacity of the lung for carbon monoxide) will be performed to include: forced vital capacity (FVC); forced expiratory volume during 1 s (FEV1); maximal mid-expiratory 
flow (FEF25-75) 
G. All patients will undergo NMR imaging unless it is contraindicated or not feasible (e.g., due to the need for sedation or general anaesthesia in very young or anxious patients). In this case, echography 
(i.e., ultrasound scan) will be used at the discretion of the investigator. 
H. Lipid accumulation in the liver will only be determined at Week 104 in patients entering the Expanded Access Programme (<18 years of age)/transitioning to commercial product (≥18 years of age). In 
patients who have opted not to participate in or are unsuitable for the Expanded Access Programme (<18 years of age)/opted not to transition to commercial product (≥18 years of age), lipid accumulation 
in the liver will be determined at Week 108. 
I. 
Genetic testing is strongly encouraged, but not mandatory and not required for determining eligibility. Patients who have not previously had genetic testing, will be asked, whether they would consent 
to genetic testing. A separate informed consent will be obtained for genetic testing. A blood sample will be collected according to central laboratory procedures specified in the ‘Laboratory Manual’ for 
genotyping at Screening (Visit 1). If it is not possible to do this at Screening (Visit 1) it can be done at a later visit. 
J. The Principal Investigator can request additional dietary counselling as clinically indicated. 
K. The 2-day diet record collected at this visit will be used to make any necessary adjustments to the patient’s diet before starting study medication. A dietary compliance check will be performed at 
Week -2. 
L. CK monitoring and evaluation 
1. If CK values are found to be elevated >5 x ULN on routine testing, the patient should be questioned about muscle symptoms. 
2. A study site physician should be alerted to the occurrence of unexplained muscle symptoms and any CK values >5 x ULN, and must take immediate action if CK is >10 x ULN. 
3. If CK values are >5 x ULN with muscle symptoms or >10 x ULN with or without muscle symptoms the following steps should be taken: 
a. Clarify the nature, duration and intensity of any muscle symptoms. 
b. Review possible predisposing factors, such as: unaccustomed exercise, heavy alcohol intake, viral illness (consider performing serology), concomitant medication and consider diagnosis of 
other conditions which cause myopathy. 
c. Physical examination for muscle tenderness, weakness and rash. 
d. Measure CK again within a few days. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
 
Version: 7.0 / Final / 09 February 2023 
Page 26 of 111 
C O N F I D E N T I A L  
e. Measure serum creatinine. 
f. 
Urine dipstick. 
g. Arrange to review the patient again in 4 to 10 days, or earlier if symptoms of myopathy appear or worsen, or if the urine becomes very dark. 
4. Discontinue study medication for CK values >10 x ULN with or without muscle symptoms. 
5. For CK values 5 to 10 x ULN: 
a. If asymptomatic, or if symptomatic but alternative explanation exists, symptoms should be followed and CK levels tested weekly until it is no longer a medical concern or symptoms worsen and 
meet criteria for any of the above. 
b. If symptomatic, and no alternative explanation exists, withhold therapy. 
6. Throughout the study, patients should be instructed to promptly report any unexplained muscle pain or weakness, particularly if associated with malaise or fever. If this should occur, CK should be 
measured as soon as possible. 
M. Draw 2 blood samples for the fasting lipid panel, of which 1 will be analysed in the local hospital laboratory and 1 will be sent to the central laboratory specified in the ‘Laboratory Manual’. 
N. Baseline values of lipid and lipoprotein parameters will be obtained as the maximum concentration (Cmax) immediately prior to LA, if applicable before start of study treatment. 
O. Bone health and bone age will be assessed by measurement of 25-hydroxyvitamin D and total uncarboxylated osteocalcin levels (as a reflection of vitamin K levels).  
P. The blood sample for testing of serum cortisol must be obtained in the early morning (6:00 to 8:00 am). 
Q. A single PK sample will be collected at Baseline, at Visit 5 (Week 4±3 days), Visit 7 (Week 12±3 days), Visit 8 (Week 16±3 days), and Visit 10 (Week 24±3 days). Two PK samples will be collected at 
least 1 hour apart at Visit 6 (Week 8±3 days) and Visit 9 (Week 20±3 days); these samples must be collected as separate blood draws (time between separate blood draws might be used for undertaking 
other procedures scheduled for the respective visit(s)). 
R. Urine pregnancy tests will be conducted in postmenarchal female adolescent patients using test strips at every scheduled visit from Visit 1 through Visit 23 and every 4 weeks after Visit 18 at 
Week 56±3 days through Week 104±1 week. 
S. Patients will be instructed to refrain from taking study medication within 8 hours prior to their study visits. They will be asked to bring all unused study medication with them to the clinical site at every 
visit (including Safety/Tolerability Visits) for a compliance check.  
T. At Visit 4, a 5-point facial hedonic scale will be used to record the child’s assessment of palatability of study medication on the first occasion that any patient who is unable to swallow the intact 
capsule(s) opens the capsule(s) and sprinkles the capsule content on a small amount (1 tablespoon) of either apple sauce or mashed banana (i.e., if a patient tries both food media, assessment will 
be made at the first instance of taking the study medication with apple sauce and the first instance of taking the study medication with mashed banana). The type of food media (apple sauce or mashed 
banana) will be captured. At Visit 5, the investigator will ask the parent(s)/legal guardian(s) to evaluate the children’s reaction to investigational product and dietary supplement administration. A 3-point 
scale that assesses the parent(s)/legal guardian(s) interpretation of the child’s reaction/facial expression will be used to determine whether they find lomitapide “pleasant”, “unpleasant” or are “not 
sure”. In addition, an assessment of ease of administration will be incorporated by asking the parent(s)/legal guardian(s) the following question: “Do you sometimes have problems in giving the 
medication to your child because he/she refuses to take it or throws it up immediately after taking it? (Yes/No).” The same question will be asked for the administration of dietary supplements. Timing 
of the reaction relative to dosing will be recorded to help distinguish between palatability of the investigational product and gastrointestinal events that are a result of the investigational products 
mechanism of action.  
U. Dietary supplements will be dispensed at the Week -2 (Run-in Compliance) Visit and will be administered daily throughout the Efficacy and Safety Phases of the study. Dietary supplements should be 
taken in the morning. 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 27 of 111 
C O N F I D E N T I A L  
2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Homozygous Familial Hypercholesterolaemia 
Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening inherited 
disorder of lipid metabolism with an estimated prevalence of 1 per 160,000 to 300,000 in the 
European population (Cuchel, Bruckert et al. 2014, Sjouke, Kusters et al. 2015).  
The Consensus Panel on Familial Hypercholesterolaemia (FH) of the European 
Atherosclerosis Society (EAS) recommends the following criteria for the diagnosis of HoFH 
(Cuchel, Bruckert et al. 2014): 
• Genetic confirmation of 2 mutant alleles at the LDL receptor (LDLR), apolipoprotein B 
(apo B), proprotein convertase subtilisin/kexin type 9 (PCSK9), or LDL-receptor adapter 
protein 1 (LDLRAP1) gene locus or  
• An untreated low-density lipoprotein cholesterol (LDL-C) >500 mg/dL (13 mmol/L) and 
treated LDL-C ≥300 mg/dL (8 mmol/L), respectively together with either  
− Cutaneous or tendon xanthomas before the age of 10 years or  
− Untreated LDL-C levels consistent with heterozygous FH in both parents.  
Significantly elevated LDL-C levels lead to premature, severe, and progressive atherosclerosis 
and development of early cardiovascular disease (CVD). The average age of death is 18 years 
if untreated and effective lipid-lowering therapy (LLT) greatly improves survival in HoFH 
(Thompson, Blom et al. 2018).  
Based on the evidence that treatment can delay the onset of CVD, primary prevention is 
suggested to start as early as possible and mainly consists of lowering LDL-C levels to 
<135 mg/dL (<3.5 mmol/L) in paediatric HoFH patients and to <100 mg/dL (<2.5 mmol/L) in 
adults. Secondary prevention comprises a decrease of LDL-C levels to <70 mg/dL 
(<1.8 mmol/L) in adults with CVD as recommended by the EAS (Cuchel, Bruckert et al. 2014).  
2.1.2 
Treatment Options and Medical Need 
Lipid-lowering Medicinal Products 
Therapeutic options include 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase 
inhibitors or statins, cholesterol absorption inhibitors such as ezetimibe, bile-acid sequestrants, 
and PCSK9 inhibitors. Statins and ezetimibe reduce LDL-C levels by about 25%. The PCSK9 
inhibitor evolocumab decreases LDL-C beyond other lipid-lowering drugs by about 20% with 
wide variability depending on receptor status, as patients with receptor-negative mutations and 
less LDLR expression and activity respond less or not at all to PCSK9 inhibitors (Santos 2018, 
Thedrez, Blom et al. 2018).  
Lipoprotein Apheresis 
A current standard of care in HoFH includes lipoprotein apheresis (LA), a physical method of 
purging the plasma of LDL-C. The International Consensus Paper on integrating LA and new 
lipid-lowering drugs considers LA plus high dose statins and ezetimibe as first-line treatment 
in HoFH, as it reduces LDL-C, CVD, and prolongs life (Stefanutti, Julius et al. 2017). 
However, the rebound phenomenon after LA described by Thompsen and Thompson in 2006 
(Thompsen and Thompson 2006) makes it necessary to perform LA sessions weekly, since 
lipid-lowering drugs induce constantly low LDL-C levels (Julius 2016). In fact, time-averaged 
LDL-lowering ranges between 26% for biweekly LA treatment to 47%, if LA is done twice a 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 28 of 111 
C O N F I D E N T I A L  
week (Thompson 2015). However, even weekly LA combined with high-dose statins and 
ezetimibe failed to prevent progression of CVD in HoFH patients (Graesdal, Bogsrud et al. 
2012). Despite combination of conventional LLT and weekly or biweekly LA, about 50% of 
HoFH patients suffer progressive atherosclerosis and major cardiovascular events 
(Giammanco, Cefalu et al. 2019).  
This fact has recently been confirmed by a publication on multimodal LLT in paediatric patients 
with HoFH, which revealed that 24% of children who started chronic LA before the age of 18 
suffered progressive CVD despite weekly LA including 1 death due to coronary and 
cerebrovascular disease. Of 17 patients with genetically proven HoFH or compound 
heterozygous (c-het) FH in this study, 12 patients underwent LA weekly and 5 patients twice a 
week. The authors concluded that early and intensified LLT including LA is needed to improve 
the outcome (Klaus, Taylan et al. 2018).  
Luirink et al. recently published a systematic review on the evidence for the safety and efficacy 
of LA in paediatric patients with HoFH. They evaluated 76 studies with 209 children starting 
LA at a mean age of 9.3 years (range 2 to 18 years). Mean pre-apheresis LDL-C levels were 
604 mg/dL (15.6 mmol/L) and were reduced by a mean of 67.2% per session using 
semiselective LA, by 63.3% using nonselective LA, and by 71.6% using selective LA. While 
xanthomas regressed or disappeared in 83% of patients, surrogate parameters of CVD 
remained stable in most patients. Of 123 patients, 24 experienced a CVD event of whom 
10 had experienced a CVD before LA onset. Six patients died at follow-up. The authors 
concluded that the impact of LA on the onset of CVD remains unclear and that more robust 
data was needed, particularly as LA is an invasive therapy with an important impact on daily 
life for children (Luirink, Determeijer et al. 2019).  
Liver Transplantation 
Liver transplantation is the only curative treatment for HoFH (Alim, Tokat et al. 2016), as it 
replaces the missing LDLR and normalises LDL-C. According to data from the European Liver 
Transplant Registry, 21 liver transplants for HoFH were performed between 1988 and 2009.  
Paediatric liver transplantation in HoFH patients has been shown to sustainably normalise 
LDL-C levels within 1 month following transplantation. However, due to the high 
transplantation-related morbidity and mortality, the shortage of donors, and the need for 
life-long immunosuppressive therapy, the EAS does not recommend liver transplantation as 
first-line therapy for HoFH (Cuchel, Bruckert et al. 2014). HEART UK even considers to 
balance the early use of lomitapide and evolocumab beyond current licensed age restriction in 
severely affected children and young adults against the risks of liver transplantation (France, 
Rees et al. 2016).  
In a longitudinal cohort of 31 molecularly defined HoFH patients enrolled in the Spanish HoFH 
registry, which is a subset of the SAFEHEART (Spanish Familial Hypercholesterolaemia 
Cohort Study, NCT02693548) registry, at inclusion 4 patients had received a liver transplant 
at a mean age of 13 years. Of these 4 patients, 2 withdrew LLT after the liver transplant, while 
2 still required moderate doses of statins. During follow-up, a further patient underwent liver 
transplant at the age of 15 years. Overall, 2 patients died, 1 because of septicaemia due to 
immunosuppression and 1 during the postoperative period (Alonso, Diaz-Diaz et al. 2016). 
One of the 31 HoFH patients started lomitapide as an adjunct to LLT and achieved an 
additional LDL-C reduction of 52% without significant AEs.  
Beyond the high transplantation-related morbidity and mortality and the need for life-long 
immunosuppressive therapy, there is some evidence that CVD is the leading cause of 
long-term morbidity and mortality in liver transplant recipients due to a proatherogenic 
lipoprotein profile (Chhatrala, Siddiqui et al. 2015) and that LDL-C independently predicts CVD 
events (Siddiqui, Arshad et al. 2019). This may contribute to the need for LLT treatment after 
liver transplant. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 29 of 111 
C O N F I D E N T I A L  
2.2 
Investigational Product 
Lomitapide is a first in class oral, selective inhibitor of microsomal transfer protein (MTP), an 
intracellular lipid-transfer protein that is found in the lumen of the endoplasmic reticulum and 
is responsible for binding and shuttling individual lipid molecules between membranes. MTP 
plays a key role in the assembly of apo B containing lipoproteins in the liver and intestines. 
Inhibition of MTP reduces lipoprotein secretion and circulating concentrations of 
lipoprotein-borne lipids including cholesterol and triglycerides. 
The European Commission (EC) granted authorisation for lomitapide under the trade name 
‘Lojuxta®’ in July 2013. Lomitapide is a “lipid modifying agent” according to the Anatomical 
Therapeutic Chemical (ATC) Classification System (ATC code C10AX12). It is indicated as an 
adjunct to a low-fat diet and other lipid-lowering medicinal products with or without LA in adult 
patients with HoFH. Genetic confirmation of HoFH should be obtained whenever possible. 
Other forms of primary hyperlipoproteinaemia and secondary causes of hypercholesterolaemia 
(e.g., nephrotic syndrome, hypothyroidism) must be excluded. 
Please refer to Section 6.1 Description of the Investigational Product for details regarding 
formulation, packaging, and labelling as well as storage of lomitapide. 
2.3 
Summary of Non-clinical Studies with Lomitapide 
Please refer to Section 2.3 of the European Public Assessment Report (EPAR) of the 
European Medicines Agency for Lojuxta® dated 30 May 2013 for a summary of non-clinical 
studies with lomitapide. 
2.4 
Summary of Clinical Studies with Lomitapide 
According to the EPAR of the European Medicines Agency for Lojuxta® dated 30 May 2013 
the clinical development programme for Lojuxta® included 15 phase I studies, 7 phase II 
studies and 3 phase III studies. In total, 1,145 healthy subjects and patients were treated, 
including 943 who received lomitapide, either as monotherapy or co-administered with other 
LLT. The majority of subjects (959 out of 1,145) were enrolled in placebo and/or 
active-controlled studies. The clinical studies were performed in accordance with Good Clinical 
Practice (GCP). Clinical studies conducted outside the community were carried out in 
accordance with the ethical standards of Directive 2001/20/EC. In support of the clinical studies 
in man, the marketing authorisation application also included 12 in vitro studies using human 
samples or human cell material. 
Please refer to Section 2.4 of the EPAR of the European Medicines Agency for Lojuxta® dated 
30 May 2013 for further details.  
2.4.1 
Clinical Pharmacology and Pharmacokinetics 
Please refer to Section 2.4 of the EPAR for Lojuxta® dated 30 May 2013 for a summary of 
clinical aspects of pharmacokinetics and pharmacodynamics of lomitapide. 
2.4.2 
Clinical Efficacy and Safety 
Global Phase III Study and Long-Term Extension Study 
The efficacy and safety of lomitapide as an adjunct to a low-fat diet and LLT with or without LA 
was investigated in a single-arm, multi-national phase III study (UP1002/AEGR-733-005, 
NCT00730236) in adult patients with HoFH. The study had a 26-week Efficacy Phase during 
which all background LLT including LA remained fixed and lomitapide was titrated to the 
maximum tolerated dose (MTD, range 5 to 60 mg, mean dose 40 mg) and a 52-week Safety 
Phase during which lomitapide dose was continued at the MTD and background LLT could be 
altered with physician discretion.  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 30 of 111 
C O N F I D E N T I A L  
Overall, 23 of 29 patients (16 male, 13 female, mean age of 30.7 years) completed the Efficacy 
Phase of the study. By Week 26, mean LDL-C decreased significantly by 40% in the 
Intent-to-treat (ITT) and by 50% in the completer population. Reductions in LDL-C were 
maintained during the Safety Phase with a mean change from Baseline to Week 56 of 44.0% 
(p<0.001) and to Week 78 of 38.4% (p<0.001). Concurrent LLT was reduced in 
15 of 23 patients (65%); 6 of 13 patients (46%) who were receiving LA either permanently 
stopped LA (n=3) or permanently increased the interval in between LA treatments (n=3). LDL-C 
values of <100 mg/dL (<2.5 mmol/L) were observed at least once in 55%, LDL-C values of 
<70 mg/dL (<1.8 mmol/L) in 31% of patients (Cuchel, Meagher et al. 2013). 
Long-term data of the extension study (AEGR-733-012, NCT00943306) that enrolled 19 of the 
23 patients who completed the pivotal study with a mean age of 30.4 years (10 male, 9 female) 
confirmed efficacy and safety of lomitapide. The median treatment duration with lomitapide 
across both studies was 5.1 years (range, 2.1 to 5.7 years).  
From Baseline through Week 246, a total of 14 (74%) patients achieved LDL-C <100 mg/dL 
(<2.5 mmol/L), and 11 (58%) patients achieved LDL-C <70 mg/dL (<1.8 mmol/L) on at least 
1 occasion. One additional patient discontinued LA in the long-term extension study. The most 
common adverse events (AEs) reported were gastrointestinal, including diarrhoea, nausea, 
dyspepsia, and vomiting. For most drug-related AEs, the incidence was lower in the extension 
study compared with the pivotal study (42.1% versus 84.2%) (Blom, Averna et al. 2017) 
LOWER Registry 
The Lomitapide Observational Worldwide Evaluation Registry (LOWER, NCT02135705, 
European PAS register number ENCEPP/SDPP/5326) is an international, multi-centre, 
observational registry to prospectively assess long-term safety and efficacy of lomitapide. The 
LOWER Registry is an EU Risk Management Plan (RMP) Category 2 study following a specific 
obligation on the exceptional marketing authorisation of lomitapide dated 31 July 2013.  
As of 01 March 2018, a total of 178 patients with a mean age of 52.1 years have been enrolled. 
The duration of lomitapide exposure ranged from 0.3 to 60.1 months with a median exposure 
duration of 21.7 months and doses ranging from 2.5 mg to 40 mg daily. 
At any time after initiating lomitapide treatment, 104 (59.4%) patients experienced a reduction 
in LDL-C by at least 50%, 117 (66.9%) patients experienced an LDL-C value <100 mg/dL 
(<2.5 mmol/L) and 73 (41.7%) patients experienced an LDL-C value of <70 mg/dL 
(<1.8 mmol/L). Mean percent changes in LDL-C and other serum lipids and lipoproteins were 
consistent with mean percent changes reported in the phase III pivotal study (Cuchel, Meagher 
et al. 2013).  
Overall, 133 (76.0%) patients experienced at least 1 AE, with diarrhoea (n=57, 32.6%) and 
nausea (n=20, 11.4%) being the most commonly reported, consistent with the prescribing 
information and the phase III clinical study (Cuchel, Meagher et al. 2013). Events that were 
considered treatment-related by the investigator were reported in approximately half of the 
patients (n=97, 55.4%), the majority of which were mild (n=48, 27.4%) or moderate (n=38, 
21.7%) with the remaining considered severe (n=10, 5.7%). The most common 
treatment-related AEs were diarrhoea (n=49, 28.0%) and nausea (n=15, 8.6%) as expected. 
Serious AEs were reported in 34 (19.4%) patients, and the SAEs experienced by >2% of 
patients were acute myocardial infarction (n=4, 2.3%), angina pectoris (n=5, 2.9%), cardiac 
failure congestive (n=3, 1.7%), coronary artery disease (n=7, 4.0%), and pneumonia (n=4, 
2.3%). Overall, no new safety signals have been identified.  
In about a quarter of enrolled patients (n=41, 23.4%), permanent discontinuation of lomitapide 
was due to AEs, mostly due to GI events (n=25, 14.3%), specifically diarrhoea (n=15, 8.6%), 
which was slightly higher than the 10% (n=3/29) of patients discontinuing due to GI AEs in the 
phase III study and increases in hepatic enzymes/liver function tests (LFTs) (n=12, 6.9%).  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 31 of 111 
C O N F I D E N T I A L  
Given the high risk associated with the extreme LDL-C levels experienced by patients with 
HoFH, the results of this analysis of data collected in the LOWER registry support the 
favourable benefit-risk profile of lomitapide when used as directed. 
Cohort Analyses and Case Studies 
There are several publications that report data in case studies and cohort analyses following 
treatment with lomitapide in the real world that show superior efficacy and similar or improved 
tolerability compared with the phase III study data that led to the exceptional approval by the 
European Medicines Agency (EMA).  
Van Lennep et al. reports data on 4 HoFH cases: Each patient was commenced on lomitapide 
according to the prescribed protocol and subjected to routine follow-up. All 4 patients 
experienced clinically meaningful reductions in LDL-C levels of 35 to 73% (Roeters van 
Lennep, Averna et al. 2015).  
Stefanutti et al. reports data on 7 patients with genetically determined HoFH who were treated 
with lomitapide in the normal course of their therapy. All patients received LA either weekly or 
biweekly. Lomitapide was administered according to the approved EU prescribing information. 
The LDL-C reductions ranged from 5% (early in treatment) to 83% with a mean reduction of 
40% (Stefanutti, Morozzi et al. 2016).  
The publication by deGoma reports in detail the case history of a patient receiving treatment 
with lomitapide in the US. The patient had a pre-apheresis LDL-C ranging from 146 to 
188 mg/dL prior to treatment with lomitapide. After 12 weeks and on a dose of 5 mg, his LDL-C 
reduced to 64 mg/dL and he stopped apheresis. The LDL-C increased slightly to 107 mg/dL 
and the lomitapide dose was increased to 10 mg. He was also able to stop treatment with 
colesevelam, ezetimibe and fenofibric acid (deGoma 2014).  
Comparably, 1 of 2 HoFH patients reported by Real et al. experienced a dramatic reduction of 
LDL-C values at lomitapide doses of 5 to 10 mg/day. The first patient maintained LDL-C levels 
<70 mg/dL (<1.8 mmol/L) and stopped LA. His brother received a dose of 20 mg/day and 
showed interapheresis LDL-C levels of <100 mg/dL(<2.5 mmol/L) (Real, Arbona et al. 2018).  
Kolovou et al. reviewed their experience in treating 4 HoFH patients with lomitapide as an 
adjunct to LLT including LA for 14 months. Two patients showed LDL-C reductions of 54% and 
65%, respectively (called hyper-responders), while LDL-C levels in 2 patients decreased by 
35% and 11% (called hypo-responders). Dr Kolovou reported the variability in response may 
be due to MTP gene expression (Kolovou, Kolovou et al. 2016).  
The biggest dataset in real world use comes from Italy and includes 15 HoFH patients treated 
for up to 3 years with mean Baseline LDL-C levels of 426.0±204.0 mg/dL despite receiving 
treatment with statins, ezetimibe and LA (in 10 of the 15 patients). With a rather low mean dose 
of 19±13.3 mg lomitapide/day as an adjunct to LLT, LDL-C was lowered by a mean of 
76.2%±16.7%. Overall, 8 of 10 patients on LA were able to discontinue LA completely, while 
the 2 remaining patients decreased the frequency of LA. After stopping LA and adjusting other 
LLT, the mean LDL-C reduction at the last timepoint was 68.2±24.8% versus Baseline. At their 
last visit, 60% of patients achieved LDL-C <100 mg/dL (<2.5 mmol/L), and 46.6% of patients 
achieved LDL-C <70 mg/dL (<1.8 mmol/L) (D'Erasmo, Cefalu et al. 2017). 
Evidence on Efficacy and Safety in Paediatric Patients 
Chacra et al. have published a case report describing a 49-month compassionate use of 
lomitapide in a 7.6-year old female child with HoFH. The patient presented with LDL-C values 
of 1,009 mg/dL at the age of 29 months. After 10 months of low-saturated fat/cholesterol diet, 
atorvastatin 5 mg/day and ezetimibe 10 mg/day were introduced. Atorvastatin was titrated to 
40 mg/day and the mean LDL-C reduction under this regimen was 44%. Due to the LDLR null 
mutations in this patient, the administration of PCSK9 inhibitors was not considered. 
Lomitapide was started at 5 mg/day at the age of 92 months when LDL-C was 428 mg/dL, as 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 32 of 111 
C O N F I D E N T I A L  
the left ventricle-aortic peak gradient of the patient had increased and valve regurgitation was 
progressive. Lomitapide was gradually titrated up to the MTD of 20 mg/day and achieved a 
37% reduction in LDL-C on top of atorvastatin and ezetimibe. Lomitapide was safe and well 
tolerated and the patient presented with adequate growth and sexual maturation. However, 
despite the efficiency of lomitapide in reducing LDL-C levels, CVD was progressive, possibly 
due to the already established damage of the aortic valve at start of treatment. The authors 
concluded that further studies with lomitapide in this very high-risk population are urgently 
warranted to establish long-term safety and efficiency and to investigate whether lomitapide 
can retard the onset and progression of CVD (Chacra, Ferrari et al. 2019). 
Ben-Omran et al. have recently reported a case series of 11 paediatric HoFH patients at a 
mean age of 11.6±1.1 years who have received treatment with lomitapide on a named-patient 
basis, as their cases have been deemed ‘urgent to treat’ due to early CVD, lack of sufficient 
response to standard of care (SOC) treatment and inability to wait for study APH-19 to start. 
These patients have received lomitapide at a mean dose of 24.5±4.3 mg/day for 
20.0±2.9 months as an adjunct to their LLT (including LA in 5 patients). Mean Baseline LDL-C 
of 419±74.6 mg/dL was reduced by 58.4±6.8% to a nadir of 176.7±46.3 mg/dL. Six patients 
achieved EAS target levels of <135 mg/dL (3.5 mmol/L), 3 of whom reduced their LA 
frequency, and 2 stopped LA completely. Adverse events were consistent with those seen in 
the phase III study in adults and in real world use. The majority of AEs consisted of 
gastrointestinal (GI) complaints, presented early in the treatment course, and resolved with 
minimal active management. Transient increases in LFTs resolved either with brief dose 
reductions or without intervention. Overall, efficacy and safety were comparable to the results 
reported in adult HoFH patients. Consistent with real-world data from adult patients, efficacy 
was higher at a lower mean dose. The authors compared their approach of dose titration based 
on LDL-C levels as opposed to MTD with the results of D’Erasmo et al. who reported a mean 
LDL-C decrease of 76.2%±16.7% at a rather low mean dose of 19±13.3 mg lomitapide/day 
(D'Erasmo, Cefalu et al. 2017). According to Ben-Omran et al. an important and positive 
outcome for 5 children in this case series was the ability to reduce or stop LA, which was a 
benefit given increasing time commitments as age advanced (Ben-Omran, Masana et al. 
2019).  
In summary, global pivotal phase III study data and real world evidence for lomitapide as an 
adjunct to a low-fat diet and LLT with or without LA in both adult and paediatric patients confirm 
the feasibility to reach EAS targets of LDL-C levels <135 mg/dL (3.5 mmol/L) in children and 
<100 mg/dL (<2.5 mmol/L) in primary or <70 mg/dL (<1.8 mmol/L) in secondary prevention in 
adults (see Figure 1). 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 33 of 111 
C O N F I D E N T I A L  
Figure 1 
Percentage of Patients Achieving EAS Treatment Goals with Lomitapide 
across Pivotal Studies and in Real-world Evidence 
 
