Clinical trial NCT05088460
Conditions: Familial Partial Lipodystrophy Metabolic Abnormalities
Sponsor: Regeneron Pharmaceuticals
Start date: 2022-02-28; Completion date: 2024-04-18
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Two cohorts are being studied based on leptin levels. Cohort A is composed of patients with baseline leptin \<8.0 ng/mL and Cohort B is composed of patients with baseline leptin 8.0 to ≤20.0 ng/mL

The primary objectives will be evaluated for patients in Cohort A only:

* To evaluate the effect of REGN4461 on fasting triglycerides (TG) in patients with elevated baseline fasting TG
* To evaluate the effect of REGN4461 on hyperglycemia in patients with elevated baseline Hemoglobin A1c (HbA1c)

The following secondary objectives of the study will be evaluated for Cohort B and for the combined set of Cohorts A plus B:

* To evaluate the effect of REGN4461 on fasting TG levels in patients with hypertriglyceridemia
* To evaluate the effect of REGN4461 on glycemic control in patients with hyperglycemia

The following secondary objectives of the study will be evaluated for Cohorts A and B separately, and for the combined set of Cohorts A plus B:

* To evaluate the effect of REGN4461 on liver fat in patients with hepatic steatosis
* To evaluate the effect of REGN4461 on hunger
* To evaluate safety and tolerability of REGN4461
* To characterize the concentration profile of REGN4461 over time
* To assess immunogenicity to REGN4461

Detailed description:

Arms: arm 1: Randomized to placebo for 12 weeks and then crossover to REGN4461 for 12 weeks arm 2: Randomized to receive REGN4461 for 24 weeks
Interventions: intervention 1: REGN4461 intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Intravenous (IV) infusion loading dose followed by subcutaneous (SC) injection weekly (QW). intervention 2: Intravenous (IV) infusion loading dose followed by subcutaneous (SC) injection weekly (QW).

Protocol documents:
Prot_000.pdf: 
IND Number: 139310 
EudraCT:  2021-000138-33 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED STUDY 
OF THE LEPR AGONIST ANTIBODY REGN4461 FOR THE 
TREATMENT OF METABOLIC ABNORMALITIES IN PATIENTS 
WITH FAMILIAL PARTIAL LIPODYSTROPHY 
Compound: 
REGN4461 
Clinical Phase: 
2 
Protocol Number: 
R4461-PLD-20100 
Protocol Version: 
Amendment 1 
Amendment 1 Date of Issue: 
See appended electronic signature page 
Original Date of Issue: 
21 May 2021 
Medical/Study Director: 
 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential:  This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national or state laws whether by 
legislation or in equity.  For the purposes of compliance with all applicable freedom of 
information laws, and regulations, and their equivalents anywhere in the world including but not 
limited to the US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior to 
disclosure to third parties of any information and/or data related to, or contained within, this 
submission, it will be given every opportunity under applicable laws to protect its commercial 
VV-RIM-00140037-2.0 Approved - 03 May 2022 GMT-5:00
NCT05088460


Clinical Study Protocol  
 
R4461-PLD-20100 Amendment 1 
 
interests and/or its trade secrets including the opportunity to object to such disclosure and/or 
provide redaction proposals. 
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Clinical Study Protocol  
 
R4461-PLD-20100 Amendment 1 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 3 
 
CONFIDENTIAL 
AMENDMENT HISTORY 
Overall Rationale for Amendment 1 
The main purpose of this amendment is to change the SC weekly maintenance dose of REGN4461 
from 
 mg QW to 
 mg QW. 
Description of Change 
Brief Rationale 
Section # and Name 
The 
maintenance 
dose 
of 
REGN4461 
has 
changed 
from 
 mg QW to 
 mg QW. 
New 
data 
from 
the 
ongoing 
REGN4461-GLD-1875 
study 
in 
patients 
with 
generalized 
lipodystrophy (GLD) have emerged 
since this protocol was finalized.  
Lower observed drug concentrations 
in these patients suggest that GLD 
patients (who have very low leptin 
levels) 
have 
faster 
REGN4461 
clearance than expected based on the 
FIH study (REGN4461-HV-1794) 
that was used as the basis for the PK 
model in both the familial partial 
lipodystrophy (FPLD) and GLD 
studies. 
Given 
the 
uncertainty 
surrounding PK in patients with 
FPLD (that share a characteristic 
with GLD patients of having low 
leptin levels), and the desire to 
ensure drug concentrations are in the 
fully therapeutic range, the dose is 
being increased to ensure study 
patients 
achieve 
a 
Ctrough 
that 
saturates target-mediated clearance 
at approximately the same serum 
concentrations as targeted with the 
original dose of 
 mg QW. This 
dose was determined using an 
updated PK model based on all 
available data. While excess weight 
loss is unlikely in FPLD, a dose 
modification rule was added for the 
dose to be reduced from 
 mg to 
 mg during Treatment Period 2 
(weeks 13-24) in case of excessive 
weight loss. 
Clinical Study Protocol Synopsis –
Treatment 
Section 1 Introduction 
Section 3.2.2 Rationale for Dose 
Selection 
Section 6.1 Study Description and 
Duration 
Figure 2 Study Flow Diagram 
Section 8.1 
Investigational 
and 
Reference Treatments 
Section 8.4.1 Dose Modification 
 
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Clinical Study Protocol  
 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name 
Patients screened under the original 
protocol may re-screen for HbA1c 
and 
triglycerides 
(the 
only 
parameters required to be repeated) 
before entering the run-in period to 
reconfirm eligibility if the screening 
window (up to 10 weeks) has been 
exceeded. 
In the GLD study there were large 
changes observed in TGs and 
HbA1c during the screening period. 
If the screening period is extended, 
we need to ensure patients still meet 
the eligibility criteria for the study. 
Section 6.1 Study Description and 
Duration 
Section 9.1.1 Footnotes for the 
Schedule of Events Table 1: 
Screening and Placebo Run-in, 
Footnote 1 
Appendix 1 Hemoglobin A1C, 
Triglyceride and Leptin 
Measurements 
Removed the sentence that imaging 
data will be destroyed after 15 years. 
Destruction of material after 15 
years only applies to biological 
samples. 
Section 9.2.2.11 Assessment of 
Hepatic Fat Content and Liver Size 
The definition of baseline has been 
added to the Statistical Methods. 
The definition was missing in the 
prior version of the protocol. 
Section 11.4 Statistical Methods 
 
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CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition/Term 
ADA 
Anti-drug antibody 
ADIPO-IR 
Adipose Insulin Resistance 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like protein 3 
APLD 
Acquired partial lipodystrophy 
ApoC3 
Apolipoprotein C3 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body mass index 
BPI-SF 
Brief Pain Inventory – Short Form 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax  
Maximum observed concentration 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
Ctrough 
Trough concentrations 
DNA 
Deoxyribonucleic acid 
DXA 
Dual-energy X-ray absorptiometry 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
(e)COA 
(electronic) Clinical Outcomes Assessment 
EDC 
Electronic data capture 
ELISA 
Enzyme Linked Immunosorbent Assay 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
Food and Drug Administration 
FFA 
Free fatty acids 
FIH 
First-in-human 
FPLD 
Familial partial lipodystrophy 
GCP 
Good Clinical Practice 
GLD 
Generalized lipodystrophy 
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GPS 
Global Patient Safety 
HADS 
Hospital anxiety and depression scale 
HbA1c 
Hemoglobin A1c 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
HOMA-IR 
Homeostatic Model Assessment for Insulin Resistance 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LEPR 
Leptin receptor 
LIPO-IR 
Lipoprotein Insulin Resistance Index 
LLN 
Lower limit of normal 
MD 
Multiple doses 
MMTT 
Mixed meal tolerance test 
MRI 
Magnetic resonance imaging 
MRI-PDFF 
Magnetic resonance imaging-derived proton density fat fraction 
NHANES 
National Health and Nutrition Examination Survey 
NIH 
National Institutes of Health 
NODM 
New onset of diabetes mellitus 
PBO 
Placebo run-in period 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PGIS 
Patient Global Impression of Severity 
PHQ-8 
8-item patient health questionnaire depression scale 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic Analysis Set 
PLD 
Partial lipodystrophy 
PRO 
Patient reported outcome 
QoL 
Quality of life 
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QW 
Weekly 
RBC 
Red blood cell 
RBQM 
Risk-Based Quality Monitoring 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
rhLeptin 
Recombinant human leptin 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SF-36 
Short form 36 
sLEPR 
soluble form of the leptin receptor 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TF 
Trunk fat %/leg fat % 
TG 
Triglyceride 
TLR 
Trunk to leg fat ratio 
TP1 
Treatment Period 1  
TP2 
Treatment Period 2 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................5 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................15 
1. 
INTRODUCTION ......................................................................................................21 
2. 
STUDY OBJECTIVES ..............................................................................................24 
2.1. 
Primary Objectives .....................................................................................................24 
2.2. 
Secondary Objectives .................................................................................................24 
2.3. 
Exploratory Objectives ...............................................................................................24 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................26 
3.1. 
Clinical Hypothesis .....................................................................................................26 
3.2. 
Rationale .....................................................................................................................26 
3.2.1. 
Rationale for Study Design .........................................................................................26 
3.2.2. 
Rationale for Dose Selection ......................................................................................30 
3.2.3. 
Rationale for Analysis ................................................................................................34 
3.3. 
Risk-Benefit ................................................................................................................34 
3.3.1. 
Risk-Benefit of REGN4461 ........................................................................................34 
4. 
ENDPOINTS ..............................................................................................................35 
4.1. 
Primary Endpoints ......................................................................................................35 
4.2. 
Secondary Endpoints ..................................................................................................35 
4.3. 
Exploratory Endpoints ................................................................................................36 
5. 
STUDY VARIABLES................................................................................................38 
5.1. 
Demographic and Baseline Characteristics ................................................................38 
5.2. 
Efficacy Variables ......................................................................................................38 
5.3. 
Safety Variables ..........................................................................................................38 
5.4. 
Pharmacokinetic Variables .........................................................................................38 
5.5. 
Immunogenicity Variables ..........................................................................................38 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................38 
6. 
STUDY DESIGN .......................................................................................................39 
6.1. 
Study Description and Duration .................................................................................39 
6.1.1. 
Description of Study Cohorts and Dose Escalation ....................................................43 
6.1.2. 
End of Study Definition ..............................................................................................43 
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6.2. 
Planned Interim Analysis ............................................................................................43 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............44 
7.1. 
Number of Patients Planned .......................................................................................44 
7.2. 
Study Population .........................................................................................................44 
7.2.1. 
Inclusion Criteria ........................................................................................................44 
7.2.2. 
Exclusion Criteria .......................................................................................................45 
7.3. 
Premature Withdrawal from the Study .......................................................................47 
7.4. 
Replacement of Patients .............................................................................................48 
8. 
STUDY TREATMENTS............................................................................................49 
8.1. 
Investigational and Reference Treatments ..................................................................49 
8.2. 
Run-in Treatment ........................................................................................................49 
8.3. 
Background Treatment ...............................................................................................49 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................50 
8.4.1. 
Dose Modification ......................................................................................................50 
8.4.2. 
Study Drug Discontinuation .......................................................................................50 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................50 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................51 
8.5. 
Management of Acute Reactions ................................................................................51 
8.5.1. 
Acute Intravenous Infusion Reactions ........................................................................51 
8.5.1.1. 
Interruption of the Intravenous Infusion .....................................................................51 
8.5.1.2. 
Termination of the Intravenous Infusion ....................................................................52 
8.5.2. 
Acute Injection Reactions ...........................................................................................52 
8.5.2.1. 
Systemic Injection Reactions ......................................................................................52 
8.5.2.2. 
Local Injection Site Reactions ....................................................................................52 
8.6. 
Method of Treatment Assignment ..............................................................................53 
8.7. 
Blinding ......................................................................................................................53 
8.8. 
Emergency Unblinding ...............................................................................................53 
8.9. 
Treatment Logistics and Accountability .....................................................................54 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................54 
8.9.2. 
Supply and Disposition of Treatments .......................................................................54 
8.9.3. 
Treatment Accountability ...........................................................................................54 
8.9.4. 
Treatment Compliance ................................................................................................54 
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8.10. 
Concomitant Medications and Procedures .................................................................54 
8.10.1. 
Prohibited Medications ...............................................................................................55 
8.10.2. 
Permitted Medications ................................................................................................55 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................56 
9.1. 
Schedule of Events .....................................................................................................56 
9.1.1. 
Footnotes for the Schedule of Events Table 1: Screening and Placebo Run-in .........60 
9.1.2. 
Footnotes for the Schedule of Events Table 2: TP1, TP2 and Off-Drug 
Follow-Up ...................................................................................................................70 
9.1.3. 
Early Termination Visit ..............................................................................................71 
9.1.4. 
Unscheduled Visits .....................................................................................................71 
9.2. 
Study Procedures ........................................................................................................71 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................71 
9.2.2. 
Efficacy Procedures ....................................................................................................71 
9.2.2.1. 
Fasting Triglycerides ..................................................................................................71 
9.2.2.2. 
Fasting Glucose ..........................................................................................................71 
9.2.2.3. 
Hemoglobin A1C ........................................................................................................72 
9.2.2.4. 
Fructosamine ...............................................................................................................72 
9.2.2.5. 
Insulin .........................................................................................................................72 
9.2.2.6. 
Lipid Panel ..................................................................................................................72 
9.2.2.7. 
Urine Creatinine and Albumin....................................................................................72 
9.2.2.8. 
Insulin Sensitivity Measurement ................................................................................72 
9.2.2.9. 
Assessment of Body Composition ..............................................................................72 
9.2.2.10. 
Bioimpedance .............................................................................................................72 
9.2.2.11. 
Assessment of Hepatic Fat Content and Liver Size ....................................................73 
9.2.3. 
Safety Procedures .......................................................................................................73 
9.2.3.1. 
Body Weight and Height ............................................................................................73 
9.2.3.2. 
Vital Signs ..................................................................................................................73 
9.2.3.3. 
Physical Examination .................................................................................................73 
9.2.3.4. 
Electrocardiogram .......................................................................................................73 
9.2.3.5. 
Menstrual History, Pregnancy Status Reporting, and Confirmation of 
Contraception ..............................................................................................................74 
9.2.3.6. 
Hypoglycemia Monitoring ..........................................................................................74 
9.2.4. 
Laboratory Testing ......................................................................................................74 
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9.2.5. 
Clinical Outcomes Assessments .................................................................................75 
9.2.5.1. 
Lipodystrophy Hunger Questionnaire ........................................................................75 
9.2.5.2. 
Brief Pain Inventory – Short Form Questionnaire ......................................................76 
9.2.5.3. 
Short Form – 36 ..........................................................................................................76 
9.2.5.4. 
Patient Health Questionnaire-8 ...................................................................................76 
9.2.5.5. 
Hospital Anxiety and Depression Scale Questionnaire ..............................................76 
9.2.5.6. 
Patient Global Impression of Severity-Hunger ...........................................................76 
9.2.5.7. 
Patient Global Impression of Severity- Pain ..............................................................77 
9.2.5.8. 
Patient Global Impression of Change- Hunger ...........................................................77 
9.2.5.9. 
Patient Global Impression of Change- Pain ................................................................77 
9.2.6. 
Drug Concentration and Measurements .....................................................................77 
9.2.7. 
Immunogenicity Measurements and Samples ............................................................77 
9.2.8. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................77 
9.2.8.1. 
Soluble LEPR (sLEPR) ..............................................................................................77 
9.2.8.2. 
Angiopoietin-Like Protein 3 (ANGPTL3) ..................................................................78 
9.2.8.3. 
Apolipoprotein C3 (APOC3) ......................................................................................78 
9.2.8.4. 
Free Fatty Acids ..........................................................................................................78 
9.2.9. 
Future Biomedical Research (Optional) .....................................................................78 
9.2.10. 
Pharmacogenomic Analysis (Optional) ......................................................................78 
10. 
SAFETY EVALUATION AND REPORTING .........................................................80 
10.1. 
Recording and Reporting Adverse Events ..................................................................80 
10.1.1. 
General Guidelines .....................................................................................................80 
10.1.2. 
Reporting Procedure ...................................................................................................81 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................81 
10.1.4. 
Other Adverse Events of Special Interest that Do Not Require Expedited 
Reporting to Sponsor ..................................................................................................82 
10.2. 
Definitions ..................................................................................................................82 
10.2.1. 
Adverse Event .............................................................................................................82 
10.2.2. 
Serious Adverse Event ................................................................................................82 
10.2.3. 
Adverse Events of Special Interest .............................................................................83 
10.2.4. 
Infusion Reactions ......................................................................................................83 
10.3. 
Evaluation of Severity and Causality .........................................................................84 
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10.3.1. 
Severity .......................................................................................................................84 
10.3.2. 
Causality .....................................................................................................................84 
10.4. 
Safety Monitoring .......................................................................................................86 
10.5. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .........................................................................................................86 
11. 
STATISTICAL PLAN................................................................................................87 
11.1. 
Statistical Hypothesis ..................................................................................................87 
11.2. 
Justification of Sample Size........................................................................................87 
11.3. 
Analysis Sets ...............................................................................................................88 
11.3.1. 
Efficacy Analysis Sets ................................................................................................88 
11.3.2. 
Safety Analysis Set .....................................................................................................88 
11.3.3. 
Pharmacokinetic Analysis Set ....................................................................................88 
11.3.4. 
Immunogenicity Analysis Set .....................................................................................88 
11.4. 
Statistical Methods ......................................................................................................88 
11.4.1. 
Patient Disposition ......................................................................................................88 
11.4.2. 
Demography and Baseline Characteristics .................................................................88 
11.4.3. 
Efficacy Analyses .......................................................................................................89 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................89 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................89 
11.4.4. 
Control of Multiplicity ................................................................................................90 
11.4.5. 
Safety Analysis ...........................................................................................................90 
11.4.5.1. 
Adverse Events ...........................................................................................................90 
11.4.5.2. 
Other Safety ................................................................................................................91 
11.4.5.3. 
Treatment Exposure ....................................................................................................91 
11.4.5.4. 
Treatment Compliance ................................................................................................91 
11.4.6. 
Pharmacokinetics ........................................................................................................92 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................92 
11.4.6.2. 
Analysis of Pharmacokinetic Parameters ...................................................................92 
11.4.7. 
Analysis of Immunogenicity Data ..............................................................................92 
11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................93 
11.5. 
Interim Analysis ..........................................................................................................93 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........93 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................94 
12.1. 
Data Management and Electronic Systems ................................................................94 
12.1.1. 
Data Management .......................................................................................................94 
12.1.2. 
Electronic Systems ......................................................................................................94 
12.2. 
Study Monitoring ........................................................................................................94 
12.2.1. 
Monitoring of Study Sites ...........................................................................................94 
12.2.2. 
Source Document Requirements ................................................................................95 
12.2.3. 
Case Report Form Requirements ................................................................................95 
12.3. 
Audits and Inspections ................................................................................................95 
12.4. 
Study Documentation .................................................................................................96 
12.4.1. 
Certification of Accuracy of Data ...............................................................................96 
12.4.2. 
Retention of Records ..................................................................................................96 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................97 
13.1. 
Good Clinical Practice Statement ...............................................................................97 
13.2. 
Informed Consent .......................................................................................................97 
13.3. 
Patients Confidentiality and Data Protection ..............................................................97 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................98 
13.5. 
Clinical Study Data Transparency ..............................................................................98 
14. 
PROTOCOL AMENDMENTS ..................................................................................99 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................100 
15.1. 
Premature Termination of the Study .........................................................................100 
15.2. 
Close-out of a Site ....................................................................................................100 
16. 
CONFIDENTIALITY ..............................................................................................100 
17. 
FINANCING AND INSURANCE ...........................................................................100 
18. 
PUBLICATION POLICY ........................................................................................100 
19. 
REFERENCES .........................................................................................................101 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................104 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................107 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events: Screening and Placebo Run-In ...................................................57 
Table 2: 
Schedule of Events: TP1, TP2 and Off-Drug Follow up ............................................62 
Table 3: 
Half-Width of the 90% Confidence Interval for Primary Endpoints ..........................87 
LIST OF FIGURES 
Figure 1: 
Preliminary Mean (±SD) Concentrations of Total REGN4461 in Serum by 
Nominal Time and Treatment Arm in Patients with Generalized 
Lipodystrophy (Study R4461-GLD-1875; PKAS) .....................................................33 
Figure 2: 
Study Flow Diagram ...................................................................................................42 
Figure 3:  Screening Triglyceride and Hemoglobin A1c Measurements ....................................105 
LIST OF APPENDICES 
APPENDIX 1. HEMOGLOBIN A1C, TRIGLYCERIDE AND LEPTIN 
MEASUREMENTS .........................................................................................105 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized Double-Blind Placebo-Controlled Study of the LEPR 
Agonist Antibody REGN4461 for the Treatment of 
Metabolic 
Abnormalities in Patients with Familial Partial Lipodystrophy 
Site Locations 
Principal Investigator 
This is a multicenter study that will take place globally. 
 
Objectives 
Primary Objectives 
The primary objectives will be evaluated for patients in cohort A (leptin 
<8.0 ng/ml) only: 
• 
To evaluate the effect of REGN4461 on fasting triglycerides (TG) in 
patients with baseline leptin <8.0 ng/mL with elevated baseline fasting 
TG (>200 mg/dL) 
• 
To evaluate the effect of REGN4461 on hyperglycemia in patients with 
baseline leptin <8.0 ng/mL with elevated baseline hemoglobin A1c 
(HbA1c; >7.0%) 
Secondary Objectives 
The following secondary objectives of the study will be evaluated for 
cohort B and for the combined set of cohorts A plus B: 
• To evaluate the effect of REGN4461 on fasting TG levels in patients 
with hypertriglyceridemia (fasting TG >200 mg/dL).   
• To evaluate the effect of REGN4461 on glycemic control in patients 
with hyperglycemia (HbA1c >7.0%) 
The following secondary objectives of the study will be evaluated for 
cohorts A and B separately, and for the combined set of cohorts A plus B: 
• To evaluate the effect of REGN4461 on liver fat in patients with hepatic 
steatosis (baseline Hepatic Fat Fraction [Magnetic resonance imaging-
derived proton density fat fraction, MRI-PDFF] ≥8.5%)  
• To evaluate the effect of REGN4461 on hunger  
• To evaluate safety and tolerability of REGN4461  
• To characterize the concentration profile of REGN4461 over time  
• To assess immunogenicity to REGN4461 
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Study Design 
This is a phase 2, randomized, double-blind, placebo-controlled study of the 
efficacy and safety of REGN4461 in patients with familial partial 
lipodystrophy (FPLD) and metabolic abnormalities (elevated fasting TG 
with or without elevated HbA1c) who are not receiving recombinant human 
leptin (rhLeptin) therapy. 
Patients 18 years of age or older with a clinical diagnosis of FPLD will 
undergo screening, including measurement of HbA1c, fasting TG, and leptin 
levels. A diagnosis of FPLD requires either a documented ClinVar 
pathogenic or likely pathogenic variant in a known FPLD gene or 
pathognomonic regional lipoatrophy by dual-energy X-ray absorptiometry 
(DXA).  In addition, patients must have metabolic abnormalities 
(hypertriglyceridemia with or without hyperglycemia) and serum leptin 
level ≤20.0 ng/mL to be included. 
The study comprises a screening period lasting up to 10 weeks, a 4-week 
single-blind placebo run-in period (PBO), a 12-week double-blind placebo-
controlled treatment period (TP1), a 12-week single-blind treatment period 
(TP2) during which all patients receive REGN4461, and a 16-week off-drug 
safety follow-up period. 
Patients will first be assigned to 1 of 2 cohorts based on baseline leptin levels 
at screening (cohort A: leptin <8.0 ng/mL; cohort B: leptin 8.0 to 
≤20.0 ng/mL).  
These cohorts will then be randomized 1:1 into the following study arms:  
• 
Study arm 1: patients randomized to receive placebo for 12 weeks 
(TP1) followed by crossover to REGN4461 treatment for 12 weeks 
(TP2).  
• 
Study arm 2: patients randomized to receive REGN4461 treatment 
for 24 weeks (TP1 and TP2). 
Randomization will be stratified according to HbA1c at screening (HbA1c 
≤7.0% or HbA1c >7.0%) within each cohort. 
Study Duration 
Study duration is up to 54 weeks. 
End of Study Definition 
The end of study is defined as the date the last patient either completes the 
last study visit, withdraws from the study, or is lost to follow-up (ie, the 
study patient can no longer be contacted by the investigator). 
Population 
 
 
Sample Size: 
Up to 40 patients will be enrolled. 
 
Target Population: 
Adult patients with a clinical diagnosis of FPLD, leptin ≤20.0 ng/mL and 
metabolic abnormalities who are not currently treated with rhLeptin.  
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Treatment 
 
 
Study Drug 
 
Dose/Route: 
REGN4461  
 mg/kg intravenously (IV) loading dose followed by weekly (QW) doses 
of 
 mg subcutaneously (SC). 
Reference Drug 
Dose/Route: 
 
Placebo matching REGN4461 is prepared in the same formulation without 
the addition of REGN4461. 
 
Schedule: 
Single-blind run-in period:  
All patients will receive an IV placebo infusion, followed by placebo SC 
QW injections administered subsequently for 3 weeks.  
Treatment period 1 (TP1):  
• 
Study arm 1: IV placebo infusion on day 1 followed by SC QW 
injections of placebo for 11 weeks starting on day 8 
• 
Study arm 2: IV REGN4461 (
 mg/kg) infusion on day 1 
followed by SC injections of REGN4461 (
 mg QW) for 
11 weeks starting on day 8 
Treatment Period 2 (TP2):   
• 
Study arm 1: IV REGN4461 (
 mg/kg) infusion and SC placebo 
on day 85, followed by SC injections of REGN4461 (
 mg QW) 
for 11 weeks starting on day 92 
• 
Study arm 2: IV placebo and SC injection of REGN4461 (
 mg) 
on day 85, followed by SC injections of REGN4461 (
 mg QW) 
for 11 weeks starting on day 92 
Endpoints 
 
 
Co-Primary: 
• 
Percent change in fasting serum TG from baseline to week 12 in 
patients with elevated baseline fasting TG (>200 mg/dL) and with 
baseline leptin <8.0 ng/mL (cohort A) 
• 
Absolute change in HbA1c from baseline to week 12 in patients 
with elevated baseline HbA1c (>7.0%) and with baseline leptin 
<8.0 ng/mL (cohort A) 
 
Secondary: 
Note: Patients in study arm 1 must meet stability criteria during TP1 (a 
change in HbA1c ≤0.5 percentage points and a change in TG ≤25%) to be 
included for specific endpoints as indicated below. 
The following secondary endpoints will be analyzed for cohort B and for the 
combined set of cohorts A plus B: 
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• 
Percent change in fasting serum TG from baseline to week 12 in 
patients with elevated baseline fasting TG (>200 mg/dL)  
• 
Absolute change in HbA1c from baseline to week 12 in patients 
with elevated baseline HbA1c (>7.0%)  
The following secondary endpoints will be analyzed for cohorts A and B 
separately, and for the combined set of cohorts A plus B: 
• 
Percent change in fasting serum TG from baseline to week 12 
compared to the percent change between week 12 and week 24 
(study arm 1) 
• 
Percent change in fasting serum TG from baseline to week 24 
(study arm 2) 
• 
Percent change in fasting serum TG after the first 12 weeks of 
exposure to REGN4461— from baseline to week 12 (study arm 2) 
and from week 12 to week 24 (study arm 1;  patients must meet 
stability criteria) 
• 
Change in HbA1c from baseline to week 12 compared to the 
change between week 12 and week 24 (study arm 1) 
• 
Change in fasting glucose from baseline to week 12 compared to 
the change between week 12 and week 24 (study arm 1) 
• 
Change in HbA1c from baseline to week 24 (study arm 2) 
• 
Change in fasting glucose from baseline to week 24 (study arm 2) 
• 
Change in HbA1c from baseline to week 12 (study arm 2) and from 
week 12 to week 24 (study arm 1; patients must meet stability 
criteria) 
• 
Change in fasting glucose from baseline to week 12 (study arm 2) 
and from week 12 to week 24 (study arm 1) 
• 
Percent change in liver fat (MRI-PDFF) from baseline to week 12, 
REGN4461 versus placebo in patients with baseline liver fat 
(MRI-PDFF) ≥8.5%. 
• 
Percent change in liver fat (MRI-PDFF) from baseline to week 12 
compared to the percent change between week 12 and week 24 
(study arm 1) in patients with baseline liver fat (MRI-PDFF)  
≥8.5%. 
• 
Percent change in liver fat (MRI-PDFF) from baseline to week 24 
(study arm 2) in patients with baseline liver fat (MRI-PDFF)  
≥8.5%. 
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• 
Percent change in liver fat (MRI-PDFF) from baseline to week 12 
(study arm 2) and from week 12 to week 24 (study arm 1) in 
patients with baseline liver fat (MRI-PDFF) ≥8.5%. 
• 
Change on the daily lipodystrophy hunger questionnaire from 
baseline to week 12 and week 24 
• 
The incidence and severity of treatment-emergent adverse events 
(TEAEs)  
• 
Concentrations of REGN4461 in serum over time 
• 
Immunogenicity of REGN4461 as determined by the incidence, 
titer and clinical impact of treatment-emergent anti-drug 
antibodies (ADAs) to REGN4461, over time compared to placebo 
 
Procedures and Assessments 
The following procedures will be performed for the sole purpose of 
determining study eligibility or characterizing the baseline characteristics of 
the 
study 
population: 
medical 
history, 
demographics, 
human 
immunodeficiency virus (HIV) serology, and hepatitis testing (hepatitis B 
surface antigen [HBsAg] and hepatitis C virus [HCV]), menstrual history, 
and pregnancy status. 
Efficacy procedures include: fasting TG assessment, fasting glucose 
assessment, HbA1c, fructosamine, insulin, lipid panel, urine creatinine and 
albumin, insulin sensitivity measurement, lipoprotein analysis by NMR, 
whole body composition by DXA, bioimpedance, liver volume and fat 
content by MRI, and patient-reported outcomes. 
Safety procedures include: body weight, height, vital signs, physical 
examination, menstrual history/pregnancy status reporting/ confirmation of 
contraception, and electrocardiogram (ECG).  
Laboratory procedures include: blood chemistry, hematology, lipid panel, 
urinalysis, pregnancy testing, and other laboratory testing. 
Statistical Plan 
 No formal statistical hypothesis testing will be performed for this study.  
The size of the study is determined by feasibility assessments. Due to the 
limited number of identified PLD patients with low leptin and moderate 
metabolic abnormalities, up to 40 patients will be enrolled.  
With a total of 40 patients (20 per cohort, randomized in the ratio of 1:1 into 
REGN4461 arm and placebo arm), the primary analysis will be carried out 
on the 20 patients in lower leptin cohort A in TP1. Not all patients will 
necessarily have HbA1c >7.0%, ie, not all of the patients will be assessed 
for the HbA1c endpoint. From the feasibility work, it is estimated that 78% 
of the patients will have elevated baseline HbA1c. With 20 patients in 
cohort A (10 patients per study arm), the half-width of the 90% confidence 
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interval in change from baseline to week 12 between the REGN4461 arm 
and the placebo arm for HbA1c is 1.4 percentage points, assuming the 
standard deviation (SD) of 1.81 %. For the TG, the half-width of the 90% 
confidence interval in logarithm transformed geometric mean ratio (GMR) 
(REGN4461 week12/baseline divided by placebo week12/baseline) is 0.67, 
assuming the SD for logarithm transformed fasting TG is 0.87. The SD is 
estimated from the subset samples of the extracted National Institutes of 
Health (NIH) study data.  
 