Figure based on Underberg J, J Clin Lipidol 2018;12(2):561-562 (Underberg, Harada-Shiba et al. 2018) showing 
percentage of patients achieving EAS treatment goals (LDL-C <135 mg/dL [3.5 mmol/L] in paediatric patients and 
LDL-C <100 mg/dL [<2.5 mmol/L] in primary and <70 mg/dL [<1.8 mmol/L] in secondary prevention in adults) at 
≥1 time point after initiating treatment with lomitapide 
IT = Italy; JP = Japan; LOWER = Lomitapide Observational Worldwide Evaluation Registry; LDL-C = Low-density 
lipoprotein C; PAED = Paediatrics; RWE = Real world evidence 
1. Underberg J, J Clin Lipidol 2018;12(2):561-562 (Underberg, Harada-Shiba et al. 2018) 
2. Cuchel M, Atherosclerosis Suppl 2014;15(2):33-45 (Cuchel, Bruckert et al. 2014) 
3. Blom DJ, Circulation 2017;136(3):332-335 (Blom, Averna et al. 2017) 
4. Harada-Shiba M, J Atheroscler Thromb 2017;24(4):402-411 (Harada-Shiba, Ikewaki et al. 2017) 
5. Underberg J, Circulation 2016;134(suppl1): A12117-A12117 (Underberg, Cannon et al. 2016) 
6. Underberg J, J Clin Lipidol 2018;12(2):561-562 (Underberg, Cannon et al. 2018) 
7. D’Erasmo L, Adv Ther 2017;34(5):1200-1210 (D'Erasmo, Cefalu et al. 2017) 
8. Ben-Omran T, Adv Ther 2019; https://doi.org/10.1007/s12325-019-00985-8 (Ben-Omran, Masana et al. 2019) 
2.5 
Rationale for Dose Selection 
Paediatric starting doses, dose escalation regimens, and appropriate maximum doses for 
different age ranges were determined using allometric scaling and physiologically-based 
pharmacokinetic modeling (PBPK) as well as simulation approaches (see Section 18.1 Source 
Documents, Lomitapide Pediatric Trial Dose Selections Using Two Approaches: Allometric 
Scaling and Physiologically-based Pharmacokinetic (PBPK) Modeling; Final Report, 
26 June 2013). 
The calculation is based on the approved dosing regimen for adults. It takes into account the 
assumptions that disease progression, response to intervention and concentration-response 
(C-R) are similar in children and adults. These assumptions are considered reasonable due to 
the genetic cause of HoFH and the mechanism of action of lomitapide.  
Figure 2 displays the proposed paediatric dose (mg) by age group and method: The 
age-dependent doses calculated by allometric scaling were combined to calculate a mean 
dose for each age group specified in the PBPK modelling. The error bars represent the 
standard deviation of the calculated mean dose. As can be seen, the proposed mean paediatric 
doses were overall 0.5 to 1 mg higher using the allometric scaling approach compared to the 
PBPK approach except in the oldest age group (see Figure 2).  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 34 of 111 
C O N F I D E N T I A L  
Figure 2 
Proposed 
Mean 
Lomitapide 
Paediatric 
Starting 
Dose 
Based 
on 
Physiologically-based Pharmacokinetic Modelling and Allometric Scaling 
 
Table 1 shows the recommended first-in-paediatric doses by age group, for which both the 
calculated doses based on PBPK modelling and allometric scaling and the availability of 
minimum dosage form strength (2 mg) and next higher dosage strength (5 mg) have been 
taken into consideration.  
Table 1 Suggested 
Lomitapide 
Starting 
Doses 
by 
Age 
Group 
Based 
on 
Physiologically-based Pharmacokinetic Modelling and Allometric Scaling 
Age Group (years) 
Suggested Starting Dose (mg) 
PBPK Modelling 
Allometric Scaling 
Recommendation 
5 to 10 
1.0 to 1.5 
1.9 to 2.5 
2.0 
11 to 15 
2.0 to 3.0 
3.3 to 4.2 
2.0 
16 to ≤17 
5.0 
4.0 to 4.5 
5.0 
PBPK = Physiologically-based Pharmacokinetic 
Please refer to Section 7.2 Treatment Schedule for corresponding starting doses, dose 
escalation regimens, and maximum doses of lomitapide by age group.  
2.6 
Known and Potential Benefits and Risks 
2.6.1 
Unmet Medical Need 
Due to their cumulative LDL-C burden, paediatric HoFH patients suffer early-onset 
atherosclerotic cardiovascular disease (ASCVD) at the age of 12.5 years and die at the age of 
18 years, if the disease is undetected or untreated (Nordestgaard, Chapman et al. 2013).  
Lipid-lowering medicinal products reduce LDL-C levels by up to 45% with wide variability 
depending on receptor status (Santos 2018, Thedrez, Blom et al. 2018). Time-averaged 
LDL-C-lowering of LA ranges between 26% for biweekly LA treatment to 47%, if LA is done 
twice a week (Thompson 2015). However, despite standard of care LLT including LA, 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 35 of 111 
C O N F I D E N T I A L  
paediatric patients with HoFH rarely achieve EAS LDL-C target levels and suffer early 
progressive CVD (Klaus, Taylan et al. 2018, Luirink, Determeijer et al. 2019).  
Since the EAS does not recommend liver transplantation as first-line therapy for HoFH (Cuchel, 
Bruckert et al. 2014) and HEART UK considers to balance the early use of lomitapide in 
severely affected children against the risks of liver transplantation (France, Rees et al. 2016), 
lomitapide is a “last-resort” treatment for paediatric patients, who respond less or not at all to 
PCSK9 inhibitors due to receptor-negative mutations with less LDLR expression and activity 
(Thedrez, Blom et al. 2018) and for those who either do not have access to LA or suffer 
progressive CVD despite receiving LLT including LA (Ben-Omran, Masana et al. 2019). 
Please refer to Section 2.1.2 Treatment Options and Medical Need for further details.  
2.6.2 
Known and Potential Benefits 
Lomitapide is a first in class oral, selective MTP inhibitor that functions independently of the 
LDLR. It is administered orally and is subject to a high first-pass effect following ingestion 
resulting in a low systemic bioavailability of approximately 7% (see Section 2.3.3 of the EPAR 
for Lojuxta® dated 30 May 2013). The pharmacodynamic activity of lomitapide is not dependent 
on systemic exposure but is directly related to local concentrations achieved in the small 
intestine and liver.  
The high first-pass effect observed to limit systemic availability of lomitapide is likely to be 
dominated by significant metabolism by CYP 3A4 inhibitors. The parent molecule is cleaved 
into 2 primary metabolites (M1 and M3) that lack activity against MTP. Systemic concentrations 
of lomitapide are low following oral administration and there is a large apparent volume of 
distribution despite a high level of protein binding. This suggests loose binding to low-affinity 
sites, mitigating the likelihood of interactions by displacement of other protein-bound drugs. 
Excretion of unchanged lomitapide is minimal by any route, and the majority of the drug 
appears as water soluble (polar) metabolites in the bile.  
Therefore, strong or moderate CYP 3A4 inhibitors are not permitted during the study as 
described in Section 7.6.3 Non-Permitted Concomitant Medication, Food or Substances. Weak 
CYP 3A4 inhibitors are only permitted during the Safety Phase of the study and doses of 
lomitapide or concomitant medication should either be administered 12 hours apart or modified 
(see Section 7.3.3 Dose Modification for Concomitant Medication).  
The central role of LDL-C in the pathophysiology of ASCVD is well established. Every 1 mmol/L 
(38.6 mg/dL) reduction in LDL-C levels is associated with a corresponding 22% decrease in 
cardiovascular mortality and 12% reduction in total mortality over 5 years (Baigent, Blackwell 
et al. 2010).  
Published evidence shows lomitapide to reduce LDL-C consistently and significantly by a 
mean 40% to 50% across the whole spectrum of molecularly-defined adult HoFH patients 
irrespective of LA and independent of LDLR function. There was no loss of efficacy in patients 
with genotypes predicting the most severely compromised LDLR function, who tend to be 
non-responsive to other therapies like statins and PCSK9 inhibitors (Hegele, Shah et al. 2018). 
Global pivotal phase III study data and real world evidence for lomitapide as an adjunct to a 
low-fat diet and LLT with or without LA confirmed the feasibility to reach EAS targets of LDL-C 
levels <135 mg/dL (3.5 mmol/L) in 55% of paediatric and <100 mg/dL (<2.5 mmol/L) in 
51 to 74% or <70 mg/dL (<1.8 mmol/L) in 28 to 58% of adult HoFH patients (see Figure 1).  
This magnitude of LDL-C reduction is unprecedented in clinical experience within the HoFH 
patient population, in whom LDL-C levels have largely proven refractory to oral therapy, 
necessitating use of regular LA to effect further reductions. For the first time, it is now feasible 
to reach target LDL-C goals and maintain these levels during chronic treatment. 
According to a modelling analysis in 149 HoFH patients LDL-C lowering of lomitapide could 
increase median life expectancy by 11.6 years and delay time to the first major cardiovascular 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 36 of 111 
C O N F I D E N T I A L  
event (MACE) by 5.7 years (Leipold, Raal et al. 2017). Correspondingly, Blom et al. have 
shown that the annualised MACE rates in HoFH patients treated with mipomersen, lomitapide 
and evolocumab were 11.4%, 2.0%, and 2.1% versus 26.1% in the pre-mipomersen exposure 
cohort of the mipomersen study (Blom, Cuchel et al. 2018). Of note, HoFH in patients in the 
lomitapide cohort was more severe as evidenced by a higher mean Baseline LDL-C value of 
336 mg/dL and a Baseline CVD rate of 93%. 
2.6.3 
Known and Potential Risks 
Inhibition of MTP is expected to cause accumulation of triglycerides in intestinal mucosa and 
hepatocytes, and malabsorption of fat and fat-soluble vitamins from the diet. Major histological 
findings from non-clinical toxicological experiments showed increased incidences of lipid 
vacuolation in small intestinal mucosal epithelium and hepatocytes.  
However, increased incidences of liver and small intestine tumours in mice were not noted in 
clinical studies and may not be expected to occur in clinical use due to the lack of genotoxicity, 
immunotoxicity, or other cellular injury associated with high levels of lomitapide exposure. In 
addition, unphysiological factors in the non-clinical experiments such as vitamin E depletion 
and severe hypocholesterolaemia will be prevented by administering dietary supplements (see 
Section 6.3 Dietary Supplements) and by closely monitoring LDL-C levels (see Section 1.2 
Flow Chart of Study and Follow-up).  
In the pivotal phase III study, 10 of 29 patients experienced elevations of ALT and/or AST 
>3 x ULN once or more during the study. Four of these patients exhibited ALT increases 
>5 x ULN. No patient discontinued treatment permanently due to LFT elevations and all 
elevations were managed either by dose reduction or temporary interruption of lomitapide as 
per protocol. Of note, 3 of 4 patients with LFT elevations >5 x ULN reported consuming 
quantities of alcohol higher than those allowed per protocol. No patient experienced elevations 
in bilirubin or AP levels (Cuchel, Meagher et al. 2013).  
During the extension study, 4 of 19 (21.1%) patients experienced a ≥5 x ULN increase in ALT 
or AST. Increases ≥5 x ULN were typically associated with concomitant use of CYP 3A4 
inhibitors or excess alcohol use. These events were successfully managed by discontinuing 
offending medication, lomitapide dose reductions or suspension, and reintroduction of 
lomitapide after normalisation of transaminases (Blom, Averna et al. 2017). 
Management of elevated hepatic aminotransferases in this study is carefully specified by an 
algorithm in Section 7.3.2 Dose Modification, Interruption or Discontinuation for Adverse 
Events. In addition, an independent DSMB will provide oversight of patient safety (see 
Section 4.3 Data Safety Monitoring Board).  
Due to the potential for lomitapide to cause elevations in ALT/AST levels, it should be used in 
caution in patients who consume alcohol. Further, caution should be exercised when 
lomitapide is co-administered with agents known to be hepatotoxic (see Section 7.6.3 
Non-Permitted Concomitant Medication, Food or Substances) and is contraindicated in 
patients with moderate to severe hepatic impairment and those with active liver disease, 
including patients with unexplained persistent abnormal liver function tests (see Section 5.2 
Exclusion Criteria). 
In the pivotal phase III study, hepatic fat was measured non-invasively using NMR. Mean 
hepatic fat content of 20 evaluable patients was 1.0% at Baseline, 8.6% at Week 26, 5.8% at 
Week 56 and 8.3% at Week 78 (Cuchel, Meagher et al. 2013). In the extension study, 
18 patients had ≥1 assessment of hepatic fat by NMR after Baseline. Median hepatic fat 
increased from 0.7% at Baseline to 6.5% at Week 78 and was 7.7%, 10.3%, and 10.2% at 
Weeks 126, 174, and 246, respectively (Blom, Averna et al. 2017). 
Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with 
lomitapide. For this reason, hepatic fat content will be measured 4 weeks after EoT in patients 
who opt not to participate in or are unsuitable for the Expanded Access Programme (EAP; 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 37 of 111 
C O N F I D E N T I A L  
<18 years of age)/opt not to transition to commercial product (≥18 years of age; see 
Section 8.1.2 Safety Assessments). 
The most common AEs in the phase III study included abdominal pain or discomfort, nausea, 
vomiting, dyspepsia, diarrhoea, and constipation. Diarrhoea was the most common symptom. 
This finding is expected since MTP inhibition is known to cause fat malabsorption and 
steatorrhea. As the occurrence and severity of GI AEs associated with the use of lomitapide 
decreases in the presence of a low-fat diet, patients will start to follow a diet supplying <20% 
of energy from fat or <30 g fat, whichever is the lesser amount at the Start of the Run-in Period, 
and will continue this diet until the EoT or through the administration of lomitapide in the EAP 
(<18 years of age) or during administration of commercial lomitapide (≥18 years of age; see 
Section 8.6.1 Diet Instructions and Diet Records).  
In the pivotal phase III study, decreased body weight was reported as an AE in 6 of 29 patients. 
All cases were assessed as mild to moderate in severity, non-serious and none led to study 
drug discontinuation. The combination of gastrointestinal (GI) symptoms (e.g., diarrhoea, 
nausea), fat malabsorption, and adherence to a strict fat-restricted diet, may result in a calorie 
deficit relative to daily requirements. Appropriate dietary supervision and monitoring is an 
important component to improve GI tolerability and the maintenance of an adequate diet to 
avoid unintended weight loss. In this study, weight will be measured at each visit after the 
Run-in Period and patients of normal or below normal body weight based on gender and 
age-specific World Health Organization (WHO) growth charts with weight loss >3% since the 
last visit will be instructed by the dietitian on how to increase caloric intake based on individual 
needs (see Section 8.6.1 Diet Instructions and Diet Records). Patients with below normal body 
weight any time during the study who continue to lose weight while on study medication despite 
all appropriate measures taken to correct for the weight loss and who are deemed to be at 
clinical risk in the judgment of the treating investigator should discontinue study medication 
and should be followed until an acceptable stable weight is reached as judged by the 
investigator (see Section 7.3.2 Dose Modification, Interruption or Discontinuation for Adverse 
Events).  
MTP inhibition with lomitapide is likely to cause a deficiency in fat-soluble vitamins, particularly 
vitamin E. Therefore, all patients in this study will receive daily oral supplementation with 
vitamin E (200 IU for patients 5 to 8 years of age, 400 IU for patients 9 to ≤17 years of age) 
and an EFA supplement containing approximately 200 mg linoleic acid, 210 mg ALA, 110 mg 
EPA, and 80 mg DHA (see Section 6.3 Dietary Supplements). 
The SPC (included in the Lojuxta® SPC in lieu of an Investigator’s Brochure [IB]; see 
Section 18.1 Source Documents) provides guidance in key areas to minimise risk to patients 
during treatment with lomitapide, which is reflected in the design of this study. Use of lomitapide 
in patients with moderate or severe hepatic impairment, active liver disease, or pregnancy is 
contraindicated (see Section 5.2 Exclusion Criteria). Contraindications also include 
co-administration with strong or moderate inhibitors of CYP 3A4 and co-administration with 
doses of simvastatin >40 mg (see Section 7.6.3 Non-Permitted Concomitant Medication, Food 
or Substances). In the presence of atorvastatin (a weak CYP 3A4 inhibitor), lomitapide should 
be taken 12 hours apart. Since patients will be required to remain on their concomitant LLT 
(including LA when applicable) established during the 6-week Run-in Period during the Efficacy 
Phase of the study through Week 24±3 days, a potential concomitant treatment with 
atorvastatin will remain unchanged during the Efficacy Phase, when lomitapide dosing will 
start. If atorvastatin is given concomitantly, it should be administered in the morning to separate 
it from lomitapide dosing by 12 hours. If during the 80-week Safety Phase it is not possible to 
administer atorvastatin and lomitapide 12 hours apart, the lomitapide dose should be reduced 
by half. After a minimum period of 4 weeks following dose reduction the patient can be 
re-challenged with a higher dose of lomitapide once these issues resolve (i.e., if atorvastatin 
can be administered 12 hours apart or if atorvastatin is discontinued), but the dose during the 
Safety Phase cannot exceed the MTD established during the Efficacy Phase unless eligibility 
for exceptional dose escalation is met (described in Section 7.3.1 Dose Escalation, Dose 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 38 of 111 
C O N F I D E N T I A L  
Reduction and Re-challenge). For patients on a stable maintenance dose of lomitapide who 
receive any other weak CYP 3A4 inhibitor, the dose of the medications should be separated 
by 12 hours (see Section 7.3.3 Dose Modification for Concomitant Medication). Use in patients 
with known significant or chronic bowel disease is also contraindicated since MTP inhibition is 
known to cause fat malabsorption and steatorrhea. Use in patients with rare hereditary 
problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose 
malabsorption, 
are 
contraindicated 
in 
accordance 
with 
EU 
guidance 
(EC Volume 3B Guidelines, Medicinal Products for Human Use, Safety, Environment and 
Information: Excipients in the Label and Package Leaflet of Medicinal Products for Human 
Use, July 2003) since the drug product contains lactose (see Section 5.2 Exclusion Criteria). 
Hepatic aminotransferase levels must be determined prior to initiating therapy, and then 
monitored prior to each dose escalation, and regularly during treatment (see Section 1.2 Flow 
Chart of Study and Follow-up). In the event that hepatic aminotransferases become elevated, 
a detailed algorithm for dose adjustment or treatment discontinuation is provided (see 
Section 7.3.2 Dose Modification, Interruption or Discontinuation for Adverse Events). This 
algorithm is based on the approach agreed with the DSMB hepatologist that was used 
successfully in the pivotal phase III study and is consistent with the FDA’s draft guidance Drug-
Induced Liver Injury: Premarketing Clinical Evaluation, October 2007. Dietary advice, including 
fat content (see Section 8.6.1 Diet Instructions and Diet Records) and supplementation with 
vitamin E and essential fatty acids (see Section 6.3 Dietary Supplements), is also specified, 
and dosing is escalated gradually to minimise GI side effects and allow for regular hepatic 
aminotransferase determination (see Section 7.2 Treatment Schedule). These elements of 
safety monitoring are designed to allow the optimum individualised dose to be selected for 
each patient in order to maximise the benefit of LDL-C reduction, ensure compliance with 
treatment, and avoid AEs. 
2.6.4 
Benefits and Risks Conclusions 
Patients with HoFH deal with a life-threatening disease every day in the absence of effective 
treatment to reduce their LDL-C to target levels. For the first time, it is now feasible to reach 
target LDL-C goals and maintain these levels during chronic treatment. LDL-C lowering of 
lomitapide was modelled to increase median life expectancy of HoFH patients by 11.6 years 
and delay time to the first MACE by 5.7 years (Leipold, Raal et al. 2017). 
Lomitapide treatment is a major advance in the treatment of a devastating disease through 
modification of a risk factor that is currently uncontrolled by available treatment interventions, 
supporting a favourable benefit-risk assessment for its use in this high-risk patient population.  
In this study, lomitapide will be carefully titrated to the MTD based upon safety, tolerability and 
LDL-C levels and safety will be monitored by an independent DSMB (see Section 4.3 Data 
Safety Monitoring Board). Therefore, the benefits will outweigh the risks. 
2.7 
Rationale of the Study and of the Study Design 
Lomitapide has been approved for use in adult patients with HoFH in the European Union (EU) 
and European Economic Area (EEA), United States of America (USA), Israel, Argentina, 
Canada, Colombia, and Japan. This study is designed to determine if lomitapide is effective 
and can be safely administered to paediatric patients with HoFH. If the efficacy and safety so 
far observed in adults is confirmed in paediatric patients, the potential exists to significantly 
lower LDL-C levels in paediatric patients with HoFH. Furthermore, the lower LDL-C levels may 
reduce atherosclerosis progression and would be expected to benefit these paediatric patients 
with HoFH. 
A single-arm, non-comparator design has been selected due to the rarity of the disease and 
because the evaluation of safety variables such as growth and sexual maturation requires 
longer term observation than would not be feasible in the context of a placebo-controlled study.  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 39 of 111 
C O N F I D E N T I A L  
In addition, similar efficacy cannot reasonably be assumed in a 2-arm design with standard of 
care LLT including LA as comparator, and, as a result, randomisation of these very high risk 
patients to placebo for longer than 6 months would not be acceptable.  
Finally, the high incidence of GI AEs expected in lomitapide-treated patients and the 
corresponding inability to keep patients and physicians blinded to treatment would introduce 
an assessment bias. 
To mitigate the disadvantages of a single-arm design, the study includes a Run-in Period of at 
least 6 weeks during which current LLT (including LA, when applicable) will be stabilised to 
establish Baseline levels allowing each patient to serve as his/her own control. Patients will 
also remain on stable LLT (including LA, when applicable) during the Efficacy Phase of the 
study through Week 24±3 days. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
Evaluate the efficacy of lomitapide as defined by the percent change in LDL-C at the MTD at 
Week 24±3 days compared to Baseline when added to stable LLT (including LA when 
applicable) in paediatric patients (5 to ≤17 years of age) with HoFH. 
3.2 
Secondary Objectives 
• Evaluate the efficacy of lomitapide in paediatric HoFH patients as assessed by: 
− Percent change from Baseline at Week 24±3 days in lipid parameters, including total 
cholesterol (TC), non high-density lipoprotein cholesterol (Non-HDL-C), very low-density 
lipoprotein cholesterol (VLDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)], and 
apolipoprotein B (apo B). 
− Percent change from Baseline in TC, non-HDL-C, LDL-C, TG, VLDL-C, Lp(a), and apo B 
at all other time-points through Week 104±1 week. 
− Change in LLT and LA from Week 24±3 days through Week 104±1 week. 
− Number (percent) of patients achieving the EAS recommended target LDL-C of 
<135 mg/dL (3.5 mmol/L) at Week 24±3 days and at any time on study. 
3.3 
Safety Objectives 
• Evaluate the long-term safety and tolerability of lomitapide in paediatric HoFH patients as 
assessed by: 
− Incidence in reported AEs and in clinically significant abnormal findings of physical 
examinations including weight and BMI, electrocardiogram (ECG), standard of care 
echocardiography (if available), vital signs, pulmonary function tests (PFT), and 
laboratory parameters including hepatic and renal function tests. 
− Effects on growth, bone health and bone age will be assessed using both measurements 
of children’s height and growth charts to track age-appropriate progress at Screening 
and from Baseline at every visit through Week 104±1 week and/or at EoT, together with 
analysis of Vitamin D and K levels at Screening, Baseline, Week 24±3 days, 
Week 56±3 days, Week 80±1 week, Week 104±1 week and/or at EoT (and at Week 108 
for patients who opt not to participate in or are unsuitable for the EAP [<18 years of 
age]/opt not to transition to commercial product [≥18 years of age]). 
− Potential effects on maturation, reproductive development, gonadotropins, and variables 
of the pituitary-adrenal axis at Screening, Baseline, Week 56±3 days, Week 104±1 week 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 40 of 111 
C O N F I D E N T I A L  
and/or at EoT will be analysed; potential effects on the levels of sex steroids will be 
analysed for patients assessed as Tanner Stage ≥2. 
− Lipid accumulation in the liver as measured by nuclear magnetic resonance (NMR) 
imaging or echography (i.e., ultrasound scan) at Baseline and at Week 24±3 days, 
Week 56±3 days, and at Week 104±1 week (for patients who opt not to participate in or 
are unsuitable for the EAP [<18 years of age)/opt not to transition to commercial product 
[≥18 years of age], lipid accumulation in the liver will be measured at Baseline, at 
Week 24±3 days, Week 56±3 days, and at Week 108). All patients will undergo NMR 
imaging unless it is contraindicated or not feasible (e.g., due to the need for sedation or 
general anaesthesia in very young or anxious patients). In this case, ultrasound scans 
will be used at the discretion of the investigator. 
3.4 
Exploratory Objectives 
• Evaluate exploratory assessments of: 
− Change from Baseline at Week 56±3 days and Week 104±1 week in mean carotid 
intima-media thickness (CIMT, mandatory) and flow-mediated dilatation (FMD, 
whenever possible). 
− The resolution and/or regression of pre-existing xanthomas at Week 56±3 days and at 
Week 104±1 week. 
− Changes from Baseline through Week 24±3 days in cholesterol and triglyceride content 
of VLDL, intermediate density lipoprotein (IDL), LDL and HDL, particle number and size 
of VLDL, LDL, and HDL as well as particle number of their respective lipoprotein 
subclasses (large, medium, and small) as assessed based on 2D NMR (Liposcale® Test) 
of pharmacokinetics (PK) samples. 
3.5 
Palatability Objective 
• Assess the palatability of the study medication using a 5-point facial hedonic scale anchored 
with descriptors, to record the children’s assessment of palatability in terms of overall liking. 
• The parent(s)/legal guardian(s) interpretation of the child’s reaction/facial expression will be 
used to determine whether they find lomitapide “pleasant”, “unpleasant” or are “not sure”. 
• Ease of administration of the study medication and dietary supplements by the 
parent(s)/legal guardian(s) will be assessed using the following question at each visit during 
the treatment phase: “Do you sometimes have problems in giving the medication to your 
child because he/she refuses to take it or throws it up immediately after taking it? (Yes/No).” 
3.6 
Pharmacokinetic Objective 
• Evaluate the PK of lomitapide in paediatric HoFH patients through sparse blood sampling. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 41 of 111 
C O N F I D E N T I A L  
4 
INVESTIGATIONAL PLAN 
All references to “the investigator” throughout this document refer to “the investigator or a 
delegated sub-investigator”. 
4.1 
Study Endpoints 
4.1.1 
Primary Endpoint 
• Percent change from Baseline in LDL-C at Week 24±3 days. 
4.1.2 
Secondary Endpoints 
• Percent change from Baseline at Week 24±3 days for the following lipid parameters: TC, 
Non-HDL-C, VLDL-C, TG, Lp(a), and apo B. 
• Percent change from Baseline at all other time points through Week 104±1 week for the 
following lipid parameters: LDL-C, TC, Non-HDL-C, VLDL-C, TG, Lp(a), and apo B. 
• Total number and percent of patients with a change from Baseline in LLT and LA from 
Week 24±3 days through Week 104±1 week. 
• Total number and percent of patients achieving the EAS recommended target LDL-C of 
<135 mg/dL (3.5 mmol/L) in paediatric HoFH patients at Week 24±3 days and at any time 
on study. 
4.1.3 
Safety Endpoints 
• Incidence of AEs overall and by severity, and relatedness. 
• Physical examinations including regular measurements of height, weight, and BMI. 
• Sexual maturation (Tanner staging). 
− In patients with Tanner Stage ≥2: Change from Baseline in sex hormones (serum 
testosterone and serum oestradiol).  
• 12-Lead safety ECG (read locally), standard of care echocardiography (if available), vital 
signs and blood pressure. 
• PFT. 
• Laboratory tests: 
− Standard haematology (complete blood count [CBC]) and clinical chemistry panels).  
− Liver function tests: ALT, AST, gamma-glutamyl transferase (GGT), alkaline 
phosphatase (AP), total bilirubin, and serum albumin. 
− High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I). 
− Creatinine kinase (CK). 
− Serum lipase. 
− Serum levels of essential fatty acids (EFA): Linoleic acid, alpha linoleic acid (ALA), 
eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and 
eicosatrienoic acid. 
− Serum concentrations of fat-soluble vitamins: Vitamin A (retinol), vitamin E (alpha 
tocopherol), ratio of vitamin E to total lipids (total cholesterol plus fasting triglycerides), 
and vitamin D (25-hydroxy-D). Levels of vitamin K will be assessed indirectly by 
measuring total and uncarboxylated levels of serum osteocalcin. (Bone health will be 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 42 of 111 
C O N F I D E N T I A L  
assessed indirectly using growth to track age-appropriate progress, and measurement 
of 25-hydroxy-D as well as total and uncarboxylated osteocalcin levels.) 
− Pituitary-adrenal hormone levels (thyroid stimulating hormone [TSH], follicle stimulating 
hormone [FSH], luteinising hormone [LH], adrenocorticotrophic hormone [ACTH], and 
morning serum cortisol).  
− Urinalysis. 
• Lipid accumulation in the liver as measured by NMR imaging or echography (i.e., ultrasound 
scan) at Baseline and at Week 24±3 days, Week 56±3 days, and at Week 104±1 week (for 
patients who opt not to participate in or are unsuitable for the EAP (<18 years of age)/opt 
not to transition to commercial product (≥18 years of age), lipid accumulation in the liver will 
be measured at Baseline and at Week 24±3 days, Week 56±3 days, and at Week 108). All 
patients will undergo NMR imaging unless it is contraindicated or not feasible (e.g., due to 
the need for sedation or general anaesthesia in very young or anxious patients). In this 
case, ultrasound scans will be used at the discretion of the investigator. 
4.1.4 
Exploratory Endpoints 
• Percent change from Baseline at Week 56±3 days and Week 104±1 week in CIMT and 
FMD. 
• Total number and percent of patients with resolution and/or regression of pre-existing 
xanthomas at Week 56±3 days and at Week 104±1 week. 
• Changes from Baseline through Week 24±3 days in cholesterol and triglyceride content of 
VLDL, IDL, LDL and HDL, particle number and size of VLDL, LDL, and HDL as well as 
particle number of their respective lipoprotein subclasses (large, medium, and small) as 
assessed based on 2D NMR (Liposcale® Test) of PK samples at Week 4±3 days, 
Week 8±3 days, 
Week 12±3 days, 
Week 16±3 days, 
Week 20±3 days 
and 
at 
Week 24±3 days. 
4.1.5 
Palatability Endpoints 
• Total number and percent of patients for each response of palatability: 
− 
Able to swallow capsule (including food media responses if used). 
− 
Palatability rating (using a 5-point facial hedonic scale). 
− 
Parent/guardian interpretation of child’s reaction/facial expression (using a 3-point 
scale). 
− 
Parent/guardian experience problems in giving medication to child because they refuse 
to take or throw up immediately after taking. 
− 
Parent/guardian experience problems in giving dietary supplement to child because 
they refuse to take or throw up immediately after taking. 
4.1.6 
Pharmacokinetic Endpoint 
• The PK data from this study will be incorporated into an existing population PK model in 
adult HoFH patients. 
4.2 
Overall Study Design 
This is a single-arm, open-label, multi-centre phase III study to evaluate the efficacy and 
long-term safety of lomitapide in paediatric patients with HoFH receiving stable LLT (including 
LA, when applicable). Each patient will participate for up to 120 weeks (about 2.5 years) in the 
study (see Figure 3).  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 43 of 111 
C O N F I D E N T I A L  
4.2.1 
Study 
The study will consist of 5 periods (see Figure 3):  
1. 
Screening Period (starting at Week -12, i.e., ≤12 weeks prior to Baseline for up to 
6 weeks). 
2. 
Stratified Enrolment and Start of Run-in Period (starting at minimum at Week -6, i.e., 
6 weeks prior to Baseline for a minimum of 6 weeks): 
• Enrolment will be stratified to ensure approximately equal numbers of patients in the 
following age groups: 5 to 10 years, 11 to 15 years, and 16 to ≤17 years (with 
≥8 patients in any individual age group). 
• Patients must be stabilised on current LLT (including LA, when applicable) and 
established on a diet supplying <20% of energy (calories) from fat or <30 g fat, 
whichever is the lesser amount. 
• Daily supplementation with vitamin E (200 international units [IU] for patients 5 to 
8 years of age, 400 IU for patients 9 to ≤17 years of age) and an EFA supplement 
containing approximately 200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg 
DHA starting at Week -2. 
3. 
Efficacy Phase (starting at Baseline, i.e., Day [D] 0 for 24 weeks±3 days): 
• Approximately 45 paediatric patients with HoFH will be treated with lomitapide given 
orally, added to their current, stable LLT (including LA, when applicable) established 
during the Run-in Period. 
• Assuming a withdrawal rate of approximately 33% by Week 24±3 days, this would 
result in 30 evaluable patients at Week 24±3 days (with ≥8 patients in any individual 
age group). 
• After stabilisation of the patient on his/her current MTD of LLT (including LA, when 
applicable) during the 6-week Run-in Period, treatment with lomitapide will be started 
as an add-on therapy on D0 of the Efficacy Phase. 
• Dosing will be initiated at the recommended starting dose and escalated to the 
maximum dose as applicable to the age groups based upon safety and tolerability in 
addition to LDL-C values (see Section 7.2 Treatment Schedule and Table 2). 
• The first dose of study medication will be administered at the study site on D0. 
• During the 24-week Efficacy Phase, patients will be required to remain on the stable 
LLT regimen (including LA, when applicable) established during the 6-week Run-in 
Period 
4. 
Safety Phase (starting at Week 24±3 days for 80±1 weeks) 
• Patients will enter the 80-week Safety Phase after the Week 24±3 days assessments 
have been completed. Each patient will continue receiving the MTD of lomitapide 
he/she achieved during the Efficacy Phase (unless criteria is met for reducing or 
increasing the dose) for an additional 80±1 weeks in the Safety Phase. 
• If after Week 24±3 days both the investigator and the sponsor consider a patient 5 to 
15 years of age to be eligible for further escalation of the lomitapide dose beyond the 
maximum recommended dose by the respective age group, the lomitapide dose can 
be increased to an extent defined by the investigator after consultation with the sponsor 
based on individual safety, efficacy, and concomitant LLT criteria. If the patient tolerates 
this new dose for ≥4 weeks, then this will be considered the new MTD. 
• If after Week 24±3 days, a patient has crossed over into the next age category, the 
study medication can be escalated to the maximum dose applicable for the new age 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 44 of 111 
C O N F I D E N T I A L  
category. If the patient tolerates this new dose for ≥4 weeks, then this will be considered 
the new MTD. 
• During the 80-week Safety Phase, the lomitapide dose can be reduced from the MTD 
due to tolerability or safety issues, and the patient can be re-challenged after a 
minimum period of 4 weeks following dose reduction with a higher dose of lomitapide 
once these issues resolve, but the dose during the Safety Phase cannot exceed the 
MTD established during the Efficacy Phase unless eligibility for exceptional dose 
escalation described above is met. 
• Adjustments to background LLT (including LA, when applicable) will be allowed at the 
discretion of the investigator.  
5. 
Follow-up (starting at Week 104±1 week for 4 weeks): 
• At Week 104±1 week, eligible patients who complete the study per protocol and are 
<18 years of age may choose to enter the EAP. Patients ≥18 years of age may opt to 
transition to commercial product under the approved product label for adults. For both 
the patient groups, a follow-up phone call will be conducted at Week 108±1 week to 
monitor safety including AE and concomitant medication reporting.  
• For patients who opt not to participate in or are unsuitable for the EAP, or patients 
≥18 years of age who opt not to transition to commercial product will discontinue 
lomitapide treatment at Week 104±1 week and enter a 4-week Follow-up period during 
which they will remain on concomitant LLT (including LA, when applicable). These 
patients will then attend in person for a Week 108±1 week visit. 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 45 of 111 
C O N F I D E N T I A L  
Figure 3 
Design of Study 
 
 
AE = adverse event; ALA = alpha-linoleic acid; DHA = docosahexaenoic acid; EFA = essential fatty acids; EPA = eicosapentaenoic acid; LA = lipoprotein apheresis; 
LDL-C = low-density lipoprotein cholesterol; LLT = lipid-lowering therapy; MTD = maximum tolerated dose 
1. Stabilise current LLT (including LA, when applicable), establish diet <20% energy from fat or <30 g fat, whichever is the lesser amount, dietary supplementation from Week -2 
(daily 200 IU [5 to 8 years of age] 400 IU [≥9 years of age] vitamin E and EFA supplement [approx. 200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA]). 
2. During the 24-week Efficacy Phase, patients will be required to remain on the stable LLT regimen (including LA, when applicable) established during the 6-week Run-in Period.  
3. Based on safety, tolerability and efficacy parameters. 
4. Adjustments to background LLT (including LA, when applicable) will be allowed at the discretion of the investigator. 
5. Dose adjustment rules apply. 
6. Eligible patients who complete the study per protocol at Week 104 and are <18 years of age may choose to enter the Expanded Access Programme. Patients ≥18 years of age 
may opt to transition to commercial product under the approved product label for adults. For both these patient groups, a follow-up phone call will be conducted at Week 
108±1 week to monitor safety including AE and concomitant medication reporting. Patients who opt not to participate in or are unsuitable for the Expanded Access Programme, 
or patients ≥18 years of age who opt not to transition to commercial product will discontinue lomitapide treatment at Week 104±1 week and enter a 4-week Follow-up period 
during which they will remain on concomitant LLT (including LA, when applicable). These patients will attend in person for a Week 108±1 week visit. 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 46 of 111 
C O N F I D E N T I A L  
4.2.2 
End of Study 
The End of Study is defined as completion of the last visit or assessment for the last patient. 
4.3 
Data Safety Monitoring Board 
An independent DSMB will be assigned to periodically review and evaluate study data for 
participant safety and to advise for continuation, modification or discontinuation in individual 
patients and of the study. Interim safety data reviews may be performed by the DSMB at their 
discretion, at any time, on an ‘as needed’ basis according to ongoing study results. 
The DSMB will have an initial organisational meeting at which time the composition, activities, 
and responsibilities of the DSMB will be detailed in a Charter as agreed upon by the sponsor 
and the DSMB members. The DSMB will be comprised of at least 3 members who are not 
otherwise involved in the conduct of the study, at least 1 of whom will be a statistician. The 
DSMB will meet at least 3 times during the conduct of the study.  
The DSMB in consultation with the sponsor will have the authority to stop the study for any 
reason including, but not limited to, unacceptable safety risks. If a patient discontinues 
treatment permanently due to a Hy’s law case or comparable signs of liver toxicity irrespective 
of origin, the DSMB will initiate an immediate recruitment stop as an urgent safety measure 
and will assess individual benefits and risks for the patients being treated with study medication 
regarding further therapy. 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
A patient will be eligible for study participation only if all of the following criteria apply: 
1. 
Male and female patients aged 5 to ≤17 years with HoFH as defined by any of the following 
criteria recommended by the Consensus Panel on Familial Hypercholesterolaemia of the 
EAS (Cuchel, Bruckert et al. 2014): 
a. 
Genetic confirmation of 2 mutant alleles at the LDLR, apo B, PCSK9, or LDLRAP1 
gene locus OR 
b. 
An untreated LDL-C >500 mg/dL (13 mmol/L) or treated LDL-C ≥300 mg/dL 
(8 mmol/L) together with either 
− 
Cutaneous or tendon xanthoma before age 10 years or  
− 
Untreated LDL-C levels consistent with heterozygous FH in both parents 
2. 
Baseline LDL-C on LLT (Cmax of LDL-C immediately prior to LA, if applicable) of either: 
a. 
>160 mg/dL (4.1 mmol/L, no documented CVD) or 
b. 
>130 mg/dL (3.4 mmol/L, established CVD defined as aortic valve disease and/or 
coronary atherosclerosis) 
3. 
Body weight ≥15 kg or BMI and height both >10th percentile according to WHO Growth 
Charts for Boys and Girls 5 to 19 Years of Age (see Appendix 4 WHO Growth Charts). 
4. 
Patient and/or his/her legal representative has/have been informed, has/have read and 
understood the patient information/informed consent form, and has/have given written 
informed assent/consent. 
5. 
Patient and/or his/her legal representative must be able and willing to follow study 
procedures and instructions, particularly that: 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 47 of 111 
C O N F I D E N T I A L  
a. 
LLT (including LA when applicable) must be stable for at least 6 weeks prior to 
Baseline (Run-in Period) and remain stable through Week 24±3 days (end of Efficacy 
Phase). 
b. 
The patient must be compliant with both the low-fat diet supplying <20% of energy 
(calories) from fat or <30 g fat, whichever is the lesser amount starting at the 
beginning of the Run-in Period and the dietary supplement regimen starting at 
Week -2 of the Run-in Period, both continuing until completion of the study (and during 
the EAP/administration of commercial product, when applicable). 
6. 
Postmenarchal female adolescents must be willing to use highly effective methods of birth 
control that, alone or in combination, result in a low failure rate (i.e., <1% per year) when 
used consistently and correctly (e.g., implant, injectable, combined oral contraceptive, 
intrauterine contraceptive device, sexual abstinence, vasectomy or vasectomised partner) 
during participation in the study (and at least 4 weeks thereafter). Postmenarchal female 
adolescent patients taking oestrogen-based oral contraceptives should be advised that 
diarrhoea and/or vomiting may reduce hormone absorption. In case of protracted or severe 
diarrhoea and/or vomiting lasting more than 2 days, the investigator should advise 
according to national practice, which additional contraceptive measures (such as sexual 
abstinence, barrier methods) should be used for 7 days after resolution of symptoms. 
7. 
Patient must be in stable physical and mental health at Screening. 
5.2 
Exclusion Criteria 
A patient will not be eligible to participate in this study, if any of the following criteria apply: 
1. 
Other 
forms 
of 
primary 
hyperlipoproteinaemia 
and 
secondary 
causes 
of 
hypercholesterolaemia (e.g., nephrotic syndrome, hypothyroidism). 
2. 
Contraindications for the use of lomitapide according to section 4.3 of the Summary of 
Product Characteristics (SPC included in the Lojuxta® SPC in lieu of an IB; see 
Section 18.1 Source Documents), such as hypersensitivity to the active substance or to 
any of the excipients listed in Section 6.1 of the SPC, known significant or chronic 
inflammatory bowel disease or malabsorption. 
3. 
Moderate (Child-Pugh B, see Appendix 1 Child-Pugh Score) or severe hepatic impairment 
(Child-Pugh C), active liver disease and/or abnormal liver function tests at Screening (AST 
or ALT >1.5 x ULN and/or total bilirubin >1.5 x ULN in the absence of Gilbert’s syndrome 
or AP >1.5 x ULN [based on appropriate age and gender normal values]).  
4. 
Serum CK >2 x ULN. 
5. 
Chronic renal insufficiency with glomerular filtration rate (GFR) <70 mL/min/1.73 m2 
calculated using the Schwartz formula (see Appendix 2 Schwartz Formula). 
6. 
Uncontrolled hypertension (defined as mean systolic and/or diastolic blood pressure ≥95% 
of normal for age and sex) despite medical therapy. 
7. 
New York Heart Association (NYHA) Class III or IV congestive heart failure. 
8. 
Precocious/delayed puberty or endocrine disorder affecting growth (e.g., hypothyroidism, 
premature adrenarche). 
9. 
History of drug abuse within the last 3 years or habitual alcohol consumption (defined as 
>1 ounce [28 g] of liquor or 4-ounce glass [113 g] of wine, or the equivalent, ≥3 times per 
week). 
10. Life expectancy predicted to be <5 years. 
11. History of a non-skin malignancy (with the exception of cervical cancer in situ) within 
3 years prior to enrolment. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 48 of 111 
C O N F I D E N T I A L  
12. Treatment with any Investigational Medicinal Product (IMP) within 6 months or 5 times the 
terminal half-life of the corresponding IMP, whichever is longer, before Screening (Visit 1).  
13. Patient is a dependent of the sponsor, of the investigational team or his/her immediate 
family. 
14. Pregnant or nursing women. 
6 
STUDY MEDICATION 
6.1 
Description of the Investigational Product 
6.1.1 
Formulation, Packaging and Labelling 
The investigational product will be supplied in high-density polyethylene bottles with polyester, 
aluminium foil, and cardboard induction seals and child-resistant polypropylene screw caps. It 
will be packed and labelled according to applicable regulatory requirements. 
Lomitapide is prepared as a crystalline methanesulfonate salt. The investigational product will 
be administered orally in opaque, hard gelatin capsules. Four bottle types will contain 
28 capsules each by 2 mg, 5 mg, 10 mg, and 20 mg strength. Each hard capsule contains 
lomitapide mesylate equivalent to its strength and the following inactive excipients: 
pregelatinised starch (maize), sodium starch glycolate (Type A), microcrystalline cellulose, 
lactose monohydrate, colloidal, anhydrous silica, and magnesium stearate.  
Please refer to the Lojuxta® SPC in lieu of an IB and to the Investigational Medicinal Product 
Dossier for the 2 mg lomitapide hard capsules regarding the excipients and colours of the 
capsule shells, which differ by strength (see Section 18.1 Source Documents). Further details 
regarding physical, chemical, and pharmaceutical properties and concerning the formulation, 
respectively are described in the EPAR Lojuxta® dated 30 May 2013, Section 2.2.  
Please refer to Section 2.2 Investigational Product for further details regarding the mechanism 
of action and therapeutic indication of lomitapide. 
6.1.2 
Storage and Stability 
Keep the bottle tightly closed in order to protect from moisture. Store below 30°C. 
6.1.3 
Drug and Dietary Supplements Accountability 
A sufficient number of lomitapide bottles will be provided to sites in bulk at appropriate intervals 
depending on the phase of the study and accrual of patients. Dietary supplements will be 
sourced locally, where possible (see Section 6.3 Dietary Supplements). The investigator, or 
the person designated by the investigator, will be responsible for dispensing the appropriate 
bottle or combination of bottles to a patient at each study visit. At each site, the investigator, or 
the person designated by the investigator, will be responsible for keeping accurate records of 
study medication accountability comprising the receipt, the dispensing, and the return of all 
used and partially unused study medication throughout the study. The drug accountability form 
should be kept up to date and will be reviewed periodically by the study monitor. Patients will 
be asked to keep all used and partially unused bottles of study medication and return them to 
the site during the scheduled visits. For drug accountability, the number of used and partially 
unused bottles and unused capsules will be counted. Compliance with dietary supplements is 
discussed with the patients at each visit and is documented in the electronic Case Report Form 
(eCRF). It is also verified by reviewing the patient Diet Records (see Section 8.6.1 Diet 
Instructions and Diet Records). After drug accountability is completed, all unused or partially 
used study medication may be returned to the sponsor or disposed of by the study site. The 
study monitor will instruct the site on the return of all study medication. A final inventory of the 
total amount of study medication and dietary supplements at each study site against the 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 49 of 111 
C O N F I D E N T I A L  
amount used and returned must be recorded. Inventory records must be readily available for 
inspection by the study monitor and/or auditor, and open to government inspection at any time. 
6.2 
Investigational Product Compliance 
Patients and their parents/legal guardians will be instructed to return all unused study 
medication and dietary supplements to the clinical site at the visits indicated in Section 1.2 
Flow Chart of Study and Follow-up. Site study team members will count and record the number 
of capsules remaining in each of the bottles and record this information on the eCRF. Study 
drug compliance checks will be performed at all visits during the Efficacy and Safety Phases 
of the study. 
6.3 
Dietary Supplements 
Patients will be administered daily oral supplementation with vitamin E (200 IU for patients 
5 to 8 years of age, 400 IU for patients 9 to ≤17 years of age) and an EFA supplement 
containing approximately 200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA. 
Dietary supplements will be dispensed during Visit 3 at Week -3 to Week -2 (Run-in 
Compliance), during Visit 4 at D0 (Baseline, Efficacy Phase), and at every visit thereafter until 
Visit 21 at Week 92±1 week. Please refer to Section 6.1.3 Drug and Dietary Supplements 
Accountability for dietary supplements accountability.  
7 
STUDY TREATMENT 
7.1 
Treatment Assignment, Blinding Procedure 
This is an open-label study, blinding of treatment is not applicable. 
7.2 
Treatment Schedule 
After stabilisation of the patient on his/her current MTD of LLT (including LA when applicable) 
during the 6-week Run-in Period, treatment with lomitapide will be started as add-on therapy 
on D0 of the Efficacy Phase.  
Lomitapide capsules will be provided in 4 dose strengths of 2 mg, 5 mg, 10 mg, and 20 mg. 
Dosing will be initiated at the recommended starting dose and escalated to the maximum dose 
as applicable to the age groups (see Table 2 and Figure 3) based upon safety and tolerability 
in addition to LDL-C values. 
Table 2 Lomitapide Starting Dose and Dose Escalation by Age Group 
Age Group 
(years) 
Lomitapide Dose (mg) 
D0 
Week 4 
±3 days 
Week 8 
±3 days 
Week 12 
±3 days 
Week 16 
±3 days 
Maximum 
5 to 10 
2 
2 
5 
10 
20 
20 (10, in Child-Pugh A) 
11 to 15 
2 
5 
10 
20 
40 
40 (20, in Child-Pugh A) 
16 to ≤17 
5 
10 
20 
40 
60 
60 (40, in Child-Pugh A) 
Each patient will take 1 to 3 capsule(s) once daily to achieve the doses specified in the titration 
scheme. The first dose of study medication will be administered at the study site on D0.  
As of D1, patients will self-administer (or the patient’s parent/legal guardian will administer to 
the patient) lomitapide orally, once daily, at approximately the same time each day. It is 
recommended to administer lomitapide at least 2 hours after the evening meal (e.g., at 
bedtime) with a glass of water on an empty stomach because the fat content of a recent meal 
may adversely impact GI tolerability. Patients who are unable to swallow the intact capsule(s) 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 50 of 111 
C O N F I D E N T I A L  
may open the capsule(s) and sprinkle the capsule content on 1 tablespoon of apple sauce or 
mashed banana, which are fat-free.  
In case of a missed dose, patients should be instructed to take missed doses of lomitapide 
only if they can be taken at least 12 hours prior to the next scheduled dose. Dietary 
supplements are suggested to be taken in the morning. Patients taking bile acid sequestrants 
should be reminded that they should take lomitapide 4 hours before or 4 hours after this class 
of medications. If atorvastatin is given concomitantly, lomitapide should be administered 
12 hours apart. 
7.3 
Dose Modifications and Interruptions 
7.3.1 
Dose Escalation, Dose Reduction and Re-challenge 
Dose Escalation 
Patients will be categorised according to disease severity as determined by the presence or 
absence of clinically evident CVD, which will be defined by documented aortic valve disease 
or coronary atherosclerosis at Baseline.  
Lomitapide will not be escalated, if LDL-C is less than the target threshold: 
• LDL-C is <100 mg/dL (<2.5 mmol/L) in patients without CVD at Baseline 
• LDL-C is <70 mg/dL (<1.8 mmol/L) in patients with CVD at Baseline 
For each of the 3 age groups, lomitapide dosing will escalate following the applicable dose 
titration scheme in Table 2 at Week 4±3 days, Week 8±3 days, and Week 12±3 days to the 
maximum allowable dose by Week 16±3 days or the MTD by Week 20±3 days based upon 
acceptable safety and tolerability criteria in addition to LDL-C values.  
Each dose must be tolerated for ≥4 consecutive weeks before being escalated to the next 
higher dose in stepwise increments. The MTD is defined as the highest dose of lomitapide 
through Week 24±3 days that does not result in tolerability or safety concerns. This is the 
highest dose that does not result in dose reduction, dosing interruption, or discontinuation, but 
may include a re-challenged dose level. 
Each patient will continue receiving the MTD of lomitapide he/she achieved during the Efficacy 
Phase (unless criteria is met for reducing or increasing the dose) for an additional 80±1 weeks 
in the Safety Phase (for a total treatment period of 2 years). 
If after Week 24±3 days both the investigator and the sponsor consider a patient 5 to 15 years 
of age to be eligible for further escalation of the lomitapide dose beyond the maximum 
recommended dose by the respective age group, the lomitapide dose can be increased to an 
extent defined by the investigator after consultation with the sponsor based on individual 
safety, efficacy, and concomitant LLT criteria. If the patient tolerates this new dose for 
≥4 weeks, then this will be considered the new MTD. 
If after Week 24±3 days, a patient has crossed over into the next age category, the study 
medication can be escalated to the maximum dose applicable for the new age category. If the 
patient tolerates this new dose for a minimum of 4 weeks, then this will be considered the new 
MTD. 
Dose Reduction and Re-challenge 
If a dose reduction is required, dosage will either be reduced to the previous tolerated dose or 
to an intermediate dose. Please note that only down-titrations to intermediate doses are 
allowed, dose escalations need to follow the guidance provided in Table 2. After resolution of 
the cause for dose reduction, patients may be re-challenged after a minimum period of 4 weeks 
following dose reduction with prior doses in stepwise increments based on dose escalation 
guidelines, but may not exceed the MTD established during the Efficacy Phase until 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 51 of 111 
C O N F I D E N T I A L  
Week 24±3 days, after which further increase is only possible if patients have crossed into the 
next age category or eligibility for exceptional dose escalation as described above is met.  
If the investigator determines that a patient is not tolerating any particular dose (per specified 
criterion), the investigator may request a dose reduction or a hold on the current dose until the 
next scheduled visit. Once the patient has stabilised on the reduced dose, the dose can be 
increased back to the next step again, and the patient may progress through subsequent dose 
increases at a minimum of 4-week intervals. If the patient does not tolerate the re-challenge 
dose, then the MTD is considered the reduced dose and will be the highest dose allowed for 
the remainder of the study. 
Weeks 0 through 24±3 days establish the MTD, Week 20±3 days is the last visit that the 
lomitapide dose can be increased, except when there has been a down-titration at/or after 
Week 16±3 days. Re-challenging will depend on the assessment of safety and tolerability 
criteria and the LDL-C value relative to the LDL-C goal of <135 mg/dL (3.5 mmol/L) and is at 
the discretion of the investigator except for Hy’s law cases or comparable signs of liver toxicity, 
irrespective of origin, in which no re-challenge will be allowed (see Section 7.4 Patient 
Discontinuation Criteria). 
The study medication can be escalated as a re-challenge dose during an unscheduled visit 
after the investigator consults with the study medical monitor, but any additional dose 
escalations, i.e., dose titration, must be made during a completed scheduled visit. In addition, 
a re-challenge with lomitapide will not be performed if the LDL-C is below the target threshold 
while the patient was receiving the reduced dose.  
During the 80-week Safety Phase, the lomitapide dose can be reduced from the MTD due to 
tolerability or safety issues, and the patient can be re-challenged with a higher dose of 
lomitapide once these issues resolve (after a minimum period of 4 weeks following dose 
reduction), but the dose during the Safety Phase cannot exceed the MTD established during 
the Efficacy Phase unless eligibility for exceptional dose escalation described above is met. 
Please refer to Section 7.3.2 Dose Modification and Interruption for Adverse Events for further 
details regarding dose reductions due to AEs and to Section 7.3.3 Dose Modification for 
Concomitant Medication for detailed information about dose reductions depending on 
concomitant medication. 
7.3.2 
Dose Modification, Interruption or Discontinuation for Adverse 
Events 
The investigator and/or DSMB have the authority to reduce study medication dosage or 
discontinue study medication in a patient if situations develop that, in the opinion of the 
investigator or DSMB, would compromise the patient's safety or successful participation in the 
study (see Section 4.3 Data Safety Monitoring Board and Section 7.4 Patient Discontinuation 
Criteria). In particular, modifications in dosage or discontinuation of treatment will be instituted 
if any of the situations below apply. 
HEPATOBILIARY GUIDELINES 
Dose Modification Based on Hepatobiliary Adverse Events 
If a patient matches the criteria referred to as “Hy’s law case” according to the European 
Association for the Study of the Liver (EASL) Clinical Practice Guidelines on Drug-induced 
Liver Injury (EASL 2019) and the FDA Guidance for Industry Drug-Induced Liver Injury 
Premarketing Clinical Evaluation (FDA 2009) or shows comparable signs of liver toxicity, 
irrespective of origin, treatment must be permanently discontinued and no re-challenge will be 
allowed. 
Upon the investigator’s discretion study medication will be discontinued permanently if a 
patient experiences any CTCAE Grade 3 or Grade 4 hepatobiliary AE (see Appendix 3 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 52 of 111 
C O N F I D E N T I A L  
Common Terminology Criteria for Adverse Events, Hepatobiliary Disorders), regardless of 
relationship to study drug.  
Biochemical Hepatobiliary Guidelines 
Note: The toxicity “levels” described below are different and separate from CTCAE “grades”. 
The toxicity levels do NOT correlate to CTCAE grades nor should they be used for grading 
AEs. 
If aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as 
nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in 
bilirubin ≥2 x ULN, study drug will be discontinued, the event will be reported to the DSMB by 
the sponsor (or its designee) immediately upon notification and the patient referred to a 
hepatologist for further work up. 
Level 4 Hepatotoxicity 
Level 4 Hepatotoxicity is defined as follows: 
• ALT or AST levels reach ≥10 x ULN at 1 single time point. Patients should be referred to a 
hepatologist or gastroenterologist for further work up.  
• In symptomatic patients, ALT >5 x ULN AND total bilirubin >2 x ULN on 2 separate 
occasions and at least 7 days apart. 
• AP is >5 x ULN on 2 separate occasions and at least 7 days apart. 
• Total bilirubin is >2 x ULN on 2 separate occasions and at least 7 days apart in the absence 
of Gilbert’s syndrome or haemolysis. 
Patients who experience confirmed Level 4 Hepatotoxicity will immediately interrupt study 
medication. Patients will return to the study site weekly or sooner if clinically indicated until 
resolution. Any Level 4 Hepatotoxicity will be reported to the DSMB by the sponsor (or its 
designee) immediately upon notification. 
Following evaluation by a hepatologist, a patient may resume lomitapide treatment if the 
Level 4 Hepatotoxicity is resolved, and in the opinion of the investigator, DSMB and sponsor, 
the benefit of treatment justifies any risk of recurrent toxicity. 
Level 3 Hepatotoxicity 
Level 3 Hepatotoxicity is defined as follows: 
• Patients who experience ALT or AST ≥5 x ULN on 2 separate occasions and at least 7 days 
apart. 
Patients who experience confirmed Level 3 Hepatotoxicity will immediately interrupt study 
medication. The patient will return to the clinic for repeat blood tests including AP, bilirubin and 
International normalised ratio (INR) every 7 days until the aminotransferase levels have fallen 
<3 x ULN. Once this occurs, study drug dosing may be resumed at the dose level below that 
associated with Level 3 Hepatotoxicity.  
If this dose level is tolerated without elevation of ALT or AST >3 x ULN, then this dose will be 
defined as the MTD. If aminotransferases increase ≥3 x ULN further dose reduction or 
interruption may be necessary consistent with the guidance provided in this protocol. 
Elevations in ALT or AST >3 x ULN that persist despite dose reduction or interruption for 
≥4 weeks will be reported to the DSMB by the sponsor (or its designee) immediately upon 
notification. Patients will be referred to a hepatologist for further work up. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 53 of 111 
C O N F I D E N T I A L  
Level 2 Hepatotoxicity 
Level 2 Hepatotoxicity is defined as follows: 
• Patients who experience ALT or AST 3.0 to 4.9 x ULN on 2 separate occasions and at least 
7 days apart. 
Patients who experience confirmed Level 2 Hepatotoxicity will have the dose of study 
medication reduced to the previous tolerated dose. The patient will return to the clinic for repeat 
blood tests including AP, bilirubin and INR every 7 days until the aminotransferase levels have 
fallen to <3 x ULN. Once this occurs, lomitapide dosing may be resumed at the dose level 
below that associated with Level 2 Hepatotoxicity.  
If this dose level is tolerated without elevation of ALT or AST >3 x ULN, then this dose will be 
defined as the MTD. If aminotransferases increase >3 x ULN further dose reduction or 
interruption may be necessary consistent with the guidance provided in this protocol. 
Elevations in ALT or AST >3 x ULN that persist despite dose interruption for ≥4 weeks will be 
reported to the DSMB by the sponsor (or its designee) immediately upon notification. Patients 
will be referred to a hepatologist for further work up. 
Level 1 Hepatotoxicity 
Level 1 Hepatotoxicity is defined as follows: 
• Patients who experience ALT or AST 1.1 to 2.9 x ULN. 
No dose modification will be required. 
Considerations for Liver Biopsy and Histopathological Guidelines 
Considerations for Liver Biopsy 
A percutaneous liver biopsy should be considered for persistent Level 2 Hepatotoxicity defined 
as AST or ALT ≥3 x ULN for ≥6 months but can also be performed at the discretion of the 
investigator. 
Histopathological Hepatobiliary Guidelines 
If a patient undergoes a liver biopsy and the specimen shows the following features, the patient 
will be discontinued from the study and followed by a hepatologist:  
• Type 3 non-alcoholic steatohepatitis (NASH) characterised by fat accumulation and 
ballooning degeneration, or  
• Type 4 NASH characterised by fat accumulation, ballooning degeneration, and either 
Mallory’s hyaline or fibrosis. 
Patients with fatty liver alone (Type 1 NASH) or fat accumulation and lobular inflammation but 
without ballooning degeneration and/or Mallory’s hyaline or fibrosis (Type 2 NASH) will 
continue on study medication, and discontinuation will be dictated by biochemical criteria. 
Creatinine Kinase Monitoring and Evaluation 
If CK values are found to be elevated >5 x ULN on routine testing, the patient should be 
questioned about muscle symptoms.  
A study site physician should be alerted to the occurrence of unexplained muscle symptoms 
and any CK values >5 x ULN, and must take immediate action if CK is >10 x ULN. 
If CK values are >5 x ULN with muscle symptoms or >10 x ULN with or without muscle 
symptoms the following steps should be taken: 
• Clarify the nature, duration and intensity of any muscle symptoms. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 54 of 111 
C O N F I D E N T I A L  
• Review possible predisposing factors, such as: unaccustomed exercise, heavy alcohol 
intake, viral illness (consider performing serology), concomitant medication and consider 
diagnosis of other conditions which cause myopathy. 
• Physical examination for muscle tenderness, weakness and rash. 
• Measure CK again within a few days. 
• Measure serum creatinine. 
• Urine dipstick. 
• Arrange to review the patient again in 4 to 10 days, or earlier if symptoms of myopathy 
appear or worsen, or if the urine becomes very dark. 
Discontinue study medication for CK values >10 x ULN with or without muscle symptoms. 
For CK values 5 to 10 x ULN: 
If asymptomatic, or if symptomatic but alternative explanation exists, symptoms should be 
followed and CK levels tested weekly until it is no longer a medical concern or symptoms 
worsen and meet criteria for any of the above. 
If symptomatic, and no alternative explanation exists, withhold therapy. 
Throughout the study, patients should be instructed to promptly report any unexplained muscle 
pain or weakness, particularly if associated with malaise or fever. If this should occur, CK 
should be measured as soon as possible. 
Dose Modification Based on Weight Loss 
Weight will be measured using a consistent approach at Screening and at each visit after the 
Run-in Period (i.e., child/adolescent always weighed in same amount of clothing, either in 
underwear, hospital gowns or by subtracting the weight of clothes). Patients of normal or below 
normal body weight based on gender and age-specific WHO growth charts (see Appendix 4 
WHO Growth Charts) with weight loss >3% since the previous visit will meet with the dietitian 
for further instruction. Patients with below normal body weight any time during the study who 
continue to lose weight while on study medication despite all appropriate measures taken to 
correct for the weight loss and who are deemed to be at clinical risk in the judgment of the 
treating investigator should discontinue study drug and be followed until an acceptable stable 
weight is reached as judged by the investigator. 
7.3.3 
Dose Modification for Concomitant Medication 
Weak Cytochrome P450 (CYP) 3A4 Inhibitors 
Medicinal products that induce CYP 3A4 would be expected to increase the rate and extent of 
metabolism of lomitapide. CYP 3A4 inducers exert their effect in a time-dependent manner, 
and may take at least 2 weeks to reach maximal effect after introduction. Conversely, on 
discontinuation, CYP 3A4 induction may take at least 2 weeks to decline. 
Co-administration of a CYP 3A4 inducer is expected to reduce the effect of lomitapide. Any 
impact on efficacy is likely to be variable. When co-administering CYP 3A4 inducers (i.e., 
aminoglutethimide, nafcillin, non-nucleoside reverse transcriptase inhibitors, phenobarbital, 
rifampicin, carbamazepine, pioglitazone, glucocorticoids, modafinil and phenytoin) with 
lomitapide, the possibility of a drug-drug interaction affecting efficacy should be considered. 
Strong or moderate cytochrome CYP 3A4 inhibitors are not permitted during the study as 
described in Section 7.6.3 Non-Permitted Concomitant Medication, Food or Substances.  
Weak cytochrome CYP 3A4 inhibitors are only permitted during the Safety Phase of the study, 
but lomitapide should be administered 12 hours apart. If atorvastatin is given concomitantly, it 
should be administered in the morning to separate it from lomitapide dosing by 12 hours. In 
case it is not possible to administer atorvastatin and lomitapide 12 hours apart, the lomitapide 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 55 of 111 
C O N F I D E N T I A L  
dose should be reduced by half, as the lomitapide dose can be reduced from the MTD due to 
tolerability or safety issues during the 80-week Safety Phase. After a minimum period of 
4 weeks following dose reduction the patient can be re-challenged with a higher dose of 
lomitapide once these issues resolve (i.e., if atorvastatin can be administered 12 hours apart 
or if atorvastatin is discontinued), but the dose during the Safety Phase cannot exceed the 
MTD established during the Efficacy Phase unless eligibility for exceptional dose escalation is 
met (described in Section 7.3.1 Dose Escalation, Dose Reduction and Re-challenge). 
HMG-CoA Reductase Inhibitors (‘Statins’) 