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1. 
INTRODUCTION 
Lipodystrophy is a rare condition in which the body is unable to produce or maintain adipose 
tissue. Partial lipodystrophy (PLD) is characterized by the selective loss of adipose tissue from 
various areas of the body. Partial lipodystrophy is a heterogeneous disease, and the extent of 
lipoatrophy varies significantly among patients. The reduced number of functional adipocytes 
leads to relative leptin deficiency and associated metabolic abnormalities due to lipids being stored 
in other tissues, including muscle and liver. These metabolic abnormalities include 
hypertriglyceridemia, insulin resistance/diabetes, and nonalcoholic fatty liver disease. Partial 
lipodystrophy patients with diabetes are at risk for complications of diabetes, including 
nephropathy. In a large fraction (one-third to one-half, based on available data) of familial partial 
lipodystrophy (FPLD) patients lipoatrophy is extensive enough to result in reduced leptin levels 
(<8.0 ng/mL), which could drive severe hunger and insulin resistance.  
The true incidence of PLD is unknown, with estimates of 2 to 3 clinical cases per million 
(Chiquette, 2017).  Most cases of PLD are familial (FPLD), and often are associated with 
pathogenic mutations in genes important for adipocyte biology. However, due to a presentation 
that overlaps with the much more common metabolic syndrome, FPLD is clinically 
underdiagnosed. Recent data point to a higher prevalence of individuals with FPLD gene variants, 
as high as 160 per million (Gonzaga-Jauregui, 2020).  
Few therapeutic options are available to patients with metabolic complications caused by PLD and 
no available treatment targets the underlying lipoatrophy. Treatments for diabetes, 
hypertriglyceridemia, and fatty liver disease are the same as in patients without lipodystrophy, 
consisting of lifestyle modifications, anti-diabetic agents (including insulin), and lipid-lowering 
therapies (eg, statins and fibrates). However, PLD patients with severe metabolic sequelae are 
often resistant to standard of care treatments. Recombinant methionyl human leptin (metreleptin, 
Myalept®) is approved in Europe and Japan for the complications of leptin deficiency in patients 
with PLD, but not in the United States. Early clinical experience demonstrated that a mixed 
population of lipodystrophy patients (80% PLD) with low leptin (<4 ng/ml) might be more likely 
to respond to metreleptin therapy (Diker-Cohen, 2015), whereas later studies indicated that PLD 
patients with higher leptin levels are also likely to respond (Endocrinologic and Metabolic Drugs 
Advisory Committee Briefing Document METRELEPTIN (BLA STN125390), 2013). Daily 
dosing of metreleptin is required and adverse effects include risk of immunogenicity with ~85% 
of patients developing binding antibodies to metreleptin. In clinical trials, ~6% of patients with 
generalized lipodystrophy developed neutralizing antibodies associated with adverse events (AEs) 
consistent with loss of endogenous leptin activity (MYALEPT [Package Insert], 2014). Thus, there 
is an unmet need for effective therapies in PLD that are safer than metreleptin, administered less 
frequently, and can treat patients who have developed neutralizing antibodies to the only approved 
therapy, metreleptin. 
REGN4461 (IgG4 isotype) is a fully human antibody that binds and activates the leptin receptor 
(LEPR). REGN4461 is not related to endogenous leptin, and therefore should not have elevated 
risks of anti-drug antibodies (ADAs) cross-reacting with endogenous leptin.  
A 2-part first-in-human (FIH) study of REGN4461 has been completed (R4461-HV-1794, Parts A 
and B). In Part A, 
 
 were studied. 
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REGN4461 was generally well-tolerated. In Part B, the effects of REGN4461 on food intake, 
appetite, body composition, and body weight in overweight or obese subjects with low baseline 
leptin levels were assessed. In FIH Part B, 12-weeks of REGN4461 treatment was associated with 
~2.2% weight loss in cohorts with low baseline leptin levels (<8.0 ng/mL) while patients who 
received placebo had weight gain of 0.6%. These findings are consistent with prior observations 
with metreleptin, and with the mechanism of action of REGN4461 as a LEPR agonist.  
A phase 2 randomized, double-blind, placebo-controlled study of efficacy and safety of 
REGN4461 in patients with generalized lipodystrophy (GLD) who are not receiving recombinant 
methionyl human leptin (rhLeptin, metreleptin) therapy (Study R4461-GLD-1875) is ongoing. In 
this GLD study, the blinded treatment period consisted of 24 weeks and included three 8-week 
periods, with each period assigned for patients to receive placebo, low dose or high dose 
REGN4461. Patients were randomized to 1 of 2 treatment arms. One treatment arm received 
placebo, low dose and high dose REGN4461 in that sequence. The other arm correspondingly 
received low dose, high dose and high dose REGN4461. All patients received a single IV loading 
dose of 
 at the beginning of the first treatment period in which they received REGN4461, 
followed by 
) SC injections that were based on baseline weight. For patients with 
baseline weight 
, the low dose was 
. 
For patients with weight 
, the low dose was 
 
. The safety and PK data in patients with GLD helped to inform the dose selected for this 
study, R4461-PLD-20100, in patients with PLD.  
Additional clinical experience with REGN4461 comes from the 18-month long treatment of a now 
20-year-old female with acquired partial lipodystrophy (APLD) and neutralizing antibodies to 
metreleptin who is being treated under an individual patient expanded access protocol. The patient 
had a marked reduction in serum triglycerides (TG), hemoglobin A1c (HbA1c) and hepatic fat 
following administration of REGN4461 out to 52 weeks of treatment. Specifically her baseline TG 
were 1288 mg/dL and had been consistently averaging less than 500 mg/dL while her drug 
concentrations were at levels predicted to be effective. Similarly, her baseline HbA1c was 9.5% 
and was reduced to 8.0%. Finally, her hepatic fat was 29.9% at baseline and was reduced to 8.0% 
during treatment with REGN4461. 
Based on preclinical and clinical studies performed to-date, it is hypothesized that low-leptin PLD 
patients will benefit from the LEPR agonist antibody, REGN4461, and therefore PLD patients 
with a range of lower leptin levels will be enrolled in order to explore the relationship between 
leptin levels and response to REGN4461 in this study. The primary analysis of this study includes 
PLD patients with leptin levels <8.0 ng/mL (cohort A). A second cohort of PLD patients with 
leptin levels 8.0 ng/mL to ≤20.0 ng/mL (cohort B) will also be assessed (separately) given analyses 
of individualized patient data from the National Institutes of Health (NIH) which indicated patients 
with leptin level ≤20.0 ng/mL had a better response to metreleptin than did those with leptin level 
>20.0 ng/mL. A combined analysis of the 2 cohorts will also be performed in order to determine 
the effect of REGN4461 on endpoints in patients with leptin levels within a broader range 
(≤20.0 ng/ml). An Investigational Use Only (IUO) assay is being developed for stratification and 
patient selection purposes; study eligibility and cohort allocation will be determined using the 
leptin Enzyme Linked Immunosorbent Assay (ELISA) developed and validated under Clinical 
Laboratory Improvement Amendments (CLIA) guidelines.  
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Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure.  
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objectives will be evaluated for patients in cohort A (leptin <8.0 ng/ml) only: 
• To evaluate the effect of REGN4461 on fasting TG in patients with baseline leptin 
<8.0 ng/mL with elevated baseline fasting TG (>200 mg/dL) 
• To evaluate the effect of REGN4461 on hyperglycemia in patients with baseline leptin 
<8.0 ng/mL with elevated baseline HbA1c (>7.0%) 
2.2. 
Secondary Objectives 
The following secondary objectives of the study will be evaluated for cohort B and for the 
combined set of cohorts A plus B: 
• To evaluate the effect of REGN4461 on fasting TG levels in patients with 
hypertriglyceridemia (fasting TG >200 mg/dL) 
• To evaluate the effect of REGN4461 on glycemic control in patients with 
hyperglycemia (HbA1c >7.0%)  
The following secondary objectives of the study will be evaluated for cohorts A and B separately, 
and for the combined set of cohorts A plus B: 
• To evaluate the effect of REGN4461 on liver fat in patients with hepatic steatosis 
(baseline Hepatic Fat Fraction [Magnetic resonance imaging-derived proton density fat 
fraction, MRI-PDFF] ≥8.5%)  
• To evaluate the effect of REGN4461 on hunger  
• To evaluate safety and tolerability of REGN4461  
• To characterize the concentration profile of REGN4461 over time  
• To assess immunogenicity to REGN4461 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study, will be evaluated for cohorts A and B separately, and for 
the combined set of cohorts A plus B: 
• To evaluate the effect of REGN4461 on insulin sensitivity  
• To evaluate the effect of REGN4461 on pain  
• To evaluate the effect of REGN4461 on depression  
• To evaluate the effect of REGN4461 on anxiety  
• To evaluate the effect of REGN4461 on body weight  
• To evaluate the effect of REGN4461 on regional body composition  
• To evaluate the effect of REGN4461 on Quality of Life (QoL)  
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• 
 
 
  
• To determine if bioimpedance measurements can be used as adequate surrogates for 
dual-energy X-ray absorptiometry (DXA) to measure regional body composition in 
patients with FPLD  
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Clinical Hypothesis 
There is no statistical hypothesis. The clinical hypothesis is that REGN4461 treatment will be 
associated with numeric improvements in metabolic abnormalities in FPLD patients with baseline 
serum leptin levels <8.0 ng/mL.  
3.2. 
Rationale 
3.2.1. 
Rationale for Study Design 
Rationale for Selection of Study Population: 
This is a randomized, double-blind, placebo-controlled, study of the efficacy and safety of 
REGN4461 in patients with FPLD and metabolic abnormalities (elevated fasting TG with or 
without elevated HbA1c) who are not receiving recombinant human leptin (rhLeptin) therapy. The 
central hypothesis is that LEPR agonism will be effective in treating metabolic complications of 
leptin deficiency in PLD patients with low baseline leptin levels. This relationship between 
baseline leptin levels and REGN4461 response was borne out in the FIH R4461-HV-1794 Part B, 
where patients with leptin levels <5 ng/mL had the most robust response (weight loss), patients 
with leptin levels 5 ng/mL to 8 ng/mL had an intermediate response, and patients with leptin >8 
ng/mL had no response.  
The primary analyses of this study, therefore, include PLD patients with leptin levels <8.0 ng/mL 
(cohort A). A second cohort of PLD patients with leptin levels 8.0 ng/mL to ≤20.0 ng/mL 
(cohort B) will also be assessed (separately) given analyses of individualized patient data from the 
NIH which indicated patients with leptin level ≤20.0 ng/mL had a better response to metreleptin 
than did those with leptin level >20.0 ng/mL. Study eligibility and cohort allocation will be 
determined using an IUO leptin ELISA. 
Partial lipodystrophy includes FPLD and APLD. The majority of patients that were studied in PLD 
metreleptin trials had FPLD. Acquired PLD patients comprise ~15% of PLD patients. Acquired 
PLD is thought to be caused by immune destruction of adipocytes. These patients can have one or 
more autoimmune diseases, eg, Type 1 diabetes, that might confound responses to leptin agonist 
therapy. For this reason, APLD patients are excluded from enrollment in this study. 
Consensus diagnostic criteria for FPLD has been elusive (Brown, 2016). The phenotype of FPLD 
is similar to “metabolic syndrome” that affects 30% of individuals in the United States (US) 
(Moore, 2017). The main clinical distinction between common metabolic syndrome and FPLD is 
the selective loss of adipose tissue in FPLD patients, which can be a subtle and often overlooked 
physical exam finding. For this reason, regional lipoatrophy and metabolic complications, while 
not sufficient, are required inclusion criteria in this study. 
A documented pathogenic gene variant in an FPLD-associated gene adds additional confidence to 
the diagnosis of FPLD. Currently Online Mendelian Inheritance in Man has categorized FPLD1-7 
of which FPLD2-7 are monogenic and caused by mutations in LMNA, PPARG, PLIN1, CIDEC, 
LIPE, and CAV1 respectively. Mutations in additional genes such as PIK3R1, ADRA2A PCYT1A, 
AKT2, ZMPSTE24, PSMB8, WRN, POLD1 and BLM have also been associated with FPLD. Of 
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note, the genetic architecture of FPLD is such that there are a multitude of variants within each 
gene, each impacting a small number of affected individuals. For the purpose of this protocol a 
pathogenic variant is defined as a variant that has been rated as pathogenic or likely pathogenic by 
ClinVar for familial partial lipodystrophy. ClinVar in turn assesses genetic variants using 
guidelines set forward by the American College of Medical Genetics and Genomics and the  
Association for Molecular Pathology (Richards, 2015). The pathogenicity of genetic variants has 
been validated by ClinVar for only a small fraction of the genetic variants that have been associated 
with FPLD in the literature. For this reason, additional objective criteria was introduced based on 
the defining attributes of PLD: selective loss and altered distribution of body fat. These criteria are 
based on DXA scans and were formulated using published data for PLD patients (Meral, 2018) 
alongside large databases of control subjects such as the National Health and Nutrition 
Examination Survey (NHANES). The DXA-based inclusion criteria quantify the increased ratio 
of trunk adipose to limb adipose tissue in FPLD subjects. DXA criteria that can discriminate 
between control and FPLD subjects were established based on the United Kingdom (UK) Biobank 
dataset and published data (Meral, 2018). The algorithm was tested with the NHANES database 
and demonstrated a specificity of >99% in females. Next the DXA algorithm was tested on an 
unpublished dataset from the NIH demonstrating a sensitivity of 95% to 97% in females. A similar 
approach was used to develop DXA criteria for FPLD in males resulting in similar sensitivity and 
specificity.  
Patients with either moderate abnormalities of both HbA1c (>7.0%) and TG (>200 mg/dL), or a 
more severe abnormality of TG (>450 mg/dL), with normal or mildly abnormal HbA1c (up to 
7.0%) are included. These inclusion criteria are met by the majority of FPLD patients and allow 
for separate analysis of REGN4461 treatment effects on each metabolic parameter.  
The study includes adult patients only. Familial PLD is generally a progressive disease with 
pubertal onset of fat loss and a long delay between signs/symptoms and diagnosis. As such there 
is not a large population of pediatric patients with high unmet medical need. 
Rationale for Study Endpoints:  
The co-primary endpoints are the change in TG from baseline to week 12, and the change in HbA1c 
from baseline to week 12 in patients in cohort A. These co-primary endpoints were specifically 
selected because improvements in either or both parameters would help address the highest unmet 
medical need for PLD patients.  
Significant heterogeneity in the response of fasting TG and HbA1c was observed in the metreleptin 
clinical trials. Given the uncertainty in treatment effect in FPLD patients and the limited number 
of FPLD patients, secondary endpoints include within-group analyses of all patients receiving their 
first 12 weeks of REGN4461. This includes individuals in study arm 1 (TP2) and study arm 2 
(TP1). In addition, for Study Arm 1, the within group change for TP1 (placebo treatment) will be 
compared to TP2 (REGN4461 treatment). 
The secondary endpoints also include analyses of fasting TG and HbA1c in the higher leptin 
cohort B. While data from Part B of REGN4461-HV-1794 suggest that a leptin level <8.0 ng/mL 
might identify individuals most likely to respond, some data suggest response to LEPR agonism 
in individuals with higher serum leptin, up to 20.0 ng/mL. Analyses of responses in cohort B will 
therefore allow for more accurate determination of a REGN4461-responsive patient population. 
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The percent change in hepatic fat (assessed by magnetic resonance imaging-derived proton density 
fat fraction [MRI-PDFF]) is a key secondary endpoint and the analysis is structured to understand 
whether there are different responses by cohort. There is 1 published study of the effects of 
metreleptin on hepatic steatosis in FPLD patients (Simha, 2012). It reported a baseline mean liver 
hepatic fat of 13.8% with a standard deviation (SD) of 6.1% in 24 patients with FPLD. In this 
open-label observational study, a 43% reduction in percent hepatic fat (SD of 27%, coefficient of 
variation of 63%) was reported after 3 months of metreleptin treatment. It is anticipated that 
REGN4461 will improve hepatic steatosis, similar to what has been observed with metreleptin 
therapy (Javor, 2005) (Oral, 2002) (Petersen, 2002) (Brown, 2018a) (Brown, 2018b).  
While HbA1c provides an excellent estimate of average glucose levels, it does not provide 
information on insulin sensitivity. Non-invasive measurements of insulin sensitivity will be used 
including the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), which 
incorporates measures of fasting insulin and glucose. Also 2 additional surrogate measurements of 
insulin sensitivity will be analyzed. First is the Lipoprotein Insulin Resistance Index (LIPO-IR) 
which incorporates the amount and size distribution of lipoproteins to estimate insulin sensitivity 
given the known changes in lipoprotein profiles that occur across a wide range of insulin sensitivity 
(Shalaurova, 2014). The final surrogate of insulin sensitivity is the Adipose Insulin Resistance 
(ADIPO-IR), which incorporates fasting serum insulin and free fatty acid (FFA) levels. 
FPLD patients are known to suffer from severe hunger, thought to be mediated by leptin 
deficiency, and this might  be improved with REGN4461 treatment. This will be measured using 
the lipodystrophy hunger questionnaire. In addition to hunger, a number of mental health issues, 
particularly depression and anxiety have been observed at high rates in lipodystrophy patients 
(Calabrò, 2020). Regeneron Pharmaceuticals, Inc. (Regeneron) hosted a lipodystrophy patient 
panel in 2018, consisting mostly of PLD patients, which also identified pain as an important 
concept to patients. A subsequent interview study with 18 PLD patients also confirmed this 
feedback. Therefore, to assess whether REGN4461 could impact these patient-centric issues, a 
number of clinical outcomes assessments (COAs) will be used in this study to assess hunger, pain, 
QoL, depression and anxiety. 
 
 It will be 
important to determine whether this potential weight loss is due to loss of adipose tissue, hepatic 
fat, or muscle mass. For this reason, body composition (whole-body DXA) will be determined at 
baseline, at the end of TP1 and TP2. The whole-body DXA provides measures of fat mass, lean 
mass, and bone mass in different regions of interest including arm, legs and trunk. Arm and leg 
lean mass is predominantly made up of skeletal muscle and is a good proxy for appendicular 
muscle mass (Kim, 2002) while a large component of trunk lean mass is organs other than skeletal 
muscle. In addition, patients will have bioimpedance measurements to assess regional fat and lean 
mass. The purpose of this is to see if bioimpedance may be used as a surrogate for the “gold 
standard” DXA body composition inclusion criteria in subjects with PLD in future studies. 
Rationale for Selected Elements of Study Design 
Screening period (up to 10 weeks duration): There is significant heterogeneity in metabolic 
abnormalities among PLD patients. One study reported a mean fasting TG in FPLD patients of 
1058 mg/dL with a SD of 1745 mg/dL (Ajluni, 2017). Fasting TG are also variable from day to 
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day within individual patients (Bookstein, 1990). Therefore, the protocol allows for multiple visits 
within the screening period for measurement of fasting TG and the averaging of multiple fasting 
TG observations will improve the accuracy of the fasting TG estimate in the baseline period. Leptin 
levels are also known to be variable and will therefore be measured at least twice during the 
screening period. 
Placebo run-in period: Enrollment in a clinical trial can significantly affect a patient’s diet and 
adherence to standard-of-care diabetes and hyperlipidemia medications, and thus impact study 
endpoints. In the initial study of metreleptin, as an example, the effect of study enrollment in 
improvement of TG was nearly as large as the effect of 1-month of metreleptin therapy 
(Oral, 2002). For this reason, a 4-week placebo run-in will be used so that any enrollment effect 
on baseline parameters occurs prior to randomization.  
Stratification: A randomized and placebo-controlled study design is chosen to test the efficacy of 
REGN4461 and control for placebo and study effects on diet. Randomization will be stratified by 
HbA1c (≤7.0% or >7.0%) within each cohort to ensure that baseline HbA1c is similar between 
study arms, as not all FPLD patients have high HbA1c.  
Treatment Periods: Two treatment periods are included to increase the number of patients who 
receive active study drug while blinded to treatment allocation, and to increase the power to detect 
within-group treatment effects and evaluate safety/tolerability. An analysis of REGN4461 
treatment effects in patients in study arm 1 (placebo during TP1 and REGN4461 during TP2) is 
therefore included in secondary endpoints. Note that for endpoints evaluated in this manner, the 
values at the end of TP1 will serve as the beginning measurement for TP2.  
The duration of the treatment periods (12 weeks per treatment period) was chosen to provide 
enough time for the primary metabolic parameters to improve. In one reported study composed of 
generalized lipodystrophy (GLD) and PLD (36% PLD), initiation of metreleptin improved, and in 
some patients normalized, fasting glucose and fasting TG within days (Brown, 2018b). In another 
report of GLD and PLD (70% PLD), the nadir in fasting TG was observed in the first month of 
metreleptin initiation (Vatier, 2016). Small reductions in HbA1c have been demonstrated within 
2-weeks of starting metreleptin treatment (n=15) (Brown, 2018b). Furthermore, in another study 
85% of the 12-month effect of metreleptin in HbA1c was observed by 4 months (1.1% reduction 
at 4 months and 1.4% reduction at 12 months) (Endocrinologic and Metabolic Drugs Advisory 
Committee Briefing Document METRELEPTIN (BLA STN125390), 2013). A 3-month treatment 
period is also long enough to see improvements in hepatic steatosis in PLD patients (Simha, 2012) 
which have been reported to improve within 2-weeks of metreleptin initiation (Brown, 2018b).  
Safety follow-up: A 16-week off-drug follow-up period will follow TP2. The length of this period 
is determined based on clinical and preclinical data suggesting that pharmacodynamic (PD) effects 
of REGN4461 should persist less than 16-weeks following the final dose. In Part B of 
REGN4461-HV-1794, subjects who lost weight during 12-weeks of REGN4461 treatment began 
to regain weight shortly after drug cessation and had returned to their approximate pre-treatment 
weights by the end of 16 weeks. The maximum observed concentration (Cmax) of REGN4461 for 
all subjects 99 days (about 14 weeks) following the final dose was 0.336 mg/L. This concentration 
is less than the Cmax of the lowest REGN4461 dose tested in a preclinical murine model of 
lipodystrophy (0.48 mg/L), which was associated with no significant PD effects (eg, change in 
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body weight or blood glucose levels). In summary, little to no pharmacological effects are 
anticipated at the end of the proposed 16-week follow-up. 
3.2.2. 
Rationale for Dose Selection 
The REGN4461 dose regimen for this study is a 
 mg/kg IV loading dose followed by QW 
maintenance doses of 
 mg SC.  
REGN4461 dose levels and dosing frequency have been selected based on PK/ PD analyses of 
body-weight effect data in healthy cynomolgus monkeys; tolerability, PK, and efficacy data from 
the FIH study in healthy volunteers (R4461-HV-1794); and preliminary PK and safety data in the 
phase 2 study in patients with GLD (R4461-GLD-1875). 
REGN4461 was well-tolerated in adult volunteers in R4461-HV-1794, with an acceptable safety 
profile. In this FIH trial, safety, tolerability, and PK were assessed in an initial single ascending 
dose portion of the trial with doses up to 
 In a second portion 
of this trial (Part B), an exploratory assessment of efficacy was evaluated in otherwise healthy 
subjects with high body mass index (BMI) and either low (<5.0 ng/mL) or higher (>8.0 ng/mL) 
leptin levels at baseline under a single regimen of a 
 
 IV maintenance doses administered every 3 weeks for a total of 12 weeks. The results 
of this study provided evidence of weight loss at trough concentrations (Ctrough) of REGN4461 (at 
the end of the dosing interval), ranging between approximately 
 mg/L. Additionally, a 
favorable safety profile was observed across this study. In comparing the concentration-time 
profiles between subjects with low and high leptin levels at baseline, subjects with low leptin levels 
tended to have lower systemic REGN4461 concentrations, indicative of faster drug clearance. 
Based on the totality of these data, the goal of the current dose selection is to achieve and maintain 
trough concentrations of REGN4461 sufficient to provide efficacy with an appropriate risk/benefit 
profile. As such, a dosing paradigm targeting a Ctrough at steady-state (Ctrough,ss) was selected that 
maximizes target engagement, as determined by predominantly linear elimination and saturation 
of target-mediated clearance.  
In the ongoing study in GLD patients (R4461-GLD-1875), 16 patients have enrolled and have 
received study drug during the double-blind treatment period at doses up to 
 mg SC QW of 
REGN4461. Of the 16 patients, 8 patients were randomized to receive 8 weeks of placebo followed 
by 16 weeks of REGN4461, and 8 patients were randomized to receive REGN4461 for the first 24 
weeks. As of 28 Mar 2022, total exposure to either REGN4461 or placebo during the double-blind 
treatment period is approximately 317 patient-weeks. Fifteen patients (93.4%) have entered the 
open label treatment period and received study drug at doses of either 
 mg SC QW (for patients 
) or 
 mg SC QW (for patients 
). Total exposure to REGN4461 during the open 
label treatment period is approximately 249 patient-weeks.  
Unblinded data is presented below using a data cutoff of 01 Dec 2021 (n=15). 
Two patients (13.3%) experienced a combined total of 4 serious adverse events (SAEs) during 
periods of exposure to REGN4461, all of which were considered not related to study drug by the 
Investigator and Sponsor. All SAEs have etiologies that can be attributed to pre-existing 
conditions. 
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• Three SAEs (Anastomotic ulcer, Stoma site infection, Acute kidney injury) occurred 
in a patient with an acquired form of lipodystrophy (which are associated with high 
rates of autoimmune disease) and pre-existing inflammatory bowel disease 
complicated by large intestine perforation and ileostomy. The patient developed a 
stoma ulcer and underwent elective surgery for resection/revision. The stoma site 
became infected and the patient underwent an elective laparotomy with stoma 
repositioning. Two weeks later, the patient developed acute kidney failure which was 
attributed to the laparotomy procedure by the Investigator.  
• One SAE (Abdominal pain upper) occurred in a patient with a history of colon 
perforation requiring colostomy. This patient has congenital GLD type 4 (CGL4), 
which is characterized by abnormal colonic motility. The patient was admitted to the 
hospital for IV antibiotics and received an enema for constipation.  
• One SAE occurred in a patient with a history of leiomyomas and recurrent uterine 
polyps who was admitted to the hospital for elective surgery to remove an endometrial 
polyp. 
One patient (6.7%) experienced 3 non-serious TEAEs of severe intensity during periods of 
exposure to REGN4461, all of which were considered not related to study drug by the Investigator. 
• Three severe TEAEs (Electrolyte imbalance, Hypocalcaemia, Acute kidney injury) 
occurred in a patient who underwent an elective laparotomy for corrective treatment of 
a stoma infection, described in further detail above, which is considered contributory 
to these events. 
One patient (6.7%) experienced 1 SAE of severe intensity while receiving placebo. This SAE was 
considered not related to study drug by the Investigator and Sponsor. 
• One SAE (Pancreatitis necrotising) occurred in a patient with underlying 
hypertriglyceridemia. Administration of a mixed meal tolerance test (MMTT) the day 
prior to event occurrence was considered a potentially contributory factor by the 
Investigator.  
The most commonly reported TEAEs (occurring in ≥2 patients and in no patients while receiving 
placebo), in patients during periods of exposure to REGN4461 in the double-blind treatment period 
include Hypoglycaemia (4 patients; 26.7%), Abdominal pain (2 patients; 13.3%), Diarrhoea (2 
patients; 13.3%), Fatigue (2 patients; 13.3%), Nasopharyngitis (2 patients; 13.3%), and 
Thrombocytopenia (2 patients; 13.3%). The most commonly reported TEAEs (occurring in ≥2 
patients), in patients in the open-label treatment period is Vomiting (2 patients; 50.0%).  
Of the 2 patients who experienced TEAEs of Thrombocytopenia during periods of exposure to 
REGN4461, a single value (nadir of 158x109/L) below the lower limit of normal (LLN) 
(163x109/L) was reported in 1 patient (baseline count of 208x109/L at screening) and persistent 
values (nadir of 134x109/L) below the LLN were reported in 1 patient (baseline count of 188x109/L 
at screening). Neither of these patients had decreases in platelet values that would be indicative of 
a risk of spontaneous bleeding, and neither reported concurrent events of any-cause bleeding.  
Hypoglycaemia was monitored as an adverse of event of special interest (AESI) in this patient 
population, all of whom had pre-existing diabetes requiring insulin therapy. The majority of 
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hypoglycaemia events reported were of mild intensity and did not meet protocol-specified criteria 
(<54 mg/dL) to qualify as an AESI. Two patients (13.3%) experienced 3 TEAEs of 
Hypoglycaemia that met the criteria to qualify as an AESI, none of which were considered related 
to study drug. Both of these patients experienced hypoglycaemia only during scheduled insulin 
sensitivity assessments (hyperinsulinemic euglycemic clamp or insulin tolerance test) involving 
high dose infusion of insulin. Hypoglycaemia events not meeting AESI criteria occurred in 3 
patients (20.0%), all of which were symptomatic and corresponded with blood glucose readings 
between 54-70 mg/dL, and none of which required medical intervention. No patients experienced 
a TEAE of Hypoglycaemia while receiving placebo. 
To date, no safety signals or concerns have been identified from the ongoing review of safety data 
from R4461-GLD-1875.  
To aid in the transition from an all IV dosing paradigm used in the FIH study (Part B) to SC dosing 
for maintenance following the initial IV loading dose, a Population PK model utilizing all existing 
REGN4461 concentration data was employed. Using this model, a 
 mg/kg IV loading dose was 
chosen to rapidly achieve target steady-state trough concentrations that should maximize target 
engagement, estimated as approximately 
 mg/L. 
Emerging PK data from the ongoing GLD study (R4461-GLD-1875; data cut-off date of 01 Dec 
2021) were assessed. The low dose (ie, 
 mg or 
 mg SC QW for body weights of 
 and 
, respectively) was predicted to achieve Ctrough of approximately 
 mg/L while the high 
dose (ie, 
 mg or 
 mg SC QW for body weights of 
 and 
, respectively) was 
predicted to achieve Ctrough of approximately 100 mg/L. However, the observed Ctrough 
concentrations from this GLD study demonstrated lower than predicted values (Figure 1). The 
Population PK model was refined to include these emerging PK data. The refined model 
demonstrated faster clearance in GLD, suggesting that the REGN4461 target-mediated clearance 
is faster in GLD patients than previously estimated for low leptin overweight/obese healthy 
subjects (Study R4461-HV-1794) presumably due to higher expression of LEPR. Therefore, the 
dose regimen for this PLD study was revised to 
 mg SC QW based on the refined Population 
PK assuming clearance values similar to those observed for GLD to achieve the Ctrough of
 mg/L 
as originally intended for this protocol. To guard against the theoretical concern of excess weight 
loss with a LEPR agonist, a dose modification rule has been incorporated to allow a reduction of 
dose in individual patients that experience excess weight loss during the second treatment period. 
Recognizing that PLD patients may have heterogenous LEPR expression, unlike the GLD patients, 
the dose modification to 
 mg SC QW will allow for mitigation of excess weight loss if 
experienced by PLD patients.  The 
 mg SC weekly dose of REGN4461 is being administered 
to a compassionate use patient with PLD, resulting in steady state trough concentrations of 
REGN4461 of approximately 
 mg/L.  
Predicted area under the curve (AUCcumulative) over the entire 24-week on-treatment period for 
patients receiving active treatment throughout (study arm 2) 
 of the 
AUCcumulative at the no observed adverse effect level (NOAEL) estimated from a PK model derived 
from 3 preclinical toxicology studies in cynomolgus monkeys. In the FIH study 
(Study R4461-HV-1794), single doses of up to 
 