Lomitapide increases plasma concentrations of statins. Patients receiving lomitapide as 
adjunctive therapy to a statin should be monitored for AEs that are associated with the use of 
high doses of statins. Statins occasionally cause myopathy. In rare cases, myopathy may take 
the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and 
can lead to fatality. All patients receiving lomitapide in addition to a statin should be advised of 
the potential increased risk of myopathy and told to report promptly any unexplained muscle 
pain, tenderness, or weakness (see Section 7.3.2 Dose Modification, Interruption or 
Discontinuation for Adverse Events, Creatinine Kinase Monitoring and Evaluation). 
Concomitant administration of >40 mg simvastatin will not be permitted during the study as 
described in Section 7.6.3 Non-permitted Concomitant Medication, Food or Substances. 
Since patients will be required to remain on their concomitant LLT (including LA, when 
applicable) established during the 6-week Run-in Period during the Efficacy Phase of the study 
through Week 24±3 days, a potential concomitant treatment with atorvastatin will remain 
unchanged during the Efficacy Phase, when lomitapide dosing will start. If atorvastatin is given 
concomitantly, it should be administered in the morning to separate it from lomitapide dosing 
by 12 hours. If during the 80-week Safety Phase it is not possible to administer atorvastatin 
and lomitapide 12 hours apart, the lomitapide dose should be reduced by half. After a minimum 
period of 4 weeks following dose reduction the patient can be re-challenged with a higher dose 
of lomitapide once these issues resolve (i.e., if atorvastatin can be administered 12 hours apart 
or if atorvastatin is discontinued), but the dose during the Safety Phase cannot exceed the 
MTD established during the Efficacy Phase unless eligibility for exceptional dose escalation is 
met (described in Section 7.3.1 Dose Escalation, Dose Reduction and Re-challenge). 
Coumarin-based Anticoagulants 
Lomitapide increases the plasma concentrations of warfarin and increases INR. Increases in 
the dose of lomitapide may lead to supratherapeutic anticoagulation, and decreases in the 
dose may lead to subtherapeutic anticoagulation. Patients taking warfarin should undergo 
regular monitoring of the INR, especially after any changes in the dose of lomitapide. The dose 
of warfarin should be adjusted as clinically indicated. 
Hepatotoxic Agents 
Caution should be exercised when lomitapide is used with other medicinal products known to 
have potential for hepatotoxicity, such as isotretinoin, amiodarone, acetaminophen (>4 g/day 
for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant 
administration of lomitapide with other hepatotoxic medicine is unknown. More frequent 
monitoring of liver function tests may be warranted. 
7.4 
Patient Discontinuation Criteria 
Patients and/or their parents/legal guardians will have the right to withdraw from the study at 
any time for any reason without prejudice to their future medical care. A patient may be 
withdrawn from the study at any time at either the investigator’s, sponsor’s, or DSMB’s 
discretion.  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 56 of 111 
C O N F I D E N T I A L  
A patient must be discontinued from the study for any of the following reasons:  
• The patient matches the criteria referred to as “Hy’s law case” according to the EASL 
Clinical Practice Guidelines on Drug-induced Liver Injury (EASL 2019) and the FDA 
Guidance for Industry Drug-Induced Liver Injury Premarketing Clinical Evaluation (FDA 
2009). Any Hy's law case or comparable signs of liver toxicity, irrespective of origin, must 
lead to permanent treatment discontinuation of the individual patient (no re-challenge 
allowed). 
• The patient and/or his/her parent/legal guardian withdraws assent/consent. 
• Pregnancy as evidenced by a positive pregnancy test. 
If a patient becomes pregnant during the study, during the follow-up, or 30 days within the 
last application of study medication, the sponsor will have to be informed within 24 hours. 
The investigator will be asked to complete a pregnancy report provided by the sponsor. 
He/she will be asked to obtain data on the course of the pregnancy, including perinatal and 
neonatal outcome (see Section 11.5.4 Other Reportable Information). 
• Any AE which, in the opinion of the investigator, places the patient at unacceptable risk, 
including intolerable AE(s) after attempted dose reduction (see Section 7.3.2 Dose 
Modification, Interruption, or Discontinuation for Adverse Events). 
The investigator will be able to withdraw patients from the study for the following reasons: 
• Hepatobiliary criteria for discontinuation 
• Hepatobiliary AE CTCAE Grade 4 (see Appendix 3 Common Terminology Criteria for 
Adverse Events, Hepatobiliary Disorders), regardless of relationship to study drug 
• Biochemical hepatobiliary guideline Level 4 Hepatotoxicity or Level 3 Hepatotoxicity that 
persists despite interruption of study drug 
• Histopathological diagnosis of Type 3 or Type 4 NASH 
• Patient is noncompliant with the study procedures or medications in the opinion of the 
investigator 
• Progression of a medical condition, which in the opinion of the investigator should preclude 
further participation of the patient in the study (e.g., excessive weight loss) 
• Administration of non-permitted concomitant medication(s), substances, or foods 
• Investigators’ decision that a change of therapy is in the patients’ best interest 
• Occurrence of an AE (including abnormal laboratory findings), which makes discontinuation 
desirable or necessary in the investigators’ and/or the patients’ opinion 
If a patient discontinues the study or the follow-up prematurely due to an AE/SAE, he/she will 
be followed up until the resolution or stabilisation of the AE/SAE. 
If a patient discontinues the study prematurely, the EoT visit assessments should be made 
(see Section 9.7 End of Treatment Visit).  
All data collected before premature discontinuation of the study will be used for analysis. 
Patients who drop out will not be replaced unless the assumptions for drop-out have been 
exceeded.  
7.5 
Overdose 
There is no specific treatment in the event of overdose. In the event of overdose, the patient 
should be treated symptomatically and supportive measures instituted as required. Liver 
function tests should be monitored. Haemodialysis is unlikely to be beneficial given that 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 57 of 111 
C O N F I D E N T I A L  
lomitapide is highly protein-bound. Please refer to the SPC, Section 4.9 (included in the 
Lojuxta® SPC in lieu of an IB; see Section 18.1 Source Documents) for further details.  
7.6 
Concomitant Medication 
All medications that the patient is taking will be recorded in the eCRF. For each concomitant 
medication, the name of the medication, start and stop date, dose, indication, frequency of 
dosing and route of administration will be recorded. During the study, only changes of 
information from the previous visit at the time points indicated in Section 1.2 Flow Chart of 
Study and Follow-up will be recorded. 
7.6.1 
Concomitant Lipid-lowering Treatment 
Patients will be required to remain on their concomitant LLT (including LA, when applicable) 
established during the 6-week Run-in Period during the Efficacy Phase of the study through 
Week 24±3 days. Patients with HoFH are expected to be following different treatment 
regimens that usually include a statin together with additional LLT such as fibrates, bile acid 
sequestrant, and ezetimibe, as well as LA.  
Each patient’s individual therapeutic regimen should not be changed during the first 
24 weeks±3 days of lomitapide treatment (Efficacy Phase). After Week 24±3 days, 
adjustments to background LLT (including LA, when applicable) may be made as necessary 
for optimal standard of care. 
LA treatment causes a sharp drop in LDL-C, followed by a rebound phase. Therefore, in 
patients undergoing LA, it is important that lipid parameters are evaluated at a time that is as 
close as possible to and before the scheduled LA treatment. Once established, this time point 
for lipid profile blood draws should always be maintained, relative to the previous LA visit, so 
that lipid profiles are always performed at the same point on the LDL-C rebound curve.  
During the Run-in Period a stable frequency regimen (i.e., LA every X number of days) will be 
established. This frequency of LA needs to be maintained during the Efficacy Phase (through 
Week 24±3 days). The frequency of LA is usually personalised to meet the patient’s needs and 
the centre’s capacity. Therefore, windows are provided in Section 1.2 Flow Chart of Study and 
Follow-up for each visit to allow flexibility when patients can be seen. If a patient is unable to 
come for an LA per his/her usual regimen, LA should be rescheduled as soon as possible. If 
LA was missed at a time a study visit was scheduled, then blood for lipid profile should be 
drawn before the LA treatment and as close as possible to the LA regimen established during 
the Run-in Period or as revised if during the Safety Phase. 
However, for Visits 4 through 21 (i.e., during the Efficacy and Safety Phase) fasting lipids must 
be drawn just prior to the LA and LA must occur ±3 days from the regimen established during 
the Run-in Period. 
7.6.2 
Permitted Concomitant Medication 
The following medication will be permitted during study and follow-up: 
• Lipid-lowering medicinal products including statins, fibrates, bile acid sequestrants, and 
PCSK9 inhibitors 
Please note: Patients who receive atorvastatin, should separate the dose of the medicinal 
products by 12 hours, e.g., by taking atorvastatin in the morning and lomitapide in the 
evening (see Section 7.3.3. Dose Modification for Concomitant Medication). Patients who 
receive bile acid sequestrants, should separate the dose of the medicinal products by 
4 hours. Concomitant administration of >40 mg simvastatin is not permitted (see 
Section 7.6.3 Non-permitted Concomitant Medication, Food or Substances). 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 58 of 111 
C O N F I D E N T I A L  
• Oestrogen-based oral contraceptives 
Please note: Postmenarchal female adolescent patients taking oestrogen-based oral 
contraceptives should be advised that diarrhoea and/or vomiting may reduce hormone 
absorption. In case of protracted or severe diarrhoea and/or vomiting lasting more than 
2 days, the investigator should advise according to national practice, which additional 
contraceptive measures (such as sexual abstinence, barrier methods) should be used for 
7 days after resolution of symptoms. 
• Supportive therapy upon the investigators’ discretion. 
The following medication will be permitted during the Safety Phase of the study: 
• If a weak CYP 3A4 inhibitor, e.g., aminoglutethimide, nafcillin, non-nucleoside reverse 
transcriptase 
inhibitors, 
phenobarbital, 
rifampicin, 
carbamazepine, 
pioglitazone, 
glucocorticoids, modafinil and phenytoin inhibitor is required during the Safety Phase, the 
dose of lomitapide should be reduced as described in Section 7.3.3 Dose Modification for 
Concomitant Medication. 
Please note: Patients who receive weak CYP 3A4 inhibitors, should separate the dose of 
the medicinal products by 12 hours.  
If atorvastatin is given concomitantly, it should be administered in the morning to separate 
it from lomitapide dosing by 12 hours. In case it is not possible to administer atorvastatin 
and lomitapide 12 hours apart, the lomitapide dose should be reduced by half (see 
Section 7.3.3 Dose Modification for Concomitant Medication). 
7.6.3 
Non-permitted Concomitant Medication, Food or Substances 
Non-permitted Concomitant Medication 
The following medication will not be permitted during the study: 
• Contraindications for the use of lomitapide according to section 4.3 of the SPC (included in 
the Lojuxta® SPC in lieu of an IB; see Section 18.1 Source Documents), such as  
− Concomitant administration of >40 mg simvastatin. 
− Concomitant use of strong or moderate CYP 3A4 inhibitors, e.g., antifungal azoles such 
as itraconazole, fluconazole, ketoconazole, voriconazole, posaconazole; macrolide 
antibiotics such as erythromycin or clarithromycin; ketolide antibiotics such as 
telithromycin; HIV protease inhibitors; the calcium channel blockers diltiazem and 
verapamil, and the anti-arrhythmic dronedarone. 
The following medication will not be permitted during the Efficacy Phase of the study: 
• Weak CYP 3A4 inhibitors, e.g., aminoglutethimide, nafcillin, non-nucleoside reverse 
transcriptase 
inhibitors, 
phenobarbital, 
rifampicin, 
carbamazepine, 
pioglitazone, 
glucocorticoids, modafinil and phenytoin. If a weak CYP 3A4 inhibitor is required during the 
Safety Phase, the dose of lomitapide should be reduced as described in Section 7.3.3 Dose 
Modification for Concomitant Medication. 
Non-permitted Concomitant Food or Substances 
The use of the following food or substances should be avoided with lomitapide: 
• Alcohol: Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. 
• Grapefruit juice: Grapefruit juice is a moderate inhibitor of CYP 3A4 and is expected to 
substantially increase exposure to lomitapide. 
• Peppermint oil or Seville oranges. 
• St. John’s Wort (i.e., Hypericum perforatum). 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 59 of 111 
C O N F I D E N T I A L  
8 
ASSESSMENTS 
Please refer to Section 1.2 Flow-Chart of Study and Follow-up for a tabular overview of 
assessments by visit.  
8.1 
Eligibility and Safety Assessments 
8.1.1 
Eligibility Assessments 
Informed Consent 
The investigator will obtain written informed assent (according to applicable local regulations) 
and/or consent from the patient and his/her parent/legal guardian before he/she will initiate any 
study-specific procedure.  
The following criteria will be assessed for eligibility prior to enrolment: 
Inclusion/Exclusion 
The investigator will assess the patient’s eligibility as outlined in Section 5.1 Inclusion Criteria 
and Section 5.2 Exclusion Criteria including confirmation of a negative urine pregnancy test in 
postmenarchal female adolescents. 
Demographics 
Age, gender, and ethnic origin will be recorded at Screening (Visit 1). 
Medical History/Current Medical Conditions 
The investigator will ask the patient and/or his/her parent/legal guardian for the patient’s 
general and disease-specific medical history and current medical conditions. Changes in 
current medical conditions, particularly cardiovascular procedures and events, will be recorded 
at each visit thereafter.  
For those patients who have had genetic testing in the past, information should be collected 
regarding the details of the alleles for the genes involved. 
Genetic Testing 
Genetic testing is strongly encouraged, but not mandatory and not required for determining 
eligibility. Patients who have not previously had genetic testing, will be asked, whether they 
would consent to genetic testing. A separate informed consent will be obtained for genetic 
testing. For those patients who have signed a separate informed consent form (ICF) for this 
procedure, a blood sample will be collected according to central laboratory procedures for 
genotyping specified in the ‘Laboratory Manual’ at Screening (Visit 1). If it is not possible to do 
this at Screening (Visit 1) it can be done at a later visit.  
Physical Examination 
The investigator will do a complete physical examination including growth and sexual 
maturation assessments of the patient (and a genitourinary, but not rectal exam at the 
investigator’s discretion) and will document height, weight, body mass index (BMI), body 
surface area (BSA) and all clinically relevant findings at Screening (Visit 1), at Visit 7 
(Week 12±3 days), Visit 10 (Week 24±3 days), Visit 18 (Week 56±3 days), at Visit 22 
(Week 104±1 week), and in case of premature discontinuation.  
At all other 4-week study visits, an abbreviated physical examination, to include a focused 
evaluation of general appearance, skin, thorax/lungs, CV, and abdomen, will be conducted. 
Xanthomas will be evaluated at every physical exam. 
Weight will be measured using a consistent approach at Screening and at each visit after the 
Run-in Period (i.e., child/adolescent always weighed in same amount of clothing, either in 
underwear, hospital gowns or by subtracting the weight of clothes):  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 60 of 111 
C O N F I D E N T I A L  
• Patients of normal or below normal body weight (based on BMI with weight loss >1.5 kg 
since the previous visit) and their parent/legal guardian will meet with the dietitian for further 
instruction.  
• Patients with below normal body weight at any time during the study who continue to lose 
weight while on study medication despite all appropriate measures taken to correct for the 
weight loss and who are deemed to be at clinical risk in the judgment of the treating 
investigator should discontinue study medication and be followed until an acceptable stable 
weight is reached as judged by the investigator (see Section 7.3.2 Dose Modification, 
Interruption or Discontinuation for Adverse Events). 
Tanner Staging 
Tanner Staging is required for this study, and every attempt should be made to collect this 
information. Tanner Staging must be completed together with the physical exam by the same 
study-affiliated clinician (e.g., paediatrician) in the most inconspicuous manner for the patient 
as possible. When Tanner Staging is not completed at a required visit, it should be performed 
at the next study visit. 
Tanner Staging assessment consists of 2 domains (pubic hair and breast development) for 
girls and 3 domains (pubic hair, penis development, and testes development) for boys. The 
Tanner Staging assessment as a reference for the completing clinician is included in Appendix 
5 Tanner Staging. A patient who reaches Stage 5 (both in pubic hair and genitalia) does not 
need to continue with Tanner staging. 
Sites should make attempts to have examiners of both gender types available and to have the 
examination performed by the same gender as the patient, where possible. Otherwise, 
patient’s parent/guardian or a study-affiliated person (e.g., nurse) who is the same gender as 
the patient should be in the same examination room with the patient while the examination is 
performed. 
8.1.2 
Safety Assessments 
Concomitant Medication 
During the Screening and Run-in Period, at Baseline, during the Efficacy and Safety Phases 
as well as during the follow-up period, all concomitant medications and treatments (including 
LA, when applicable) will be recorded. The name, start and stop date, dosage, indication, 
frequency and route of administration of all medications as well as the name, start and stop 
date, indication, and frequency of all treatments will be recorded on the eCRF at first report 
and again only if anything has changed since the last visit. 
Adverse Events 
Adverse events occurring before the first administration of study medication will be recorded 
in the Medical History/Current Medical Conditions section of the eCRF. AEs occurring during 
the Efficacy and Safety Phases, and during the follow-up period until 30 days after the last 
administration of study medication will be recorded in the AE section of the eCRF. During the 
Screening and Run-in Period (<D0) and at Baseline (D0 of the Efficacy Phase) before study 
medication administration, AEs related to study procedures should also be reported. For 
reporting of AEs, please refer to Section 11.2 Recording of Adverse Events and Serious 
Adverse Events.  
Serious Adverse Events 
Serious AEs will be recorded in the SAE section of the eCRF during the Screening and Run-in 
Period, at Baseline, during the Efficacy and Safety Phases as well as during the follow-up 
period. For reporting of SAEs, please refer to Section 11.5 Immediately Reportable 
Information. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 61 of 111 
C O N F I D E N T I A L  
Vital Signs 
Vital signs, including systolic and diastolic blood pressure, heart rate, body temperature, and 
respiratory rate, will be measured at Screening (Visit 1), at Baseline (Visit 4), and at every visit 
thereafter (see Section 1.2 Flow Chart of Study and Follow-up). Blood pressure and heart rate 
will be measured after 5 minutes of rest in a sitting position. 
Electrocardiogram 
A 12-lead ECG will be recorded and read locally at Baseline (Visit 4), at Visit 10 
(Week 24±3 days), Visit 18 (Week 56±3 days), Visit 20 (Week 80±1 week), and at EoT 
(Week 104±1 week) (see Section 1.2 Flow Chart of Study and Follow-up).  
Electrocardiograms will be obtained after the patient has been supine for 5 minutes. The ECG 
recordings are to be reviewed by the investigator and classified as ‘normal’ or ‘abnormal’. 
Abnormal ECGs must in addition be classified as ‘abnormal, clinically significant’ or ‘abnormal, 
not clinically significant’. The reason(s) for ‘abnormal’ findings should be documented. 
Abnormal, clinically significant findings occurring after first administration of study medication 
should be reported as an AE (unless already pre-existing at Baseline with the same severity). 
Standard of Care Echocardiography 
It is anticipated that echocardiography will be performed annually as standard of care in this 
patient population. For this study, echocardiography is not mandated but data/results will be 
included as part of the study safety data. Information in relation to the most recent 
echocardiography on file (if available) will be documented in the eCRF at the following visits: 
Baseline (Visit 4), Visit 10 (Week 24±3 days), Visit 18 (Week 56±3 days), and at EoT 
(Week 104±1 week) (see Section 1.2 Flow Chart of Study and Follow-up). 
Pulmonary Function Test 
Pulmonary function tests, i.e., spirometry with DL,CO (diffusion capacity of the lung for carbon 
monoxide) will be performed to include: forced vital capacity (FVC); forced expiratory volume 
during 1 s (FEV1) and maximal mid-expiratory flow (FEF25-75) at Baseline (D0), Visit 10 
(Week 24±3 days), Visit 18 (Week 56±1 week), and at EoT (Week 104±1 week) (see 
Section 1.2 Flow Chart of Study and Follow-up).  
Nuclear Magnetic Resonance Imaging 
The terms Magnetic Resonance Imaging (MRI) and Nuclear Magnetic Resonance (NMR) are 
synonymous as are echography and ultrasound scan.  
Lipid accumulation in the liver (i.e., hepatic fat content) will be assessed at Baseline (D0), 
Visit 10 (Week 24±3 days), Visit 18 (Week 56±1 week), and at EoT (Week 104±1 week) in 
patients entering the EAP (<18 years of age)/transitioning to commercial product (≥18 years 
of age) or at Follow-up (Week 108) in patients who opt not to participate in or are unsuitable 
for the EAP (<18 years of age)/opt not to transition to commercial product (≥18 years of age; 
see Section 1.2 Flow Chart of Study and Follow-up). All patients will undergo NMR imaging 
unless it is contraindicated or not feasible (e.g., due to the need for sedation or general 
anaesthesia in very young or anxious patients). In this case, ultrasound scans will be used at 
the discretion of the investigator. The NMR images will be processed by a central reader, the 
ultrasound scans will be interpreted locally. 
Safety Laboratory Assessments 
The following safety laboratory tests are to be conducted as outlined in Section 1.2 Flow Chart 
of Study and Follow-up. See Appendix 6 Laboratory Tests for a comprehensive list of all 
laboratory tests to be performed. The total blood volume collected from each patient for the 
entire study is within the guidelines set forth by the WHO (Howie 2011). 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 62 of 111 
C O N F I D E N T I A L  
Comprehensive Metabolic Panel and Liver Function Tests 
The comprehensive metabolic panel includes sodium (Na), potassium (K), calcium (Ca), 
carbon dioxide, chloride (Cl), blood glucose (BG), C-reactive protein (CRP), renal parameters 
(blood urea nitrogen [BUN], creatinine), creatinine kinase (CK), total protein, and albumin.  
Liver function tests include alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (AP) and total bilirubin 
including direct and indirect bilirubin.  
Fasting Lipid Panel 
The patient should be fasting for at least 8 hours, except for water and medications, prior to 
drawing the fasting lipid panel. The fasting lipid panel includes the efficacy parameters TC, 
LDL-C, VLDL-C, calculated Non-HDL-C, TG, apo B, and Lp(a) (see Section 8.3.1 Fasting Lipid 
Panel) and the safety parameters high-density lipoprotein cholesterol (HDL-C) and 
apolipoprotein A-I (apo A-I). 
As the fasting lipid panel will be analysed at both the local hospital laboratory and the central 
laboratory, 2 separate samples must be drawn (see Section 10 Collection, Storage, and 
Shipment of Laboratory Samples). 
Complete Blood Count 
The complete blood count (CBC) includes white blood cell count, haemoglobin, haematocrit, 
platelet count, red blood cell count, red cell distribution width, mean corpuscular volume (MCV), 
mean corpuscular haemoglobin (MCH), and mean corpuscular haemoglobin concentration 
(MCHC). 
Fat-Soluble Vitamin Levels 
Vitamin A (retinol), vitamin E (alpha tocopherol), and vitamin D (25-hydroxy-D) will be 
assessed by measuring serum concentrations of the individual vitamins. In addition, vitamin E 
will also be reported as the ratio of alpha tocopherol/total lipids (TC + fasting TG). Levels of 
vitamin K will be assessed indirectly by measuring carboxylation of serum osteocalcin (ratio 
uncarboxylated osteocalcin/total osteocalcin). 
Fat-soluble vitamin levels will be analysed at the central laboratory specified in the ‘Laboratory 
Manual’ (see Section 10 Collection, Storage, and Shipment of Laboratory Samples). 
Serum Levels of Essential Fatty Acids (EFA) 
The Essential Fatty Acid (EFA) profile comprises serum levels of linoleic acid, alpha linoleic 
acid (ALA), arachidonic acid (AA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), 
and eicosatrienoic acid.  
Serum levels of EFA will be analysed at the central laboratory specified in the ‘Laboratory 
Manual’ (see Section 10 Collection, Storage, and Shipment of Laboratory Samples). 
Hormones 
Thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), serum cortisol, 
and sex hormones (serum follicle stimulating hormone [FSH] and luteinising hormone [LH]) will 
be assessed. The blood sample for testing of serum cortisol must be obtained in the early 
morning (6:00 to 8:00 a.m.). For patients who are Tanner Stage ≥2, serum oestradiol will be 
assessed for female patients and serum testosterone will be assessed for male patients. 
Urinalysis 
Urinalysis includes the assessment of urine colour, turbidity, pH, glucose, bilirubin, ketones, 
blood, protein, and white blood cells. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 63 of 111 
C O N F I D E N T I A L  
Pregnancy Tests 
Urine pregnancy tests will be conducted in postmenarchal female adolescent patients using 
test strips at every scheduled visit from Visit 1 through Visit 23 and every 4 weeks after Visit 18 
at Week 56±3 days through Week 104±1 week. 
If a patient becomes pregnant during the study, during the follow-up, or 30 days within the last 
application of study medication, the study medication must be discontinued immediately (see 
Section 7.4 Patient Discontinuation Criteria) and the sponsor will have to be informed within 
24 hours.  
The investigator will be asked to complete a pregnancy report provided by the sponsor. He/she 
will be asked to obtain data on the course of the pregnancy, including perinatal and neonatal 
outcome (see Section 11.5.4 Other Reportable Information). 
Bone Health 
Bone health will be assessed indirectly using growth to track age-appropriate progress, and 
measurement of 25-hydroxy-D and total and uncarboxylated osteocalcin levels (as reflection 
of vitamin K levels). Effects on growth, bone health and bone age will be assessed using both 
measurements of children’s height and growth charts to track age-appropriate progress at 
Screening and from Baseline at every visit through Week 104±1 week and/or at EoT, together 
with analysis of Vitamin D and K levels at Screening, Baseline, Week 24±3 days, 
Week 56±3 days, Week 80±1 week, Week 104±1 week and/or at EoT (and at Week 108 for 
patients who opt not to participate in or are unsuitable for the EAP [<18 years of age]/opt not 
to transition to commercial product [≥18 years of age]). 
8.2 
Pharmacokinetics 
Plasma levels of lomitapide will be measured. Baseline PK will be taken at D0. Steady-state 
PK from Visit 5 (Week 4±3 days) through Visit 10 (Week 24±3 days) will be evaluated. Single 
PK samples will be collected at Visit 5 (Week 4±3 days), Visit 7 (Week 12±3 days), Visit 8 
(Week 16±3 days), and at Visit 10 (Week 24±3 days). Two PK samples will be collected at 
least 1 hour apart at Visit 6 (Week 8±3 days) and at Visit 9 (Week 20±3 days); these samples 
must be collected as separate blood draws (time between separate blood draws might be used 
for undertaking other procedures scheduled for the respective visit(s)). 
All samples taken are trough samples of about 3.5 mL each (the volume of blood taken might 
be adjusted based on the body weight of the patient and central laboratory procedures). 
Samples will not be taken in duplicate. The date and time of the patient’s last lomitapide dose 
and the date and time of the sample(s) should be recorded in the eCRF.  
8.3 
Assessment of Efficacy 
8.3.1 
Fasting Lipid Panel 
The patient should be fasting for at least 8 hours, except for water and medications, prior to 
drawing the fasting lipid panel. The fasting lipid panel includes TC, LDL-C, VLDL-C, calculated 
Non-HDL-C, TG, apo B, and Lp(a) and the safety parameters HDL-C and apo A-I (see 
Section 8.1.2 Safety Assessments).  
At Screening (Visit 1), LDL-C may be estimated from the Friedewald formula if TG are 
<400 mg/dL; however, if TG are ≥400 mg/dL, LDL-C will be measured directly. 
Friedewald formula: 𝐿𝐿𝐿𝐿𝐿𝐿-𝐶𝐶= 𝑇𝑇𝑇𝑇−(𝐻𝐻𝐻𝐻𝐻𝐻-𝐶𝐶+
𝑇𝑇𝑇𝑇
5 ) 
At all other visits, LDL-C is measured directly. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 64 of 111 
C O N F I D E N T I A L  
For patients on LA, fasting lipid panels must be drawn at all assessments required by the 
protocol and (as applicable) are to be obtained immediately before the scheduled LA treatment 
(see Section 7.6.1 Concomitant Lipid-Lowering Treatment). 
As the fasting lipid panel will be analysed at both the local hospital laboratory and the central 
laboratory, 2 separate samples must be drawn (see Section 10 Collection, Storage, and 
Shipment of Laboratory Samples). 
8.3.2 
LDL-C Treatment Criteria 
The LDL-C values for Screening (Visit 1) and Week -3 to Week -2 (Visit 2) must be as follows 
for a patient to be eligible to begin treatment on D0. 
Baseline LDL-C on LLT (Cmax of LDL-C immediately prior to LA, if applicable) of either: 
a. 
>160 mg/dL (4.1 mmol/L, no documented CVD) or 
b. 
>130 mg/dL (3.4 mmol/L, established CVD defined as aortic valve disease and/or 
coronary atherosclerosis) 
8.4 
Exploratory Assessments 
8.4.1 
Regression or Resolution of Xanthomas 
The patient’s xanthomas (tendon and cutaneous, size and location) will be evaluated during 
physical examination at Screening (Visit 1), at Baseline (Visit 4, D0) and at every visit 
thereafter.  
8.4.2 
Assessment of Carotid Intima-Media Thickness and Flow-mediated 
Dilation 
Carotid intima-media thickness (CIMT, mandatory) and flow-mediated dilation (FMD, 
whenever possible) will be assessed using ultrasound scan to evaluate carotid atherosclerotic 
vascular disease and brachial artery dilation after a transient period of forearm ischaemia at 
Baseline (Visit 4, D0), at Visit 18 (Week 56±3 days), and at EoT (Week 104±1 week).  
8.4.3 
Liposcale® Test 
The Liposcale® Test will be used to assess changes from Baseline through Week 24±3 days 
in cholesterol and triglyceride content of VLDL, IDL, LDL and HDL, particle number and size 
of VLDL, LDL, and HDL as well as particle number of their respective lipoprotein subclasses 
(large, medium, and small), from PK samples at Week 4±3 days, Week 8±3 days, 
Week 12±3 days, Week 16±3 days, Week 20±3 days and Week 24±3 days. For this 2D NMR 
analysis, 200 µL aliquots will only be taken from each PK sample at the central laboratory 
specified in the ‘Laboratory Manual’, if sufficient sample material has been provided and would 
otherwise be discarded. No additional blood sampling from the patient at the site will be 
required (see Section 10 Collection, Storage and Shipment of Laboratory Samples). 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 65 of 111 
C O N F I D E N T I A L  
8.5 
Palatability 
Palatability will be assessed using a 5-point facial hedonic scale, anchored with descriptors, to 
record the children’s assessment of palatability in terms of overall liking (see Figure 4). 
Figure 4 
Example of a 5-Point Facial Hedonic Scale Used for Hedonic Ratings by 
Children (Guinard 2000) 
 