 IV every 3 weeks for 3 doses following a 
 were 
administered to healthy subjects and overweight/obese subjects, respectively.  The mean Cmax 
values following the 
 were >7-fold and >2-fold 
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higher, respectively, than predicted mean Cmax for the 
 mg SC QW dose regimen proposed for 
this study. The mean Ctrough concentrations following the 
 mg/kg IV MD ranged from 60.7 mg/L 
to 160 mg/L across cohorts, and, therefore, were approximately 0.6-fold to 1.6-fold the predicted 
mean Ctrough for the 
 mg SC QW dose regimen proposed for this study. REGN4461 was well 
tolerated in Study R4461-HV-1794 at these exposures. 
Given the existing clinical and non-clinical safety data, the risk/benefit, and the observed trend of 
lower systemic concentrations in subjects with low leptin levels, a dosing regimen predicted to 
achieve exposures within the range associated with efficacy is supported.  
Figure 1: 
Preliminary Mean (±SD) Concentrations of Total REGN4461 in Serum by 
Nominal Time and Treatment Arm in Patients with Generalized 
Lipodystrophy (Study R4461-GLD-1875; PKAS) 
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3.2.3. 
Rationale for Analysis 
The primary analyses are between-group comparisons (change in REGN4461 arm between 
baseline and week 12 versus change in placebo arm between baseline and week 12). The HbA1c 
and TG endpoints will be analyzed only in those individuals with corresponding pre-specified 
elevated baseline values. This will maximize our ability to determine treatment effects in a small 
study with heterogeneous baseline characteristics and inclusion criteria (Section 7.2.1). 
3.3. 
Risk-Benefit 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the Sponsor does not intend to screen any patients in this study until 
the impact of the COVID-19 pandemic is deemed manageable and no longer interfering with the 
conduct of trials at individual sites, and patients can safely participate in this study. Until then, the 
Sponsor plans to obtain approvals from Health Authorities/Ethics Committees to enable initiation 
of study sites for this study, as allowed by local laws and regulations. 
3.3.1. 
Risk-Benefit of REGN4461 
As part of its therapeutic benefits, REGN4461 is expected to increase insulin sensitivity in patients 
with FPLD. If FPLD patients are taking medications with the potential to cause hypoglycemia 
(insulins or sulfonylureas), a rapid improvement in insulin sensitivity could result in hypoglycemia 
if the doses of insulin and sulfonylurea are not adjusted properly during the study. With any study 
involving diabetics there is a chance of hyperglycemia as well. For this reason, adverse events of 
special interest (AESIs) related to hypoglycemia, new onset of diabetes mellitus (NODM), and the 
development of new or worsening autoimmune disease have been defined for this study and 
require expedited reporting to the Sponsor (see Section 10.1.3 for a detailed description). 
However, the potential benefits of REGN4461 to improve metabolic abnormalities in patients with 
FPLD outweighs these potential risks. A risk-benefit statement with respect to the overall 
development program is provided in the latest version of the Investigator’s Brochure. 
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4. 
ENDPOINTS 
4.1. 
Primary Endpoints 
The co-primary endpoints are: 
• Percent change in fasting serum TG from baseline to week 12 in patients with elevated 
baseline fasting TG (>200 mg/dL) and with baseline leptin <8.0 ng/mL (cohort A) 
• Absolute change in HbA1c from baseline to week 12 in patients with elevated baseline 
HbA1c (>7.0%) and with baseline leptin <8.0 ng/mL (cohort A) 
4.2. 
Secondary Endpoints 
Note: Patients in study arm 1 must meet stability criteria during TP1 (a change in HbA1c ≤0.5 
percentage points and a change in TG≤25%) to be included for specific endpoints as indicated 
below. 
The following secondary endpoints will be analyzed for cohort B and for the combined set of 
cohorts A plus B: 
• Percent change in fasting serum TG from baseline to week 12 in patients with elevated 
baseline fasting TG (>200 mg/dL)  
• Absolute change in HbA1c from baseline to week 12 in patients with elevated baseline 
HbA1c (>7.0%)  
The following secondary endpoints will be analyzed for cohorts A and B separately, and for the 
combined set of cohorts A plus B: 
• Percent change in fasting serum TG from baseline to week 12 compared to the 
percent change between week 12 and week 24 (study arm 1) 
• Percent change in fasting serum TG from baseline to week 24 (study arm 2) 
• Percent change in fasting serum TG after the first 12 weeks of exposure to 
REGN4461— from baseline to week 12 (study arm 2) and from week 12 to week 24 
(study arm 1; patients must meet stability criteria) 
• Change in HbA1c from baseline to week 12 compared to the change between week 12 
and week 24 (study arm 1) 
• Change in fasting glucose from baseline to week 12 compared to the change between 
week 12 and week 24 (study arm 1) 
• Change in HbA1c from baseline to week 24 (study arm 2) 
• Change in fasting glucose from baseline to week 24 (study arm 2) 
• Change in HbA1c from baseline to week 12 (study arm 2) and from week 12 to week 24 
(study arm 1; patients must meet stability criteria) 
• Change in fasting glucose from baseline to week 12 (study arm 2) and from week 12 
to week 24 (study arm 1) 
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• Percent change in liver fat (MRI-PDFF) from baseline to week 12, REGN4461 versus 
placebo in patients with baseline liver fat (MRI-PDFF) ≥8.5%.  
• Percent change in liver fat (MRI-PDFF) from baseline to week 12 compared to the 
percent change between week 12 and week 24 (study arm 1) in patients with baseline 
liver fat (MRI-PDFF) ≥8.5%. 
• Percent change in liver fat (MRI-PDFF) from baseline to week 24 (study arm 2) in 
patients with baseline liver fat (MRI-PDFF) ≥8.5%. 
• Percent change in liver fat (MRI-PDFF) from baseline to week 12 (study arm 2) and 
from week 12 to week 24 (study arm 1) in patients with baseline liver fat (MRI-PDFF) 
≥8.5%. 
• Change on the daily lipodystrophy hunger questionnaire from baseline to week 12 and 
week 24 
• The incidence and severity of treatment-emergent adverse events (TEAEs)  
• Concentrations of REGN4461 in serum over time 
• Immunogenicity of REGN4461 as determined by the incidence, titer and clinical 
impact of treatment-emergent ADAs to REGN4461, over time compared to placebo 
4.3. 
Exploratory Endpoints 
Note: All exploratory endpoints will be analyzed for cohorts A and B separately as well as the 
combined set of cohorts A plus B. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
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5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demographics (eg, age, race, weight, height, etc), 
disease characteristics (including fasting glucose, HbA1c, fasting insulin, low-density lipoprotein 
cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], fasting TG, total cholesterol, 
leptin levels, BMI, percentages of body fat and liver fat, trunk/leg fat ratio derived from DXA 
[TLR; trunk fat %/leg fat %], FPLD type [or gene/variant], HOMA-IR, FFA, and ADIPO-IR), 
medical history (eg, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease [NAFLD]), 
and medication history (including lipid modifying therapies and control of diabetes) for each 
patient.  
5.2. 
Efficacy Variables 
Efficacy variables include TG, HbA1c, fasting glucose, fasting TG, liver fat content (MRI-PDFF), 
and lipodystrophy hunger questionnaire outcomes.  
5.3. 
Safety Variables 
Safety variables include AEs, body weight, vital signs, 12-lead electrocardiogram (ECG), physical 
examination, and laboratory safety tests. 
5.4. 
Pharmacokinetic Variables 
The PK variable is the concentration of total REGN4461 at each time point. Samples in this study 
will be collected using a sparse sampling schedule, eg, only 1 blood sample for drug concentration 
measurement is collected at any single clinic visit, except on day 1 and day 85, corresponding to 
study drug infusions where multiple samples will be taken on the same day.  
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and time-point/visit. Samples in this study 
will be collected at the clinic visits. 
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Pharmacodynamic and biomarker variables include markers of insulin sensitivity, perception of 
pain, symptoms of depression and anxiety, body weight, regional body composition, perception of 
quality of life, potential biomarkers of safety and efficacy of REGN4461 administration (ie, 
markers of insulin resistance, hepatic steatosis, and hypertriglyceridemia including ANGPTL3 and 
ApoC3), and fat measures and fat ratios as measured by bioimpedance and DXA.  
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This is a phase 2, randomized, double-blind, placebo-controlled study of the efficacy and safety of 
REGN4461 in patients with FPLD and metabolic abnormalities (elevated fasting TG with or 
without elevated HbA1c) who are not receiving rhLeptin therapy. 
Patients 18 years of age or older with a clinical diagnosis of FPLD will undergo screening, 
including measurement of HbA1c, fasting TG, and leptin levels. A diagnosis of FPLD requires 
either a documented ClinVar pathogenic or likely pathogenic variant in a known FPLD gene or 
pathognomonic regional lipoatrophy by DXA. In addition, patients must have metabolic 
abnormalities (hypertriglyceridemia with or without hyperglycemia) and leptin level ≤20.0 ng/mL 
to be included. 
The study comprises a screening period lasting up to 10 weeks, a 4-week single-blind placebo run-
in period (PBO), a 12-week double-blind placebo-controlled treatment period (TP1), a 12-week 
single-blind treatment period (TP2) during which all patients receive REGN4461, and a 16-week 
off-drug safety follow-up period (Figure 2). All study drug will be given by study staff and not 
administered by the patient. 
Screening period (up to 10 weeks duration); day -98 up to day -29  
Patients will undergo screening assessments as per the Schedule of Events (Table 1) to determine 
their eligibility. These include, but are not limited to a whole-body DXA scan, HbA1c, fasting TG 
and leptin levels.  Patients will have repeated assessments of fasting TG and leptin given their 
biological variability as detailed in Appendix 1 and summarized below:  
• Initially, 2 measurements of fasting TG levels will be performed. If the 2 measurements 
are concordant (fall into the same TG range: (i) less than or equal to 200 (ii) greater 
than 200 and less than or equal to 450 (iii) greater than 450 mg/dL ) the measures will 
be sufficient to determine eligibility; if they are discordant, a third measure will be 
obtained and the geometric average of the 3 measures will determine patient eligibility.  
• Initially, 2 measurements of leptin levels will be performed. If the 2 measurements are 
concordant (fall into the same leptin range: (i) less than 8.0 (ii) greater than or equal to 
8.0 and less than or equal to 20.0  (iii) greater than 20.0 ng/mL) the measures will be 
sufficient to determine patient disposition; if they are discordant, a third measure will 
be obtained and the arithmetic average of the 3 measures will determine patient 
disposition. Patients will be assigned to a cohort based on the mean baseline leptin 
levels (<8.0 ng/mL [cohort A] or 8.0 to 20.0 ng/mL [cohort B]; Section 6.1.1). 
• For those patients screened and found eligible under the original protocol, HbA1c and 
triglycerides assessments will be repeated to reconfirm eligibility of the patient if the 
screening window of 10 weeks has been exceeded by the time the relevant approvals 
for Protocol Amendment 1 are in place. Patients screened under the original protocol 
who do not enter the placebo run-in period within the prescribed visit window will not 
be considered screen failures, nor will they be considered a deviation provided repeat 
HbA1c and triglycerides are obtained prior to initiating the placebo run-in as part of 
Amendment 1. Note: patients who enter screening under the amendment will be 
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required to adhere to the 10-week screening schedule or it will be considered a 
deviation. 
4-week single blind placebo run-in period (PBO); day -28 to day -1  
All patients who meet eligibility criteria will receive placebo by IV infusion on day -28, followed 
by SC QW injections of placebo starting at day -21. Patients will be observed at least 4 hours after 
IV infusion to maintain study blinding. Fasting lipid and glucose levels will be collected weekly. 
Patients will receive training on electronic COA (eCOA) using a device to record COA measures 
such as hunger, pain, QoL, depression, and anxiety disorders. Patients will undergo baseline body 
composition by DXA and bioimpedance. Additionally, 2 baseline assessments of liver volume 
(MRI) and liver fat content (MRI-PDFF) will be performed; the first and second MRI must be 
performed on separate days. 
12-week double-blind placebo-controlled treatment period (TP1); Day 1 until week 12 
Baseline testing occurs in the screening period and the placebo run-in period (see Table 1). After 
baseline testing, patients in each cohort will be randomized 1:1 to study arm 1 (placebo in TP1 and 
REGN4461 in TP2) or study arm 2 (REGN4461 in TP1 and TP2), and stratified based on screening 
HbA1c (HbA1c ≤7.0% or HbA1c >7.0%) within each cohort.  
On day 1, the first dose will be administered IV (
 mg/kg REGN4461 or placebo) and patients 
will be observed for at least 4 hours. Starting on day 8, patients will receive matched volumes of 
SC administered REGN4461 (
 mg QW) or placebo, respectively, once weekly for a total of 11 
SC doses. Fasting blood draws will be taken every 2 weeks according to Table 2. 
During the final 2 weeks of TP1, fasting blood draws will be performed weekly (weeks 10, 11, 
12). The mean (geometric for TG and arithmetic for all other measures) of these 3 measurements 
will be taken as the end measure of TP1 and beginning measurement for TP2. Bioimpedance will 
be assessed during a mandatory in-clinic study visit (week 12). At the end of TP1, patients will 
undergo liver MRI and whole-body DXA. 
12-week single-blind treatment period (TP2); Day 85 until week 24   
On day 85 (week 12), patients will receive double-blind dosing in order to maintain blinding to 
study arm assignment and will then be observed for at least 4 hours:  
• Study arm 1: IV loading dose of REGN4461 (
 mg/kg) followed by SC placebo;  
• Study arm 2: placebo IV infusion followed by SC REGN4461 (
 mg). 
Starting at week 13, REGN4461 (
 mg SC QW) will be administered in a single-blind manner 
to patients in both study arms (patient remains blinded to treatment allocation). Fasting TG and 
glucose measurements will occur every 2 weeks through week 20 (Table 2). During the final 
2 weeks of TP2, fasting blood draws will be performed weekly (weeks 22, 23, 24). The mean 
(geometric for TG and arithmetic for all other measures) of these 3 measurements will be taken as 
the end measure of TP2. Bioimpedance will be assessed during the mandatory in-clinic visit (week 
24). At week 24, patients will undergo liver MRI and whole-body DXA. 
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16-week off-drug safety follow-up period; Day 169 until week 40 
This period will be used to monitor efficacy (glycemic, lipid parameters, daily lipodystrophy 
hunger patient reported outcome [PRO]), safety (hematology, chemistry, urinalysis, vital signs and 
AEs), PK and PD assessments as REGN4461serum concentrations decline. 
All non-mandatory in-clinic outpatient visits are eligible for home nursing visits if the service is 
supported in the relevant country/location of the site and will be referred to as 'remote visits'; the 
patient can use this service for all or some of the eligible visits.  
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Figure 2: 
Study Flow Diagram 
 
 
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6.1.1. 
Description of Study Cohorts 
The study will enroll 2 cohorts: 
• Cohort A: FPLD patients with serum leptin <8.0 ng/mL  
• Cohort B: FPLD patients with serum leptin 8.0 to ≤20.0 ng/mL  
Cohort assignment is based on at least 2 and at maximum 3 leptin measurements obtained during 
the screening period.  
Patients in each cohort will be randomized 1:1 to a study arm and stratified based on screening 
HbA1c (HbA1c ≤7.0% or HbA1c >7.0%).  
• Study arm 1: patients randomized to placebo for 12 weeks who will crossover to 
REGN4461 for 12 weeks 
• Study arm 2: patients randomized to receive REGN4461 for 24 weeks 
The total planned enrollment is 40 patients: 20 patients in each cohort (A and B); and 10 patients 
within each study arm (1 and 2) per cohort.  
6.1.2. 
End of Study Definition 
The end of study is defined as the date the last patient either completes the last study visit, 
withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted 
by the investigator).  
6.2. 
Planned Interim Analysis 
No formal interim analysis will be performed in the study. Periodic data reviews may be performed 
by selected unblinded Sponsor physicians and a statistician with no direct involvement in the study. 
A first-step analysis will occur after the last patient completes week 12. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
A total of 40 patients are planned, with 20 patients per cohort (A and B). Each cohort will be 
randomized 1:1 into study arm 1 or study arm 2.  
7.2. 
Study Population 
Adult patients with a clinical diagnosis of FPLD, leptin ≤20.0 ng/mL and metabolic abnormalities 
who are not currently treated with rhLeptin.  
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female, ≥18 years of age at the screening visit.  
2. Clinical diagnosis of familial partial lipodystrophy: 
a) 
Altered body fat distribution including lipoatrophy at one or more sites, as determined 
by physical examination 
AND 
b) Metabolic sequelae of partial lipodystrophy, as evidenced by a medical history of at 
least 1 of the following:  
i) 
Fasting hypertriglyceridemia as evidence by multiple readings >150 mg/dL  
ii) Diabetes as evidenced by American Diabetes Association criteria 
iii) Hepatic steatosis as evidenced by liver ultrasound (Grade II-III) or MRI-PDFF 
(>5.6%) 
AND EITHER (c) or (d) 
c) 
History of known pathogenic mutation in an FPLD-related gene (Section 3.2.1)  
OR 
d) 
 
 
 
 
 
 
 
 
 
 
3. 
 Fasting leptin level ≤20.0 ng/mL 
Note: Refer to Appendix 1 for actions based on leptin results. 
4. Presence of significant metabolic abnormalities satisfying 1 of the following: 
a) HbA1c >7.0% AND fasting TG >200 mg/dL  
OR  
b) Fasting TG >450 mg/dL 
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5. Stable body weight within the 3 months prior to screening (no gain or loss of  >5% current 
weight) 
6. Stable diet during the past 3 months defined as no major change in macronutrient 
composition (eg, starting or stopping diets such as Adkins, Paleo, Vegetarianism, 
Veganism). 
7. No clinically meaningful change in diabetes medication regimen in the 3 months prior to 
screening (addition, subtraction, or change in dosing). Changes in insulin dosing within 
3 months are allowed if the change is <30% of the total daily dose. 
8. No clinically meaningful change (addition, subtraction, or dose change) in medications for 
hyperlipidemia taken by prescription or over the counter (including fish oil or niacin) for 
the past 3 months prior to screening. 
9. Willing and able to comply with clinic visits and study-related procedures. 
Note: patients incapable of completing COA assessments or unable to undergo MRI 
will not be excluded. 
10. Provide informed consent signed by study patient or legally acceptable representative. 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Treatment with metreleptin within 3 months of the screening visit 
2. Patients with a diagnosis of generalized lipodystrophy 
3. Patients with a diagnosis of acquired lipodystrophy 
4. Patients with a medical history of bone marrow transplant, use of an immune check-point 
inhibitor, or central nervous system tumor involving the hypothalamus. 
5. Patients with clinically significant hematologic abnormalities such as neutropenia, 
lymphopenia, or lymphadenopathy at screening 
6. Treatment with over-the-counter or prescription medications for weight loss begun within 
3 months prior to the screening visit 
7. Treatment with oral glucocorticoids >7.5 mg prednisone equivalents per day or plans to 
begin treatment with oral glucocorticoids >7.5 mg prednisone equivalents per day during 
the study period 
8. Treatment with oral estrogens begun within 6 months prior to the screening visit 
9. Any malignancy, eg, lymphoma, within the past 1 year, prior to screening visit except for 
fully treated basal cell or squamous epithelial cell carcinomas of the skin or carcinoma in 
situ of the cervix or anus 
10. Estimated glomerular filtration rate (GFR) of <30 mL/min/1.73 m2 based on the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-Epi) equation at screening 
11. History of heart failure hospitalization, myocardial infarction, stroke, clinically-significant 
arrhythmia (eg, ventricular tachycardia, or any arrhythmia requiring medication adjustment 
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to control), transient ischemic attack, unstable angina, percutaneous or surgical 
revascularization procedure (coronary, carotid, or peripheral vascular), or intracardiac 
device placement (eg, pacemaker) within 3 months before the screening visit 
12. Advanced heart failure (New York Heart Association Class 3 to 4) or severe and 
uncontrolled hypertension at screening 
13. Current diagnosis of Type 1 diabetes mellitus 
14. History of human immunodeficiency virus (HIV) or HIV seropositivity at screening visit  
15. Uncontrolled infection with hepatitis B or hepatitis C infection or known active 
tuberculosis at screening. 
Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at screening. 
Patients with hepatitis B (HBV sAg+) who have controlled infection (serum HBV DNA 
polymerase chain reaction (PCR) that is below the limit of detection AND receiving anti-
viral therapy for hepatitis B) are permitted. Patients with controlled infections must 
undergo periodic monitoring of HBV DNA per local standards. Patients must remain on 
anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. 
Patients who are hepatitis C virus antibody-positive (HCVAb+) who have controlled 
infection (undetectable HCV RNA by PCR either spontaneously or in response to a 
successful prior course of anti-HCV therapy) are permitted. 
16. A patient who has a documented, positive reverse-transcriptase polymerase chain reaction 
(RT-PCR) or serology test for severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) may be enrolled provided the patient has: (A) Recovered from COVID-19 
(all COVID-19-related symptoms and major clinical findings which can potentially affect 
the safety of the patient should be resolved), and (B) Had 2 negative results from a health 
authority-authorized nucleic acid amplification (PCR) test for SARS-CoV-2 taken at least 
48 hours apart, or (C) Documented vaccination. 
17. Participation in any clinical research study evaluating an investigational product (IP) or 
therapy within 3 months and less than 5 half-lives of IP prior to the screening visit. 
Participation in clinical research studies that only involve procedures (eg, muscle biopsies, 
glycemic clamps) or testing (eg, MRI) that will not interfere with the current study is 
permitted. 
18. Any physical examination findings and/or history of any illness that, in the opinion of the 
study investigator, might confound the results of the study or pose an additional risk to the 
patient by their participation in the study 
19. Alcohol consumption >21 drinks per week for males or >14 drinks per week for females 
20. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the Sponsor. 
21. Pregnant or breastfeeding women. 
22. Women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to the beginning of the placebo run-in period,  during the 
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study, and for at least 16 weeks after the last dose. Highly effective contraceptive measures 
include:  
a.  Stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable), associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening   
Note: If patients are using oral estrogen hormonal contraception, they must have 
initiated it at least 6 months prior to the screening visit. 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
c. bilateral tubal ligation; 
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual 
partner of the WOCBP study participant and that the vasectomized partner has obtained 
medical assessment of surgical success for the procedure); and/or 
e. sexual abstinence†, ‡. 
*WOCBP are defined as women who are fertile following menarche until becoming 
postmenopausal, unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
A postmenopausal state is defined as age >50 years old and with no periods for 12 months. 
†Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method are not 
acceptable methods of contraception. Female condom and male condom should not be used 
together.  
23. Sexually active adult men who are unwilling to use the following forms of medically 
acceptable birth control during the study drug treatment period and for 16 weeks after the 
last dose of study drug: vasectomy with medical assessment of surgical success OR 
consistent use of a condom. Sperm donation is prohibited during the study and for 16 weeks 
after the last dose of study drug. 
7.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
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Patients who are withdrawn prematurely from the study will be asked to complete the early 
termination (ET) visit, and associated end of treatment (EOT) assessments, as described in 
Section 9.1.3. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.4.2. 
7.4. 
Replacement of Patients 
Patients prematurely withdrawn from the study can be replaced, if needed, to ensure an adequate 
number of evaluable patients. The Medical/Study Director, in cooperation with the Study 
Biostatistician, will decide whether to replace a withdrawn patient. 
Patients enrolled and withdrawn from the study any time prior to randomization will not be 
considered evaluable for assessment and will be replaced with another patient. All patients who 
have received a dose of study drug will be included in an as treated analysis. 
If a patient is replaced after randomization, the replacement patient will receive the randomization 
assignment of the patient s/he is replacing. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
The REGN4461 dose regimen for this study is 
 mg/kg IV followed by doses of 
 mg SC QW. 
Placebo product to match to REGN4461 is prepared in the same formulation without the addition 
of REGN4461. All administration of REGN4461 or placebo is to be performed by study staff and 
no self-administration of REGN4461 or placebo will occur.  
Dosing Schedule: 
• Single-blind run in: all patients will receive an IV placebo infusion on day -28, 
followed by placebo SC QW injections administered subsequently for 3 weeks 
starting on day -21. 
• Treatment period 1:  
− Study arm 1: IV placebo infusion on day 1 followed by SC QW injections of 
placebo for 11 weeks starting on day 8 
− Study arm 2: IV REGN4461 (
 mg/kg) infusion on day 1 followed by SC 
injections of REGN4461 (
 mg QW) for 11 weeks starting on day 8 
• Treatment Period 2:   
− Study arm 1: IV REGN4461 (
 mg/kg) infusion followed by SC placebo on 
day 85, followed by SC injections of REGN4461 (
 mg QW) for 11 weeks 
starting on day 92 
− Study arm 2: IV placebo followed by SC injection of REGN4461 (
 mg) on 
day 85, followed by SC injections of REGN4461 (
 mg QW) for 11 weeks 
starting on day 92 
Investigational drug formulation and instructions on dose preparation are provided in the pharmacy 
manual for in-clinic visits and in the nursing manual for remote visits. 
8.2. 
Run-in Treatment 
There will be a 4-week single-blind placebo run-in period (day -28 to day -1). At the beginning of 
the placebo run-in period, patients will receive an IV placebo infusion, followed 1 week later by 
SC QW injections of placebo, administered for 3 weeks. 
8.3. 
Background Treatment 
Standard of care for metabolic abnormalities including stable (ie, no changes within the past 
3 months of the screening visit) medications for diabetes and hyperlipidemia. 
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8.4. 
Dose Modification and Study Treatment Discontinuation Rules 
8.4.1. 
Dose Modification 
After treatment period 1, REGN4461 dose level may be decreased from 
 mg to 
 mg if the 
following criteria are met: 
1. for patients with baseline BMI >20: either BMI<20 kg/m2 OR weight loss >10%  
2. for patients with baseline BMI ≤20: in the opinion of the study investigator the weight 
loss is adverse  
For patients with BMI >20 kg/m2, any decision to decrease the dose level will be made by the 
Sponsor, in discussion with the investigator. 
If a patient’s dose is reduced from 
 mg to 
 mg, their dose cannot be increased during TP2. 
8.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug before entering TP1 (day 1) will be 
contacted to assess any adverse events (AEs) but will not be asked to return for the remaining 
study visits. 
Patients who permanently discontinue from study drug after entering TP1 should be encouraged 
to remain in the study. Those who agree and do not withdraw from the study will be asked to return 
to the clinic for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 9.1.3. 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Confirmation of pregnancy as evidenced by a positive serum pregnancy test 
• Serious or severe allergic reactions considered related to study drug 
• Severe liver injury or dysfunction for which no other reason can be found to explain, 
such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug 
capable of causing the observed injury. Liver injury is defined as follows: 
• For individuals with normal baseline transaminase and liver enzyme levels: 
− Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X upper 
limit of normal (ULN) or 
− ALT or AST >5X ULN on consecutive visits at least 2 weeks apart or 
− ALT or AST >3X ULN and total bilirubin >2X ULN (or international normalized 
ratio [INR] >1.5) 
• For individuals with abnormal baseline transaminase and liver enzyme levels: 
− ALT or AST >3X over baseline and total bilirubin >2X over baseline (or INR >1.5) 
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• Patient withdraws consent 
• Investigator’s clinical judgment that it is in the best interest of the patient  
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
The investigator may temporarily discontinue study drug dosing at any time, even without 
consultation with the medical monitor if the urgency of the situation requires immediate action in 
the patient’s best interest and as clinically indicated. However, the Regeneron medical monitor 
should be contacted as soon as possible. Resumption of study drug dosing requires consultation 
and agreement between the investigator and the Regeneron medical monitor. 
A special case for temporary discontinuation of study drug relates to a positive urine pregnancy 
test If there is a positive urine pregnancy test, a confirmatory serum pregnancy test will be 
performed. Study treatment will not be administered until a negative serum pregnancy test is 
obtained. If the serum pregnancy test is negative the patient can continue in the study. A positive 
serum pregnancy test will result in permanent discontinuation of study drug administration. 
If a patient requires a prohibited medication at any time during the study, the principal investigator 
should contact the Regeneron medical monitor (except for illness requiring prompt treatment). 
Based on the discussions, study drug may be continued or temporarily or permanently 
discontinued. 
8.5. 
Management of Acute Reactions  
8.5.1. 
Acute Intravenous Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use. All infusion reactions must be reported as AEs (as defined in Section 10.2.4) and 
graded using the grading scales as instructed in Section 10.3.1. 
8.5.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• Sustained/severe cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
• Hypotension 
• Dyspnea (shortness of breath) 
• Vomiting 
• Flushing 
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The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
8.5.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
• Anaphylaxis* 
• Laryngeal/pharyngeal edema 
• Severe bronchospasm 
• Chest pain 
• Seizure 
• Severe hypotension 
• Other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, 
etc.) 
• Any other symptom or sign that, in the opinion of the investigator, warrants termination 
of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE 
FOLLOWING: 
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
8.5.2. 
Acute Injection Reactions 
8.5.2.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. All injection reactions must be reported as AEs (as defined in Section 10.2.1) 
and graded using the grading scales as instructed in Section 10.3.1. 
Acute systemic reactions following injection of study drug by SC administration should be treated 
using clinical judgment to determine the appropriate response according to typical clinical practice.  
8.5.2.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.3.1. 
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8.6. 
Method of Treatment Assignment 
All patients will enter a 10-week screening period during which screening assessments will be 
performed, including fasting TG and leptin levels, to determine eligibility. All eligible patients 
will enter the 4-week single-blind placebo run-in period. Upon completion of the 4-week run-in 
period, up to 40 patients will be randomized in a 1:1 ratio to study arm 1 (placebo in TP1 and 
REGN4461 in TP2) or study arm 2 (REGN4461 in TP1 and TP2) according to a central 
randomization scheme provided by an interactive voice response system (IVRS)/interactive web 
response system (IWRS) to the designated study pharmacist (or qualified designee). 
Randomization will be stratified according to HbA1c levels (HbA1c ≤7.0% or HbA1c >7.0% at 
the screening visit) within each cohort. 
8.7. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study. The Regeneron Medical/Study Director, Study 
Monitor, and any other Regeneron and contract research organization (CRO) personnel who are 
in regular contact with the study site will remain blinded to all patient randomization assignments. 
Investigators and the sponsor will be blinded to specific endpoints, including, but not limited to 
HbA1c, fasting glucose, fasting TG and other lipids, and MRI imaging, for the entire length of the 
treatment period (up to week 24).  
Selected individuals not involved in the conduct of the study may have access to unblinded data, 
as needed, for safety review or other data review.  
8.8. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy) and when a treatment decision is contingent 
on knowing the patient’s treatment assignment. Study drug will be discontinued for patients whose 
treatment has been unblinded (Section 8.4.2).  
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the patient. Unblinding is performed using the 
IVRS/IWRS, which will notify Regeneron.  
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient's treatment 
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assignment. In the event there is no study pharmacist, the individual at the site fulfilling that role 
will be the only unblinded member of the site personnel. 
8.9. 
Treatment Logistics and Accountability 
8.9.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.9.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed/returned to the sponsor 
or designee. 
8.9.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication 
• dispensed to each patient 
• returned from each patient (if applicable), and 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
8.9.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.10. 
Concomitant Medications and Procedures 
Any treatment administered and/or procedures (eg, vaccination, apheresis) performed from the 
time of informed consent to the end of the follow-up period will be considered concomitant 
medication and/or procedures, respectively. This includes medications and/or procedures that were 
started before the study and are ongoing during the study.  
Every attempt should be made to keep concomitant medications, including over-the-counter 
medications and dietary supplements, stable throughout the entire duration of the study, unless in 
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the judgement of the treating physician a safety concern warrants medication addition, 
discontinuation, or a dose modification. 
Documentation of concomitant medications and/or procedures, including medication dosing, will 
occur at the time points specified in Table 1 and Table 2. Changes in concomitant medication and 
procedures that occur during the course of the study must be recorded. 
8.10.1. 
Prohibited Medications 
Prohibited medications are: 
• Recombinant human leptin (metreleptin, Myalept), starting 3 months prior to study 
start and throughout the duration of the study 
• Treatment with over-the-counter or prescription medications for weight loss begun 
within 3 months prior to the screening visit 
8.10.2. 
Permitted Medications 
All medications except those listed in Section 8.10.1 are permitted. 
Diabetes medications: If a patient is taking diabetes medications at the beginning of the study, 
study drug will be added to existing therapy. Insulin and insulin secretagogues (eg, sulfonylureas) 
may be decreased in dose or discontinued in response to low blood glucose levels (fasting glucose 
<90 mg/dL), a large and clinically-significant decrease in fasting blood sugar (eg, 50% decrease 
in fasting glucose from prior values) signs/symptoms consistent with hypoglycemia, or if a safety 
concern arises. Otherwise, all attempts should be made to continue the patient’s current diabetes 
medication regimen. New hyperglycemia requiring medical treatment (rescue therapy) should be 
managed with insulin and reported as an AESI according to Section 10.2.3.  
New hyperglycemia requiring treatment is defined as follows: 
Fasting glucose ≥250 mg/dL on 2 occasions including symptoms consistent with hyperglycemia 
AND increase in fasting glucose >50 mg/dL above baseline 
The insulin dose used will be determined by the treating physician after careful review of the 
patient’s diabetes history and prior diabetes treatment history, and all treatment decisions will be 
recorded.  
Lipid-lowering medications: If a patient is taking lipid-lowering medications at the beginning of 
the study, study drug will be added to existing therapy. No changes (addition, discontinuation, or 
dose adjustments) to lipid lowering medications (prescription or over the counter and including 
fish-oil and niacin) should be made during the course of the study, unless needed for safety.  
Glucocorticoids are permitted so long as the patient has been on a low dose (ie,  ≤7.5 mg 
prednisone equivalents daily) which has been stable for 6 months prior to screening, with no plans 
for increasing the dose during the study. 
Oral estrogens are permitted as long as they have been initiated at least 6 months prior to the 
screening visit. Estrogens are permitted for routes other than oral. 
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CONFIDENTIAL 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures in response to 
COVID-19 are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency. 
Study assessments and procedures are presented by study period and visit in Table 1 and Table 2. 
 