Palatability will be assessed on the first occasion that any patient who is not able to swallow 
the intact capsule(s) takes lomitapide by opening and sprinkling the capsule onto either food 
media (i.e., if a patient tries both food media, assessment will be made at the first instance of 
taking the study medication with apple sauce and the first instance of taking the study 
medication with mashed banana).  
The investigator or a study team member will also ask the parent(s)/legal guardian(s) to 
evaluate the children’s reaction to investigational product and dietary supplement 
administration. A 3-point scale that assesses the parent(s)/legal guardian(s) interpretation of 
the child’s reaction/facial expression will be used to determine whether they find lomitapide 
“pleasant”, “unpleasant” or are “not sure”.  
In addition, an assessment of ease of administration will be incorporated by asking the 
parent(s)/legal guardian(s) the following question at each visit during the treatment phase: “Do 
you sometimes have problems in giving the medication to your child because he/she refuses 
to take it or throws it up immediately after taking it? (Yes/No).” The same question will be asked 
for the administration of dietary supplements. 
Timing of the reaction relative to dosing will be recorded to help distinguish between palatability 
of the investigational product and GI events that are a result of the investigational products 
mechanism of action.  
8.6 
Other Assessments 
8.6.1 
Diet Instructions and Diet Records 
The occurrence and severity of GI AEs associated with the use of lomitapide decreases in the 
presence of a low-fat diet. Patients will start to follow a diet supplying <20% of energy from fat 
or <30 g fat, whichever is the lesser amount at Visit 2 (Start of the Run-in Period) and will 
continue this diet until the EoT (and throughout the EAP [<18 years of age]/administration of 
commercial product [≥18 years of age], when applicable).  
A dietitian will provide dietary counselling to the patients and their parents/legal guardians from 
Visit 2 (Start of the Run-in Period) through Visit 5 (Week 4±3 days). Patients and parents/legal 
guardians will be instructed on how to consume <20% energy from fat or <30 g fat, whichever 
is the lesser amount. Instructions will include detailed information concerning the role of dietary 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 66 of 111 
C O N F I D E N T I A L  
fat and GI-related symptoms and patients will be encouraged to pay special attention to foods 
they eat when/if they experience these symptoms. The dietitian will review current eating habits 
in order to point out needed changes and address potential adherence problems. The dietitian 
will provide diet instructions that are tailored to each patient’s caloric needs to promote healthy 
weight maintenance.  
The dietitian will also review compliance with the diet and discuss any issues or concerns the 
patient and his/her parents/legal guardians may have with the diet at Visit 3 (Week -3 to 
Week -2). The dietitian will inform patients and their parents/legal guardians to call him/her to 
discuss over the phone or schedule a meeting to address any diet-related questions or 
concerns at any time during the study. Additional resources pertaining to the diet will be 
available to the dietitian and the patient and his/her parent/legal guardian. 
Weight will be measured using a consistent approach at Screening and at each visit after the 
Run-in Period (i.e., child/adolescent always weighed in same amount of clothing, either in 
underwear, hospital gowns or by subtracting the weight of clothes). Patients of normal or below 
normal body weight with weight loss >3% since the last visit will be instructed by the dietitian 
on how to increase caloric intake based on individual needs. The standard recommended fat 
intake for children >2 years old is to follow a diet with <30% energy from fat, hence, decreasing 
dietary fat intake to <20% or <30 g fat, whichever is the lesser amount should not pose any 
risk to patients of any age that may be enrolled in this study. 
The investigator can request additional dietary counselling as clinically indicated. At the same 
visits, 2-Day Diet Records will be given to the patients and their parents/legal guardians.  
In order to assess dietary compliance and to provide information for interpreting possible GI 
AEs, patients will be instructed to document all food and beverages consumed periodically 
throughout the study, using Diet Records. A 2-Day Diet Record will be dispensed and returned 
from Visit 2 (Start of the Run-in Period) through Visit 21 (Week 92±1 week).  
If diet-related problems are noted during the study, e.g., weight loss or GI-related complaints 
such as diarrhoea, the patients may be requested to fill out additional Diet Records. Note that 
Diet Records collected during the Run-in Period do not get analysed, but are used by the 
dietitian on site to assess compliance before beginning lomitapide treatment. 
Patients treated with lomitapide and their parents/legal guardians should be advised of the 
potential risk of dehydration in relation to GI AEs and take precautions to avoid fluid depletion. 
Please refer to Section 6.3 Dietary Supplements for details regarding oral supplementation 
with vitamin E and essential fatty acids. 
9 
VISIT SCHEDULE 
The visit schedule is summarised in Section 1.2 Flow Chart of Study and Follow-up. The 
calculation of all study days is based on D0, which is defined as the day of the first application 
of study medication. 
9.1 
Screening Period (Starting at Week -12, i.e., ≤12 Weeks Prior to 
Baseline for a Minimum of 6 Weeks), Visit 1 
Study sites might contact patients who are registered in centre-specific databases to inform 
them about the study and to invite them for screening.  
The investigator will have to obtain written informed assent/consent (according to applicable 
local regulations) from the patient and written informed consent from his/her parent/legal 
guardian before any study-related procedure will be initiated (see Section 14.3 Patient and 
Parent/Legal Guardian Information and Informed Consent). If the patient and his/her 
parent/legal guardian consent to the optional genetic testing, written informed consent for 
genetic testing will also be obtained.  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 67 of 111 
C O N F I D E N T I A L  
9.1.1 
Visit 1 (Up to Week -12) 
During Visit 1 up to Week -12, the following will be completed: 
• Confirmation of patient eligibility using the inclusion criteria (see Section 5.1 Inclusion 
Criteria) and exclusion criteria (see Section 5.2 Exclusion Criteria)  
• Record of general and disease-specific medical history and current medical conditions 
including cardiovascular procedures and events 
• Record of demographic data (age, gender, and ethnic origin) 
• Complete physical examination of the patient (and a genitourinary, but not rectal exam at 
the investigator’s discretion) including the documentation of height, weight, BMI, BSA and 
all clinically relevant findings, such as xanthomas (see Section 8.1.1 Eligibility 
Assessments) 
• Determination of sexual maturation based on Tanner staging (see Section 8.1.1 Eligibility 
Assessments and Appendix 5 Tanner Staging) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Complete blood count 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
− Serum level of essential fatty acids 
− Fat-soluble vitamin levels 
− Hormones (TSH, ACTH, serum cortisol [to be measured between 06:00 and 08:00 a.m.], 
FSH, LH) 
− In patients who are Tanner Stage ≥2, serum oestradiol will be assessed for female 
patients and serum testosterone will be assessed for male patients 
• Urinalysis (urine colour, turbidity, pH, glucose, bilirubin, ketones, blood, protein, and white 
blood cells) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Genetic testing in patients who have not previously had genotyping and who have 
consented to this procedure (collection of a blood sample according to central laboratory 
procedures specified in the ‘Laboratory Manual’, see Section 8.1.1 Eligibility Assessments). 
If it is not possible to do genetic testing at Screening (Visit 1) it can be done at a later visit. 
9.2 
Re-screening 
If the patient is a screen failure, he/she can be re-screened on 2 separate occasions within 
2 weeks of the previous (re-)screening. The patient can only be re-screened for the purpose 
of repeating LDL-C (inclusion criterion 2), serum CK (exclusion criterion 4) or blood pressure 
(exclusion criterion 6) measurement(s), as deemed appropriate by the investigator, since these 
parameters might change within a short timeframe. A new screening for eligibility based on all 
other inclusion and exclusion criteria is not possible, because they are not expected to change 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 68 of 111 
C O N F I D E N T I A L  
within a short timeframe. The patient must be reconsented for the re-screening procedure(s); 
however, to reduce study burden and blood draws in this paediatric patient population, other 
screening procedures must not be repeated. The patient will be assigned a new patient 
number. 
9.3 
Stratified Enrolment and Start of Run-in Period (Starting at 
Minimum at Week -6, i.e., 6 Weeks Prior to Baseline for a 
Minimum of 6 Weeks, Visits 2 to 3 
9.3.1 
Visit 2 (Stratified Enrolment and Start of Run-in Period, at Minimum 
Week -6) 
Upon confirmation of eligibility, patients will come back to the study site for Visit 2 (at minimum 
Week -6) for stratified enrolment and to start the Run-in Period. At Visit 2, the following 
procedures will be conducted: 
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) 
• Dispensing of 2-Day Diet record (used to enable adjustments to the patient’s diet before 
starting study drug; see Section 8.6.1 Diet Instructions and Diet Records) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.3.2 
Visit 3 (Compliance, Week -3 to Week -2) 
The patient will visit the study site for Visit 3 (Week -3 to Week -2) and must present in fasting 
state. The following procedures will be conducted:  
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) 
• Dispensing of new and collection of old 2-Day Diet records (see Section 8.6.1 Diet 
Instructions and Diet Records) 
• Collection of blood samples for fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
• Dispensing of dietary supplements (see Section 6.3 Dietary Supplements) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.4 
Efficacy Phase (Baseline, D0 to Week 24±3 days), Visits 4 to 10 
9.4.1 
Visit 4 (Baseline, D0) 
The patient will visit the study site for the Baseline assessment of the Efficacy Phase at Visit 4 
(D0) and must present in fasting state. The following procedures will be conducted:  
• Confirmation of patient eligibility using the inclusion criteria (see Section 5.1 Inclusion 
Criteria) and exclusion criteria (see Section 5.2 Exclusion Criteria)  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 69 of 111 
C O N F I D E N T I A L  
• Abbreviated physical examination (including a focused evaluation of general appearance, 
skin, thorax/lungs, CV, abdomen, and xanthomas) and record of height, weight, BMI, and 
BSA (see Section 8.1.1 Eligibility Assessments) 
• Determination of sexual maturation based on Tanner staging (see Section 8.1.1 Eligibility 
Assessments and Appendix 5 Tanner Staging) 
• Record of 12-lead ECG (read locally, see Section 8.1.2 Safety Assessments) 
• Collection of information in relation to the most recent standard of care echocardiography 
on file (if available, see Section 8.1.2 Safety Assessments) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• Pulmonary Function Test (see Section 8.1.2 Safety Assessments) 
• NMR imaging of liver for hepatic fat assessment; if NMR imaging is contraindicated or not 
feasible (e.g., due to the need for sedation or general anaesthesia in very young or anxious 
patients), ultrasound scans will be used at the discretion of the investigator (see 
Section 8.1.2 Safety Assessments) 
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) 
• Dispensing of new and collection of old 2-Day Diet records (see Section 8.6.1 Diet 
Instructions and Diet Records) 
• Carotid intima-media thickness (CIMT, mandatory) and flow-mediated dilation (FMD, 
whenever possible) using ultrasound scan (see Section 8.4.2 Assessment of Carotid 
Intima-Media Thickness and Flow-mediated Dilation) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Complete blood count 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
− Serum level of essential fatty acids 
− Serum lipase 
− Fat-soluble vitamin levels 
− Hormones (TSH, ACTH, serum cortisol [to be measured between 06:00 and 08:00 a.m.], 
FSH, LH) 
− In patients who are Tanner Stage ≥2, serum oestradiol will be assessed for female 
patients and serum testosterone will be assessed for male patients 
− Pharmacokinetics (single trough sample, date and time of the patient’s last lomitapide 
dose and time of the sample should be recorded in the eCRF) 
• Urinalysis (urine colour, turbidity, pH, glucose, bilirubin, ketones, blood, protein, and white 
blood cells) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Dispensing of dietary supplements and collection of used dietary supplement bottles as 
needed (see Section 6.3 Dietary Supplements) 
• Dispensing of study medication (see Section 7.2 Treatment Schedule): The first dose of 
study medication will be administered at the study site.  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 70 of 111 
C O N F I D E N T I A L  
• Palatability assessment: A 5-point facial hedonic scale will be used to record the child’s 
assessment of palatability of study medication on the first occasion that any patient who is 
unable to swallow the intact capsule(s) and opens the capsule(s) and sprinkles the capsule 
content on a small amount (1 tablespoon) of either apple sauce or mashed banana (i.e., if 
a patient tries both food media, assessment will be made at the first instance of taking the 
study medication with apple sauce and the first instance of taking the study medication with 
mashed banana). The type of food media (apple sauce or mashed banana) will be captured 
(see Section 8.5 Palatability) 
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.4.2 
Visits 5, 6, 8, and 9 (Week 4±3 days, Week 8±3 days, Week 16±3 days, 
and Week 20±3 days) 
The patient will visit the study site for Visits 5, 6, 8 and 9 of the Efficacy Phase and must present 
in fasting state. The following procedures will be conducted:  
• Abbreviated physical examination (including a focused evaluation of general appearance, 
skin, thorax/lungs, CV, abdomen, and xanthomas) and record of height, weight, BMI, and 
BSA (see Section 8.1.1 Eligibility Assessments) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) at Visit 5 
(Week 4±3 days) only and as clinically indicated thereafter 
• Dispensing of new and collection of old 2-Day Diet records (see Section 8.6.1 Diet 
Instructions and Diet Records) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
− Pharmacokinetics (single trough samples at Visit 5 [Week 4±3 days] and Visit 8 
[Week 16±3 days]; date and time of the patient’s last lomitapide dose and time of the 
sample should be recorded in the eCRF) 
− Two PK samples will be collected at least 1 hour apart at Visit 6 (Week 8±3 days) and 
Visit 9 (Week 20±3 days); date and time of the patient’s last lomitapide dose and time of 
the samples should be recorded in the eCRF; these samples must be collected as 
separate blood draws (time between separate blood draws might be used for undertaking 
other procedures scheduled for the respective visit(s)). 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Dispensing of dietary supplements and collection of used dietary supplement bottles as 
needed (see Section 6.3 Dietary Supplements) 
• Dispensing of study medication and collection of used study medication bottles as needed 
(see Section 7.2 Treatment Schedule). 
• Study medication compliance check (see Section 6.2 Investigational Product Compliance) 
• Palatability assessment (see Section 8.5 Palatability):  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 71 of 111 
C O N F I D E N T I A L  
− The investigator will ask the parent(s)/legal guardian(s) to evaluate the children’s 
reaction to investigational product and dietary supplement administration. A 3-point scale 
that assesses the parent(s)/legal guardian(s) interpretation of the child’s reaction/facial 
expression will be used to determine whether they find lomitapide “pleasant”, 
“unpleasant” or are “not sure”.  
− In addition, an assessment of ease of administration will be incorporated by asking the 
parent(s)/legal guardian(s) the following question at each visit during the treatment 
phase: “Do you sometimes have problems in giving the medication to your child because 
he/she refuses to take it or throws it up immediately after taking it? (Yes/No).” The same 
question will be asked for the administration of the dietary supplements. 
− Timing of the reaction relative to dosing will be recorded to help distinguish between 
palatability of the investigational product and GI events that are a result of the 
investigational products mechanism of action.  
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.4.3 
Visit 7 (Week 12±3 days) 
The patient will visit the study site for Visit 7 of the Efficacy Phase and must present in fasting 
state. The following procedures will be conducted:  
• Complete physical examination of the patient (and a genitourinary, but not rectal exam at 
the investigator’s discretion) including the documentation of height, weight, BMI, BSA and 
all clinically relevant findings, such as xanthomas (see Section 8.1.1 Eligibility 
Assessments) 
• Determination of sexual maturation based on Tanner staging (see Section 8.1.1 Eligibility 
Assessments and Appendix 5Tanner Staging) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) as clinically 
indicated 
• Dispensing of new and collection of old 2-Day Diet records (see Section 8.6.1 Diet 
Instructions and Diet Records) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
− Pharmacokinetics (single trough sample, date and time of the patient’s last lomitapide 
dose and time of the sample should be recorded in the eCRF) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Dispensing of dietary supplements and collection of used dietary supplement bottles as 
needed (see Section 6.3 Dietary Supplements) 
• Dispensing of study medication and collection of used study medication bottles as needed 
(see Section 7.2 Treatment Schedule). 
• Study medication compliance check (see Section 6.2 Investigational Product Compliance) 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 72 of 111 
C O N F I D E N T I A L  
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.4.4 
Visit 10 (Week 24±3 days) 
The patient will visit the study site for Visit 10 of the Efficacy Phase and must present in fasting 
state. The following procedures will be conducted:  
• Complete physical examination of the patient (and a genitourinary, but not rectal exam at 
the investigator’s discretion) including the documentation of height, weight, BMI, BSA and 
all clinically relevant findings, such as xanthomas (see Section 8.1.1 Eligibility 
Assessments) 
• Determination of sexual maturation based on Tanner staging (see Section 8.1.1 Eligibility 
Assessments and Appendix 5Tanner Staging) 
• Record of 12-lead ECG (read locally, see Section 8.1.2 Safety Assessments) 
• Collection of information in relation to the most recent standard of care echocardiography 
on file (if available, see Section 8.1.2 Safety Assessments) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• Pulmonary Function Test (see Section 8.1.2 Safety Assessments) 
• NMR imaging of liver for hepatic fat assessment; if NMR imaging is contraindicated or not 
feasible (e.g., due to the need for sedation or general anaesthesia in very young or anxious 
patients), ultrasound scans will be used at the discretion of the investigator (see 
Section 8.1.2 Safety Assessments) 
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) as clinically 
indicated 
• Dispensing of new and collection of old 2-Day Diet records (see Section 8.6.1 Diet 
Instructions and Diet Records) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
− Serum levels of essential fatty acids 
− Serum lipase 
− Fat-soluble vitamin levels 
− Pharmacokinetics (single trough sample, date and time of the patient’s last lomitapide 
dose and time of the sample should be recorded in the eCRF) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Dispensing of dietary supplements and collection of used dietary supplement bottles as 
needed (see Section 6.3 Dietary Supplements) 
• Dispensing of study medication and collection of used study medication bottles as needed 
(see Section 7.2 Treatment Schedule). 
• Study medication compliance check (see Section 6.2 Investigational Product Compliance) 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 73 of 111 
C O N F I D E N T I A L  
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.5 
Safety Phase (Week 28±3 Days to Week 92±1 Week), Visits 11 to 
21 
9.5.1 
Visits 11 to 17 (Week 28±3 days, Week 32±3 days, Week 36±3 days, 
Week 40±3 days, Week 44±3 days, Week 48±3 days, and 
Week 52±3 days) 
The patient will visit the study site for Visits 11 through 17 of the Safety Phase and must present 
in fasting state. The following procedures will be conducted:  
• Abbreviated physical examination (including a focused evaluation of general appearance, 
skin, thorax/lungs, CV, abdomen, and xanthomas) and record of height, weight, BMI, and 
BSA (see Section 8.1.1 Eligibility Assessments) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) as clinically 
indicated 
• Dispensing of new and collection of old 2-Day Diet records (see Section 8.6.1 Diet 
Instructions and Diet Records) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Dispensing of dietary supplements and collection of used dietary supplement bottles as 
needed (see Section 6.3 Dietary Supplements) 
• Dispensing of study medication and collection of used study medication bottles as needed 
(see Section 7.2 Treatment Schedule). 
• Study medication compliance check (see Section 6.2 Investigational Product Compliance) 
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.5.2 
Visit 18 (Week 56±3 days) 
The patient will visit the study site for Visit 18 of the Safety Phase and must present in fasting 
state. The following procedures will be conducted:  
• Complete physical examination of the patient (and a genitourinary, but not rectal exam at 
the investigator’s discretion) including the documentation of height, weight, BMI, BSA and 
all clinically relevant findings, such as xanthomas (see Section 8.1.1 Eligibility 
Assessments) 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 74 of 111 
C O N F I D E N T I A L  
• Determination of sexual maturation based on Tanner staging (see Section 8.1.1 Eligibility 
Assessments and Appendix 5 Tanner Staging) 
• Record of 12-lead ECG (read locally, see Section 8.1.2 Safety Assessments) 
• Collection of information in relation to the most recent standard of care echocardiography 
on file (if available, see Section 8.1.2 Safety Assessments) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• Pulmonary Function Test (see Section 8.1.2 Safety Assessments) 
• NMR imaging of liver for hepatic fat assessment; if NMR imaging is contraindicated or not 
feasible (e.g., due to the need for sedation or general anaesthesia in very young or anxious 
patients), ultrasound scans will be used at the discretion of the investigator (see 
Section 8.1.2 Safety Assessments) 
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) as clinically 
indicated 
• Dispensing of new and collection of old 2-Day Diet records (see Section 8.6.1 Diet 
Instructions and Diet Records) 
• Carotid intima-media thickness (CIMT, mandatory) and flow-mediated dilation (FMD, 
whenever possible) using ultrasound scan (see Section 8.4.2 Assessment of Carotid 
Intima-Media Thickness and Flow-mediated Dilation) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Complete blood count 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
− Serum levels of essential fatty acids 
− Serum lipase 
− Fat-soluble vitamin levels 
− Hormones (TSH, ACTH, serum cortisol [to be measured between 06:00 and 08:00 a.m.], 
FSH, LH) 
− In patients who are Tanner Stage ≥2, serum oestradiol will be assessed for female 
patients and serum testosterone will be assessed for male patients 
• Urinalysis (urine colour, turbidity, pH, glucose, bilirubin, ketones, blood, protein, and white 
blood cells) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Dispensing of dietary supplements and collection of used dietary supplement bottles as 
needed (see Section 6.3 Dietary Supplements) 
• Dispensing of study medication and collection of used study medication bottles as needed 
(see Section 7.2 Treatment Schedule). 
• Study medication compliance check (see Section 6.2 Investigational Product Compliance) 
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 75 of 111 
C O N F I D E N T I A L  
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.5.3 
Visits 19 to 21 (Week 68±1 week, Week 80±1 week, and 
Week 92±1 week) 
The patient will visit the study site for Visits 19 through 21 of the Safety Phase and must present 
in fasting state. The following procedures will be conducted:  
• Abbreviated physical examination (including a focused evaluation of general appearance, 
skin, thorax/lungs, CV, abdomen, and xanthomas) and record of height, weight, BMI, and 
BSA (see Section 8.1.1 Eligibility Assessments) 
• Record of 12-lead ECG (read locally, Visit 20 only, see Section 8.1.2 Safety Assessments) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) as clinically 
indicated 
• Dispensing of new and collection of old 2-Day Diet records (see Section 8.6.1 Diet 
Instructions and Diet Records) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
− Serum levels of essential fatty acids (Visit 20 only) 
− Fat-soluble vitamin levels (Visit 20 only) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Dispensing of dietary supplements and collection of used dietary supplement bottles as 
needed (see Section 6.3 Dietary Supplements) 
• Dispensing of study medication and collection of used study medication bottles as needed 
(see Section 7.2 Treatment Schedule). 
• Study medication compliance check (see Section 6.2 Investigational Product Compliance) 
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.6 
Unscheduled Visits 
Unscheduled visits should be performed whenever necessary, e.g., in case of AEs or SAEs. 
Evaluations and/or assessments should be performed, as deemed appropriate by the 
investigator based on the nature of the event prompting an unscheduled visit. 
The results of all examinations during an unscheduled visit should be documented in the 
patient’s file and should be recorded in the eCRF. If a patient is withdrawn from the study, all 
examinations scheduled for the EoT visit should be performed. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 76 of 111 
C O N F I D E N T I A L  
9.7 
End of Treatment (Week 104±1 week), Visit 22 
The EoT visit should be performed for all patients at Week 104 and should also be performed 
at any time if the patient is prematurely discontinued from the study. The patient must present 
in fasting state. The following procedures will be conducted: 
• Complete physical examination of the patient (and a genitourinary, but not rectal exam at 
the investigator’s discretion) including the documentation of height, weight, BMI, BSA and 
all clinically relevant findings, such as xanthomas (see Section 8.1.1 Eligibility 
Assessments) 
• Determination of sexual maturation based on Tanner staging (see Section 8.1.1 Eligibility 
Assessments and Appendix 5 Tanner Staging) 
• Record of 12-lead ECG (read locally, see Section 8.1.2 Safety Assessments) 
• Collection of information in relation to the most recent standard of care echocardiography 
on file (if available, see Section 8.1.2 Safety Assessments) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• Pulmonary Function Test (see Section 8.1.2 Safety Assessments) 
• NMR imaging of liver for hepatic fat assessment; if NMR imaging is contraindicated or not 
feasible (e.g., due to the need for sedation or general anaesthesia in very young or anxious 
patients), ultrasound scans will be used at the discretion of the investigator (see 
Section 8.1.2 Safety Assessments) 
• Dietary counselling (see Section 8.6.1 Diet Instructions and Diet Records) as clinically 
indicated 
• Collection of old 2-Day Diet records (see Section 8.6.1 Diet Instructions and Diet Records) 
• Carotid intima-media thickness (CIMT, mandatory) and flow-mediated dilation (FMD, 
whenever possible) using ultrasound scan (see Section 8.4.2 Assessment of Carotid 
Intima-Media Thickness and Flow-mediated Dilation) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Complete blood count 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
− Serum levels of essential fatty acids 
− Serum lipase 
− Fat-soluble vitamin levels 
− Hormones (TSH, ACTH, serum cortisol [to be measured between 06:00 and 08:00 a.m.], 
FSH, LH) 
− In patients who are Tanner Stage ≥2, serum oestradiol will be assessed for female 
patients and serum testosterone will be assessed for male patients 
• Urinalysis (urine colour, turbidity, pH, glucose, bilirubin, ketones, blood, protein, and white 
blood cells) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 77 of 111 
C O N F I D E N T I A L  
• Collection of used dietary supplement bottles as needed (see Section 6.3 Dietary 
Supplements) 
• Collection of used study medication bottles as needed (see Section 7.2 Treatment 
Schedule). 
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 
9.8 
Follow-up (Week 108), Visit 23 
9.8.1 
Visit 23 (Week 108) 
Patients entering the EAP (<18 years of age)/transitioning to commercial product (≥18 years 
of age) will have a follow-up phone call at Week 108±1 week to monitor safety including AE 
and concomitant medication reporting. Patients who have opted not to participate in or are 
unsuitable for the EAP (<18 years of age)/opted not to transition to commercial product (≥18 
years of age) will return for an in person safety Follow-up Visit at Week 108. The patient must 
present in fasting state. The following procedures will be conducted: 
• Abbreviated physical examination (including a focused evaluation of general appearance, 
skin, thorax/lungs, CV, abdomen, and xanthomas) and record of height, weight, BMI, and 
BSA (see Section 8.1.1 Eligibility Assessments) 
• Measurement of vital signs and blood pressure (see Section 8.1.1 Eligibility Assessments) 
• NMR imaging of liver for hepatic fat assessment; if NMR imaging is contraindicated or not 
feasible (e.g., due to the need for sedation or general anaesthesia in very young or anxious 
patients), ultrasound scans will be used at the discretion of the investigator (see 
Section 8.1.2 Safety Assessments) 
• Collection of blood samples for the following tests (see Section 8.1.2 Safety Assessments): 
− Complete blood count 
− Comprehensive metabolic panel 
− Liver function tests 
− Fasting lipid panel (see Section 8.3.1 Fasting Lipid Panel) 
− Serum levels of essential fatty acids 
− Fat-soluble vitamin levels 
• Urinalysis (urine colour, turbidity, pH, glucose, bilirubin, ketones, blood, protein, and white 
blood cells) 
• A urine pregnancy test in all postmenarchal female adolescents (see Section 8.1.2 Safety 
Assessments) 
• Record of concomitant medication including LLT and/or LA when applicable (see 
Section 7.6.1 
Concomitant 
Lipid-lowering 
Treatment 
and 
Section 8.1.2 
Safety 
Assessments) 
• Enquiry about any AEs/SAEs and record in the AE section of the eCRF. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 78 of 111 
C O N F I D E N T I A L  
10 
COLLECTION, STORAGE AND SHIPMENT OF 
LABORATORY SAMPLES 
The following laboratory tests will be performed at the local hospital laboratories to allow for 
taking therapeutic decisions upon availability of results:  
1. 
Comprehensive Metabolic Panel: Na, K, Ca, carbon dioxide, Cl, BG, CRP, BUN, 
creatinine, CK, total protein, and albumin 
2. 
Serum Lipase 
3. 
Liver Function Tests: ALT, AST, GGT, AP, and total bilirubin including direct and indirect 
bilirubin 
4. 
Fasting Lipid Panel: TC, LDL-C, VLDL-C, calculated Non-HDL-C, TG, apo B, Lp(a), 
HDL-C, and apo A-I 
Please note: Fasting lipid panels will also be analysed in the central laboratory specified 
in the ‘Laboratory Manual’. As the fasting lipid panel will be analysed at both the local 
hospital laboratory and the central laboratory, 2 separate samples must be drawn. 
5. 
Complete Blood Count: White blood cell count, haemoglobin, haematocrit, platelet count, 
red blood cell count, red cell distribution width, MCV, MCH, and MCHC 
6. 
Hormones: TSH, ACTH, serum cortisol, FSH and LH; the blood sample for testing of 
serum cortisol must be obtained in the early morning (6:00 to 8:00 a.m.) 
7. 
Sex hormones (in patients who are Tanner Stage ≥2): serum oestradiol for female patients 
and serum testosterone for male patients 
8. 
Urinalysis: urine colour, turbidity, pH, glucose, bilirubin, ketones, blood, protein, and white 
blood cells 
9. 
Pregnancy Test: Urine pregnancy test strips will be provided to the sites for conducting 
urine pregnancy tests in female postmenarchal adolescent patients. 
The following laboratory tests will be performed at the central laboratories specified in the 
‘Laboratory Manual’:  
1. 
Genetic Testing: For those patients who have signed a separate ICF for genetic testing, a 
blood sample will be collected according to central laboratory procedures for genotyping 
specified in the ‘Laboratory Manual’ at Screening (Visit 1) or at a later visit. 
2. 
Fasting Lipid Panel: TC, LDL-C, VLDL-C, calculated Non-HDL-C, TG, apo B, Lp(a), 
HDL-C, and apo A-I 
Please note: As the fasting lipid panel will be analysed at both the local hospital laboratory 
and the central laboratory, 2 separate samples must be drawn. All samples will be kept for 
up to 2 years after the study is completed. 
3. 
Fat-Soluble Vitamin Levels: Retinol, alpha tocopherol, 25-hydroxy-D, ratio of alpha 
tocopherol/total lipids (TC + fasting TG), ratio uncarboxylated osteocalcin/total osteocalcin 
4. 
Serum Levels of EFA: Linoleic acid, ALA, AA, DHA, EPA, and eicosatrienoic acid 
5. 
Pharmacokinetics: Lomitapide; pharmacokinetics will be sampled, processed and shipped 
to the central pharmacokinetics laboratory as described in the ‘Laboratory Manual’.  
6. 
Liposcale® Test: The central laboratory specified in the ‘Laboratory Manual’ will take 
aliquots from each PK sample for the exploratory Liposcale® Test, if sufficient sample 
material has been provided and would otherwise be discarded (see ‘Laboratory Manual’ 
for further details). Neither additional blood sampling nor processing or shipping of 
separate samples for the Liposcale® Test will be required at the site.  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 79 of 111 
C O N F I D E N T I A L  
11 
DRUG SAFETY 
The investigator is responsible for the detection and documentation of events meeting the 
definition of an AE or an SAE as provided in Section 11.1 Definitions. This includes the 
evaluation of its seriousness, its severity, and the causal relationship to the investigational 
product and/or concomitant therapy (see Section 11.2 Recording of Adverse Events and 
Serious Adverse Events). 
At each visit, the patient and parent/legal guardian will be asked whether any AEs have 
occurred. A diagnosis of the event based on signs, symptoms and/or other clinical information 
should be established if possible. The diagnosis should be recorded as an AE and/or SAE in 
the corresponding section of the eCRF rather than the individual symptoms. If no diagnosis is 
known and neither clinical signs nor symptoms are present, the abnormal finding should be 
recorded. 
The patient should be observed and monitored carefully until the AE has resolved, the 
condition has stabilised or its cause has been identified. The investigator will be responsible 
to ensure that follow-up will include any supplemental investigations that may be indicated to 
elucidate the nature and/or the cause of the event. 
11.1 
Definitions 
The definitions in this section follow the tripartite harmonised International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Guidelines E6 ‘Good Clinical Practice (GCP)’ and E2A ‘Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting’. 
11.1.1 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the medicinal 
product, whether or not considered related to the medicinal product. 
11.1.2 
Adverse Drug Reaction 
Adverse Drug Reactions (ADRs) are all noxious and unintended responses to a medicinal 
product related to any dose. The phrase ‘responses to a medicinal product’ means that a 
causal relationship between a medicinal product and an AE is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 
All AEs judged by the reporting investigator or the sponsor as having a reasonable causal 
relationship to the study medication qualify as ADRs. 
11.1.3 
Unexpected Adverse Drug Reaction 
If the nature or severity of the ADR is not consistent with the Lojuxta® SPC in lieu of an IB 
(Serious Adverse Reactions Expected in the Paediatric Population Table Page 1; see 
Section 18.1 Source Documents), it is an unexpected ADR. 
11.1.4 
Serious Adverse Event or Adverse Drug Reaction 
Special medical or administrative criteria are needed to define reactions that, either due to their 
nature (‘serious’) or due to the significant, unexpected information they provide, justify 
expedited reporting. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 80 of 111 
C O N F I D E N T I A L  
Please refer to Section 11.2.2 Assessment of Severity for the difference between the terms 
‘serious’ and ‘severe’.  
An SAE or serious ADR (SADR) is any untoward medical occurrence or effect that at any dose: 
• Results in death (death is an outcome, the condition leading to death is the SAE) 
• Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event, which hypothetically 
might have caused death if it were more severe. 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
Medical and scientific judgment should be exercised in deciding whether an AE is serious in 
other situations. Important AEs may not be immediately life-threatening, result in death or 
hospitalisation, but may jeopardise the patient or may require intervention to prevent one of 
the other outcomes listed above. These should also be considered serious.  
11.1.5 
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a suspected adverse reaction 
related to the study medication that is both unexpected and serious.  
The nature or severity of the unexpected ADR is not consistent with the Lojuxta® SPC in lieu 
of an IB (Serious Adverse Reactions Expected in the Paediatric Population Table Page 1; see 
Section 18.1 Source Documents). 
If the investigator or the Medical Monitor judges an SAE not previously documented in the 
Lojuxta® SPC in lieu of an IB (Serious Adverse Reactions Expected in the Paediatric 
Population Table Page 1; see Section 18.1 Source Documents) to be related to study 
medication, the event will qualify as SUSAR and will be subject to expedited regulatory 
reporting. 
11.1.6 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) include the following: 
• Hepatic, small bowel/intestinal, pancreatic and colorectal tumours 
• Hepatic abnormalities 
– Elevations of hepatic transaminases resulting in discontinuation of lomitapide 
– Elevations of hepatic transaminases >3 x ULN that persist despite dose reduction or 
interruption 
– Elevations of hepatic transaminases ≥5 x ULN 
– Symptomatic liver injury 
– Other hepatic evaluation and testing or any histology obtained from liver biopsy and 
imaging evaluations 
• Gastrointestinal effects 
– Events leading to permanent treatment discontinuations 
– Hospitalisation due to gastrointestinal events 
– Events triggering additional investigations such as endoscopy 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 81 of 111 
C O N F I D E N T I A L  
• Major congenital anomalies 
Enhanced Pharmacovigilance will include systematically collecting and reviewing AESIs. In 
addition to reporting AESIs within 15 calendar days (see Section 11.5.2 Reporting of Adverse 
Events of Special Interest), they will be discussed in relevant safety aggregate reports.  
The AESIs will also be diligently followed-up with the investigators using specialised query 
follow-up forms and they will also be identified as potential signals that will be reviewed during 
routine monthly signal detection activities (see Section 11.5.2 Reporting of Adverse Events of 
Special Interest). 
11.2 
Recording of Adverse Events and Serious Adverse Events 
The definitions in this section follow the ‘Detailed Guidance on the Collection, Verification and 
Presentation of Adverse Event/Reactions Reports Arising from Clinical Trials on Medicinal 
Products for Human Use (CT-3)’ of the EC and the EMA ‘Note for Guidance – EudraVigilance 
Human – Processing of Safety Messages and Individual Case Safety Reports (ICSRs).  
11.2.1 
Assessment of Seriousness 
See Section 11.1.4 Serious Adverse Event or Adverse Drug Reaction for the definition of SAEs 
and SADRs. 
11.2.2 
Assessment of Severity 
The severity of AEs will be evaluated according to the Common Terminology Criteria for 
Adverse Events (CTCAE), version 5.0 (Section 18.1 Source Documents). 
The terms ‘severe’ and ‘serious’ are not synonymous:  
• Severity: The term ‘severe’ is often used to describe the intensity of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache).  
• Seriousness: The term ‘serious’ is based on patient/event outcome or action criteria 
usually associated with events that pose a threat to a patient's life or functioning. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
If an AE term is not listed in the CTCAE classification, the severity of the event should be 
assessed as follows: 
• Grade 1 (mild): The AE is noticeable to the patient but does not interfere with routine 
activity. 
• Grade 2 (moderate): The AE interferes with routine activity but responds to symptomatic 
therapy or rest. 
• Grade 3 (severe): The AE significantly limits the patient's ability to perform routine activities 
despite symptomatic therapy. 
• Grade 4 (life-threatening): The patient is at immediate risk of death. 
• Grade 5 (death): Death related to the AE. 
11.2.3 
Assessment of Causality 
Careful medical judgment of the investigator is necessary to determine if there is a causal 
relationship between an AE and the investigational product.  
If there are facts (evidence) or arguments to suggest a reasonable relationship between the 
AE and the investigational product, the investigator will make a determination of a ‘reasonable 
causal relationship’. In all other cases, there is a ‘non-reasonable causal relationship’ 
between the AE and the investigational product. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 82 of 111 
C O N F I D E N T I A L  
To provide sufficient guidance for the investigator, which previously known assessments of 
causality now fall under the categories of ‘reasonable causal relationship’ and ‘non-reasonable 
causal relationship’, the former assessments of causality are listed below for information only. 
Please note that both the SAE forms and the eCRF will only offer the choice between 
‘reasonable causal relationship’ and ‘non-reasonable causal relationship’. 
Former assessments of causality qualifying for ‘reasonable causal relationship’ (for guidance 
and information only): 
• Certain: A clinical event, including laboratory test abnormality occurring in a plausible time 
relationship to drug administration, which cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (de-challenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically definitive, 
using a satisfactory re-challenge procedure if necessary. 
• Probable: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or 
other drugs or chemicals, which follows a clinically reasonable response on withdrawal 
(de-challenge). Re-challenge information is not required to fulfil this definition. 
• Possible: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on drug withdrawal may be lacking or 
unclear. 
Former assessment of causality qualifying for ‘non-reasonable causal relationship’ (for 
guidance and information only): 
• Unlikely: A clinical event, including laboratory test abnormality, with a temporal relationship 
to drug administration, which makes a causal relationship improbable, and in which other 
drugs, chemicals or underlying disease provide plausible explanations. 
11.3 
Monitoring Laboratory Assessments 
Please refer to Section 10 Collection, Storage and Shipment of Laboratory Samples for 
laboratory tests that will be performed at the local hospital laboratories to allow for taking 
therapeutic decisions upon availability of results. The clinical laboratory values are to be 
reviewed by the investigator and classified as ‘normal’ or ‘abnormal’. Abnormal laboratory 
values must in addition be classified as ‘abnormal, clinically significant’ or ‘abnormal, not 
clinically significant’. The reason(s) for ‘abnormal’ findings should be documented. Abnormal, 
clinically significant findings occurring after first administration of study medication should be 
reported as an AE (unless already pre-existing at Baseline with the same severity). 
Please note that fasting lipid panels will also be analysed in the central laboratory specified in 
the ‘Laboratory Manual’ (see Section 10 Collection, Storage and Shipment of Laboratory 
Samples). 
11.4 
Documenting of Adverse Events and Serious Adverse Events 
All information regarding AEs and SAEs, whether reported by the patient/parent/legal guardian 
or observed by the investigator, must be documented in the patient’s medical record and 
recorded in the AE/SAE section of the eCRF. For SAEs, the paper SAE form in the investigator 
site file must also be completed (see Section 11.5.1 Reporting of Serious Adverse Events). 
The investigator is responsible for recording and reporting AEs observed from the first dose of 
study medication (D0) until follow-up at Week 108.  
All AEs occurring during Screening (i.e., after obtaining the patient’s written consent, but before 
starting study medication) should be recorded in the Medical History/Current Medical 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 83 of 111 
C O N F I D E N T I A L  
Conditions section of the eCRF, except those resulting from a protocol-mandated procedure, 
which should be reported in the AE/SAE section of the eCRF. 
All patients will be followed-up for AEs/SAEs until the resolution or stabilisation of the 
AEs/SAEs. At the end of the study, the Medical Monitor will review all ongoing AEs/SAEs. For 
patients who enter the EAP, all ongoing AEs/SAEs will be followed up during the EAP. For all 
other patients, the Medical Monitor will determine appropriate follow-up required for any 
ongoing AEs/SAEs with the corresponding investigator for the respective patient.  
If an investigator learns of an SAE to be reasonably related to study medication any time after 
study medication dosing has stopped, he/she should promptly notify the sponsor. 
11.5 
Immediately Reportable Information 
11.5.1 
Reporting of Serious Adverse Events 
All SAEs should be reported immediately, i.e., within 24 hours of learning that the event meets 
the definition of an SAE. The investigator should complete the SAE report form in the 
investigator site file and send the initial SAE report within 24 hours to the Pharmacovigilance 
Department at APH-19-Safety@emmes.com. 
If the SAE is fatal or life-threatening and is considered at least possibly related to the study 
medication, the completed SAE form should be sent to the Safety and Pharmacovigilance 
Department immediately. 
The minimum information required for the initial SAE report is: 
• Identifiable patient 
• Identifiable reporter 
• Investigational product 
• Description of the event 
If relevant information is missing at the time of the initial SAE report, the reporter should provide 
it in follow-up SAE report(s) upon availability. The follow-up report should contain new, updated 
or corrected information. It should further describe whether the event has resolved or 
continues, and if and how it was treated including documentation of all supportive actions 
taken.  
11.5.2 
Reporting of Adverse Events of Special Interest 
All AESIs (see Section 11.1.6 Adverse Events of Special Interest) should be reported within 
15 calendar days. The investigator should complete the AESI report form in the investigator 
site file and send the initial AESI report to the Pharmacovigilance Department at 
APH-19-Safety@emmes.com. 
The minimum information required for the initial AESI report is: 
• Identifiable patient 
• Identifiable reporter 
• Investigational product 
• Description of the event 
If relevant information is missing at the time of the initial AESI report, the reporter should 
provide it in follow-up AESI report(s) upon availability. The follow-up report should contain new, 
updated or corrected information. It should further describe whether the event has resolved or 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 84 of 111 
C O N F I D E N T I A L  
continues, and if and how it was treated including documentation of all supportive actions 
taken.  
All AESIs will be diligently followed-up using specialised query follow-up forms. They will be 
systematically collected, reviewed, and discussed in relevant safety aggregate reports. AESIs 
will be identified as potential signals that will be reviewed during routine monthly signal 
detection activities.  
Specific hepatic and gastro-intestinal abnormalities, hepatic fibrosis, primary hepatic tumours, 
small bowel/intestinal or pancreatic tumours and major congenital abnormalities will be 
reported expeditedly.  
11.5.3 
Reporting Safety Observations by the Investigator to the IEC/IRB 
At each clinical site, the Principal Investigator is responsible for promptly notifying the relevant 
IEC/IRB of the following information, as applicable: 
• All SAEs and subsequent follow-up information. 
• Any SAE reports and follow-up reports received from the sponsor or the sponsor’s 
designee. 
11.5.4 
Other Reportable Information: Pregnancy 
In the event that a patient is confirmed to be pregnant during the study or during follow-up, the 
investigational product must be discontinued immediately and permanently.  
Any pregnancy or fathering of a child, which occurs up to 30 days within the last application of 
study medication should immediately be reported. The investigator will be asked to complete 
a pregnancy report provided by the sponsor. In addition, the investigator should provide 
follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome. 
12 
STATISTICAL ANALYSIS 
12.1 
Statistical Methods 
The primary efficacy analysis will be conducted once all patients have completed (or withdrawn 
prior to Visit 10) at Week 24±3 days (End of the Efficacy Phase). The primary efficacy analysis 
will include the key primary/secondary efficacy data, all safety data available up to the data 
cut-off date of the last patient reaching Week 24±3 days, and PK parameter analysis. The 
reporting of Week 24±3 days data will allow for an early submission of an application for 
regulatory approval of Lojuxta® in the paediatric indication. The final statistical analysis will be 
performed when all patients have completed the Follow-up Visit (Visit 23) at Week 108±7 days. 
Efficacy, safety, and exploratory data collected during both the Safety Phase and follow-up will 
be included.  
No interim efficacy analyses for efficacy and/or futility will be performed as outlined in 
Section 12.3.3 Interim Analysis. 
12.1.1 
Tests of Hypotheses and Significance Levels 
The primary and secondary efficacy parameters collected during the Efficacy Phase of the 
study will be statistically tested using a 2-sided test at the 5% significance level. 
To address the efficacy objectives, the efficacy parameters will be tested sequentially in a 
step-wise fashion, thereby controlling the overall type I error. First, the primary testing for 
percent change from Baseline in LDL-C at Week 24±3 days will be performed. If this test is 
statistically significant with a 2-sided α = 0.05 and is statistically significant in a positive 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 85 of 111 
C O N F I D E N T I A L  
direction, then the tests of the secondary hypotheses will be performed in the following 
specified order at Week 24±3 days: 
1. 
Non-HDL-C 
2. 
TC 
3. 
VLDL-C 
4. 
apo B 
5. 
TG 
6. 
Lp(a) 
If at any step of the testing procedure a non-significant p-value is reached, further tests in the 
sequence will be performed and p-values will be reported as a measure of the strength of effect 
without declaring statistical significance. 
Analysis of other secondary endpoints collected during the Efficacy Phase and of endpoints 
collected during the Safety Phase will be analysed without adjustment for multiplicity. 
12.1.2 
Determination of Sample Size 
At least 30 evaluable patients (≥8 patients in each of the following age groups, determined by 
age at Baseline: 5 to 10 years, 11 to 15 years, and 16 to ≤17 years) are required at 
Week 24±3 days to provide 92% power, assuming a 25% reduction from Baseline in LDL-C 
with a standard deviation (SD) of 40% and a 2-sided α of 0.05. To allow for up to 33% dropout 
during the Efficacy Phase (prior to Week 24±3 days), an additional 15 patients will be enrolled, 
resulting in a total sample size of approximately 45 patients. Enrolment will be stratified to 
ensure approximately equal numbers of patients in the following age groups: 5 to 10 years, 
11 to 15 years, and 16 to ≤17 years.  
As a conservative assumption, the estimated 25% mean reduction represents approximately 
60% of the 41% mean reduction from Baseline to Week 26/End of Efficacy Phase seen in the 
adult study UP1002/733-005, Intent-to-Treat (ITT) Population. This is the same assumption 
that was used for the sample size in the adult study. The SD represents an approximate 1/3 
increase from the 31% SD observed in the adult study. This increase in SD was used to 
account for potentially increased variability across the 3 age groups. 
12.2 
Definition of Study Populations 
The statistical analysis will be based on the following study populations: 
• The safety analysis set (SAF) will include all patients treated with at least 1 dose of study 
medication. The SAF will be used for all safety analyses.  
• The full analysis set (FAS) will include all patients in the SAF who receive at least 1 dose of 
study medication and who have a Baseline and at least 1 post-Baseline measurement of 
LDL-C. The FAS will be used for all efficacy analyses.  
• All patients from the FAS will be assigned to a completer analysis set (CAS), if they have 
not discontinued the study during the Efficacy Phase (up to Week 24) irrespective of the 
reason for discontinuation. The CAS will be used for all efficacy analyses during the Efficacy 
Phase. 
• Patients who reasonably adhered to all protocol conditions i.e., who have met the eligibility 
criteria and will have received planned study medication without important protocol 
deviations considered to have a serious impact on the efficacy results with the Efficacy 
Phase of the study, will constitute the per-protocol analysis set (PP). The PP will be used 
for supplementary efficacy analyses during the Efficacy Phase. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 86 of 111 
C O N F I D E N T I A L  
The data obtained will be used to check whether the study protocol was adhered to (e.g., 
inclusion and exclusion criteria, time windows, concomitant medication). Case-by-case 
decisions regarding exclusions of patients from the PP analysis will be made in a data review 
meeting. 
Patients who are not treated will not be assigned to any of these analysis sets. All participants 
who pass Screening and enter the run-in period, irrespective of whether they received study 
medication, will be included in the Enrolled Set. 
The FAS will serve as the primary population for the analysis of efficacy data in this study. 
Specifically, the primary, confirmatory endpoint analysis will be done using the FAS. In 
addition, efficacy analyses will be done using the PP and the CAS, serving as sensitivity 
analyses. Safety analyses will be conducted using the SAF. 
12.3 
Planned Analysis 
Full details of the planned analyses will be documented in a Statistical Analysis Plan prior to 
database lock. The primary estimand will be a ‘treatment policy’ estimand which will be defined 
in the Statistical Analysis Plan. 
12.3.1 
Disposition and Exposure 
Patient disposition, medical history, prior and concomitant medication use including current 
LLT and LA, and study medication exposure will be summarised. 
12.3.2 
Demographic Data and other Baseline Characteristics 
Demographics and other Baseline characteristics will be summarised in total and by age group 
by means of summary statistics (number of patients, mean, standard deviation, minimum, 
median, maximum) for continuous variables and by absolute and relative frequencies for 
categorical variables. Baseline characteristics are defined as all results of the examinations 
performed prior to the first administration of study medication. 
Relevant demographic and Baseline characteristics will be summarised using descriptive 
statistics. These variables include: 
• Demographic variables: Age, gender, race, and ethnicity 
• Baseline: 
− Height, weight, BMI, and BSA 
− LDL-C, TC, Non-HDL-C, VLDL-C, Lp(a), TG, and apo B 
− Disease characteristics 
12.3.3 
Interim Analysis 
No interim efficacy analyses for efficacy and/or futility will be performed. 
The primary efficacy analysis and final statistical analysis will be performed as described in 
Section 12.1 Statistical Methods. 
An independent DSMB will periodically review the safety data as described in Section 4.3 Data 
Safety Monitoring Board. 
12.3.4 
Planned Analysis for Primary Endpoint 
The primary efficacy endpoint, percent change from Baseline in directly measured LDL-C at 
Week 24±3 days, will be analysed using the one-sample t-test to test the null hypothesis that 
the percentage change from Baseline is equal to zero against the alternative hypothesis the 
percentage change from Baseline is not equal to zero. The percentage change at 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 87 of 111 
C O N F I D E N T I A L  
Week 24±3 days, together with the corresponding 2-sided 95% confidence interval and 
p-value will be presented. Missing data will be imputed using last observation carried forward 
(LOCF). The analysis will be based on the FAS Population.  
A sensitivity analysis will be performed using a Mixed Model Repeated Measures (MMRM) 
model with the missing at random assumption (i.e., missing data will not be imputed using 
LOCF or any other method). The analysis will be based on the FAS Population. 
Supplementary analyses will include the one-sample t-test and summaries based on the PP 
and CAS. 
Sub-group analyses will be conducted using an Analysis of Covariance (ANCOVA) model to 
estimate the mean percentage change and 2-sided 95% confidence intervals within each 
sub-group at Week 24±3 days. Sub-group analyses will be performed for the 3 age groups and 
also based on documented CVD history, established CVD history, concomitant LLT 
medication, and dose reduction of study medication. These analyses will be based on the FAS 
Population. 
12.3.5 
Planned Analysis for Secondary Endpoints 
The secondary lipid parameter endpoints will be analysed as described for the primary 
endpoint in Section 12.3.4 Planned Analysis for Primary Endpoint. 
As secondary analyses of the pattern of LDL-C and lipid parameter change over time, a MMRM 
model will be used, including all available data (all visits from Baseline through 
Week 104±1 week). Observed changes and percent changes from Baseline at each timepoint 
will be summarised. 
Number and percentage of patients treated with standard LLT (including LA when applicable) 
will be summarised overall and by age group. Any dose increases of standard LLT/increased 
frequency of LA will be summarised. 
Number and percentage of patients with LDL-C falling below the target level will be 
summarised by study visit at any time up to Week 24±3 days and at any time up to Week 104 
by age group and overall. 
12.3.6 
Planned Analysis for Safety Endpoints 
Safety will be assessed using the SAF Population, including all patients who receive any 
amount of study medication, and will be based on evaluation of AEs, laboratory data, vital signs 
and physical examination findings, height, weight, BSA and BMI, ECG, echocardiography (if 
available) and hepatic fat. Safety data summary statistics will be presented overall and by age 
group. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
for purposes of summarisation. All AEs occurring during the study will be included in by-patient 
data listings and will be summarised overall and by age group. Events leading to death, SAEs, 
and events resulting in study discontinuation will be summarised. Adverse events of special 
interest, such as hepatobiliary AEs and hepatotoxicity of different levels, will be summarised 
(see Section 11.1.6 Adverse Events of Special Interest). 
Reported clinical laboratory results and changes from Baseline will be summarised using 
descriptive statistics overall and by age group. Shift tables and summaries of potentially 
clinically significant findings will be presented. Reported values and changes from Baseline for 
vital signs, ECG findings, and echocardiography (if available) will be summarised by time point 
overall and by age group. For lipid accumulation in the liver, the number and percentage of 
patients with liver fat content ≤10%, >10% and ≤20%, and >20% will be summarised overall 
and by age group. Changes from Baseline over time will be presented in shift tables for ECG 
results, echocardiography (if available) and lipid accumulation in the liver. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 88 of 111 
C O N F I D E N T I A L  
To assess sexual maturation, changes from Baseline in Tanner staging results will be 
presented in shift tables and graphically. 
12.3.7 
Planned Analysis for Exploratory Endpoints 
The percentage change from Baseline in mean CIMT and mean FMD at Week 56±3 days and 
at Week 104±1 week will be assessed overall and by age group. 
The number and percentage of patients with (tendon/cutaneous) xanthomas present, and 
locations, will be summarised overall and by age group at Baseline, Week 56±3 days and 
Week 104±1 week. The number and percentage of patients with resolution and regression of 
pre-existing xanthoma (Baseline) to Week 56±3 days and Week 104±1 week will be 
summarised overall and by age group. 
Changes from Baseline in parameters assessed by the Liposcale® Test will be summarised at 
Week 4±3 days, Week 8±3 days, Week 12±3 days, Week 16±3 days, Week 20±3 days and at 
Week 24±3 days. 
12.3.8 
Planned Analysis for Palatability Endpoints 
The number and percentage of patients responding to each question regarding palatability will 
be presented over time overall and by age group. 
12.3.9 
Planned Analysis for Pharmacokinetic Endpoint 
PK data will be used in population PK/PD modelling for the lomitapide program. This will be 
described in a separate document. 
12.4 
Statistical Criteria for Study Termination 
No interim analysis for futility will be performed. Therefore, no criteria for early termination of 
the study from a statistical perspective are considered. 
12.5 
Handling of Missing Data 
Care will be taken during the conduct of this study to minimise the amount of missing data. 
The FAS will be used for the primary analysis of all efficacy endpoints. Each patient in the FAS 
will have a Baseline value and at least one post-Baseline value. Because this is a single-arm 
study, for patients who have missing data at the time point of interest, the LOCF approach will 
be used in all Efficacy Phase analyses. However, for the fasting lipid panel, it is not appropriate 
to carry forward Screening/run-in period values if a Baseline value is missing as this value 
would be obtained prior to stabilisation of the patient on LLT so LOCF will not be used for these 
analyses. 
12.6 
Time Windows 
Data as evaluated during regular visits will be analysed in accordance to the respective visit. 
Time window violations will only be considered for lipid data analyses and for analyses using 
the PP. Visit windows will be defined in the Statistical Analysis Plan. A data review meeting 
will be performed prior to data base lock and it may be decided to exclude single visits from 
the PP analyses due to time window violation. For time to event analyses, the exact visit dates 
and D0 will be taken for calculating the time to event.  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 89 of 111 
C O N F I D E N T I A L  
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Pre-study Documentation 
Prior to enrolment of patients at a study site, specific regulatory documents must be available, 
such as Independent Ethics Committee (IEC)/Institutional Review Board (IRB) approval and 
curricula vitae of investigators and study staff. Amryt Pharmaceuticals DAC will inform the 
investigator which documents need to be provided according to the applicable regulatory 
requirements. 
13.2 
Monitoring 
Amryt Pharmaceuticals DAC will appoint qualified and appropriately trained persons to monitor 
the study and the FU. Monitors will periodically contact the site and perform site visits in 
accordance with applicable regulations, GCP and Amryt Pharmaceuticals DAC approved 
procedures. Study objectives, study design, and enrolment rate will determine the extent, 
nature and frequency of site visits. 
The monitor will contact the site before the start of the study to discuss the protocol and data 
collection procedures with the site study team members. 
During site visits, the monitor will: 
• Check and assess the progress of the study 
• Review study data collected 
• Perform source data verification 
• Identify any issues and address their resolution 
Aim of the site visits is to verify that: 
• The data are authentic, accurate and complete 
• The safety and rights of patients are being protected 
• The study is conducted in accordance with the approved protocol (and any subsequent 
amendment), GCP and all applicable regulatory requirements 
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues. 
The study monitor will record any protocol deviations identified, including, but not limited to, 
patients that were enrolled even though they did not meet all eligibility criteria, patients who 
took concomitant medications specifically prohibited by the protocol, patients who received an 
incorrect dose of study medication, and patients who failed to comply with the protocol-defined 
dietary restrictions. The Investigator and study team members will collaborate with the study 
monitor to identify the reason for each protocol deviation.  
At study closure, the monitor will conduct all activities as indicated in Section 13.4 Study and 
Site Closure. 
13.3 
Data Management and Processing 
Amryt Pharmaceuticals DAC is responsible for data quality control. Each study site is 
responsible for the data documentation and for the maintenance of patient files. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 90 of 111 
C O N F I D E N T I A L  
13.3.1 
Data Collection 
The investigator or an authorised delegate from the study staff will have to complete an eCRF 
for each patient enrolled including patients who discontinue prematurely. If a patient withdraws 
from the study, the reason should be noted in the eCRF if possible. If a patient is withdrawn 
from the study because of a treatment-limiting AE, thorough efforts should be made to clearly 
document the outcome. 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the sponsor in the eCRFs and in all required reports. 
13.3.2 
Data Management Procedures 
A separate ‘Data Management Plan’ will detail data management vendors, systems and 
processes. 
13.3.3 
Data Verification Procedures 
Data will be checked systematically according to a pre-specified ‘Data Validation Plan’ after 
they have been entered into the study database. Queries will be created for errors or missing 
data and clarified by the study monitor at the investigational site.  
13.3.4 
Coding 
All AEs and concomitant diseases will be coded according to MedDRA and all concomitant or 
previous medication based on the World Health Organization (WHO) Drug Dictionary. 
13.3.5 
Procedures for Analysis of Consistency and Medical Plausibility 
A data review meeting will be conducted as soon as all data of the study and the follow-up 
period has been entered into the eCRF and the database has been confirmed as ‘clean’. After 
resolution of all remaining queries, the Statistical Analysis Plan will be finalised and the 
database will be locked. All changes to the data will be kept in an audit trail. 
13.3.6 
Data to be Recorded Directly into the Electronic Case Report Form 
The eCRF will serve as source document for the ethnic origin, which will only be recorded for 
the study.  
13.4 
Study and Site Closure 
Upon completion of the study or premature study (site) closure, the monitor and the investigator 
will be responsible for 
• Return of all study data to Amryt Pharmaceuticals DAC 
• Data clarification and/or resolution 
• Accounting, reconciliation and return of used and unused study medication 
• Review of study site records for completeness 
• Return of all study specific equipment to Amryt Pharmaceuticals DAC 
Amryt Pharmaceuticals DAC reserves the right to suspend or prematurely discontinue this 
study at either a single site or at all sites at any time for any reason. Amryt 
Pharmaceuticals DAC will inform the investigator(s), the IECs/IRBs, and the regulatory 
authorities if the study will be suspended or stopped prematurely.  