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Table 1: 
Schedule of Events: Screening and Placebo Run-In 
Study Period 
Screening 1,2 
Placebo Run-In 
  
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic Outpatient 
visit or Remote visit 3 
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic 
Outpatient visit or 
Remote visit 3 
Visit Number: 
1 
24 
(3)4  
4 
5 
6 
7 
Day: 
-98 to -63 
-91 to -
49 
-77 to -49 
-28 
-21 
-14 
-7 
±visit window (d): 
  
  
  
±3 
±3 
±3 
±3 
Week: 
week -14  
to -9 
week -13 
to -7 
week-11 
to -7 
week -4 
week 
-3 
week 
-2 
week 
-1 
Screening  
  
  
  
  
  
  
  
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
X 
 
 
 
Medical History 5 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Confirm partial lipodystrophy 
diagnosis 
X 
 
 
 
 
 
 
HIV serology and hepatitis 
testing (HBsAg,  HCV) 
X 
 
 
 
 
 
 
Treatment 
  
  
  
  
  
  
  
Placebo Administration for Run-
In IV 1  
  
  
  
X 
 
 
 
Placebo Administration for Run-
In SC 
 
 
 
 
X 
X 
X 
Concomitant Meds and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
Monitoring/dose adjustments for 
antidiabetic and lipid lowering 
medication 6 
  
  
  
X 
X 
X 
X 
Safety 7 
  
  
  
  
  
  
  
Vital Signs 8 
X 
  
  
X 
X 
X 
X 
Height 
X 
  
  
  
  
  
  
Weight 9 
X 
  
  
X 
  
  
X 
Physical Examination 
X 
  
  
X 
  
  
  
Waist and hip circumference 
X 
 
 
X 
 
 
 
Electrocardiogram 10 
X 
  
  
 
  
  
  
Adverse Events 
X 
 X 
X  
X 
X 
X 
X 
Menstrual history, pregnancy 
status reporting, and 
confirmation of contraception 
 X 
  
  
X 
  
X 
  
Laboratory Testing 11 
  
  
  
  
  
  
  
Hematology 
X 
  
  
X 
  
X 
  
Blood Chemistry 
X 
  
  
X 
  
X 
  
Pregnancy Test (WOCBP)12 
Serum 
  
  
Urine 
  
Urine 
  
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Page 58 
 
CONFIDENTIAL 
Study Period 
Screening 1,2 
Placebo Run-In 
  
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic Outpatient 
visit or Remote visit 3 
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic 
Outpatient visit or 
Remote visit 3 
Visit Number: 
1 
24 
(3)4  
4 
5 
6 
7 
Day: 
-98 to -63 
-91 to -
49 
-77 to -49 
-28 
-21 
-14 
-7 
±visit window (d): 
  
  
  
±3 
±3 
±3 
±3 
Week: 
week -14  
to -9 
week -13 
to -7 
week-11 
to -7 
week -4 
week 
-3 
week 
-2 
week 
-1 
Urinalysis 
X 
  
   
  
  
  
  
Leptin13,14 
X 
X 
X 
  
X 
  
X 
Efficacy11 
  
  
  
  
  
  
  
Lipid panel14 
  
  
  
X 
  
  
  
Free Fatty Acids14 
 
 
 
X 
 
X 
 
Fasting Triglycerides13,14 
X 
X 
X 
X 
X 
X 
X 
Fasting Glucose 14 
X 
  
  
X 
X 
X 
X 
HbA1c 
X 
  
  
X 
  
  
  
Fructosamine  
X 
  
  
X 
  
X 
  
Insulin 14 
  
  
  
X 
  
X 
  
NMR Lipid panel LDL-C, 
HDL-C, total-Cholesterol 14 
  
  
  
X 
  
  
  
Urine Creatinine and Albumin 
  
  
  
X 
  
  
  
Patient eCOA Training15 
  
  
  
X 
  
  
  
Daily Lipodystrophy Hunger 
questionnaire  
  
  
  
 
BPI-SF questionnaire 
  
  
  
X 
  
  
  
PHQ-8 questionnaire 
  
  
  
X 
  
  
  
SF-36 questionnaire 
 
 
 
X 
 
 
 
HADS questionnaire 
  
  
  
X 
  
  
  
Patient Global Impression of 
Severity- Hunger 
  
  
  
X 
  
  
  
Patient Global Impression of 
Severity- Pain 
  
  
  
X 
  
  
  
Bioimpedance 
X 
 
 
X 
 
 
 
DXA 
X16 
  
X16 
Liver volume (MRI) and liver fat 
content (MRI-PDFF) 
  
  
  
X16 
Biomarkers 
Procedure/Samples  
  
  
  
  
  
  
  
Apolipoprotein C3 (ApoC3)11,14 
  
  
  
X 
  
  
  
ANGPTL311,14 
  
  
  
X 
  
  
  
X  
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Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
Study Period 
Screening 1,2 
Placebo Run-In 
  
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic Outpatient 
visit or Remote visit 3 
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic 
Outpatient visit or 
Remote visit 3 
Visit Number: 
1 
24 
(3)4  
4 
5 
6 
7 
Day: 
-98 to -63 
-91 to -
49 
-77 to -49 
-28 
-21 
-14 
-7 
±visit window (d): 
  
  
  
±3 
±3 
±3 
±3 
Week: 
week -14  
to -9 
week -13 
to -7 
week-11 
to -7 
week -4 
week 
-3 
week 
-2 
week 
-1 
Future biomedical research 
serum and plasma samples 
(Optional) 
  
  
  
X 
  
  
  
Pharmacogenomics Sub-study (Optional)   
  
  
  
  
  
  
Blood sample for DNA 
isolation17  
X  
  
  
 
  
  
  
Abbreviations: 
ANGPTL3=angiopoietin-like 
protein 
3; 
BPI-SF=brief 
pain 
inventory 
– 
short 
form; 
DNA=deoxyribonucleic acid; DXA=dual-energy X-ray absorptiometry; eCOA=electronic clinical outcome 
assessment; HADS=hospital anxiety and depression scale; HbA1c=hemoglobin A1c; HBsAg=hepatitis B surface 
antigen; HCV=hepatitis C virus; ; MRI=magnetic resonance imaging; MRI-PDFF=MRI-derived proton density fat 
fraction; NMR=nuclear magnetic resonance; PHQ-8=8-item patient health questionnaire depression scale; 
SC=subcutaneous; SF-36=short form 36; WOCBP=women of child-bearing potential; HDL-C=high density 
lipoprotein cholesterol; LEPR=soluble leptin receptor; l; IV=intravenous; LDL-C=low density lipoprotein cholesterol  
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CONFIDENTIAL 
9.1.1. 
Footnotes for the Schedule of Events Table 1: Screening and Placebo Run-in 
1. Patients may be re-screened if they fail the screening for reasons related to incidental or 
transitory conditions (eg, medication use, concomitant illness, medical condition). If 
patients are re-screened within the original 10-week screening period, only screening 
test(s) (eg, an out-of-range lab value) that resulted in initial screen failure should be 
repeated. All patients will be monitored for 4 hours following IV placebo infusion to 
maintain study blinding. For those patients screened and found eligible under the original 
protocol, HbA1c and triglycerides assessments will be repeated to reconfirm eligibility of 
the patient if the screening window of 10 weeks has been exceeded by the time the relevant 
approvals for Protocol Amendment 1 are in place. 
2. Procedures may be conducted on different days during the screening period, if needed. 
Blood draws for laboratory testing at the screening visit will be collected in a fasted state 
(after at least approximately a 12-hour fast). The duration of fasting may be shortened for 
patients with a documented clinical contraindication to fasting. 
3. Procedures may be conducted by trained study staff at a remote location (ie, at home visits, 
work, and/or school). 
4. Visit 2 has to occur at least 7 days after visit 1. Visit 3 is conditional upon the results of 
results from visit 1 and visit 2. Visit 3 may not be required in all patients depending on the 
results from visit 1 and visit 2.  
5. Medical history should include detailed lipodystrophy history including prior 
medication/IPs, genetic diagnosis (if known), and results of any previous anti-metreleptin 
antibody testing (if applicable). 
6. Monitoring by qualified study personnel may be performed as a telephone contact or an in-
clinic or inpatient assessment. A telephone contact may be converted to an in-person site 
visit if in the opinion of qualified study personnel that a direct, in-person assessment would 
aid assessment of safety or clarify concomitant medication use and adjustment. For diabetic 
patients, all monitoring assessments will include asking about symptoms of hypoglycemia 
(per local standards), a review of the patient’s home glucometer readings (if applicable), 
and patient education regarding the importance of blood glucose monitoring and how to 
recognize symptoms of hypoglycemia (per local standards). Diabetic patients should be 
reminded to call the site if any signs or symptoms of hypoglycemia occur. 
7. All safety assessment should be performed before study drug administration. 
8. Vital signs should be recorded prior to IV study drug infusion, and approximately 
120 minutes post-IV infusion or prior to SC study drug injection. 
9. Body weight should be measured with patient in a gown after voiding (empty bladder) 
using a calibrated scale. Patients should empty pockets and remove shoes, belts, outer-layer 
clothing, or any other heavy wearable prior to being weighed. 
10. The ECG can be performed up to 24 hours prior to study drug administration. 
11. Blood (for safety, efficacy and biomarkers) and urine samples are to be collected before 
study drug administration, unless otherwise indicated. For patients undergoing apheresis, 
study assessments are to be performed and blood samples are to be collected immediately 
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Clinical Study Protocol  
 
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CONFIDENTIAL 
before the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
12. If there is a positive urine pregnancy test, a confirmatory serum pregnancy test will be 
performed. Study treatment will not be administered until a negative serum pregnancy test 
is obtained. If the serum pregnancy test is negative the patient can continue in the study. A 
positive serum pregnancy test will result in permanent stopping of study drug 
administration. 
13. Please refer to Appendix 1 for actions based on Hb1Ac, TG, and leptin results.  
14. Patients must be in a fasted state (after at least approximately a 12-hour fast). The duration 
of fasting may be shortened for patients with a documented clinical contraindication to 
fasting.  
15. Patients must receive eCOA training at the time they receive the eCOA device.  
16. Two DXA scans will be performed as follows: Screening DXA will be performed at either 
visit 1 or visit 2. The second DXA will be performed during the run-in period and can be 
performed from day -28 to day 1 prior to dosing of study drug. Two baseline liver volume 
and liver fat content MRI-PDFF scans will be obtained from day -28 to day 1 prior to 
dosing. These 2 MRI-PDFF scans must be performed on separate days at least 24 hours 
apart and up to a maximum of 28 days apart. Patients may be required to fast at least 5 hours 
prior to the scans. 
17. DNA should be collected at visit 1, but can be collected at any visit after obtaining consent. 
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Clinical Study Protocol  
 
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CONFIDENTIAL 
Table 2: 
Schedule of Events: TP1, TP2 and Off-Drug Follow up  
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Patient Disposition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
(REGN4461/Placebo)2 
(IV) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
(REGN4461/Placebo)2 
(SC) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
 
 
 
 
 
Concomitant 
Medications and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
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Clinical Study Protocol  
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 63 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Monitoring dose 
adjustments for 
antidiabetic and lipid 
lowering medication 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
Safety4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
Weight6 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Waist and hip 
circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
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Clinical Study Protocol  
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 64 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Menstrual history, 
pregnancy status 
reporting, and 
Confirmation of 
contraception 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Laboratory Testing7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy Test 
(WOCBP)8 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Leptin9 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Efficacy7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol  
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 65 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Fasting Triglycerides9 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X X 
X 
X 
X 
X 
Lipid Panel9 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Fasting Glucose9 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X X 
X 
X 
X 
X 
HbA1c 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Fructosamine 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Insulin9 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Free Fatty Acids9 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
NMR Lipid panel 
LDL-C, HDL-C, total-
Cholesterol9 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Urine  Creatinine and 
Albumin 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
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Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Daily Lipodystrophy 
Hunger questionnaire  
 
BPI-SF questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
SF-36 questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
PHQ-8 questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
HADS questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Patient Global 
Impression of Severity-
Hunger 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Patient Global 
Impression of Severity- 
Pain 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
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Page 67 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Patient Global 
Impression of Change- 
Hunger 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Patient Global 
Impression of Change- 
Pain 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Bioimpedance 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
DXA10 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Liver volume (MRI) and 
liver fat content (MRI-
PDFF)10 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
PK/Drug 
Concentration and 
ADA Samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Biomarkers 
Procedure/Samples7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ADA=antidrug antibodies; ANGPTL3=angiopoietin-like protein 3; BPI-SF=brief pain inventory – short form; DNA=deoxyribonucleic acid; 
DXA=dual-energy X-ray absorptiometry; EOS=end of study; EOT=end of treatment; ET=early termination; HADS=hospital anxiety and depression scale; 
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HbA1c=hemoglobin A1c; HDL-C=high density lipoprotein cholesterol; IV=intravenous; LDL-C=low density lipoprotein cholesterol; MRI=magnetic resonance 
imaging; NMR=nuclear magnetic resonance; PK=pharmacokinetic; SC=subcutaneous; sLEPR=soluble leptin receptor; WOCBP=women of childbearing 
potential  
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CONFIDENTIAL 
9.1.2. 
Footnotes for the Schedule of Events Table 2: TP1, TP2 and Off-Drug 
Follow-Up 
1. Randomization can occur within 24 hours prior to day 1 study drug administration if 
necessary.  
2. All patients will be monitored for 4 hours following infusion on day 1 and day 85.  For 
patients undergoing apheresis, study drug will be administered after the apheresis 
procedure. 
3. Monitoring by qualified study personnel may be performed as a telephone contact or an in-
clinic or inpatient assessment. A telephone contact may be converted to an in-person site 
visit if in the opinion of qualified study personnel a direct, in-person assessment would aid 
assessment of safety or clarify concomitant medication use and adjustment. For diabetic 
patients, all monitoring assessments will include asking about  symptoms of hypoglycemia 
(per local standards), a review of the patient’s home glucometer readings (if applicable), 
and patient education regarding the importance of blood glucose monitoring and how to 
recognize symptoms of hypoglycemia (per local standards). Diabetic patients should be 
reminded to call the site if any signs or symptoms of hypoglycemia occur. 
4. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
5. Vital signs should be recorded prior to IV study drug infusion, and approximately 
120 minutes post-IV infusion (on day 1 and day 85) and prior to SC study drug injection 
(on day 85).  
6. Body weight should be measured after voiding (empty bladder) using a calibrated scale. 
Patients should empty pockets and remove shoes, belts, outer-layer clothing, or any other 
heavy wearable prior to being weighed. 
7. Study assessments, urine, and blood (safety, efficacy and biomarkers) samples will be 
collected before study drug administration, unless otherwise indicated. For patients 
undergoing apheresis, study assessments, urine, and blood samples will be collected 
immediately before the lipid-apheresis procedure.  
8. If there is a positive urine pregnancy test, a confirmatory serum pregnancy test will be 
performed. Study treatment will not be administered until a negative serum pregnancy test 
is obtained. If the serum pregnancy test is negative, the patient can continue in the study. 
A positive serum pregnancy test will result in permanent stopping of study drug 
administration. 
9. Patients must be in a fasted state (after at least approximately a 12-hour fast). The duration 
of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
10. Liver volume (MRI) and liver fat content (MRI-PDFF) and whole body DXA scans may 
be performed up to14 days prior to visits 20 and 32. Patients may be required to fast at least 
5 hours prior to the scans. 
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11. Collection of blood samples for drug concentration/sLEPR on days 1 and 85 will be 
pre-infusion and again at the end of infusion (0 to 15 mins after the end of the infusion). 
On other visits, drug concentration/sLEPR samples will be collected pre-dose.  
12. Early termination (ET)/End of treatment (EOT) visit consists of the end of study 
assessments. 
9.1.3. 
 Early Termination Visit 
Patients who withdraw from the study will be asked to return to the clinic for 2 visits: an EOT/ET 
visit and an end of study visit. The EOT/ET visit should take place within 5 days of treatment 
discontinuation, if possible. A final end of study visit should take place with assessments 16 weeks 
after the last dose of study drug as described in Table 2. 
Patients who have discontinued study drug but who remain in the study will enter the off-drug 
follow-up period (Table 2) after completing the early termination visit. In the off-drug follow-up 
period, patients will continue with monthly visits until 16 weeks after last dose of study drug. Each 
of these monthly visits will consist of safety assessments, including laboratory tests. 
Sexually active patients who discontinue the study prematurely should be reminded to maintain 
highly effective contraceptive measures for 16 weeks after the last dose of study drug.  
9.1.4. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. An unscheduled visit may be performed as a remote visit or an 
outpatient in-clinic visit. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population: medical history, demographics, HIV serology, and 
hepatitis testing (HBsAg, HCV). 
9.2.2. 
Efficacy Procedures 
9.2.2.1. 
Fasting Triglycerides 
Samples should be collected after the patients have fasted for at least approximately 12 hours. The 
duration of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. Sample times are provided in Table 1 and Table 2. 
9.2.2.2. 
Fasting Glucose 
Samples should be collected after the patients have fasted for at least approximately 12 hours. The 
duration of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. Sample times are provided in Table 1 and  Table 2. 
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9.2.2.3. 
Hemoglobin A1C 
Hemoglobin A1C will be collected at visits according to Table 1 and  Table 2. 
9.2.2.4. 
Fructosamine 
Samples for fructosamine will be collected at visits according to Table 1 and  Table 2. 
9.2.2.5. 
Insulin 
Samples for insulin will be collected at visits according to Table 1 and Table 2. 
9.2.2.6. 
Lipid Panel  
Samples for lipid panel LDL-C, HDL-C, total cholesterol, and Apolipoprotein B will be collected 
at visits according to Table 1 and Table 2. For patients with TG >400 mg/dL, direct LDL-C 
measurement will be used. While the standard lipid panel measures the concentrations of these 
lipoproteins,  lipoprotein size will be analyzed by NMR in a separate sample.  
Samples should be collected after the patients have fasted for at least approximately 12 hours. The 
duration of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
9.2.2.7. 
Urine Creatinine and Albumin 
Samples for urine  creatinine and albumin will be collected at visits according to Table 1 and  
Table 2. 
9.2.2.8. 
Insulin Sensitivity Measurement 
Insulin sensitivity will be assessed using non-invasive measurements of insulin sensitivity 
including the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) which 
incorporates measures of fasting insulin and glucose. 
 
 
 
 
 Samples for fasting glucose and insulin, and free 
fatty acids will be collected at visits according to Table 1 and Table 2. 
9.2.2.9. 
Assessment of Body Composition 
Whole body DXA imaging will be performed per the schedule outlined in Table 1 and Table 2. 
Patients may be required to fast at least 5 hours prior to the DXA scan. The duration of fasting 
may be shortened for patients with a documented clinical contraindication to fasting. In addition 
to standard body composition parameters from DXA, a trunk/leg fat ratio (TLR) will be calculated 
as trunk fat%/leg fat%. 
9.2.2.10. Bioimpedance 
Bioimpedance will be assessed for all patients according to Table 1 and Table 2 .  
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9.2.2.11. Assessment of Hepatic Fat Content and Liver Size 
Patients will undergo MRI scans to examine hepatic volume and fat content. Liver fat content 
analysis (MRI-PDFF) will be performed only at sites with advanced liver fat quantitation 
capability. Patients for whom MRI is contraindicated (eg, pacemaker) are still eligible to 
participate in the study but will not undergo MRI scans.  
MRI will be performed per the schedule outlined in Table 1 and Table 2. 
Patients may be required to fast at least 5 hours prior to an MRI scan. The duration of fasting may 
be shortened for patients with a documented clinical contraindication to fasting. Details of the MRI 
imaging protocol are included in the imaging manual.  
Imaging data may be utilized for future biomedical research of REGN4461, GLD, and related 
diseases. The results of these future biomedical research analyses will not be presented in the 
clinical study report. 
Note: The imaging scans in this study are performed for research purposes only. These research 
imaging scans are not intended to provide diagnosis of any disease. If any clinically significant 
findings are detected during the course of this study by the site’s radiologist, the investigative 
site/investigator should comply with any country, local or institutional requirements and standard 
of care guidelines in communicating these findings to the study patient. 
9.2.3. 
Safety Procedures 
9.2.3.1. 
Body Weight and Height 
Body weight will be assessed using calibrated scales according Table 1. Patients should void 
(empty bladder) prior to weight assessment. Patients should be wearing undergarments only and 
no shoes during weight assessments. Body weight will be recorded to the nearest 0.1 kg. 
For measuring height, patients will be instructed to remove footwear and stand upright with their 
heels together. BMI will be calculated based on weight and height. 
9.2.3.2. 
Vital Signs 
Vital signs, including temperature, blood pressure, pulse and respiration will be collected after the 
patient has been sitting or in a supine position at time points according Table 1. 
9.2.3.3. 
Physical Examination 
A thorough and complete physical examination including waist and hip circumference will be 
performed at time points according to Table 1. Care should be taken to examine and assess any 
abnormalities that may be present, as indicated by the patient’s medical history.  
9.2.3.4. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to Table 1 and Table 2. Heart 
rate will be recorded from the ventricular rate and the PR, QRS, and QT and QTcF intervals will 
be recorded. The ECG strips or reports will be retained with the source. 
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9.2.3.5. 
Menstrual History, Pregnancy Status Reporting, and Confirmation of 
Contraception 
Assessment of menstrual cycle history for WOCBP will be conducted at baseline and at the visits 
specified in Table 1 and Table 2, to identify any changes in occurrence, frequency, or duration 
following study drug treatment.  
9.2.3.6. 
Hypoglycemia Monitoring 
It is recommended that all diabetic patients prescribed insulin or insulin secretagogues 
(eg, sulfonylureas or glinides) should be instructed to routinely monitor finger stick blood glucose 
using a glucometer.  
Monitoring by qualified study personnel may be performed as a telephone contact or in-clinic 
assessment at the visits specified in Table 1 and Table 2. A telephone contact may be converted to 
an in-person site visit if in the opinion of qualified study personnel that a direct, in-person 
assessment would aid assessment of safety or clarify concomitant medication use and adjustment. 
For diabetic patients, all monitoring assessments will include asking about symptoms of 
hypoglycemia (per local standards), a review of the patient’s home glucometer readings (if 
applicable), and patient education regarding the importance of blood glucose monitoring and how 
to recognize symptoms of hypoglycemia (per local standards). Diabetic patients should be 
reminded to call the site if any signs or symptoms of hypoglycemia occur. 
9.2.4. 
Laboratory Testing 
Detailed instructions for sample collection, along with the location for analysis, are in the 
laboratory manual provided to study sites.  
Samples for laboratory testing will be collected at visits according to Table 1 and Table 2. On 
study visit days during which study drug will be administered, the laboratory samples are to be 
collected before the dose of study drug unless otherwise stated.  
Fasting is only required for laboratory tests described as “fasting” (eg, fasting TG, fasting lipid 
panel, and fasting glucose).  
Blood Chemistry  
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Uric acid 
Chloride 
Blood urea nitrogen (BUN) 
Creatine phosphokinase (CPK) 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Gamma-glutamyl transferase (GGT) 
Calcium 
Alanine aminotransferase (ALT) 
Gamma-glutamyl transferase (GGT) 
Fasting Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
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White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
 
 
Urinalysis  
Color 
Glucose 
Clarity 
Blood 
pH 
Bilirubin 
Specific gravity 
Leukocyte esterase 
Ketones 
Nitrite 
Protein 
WBC 
 
Fasting Lipid Panel 
LDL-C  
Apolipoprotein B 
 
HDL-C 
Triglycerides 
Total Cholesterol  
 
 
 
Other Laboratory Tests 
Fasting Leptin 
Pregnancy test (serum/urine) 
Fasting Free Fatty Acids 
Hepatitis B surface antigen (sAg) 
HIV (Ab) 
HbA1c 
Fasting Apolipoprotein C3 
Fructosamine 
Hepatitis C (Ab) 
Fasting ANGPTL3 
Urine albumin and creatinine 
 
 
 
 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.5. 
Clinical Outcomes Assessments 
9.2.5.1. 
Lipodystrophy Hunger Questionnaire  
The lipodystrophy hunger questionnaire was developed in order to assess hunger related behaviors 
among patients with lipodystrophy and was developed in accordance with the Food and Drug 
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Administration’s (FDA’s) guidance on PRO development. Patients will complete the PRO 
assessments daily. The Hunger questionnaire is self-administered and contains 4 items. 
9.2.5.2. 
Brief Pain Inventory – Short Form Questionnaire 
The BPI-SF measures pain and its interference with daily lives.  It is a self-administered measure 
which consists of 15 items. There are 4 pain questions, measured on a 0 to 10 scale, where 0 is “no 
pain” and 10 is the “pain as bad as you can imagine.”  There are 7 interference questions, where 0 
is “does not interfere” and 10 is “completely interferes.”  The remaining items are not numerically 
scored.  There is no scoring algorithm, but “worst pain” or the arithmetic mean of the 4 severity 
items can be used as measures of pain severity; the arithmetic mean of the 7 interference items can 
be used as a measure of pain interference. 
9.2.5.3. 
Short Form – 36 
The Short Form – 36 Survey (SF-36) is a 36-item self-administered PRO measure assessing health-
related quality of life (HRQoL) concepts relevant across age, disease, and treatment group. The 
SF-36 assesses physical functioning, limitations due to physical health bodily pain, general health, 
vitality, social functioning, limitations due to emotional problems, and mental health. Patients 
answer questions assessing these concepts over the previous week using 3-, 5-, or 6-point Likert 
scales; scores range from 0 to 100, with higher scores indicating better health.  
9.2.5.4. 
Patient Health Questionnaire-8  
The 8-item PHQ-8 is a self-administered instrument to measure depression. The PHQ-8 consists 
of 8 items each of which is scored 0 to 3, providing a 0 to 24 severity score. Scores of 5, 10, 15, 
and 20 represent cut points for mild, moderate, moderately severe and severe depression, 
respectively. 
If a patient scores between 10 to 14 on the PHQ-8, s/he should be referred to a mental health 
professional – if a referral is not deemed necessary, then the investigator must document why. 
A referral is mandatory if the PHQ-8 ≥15 or is deemed necessary by the investigator. 
9.2.5.5. 
Hospital Anxiety and Depression Scale Questionnaire 
The Hospital Anxiety and Depression Scale (HADS) questionnaire is an instrument for screening 
anxiety and depression in non-psychiatric populations; repeated administration also provides 
information about changes to a patient’s emotional state over time (Zigmond, 1983) 
(Herrmann, 1997). The HADS consists of 14 items, 7 each for anxiety and depression symptoms; 
possible scores range from 0 to 21 for each subscale. The following cut-off scores are 
recommended: 0 to 7 normal, 8 to 10 borderline abnormal, 11 to 21 abnormal. For this study, only 
the 7 anxiety questions will be scored.   
9.2.5.6. 
Patient Global Impression of Severity-Hunger 
The Patient Global Impression of Severity (PGIS) – Hunger is a self-administered PRO assessing 
the patient’s perception of their overall severity of hunger. The PGIS is not an efficacy measure; 
rather, it is an anchor-based assessment used to interpret meaningful change of the Hunger PRO.  
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9.2.5.7. 
Patient Global Impression of Severity- Pain 
The PGIS – Pain is a self-administered PRO assessing the patient’s perception of their overall 
severity of pain. The PGIS is not an efficacy measure; rather, it is an anchor-based assessment 
used to interpret meaningful change of the BPI-SF.  
9.2.5.8. 
Patient Global Impression of Change- Hunger 
The Patient Global Impression of Change (PGIC) – Hunger is a self-administered PRO assessing 
the patient’s perception of their overall change in hunger since the beginning of the study. The 
PGIC is not an efficacy measure; rather, it is an anchor-based assessment used to interpret 
meaningful change of the Hunger PRO.  
9.2.5.9. 
Patient Global Impression of Change- Pain 
ThePGIC– Pain is a self-administered PRO assessing the patient’s perception of their overall 
change in pain since the beginning of the study. The PGIC is not an efficacy measure; rather, it is 
an anchor-based assessment used to interpret meaningful change of the pain via the BPI-SF. 
All COAs will be performed as outlined in Table 1 and Table 2. 
9.2.6. 
Drug Concentration and Measurements 
 