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 91 of 111 
C O N F I D E N T I A L  
13.5 
Audits and Inspections 
Amryt Pharmaceuticals DAC or its designee may conduct a quality assurance audit of this 
study to evaluate compliance with the protocol and the principles of GCP. The investigator 
agrees to allow the auditor direct access to all relevant documents and to allocate his/her time 
and the time of his/her staff to the auditor to discuss findings and any relevant issues. 
Regulatory agencies may conduct a regulatory inspection of this study. If a regulatory authority 
requests an inspection, the investigator must inform Amryt Pharmaceuticals DAC immediately 
about this request. The investigator agrees to allow the inspector(s) direct access to all relevant 
documents and to allocate his/her time and the time of his/her staff to the inspector(s) to 
discuss findings and any relevant issues. 
14 
LEGAL AND ETHICAL REQUIREMENTS 
This study will be conducted in accordance with the harmonised tripartite ICH Guidelines for 
GCP and all applicable laws and regulations, including the Declaration of Helsinki, June 1964, 
as modified by the 64th World Medical Association General Assembly, Fortaleza, Brazil, 
October 2013 (see Appendix 7 Declaration of Helsinki). 
14.1 
Regulatory Authority Approval 
Documents required for the application of this study will be submitted to the responsible 
competent authority according to the applicable country-specific laws and regulations. The 
study will not start until the competent authority authorises the study. 
14.2 
Independent Ethics Committee/Institutional Review Board 
This protocol, any amendments if applicable, any material provided to the patient (such as 
patient information, informed consent form and patient questionnaires) as well as additional 
documents, which may be required by national regulations and the IEC/IRB, will be submitted 
to the competent IEC/IRB for review and approval.  
Written approval from the IEC/IRB must be obtained before starting the study, and must be 
documented in a letter specifying the date on which the IEC/IRB met and granted the approval. 
The IEC/IRB approval letter must identify all documents approved by listing the study number, 
study title, study sites/investigators, date and version of study protocol, date and version of 
patient information/informed consent form. A list of IEC/IRB members should be attached to 
the approval letter. 
Any subsequent modifications made to the protocol or to any other documents that must be 
reviewed by the IEC/IRB must also be submitted to the IEC/IRB in accordance with local 
procedures and regulatory requirements. 
14.3 
Patient and Parent/Legal Guardian Information and Informed 
Consent 
In addition to information sheets and consent/assent forms for patients (according to applicable 
local regulations), parent/legal guardian information sheets and consent forms will be 
prepared. 
The investigator will explain the aims, methods, objectives and potential risks and benefits of 
the study to the patient and the parent/legal guardian and will obtain written informed 
consent/assent from the patient (according to applicable local regulations) and written informed 
consent from the parent/legal guardian before he/she will initiate any study-specific procedure.  
The patient and the parent/legal guardian will have sufficient time to ask and resolve any 
questions pertaining to participation in the study, and to consider study participation. In the 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 92 of 111 
C O N F I D E N T I A L  
event that a patient is unable to read or will only be able to provide verbal informed consent, 
the parent/legal guardian may act on the patients’ behalf. 
The investigator will also explain to the patient and the parent/legal guardian that the patient 
will be free to refuse entering the study or to withdraw from it at any time for any reason. Neither 
the refusal to give consent nor the withdrawal of consent will result in discrimination of the 
patient, in particular regarding his/her subsequent medical treatment.  
The patient (according to applicable local regulations) and the parent/legal guardian will be 
asked to review, sign, and date the informed consent form. He/she will receive a copy of the 
signed informed consent form, including the investigator’s signature. The investigator will retain 
the original document. 
The eCRF for this study will contain a section for documenting informed patient consent, which 
needs to be completed appropriately. The consent form will be reviewed and updated if the 
risk/benefit assessment changes or if amendments to the protocol affect the patients’ 
participation in the study. All patients (including those already being treated) and their 
parents/legal guardians will be informed about the new information. Patients are only allowed 
to further participate in the study if they and their parents/legal guardians agree to sign the 
amended form, indicating that they reconsent to participate in the study.  
14.4 
Data Protection 
Medical information about individual patients obtained in the course of this study is confidential 
and may not be disclosed to third parties, except authorised monitors, auditors or inspectors. 
Confidentiality will be ensured by the use of patient numbers for the identification of each 
patient; these patient numbers will also be used for patient data in the patient files and eCRFs. 
The investigator should keep a patient enrolment log showing codes, names and addresses 
and should maintain documents, e.g., patients’ written consent forms, in strict confidence. 
14.5 
Notification of Primary Care Physician 
The investigator should notify the patients’ primary care physician of the patients’ participation 
in the study, if applicable and agreed by the patient and his/her parent/legal guardian. 
14.6 
Investigator Reporting Requirements 
The investigator will ensure that site study team members will promptly bring AEs/SAEs to 
his/her attention. He/she will report all AEs/SAEs as described in Section 11.4 Documenting 
of Adverse Events and Serious Adverse Events and Section 11.5 Immediately Reportable 
Information. The investigator will inform his/her IEC/IRB of any SAE in accordance with the 
local reporting requirements. 
14.7 
Record Retention 
Upon closure of the study, the investigator/study site will maintain a copy of all study records 
in a safe and designated location at the study site in accordance with applicable regulatory 
requirements. Amryt Pharmaceuticals DAC will inform the investigator/study site of the time for 
retaining these records to comply with applicable regulatory requirements. 
Essential documents as defined in the ICH E6 Guideline of GCP must be retained until 
• 2 years after the last approval of a marketing application in an ICH region 
• There are no pending or contemplated marketing applications in an ICH region 
• 2 years will have elapsed since the formal discontinuation of clinical development of the 
investigational product 
• Longer if required by the applicable regulatory requirement(s)/the sponsor 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 93 of 111 
C O N F I D E N T I A L  
Unless other Union law (outside of the EU) requires archiving for a longer period, the sponsor 
and the investigator will archive the content of the clinical trial master file for at least 25 years 
after the completion or discontinuation of the study. The medical files of patients will be 
archived in accordance with local regulations. 
15 
PROTOCOL AMENDMENTS 
All protocol amendments must be submitted to the competent IECs/IRBs and Regulatory 
Agencies for information and/or approval in accordance with local requirements. If applicable, 
approval must be awaited before changes can be implemented, except for changes necessary 
to eliminate an immediate hazard to patients. 
16 
DISCLOSURE OF INFORMATION 
All data and records generated during the study except for patient medical records and all 
inventions discovered in the course of conducting the study, whether patentable or not, are the 
sole and exclusive property of Amryt Pharmaceuticals DAC. 
The investigator and site study team members will keep strictly confidential any information 
provided by Amryt Pharmaceuticals DAC related to this study and all data and records 
generated in the course of conducting the study. They will not use the information, data or 
records for any other purpose than conducting the study without prior written approval of Amryt 
Pharmaceuticals DAC. 
Amryt Pharmaceuticals DAC will prepare an integrated clinical study report in accordance with 
the harmonised tripartite ICH E3 Guideline ‘Structure and Content of Clinical Study Reports’ 
after completion of the study. 
16.1 
Publication of Study Findings 
Negative and positive results of this study will be presented at scientific meetings and/or will 
be published in a peer reviewed scientific or medical journal. By signing the clinical study 
agreement, the investigator agrees that the results of the clinical study may be used for 
publication. The first publication or disclosure shall be a complete, joint multi-centre publication 
or disclosure. Authorship will be discussed with all parties involved, depending on such 
considerations as recruitment. A premature publication or disclosure of partial results is not 
possible. 
The investigator(s) may use the scientific data generated during the study for non-commercial 
purposes, e.g., for scientific publications of any kind only after prior written consent of Amryt 
Pharmaceuticals DAC. The investigator(s) will allow Amryt Pharmaceuticals DAC to review the 
proposed publication or disclosure prior to submission for publication, presenting, using for 
instructional purposes or otherwise disclosing the results of the study. 
If Amryt Pharmaceuticals DAC supposes the proposed publication or disclosure to risk Amryt’s 
ability to patent any invention related to the study, the publication or disclosure will be modified 
or delayed to allow Amryt Pharmaceuticals DAC to file a patent application.  
17 
COMPENSATION FOR INJURIES 
Insurance coverage for damages emerging from the study and involving study patients treated 
with the study medication will be provided according to applicable legal requirements. The 
investigator must inform the patient and parent/legal guardian accordingly and must point out 
that the patient should seek the investigators’ consent before undergoing other medical 
treatment, whenever possible. The investigator will advise patients and parents/legal 
guardians that they must inform the investigator immediately of any injury that might have been 
caused by study participation. 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 94 of 111 
C O N F I D E N T I A L  
18 
REFERENCES 
18.1 
Source Documents 
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 dated 
27 November 2017, U.S. Department of Health and Human Services, National Institutes of 
Health, National Cancer Institute, 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_8.5x11.pdf, accessed 19 July 2019 
European Medicines Agency, Lojuxta®, European Public Assessment Report, 30 May 2013, 
https://www.ema.europa.eu/en/documents/assessment-report/lojuxta-epar-public-
assessment-report_en.pdf (accessed 19 July 2019) 
Lojuxta® Summary of Product Characteristics in lieu of an Investigator’s Brochure including the 
Lojuxta® Summary of Product Characteristics, 23 April 2018; Final Report, 17 September 2020 
Investigational Medicinal Product Dossier, Lomitapide 2 mg hard gelatin capsules, Version 1.0, 
July 2019 
Lomitapide Observational Worldwide Evaluation Registry (LOWER, NCT02135705, 
https://clinicaltrials.gov/ct2/show/NCT02135705?cond=Lomitapide+Observational+Worldwide
+Evaluation+Registry+LOWER%2C+NCT02135705&rank=1 
[accessed 
19 July 2019], 
European 
PAS register 
number 
ENCEPP/SDPP/5326 
http://www.encepp.eu/encepp/viewResource.htm?id=20494 [accessed 19 July 2019]) 
Lomitapide Pediatric Trial Dose Selections Using Two Approaches: Allometric Scaling and 
Physiologically-based Pharmacokinetic (PBPK) Modeling; Final Report, 26 June 2013 
18.2 
Literature 
Alim, A., Y. Tokat, Y. Erdogan, Z. Gokkaya, M. Dayangac, Y. Yuzer and A. Oezcelik (2016). 
"Liver transplantation for homozygote familial hypercholesterolemia: the only curative 
treatment." Ped Transplant 20(8): 1060-1064. 
Alonso, R., J. L. Diaz-Diaz, F. Arrieta, F. Fuentes-Jimenez, R. de Andres, P. Saenz, G. Ariceta, 
J. I. Vidal-Pardo, F. Almagro, R. Argueso, P. Prieto-Matos, J. P. Miramontes, X. Pinto, J. 
Rodriguez-Urrego, L. Perez de Isla and P. Mata (2016). "Clinical and molecular characteristics 
of homozygous familial hypercholesterolemia patients: Insights from SAFEHEART registry." J 
Clin Lipidol 10(4): 953-961. 
Baigent, C., L. Blackwell, J. Emberson, L. E. Holland, C. Reith, N. Bhala, R. Peto, E. H. Barnes, 
A. Keech, J. Simes and R. Collins (2010). "Efficacy and safety of more intensive lowering of 
LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials." 
Lancet 376(9753): 1670-1681. 
Ben-Omran, T., L. Masana, G. Kolovou, G. Ariceta, F. J. Novoa, A. M. Lund, M. P. Bogsrud, 
M. Araujo, O. Hussein, D. Ibarretxe, R. M. Sanchez-Hernandez and R. D. Santos (2019). 
"Real-World Outcomes with Lomitapide Use in Paediatric Patients with Homozygous Familial 
Hypercholesterolaemia." Adv Ther. 
Blom, D. J., M. R. Averna, E. A. Meagher, H. du Toit Theron, C. R. Sirtori, R. A. Hegele, P. K. 
Shah, D. Gaudet, C. Stefanutti, G. B. Vigna, D. Larrey, L. T. Bloedon, P. Foulds, D. J. Rader 
and M. Cuchel (2017). "Long-Term Efficacy and Safety of the Microsomal Triglyceride Transfer 
Protein Inhibitor Lomitapide in Patients With Homozygous Familial Hypercholesterolemia." 
Circulation 136(3): 332-335. 
Blom, D. J., M. Cuchel, M. Ager and H. Phillips (2018). "Target achievement and 
cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia." 
Orphanet J Rare Dis 13(1): 96. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 95 of 111 
C O N F I D E N T I A L  
Chacra, A. P. M., M. C. Ferrari, V. Z. Rocha and R. D. Santos (2019). "Case report: The 
efficiency and safety of lomitapide in a homozygous familial hypercholesterolemic child." J Clin 
Lipidol. 
Chhatrala, R., M. B. Siddiqui, R. T. Stravitz, C. Driscoll, A. Sanyal, C. Sargeant, V. Luketic, A. 
Sharma, R. Sterling, S. Matherly, P. Puri and M. S. Siddiqui (2015). "Evolution of serum 
atherogenic risk in liver transplant recipients: Role of lipoproteins and metabolic and 
inflammatory markers." Liver Transpl 21(5): 623-630. 
Cuchel, M., E. Bruckert, H. N. Ginsberg, F. J. Raal, R. D. Santos, R. A. Hegele, J. A. 
Kuivenhoven, B. G. Nordestgaard, O. S. Descamps, E. Steinhagen-Thiessen, A. Tybjaerg-
Hansen, G. F. Watts, M. Averna, C. Boileau, J. Boren, A. L. Catapano, J. C. Defesche, G. K. 
Hovingh, S. E. Humphries, P. T. Kovanen, L. Masana, P. Pajukanta, K. G. Parhofer, K. K. Ray, 
A. F. Stalenhoef, E. Stroes, M. R. Taskinen, A. Wiegman, O. Wiklund and M. J. Chapman 
(2014). "Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians 
to improve detection and clinical management. A position paper from the Consensus Panel on 
Familial Hypercholesterolaemia of the European Atherosclerosis Society." Eur Heart J 35(32): 
2146-2157. 
Cuchel, M., E. A. Meagher, H. du Toit Theron, D. J. Blom, A. D. Marais, R. A. Hegele, M. R. 
Averna, C. R. Sirtori, P. K. Shah, D. Gaudet, C. Stefanutti, G. B. Vigna, A. M. Du Plessis, K. J. 
Propert, W. J. Sasiela, L. T. Bloedon and D. J. Rader (2013). "Efficacy and safety of a 
microsomal triglyceride transfer protein inhibitor in patients with homozygous familial 
hypercholesterolaemia: a single-arm, open-label, phase 3 study." Lancet 381(9860): 40-46. 
D'Erasmo, L., A. B. Cefalu, D. Noto, A. Giammanco, M. Averna, P. Pintus, P. Medde, G. B. 
Vigna, C. Sirtori, L. Calabresi, C. Pavanello, M. Bucci, C. Sabba, P. Suppressa, F. Natale, P. 
Calabro, T. Sampietro, F. Bigazzi, F. Sbrana, K. Bonomo, F. Sileo and M. Arca (2017). 
"Efficacy of Lomitapide in the Treatment of Familial Homozygous Hypercholesterolemia: 
Results of a Real-World Clinical Experience in Italy." Adv Ther 34(5): 1200-1210. 
deGoma, E. M. (2014). "Lomitapide for the management of homozygous familial 
hypercholesterolemia." Rev Cardiovasc Med 15(2): 109-118. 
EASL (2019). "EASL Clinical Practice Guidelines: Drug-induced liver injury." J Hepatol 70(6): 
1222-1261. 
FDA (2009). Guidance for Industry Drug‑Induced Liver Injury: Premarketing Clinical 
Evaluation. D. Safety. Silver Spring, MD, U.S. Department of Health and Human Services, 
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER). 
France, M., A. Rees, D. Datta, G. Thompson, N. Capps, G. Ferns, U. Ramaswami, M. Seed, 
D. Neely, R. Cramb, C. Shoulders, M. Barbir, A. Pottle, R. Eatough, S. Martin, G. Bayly, B. 
Simpson, J. Halcox, R. Edwards, L. Main, J. Payne and H. Soran (2016). "HEART UK 
statement on the management of homozygous familial hypercholesterolaemia in the United 
Kingdom." Atherosclerosis 255: 128-139. 
Giammanco, A., A. B. Cefalu, D. Noto and M. R. Averna (2019). "Therapeutic options for 
homozygous familial hypercholesterolemia: the role of Lomitapide." Curr Med Chem. 
Graesdal, A., M. P. Bogsrud, K. B. Holven, M. S. Nenseter, I. Narverud, G. Langslet, M. Brekke, 
K. Retterstol, K. E. Arnesen and L. Ose (2012). "Apheresis in homozygous familial 
hypercholesterolemia: the results of a follow-up of all Norwegian patients with homozygous 
familial hypercholesterolemia." J Clin Lipidol 6(4): 331-339. 
Guinard, J.-X. (2000). "Sensory and consumer testing with children." Trends in Food Science 
& Technology 11(8): 273-283. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 96 of 111 
C O N F I D E N T I A L  
Harada-Shiba, M., K. Ikewaki, A. Nohara, Y. Otsubo, K. Yanagi, M. Yoshida, Q. Chang and P. 
Foulds (2017). "Efficacy and Safety of Lomitapide in Japanese Patients with Homozygous 
Familial Hypercholesterolemia." J Atheroscler Thromb 24(4): 402-411. 
Hegele, R. A., P. K. Shah, K. DiGioia, A. Jurecka and D. Blom (2018). "Efficacy of Lomitapide 
Across the Spectrum of Homozygous Familial Hypercholesterolemia." Atherosclerosis 
Supplements 32: 149. 
Howie, S. R. (2011). "Blood sample volumes in child health research: review of safe limits." 
Bull World Health Organ 89(1): 46-53. 
Julius, U. (2016). "Lipoprotein apheresis in the management of severe hypercholesterolemia 
and of elevation of lipoprotein(a): current perspectives and patient selection." Med Devices 
(Auckl) 9: 349-360. 
Klaus, G., C. Taylan, R. Buscher, C. P. Schmitt, L. Pape, J. Oh, J. Driemeyer, M. Galiano, J. 
Konig, C. Schurfeld, R. Spitthover, J. R. Schaefer, L. T. Weber, A. Heibges and R. Klingel 
(2018). "Multimodal lipid-lowering treatment in pediatric patients with homozygous familial 
hypercholesterolemia-target attainment requires further increase of intensity." Pediatr Nephrol 
33(7): 1199-1208. 
Kolovou, G. D., V. Kolovou, A. Papadopoulou and G. F. Watts (2016). "MTP Gene Variants 
and Response to Lomitapide in Patients with Homozygous Familial Hypercholesterolemia." J 
Atheroscler Thromb 23(7): 878-883. 
Leipold, R., F. Raal, J. Ishak, K. Hovingh and H. Phillips (2017). "The effect of lomitapide on 
cardiovascular outcome measures in homozygous familial hypercholesterolemia: A modelling 
analysis." Eur J Prev Cardiol 24(17): 1843-1850. 
Luirink, I. K., J. Determeijer, B. A. Hutten, A. Wiegman, E. Bruckert, C. P. Schmitt and J. W. 
Groothoff (2019). "Efficacy and safety of lipoprotein apheresis in children with homozygous 
familial hypercholesterolemia: A systematic review." Journal of Clinical Lipidology 13(1): 31-
39. 
Nordestgaard, B. G., M. J. Chapman, S. E. Humphries, H. N. Ginsberg, L. Masana, O. S. 
Descamps, O. Wiklund, R. A. Hegele, F. J. Raal, J. C. Defesche, A. Wiegman, R. D. Santos, 
G. F. Watts, K. G. Parhofer, G. K. Hovingh, P. T. Kovanen, C. Boileau, M. Averna, J. Boren, 
E. Bruckert, A. L. Catapano, J. A. Kuivenhoven, P. Pajukanta, K. Ray, A. F. Stalenhoef, E. 
Stroes, M. R. Taskinen and A. Tybjaerg-Hansen (2013). "Familial hypercholesterolaemia is 
underdiagnosed and undertreated in the general population: guidance for clinicians to prevent 
coronary heart disease: consensus statement of the European Atherosclerosis Society." Eur 
Heart J 34(45): 3478-3490a. 
Real, J., C. Arbona, R. Goterris and J. F. Ascaso (2018). "Management of homozygous familial 
hypercholesterolaemia in two brothers." BMJ Case Rep 2018. 
Roeters van Lennep, J., M. Averna and R. Alonso (2015). "Treating homozygous familial 
hypercholesterolemia in a real-world setting: Experiences with lomitapide." J Clin Lipidol 9(4): 
607-617. 
Santos, R. D. (2018). "Expression of LDLRs (Low-Density Lipoprotein Receptors), 
Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 
9) Inhibition in Homozygous Familial Hypercholesterolemia: Connecting the Dots." Arterioscler 
Thromb Vasc Biol 38(3): 481-483. 
Siddiqui, M. B., T. Arshad, S. Patel, E. Lee, S. Albhaisi, A. J. Sanyal, R. T. Stravitz, C. Driscoll, 
R. K. Sterling, T. Reichman, C. Bhati and M. S. Siddiqui (2019). "Small Dense Low-Density 
Lipoprotein Cholesterol Predicts Cardiovascular Events in Liver Transplant Recipients." 
Hepatology. 
Sjouke, B., D. M. Kusters, I. Kindt, J. Besseling, J. C. Defesche, E. J. Sijbrands, J. E. Roeters 
van Lennep, A. F. Stalenhoef, A. Wiegman, J. de Graaf, S. W. Fouchier, J. J. Kastelein and G. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 97 of 111 
C O N F I D E N T I A L  
K. Hovingh (2015). "Homozygous autosomal dominant hypercholesterolaemia in the 
Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome." Eur Heart J 
36(9): 560-565. 
Stefanutti, C., U. Julius, G. F. Watts, M. Harada-Shiba, M. Cossu, V. J. Schettler, G. De 
Silvestro, H. Soran, J. R. Van Lennep, L. Pisciotta, H. U. Klor, K. Widhalm and P. M. Moriarty 
(2017). "Toward an international consensus-Integrating lipoprotein apheresis and new lipid-
lowering drugs." J Clin Lipidol 11(4): 858-871.e853. 
Stefanutti, C., C. Morozzi, S. Di Giacomo, B. Sovrano, D. Mesce and A. Grossi (2016). 
"Management of homozygous familial hypercholesterolemia in real-world clinical practice: A 
report of 7 Italian patients treated in Rome with lomitapide and lipoprotein apheresis." J Clin 
Lipidol 10(4): 782-789. 
Thedrez, A., D. J. Blom, S. Ramin-Mangata, V. Blanchard, M. Croyal, K. Chemello, B. Nativel, 
M. Pichelin, B. Cariou, S. Bourane, L. Tang, M. Farnier, F. J. Raal and G. Lambert (2018). 
"Homozygous Familial Hypercholesterolemia Patients With Identical Mutations Variably 
Express the LDLR (Low-Density Lipoprotein Receptor): Implications for the Efficacy of 
Evolocumab." Arterioscler Thromb Vasc Biol 38(3): 592-598. 
Thompsen, J. and P. D. Thompson (2006). "A systematic review of LDL apheresis in the 
treatment of cardiovascular disease." Atherosclerosis 189(1): 31-38. 
Thompson, G. R. (2015). "Managing homozygous familial hypercholesterolaemia from cradle 
to grave." Atheroscler Suppl 18: 16-20. 
Thompson, G. R., D. J. Blom, A. D. Marais, M. Seed, G. J. Pilcher and F. J. Raal (2018). 
"Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment 
level of serum cholesterol." Eur Heart J 39(14): 1162-1168. 
Underberg, J., C. Cannon, D. Larrey, L. Makris, C. Schwamlein, H. Phillips, L. Bloeden and D. 
Blom (2016). "Abstract 12117: Global Real-World Data on the Use of Lomitapide in Treating 
Homozygous Familial Hypercholesterolemia: The Lomitapide Observational Worldwide 
Evaluation Registry (LOWER), Two-Year Data." Circulation 134(suppl_1): A12117-A12117. 
Underberg, J., C. P. Cannon, D. Larrey, L. Makris, A. Jurecka and D. Blom (2018). "Long-term 
Safety and Efficacy of Lomitapide in Patients with Homozygous Familial Hypercholesterolemia: 
Three-Year Data from LOWER." Atherosclerosis Suppl 32: 24. 
Underberg, J., M. Harada-Shiba, R. Hegele, P. McCullough, K. DiGioia, A. Jurecka, C. 
Stefanutti and D. Blom (2018). "LDL-C Therapeutic Target Attainment in Patients with 
Homozygous Familial Hypercholesterolemia treated with Lomitapide." Journal of Clinical 
Lipidology 12(2): 561-562. 
 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 98 of 111 
C O N F I D E N T I A L  
19 
APPENDICES 
Appendix 1 Child-Pugh Score 
 