 
 
 
9.2.7. 
Immunogenicity Measurements and Samples  
 
9.2.8. 
Pharmacodynamic and Exploratory Biomarker Procedures  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
9.2.8.1. 
Soluble LEPR (sLEPR) 
Leptin circulates in the bloodstream both as a free entity and also can be bound to an sLEPR, which 
is generated via shedding of the LEPR ectodomain (Sinha, 1996) (Lammert, 2001). Soluble LEPR 
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is present in circulation of healthy subjects and patients with disease. It is a non-signaling form of 
the leptin receptor that is able to bind to leptin and may regulate its bioavailability (Lou, 2010). It 
is possible that REGN4461 bioavailability might be influenced by sLEPR levels. It is also possible 
that sLEPR levels might be influenced by REGN4461, either through increasing sLEPR stability 
or shedding from LEPR. Therefore, sLEPR will be assessed at time points noted in Table 1 and 
Table 2. 
9.2.8.2. 
Angiopoietin-Like Protein 3 (ANGPTL3) 
Angiopoietin-like protein 3 is an endogenous inhibitor of lipoprotein lipase, which regulates 
circulating levels of TG and LDL-C (Tikka, 2016). Levels of ANGPTL3 can be regulated by 
feeding, leptin, and/or insulin (Minicocci, 2012) (Nidhina Haridas, 2015). Levels of ANGPTL3 
are elevated in patients with lipodystrophy and are reduced after treatment with 
metreleptin(Muniyappa, 2017). The reduction of ANGPTL3 following metreleptin treatment 
might affect lipase clearance of TG-rich lipoproteins. Therefore, ANGPTL3 might be a PD marker 
of REGN4461 activity, increasing leptin receptor signaling. ANGPTL3 will therefore be assessed 
at time points noted in Table 1 and Table 2. Modulation of ANGPTL3 is an exploratory measure. 
9.2.8.3. 
Apolipoprotein C3 (APOC3)  
Apolipoprotein C3 is an abundant lipoprotein in the blood and found on chylomicrons, VLDL, 
LDL and HDL particles.  APOC3 is synthesized and secreted by hepatocytes in the liver, inhibits 
lipoprotein lipase and hepatic lipase, and modulates many known cardiovascular disease risk 
factors inclusive of atherosclerosis and coronary heart disease. APOC3 will be measured in blood 
from samples collected at timepoints indicated in Table 1 and Table 2. Modulation of APOC3 by 
REGN4461 activity is an exploratory measure. 
9.2.8.4. 
Free Fatty Acids 
Free Fatty Acids (FFA) represent metabolic byproducts of long-chain molecules from lipid-
carboxylic acids in fat and other tissues. Free Fatty Acids will be measured in blood from samples 
collected at timepoints indicated in in Table 1 and Table 2. Modulation of FFA by REGN4461 is 
an exploratory measure. 
9.2.9. 
Future Biomedical Research (Optional) 
Patients who agree to participate in the future biomedical research (FBR) sub-study will be 
required to consent to this optional sub-study before samples are banked for FBR. Additional 
samples will be collected for FBR. Residual biomarker samples for study-related research, as well 
as unused PK and ADA samples, will be stored for up to 15 years after the final date of the database 
lock (or for a shorter time period if required per regional laws and regulations). The samples may 
be utilized for FBR that may or may not be directly related to the study, including being used as 
reference samples and assay development or validation. The results of these future biomedical 
research analyses will not be presented in the CSR. 
9.2.10. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples. Whole blood samples for DNA extraction 
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should be collected on day 1/baseline (predose; Table 1), but can be collected at a later study visit.  
DNA samples will be collected for pharmacogenomics analyses to understand the genetic 
determinants of efficacy and safety associated with the treatments in this study and the molecular 
basis of PLD and related diseases. These samples will be single-coded as defined by the 
International Council on Harmonisation (ICH) guideline E15. Samples will be stored for up to 
15 years after the final date of the database lock (or for a shorter time period if required per regional 
laws and regulations). If there are specific site or country requirements involving the 
pharmacogenomic analyses with which the sponsor is unable to comply, samples will not be 
collected at those sites.  
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to REGN4461, other PLD clinical outcome measures and possible AEs. In 
addition, associations between genomic variants and prognosis or progression of PLD as well as 
related lipodystrophic and metabolic diseases may also be studied. These data may be used or 
combined with data collected from other studies to identify and validate genomic markers related 
to the study drug, target pathway, or PLD and related diseases.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, may also be performed. The 
list of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period. Results from the genomic analyses will not be 
reported in the CSR. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all AEs occurring during the study data collection, from 
the time of signing the informed consent form (ICF) to the end of the study (see Section 11.4.5.1). 
Medical conditions that existed or were diagnosed prior to the signing of the Informed Consent 
will be recorded as part of medical history. Abnormal laboratory values and vital signs observed 
at the time of Informed Consent should also be recorded as medical history. Any subsequent 
worsening (ie, any clinically significant change in frequency and/or intensity) of a pre-existing 
condition that is temporally associated with the use of the study drug should also be recorded as 
an AE.  
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient. Adverse events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit. Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. The Investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2. 
The Investigator’s assessment must be clearly documented in the site’s source documentation with 
the Investigator’s signature. The Investigator should follow up on serious adverse events (SAEs) 
(and AESIs) until they have resolved or are considered clinically stable; AEs should be followed 
until they are resolved or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available. If the signs and symptoms are distinct and do not suggest a 
common diagnosis, report them as individual entries of AE or SAE.  
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, lead to study drug discontinuation, dose reduction, require corrective 
treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization). A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-planned (prior to 
signing the Informed Consent Form) procedures, treatments requiring hospitalization for 
pre-existing conditions that do not worsen in severity, and admission for palliative or social care 
should not be reported as SAEs (see Section 10.2 for Definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Any SAE that may occur subsequent to the reporting period (end of the on-treatment period) that 
the Investigator assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.  
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10.1.2. 
Reporting Procedure  
All adverse events (serious and non-serious) must be reported to the sponsor with investigator’s 
assessment of the event’s seriousness, severity, and causality to the (when applicable: blinded) 
study drug. For SAEs and AESIs, a detailed narrative summarizing the course of the event, 
including its evaluation, treatment, and outcome should be provided on the AE CRF. Specific or 
estimated dates of event onset, treatment, and resolution should be included, when available. 
Medical history, concomitant medications, and laboratory data that are relevant to the event should 
also be summarized in the narrative. For fatal events, the narrative should state whether an autopsy 
was or will be performed, and include the results if available. Information not available at the time 
of the initial report must be documented in a follow-up report. Source documents (including 
hospital or medical records, diagnostic reports, etc.) will be summarized in the narrative on the AE 
CRF, and retained at the study center and available upon request.  
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event.  
• SAEs. 
• Selected Adverse Events of Special Interest (AESI; serious and nonserious):  
Adverse events of special interest for this study include the following:   
− Hypoglycemia, defined as blood glucose <54 mg/dL, regardless of symptoms. 
− NODM 
For patients with no diabetes at baseline: 
a. Two values of fasting (≥8 hours) plasma glucose ≥126 mg/dL (7.0 mmol) during the 
treatment period 
OR 
b. Two values of HbA1c ≥6.5% (48 mmol/mol) during the treatment period 
Patients who meet either of these criteria during the placebo run-in period will be 
considered to have diabetes at baseline. 
− Hyperglycemia requiring treatment, defined as: 
a. HbA1c ≥10.5% AND increase in HbA1c of ≥1.5% from baseline value 
OR 
b. Fasting glucose ≥250 mg/dL on 2 occasions including symptoms consistent with 
hyperglycemia AND increase in fasting glucose >50 mg/dL above baseline 
− Development of new or worsening of autoimmune disease 
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− Moderate or severe hypersensitivity reactions 
− Moderate or severe infusion reactions 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• Pregnancy:  Although pregnancy is not considered an AE, it is the responsibility of 
the investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female or female partner of a male, during the study or 
within 16 weeks of the last dose of study drug. Any complication of pregnancy 
affecting a female study patient or female partner of a male study patient, and/or fetus 
and/or newborn that meets the SAE criteria must be reported as an SAE. Outcome for 
all pregnancies should be reported to the sponsor. 
• Symptomatic Overdose: Accidental or intentional overdose of at least 2 times the  
intended dose of study drug within the intended therapeutic window, if associated with 
an AE. 
For the AESIs based on a laboratory value, the AESI must be reported to Sponsor within 
24 hours once the investigator confirms the abnormal laboratory value. 
10.1.4. 
Other Adverse Events of Special Interest that Do Not Require Expedited 
Reporting to Sponsor 
Although these AESIs do not require expedited reporting to the sponsor, the following events are 
of interest and will involve the collection of additional details in separate CRFs: 
• Injection site reaction due to study treatment administration 
• Mild infusion reactions due to study treatment administration 
• Mild hypersensitivity reactions due to study treatment administration 
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
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• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
In-patient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing hospitalization 
is defined as a hospital stay that is longer than was originally anticipated for the event 
or is prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
interest specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it.  
Adverse events of special interest for this study are detailed in Section 10.1.3.  
10.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
after the infusion is completed. All infusion reactions must be reported as AEs (defined  
in Section 10.2.1) and graded using the grading scales as instructed in Section 10.3.1. 
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10.3. 
Evaluation of Severity and Causality 
10.3.1. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient normal functioning level. It may 
be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms, but may be 
given because of personality of the patient. 
Moderate:  Produces some impairment of functioning but is not hazardous to health. It is 
uncomfortable or an embarrassment. Treatment for symptom may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient’s health. Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
Mild:  Mild transient reaction; infusion interruption not indicated; intervention not indicated. 
Moderate:  Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated 
for ≤24 hours. 
Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for 
clinical sequelae; life-threatening consequences; urgent intervention indicated; death. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade: 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires ER 
visit or hospitalization; necrosis or exfoliative dermatitis 
10.3.2. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
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judgment, and the following definitions. The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
Include the following when applicable] For double blinded studies using an active comparator, the 
investigator should consider all study drugs in determining event causality.  
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset versus time drug was administered 
• Nature of the reactions: immediate versus long term 
• Clinical and pathological features of the events  
• Existing information about the drug and same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is predicted 
by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
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• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified procedure, 
or can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
10.4. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments (eg, 
Global Patient Safety (GPS); Biostatistics and Data Management). Safety monitoring will be 
performed on an ongoing basis (eg, individual review of SAEs) and on a periodic cumulative 
aggregate basis. 
10.5. 
Notifying Health Authorities, Institutional Review Board/Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, IECs/IRBs, and the 
participating investigators of any SUSARs (Suspected Unexpected Serious Adverse Reactions) 
occurring in other study centers or other studies of the active study drug (REGN4461), as 
appropriate per local reporting requirements. In addition, the sponsor and/or CRO will comply 
with any additional local safety reporting requirements. All notifications to investigators will 
contain only blinded information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the Institutional Review Board (IRB)/Ethics Committee (EC) unless 
delegated to the sponsor. 
Event expectedness for study drug (REGN4461) is assessed against the Reference Safety 
Information section of the Investigator’s Brochure that is effective for expedited safety reporting.  
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the Clinical Study Report to health authorities and IECs/IRB as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP will 
be revised prior to the end of the study to accommodate amendments to the clinical study protocol 
and to make changes to adapt to unexpected issues in study execution and data that may affect the 
planned analyses.  The final SAP will be issued before the first database lock. 
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis 
No formal statistical hypothesis testing will be performed for this study. Based on the sample 
size, the analysis will be focused on estimation of the treatment effect. 
11.2. 
Justification of Sample Size 
The primary objective is to estimate the treatment effect of REGN4461 on glycemic and lipid 
parameters. The co-primary endpoints are the percent change in TG and change in HbA1c from 
baseline to week 12 between the placebo and REGN4461 arms in cohort A. 
The size of the study is determined by feasibility assessments. Due to the limited number of 
identified PLD patients with low leptin and moderate metabolic abnormalities, up to 40 patients 
will be enrolled.  
With a total of 40 patients (20 per cohort, randomized in the ratio of 1:1 into the REGN4461 arm 
and the placebo arm), the primary analysis will be carried out on the 20 patients in the lower leptin 
cohort A in TP1. The fact that it is unlikely that all of the patients will have HbA1c >7.0%, ie, not 
all of the patients will be assessed for the HbA1c endpoint, has also been accounted for. From the 
feasibility work, it is estimated that 78% of the patients will have elevated baseline HbA1c. With 
20 patients in cohort A (10 patients per study arm; Table 3), the half-width of the 90% confidence 
interval in change from baseline to week 12 between the REGN4461 arm and the placebo arm for 
HbA1c is 1.4 percentage points, assuming the SD of 1.81%. For TG, the half-width of the 90% 
confidence interval in logarithm transformed geometric mean ratio (GMR) (REGN4461 
week12/baseline divided by placebo week12/baseline) is 0.67, assuming the SD for logarithm 
transformed fasting TG is 0.87. The SD is estimated from the subset samples of the extracted NIH 
study data.  
Table 3: 
Half-Width of the 90% Confidence Interval for Primary Endpoints 
Endpoint 
Number of Patients per Group 
in the Subset 
Half of the 90% confidence 
interval** 
HbA1c*  
7 
1.72% 
8 
1.59% 
HbA1c† 
10 
1.4% 
Fasting TG† 
0.67 
*Assuming 78% of the patients have elevated baseline HbA1c.  
**The estimate of treatment effects for drug for HbA1c are -1.18%, and -52% for fasting TG. After adjusting for 
placebo effect, the between-group treatment effect estimate for HbA1c are -0.98%, and -47% for fasting TG. 
Assuming SD for HbA1c is 1.81%, and logarithm transformed fasting TG is 0.87 (SD of HbA1c and fasting TG is 
extracted from NIH study data). 
†Assuming all patients have baseline HbA1c >7.0% and TG >200 mg/dL. 
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11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients who received any study drug and have 
at least 1 post-baseline assessment; it is based on the treatment allocated (as randomized).  Efficacy 
endpoints will be analyzed using the FAS. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
11.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result following the first dose of study drug. 
11.3.4. 
Immunogenicity Analysis Set 
The ADA analysis set includes all patients who received study drug and had at least 1 non-missing 
ADA result following the first dose of study drug. 
11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, SD, Q1, median, Q3, minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Unless otherwise specified, baseline is defined as the last available measurement obtained before 
the first dose of double-blind study drug. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients who have signed the ICF 
• The total number of randomized patients that received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
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11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
The co-primary endpoints are the percent change in fasting serum TG from baseline to week 12 
and the absolute change in HbA1c from baseline to week 12 between REGN4461 and the placebo 
arm in cohort A (leptin <8.0 ng/mL) patients. The glycemic endpoint will be evaluated in the subset 
of patients with baseline HbA1c > 7.0%. The fasting TG endpoint will be evaluated in the subset 
of patients with baseline TG >200 mg/dL. Logarithm transformation will be performed to 
normalize the fasting TG. 
Summary statistics including the mean change (or percent change) from baseline, standard error 
(SE), corresponding 95% confidence interval, and nominal p-value will be provided by treatment 
group, using a mixed effect repeated measurement model (MMRM), which will account for the 
missing data. Nominal p-values will be provided as a measure of the strength of evidence. The 
model includes the factors (fixed effects) for treatment, week, randomization strata (screening 
HbA1c ≤7.0% or HbA1c >7.0%), strata-by-week interaction, and treatment-by-week interaction. 
Relevant baseline HbA1c, and/or TG will be included as a continuous covariate. Log-transformed 
TG will be transformed into percentage for presentation.  
A non-parametric ranked analysis of covariance (ANCOVA) will be performed for the percent 
change in fasting serum TG from baseline to week 12 as a sensitivity analysis. The ranked 
ANCOVA model will be able to provide significance of the treatment effect as compared to 
placebo. Nominal p-values will be provided as a measure of the strength of evidence. Median 
treatment difference and 95% confidence interval can be derived from the Hodges-Lehmann 
estimation and Moses distribution free confidence interval respectively. 
For the co-primary endpoints, mean changes (±SE) will be plotted over time by the treatment 
group. A spaghetti plot will be provided for co-primary endpoints by the treatment group. The 
intra-subject and inter-subject variability may be evaluated if data is appropriate. 
11.4.3.2. Secondary Efficacy Analysis 
For the secondary analysis, the change from baseline to week 12 will be compared to the change 
between week 12 and week 24 for study arm 1 to evaluate the treatment effect of REGN4461 on 
HbA1c and fasting TG.  
For continuous secondary endpoints measured in the double-blind period, summary statistics, 
including the mean (or median) change from baseline, SE, 95% confidence interval, and  nominal 
p-value when appropriate will be provided using the MMRM or ranked ANCOVA (fasting TG 
only). Descriptive statistics may be provided by subtype of PLD mutations. 
For categorical secondary endpoints, appropriate tests, eg,: Fisher’s exact test, will be used to 
evaluate the treatment effect.  
In addition to the summary statistics described above, mean changes (±SE) will be plotted over 
time by the treatment group. A spaghetti plot will be provided for co-primary endpoints by the 
treatment group. 
When combining patients from study arm 1 and study arm 2 for determining within-group effects 
after 12 weeks of REGN4461 treatment, patients in study arm 1 will only be included if they meet 
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stability criteria for TP1 (when they are receiving placebo). The stability criteria are a change in 
HbA1c ≤0.5 percentage points and a change in TG ≤25%.  
11.4.4. 
Control of Multiplicity 
Not applicable. 
11.4.5. 
Safety Analysis 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The on-treatment period is defined as the day from first dose of study drug to the last 
dose of study drug plus 7 days.  
• The posttreatment period is defined as the end of the on-treatment period to the last 
study visit. 
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the on-treatment period. 
TEAEs will be summarized for each of the following periods: double-blind treatment period, 
single-blind treatment period, follow-up period, and combined across the treatment periods and 
follow-up period. Adverse events that occur prior to treatment period 1 (day 1) will be listed. 
Analysis 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®).   
Summaries of all TEAEs by treatment group will include: 
• Overview of TEAEs, ie, overall number (%) of patients with any TEAE, related 
TEAEs, serious TEAE, TEAEs leading to death, TEAEs leading to study 
discontinuation,  or AESIs 
• All TEAEs by primary SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.3.1), 
presented by SOC and PT 
• TEAEs by causality relationship to treatment (related, not related), presented by SOC 
and PT 
• Treatment-emergent SAEs by primary SOC and PT  
• Treatment-emergent AESIs  
• Treatment-emergent AEs leading to discontinuation by primary SOC and PT 
• Treatment-emergent SAEs leading to death, by primary SOC and PT 
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Deaths and other SAEs will be summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be 
summarized by treatment group. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all patients 
and separately for patients in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
11.4.5.3. Treatment Exposure 
The duration of exposure during each study part will be presented by treatment group and study 
period, calculated as: 
(Date of last study drug injection in the specific study part – date of first study drug injection 
in the specific study part) + 7 days 
Number (%) of patients exposed to study drug during the study will be presented for each treatment 
group and study period. 
In addition, duration of exposure during the study will be summarized for each treatment group 
using number of patients, means, SD, minimums, medians, and maximums. 
A summary of the number of doses by treatment group and study period will be provided. 
11.4.5.4. Treatment Compliance 
The compliance with study treatment will be calculated as follows: 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 % = 100% × # 𝑎𝑐𝑡𝑢𝑎𝑙 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛𝑠
# 𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛𝑠 
The treatment compliance will be presented by specific ranges for each treatment group and study 
period. The ranges of interest will be specified in the SAP. 
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11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data  
Descriptive statistics of concentrations of total REGN4461 in serum will be presented at each 
sampling time point. Plots of individual concentrations of total REGN4461 in serum will be 
presented by actual time point. Plots of summary statistics of individual concentrations of total 
REGN4461 in serum will be presented by nominal time point. No formal statistical analysis will 
be performed. 
11.4.6.2. Analysis of Pharmacokinetic Parameters  
Pharmacokinetic parameters may include, but are not limited to, the following: 
• Cmax – peak concentration 
• Ctrough – pre-dose concentrations both prior to and at steady-state 
11.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response observed:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses <9-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative 
− Treatment-emergent ADA response may be further characterized as persistent, 
transient, or indeterminate 
− Persistent Response – Treatment-emergent ADA positive response with 2 or more 
consecutive ADA positive sampling time points, separated by at least 16-week 
period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples. 
− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples. 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment boosted ADA response, defined as any post-dose positive ADA assay 
response that is 9-fold over baseline titer levels when baseline is positive in the ADA 
assay  
• Maximum ADA titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
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− High (titer >10,000)  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
positivity presented by patient, time point, and dose cohort/group will be provided. Incidence of 
treatment-emergent ADA will be assessed as absolute occurrence (N) and percent of patients (%), 
grouped by study cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs on individual PK profiles 
evaluated.  Assessment of impact of ADA on safety and efficacy may be provided. 
11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
Descriptive statistics of biomarkers by study visit and by treatment group will be generated. 
Summary statistics of biomarkers including mean and medians will be evaluated for change from 
baseline through the end of study.  
11.5. 
Interim Analysis 
No formal interim analysis is planned. Periodic data reviews may be performed by selected 
unblinded Regeneron personnel with no direct involvement in the study conduct. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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12. 
 QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history) will be done using internationally 
recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC), Medidata 
Rave.  
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
• eCOA system – capture COA 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk-based approach to study monitoring and oversight, aligned 
with risk based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-Based Quality Monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as sponsor, or via our CRO partners. 
RBQM strategies include: reduced source data verification (SDV), targeted source data review 
(SDR), the use of off-site/remote and triggered on-site monitoring visits, and Centralized 
Monitoring to identify site level risks and study level trends. The investigator must allow study-
related monitoring activities to occur. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
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that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and CRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel. All required CRFs must be 
completed for each patient screened in the study. The investigator must ensure the accuracy, 
completeness, and timeliness of the data reported to the sponsor in the CRFs. After review of the 
clinical data for each patient, the investigator must provide an electronic signature. A copy of each 
patient CRF casebook is to be retained by the investigator as part of the study record and must be 
available at all times for inspection by authorized representatives of the sponsor and regulatory 
authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
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pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand. The ICF should be signed and dated by the patient and by the 
investigator or authorized designee who reviewed the ICF with the patient.  
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients must be informed of the new information and provide their written 
consent if they wish to continue in the study. The original signed revised ICF must be maintained 
in the patient’s study record and a copy must be given to the patient. 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
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13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator. The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment. Where required per local legislation, regulatory authority approval will also 
be sought.  
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. Reasons 
may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
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MYALEPT 
[Package 
Insert]. 
Bristol-Myers 
Squibb 
Company 
and 
AstraZeneca. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125390s000lbl.pdf. Published 2014. 
 
Nidhina Haridas PA, Soronen J, Sadevirta S, Mysore R, Quagliarini F, Pasternack A, et al. 
Regulation of Angiopoietin-Like Proteins (ANGPTLs) 3 and 8 by Insulin. J Clin Endocrinol Metab 
2015; 100(10):E1299-1307. 
 
Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, et al. Leptin-replacement therapy 
for lipodystrophy. N Engl J Med 2002; 346(8):570-578. 
 
Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, et al. Leptin reverses insulin resistance 
and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002; 109(10):1345-1350. 
 
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for 
the interpretation of sequence variants: a joint consensus recommendation of the American College 
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of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 
2015; 17(5):405-424. 
 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. Ann Emerg Med 2006; 47(4):373-380. 
 
Shalaurova I, Connelly MA, Garvey WT,Otvos JD. Lipoprotein insulin resistance index: a 
lipoprotein particle-derived measure of insulin resistance. Metab Syndr Relat Disord 2014; 
12(8):422-429. 
 
Simha V, Subramanyam L, Szczepaniak L, Quittner C, Adams-Huet B, Snell P, et al. Comparison 
of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic 
patients with familial partial lipodystrophy of the Dunnigan variety. J Clin Endocrinol Metab 2012; 
97(3):785-792. 
 
Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J, et al. Evidence 
of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-
term fasting. J Clin Invest 1996; 98(6):1277-1282. 
 
Tikka A,Jauhiainen M. The role of ANGPTL3 in controlling lipoprotein metabolism. Endocrine 
2016; 52(2):187-193. 
 
Vatier C, Fetita S, Boudou P, Tchankou C, Deville L, Riveline J, et al. One-year metreleptin 
improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes. 
Diabetes Obes Metab 2016; 18(7):693-697. 
 
Zigmond AS,Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 
67(6):361-370. 
 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Randomized Double-Blind Placebo-Controlled Study of the 
LEPR Agonist Antibody REGN4461 for the Treatment of Metabolic Abnormalities in Patients 
with Familial Partial Lipodystrophy and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved. I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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APPENDIX 1. HEMOGLOBIN A1C, TRIGLYCERIDE AND LEPTIN 
MEASUREMENTS 
HbA1c and TG 
The actions taken based on triglycerides (TG) will depend on the screening hemoglobin A1C 
(HbA1c), as presented in Figure 3 and described below. Two fasting TG tests will be performed 
during the screening period.  
If the HgbA1C is >7.0 and both screening TG>200 mg/dL, the patient will screen pass. If 
HbA1c is >7.0 and both screening TG<200 mg/dL, the patient will screen fail. If the HbA1c 
is >7.0 and 1 screening TG is >200 and the other is <200 mg/dL, a third screening TG will 
be obtained to determine the geometric mean of the three fasting triglyceride values. If the 
geometric mean TG  is >200 mg/dL, the patient screen-passes and if the geometric mean 
TG is <200 mg/dL, the patient screen fails.  
If HbA1c is <7.0% and both screening TG >450 mg/dL, the patient screen passes. If HbA1c 
<7.0% and both screening TG <450 mg/dL, patient screen fails. If HbA1c is <7.0% and 
1 screening TG is >450 mg/dL and the other screening TG is <450 mg/dL, a third screening 
TG will be obtained, and the geometric mean of the 3 fasting TG values will be determined. 
If the geometric mean is >450 mg/dL, the patients screen passes and if the geometric mean 
<450 mg/dL, the patient screen fails.  
For those patients screened and found eligible under the original protocol, screening triglycerides 
assessments will be repeated if the screening window of 10 weeks has been exceeded before the 
beginning of the placebo run-in period (visit 4). Visit 4 cannot occur until the relevant approvals 
for Protocol Amendment 1 are in place. 
Figure 3:  Screening Triglyceride and Hemoglobin A1c Measurements 
 
 
Leptin 
Two tests of leptin will be performed with an Investigational Use Only (IUO) Enzyme Linked 
Immunosorbent Assay (ELISA). If the 2 leptin levels are concordant for the 3 leptin ranges being 
considered (<8.0 ng/mL for cohort A, 8.0 to ≤20.0 ng/mL for cohort B, >20.0 ng/mL: not 
qualifying for study) the appropriate action will be taken based on that range (assigned to cohort 
A, B, or screen fail). If the 2 leptin values are discordant (fall in different ranges), a third leptin 
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level will be obtained, and the appropriate action will be taken on the arithmetic average of the 
3 leptin levels. 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
 A Randomized Double-Blind Placebo-Controlled Study of the LEPR Agonist 
Antibody REGN4461 for the Treatment of Metabolic Abnormalities in Patients with Familial 
Partial Lipodystrophy  
Protocol Number: R4461-PLD-20100 
Protocol Version:  R4461-PLD-20100 Amendment 1 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
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Signature Page for VV-RIM-00140037 v2.0
Signature Page for VV-RIM-00140037 v2.0 Approved
Approval/eSignature
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Approval/eSignature
03-May-2022 15:45:03 GMT+0000
Approval/eSignature
03-May-2022 19:21:18 GMT+0000
Approval/eSignature
04-May-2022 00:45:55 GMT+0000
                                        VV-RIM-00140037-2.0 Approved - 03 May 2022 GMT-5:00

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL
A RANDOMIZED, DOUBLE-BLIND PLACEBO-CONTROLLED STUDY 
OF THE LEPR AGONIST ANTIBODY REGN4461 FOR THE 
TREATMENT OF METABOLIC ABNORMALITIES IN PATIENTS WITH 
FAMILIAL PARTIAL LIPODYSTROPHY  
Compound 
Mibavademab (REGN4461) 
Protocol Number 
R4461-PLD-20100 
Clinical Phase 
Phase 2 
Sponsor 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician 
 
Project Biostatistician 
 
Clinical Trial Manager 
 
Study Medical Director 
 
Version / Date 
V 1.0 / May 16, 2024 
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Protocol: R4461-PLD-20100 
Statistical Analysis Plan 
Date: May 16, 2024 
 
CONFIDENTIAL 
Page 2 of 88 
 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
See appended electronic signature page 
Study Biostatistician  
 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist 
 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
 
 
See appended electronic signature page 
Study Director 
 
 
 
See appended electronic signature page 
Study Global Patient Safety 
 
 
 
See appended electronic signature page 
Project Biostatistician
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
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Statistical Analysis Plan V1.0 
 
Date: May 16, 2024 
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CONFIDENTIAL 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................8 
1. 
OVERVIEW ...............................................................................................................12 
1.1. 
Background/Rationale ................................................................................................12 
1.2. 
Study Objectives .........................................................................................................13 
1.2.1. 
Primary Objectives .....................................................................................................13 
1.2.2. 
Secondary Objectives .................................................................................................13 
1.2.3. 
Exploratory Objectives ...............................................................................................13 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................14 
1.2.5. 
Revision History for Statistical Analysis Plan Version 1 ...........................................15 
2. 
INVESTIGATION PLAN ..........................................................................................15 
2.1. 
Study Design and Randomization ..............................................................................15 
2.2. 
Justification of Sample Size........................................................................................16 
3. 
ANALYSIS POPULATIONS ....................................................................................17 
3.1. 
Efficacy Analysis Sets ................................................................................................17 
3.1.1. 
Full Analysis Set (FAS) ..............................................................................................17 
3.2. 
Safety Analysis Sets (SAF) ........................................................................................17 
3.2.1. 
Double-Blind Safety Analysis Set ..............................................................................17 
3.2.2. 
Single-Blind Safety Analysis Set ................................................................................18 
3.3. 
Pharmacokinetic (PK) Analysis Set............................................................................18 
3.4. 
Immunogenicity Analysis Set .....................................................................................18 
3.5. 
Clinical Outcome Assessment ....................................................................................18 
4. 
ANALYSIS VARIABLES .........................................................................................18 
4.1. 
Demographic and Baseline Characteristics ................................................................18 
4.2. 
Medical History ..........................................................................................................20 
4.3. 
Prior and Concomitant Medications ...........................................................................20 
4.4. 
Prohibited Medications and Procedures During Study ...............................................21 
4.5. 
Patient Disposition ......................................................................................................21 
4.6. 
Study Treatment Exposure and Compliance Variables ..............................................23 
4.7. 
Efficacy Variables ......................................................................................................24 
4.7.1. 
Primary Efficacy Variables .........................................................................................24 
4.7.2. 
Secondary Efficacy Variables .....................................................................................24 
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4.7.3. 
SBTP-specific Secondary Efficacy Variables ............................................................25 
4.8. 
Safety Variables ..........................................................................................................25 
4.8.1. 
Adverse Events Variables ...........................................................................................25 
4.8.1.1. 
Adverse Events and Serious Adverse Events .............................................................25 
4.8.1.2. 
Adverse Events of Special Interest .............................................................................26 
4.8.1.3. 
Adverse Events of Interest ..........................................................................................26 
4.8.1.4. 
Events Causing Death .................................................................................................27 
4.8.2. 
Laboratory Safety Variables .......................................................................................27 
4.8.3. 
Vital Signs ..................................................................................................................28 
4.8.4. 
12-Lead Electrocardiography (ECG) ..........................................................................28 
4.8.5. 
Physical Examination Variables .................................................................................28 
4.9. 
Other Variables ...........................................................................................................28 
4.10. 
Pharmacokinetic Variables .........................................................................................29 
4.11. 
Immunogenicity Variables ..........................................................................................29 
4.12. 
Clinical Outcomes Assessment ...................................................................................29 
4.12.1. 
Hunger ........................................................................................................................29 
4.12.2. 
Pain .............................................................................................................................30 
4.12.3. 
Anxiety and Depression ..............................................................................................31 
4.12.4. 
Quality of Life ............................................................................................................31 
5. 
STATISTICAL METHODS .......................................................................................31 
5.1. 
Demographics and Baseline Characteristics ...............................................................31 
5.2. 
Medical History ..........................................................................................................32 
5.3. 
Prior and Concomitant Medications ...........................................................................32 
5.4. 
Prohibited Medications ...............................................................................................33 
5.5. 
Patient Disposition ......................................................................................................33 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................33 
5.6.1. 
Exposure to Investigational Product ...........................................................................33 
5.6.2. 
Study Treatment Compliance .....................................................................................33 
5.7. 
Analyses of Efficacy Variables ..................................................................................34 
5.7.1. 
Analysis of Primary Efficacy Variables .....................................................................34 
5.7.1.1. 
Percent Change in Fasting TG from Baseline to Week 12 .........................................34 
5.7.1.2. 
Change in HbA1c from Baseline to Week 12 ............................................................35 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................36 
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5.7.2.1. 
Continuous Endpoints Anticipated to have a Normal Distribution ............................36 
5.7.2.2. 
Continuous Endpoints Anticipated to have a Non-normal Distribution .....................41 
5.8. 
Analysis of Safety Data ..............................................................................................42 
5.8.1. 
Adverse Events ...........................................................................................................43 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................44 
5.8.3. 
Adverse Events of Interest ..........................................................................................44 
5.8.4. 
Clinical Laboratory Measurements.............................................................................44 
5.8.5. 
Analysis of Vital Signs ...............................................................................................45 
5.8.6. 
Analysis of 12-Lead ECG ...........................................................................................45 
5.8.7. 
Physical Exams ...........................................................................................................46 
5.8.8. 
Treatment Exposure and Treatment Compliance .......................................................46 
5.9. 
Analysis of Other Variables ........................................................................................46 
5.10. 
Analysis of Pharmacokinetic Variables ......................................................................47 
5.11. 
Analysis of Immunogenicity Data ..............................................................................47 
5.11.1. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................48 
5.11.1.1. 
Immunogenicity and Exposure ...................................................................................48 
5.11.1.2. 
Immunogenicity and Safety and Efficacy ...................................................................48 
5.12. 
Analysis of Clinical Outcome Assessment .................................................................49 
6. 
DATA CONVENTIONS ............................................................................................49 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................49 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................49 
6.3. 
Data Handling Convention for Missing Data .............................................................49 
6.4. 
Visit Windows ............................................................................................................50 
6.5. 
Unscheduled Assessments ..........................................................................................50 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................51 
6.7. 
Statistical Technical Issues .........................................................................................51 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................51 
7.1. 
Interim Analysis ..........................................................................................................51 
7.2. 
First Step Analysis ......................................................................................................51 
7.3. 
Second Step Analysis .................................................................................................51 
7.4. 
Final Analysis .............................................................................................................51 
7.5. 
Additional Rules .........................................................................................................51 
8. 
SOFTWARE ...............................................................................................................52 
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CONFIDENTIAL 
9. 
REFERENCES ...........................................................................................................53 
10. 
APPENDIX.................................................................................................................54 
10.1. 
Summary of Statistical Analyses ................................................................................54 
10.2. 
Windows for Analysis Time Points ............................................................................54 
10.3. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ ..............................65 
10.4. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................66 
10.5. 
Biomarker-NMR Lipoprotein analysis .......................................................................70 
10.6. 
DXA Variable List ......................................................................................................71 
10.7. 
Schedule of Events .....................................................................................................73 
10.7.1. 
Footnotes for the Schedule of Events Table 21: Screening and Placebo Run-
in .................................................................................................................................76 
10.7.2. 
Footnotes for the Schedule of Events Table 22: TP1, TP2 and Off-Drug 
Follow-Up ...................................................................................................................87 
10.7.3. 
Early Termination Visit ..............................................................................................88 
10.7.4. 
Unscheduled Visits .....................................................................................................88 
 
 
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CONFIDENTIAL 
LIST OF TABLES 
Table 1: Summary of Study Arms .................................................................................................16 
Table 2: Half-Width of the 90% Confidence Interval for Primary Endpoints ...............................17 
Table 3. Summary of Statistical Estimates and Comparisons in Normally-distributed 
Secondary Endpoints ..................................................................................................37 
Table 4. Summary of Descriptive Statistics for Patients Randomized to REGN4461 in 
Normally-distributed Secondary Endpoints for the combined DBTP and 
SBTP Analysis ............................................................................................................38 
Table 5. Summary of Descriptive Statistics in Normally Distributed Secondary 
Endpoints based on REGN4461 Exposure .................................................................38 
Table 6. Summary of Statistics for Patients Randomized to Placebo in Normally 
distributed Secondary Endpoints ................................................................................39 
Table 7. Summary of Statistical Estimates, Comparisons, and Descriptive Statistics in 
Fasting-TG Secondary Endpoints ...............................................................................41 
Table 8: General Global Analysis Windows .................................................................................56 
Table 9: Analysis Windows for Vital Sign ....................................................................................57 
Table 10: Analysis Windows for Body Weight .............................................................................59 
Table 11: Efficacy Analysis Windows for Fasting Triglycerides and Fasting Glucose ................60 
Table 12: Efficacy Analysis Windows for HbA1c ........................................................................61 
Table 13: Efficacy Analysis Windows for Daily Lipodystrophy Hunger Questionnaire ..............62 
Table 14: Efficacy Analysis Windows for DXA, MRI, NMR Lipid, and Bioimpedance .............63 
Table 15: Double-blind treatment period – Period Windows ........................................................64 
Table 16: Single-blind treatment period – Period Windows .........................................................64 
Table 17: Double-blind treatment-emergent adverse event period – Period Windows .................64 
Table 18: Single-blind treatment-emergent adverse event period – Period Windows ..................64 
Table 19: Summary of AESIs and the Methods of Data Collections and Derivations ..................65 
Table 20: Criteria for Potentially Clinically Significant Values (PCSV) ......................................66 
Table 21: Schedule of Events: Screening and Placebo Run-In ......................................................74 
Table 22: Schedule of Events: TP1, TP2, and Off-Drug Follow up ..............................................79 
 
LIST OF FIGURES 
Figure 1: Study Flow Diagram ......................................................................................................15 
 
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CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
ADIPO-IR 
Adipose Insulin Resistance 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
ARH 
Autoregressive heterogeneous 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
APLD 
Acquired partial lipodystrophy 
ApoC3 
Apolipoprotein C3 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
BMI 
Body mass index 
BPI-SF 
Brief Pain Inventory – Short Form 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMQ 
Company MedDRA queries 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CV 
Cardiovascular 
DBTP 
Double-blind treatment period 
DLHQ 
Daily Lipodystrophy Hunger Questionnaire 
DNA 
Deoxyribonucleic acid 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
(e)COA 
(electronic) Clinical Outcomes Assessment 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
ELISA 
Enzyme Linked Immunosorbent Assay 
EOT 
End of treatment 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FFA 
Free fatty acids 
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CONFIDENTIAL 
FPLD 
Familial partial lipodystrophy 
HADS 
Hospital anxiety and depression scale 
HbA1c 
Hemoglobin A1c 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HLGT 
High level group term 
HLT 
High level term 
HOMA-IR 
Homeostatic Model Assessment for Insulin Resistance 
HRQoL 
health-related quality of life  
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IUO 
Investigational use only  
IV 
Intravenously 
IVRS 
Interactive voice response system 
LSM 
Least squares mean 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LEPR 
Leptin receptor 
LIPO-IR 
Lipoprotein Insulin Resistance Index 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model with repeated measures 
MRI 
Magnetic resonance imaging 
MRI-PDFF 
Magnetic resonance imaging-derived proton density fat fraction 
NAS 
Non-alcoholic fatty liver disease activity score 
NIH 
National Institutes of Health 
NODM 
New onset of diabetes mellitus 
PBO 
Placebo run-in period 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
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CONFIDENTIAL 
PDFF 
Proton Density Fat Fraction 
PGIS 
Patient Global Impression of Severity 
PHQ-8 
8-item patient health questionnaire depression scale 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PLD 
Partial lipodystrophy 
PRO 
Patient reported outcomes 
PT 
Preferred term 
QoL 
Quality of life 
QW 
Every week 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
rhLeptin 
Recombinant human leptin 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SF-36 
Short Form-36 survey 
sLEPR 
soluble form of the leptin receptor 
SMQ 
Standard MedDRA queries 
SOC 
System organ class 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TF 
Trunk fat %/leg fat % 
TG 
Triglyceride 
TLR 
Trunk to leg fat ratio 
TP1 
Treatment Period 1 for double-blind treatment period 
TP2 
Treatment Period 2 for single-blind treatment period 
ULN 
Upper limit of normal 
WBC 
White blood cell 
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CONFIDENTIAL 
WHO-DD 
WHO Drug dictionary 
WOCBP 
Women of childbearing potential 
 
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CONFIDENTIAL 
1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data collected in R4461-PLD-20100 study.  
This plan may be revised during the study to accommodate protocol amendments and adapt to 
unexpected issues in study execution that may affect planned analyses. These revisions will be 
based on data review, and a final plan will be issued prior to the final database lock. 
1.1. 
Background/Rationale 
This Phase 2, randomized, double-blind, placebo-controlled study is designed to evaluate the 
efficacy and safety of mibavademab (or REGN4461) in patients with familial partial lipodystrophy 
and metabolic abnormalities (elevated fasting TG with or without elevated HbA1c) who are not 
receiving rhLeptin (metreleptin) therapy. This study will compare the efficacy and safety of 
mibavademab to placebo.  
Lipodystrophy is a rare condition in which the body is unable to produce or maintain adipose 
tissue. Partial lipodystrophy (PLD) is characterized by the selective loss of adipose tissue from 
various areas of the body. Partial lipodystrophy is a heterogeneous disease, and the extent of 
lipoatrophy varies significantly among patients. The reduced number of functional adipocytes can 
lead to relative leptin deficiency and associated metabolic abnormalities due to lipids being stored 
in other tissues, including muscle and liver. These metabolic abnormalities include 
hypertriglyceridemia, insulin resistance/diabetes, and nonalcoholic fatty liver disease. Partial 
lipodystrophy patients with diabetes are at increased risk for complications of diabetes, including 
nephropathy. In a large fraction of familial partial lipodystrophy (FPLD) patients (one-third to one-
half, based on available data), lipoatrophy is extensive enough to result in reduced leptin levels 
(<8.0 ng/mL), which could drive severe hunger and insulin resistance.  
The true incidence of PLD is unknown, with estimates of 2 to 3 clinical cases per million 
(Chiquette, 2017).  Most cases of PLD are familial (FPLD), and often are associated with 
pathogenic mutations in genes important for adipocyte biology. However, due to a presentation 
that overlaps with the much more common metabolic syndrome, FPLD is clinically 
underdiagnosed. Recent data point to a higher prevalence of individuals with FPLD gene variants, 
as high as 160 per million (Gonzaga-Jauregui, 2020) .  
Mibavademab is a human antibody that binds and activates the leptin receptor (LEPR) independent 
of leptin binding. Mibavademab is not related to endogenous leptin, and therefore should not have 
the risk of anti-drug antibodies (ADAs) cross-reacting with and neutralizing endogenous leptin.  
Based on preclinical and clinical studies performed to-date, it is hypothesized that low-leptin 
familial PLD (FPLD) patients will benefit from treatment with mibavademab, and therefore FPLD 
patients with a range of lower leptin levels will be enrolled to explore the relationship between 
leptin levels and response to mibavademab in this study. The primary analysis of this study 
includes FPLD patients with leptin levels <8.0 ng/mL (Cohort A). A second cohort of FPLD 
patients with leptin levels of 8.0 ng/mL to ≤20.0 ng/mL (Cohort B) will also be assessed 
(separately) given analyses of individualized patient data from the National Institutes of Health 
(NIH), which indicated that patients with leptin ≤20.0 ng/mL had a better response to metreleptin 
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than did those with leptin >20.0 ng/mL. An analysis of the combined set of cohorts A plus B (also 
named as combined Cohort A+B that includes all patients in Cohort A and Cohort B) will also be 
performed to determine the effect of mibavademab on endpoints in patients with leptin levels 
within the broader range (≤20.0 ng/ml). An Investigational Use Only (IUO) leptin assay (ie, 
investigational human leptin assay) is being developed for stratification and patient selection 
purposes; study eligibility and cohort allocation will be determined using this leptin Enzyme 
Linked Immunosorbent Assay (ELISA) developed and validated under Clinical Laboratory 
Improvement Amendments (CLIA) guidelines.   
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure.  
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objectives will be evaluated for patients in cohort A (leptin <8.0 ng/ml) only: 
• To evaluate the effect of mibavademab on fasting TG in patients with baseline leptin 
<8.0 ng/mL and with elevated baseline fasting TG (>200 mg/dL) 
• To evaluate the effect of mibavademab on hyperglycemia in patients with baseline 
leptin <8.0 ng/mL and with elevated baseline HbA1c (>7.0%) 
1.2.2. 
Secondary Objectives 
The following secondary objectives of the study will be evaluated for cohort B and for the 
combined set of cohorts A plus B: 
• To evaluate the effect of mibavademab on fasting TG levels in patients with 
hypertriglyceridemia (screening fasting TG >200 mg/dL) 
• To evaluate the effect of mibavademab on glycemic control in patients with 
hyperglycemia (screening HbA1c >7.0%)  
The following secondary objectives of the study will be evaluated for cohorts A and B separately, 
and for the combined set of cohorts A plus B: 
• To evaluate the effect of mibavademab on liver fat in patients with hepatic steatosis 
(baseline Hepatic Fat Fraction [Magnetic resonance imaging-derived proton density 
fat fraction, MRI-PDFF] ≥8.5%)  
• To evaluate the effect of mibavademab on hunger  
• To evaluate safety and tolerability of mibavademab  
• To characterize the concentration profile of mibavademab over time  
• To assess immunogenicity to mibavademab 
1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study, will be evaluated for cohorts A and B separately, and for 
the combined set of cohorts A plus B: 
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• To evaluate the effect of mibavademab on insulin sensitivity  
• To evaluate the effect of mibavademab on pain  
• To evaluate the effect of mibavademab on depression  
• To evaluate the effect of mibavademab on anxiety  
• To evaluate the effect of mibavademab on body weight  
• To evaluate the effect of mibavademab on regional body composition  
• To evaluate the effect of mibavademab on Quality of Life (QoL)  
• To study the activity of mibavademab (including biomarker discovery related to 
safety and efficacy of mibavademab), the leptin pathway and FPLD (including insulin 
resistance, hepatic steatosis, and hypertriglyceridemia)  
• To determine if bioimpedance measurements can be used as adequate surrogates for 
dual-energy X-ray absorptiometry (DXA) to measure regional body composition in 
patients with FPLD  
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
The content of this SAP reflects the content of the statistical section of Protocol R4461-PLD-
20100 Amendment 1 with the following exceptions: 
• Protocol Section 4. Endpoints: The definitions of endpoints are clarified in SAP 
Section 5.7 by replacing: 
− “elevated baseline fasting TG” into “screening TG” 
− “elevated baseline HbA1c” for defining subgroup into “screening HbA1c” to 
match HbA1c strata (screening HbA1c ≤7.0%, >7.0%) 
− “baseline leptin” for defining Cohort into “screening leptin” 
• Protocol Section 11.3.2. Safety Analysis Set: Safety analysis set (SAF) is replaced 
with DB SAF and SB SAF as follows in SAP Section 3.2: 
− DB SAF includes all randomized patients who received any double-blind study 
drug. 
− SB SAF includes all the patients in the double-blind SAF who also received at 
least 1 study drug in the single-blind treatment period.    
• Protocol Section 11.4.5.4. Treatment Compliance: Compliance % calculation is 
replaced with study treatment administration interval compliance in SAP Section 
5.8.8.  
• Protocol Section 11.4.3. Efficacy Analyses: The randomization strata per IVRS in the 
analysis models (eg, MMRM) are replaced with actual strata in SAP Section 5.7 to 
reflect the actual disease characteristic for statistical modeling. 
• Protocol Section 11.4.3. Efficacy Analyses: Due to the early termination of the study 
and subsequent limited number of participants enrolled, only descriptive summaries 
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and line plots for fasting TG, HbA1c, fasting glucose, liver fat (MRI-PDFF), and 
Daily Lipodystrophy Hunger Questionnaire (DLHQ) over time will be provided by 
treatment group. Spaghetti plots for fasting TG, HbA1c, fasting glucose, liver fat 
(MRI-PDFF), and DLHQ will be provided for individual patient data across visits for 
the endpoints by treatment group if applicable.  
• SAP Section 7 Timing of Statistical Analyses: First Step Analysis and Second Step 
Analysis will not be performed.  
1.2.5. 
Revision History for Statistical Analysis Plan Version 1 
This is the original version of the SAP. 
2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
The study consists of the following 5 periods (Figure 1):  
• A screening period up to 10-weeks  
• A placebo run-in period (PBO) for 4 weeks 
• A randomized double-blind placebo-controlled treatment period (TP1 or DBTP) for 
12 weeks 
• A single-blind treatment period (TP2 or SBTP) during which all patients receive 
mibavademab for 12 weeks 
• An off-drug safety follow-up period for 16 weeks 
Figure 1: Study Flow Diagram 
Patients 18 years of age or older with a clinical diagnosis of FPLD will undergo screening, 
including measurement of HbA1c, fasting TG, and leptin levels. A diagnosis of FPLD requires 
either a documented ClinVar pathogenic or likely pathogenic variant in a known FPLD gene or 
pathognomonic regional lipoatrophy by DXA. In addition, patients must have metabolic 
abnormalities (elevated fasting TG with or without elevated HbA1c) and leptin level ≤20.0 ng/mL 
to be included. 
After the screening period of up to 10 weeks, eligible patients will be assigned to one of the 
following two leptin cohorts based on the mean screening leptin levels: 
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• Cohort A: FPLD patients with serum leptin <8.0 ng/mL  
• Cohort B: FPLD patients with serum leptin 8.0 to ≤20.0 ng/mL  
Then, these patients will begin the single-blind 4-week placebo run-in period.  
On Day 1 after the placebo run-in period, each cohort of patients will be centrally randomized via 
interactive voice response system (IVRS) in a 1:1 ratio to Arm 1 or Arm 2:  
• Arm 1: placebo 
• Arm 2: mibavademab 
Subjects will be stratified based on screening HbA1c (HbA1c ≤7% or HbA1c >7%) to ensure 
equal representation of patients with elevated HbA1c in each study arm. Schedules of study 
treatments and follow-up periods are summarized in Table 1. 
Table 1: Summary of Study Arms 
 
 
Arm 1 
Arm 2 
Double-
blind 
Treatment 
Period 
(DBTP) 
Day 1 (IV loading dose based on 
weight) 
Placebo IV 
 mg/kg mibavademab IV 
Day 8 onwards (for 11 weekly 
maintenance doses)  
Placebo SC QW 
 mg mibavademab SC 
QW 
Single-
blind 
Treatment 
Period 
(SBTP) 
Day 85 (IV loading dose based on 
weight) 
 mg/kg mibavademab IV 
followed by  
Placebo SC 
Placebo IV followed by 
 
mg mibavademab SC 
Day 92 (for 11 weekly doses) 
 mg mibavademab SC QW 
 
Day 169 until week 40 
Off-Drug Safety Follow-up 
The study event table is presented in Appendix 10.7. 
2.2. 
Justification of Sample Size 
The size of the study is determined by feasibility assessments. Due to the limited number of 
identified FPLD patients with low leptin and moderate metabolic abnormalities, up to 40 patients 
will be enrolled.  
With a total of 40 patients (20 per cohort, randomized in the ratio of 1:1 into Arm 1 and Arm 2), 
the primary analysis will be carried out on the 20 patients in the lower leptin Cohort A in DBTP. 
The fact that it is unlikely that all of the patients will have HbA1c >7.0%, ie, not all of the patients 
will be assessed for the HbA1c endpoint, has also been accounted for. From the feasibility work, 
it is estimated that 78% of the patients will have elevated screening HbA1c. With 20 patients in 
Cohort A (10 patients per study arm; Table 2), the half-width of the 90% confidence interval of 
the difference in change from baseline to week 12 between Arm 1 and Arm 2 for HbA1c is 1.4 
percentage points, assuming a SD of 1.81%. For TG, the half-width of the 90% confidence interval 
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in logarithm-transformed geometric mean ratio (GMR) (mibavademab week12/baseline divided 
by placebo week12/baseline) is 0.67, assuming the SD for logarithm-transformed fasting TG is 
0.87. The SD estimates are from the FPLD subset samples of the extracted NIH study data (Diker-
Cohen. 2015).  
Table 2: Half-Width of the 90% Confidence Interval for Primary Endpoints 
Endpoint 
Number of Patients per Group 
in the Subset 
Half of the 90% confidence 
interval** 
HbA1c*  
7 
1.72% 
8 
1.59% 
HbA1c† 
10 
1.4% 
Fasting TG† 
0.67 
*Assuming 78% of the patients have elevated screening HbA1c.  
**The estimates of treatment effects of drug at the end of the DBTP (week 12) are -1.18% for HbA1c, and -52% for 
fasting TG. After adjusting for placebo effect, the between-group treatment effect estimates are -0.98% for HbA1c, 
and -47% for fasting TG. SD for HbA1c is assumed to be 1.81%, and for logarithm-transformed fasting TG is assumed 
to be 0.87 (SD estimates extracted from NIH study data). 
†Assuming all patients have baseline HbA1c >7.0% and TG >200 mg/dL. 
3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), below are the patient populations defined 
for statistical analysis. The efficacy analysis population is the full analysis set.  Additional 
patient populations include safety analysis sets, pharmacokinetic analysis set, immunogenicity 
analysis set, and clinical outcome assessment set. For the purposes of the definitions below, a 
patient is considered randomized to study treatment when they have been screened and received 
a randomization number and are recorded in the IVRS/IWRS database. 
3.1. 
Efficacy Analysis Sets 
3.1.1. 
Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients who received any study drug in 
DBTP and have at least 1 post-baseline assessment. Patients in the FAS population will be 
analyzed according to the treatment group allocated by randomization (as-randomized). Efficacy 
endpoints will be analyzed using the FAS.   
3.2. 
Safety Analysis Sets (SAF) 
3.2.1. 
Double-Blind Safety Analysis Set 
The double-blind safety analysis set (DB SAF) includes all randomized patients who received any 
double-blind study drug. Patients will be analyzed according to the treatment received (as treated). 
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
double-blind SAF.  
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In addition:   
• Randomized patients for whom it is unclear whether they took the study drug will be 
included in the DB SAF as randomized. 
• For randomized patients receiving both mibavademab and placebo study treatment in 
the DBTP, the treatment group allocation for as-treated analysis will be 
mibavademab. 
3.2.2. 
Single-Blind Safety Analysis Set 
The single-blind safety analysis set (SB SAF) includes all randomized patients who received any 
single-blind study drug.   
3.3. 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set is defined as all randomized patients who received any study drug and have 
at least 1 non-missing measurement of mibavademab concentration following the first dose of 
study drug.  Treatment assignments for DBTP are based on the actual treatment received (as 
treated). 
3.4. 
Immunogenicity Analysis Set 
The ADA analysis set includes all treated patients who received any amount of study drug 
(active or placebo) and had at least one non-missing anti-drug antibody result following the first 
dose of study drug. The ADA analysis set is based on the actual treatment received (as treated). 
3.5. 
Clinical Outcome Assessment 
The analyses for Clinical Outcome Assessments (COA) will be performed on all randomized 
patients who received any study treatment. Patients will be analyzed according to the treatment 
received (as treated). Further for each scale:  
• For the daily lipodystrophy hunger questionnaire, patients will be included when a 
baseline and at least one-week post-baseline scores are available. 
• For the remaining COA item (eg, quality-of-life questionnaire, etc.), patients will be 
included when a baseline and at least one post-baseline score is available.  
4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
For each patient, demographic and baseline characteristics will be obtained from the last 
available value up to the date of the first double blind study treatment administration (ie, baseline 
definition).  
All baseline safety and efficacy parameters (apart from those listed below) will be presented 
along with the summary statistics in the safety and efficacy sections. The following variables 
will be summarized: 
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Demographic Characteristics 
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other, Pacific Islander, Not Reported, Other) 
• Age in years (quantitative and qualitative variable: ≥18 to <45, ≥45 to <65, ≥65 to 
<75, and ≥75 years) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
Baseline Characteristics 
• Baseline Weight (kg)  
• Baseline Height (cm) 
• Baseline Body mass index (BMI) in kg/m² (quantitative and qualitative variable 
defined as <30, ≥30) 
• Leptin by sex (leptin in male, leptin in female) 
• Strata on leptin 
− Randomization strata as reported in the IVRS, leptin (≤ 8mg/dL or 8 mg/dL to 20 
mg/dL) 
− Actual strata as reported in the clinical database, leptin (≤ 8mg/dL or 8 mg/dL to 
20 mg/dL) 
• Baseline Disease Characteristics  
• Fasting TG in mg/dL quantitative variable and qualitative variable defined as: >200 to 
≤450, and >450)    
• HbA1c (quantitative variable)  
• Strata on screening HbA1c 
− Randomization strata as reported in the IVRS, screening HbA1c (≤7% or >7%) 
− Actual strata as reported in the clinical database, screening HbA1c (≤7% or >7%) 
• Fasting glucose  
• Liver volume from MRI and liver fat content from MRI-PDFF 
• Insulin (quantitative variable and qualitative variable defined as: Yes/No) 
• Lipid Panel 
− Low density lipoprotein cholesterol (LDL-C)  
− High-density lipoprotein cholesterol (HDL-C) 
− Total Cholesterol (TC)  
− Apolipoprotein B   
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• Biomarker-Lipoprotein NMR Analysis (Note: List of data fields reported in the 
biomarker-lipoprotein NMR are listed in Appendix 10.5.) 
• Body Composition from DXA 
− Total lean mass 
− Total fat mass 
− Trunk fat mass 
− Percentage of body fat 
− Trunk/leg fat ratio (TLR; trunk fat %/leg fat %) 
4.2. 
Medical History 
As applicable, patient medical history will be dictionary coded by primary system organ class, 
high level term, and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA), specifically the latest MedDRA version at the time of the first database lock.  
FPLD disease history will be assessed by the following variables:  
• FPLD related medical history (Yes/No) 
• Time from diagnosis to study treatment randomization (years) 
• FPLD type  
• Genetic variant known (Yes/No): if yes, then list. 
• Pathogenic variant as determined by ClinVar (Yes/No) 
• Method of diagnosis of FPLD 
 