Parameter 
Points 
1 
2 
3 
Encephalopathy 
None 
Mild to moderate 
(CTCAE Grade 1/2) 
Severe 
(CTCAE Grade 3/4) 
Ascites 
None 
Mild to moderate 
(Diuretics responsive) 
Severe  
(Diuretics refractory) 
Bilirubin (mg/dL) 
<2 
2 to 3 
>3 
Albumin (g/dL) 
>3.5 
2.8 to 3.5 
<2.8 
Prothrombin time 
 
 
 
• 
Seconds prolonged 
<4 
4 to 6 
>6 
• 
International normalised ratio 
<1.7 
1.7 to 2.3 
>2.3 
Child-Turcotte-Pugh Class obtained by adding score for each parameter (total points) 
Class A 
5 to 6 points 
(least severe liver disease) 
Class B 
7 to 9 points 
(moderately severe liver disease) 
Class C 
10 to 15 points 
(most severe liver disease) 
Sources:  
C. G. Child, J. G. Turcotte: Surgery and portal hypertension. In: C. G. Child (Editor): The liver and portal 
hypertension. Saunders, Philadelphia 1964, P. 50–64. 
R. N. Pugh, I. M. Murray-Lyon, J. L. Dawson, M. C. Pietroni, R. Williams: Transection of the oesophagus for bleeding 
oesophageal varices. In: British Journal of Surgery. Volume 60, Issue 8, August 1973, P. 646–649, ISSN 0007-
1323. PMID 4541913. 
 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 99 of 111 
C O N F I D E N T I A L  
Appendix 2 Schwartz Formula 
 
𝐺𝐺𝐺𝐺𝐺𝐺 (𝑚𝑚𝑚𝑚/ min 𝑝𝑝𝑝𝑝𝑝𝑝 1.73 𝑚𝑚2) = 39.1 ቎ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 (𝑚𝑚)
𝑆𝑆𝑆𝑆𝑆𝑆 (𝑚𝑚𝑚𝑚
𝑑𝑑𝑑𝑑)
቏
0.516
𝑥𝑥 ቎
1.8
𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝐶𝐶 (𝑚𝑚𝑚𝑚
𝐿𝐿)
቏
0.294 
[1.099]𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 ൤ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 (𝑚𝑚)
1.4
൨
0.188
 
 
Bedside calculation of 0.413*(height/serum creatinine) provides a good approximation to the 
estimated GFR formula. 
 
Source: G. J. Schwartz, A. Munoz, M. F. Schneider, R. H. Mak, F. Kaskel, B. A. Warady, S. L. Furth: New Equations 
to Estimate GFR in Children with CKD. Journal of the American Society of Nephrology 2009, Volume 20, Issue 3, 
P. 629-637. 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 100 of 111 
C O N F I D E N T I A L  
Appendix 3 Common Terminology Criteria for Adverse Events (CTCAE), 
Hepatobiliary Disorders 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 101 of 111 
C O N F I D E N T I A L  
 
Source: Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 dated 27 November 2017, U.S. 
Department of Health and Human Services, National Institutes of Health, National Cancer Institute, 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.p
df, accessed 01 September 2020 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 102 of 111 
C O N F I D E N T I A L  
Appendix 4 WHO Growth Charts for Boys and Girls 5 to 19 Years of Age 
Appendix-Figure 1 BMI-For-Age, Boys, 5 to 19 Years of Age 
 
Source: https://www.who.int/growthref/cht_bmifa_boys_perc_5_19years.pdf, accessed 01 September 2020 
Appendix-Figure 2 BMI-For-Age, Girls, 5 to 19 Years of Age 
 
Source: https://www.who.int/growthref/cht_bmifa_girls_perc_5_19years.pdf, accessed 01 September 2020 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 103 of 111 
C O N F I D E N T I A L  
Appendix-Figure 3 Height-For-Age, Boys, 5 to 19 Years of Age 
 
Source: https://www.who.int/growthref/cht_hfa_boys_perc_5_19years.pdf, accessed 01 September 2020 
Appendix-Figure 4 Height-For-Age, Girls, 5 to 19 Years of Age 
 
Source: https://www.who.int/growthref/cht_hfa_girls_perc_5_19years.pdf, accessed 01 September 2020 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 104 of 111 
C O N F I D E N T I A L  
Appendix 5 Tanner Staging 
Appendix-Table 1 Classification of Sex Maturity Stages in Girls 
Stage 
Pubic Hair 
Breasts 
1 
Preadolescent 
Preadolescent 
2 
Sparse, lightly pigmented, straight, medial 
border of labia 
Breast and papilla elevated as small 
mound, areolar diameter increased 
3 
Darker, beginning to curl, increased amount 
Breast and areola enlarged, no contour 
separation 
4 
Coarse, curly, abundant but amount less 
than adult 
Areola and papilla form secondary mound 
5 
Adult feminine triangle, spread to medial 
surface of thighs 
Mature, nipple projects, areola part of the 
general breast contour 
Appendix-Table 2 Classification of Sex Maturity Stages in Boys 
Stage 
Pubic Hair 
Penis 
Testes 
1 
None 
Preadolescent 
Preadolescent 
2 
Scanty, long, slightly 
pigmented 
Slight enlargement 
Enlarged scrotum, pink 
texture altered 
3 
Darker, starts to curl, small 
amount 
Longer 
Larger 
4 
Resembles adult type but 
less in quantity; coarse, 
curly 
Larger, glans and breadth 
increase in size 
Larger, scrotum dark 
5 
Adult distribution, spread to 
medial surface of thighs 
Adult size 
Adult size 
Sources:  
W. A. Marshall, J. M. Tanner: Variations in pattern of pubertal changes in girls. In: Archives of Disease in Childhood 
1969, Volume 44, P. 291–303. 
W. A. Marshall, J. M. Tanner: Variations in pattern of pubertal changes in boys. In: Archives of Disease in Childhood 
1970, Volume 45, P. 13–23. 
 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 105 of 111 
C O N F I D E N T I A L  
Appendix 6 Laboratory Tests 
 
Category, Panel 
Parameters 
Haematology 
 
• Complete Blood Count (CBC) 
Haematocrit 
 
Haemoglobin 
 
Mean corpuscular haemoglobin (MCH) 
 
Mean corpuscular haemoglobin concentration (MCHC) 
 
Mean corpuscular volume (MCV) 
 
Platelet count 
 
Red blood cell count 
 
Red cell distribution width 
 
White blood cell count 
Serum chemistry 
 
• Metabolic panel 
Albumin 
 
Blood glucose (BG) 
 
Blood urea nitrogen (BUN) 
 
Calcium (Ca) 
 
Carbon dioxide 
 
Chloride (Cl) 
 
Creatinine 
 
Creatinine kinase (CK) 
 
C-reactive protein (CRP) 
 
Potassium (K) 
 
Sodium (Na) 
 
Total protein 
 
Serum lipase 
• Fasting lipid panel 
apolipoprotein A-I (apo A-I) 
 
apolipoprotein B (apo B) 
 
High-density lipoprotein cholesterol (HDL-C) 
 
Lipoprotein(a) [Lp(a)] 
 
Low-density lipoprotein cholesterol (LDL-C) 
 
Non high-density lipoprotein cholesterol (Non-HDL-C) 
 
Total cholesterol (TC) 
 
Triglycerides (TG) 
 
Very low-density lipoprotein cholesterol (VLDL-C) 
• Liver function tests (LFTs) 
Alanine aminotransferase (ALT) 
 
Aspartate aminotransferase (AST) 
 
Alkaline phosphatase (AP) 
 
Gamma-glutamyl transferase (GGT) 
 
Total bilirubin 
 
Direct bilirubin 
 
Indirect bilirubin 
• Essential fatty acids (EFA) 
Arachidonic acid (AA) 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 106 of 111 
C O N F I D E N T I A L  
Category, Panel 
Parameters 
• Essential fatty acids (EFA) 
Alpha linoleic acid (ALA) 
 
Docosahexaenoic acid (DHA) 
 
Eicosapentaenoic acid (EPA) 
 
Eicosatrienoic acid 
 
Linoleic acid 
• Fat-soluble vitamin levels 
Retinol (Vitamin A) 
 
25-hydroxy-D (Vitamin D) 
 
Alpha tocopherol (Vitamin E) 
 
Ratio alpha tocopherol/total lipids 
 
Ratio uncarboxylated osteocalcin/total osteocalcin 
• Hormones 
Thyroid stimulating hormone (TSH) 
 
Adrenocorticotrophic hormone (ACTH) 
 
Serum cortisolL 
 
Follicle stimulating hormone (FSH) 
 
Luteinising hormone (LH) 
• Sex hormones (Tanner Stage ≥2) 
Serum testosterone 
 
Serum oestradiol 
• Pharmacokinetics 
Lomitapide 
Urine 
 
• Urinalysis 
Bilirubin 
 
Blood 
 
Colour 
 
Glucose 
 
Ketones 
 
pH 
 
Protein 
 
Turbidity 
 
White blood cells 
• Urine pregnancy test 
 
 
 
 
 
 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 107 of 111 
C O N F I D E N T I A L  
Appendix 7 Declaration of Helsinki 
World Medical Association Declaration of Helsinki 
Ethical Principles for Medical Research 
Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 108 of 111 
C O N F I D E N T I A L  
or other health care professionals and never with the research subjects, even though they have given 
consent.  
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the environment. 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and 
if the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens.  
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation.  
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed.  
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm.  
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used 
for research must be respected. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 109 of 111 
C O N F I D E N T I A L  
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol.  
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent 
in its functioning, must be independent of the researcher, the sponsor and any other undue influence 
and must be duly qualified. It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. 
No amendment to the protocol may be made without consideration and approval by the committee. 
After the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical research must 
be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods used to deliver 
the information.  
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed.  
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorised representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the group represented by the potential subject, the research cannot instead be 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 110 of 111 
C O N F I D E N T I A L  
performed with persons capable of providing informed consent, and the research entails only minimal 
risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to 
give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorised representative. The potential subject’s dissent should 
be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research group. In such circumstances the 
physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances:  
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or  
Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention  
and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial 
in the trial. This information must also be disclosed to participants during the informed consent 
process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject.  
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness 
and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication. 

Amryt Pharmaceuticals DAC 
Study Protocol APH-19 
Version: 7.0 / Final / 09 February 2023 
Page 111 of 111 
C O N F I D E N T I A L  
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available.