4.3. 
Prior and Concomitant Medications 
All medications taken from the time of informed consent to the final study visit, including 
medications that were started before the study and are ongoing during the study, will be reported 
in Concomitant Medications CRF.  
All medications will be dictionary coded using the World Health Organization-Drug Dictionary 
(WHO-DD) to both an anatomic category and a therapeutic category, with the latest version at 
the time of the first database lock.  Drug names will be matched to respective Anatomical-
Therapeutic-Chemical (ATC) classification, although a drug can be matched to more than one 
ATC classification (ie, patients can be counted in several categories for the same medication). 
Prior medications, concomitant medications, and post-treatment medications are defined below 
and will be applied in the respective treatment periods (DBTP and SBTP). 
• Prior medications are defined as medications for which the stop date is before the date 
of the first DBTP study treatment administration. 
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• Concomitant medications are defined as medications that are administered to the 
patients during the respective double-blind and single-blind study treatment periods. 
Specifically: 
− Start date of the concomitant medication is on or after the first study treatment 
administration in respective study treatment periods (≥ Day 1 for DBTP, or ≥ Day 
of the first single-blind study treatment administration for SBTP); or 
− Start date of the concomitant medication is before the first study treatment 
administration in respective study treatment periods and is “Ongoing” during the 
treatment emergent period; or   
− Start date of the concomitant medication is before the first study treatment 
administration in respective study treatment periods, and the end date is on or 
after the first study treatment administration in respective study treatment periods 
(≥ Day 1 for DBTP, or ≥ Day of the first single-blind study treatment 
administration for SBTP).  
The concomitant medication treatment emergent periods are defined as:  
− For concomitant medications in DBTP, the double-blind treatment emergent 
period is defined from the day of the first double-blind study treatment 
administration to (1) the last day of double-blind study treatment + 112 days (for 
patients who do not continue into the SBTP); (2) to the day of the first single-
blind study treatment administration (for patients who enter the SBTP).  
− For concomitant medications in SBTP, the single-blind treatment emergent period 
is defined from the day of the first single-blind study treatment administration to 
the last day of single-blind study treatment administration + 112 days.  
Note: In the case that the medication start day is before first study treatment 
administration and both ongoing status and stop date are missing, the medication will 
be assumed to be concomitant. 
• Post-treatment medications are defined as medications for which the start date is after 
last date of study treatment administration + 112 days (≥ last study treatment +112 
days).   
4.4. 
Prohibited Medications and Procedures During Study 
The definitions of prohibited medications and procedures are described in the Section 8.10.1 of 
the protocol. They will be reviewed and identified by the study clinician and reported in protocol 
deviations.   
4.5. 
Patient Disposition 
Patient disposition will include the description of patient status at major milestone decisions in 
the study, as well as the patient analysis populations.   
For patient study status, patient milestone categories for the DBTP are defined below.  As 
applicable, percentages will be calculated using the number of randomized patients in the 
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denominator, with two exceptions.  Specifically, the two exceptions will be for the screened and 
non-randomized categories, which will not have associated percentages shown.  
• The total number of screened patients defined as having signed ICF.  
• The total number of screen failure (SF) patients. 
• The total number of randomized patients, defined as all screened patients with a 
double-blind treatment kit number allocated and recorded in the IVRS database, 
regardless of whether the treatment kit was used. 
• The total number of patients randomized but not receiving study treatment. 
• The total number of patients randomized and receiving study treatment. 
• The total number of patients who completed the DBTP, defined as at least 11 weeks 
of study treatment administration and week 12 visit performed. 
• The total number of patients who prematurely discontinued study treatment during 
the DBTP and the reasons for discontinuation collected on the study completion 
eCRF.  
• The total number of patients who do not proceed into SBTP and complete the last 
study follow-up visit (ie, 16-week follow-up period). 
Patient SBTP milestone categories are defined below.  As applicable, percentages will be 
calculated using a denominator of the number of patients administered single-blind study 
treatment.  
• The total number of patients receiving study treatment in single-blind treatment 
period 
• The total number of patients ongoing in SBTP (applicable for first-step analysis) 
• The total number of patients who completed the SBTP, defined as at least 23 weeks 
of study treatment administration and week 24 visit performed. 
• The total number of patients who prematurely discontinued study treatment during 
the SBTP, and the reasons for discontinuation collected on the study completion 
eCRF. 
• The total number of patients from SBTP who complete the last study follow-up visit 
(ie, 16-week follow-up period). 
The following patient populations for analyses are defined in Section 3: 
• Efficacy population: Full analysis set (FAS) 
• Double-blind safety analysis set (DB SAF) 
• Single-blind safety analysis set (SB SAF) 
• Pharmacokinetic (PK) Analysis Set 
• Immunogenicity (ADA) Analysis Set  
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The following patient listings will provide the details from the patient disposition table. 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patient prematurely discontinued from treatment, along with reasons for 
discontinuation 
4.6. 
Study Treatment Exposure and Compliance Variables 
Study treatment exposure variables for study drug administered during the DBTP are listed 
below with associated definitions: 
• Patient duration of DBTP SC study treatment exposure in weeks defined as: (last 
double-blind SC study treatment administration date – first double-blind SC study 
treatment administration date+7)/7. Values will be rounded to one decimal place.  
• The total number of DBTP SC study treatment injections by patient.  
• The following categories will be used for DBTP SC treatment exposure at 1-week 
intervals: ≥1 day and <1 week, ≥1 week and <2 weeks, ≥2 weeks and <3 weeks, ≥3 
weeks and <4 weeks, …, ≥10 weeks and <11 weeks, ≥11 weeks. 
• The total number of DBTP IV study treatment administrations by patient.  
Study treatment exposure variables for study drug administered during the SBTP are listed below 
with associated definitions: 
• Patient duration of SBTP SC study treatment exposure in weeks defined as: (last 
single-blind SC treatm.ent administration date – first single-blind SC treatment 
administration date+7)/7. Values will be rounded to one decimal place.  
• The total number of SBTP SC study treatment injections by patient.  
• The following categories will be used for SBTP SC treatment exposure at 1-week 
intervals: ≥1 day and <1 weeks, ≥1 weeks and <2 weeks, ≥2 weeks and <3 weeks, ≥3 
weeks and <4 weeks, …, ≥22weeks and <23 weeks, ≥23 weeks. 
• The total number of SBTP IV study treatment administrations by patient.  
Cumulative study treatment exposure variables combining DBTP and SBTP are listed below for 
all patients who received mibavademab in the DBTP: 
• Cumulative patient duration of SC study treatment exposure in weeks defined as: 
DBTP SC treatment exposure + SBTP SC exposure. 
• Cumulative total number of SC treatment administration by patient defined as: DBTP 
SC injections + SBTP SC injections.  
• The following categories will be used for cumulative patient mibavademab treatment 
exposure in the study at 1-week intervals:  ≥1 day and <1 weeks, ≥1 weeks and <2 
weeks, ≥2 weeks and <3 weeks, ≥3 weeks and <4 weeks, …, ≥22 weeks and <23 
weeks, ≥23 weeks.  
• The total number of DBTP and SBTP IV study treatment administrations by patient.  
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With respect to patient treatment administration compliance, because the study treatment is 
administered either during the investigative site visits or by a visiting nurse, study compliance 
will be accessed by frequency for study drug administration for respective treatment periods 
(DBTP, SBTP), specifically: 
• The administration frequency for DBTP SC study treatment administration will be 
defined for each patient as the average number of days between 2 consecutive SC 
study drug administration during DBTP: (last double-blind SC administration date – 
first double-blind SC administration date) / (number of SC administrations during 
DBTP), for patients receiving at least 2 SC administrations during DBTP. 
• The administration frequency for SBTP SC study treatment administration will be 
defined for each patient as the average number of days between 2 consecutive SC 
study drug administration during SBTP: (last single-blind SC administration date – 
first single-blind SC administration date) / (number of SC administrations during 
SBTP), for patients receiving at least 2 SC administrations during SBTP. 
In the DBTP, all important and minor protocol deviations potentially impacting efficacy 
analyses, randomization, and drug-dispensing irregularities, as well as other deviations, will be 
collected and reviewed on an ongoing basis throughout the study as described in the Protocol 
Deviation Plan (PDP).  Both monitoring collected and programmatically derived deviations are 
listed and defined in the PDP.  
4.7. 
Efficacy Variables 
Efficacy will be assessed through the following parameters: fasting TG, HbA1c, fasting glucose, 
liver fat content as measured by MRI-PDFF, and lipodystrophy hunger questionnaire outcomes.  
4.7.1. 
Primary Efficacy Variables 
The two primary endpoints of the study are: 
• Percent change in fasting serum TG from baseline to week 12.  
• Absolute change in HbA1c from baseline to week 12. 
4.7.2. 
Secondary Efficacy Variables 
The secondary endpoints include:  
• Percent change in fasting serum TG from baseline to week 24.  
• Absolute change in HbA1c from baseline to week 24. 
• Change in fasting glucose from baseline to week 12. 
• Change in fasting glucose from baseline to week 24. 
• Percent change in liver fat (MRI-PDFF) from baseline to week 12. 
• Percent change in liver fat (MRI-PDFF) from baseline to week 24. 
• Change on the daily lipodystrophy hunger questionnaire from baseline to week 12. 
• Change on the daily lipodystrophy hunger questionnaire from baseline to week 24. 
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4.7.3. 
 SBTP-specific Secondary Efficacy Variables 
SBTP-specific secondary efficacy endpoints include:  
• Percent change in fasting serum TG from week 12 to week 24.  
• Absolute change in HbA1c from week 12 to week 24. 
• Change in fasting glucose from week 12 to week 24. 
• Percent change in liver fat (MRI-PDFF) from week 12 to week 24. 
4.8. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, physical examination, and ECG. Unless otherwise noted, the baseline 
value is defined as the last available value before the first dose of double-blind study treatment.        
4.8.1. 
Adverse Events Variables 
The period of safety observation starts from the time when the patient gives informed consent 
and continues into the following periods: 
• The pre-treatment period is defined from the day the ICF is signed to the time of the 
first dose of double-blind study treatment administration. 
• The double-blind treatment-emergent adverse event (DB TEAE) period is defined 
from the time of the first dose of double-blind study treatment administration to the 
day of the last dose of double-blind study treatment administration + 112 days (16 
weeks) for those patients not proceeding into SBTP, or up to the time of the first dose 
of SBTP study treatment administration for those patients proceeding into the SBTP. 
• The single-blind treatment-emergent adverse event (SB TEAE) period is defined from 
the time of the first single-blind study treatment administration to the day of the last 
single-blind study treatment administration + 112 days (16 weeks).  
• The post-treatment period is defined from the day after the end of the respective 
TEAE period to the last study visit. 
4.8.1.1. 
Adverse Events and Serious Adverse Events 
Adverse events (including serious adverse events (SAE), AEs causing permanent treatment 
discontinuation, deaths, and AEs of special interest) are recorded from the time of signed 
informed consent until the end of study. All AEs diagnosed by the Investigator will be reported 
and described. 
All AEs will be dictionary coded by “lowest level term (LLT)”, “preferred term (PT)”, “high 
level term (HLT)”, “high level group term (HLGT)” and associated primary “system organ class 
(SOC)” using the latest version of MedDRA at the time of the first database lock. 
Adverse Event Observation Period  
• Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
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• TEAEs are AEs that developed or worsened or became serious during the respective 
TEAE period.  
• Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
4.8.1.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner. AESIs will be recorded on the 
adverse event e-CRF using dedicated tick boxes, and/or identified using standard MedDRA 
queries (SMQ), company MedDRA queries (CMQ), MedDRA terms, and/or applicable 
laboratory assessments. Appendix 10.3 contains the definitions used to identify AESIs: 
The AESIs include: 
• Hypoglycemia, defined as blood glucose <54 mg/dL (eCRF, lab data) 
• New onset diabetes mellitus (NODM) (eCRF, lab data) 
• For patients with no diabetes at baseline, NODM is defined using the following lab 
parameters: 
a. Two values of fasting (≥8 hours) plasma glucose ≥126 mg/dL (7.0 mmol) during 
the treatment period 
OR 
b. Two values of HbA1c ≥6.5% (48 mmol/mol) during the treatment period 
 
• Hyperglycemia requiring treatment (eCRF, lab data), defined using the following lab 
parameter: 
a. HbA1c ≥10.5% AND at the same visit an increase in HbA1c of ≥1.5% from 
baseline value  
OR 
b. Fasting glucose ≥250 mg/dL on 2 occasions including symptoms consistent with 
hyperglycemia AND increase in fasting glucose >50 mg/dL above baseline 
• Development of new or worsening of autoimmune disease (eCRF) 
• Moderate or severe hypersensitivity reactions (CMQ, eCRF) 
• Moderate or severe infusion reactions (eCRF) 
4.8.1.3. 
Adverse Events of Interest 
Adverse events of interest are AE’s for which additional documentation is collected. Adverse 
events of interest include: 
• Injection site reaction, collected from the eCRF  
• Mild infusion reaction collected from the eCRF 
• Mild hypersensitivity reactions from the eCRF 
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4.8.1.4. 
Events Causing Death 
The observation periods for patient deaths are per the observation periods defined above.  
• Death on-treatment:  deaths occurring during the respective TEAE period. 
• Death post-treatment:  deaths occurring during the post-treatment period. 
 
4.8.2. 
Laboratory Safety Variables 
Clinical laboratory tests will consist of blood analyses (including hematology, clinical chemistry 
and other) and urinalysis. Clinical laboratory values will be converted and analyzed in 
international units and US conventional units, with associated normal ranges provided by the 
central laboratory. Both actual test values and “change from baseline” values (defined as the 
post-baseline value minus the baseline value) will be used in the result summaries.  Potentially 
clinically significant values (PCSV) ranges will be applied to the laboratory test values as 
applicable (see Appendix 10.4 for PCSV definitions). For those laboratory tests that do not have 
PCSV ranges, central laboratory normal ranges will be applied to identify out-of-range values.  
All laboratory samples will be collected before study treatment administration during the 
protocol scheduled visits, unless otherwise indicated.  
Unless otherwise specified below, blood samples for clinical laboratories will be collected at the 
protocol scheduled visits, and visits will be assigned to the Global Analysis Windows 
(See Appendix 10.2). The laboratory parameters (excluding those considered as efficacy 
parameters) will be classified as follows: 
Hematology: 
• Red blood cells and platelets:  hemoglobin, hematocrit, erythrocytes count, platelets 
count, red blood indices 
• White blood cells: white blood cells, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils 
Clinical chemistry: 
• Electrolytes:  sodium, potassium, chloride, carbon dioxide, calcium 
• Metabolism:  fasting glucose, total protein, albumin, Creatine phosphokinase 
• Renal function:  creatinine, blood urea nitrogen (BUN), uric acid 
• Liver function:  Alanine aminotransferase (ALT), aspartate aminotransferases (AST), 
alkaline phosphatase (ALP), total bilirubin, LDH, Gamma-glutamyl transferase 
(GGT) 
Fasting Lipid Panel 
• HDL-C, LDL-C, TC, Apo B, TG, NMR lipoprotein analysis 
Urinalysis 
• Color, clarity, pH, specific gravity, ketones, protein, glucose, blood, bilirubin, 
leukocyte esterase, nitrite, WBC, RBC 
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Other 
• Fasting Leptin, Pregnancy test (serum/urine), Fasting Free Fatty Acids, Hepatitis B 
surface antigen (sAg), HIV (Ab), HbA1c, Fasting Apolipoprotein C3, Fructosamine, 
Hepatitis C (Ab), Fasting ANGPTL3, Urine albumin and creatinine 
4.8.3. 
Vital Signs 
Vital signs parameters will include weight (kg), height (cm), BMI (kg/m2), respiratory rate 
(breaths/min), temperature (C), systolic and diastolic blood pressures (mmHg), and pulse (bpm) 
after the patient has been sitting or in the supine position. Both actual values and “change from 
baseline” values (defined as the post-baseline value minus the baseline value) will be used in the 
result summaries, and visits will be assigned to the Global Analysis windows (see Appendix 
10.2). Potentially clinically significant values (PCSV) ranges will be applied to the vital sign 
parameter values as applicable (see Appendix 10.4 for PCSV definitions).   
4.8.4. 
12-Lead Electrocardiography (ECG) 
A standard 12-lead ECG will be performed at specified time points according to Appendix 10.7.  
Heart rate will be recorded from the ventricular rate and the PR, QRS, and QT and QTcF 
intervals will be recorded. Electrocardiogram assessments will be described as normal or 
abnormal, and visits will be assigned to the Global Analysis Windows (see Appendix 10.2). 
Potentially clinically significant values (PCSV) ranges will be applied to the selected ECG 
parameter values as applicable (see Appendix 10.4 for PCSV definitions).   
4.8.5. 
Physical Examination Variables 
Physical examination will be conducted at the protocol scheduled visits (See Appendix 10.7 for 
schedule of event). The result is an outcome of normal, abnormal, and if abnormal then clinically 
significant (Yes/No, not examined), and visits will be assigned to the Global Analysis Windows 
(see Appendix 10.2). 
4.9. 
Other Variables 
Other assessment endpoints are listed and defined below. Protocol schedule visits will be 
assigned to Analysis Windows (See Appendix 10.2). 
• Change from baseline in body composition (including absolute and percent lean mass 
and fat mass) using DXA at weeks 12 and 24 (only at sites with whole body DXA 
capability). DXA analysis will occur on variables included but not limited to those 
listed in Appendix 10.6.  
• Change from baseline 
 
• Change from baseline 
 
• Change from baseline 
 
• Change from baseline 
 
• Change from baseline 
 
 
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4.10. 
Pharmacokinetic Variables 
Pharmacokinetic (PK) variables include concentrations of total drug and time as specified in the 
protocol.  
4.11. 
Immunogenicity Variables  
The immunogenicity variables include anti-drug antibody (ADA) status, and titer at nominal 
sampling time/visit. Serum samples for ADA will be collected at the clinic visits specified in 
Appendix 10.7.  
4.12. 
Clinical Outcomes Assessment 
4.12.1. 
Hunger  
Daily Lipodystrophy Hunger Questionnaire  
The daily lipodystrophy hunger questionnaire was developed to assess hunger related behaviors 
among patients with lipodystrophy. Patients will complete the PRO assessments daily. The 
Hunger questionnaire is self-administered and contains 4 items:  highest level of hunger, lowest 
level of hunger, how much time felt hungry, and frequency of fullness after eating meals or 
snacks. Each item is furnished with 5 response categories; and a numerical value is assigned to 
each response category as follows: 
 
 
Patient Global Impression of Severity-Hunger 
The Patient Global Impression of Severity (PGI-S) – Hunger is an anchor-based assessment used 
to interpret meaningful change of the Hunger PRO. PGI-S–Hunger endpoints consists of the 
number and percentage of responses for each category at baseline and weeks 12 and 24 as well as 
categorical shift responses from baseline to week 12 and 24. 
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Patient Global Impression of Change- Hunger 
The Patient Global Impression of Change (PGI-C) – Hunger is an anchor-based assessment used 
to interpret meaningful overall change of the Hunger PRO. PGI-C–Hunger endpoints consists of 
the number and percentage of responses for each category at weeks 12 and 24. 
4.12.2. 
Pain 
Brief Pain Inventory – Short Form Questionnaire 
The BPI-SF measures pain and its interference with daily lives.  It is a self-administered measure 
which consists of 9 items including:  
• 1 historical pain item: “Have you had pain other than these every- day kinds of pain 
today?” (Yes = 1 /  No = 0). The proportion of “Yes” will be used as a measure of 
historical pain status. 
• 1 pain-location item that identifies the body area that hurts the most on a diagram. 
• 4 pain-severity items, measured on a 0 to 10 scale, where 0 is “no pain” and 10 is the 
“pain as bad as you can imagine.”  The arithmetic mean for each of the 4 severity 
items will be used as the measure of the pain severity for the item.  
• 2 pain-relief items: 
− “What treatments or medications are you receiving for your pain?” 
− “In the last 24 hours, how much relief have pain treatments or medications provided?” 
This question is measured on a 0% to 100% scale, where 0% is “no relief” and 
100% is the “complete relief.”   
• 1 pain-interference item that includes 7 sub questions, where 0 is “does not interfere” 
and 10 is “completely interferes.”  The arithmetic mean of the 7 interference items 
will be used as a measure of pain interference. 
 
Patient Global Impression of Severity- Pain 
The Patient Global Impression of Severity (PGI-S) – Pain is a self-administered PRO assessing 
the patient’s perception of their overall severity of pain. The PGI-S–Pain is an anchor-based 
assessment used to interpret meaningful change of the BPI-SF. PGI-S–Pain endpoints consists of 
the number and percentage of responses for each category at baseline and weeks 12 and 24 as well 
as categorical shift responses from baseline to week 12 and 24. 
Patient Global Impression of Change- Pain 
The Patient Global Impression of Change (PGI-C) – Pain is a self-administered PRO assessing the 
patient’s perception of their overall change in pain since the beginning of the study. The PGI-C–
Pain is an anchor-based assessment used to interpret meaningful change of the pain via the BPI-
SF. PGI-C–Pain endpoints consists of the number and percentage of responses for each category 
at weeks 12 and 24. 
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4.12.3. 
Anxiety and Depression 
Patient Health Questionnaire-8  
The 8-item PHQ-8 is a self-administered instrument to measure depression. The PHQ-8 consists 
of 8 items each of which is scored 0 to 3, providing a 0 to 24 severity score. Scores of 5, 10, 15, 
and 20 represent cut points for mild, moderate, moderately severe, and severe depression, 
respectively. 
If a patient scores between 10 to 14 on the PHQ-8, s/he should be referred to a mental health 
professional – if a referral is not deemed necessary, then the investigator must document why. 
A referral is mandatory if the PHQ-8 ≥15 or is deemed necessary by the investigator. 
Hospital Anxiety and Depression Scale Questionnaire 
The Hospital Anxiety and Depression Scale (HADS) questionnaire is an instrument for screening 
anxiety and depression in non-psychiatric populations; repeated administration also provides 
information about changes to a patient’s emotional state over time (Zigmond, 1983; Herrmann, 
1997). The HADS consists of 14 items, 7 each for anxiety and depression symptoms; possible 
scores range from 0 to 21 for each subscale. The following cut-off scores are recommended: 0 to 
7 normal, 8 to 10 borderline abnormal, 11 to 21 abnormal. For this study, only the 7 anxiety 
questions will be scored.   
4.12.4. 
Quality of Life 
Short Form – 36 
The Short Form – 36 Survey (SF-36) is a 36-item self-administered PRO measure assessing 
health-related quality of life (HRQoL) concepts relevant across age, disease, and treatment 
group. The SF-36 assesses physical functioning, limitations due to physical health bodily pain, 
general health, vitality, social functioning, limitations due to emotional problems, and mental 
health. Patients answer questions assessing these concepts over the previous week using 3-, 5-, or 
6-point Likert scales; scores range from 0 to 100, with higher scores indicating better health. 
These eight scales can be aggregated into two summary measures: Physical (PCS) and Mental 
(MCS) Component Summary scores. The SF-36 endpoints include change from baseline in PCS 
and MCS at weeks 12 and 24. 
5. 
STATISTICAL METHODS 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized twice, specifically by study 
treatment and overall for the study in the DBTP, and again in the SBTP by DB treatment group 
and overall for the study, unless otherwise noted.  
DBTP summaries will be descriptively presented containing all patients in the DB SAF by 
treatment group and overall for the study, as well as by treatment group and overall for the study 
within each of the stratification factors (Cohort [A or B] and screening HbA1c [≤7% or >7%]).   
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Continuous data will be summarized using the number of patients, mean, SD, median, minimum, 
and maximum for each treatment group and for each of the strata. First quartile (Q1) and third 
quartile (Q3) will be also provided for baseline fasting triglyceride. Categorical and ordinal data 
will be summarized using the number and percentage of patients in each group. 
As applicable, other safety baseline data not listed in Section 4.1 will be presented collectively in 
the descriptive statistics summary tables containing respective post-baseline data. 
SBTP summaries will be descriptively presented containing all patients in the SB SAF by DB 
treatment group (mibavademab, placebo) and overall for the study, unless otherwise noted. 
Parameters listed in Section 4.1 will be summarized in SBTP as described for the DBTP 
summaries. 
5.2. 
Medical History 
Medical history will be descriptively summarized twice, specifically by study treatment and 
overall for the study in the DBTP, and again in the SBTP by DB treatment group and overall for 
the study, unless otherwise noted. DBTP summaries will be presented containing all patients in 
the DB SAF, and SBTP summaries will be presented with patients in the SB SAF. 
All reported patient medical history will be presented by PT, primary SOC and HLT.  The tables 
will be presented by SOC sorted alphabetically and in decreasing patient frequency of HLT based 
on the incidence in the study. 
Patient disease characteristics as described in Section 4.2 will be summarized in the DB SAF.  
5.3. 
Prior and Concomitant Medications  
All prior medications, dictionary coded by WHO-DD, will be descriptively summarized by study 
treatment and overall for the study, in the DBTP for patients in the DB SAF. Summaries will 
present patient counts (and percentages) for all prior medications, by decreasing frequency of the 
overall incidence of ATC followed by therapeutic class.  In case of equal frequency across 
anatomic or therapeutic categories, alphabetical order will be used. Patients will be counted once 
in each ATC category (anatomic or therapeutic) linked to the medication but may be counted 
several times for the same medication.  
For patients in the DB SAF, all concomitant medications during the DBTP, dictionary coded by 
WHO-DD, will be descriptively summarized by study treatment in the DBTP for patients in the 
DB SAF. Summaries will present patient counts (and percentages) for the concomitant 
medication groups described in Section 4.3 for all concomitant medications, by decreasing 
frequency of the incidence of ATC followed by therapeutic class.  In case of equal frequency 
across anatomic or therapeutic categories, alphabetical order will be used. Patients will be 
counted once in each ATC category (anatomic or therapeutic) linked to the medication, hence 
may be counted several times for the same medication.   
For the SBTP, concomitant medications will be dictionary coded by WHO-DD and will be 
descriptively summarized as described for the DBTP. For patient in the SB SAF, medications 
will be summarized by DB treatment group (ie, mibavademab, placebo) and overall for the 
SBTP.  
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5.4. 
Prohibited Medications  
Listing of prohibited medications will be provided for the patients in the safety analysis set for 
the DBTP and respective SBTP. Prohibited medications are listed in the protocol and identified 
through medical review. 
5.5. 
Patient Disposition 
Patient disposition includes the description of patient status at major milestone decisions in the 
study as described in Section 4.5, as well as the patient analysis populations. Patient disposition 
and analysis populations will be summarized two times, specifically by study treatment group 
and overall (including screened patients and screen failures) for the patients in the DBTP, and 
again in the SBTP by DB treatment group and all patients receiving single-blind study treatment, 
unless otherwise noted. Exception listings will be generated for any patient treated but not 
randomized, randomized but not treated, and treated differently than randomized.  
5.6. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure and compliance for the DBTP described in Section 4.6 
will be assessed and summarized by treatment group, for patients in the DB SAF. The extent of 
study treatment exposure for the SBTP described in Section 4.6 will be assessed and summarized 
for all patients and by DB treatment group for patients in the SB SAF. 
5.6.1. 
Exposure to Investigational Product 
Study treatment SC exposure in the DBTP and SBTP will be descriptively summarized for 
treatment duration and total number of injections as described in Section 4.6. Treatment duration 
and total number of injections will be summarized using the number of patients with data, 
mean, SD, median, minimum, and maximum. Additionally, the frequency of patients receiving 
study treatments at each weekly protocol scheduled visit will be summarized by number of 
patients (%). 
For study treatment IV administration in the DBTP and SBTP, total number of infusions will be 
summarized using the number of patients with data, mean, SD, median, minimum, and 
maximum. 
Additionally, mibavademab dosing SC exposure will be summarized cumulatively across the 
study, combining DBTP and SBTP for patients who received mibavademab in the DBTP. 
5.6.2. 
Study Treatment Compliance 
The SC treatment compliance will be assessed by SC administration frequency for a treatment 
period (DBTP, SBTP), which is defined for each patient as the average number of days between 
2 consecutive SC administrations during the treatment period: (last SC administration date – first 
SC administration date) / (total number of SC administrations during the treatment period - 1), 
for participants receiving at least 2 SC administrations during the treatment period.  
Descriptive statistics of the SC administration frequency will be summarized separately for 
DBTP and SBTP by mean, SD, median, minimum, and maximum.  Further, study treatment 
injection interruptions and incomplete injections with reason will be provided in a patient listing 
for those patients with incomplete injections.  
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Important protocol deviations will be summarized. Both monitored and derived protocol 
deviations will be summarized for important deviation categories by count (percentage), and 
again by type of important deviation (patient count and percentage).  
5.7. 
Analyses of Efficacy Variables 
For statistics where international and conventional units do not impact the results (eg, means and 
least square (LS) means for percent changes from baseline, statistical testing for both percent and 
absolute changes from baseline, rates of patients below a threshold), derivations will be 
calculated and statistical models will be run using conventional units. For other statistics (eg, 
descriptive statistics at baseline and over time, absolute changes from baseline), derivations will 
be presented in both international and conventional units. 
All efficacy assessment values obtained during the study (scheduled or unscheduled) can be used 
to provide a value for the efficacy endpoints as appropriate.  
All efficacy measurements will be assigned to Efficacy Analysis Windows defined in Appendix 
10.2, with the intent to provide an assessment for week 1 to 24 time points. For all visits post-
baseline, the value used for the analyses at a given time point (eg, at week 12) is the value 
obtained within the corresponding efficacy analysis window. If multiple values exist for an 
analysis window, the value obtained closest to the targeted time of the window will be used as 
appropriate. Unless otherwise specified, the baseline value is defined as the last available 
measurement before the first double-blind study treatment administration. For patients 
randomized and not treated, the baseline value is defined as the last available value prior to the 
date of randomization.    
Statistical analyses for the primary efficacy endpoints will be completed during the first step 
efficacy analysis (Section 7). Remaining descriptive efficacy analyses will be completed during 
the second step analyses.  
5.7.1. 
Analysis of Primary Efficacy Variables  
For the two primary efficacy variables, the primary analyses will be conducted in Cohort A 
(screening baseline leptin <8.0) for the following patient subgroups: 
• Fasting serum TG percent change from baseline to week 12: patients with screening 
fasting TG >200 mg/dL  
• HbA1c absolute change from baseline to week 12: patients with screening HbA1c 
>7.0%  
5.7.1.1. 
Percent Change in Fasting TG from Baseline to Week 12 
Percent change from baseline to week 12 in fasting serum TG, will be analyzed in the FAS 
population for the Cohort A patients with elevated baseline fasting TG >200 mg/dL by using a 
mixed-effect model with repeated measures (MMRM) approach. The MMRM model will 
include the following effects: fixed categorical treatment groups (Placebo versus mibavademab), 
time points (weeks 2, 4, 6, 8, 10, 11, and 12), actual strata (screening HbA1c ≤7.0%, >7.0%), 
strata-by-time-point interaction, and treatment-group-by-time-point interaction, as well as the 
continuous fixed covariates of baseline TG value and baseline value-by-time point 
interaction. Logarithm transformation will be performed to normalize the fasting TG. 
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Post-baseline data available up to and including the week 12 efficacy analysis window for fasting 
TG (Table 11 in Appendix 10.2) will be used and missing data are accounted for by the MMRM. 
Measurements on not-fasting patients will be excluded. Contrast and estimate statements will be 
used to assess baseline adjusted least-squares (LS) means estimates at week 12 for each 
treatment group with their corresponding 95% confidence intervals. The LS means at week 12 
will be back-transformed into the geometric means to ease clinical interpretation of the result. 
The difference between the two study treatment groups (mibavademab, placebo) in geometric 
means will be provided along with its corresponding 95% confidence interval, and nominal p-
value.  
To support interpretation of the TG results at week 12, descriptive summaries will be provided at 
each protocol specified DBTP visit. Median percent changes (with Q1 and Q3 bars) will be 
plotted across visits by treatment group. A spaghetti plot will be provided for individual patient 
data across visits by treatment group.  
Sensitivity Analysis 
• A non-parametric approach will be performed on the primary efficacy endpoint for 
comparing the mibavademab and placebo. Specifically, the percent change in fasting 
serum TG from baseline to week 12 will be ranked for an analysis of covariance (ranked 
ANCOVA). For the case >5% missing data at week 12, missing data will be imputed 
using multiple imputation based on other observed measurements. The ranked 
ANCOVA model will be able to provide significance of the treatment effect as 
compared to placebo. Nominal p-values will be provided as a measure of the strength 
of evidence. Median treatment difference and its 95% confidence interval can be 
derived from the Hodges-Lehmann estimation and Moses distribution free confidence 
interval respectively. 
• To assess the impact of a systemic dosing error on the primary efficacy endpoint, the 
primary efficacy analysis will be performed excluding affected patients. Patients 
known to be under dosed at the time of database lock will be identified for this analysis 
before database lock.  Any additional patients determined to be affected post-database 
lock will be separately identified. 
5.7.1.2. 
Change in HbA1c from Baseline to Week 12 
Absolute change from baseline to week 12 in HbA1c, will be analyzed in the FAS population for 
the Cohort A patients using a mixed-effect model with repeated measures (MMRM) approach. 
The MMRM model will include the following effects: fixed categorical treatment groups 
(Placebo, mibavademab), time points (weeks 4, 6, 10, and 12), actual strata (screening HbA1c 
≤7.0%, >7.0%), strata-by-time-point interaction, and treatment-group-by-time-point interaction, 
as well as the continuous fixed covariates of baseline HbA1c value and baseline value-by-time 
point interaction. An unstructured covariance matrix will be used to model the within patient 
errors. In the case that the unstructured covariance matrix does not converge, then a structured 
covariance matrix such as autoregressive heterogeneous [ARH] will be assessed.  
Post-baseline data available up to and including the week 12 efficacy analysis window for 
HbA1c (Table 12 in Appendix 10.2) will be used and missing data are accounted for by the 
MMRM. Contrast and estimate statements will be used to assess baseline adjusted least-squares 
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(LS) means estimates at week 12 in the actual strata of screening HbA1c>7.0% for each 
treatment subgroup with their corresponding standard errors and 95% confidence intervals. The 
difference of the study treatment HbA1c mean changes from baseline to week 12 for patients 
with screening HbA1c>7.0% will be provided along with its corresponding 95% confidence 
interval, and nominal p-value.  
To support interpretation of the HbA1c results at week 12, descriptive summaries will be 
provided at each protocol specified DBTP visit. Mean changes (±SE) will be plotted across visits 
by treatment group. A spaghetti plot will be provided for individual patient data across visits by 
treatment group.  
5.7.2. 
Analysis of Secondary Efficacy Variables  
Statistical analyses for the secondary efficacy endpoints (defined in Section 4.7.2) and SBTP-
specific secondary efficacy endpoints (described in Section 4.7.3) will be performed in the FAS 
population.  
All measurements, scheduled or unscheduled, will be assigned to efficacy analysis windows 
defined in Appendix 10.2 in order to provide an assessment for these time points. For fasting TG, 
measurements on not-fasting patients will be excluded; the median percent changes (with Q1 and 
Q3 bars) will be plotted across visits by treatment group.   
Multiple types of measurements are planned to be analyzed during differing time points in the 
trial, specifically continuous measurements expected to have a normal distribution (example:  
absolute change in HbA1c) and continuous measurements expected to have a non-normal 
distribution (example: TG). 
The following patient groups are also used for analyzing secondary efficacy variables:  
• Combined Cohort A+B include all patients in Cohort A and Cohort B as defined in 
Section 2.1.  
• DBTP-stable patient is defined as a patient who meets both of the following two 
stability criteria: 
− Absolute change in HbA1c from baseline to week 12 ≤ 0.5% 
− Percent change in fasting serum TG from baseline to week 12 ≤ 25% 
5.7.2.1. 
Continuous Endpoints Anticipated to have a Normal Distribution 
Continuous secondary variables defined in Section 4.7.2 and Section 4.7.3 anticipated to have a 
normal distribution (including HbA1c, fasting glucose, and liver fat) will be analyzed using a 
similar MMRM model as described for the primary endpoint in HbA1c.   
Daily lipodystrophy hunger questionnaire (DLHQ) will be descriptively summarized from 
baseline to week 12 and again from baseline to week 24.  Mean changes in monthly averaged 
DLHQ scores (±SE) will be plotted across visits by treatment group; a spaghetti plot will be 
provided for individual patient data across visits by treatment group. Monthly averaging 
windows of the DLHQ scores are defined in the Efficacy Analysis Windows for Daily 
Lipodystrophy Questionnaire (See Appendix 10.2). If a participant reported less than 10 scores 
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within a monthly averaging window for a DLHQ item, the averaged score will be assigned a 
missing value.     
The statistical estimates, comparisons, and descriptive statistics for these secondary efficacy 
variables are summarized in Table 3, Table 4, Table 5, and Table 6. 
Table 3. Summary of Statistical Estimates and Comparisons in Normally-distributed 
Secondary Endpoints 
Endpoint 
Cohort for Modeling 
Analysis Method / Estimates 
Comparisons 
• Absolute 
change 
in 
HbA1c 
from 
baseline 
to week 
12.  
• Separately 
for Cohort 
B and 
Cohort 
A+B 
MMRM / Least-squares (LS) 
means with their 
corresponding standard 
errors and 95% confidence 
intervals. 
Note: Strata level = 
HbA1c>7.0%.  
Note: Post baseline visits to 
include in the model are 
weeks 4, 6, 10, and 12.   
REGN4461 
versus Placebo 
with nominal p-
value. 
• Change 
in 
fasting 
glucose 
from 
baseline 
to week 
12. 
• Separately 
for Cohort 
A, Cohort 
B, and 
Cohort 
A+B 
MMRM / Least-squares (LS) 
means with their 
corresponding standard 
errors and 95% confidence 
intervals. 
Note: Strata level = 
HbA1c>7.0%. 
Note: Post baseline visits to 
include in the model are 
weeks 2, 4, 6, 8, 10, 11, and 
12.   
REGN4461 
versus Placebo 
with nominal p-
value. 
• Percent 
change 
in liver 
fat 
(MRI-
PDFF)  
from 
baseline 
to week 
12  
• Separately 
for Cohort 
A, Cohort 
B, and 
Cohort 
A+B 
MMRM / Least-squares (LS) 
means with their 
corresponding standard 
errors and 95% confidence 
intervals. 
Note: patient subgroup = 
baseline MRI-PDFF ≥8.5% 
Note: Post baseline visit at 
week 12.   
REGN4461 
versus Placebo 
with nominal p-
value. 
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Table 4. Summary of Descriptive Statistics for Patients Randomized to REGN4461 in 
Normally-distributed Secondary Endpoints for the combined DBTP and SBTP 
Analysis 
NOTE: These descriptive statistics will be presented three times, specifically in Cohort A, Cohort B, and Cohort 
A+B. 
Endpoint 
Descriptive Statistics 
• Absolute 
change in 
HbA1c from 
baseline to 
week 24 
For Arm 2, descriptive summaries will be provided at each 
protocol specified visit up to week 24; mean changes (±SE) will 
be plotted across visits by treatment group; a spaghetti plot will 
be provided for individual patient data across visits by treatment 
group. These descriptive statistics will be provided twice, 
specifically for patients with baseline HbA1c>7% and again for 
All Patients. 
• Change in 
fasting glucose 
from baseline 
to week 24  
For Arm 2, descriptive summaries will be provided at each 
protocol specified visit up to week 24; mean changes (±SE) will 
be plotted across visits by treatment group; a spaghetti plot will 
be provided for individual patient data across visits by treatment 
group. These descriptive statistics will be provided twice, 
specifically for patients with baseline HbA1c>7% and again for 
All Patients. 
• Percent change 
in liver fat 
(MRI-PDFF) 
from baseline 
to week 24  
For patients with hepatic steatosis (baseline MRI-PDFF ≥8.5%) 
in Arm 2, descriptive summaries will be provided at each 
protocol specified visit up to week 24; mean changes (±SE) will 
be plotted across visits by treatment group; a spaghetti plot will 
be provided for individual patient data across visits by treatment 
group. 
 
Table 5. Summary of Descriptive Statistics in Normally Distributed Secondary Endpoints 
based on REGN4461 Exposure 
NOTE: Efficacy data for study treatment arm 1 (placebo) and arm 2 (REGN4461) will be combined by re-aligning 
to the first REGN4461 treatment administration, specifically study day 1 for arm 2 and week 12 for arm 1 will 
become REGN4461 Day 1. These descriptive statistics will be presented three times, specifically in Cohort A, 
Cohort B, and Cohort A+B. 
Endpoints 
Descriptive Statistic 
• Absolute change in HbA1c from 
baseline to week 12 
• HbA1c mean changes from REGN4461 
Day 1 to REGN4461 week 12 for 
combined DBTP-stable Arm 1 patients 
and Arm 2 patients will be provided along 
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• Absolute change in HbA1c from 
week 12 to week 24 
with its corresponding 95% confidence 
interval. 
• Change in fasting glucose from 
baseline to week 12 
• Change in fasting glucose from week 
12 to week 24 
• Fasting glucose mean changes from 
REGN4461 Day 1 to REGN4461 week 12 
for combined Arm 1 and Arm 2 patients 
will 
be 
provided 
along 
with 
its 
corresponding 95% confidence interval. 
• Percent change in liver fat (MRI-
PDFF) from baseline to week 12 
• Percent change in liver fat (MRI-
PDFF) from week 12 to week 24 
• Liver fat (MRI-PDFF) mean changes 
from REGN4461 Day 1 to REGN4461 
week 12 for combined Arm 1 and Arm 2 
in patients with hepatic steatosis 
(baseline MRI-PDFF ≥8.5%) will be 
provided along with its corresponding 
95% confidence interval. 
 
Table 6. Summary of Statistics for Patients Randomized to Placebo in Normally distributed 
Secondary Endpoints 
NOTE: These statistical estimates and descriptive statistics will be presented three times, specifically in Cohort A, 
Cohort B, and Cohort A+B. 
Endpoints 
Estimates 
Comparison 
• Absolute change in 
HbA1c from 
baseline to week 12  
• Absolute change in 
HbA1c from week 
12 to week 24  
• For Arm 1, baseline 
adjusted least-squares 
(LS) mean estimate at 
week 12 and week 12 
adjusted least-squares 
(LS) mean estimate at 
week 24 will be provided 
along with the 
corresponding standard 
errors and 95% 
confidence intervals. 
MMRM / Least-squares (LS) means 
with their corresponding standard 
errors and 95% confidence intervals. 
Note: Treatment Group = Arm 1; 
Strata level = HbA1c>7.0%.  
• Note: Post baseline visits 
to include in the model are 
• For Arm 1, 
difference 
between the 
HbA1c mean 
changes from 
week 12 to week 
24 and from 
baseline to week 
12 will be 
provided along 
with its 
corresponding 
95% confidence 
interval, and 
nominal p-value 
when appropriate.  
•  
• REGN4461 in 
Arm 1 SBTP 
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weeks 4, 6, 10, 12, 16, 18, 
22, and 24.   
versus Placebo 
Arm 1 DBTP 
• Change in fasting 
glucose from 
baseline to week 12 
• Change in fasting 
glucose from week 
12 to week 24  
• For Arm 1, baseline 
adjusted least-squares 
(LS) means estimates at 
week 12 and week 12 
adjusted least-squares 
(LS) means estimates at 
week 24 will be provided 
along with the 
corresponding standard 
errors and 95% 
confidence intervals. 
• Within Arm 1 
patients, 
difference 
between the 
fasting glucose 
mean changes 
from week 12 to 
week 24 and 
from baseline to 
week 12 will be 
provided along 
with its 
corresponding 
95% confidence 
interval, and 
nominal p-value.  
• Percent change in 
liver fat (MRI-
PDFF) from baseline 
to week 12  
• Percent change in 
liver fat (MRI-
PDFF) from week 12 
to week 24 
• For Arm 1 patients with 
hepatic steatosis (baseline 
MRI-PDFF ≥8.5%), 
baseline adjusted least-
squares (LS) means 
estimates at week 12 and 
week 12 adjusted least-
squares (LS) means 
estimates at week 24 will 
be provided along with 
their corresponding 
standard errors and 95% 
confidence intervals. 
• Difference 
between the liver 
fat percent mean 
changes from 
week 12 to week 
24 and from 
baseline to week 
12 will be 
provided along 
with its 
corresponding 
95% confidence 
interval, and 
nominal p-value. 
 
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5.7.2.2. 
Continuous Endpoints Anticipated to have a Non-normal Distribution 
Continuous secondary efficacy variables defined in Section 4.7.2 and Section 4.7.3 anticipated to 
have a non-normal distribution (ie, TG) will be analyzed using the same MMRM model as 
described for the primary endpoint in TG.   
For comparisons that defined on the DBTP-stable Arm 1 patients, the MMRM model will be 
fitted again to exclude the Arm 1 patients who do not meet the DBTP-stability criteria. The LS 
means will be back-transformed into the geometric means to ease clinical interpretation of the 
result. Table 7 summarizes the statistical analysis methods that will be performed for the 
secondary efficacy variables in fasting TG. 
 
Table 7. Summary of Statistical Estimates, Comparisons, and Descriptive Statistics in 
Fasting-TG Secondary Endpoints 
Endpoints 
Cohort 
Estimates 
Statistics 
• Percent 
change 
in 
fasting 
TG 
from 
baseline 
to week 
12. 
• Separately 
for Cohort 
B and 
Cohort 
A+B 
Baseline adjusted least-
squares (LS) means 
estimates at week 12 for 
each treatment subgroup 
with their corresponding 
standard errors and 95% 
confidence intervals. The 
LS means at week 12 
will be back-transformed 
into the geometric 
means. 
Difference of the 
study treatment TG 
geometric mean 
changes from 
baseline to week 12 
will be provided 
along with its 
corresponding 95% 
confidence interval, 
and nominal p-value.  
• Percent 
change 
in 
fasting 
TG 
from 
baseline 
to week 
24  
• Separately 
for Cohort 
A, Cohort 
B, and 
Cohort 
A+B 
N/A 
For Arm 2 patients, 
descriptive 
summaries will be 
provided at each 
protocol specified 
visit up to week 24; 
median percent 
changes with Q1 and 
Q3 bars will be 
plotted across visits; 
a spaghetti plot will 
be provided for 
individual patient 
data across visits.  
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• Percent change 
in fasting TG 
from baseline to 
week 12  
• Percent change 
in fasting TG 
from week 12 to 
week 24  
• Separately 
for Cohort 
A, Cohort 
B, and 
Cohort 
A+B 
For Arm 1, baseline 
adjusted least-squares 
(LS) means estimates at 
week 12 and week 12 
adjusted least-squares 
(LS) means estimates at 
week 24 will be provided 
with the corresponding 
standard errors and 95% 
confidence intervals. The 
LS means will be back-
transformed into the 
geometric means. 
For Arm 1, 
difference between 
the fasting TG 
geometric means 
from week 12 to 
week 24 and from 
baseline to week 12 
will be provided 
along with its 
corresponding 95% 
confidence interval, 
and nominal p-value 
when appropriate. 
• Percent change 
in fasting TG 
from baseline to 
week 12  
• Percent change 
in fasting TG 
from week 12 to 
week 24  
• Separately 
for Cohort 
A, Cohort 
B, and 
Cohort 
A+B 
N/A 
Fasting TG median 
change from 
REGN4461 Day 1 to 
REGN4461 week 12 
for combined Arm 1 
and Arm 2 patients 
will be provided 
along with Q1 and 
Q3 bars. 
 
5.8. 
Analysis of Safety Data 
The summary of safety results will be presented separately for the DBTP and SBTP, unless 
otherwise noted. Safety summaries for the DBTP will be presented by treatment group (ie, 
mibavademab, placebo) containing patients from the DB SAF. Safety summaries for the SBTP 
will be presented by all patients and by study treatment group in DBTP (ie, DB mibavademab, 
DB placebo), for patients in the SB SAF. No formal inferential testing will be performed for 
either period. Summaries will be descriptive in nature.  
General common rules 
All safety analyses will be performed, unless otherwise specified, using the following common 
rules: 
• Safety data in patients who do not belong to the safety analysis sets (ie, exposed but 
not randomized) will be listed separately. 
• Potentially Clinically Significant Values (PCSVs) or Potentially Clinically Significant 
Abnormalities (PCSAs) are defined as abnormal values considered medically 
important by the Sponsor according to predefined criteria/thresholds based on 
literature review and defined by the Sponsor for clinical laboratory tests, vital signs, 
ECG (PCSV version dated January 2009 [Appendix 10.4]).  
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• PCSV criteria will determine which patients had at least 1 PCSV during the 
respective TEAE period, taking into account all evaluations including unscheduled or 
repeated evaluations. 
• The treatment-emergent PCSV denominator for a given parameter will be based on 
the number of patients assessed for that given parameter at least once during the 
respective TEAE period. 
• All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned 
to the Global Analysis Windows defined in Appendix 10.2 to provide an assessment 
for the screening visit through follow-up visit time points. 
• For quantitative safety parameters including central laboratory measurements and 
vital sign scores, descriptive statistics will be used to summarize observed values and 
change from baseline values by visit.  
• Unless otherwise specified, in the case of multiple assessments within an analysis 
window, the assessment closest to the protocol planned visit study day will be used in 
analysis. 
5.8.1. 
Adverse Events  
In general, the primary focus of AE reporting will be on TEAEs summarized in respective TEAE 
period, specifically the DBTP and SBTP.   
If an AE onset date (occurrence, worsening, or becoming serious) is incomplete, an imputation 
algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment.  The algorithm for imputing date of onset will be conservative and will classify 
an AE as treatment-emergent unless there is definitive information to determine pre-treatment or 
post-treatment status.  Details on classification of AEs with missing or partial onset dates are 
provided in Section 6.3. 
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC and PT.  In addition, incidence tables by SOC and PT will be 
provided for all TEAEs, serious TEAEs, and TEAEs leading to permanent treatment 
discontinuation. Multiple occurrences of the same event in the same patient will be counted only 
once in the tables. For tables presenting severity of events, the worst severity will be chosen for 
patients with multiple instances of the same event. The denominator for computation of 
percentages is the respective safety analysis set within each treatment group. 
AE incidence tables will present data by SOC and PT and summarize the number (n) and 
percentage (%) of patients experiencing an AE. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated: 
• Overview of TEAEs, summarizing number (%) of patients with: 
− Any TEAE 
− Serious TEAE 
− TEAEs related to study treatment 
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− TEAE leading to death 
− TEAE leading to treatment discontinuation 
• All TEAEs by primary SOC and PT 
• Number (%) of patients experiencing common TEAE(s) presented by primary SOC 
and PT (PT incidence ≥ 2 patients in any treatment group)  
• All TEAEs causality relationship (related/not related) to study treatment, presented by 
SOC and PT 
• All TEAEs by maximum severity (ie, mild, moderate, or severe), presented by SOC 
and PT 
Analysis of all treatment emergent serious adverse event(s) 
• All Serious TEAEs by primary SOC and PT 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAEs leading to permanent treatment discontinuation, by primary SOC and PT 
Patient Deaths 
The following summaries of deaths will be generated. 
• Number (%) of patients who died by study period (TEAE) and reason for death 
• TEAEs leading to death (death as an outcome on the AE CRF page, as reported by 
the Investigator) by SOC and PT 
5.8.2. 
Analysis of Adverse Events of Special Interest  
Treatment-emergent adverse events of special interest (AESI), as listed in Section 4.8.1.2, will be 
presented by SOC and PT as applicable.  AESI are defined by SMQ, CMQ, lab data, and/or 
dedicated e-CRF are summarized by frequency (%) as described in Appendix 10.3. 
5.8.3. 
Adverse Events of Interest 
Treatment emergent adverse events for mild infusion reactions, mild hypersensitivity reactions, 
and injection site reactions (ISR) as defined in Section 4.8.1.3 will be summarized by patient 
frequency (%)  by SOC and PT. 
Treatment emergent adverse events for infusion reactions and hypersensitivity reactions will also 
be summarized regardless of severity by SOC and PT. 
5.8.4. 
Clinical Laboratory Measurements  
General clinical laboratory parameter actual values (quantitative) and change from baseline 
values will be descriptively summarized at baseline and each post-baseline visit (collected up to 
the day of last dose of study treatment + 14 days). These parameters will be presented by the 
biological functions defined in Section 4.8.2.  
Individual patient laboratory parameter measurements will be additionally evaluated by PCSV 
criteria (See Appendix 10.4), specifically identifying patients with at least one post-baseline 
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measurement that meets the PCSV criteria within the respective TEAE period. These laboratory 
parameters will be presented by the biological functions defined in Section 4.8.2. The incidence 
of PCSVs at any time during the respective TEAE period will be summarized regardless of the 
baseline level, and again according to the following baseline categories: 
• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
Patient listings of laboratory measurements that meet PCSV criteria will be provided for the 
report appendix.  For those laboratory parameters that don’t have an associated PCSV criteria, 
similar summary tables can be provided based on measurements outside the central laboratory 
normal ranges, if applicable. 
5.8.5. 
Analysis of Vital Signs 
The vital sign actual values and change from baseline values obtained will be descriptively 
summarized at baseline and each post-baseline visit, collected up until the day of the last dose of 
study treatment + 14 days. 
Individual patient vital sign measurements (regardless of sitting position) will be additionally 
evaluated by PCSV criteria, specifically identifying patients with at least one post-baseline 
measurement that meets the PCSV criteria within the TEAE period.  The incidence of PCSVs at 
any time during the respective TEAE period will be summarized regardless of the baseline level, 
and again according to the following baseline categories: 
• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
Patient listings of vital sign measurements that meet PCSV criteria will be provided for the 
report appendix.   
5.8.6. 
Analysis of 12-Lead ECG 
ECG results will be presented through an overall interpretation of ECG status and by ECG 
parameters (HR, PR, QRS, QT and QTcF), collected up until the day of the last dose of study 
treatment + 14 days.  
• ECG parameters will be summarized through an overall interpretation of ECG status, 
specifically normal or abnormal (includes clinically significant (Yes/No)). The count 
and percentage of patients with at least 1 abnormal post-baseline ECG during the 
respective TEAE period will also be summarized according to the following baseline 
status categories:  
− Normal/missing 
• Abnormal 
− Individual patient ECG measurements will be additionally evaluated by PCSV 
criteria, specifically identifying patients with at least one post-baseline 
measurement that meets the PCSV criteria within the TEAE period.  The 
incidence of PCSVs at any time during the respective TEAE period will be 
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summarized regardless of the baseline level, and again according to the following 
baseline categories: 
• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
− Patient listings of ECG measurements that meet PCSV criteria will be provided 
for the report appendix.   
5.8.7. 
Physical Exams 
A list of patients with any clinically significant abnormality results will be generated. 
5.8.8. 
Treatment Exposure and Treatment Compliance 
The duration of exposure during each study part in weeks will be presented by treatment group 
and study period, calculated as: 
(Date of last study drug injection in the specific study part – date of first study drug injection 
in the specific study part + 7 days)/7 
Number (%) of patients exposed to study drug during the study will be presented for each treatment 
group and study period. 
In addition, duration of exposure during the study will be summarized for each treatment group 
using number of patients, means, SD, minimums, medians, and maximums. 
A summary of the number of doses by treatment group and study period will be provided. 
The compliance with study treatment will be calculated as follows: 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 % = 100% × # 𝑎𝑐𝑡𝑢𝑎𝑙 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛𝑠
# 𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛𝑠 
The treatment compliance will be presented by specific ranges for each treatment group and study 
period.  
 
5.9. 
Analysis of Other Variables 
All measurements, scheduled or unscheduled, will be assigned to the Analysis Windows 
(Appendix 10.2) in order to provide an assessment for all post-baseline visit.   
Change from baseline liver volume and hepatic fat content by MRI will be descriptively 
summarized by treatment group (Arm 1, Arm 2) and cohort (Cohort A, Cohort B, and combined 
Cohort A+B) at weeks 12 and 24 for patient in the MRI analysis set. Mean difference between 
treatments with associated 95% CI will also be provided at week 12. 
Change from baseline in body composition (including lean mass and fat mass) using DXA at 
weeks 12 and 24 will be descriptively summarized by treatment group (Arm 1, Arm 2) and 
cohort (Cohort A, Cohort B, combined Cohort A+B) in patients in FAS and have at least one 
post-baseline assessment. 
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Change from baseline in leptin level at weeks 12 and 24, will be descriptively summarized by 
treatment group (Arm 1, Arm 2) and cohort (Cohort A, Cohort B, combined Cohort A+B) in 
patients in FAS and have at least one post-baseline assessment.  
 
 
  
Summary statistics will include the number of patients with data, mean, SD, median, minimum, 
maximum, Q1 and Q3. 
5.10. 
Analysis of Pharmacokinetic Variables  
Descriptive statistics for concentrations of total drug will be presented. Mean concentrations will 
be tabulated by visit and treatment group, with concentrations below the LLOQ set to zero. Plots 
of the mean concentrations (linear and log scales) will be presented by nominal sampling time. 
Plots of the individual concentrations (linear and log scales) will be presented by actual sampling 
time. In the linear-scaled plots, concentrations below the LLOQ will be set to zero; in the log-
scaled plots, concentrations below the LLOQ will be imputed as LLOQ/2. Where appropriate, 
relationship between concentrations of total drug and other pharmacodynamic biomarkers 
including, but not limited to, changes in endpoints of interest (eg, HbA1c, glucose, and TG) may 
be evaluated descriptively.  
5.11. 
Analysis of Immunogenicity Data 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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− Transient - Not persistent or indeterminate, regardless of any missing samples 
− Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
• The maximum titer category of each patient is classified as: 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
− Samples that are positive in ADA assay may be assessed for the presence of 
neutralizing anti-drug antibodies (NAb) when NAb assay is available.   
• The following will be summarized by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative patients 
• Number (n) and percent (%) of patients with pre-existing ADA 
• Number (n) and percent (%) of treatment-emergent ADA positive patients 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients 
− Listing of all ADA titer levels will be provided for patients with pre-existing, 
treatment-emergent, and treatment-boosted ADA response. 
5.11.1. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.11.1.1. Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to mibavademab will be 
explored by treatment groups. Plots of individual mibavademab concentration time profiles may 
be provided to examine the potential impact of ADA by maximum titer on these profiles.  
5.11.1.2. Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety will be explored with a 
primary focus on adverse events during the TEAE period. 
• Injection site reaction (serious or severe and lasting 24 hours or longer)  
• Infusion reactions   
• Hypersensitivity (SMQ: Hypersensitivity [Narrow])  
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− Potential association between immunogenicity variables and efficacy endpoints 
may be explored (eg, scatter plot or spaghetti plot).The safety and efficacy 
analyses mentioned above will be conducted using the following categories: 
• ADA Positive 
− Treatment-emergent 
− Treatment-boosted 
• Maximum post-baseline titer category 
5.12. 
Analysis of Clinical Outcome Assessment 
The summary of results for clinical outcomes assessments will be presented by treatment groups 
(Arm 1, Arm 2) and by cohorts (Cohort A, Cohort B) containing patients from the full analysis 
set, unless otherwise specified.  
The baseline value is defined as the last available measurement prior to the time of the first 
double-blind study treatment administration. All measurements, scheduled or unscheduled, will 
be assigned to the Global Analysis Windows (Appendix 10.2) to provide an assessment for all 
post-baseline visit.   
For the SF-36, raw value and change from baseline will be summarized using mean, median, SD, 
min, max, Q1, Q3 for each post baseline visit among the SF-36 analysis set. 
6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment is programmatically defined as the last 
available measurement prior to the time of the first double-blind study treatment administration. 
For patients randomized and not treated, the baseline value is defined as the last available value 
prior to the date of randomization. 
6.2. 
Data Handling Convention for Efficacy Variables  
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 5.7. 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings.  This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Date and Time of First/Last Study Treatment 
The date and time of study drug administration are filled in e-CRF. No missing data is expected. 
Date of first/last administration is the first/last start date of study drug provided in e-CRF. 
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Adverse Event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
When the partial AE date/time information does not indicate that the AE started prior to study 
treatment or after the TEAE period, the AE will be classified as treatment-emergent. 
Medication/Procedure 
No imputation of medication/procedure start/end dates or times will be performed.  If a 
medication date or time is missing or partially missing and it cannot be determined whether it 
was taken prior or concomitantly or stopped prior to the first study treatment administration, it 
will be considered as concomitant medication/procedure. 
Potentially Clinically Significant Value (PCSV) 
If a patient has a missing baseline value, this patient will be grouped in the category 
“normal/missing at baseline.” 
For PCSVs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSV will be based 
only on the second condition. 
For a PCSV defined on a threshold and/or a normal range, this PCSV will be derived using this 
threshold if the normal range is missing. For example, for eosinophils, the PCSV is >0.5 giga/L 
or >ULN if ULN ≥0.5 giga/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized nor included in the 
computation of PCSVs. 
6.4. 
Visit Windows 
Visit windows will be programmatically imposed on those efficacy and safety measures 
repeatedly collected over the course of the study. These visit windows are derived from the 
number of days in study, specifically assigning day ranges to represent the study assessment 
schedule provided in the protocol.  Data analyzed by time point (including efficacy, laboratory 
safety data, vital signs, and ECG) will be summarized using the analysis windows given in 
Appendix 10.2. These analysis windows will be applicable for all efficacy and safety analyses, 
and they are defined to provide more homogeneous data for time point-specific analyses. If 
multiple valid values of a variable exist within an analysis window, the nearest from the targeted 
study day will be selected for analysis, unless otherwise specified. If the difference is a tie, the 
value after the targeted study day will be used. If multiple valid values of a variable exist within 
a same day, then the first value of the day will be selected when time is available, else the 
scheduled visit will be selected. 
6.5. 
Unscheduled Assessments 
For efficacy, safety laboratory data, vital signs, and ECG, unscheduled visit measurements may 
be used to provide a measurement for a time point, including baseline, if appropriate according 
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to their definitions. The measurements may also be used to determine abnormal values, AESIs, 
and PCSVs. 
6.6. 
Pooling of Centers for Statistical Analyses 
Not applicable. 
6.7. 
Statistical Technical Issues 
Not applicable.  
7. 
TIMING OF STATISTICAL ANALYSES 
7.1. 
Interim Analysis 
No formal interim analysis is planned. Periodic data reviews may be performed by selected 
unblinded Regeneron personnel with no direct involvement in the study conduct. 
7.2. 
First Step Analysis  
The first-step analysis will be conducted as soon as all patients have been randomized and all 
data through week 12 has been entered, cleaned, and locked. The first-step analysis will be 
conducted on all randomized patients who receive study treatment. These statistical analyses will 
include the primary and secondary endpoints collected during the double-blind period. All 
subsequent protocol work can be generated in an unblind-blind manner (study treatment 
assignments, primary efficacy variables, and applicable secondary efficacy variables), excluding 
the investigative sites. 
7.3. 
Second Step Analysis  
The second step analysis will be conducted as soon as all patients have been randomized and all 
data through week 24 has been entered, cleaned, and locked. The second-step analysis will be 
conducted on all randomized patients who receive study treatment. These statistical analyses will 
include the secondary endpoints collected during the single-blind period.  
7.4. 
Final Analysis 
The final analysis will be conducted at the end of the study, and will consist of the final analysis 
for efficacy, pharmacokinetic and safety measures. 
7.5. 
Additional Rules 
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will apply for the first-step analysis: 
• Any assessments within the Efficacy Analysis Windows (Appendix 10.2) up to the 
SBTP week 24 visit will be taken into account (may include few unscheduled lipid 
data soon after the cut-off date).  
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• Patients without end of treatment visit performed at the time of the cut-off date will 
be considered as ongoing and exposed up to the cut-off date.  
• Patients who did not complete the respective treatment period nor prematurely 
discontinued the study treatment at cut-off date will be: 
− Analyzed as “ongoing” in the disposition summary. 
− Their TEAE period and treatment period will end at the respective data cut-off 
date. 
− Their treatment duration will be derived by considering date of cut-off as last 
administration date.  
− Analyses of number of IP administrations, and mean IP administration frequency 
will be performed up to the last administration reported in the e-CRF up to the 
cut-off date.  
− AEs occurring, worsening or becoming serious after the cut-off date will not be 
included in the analyses. However, any available outcome before database lock, 
regardless of timing in relation to the cut-off date, of an adverse event starting 
prior to the cut-off date will be taken into account. Medications, treatment 
discontinuations/completions and deaths occurring after the cut-off date will not 
be included in the analyses.  
− Post-treatment period, and post-study period are not applicable for ongoing 
patients. Analyses of post-study deaths and post-treatment medications will be 
performed for patients who either completed or prematurely discontinued the 
treatment before or at the data cut-off date. 
− Analysis of status at last study contact and proportion of patients with insufficient 
follow-up will be provided for patients who either completed or prematurely 
discontinued the treatment before or at the data cut-off date. 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
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9. 
REFERENCES 
1. Chiquette E, Oral EA, Garg A, Araújo-Vilar D,Dhankhar P. Estimating the prevalence of 
generalized and partial lipodystrophy: findings and challenges. Diabetes Metab Syndr 
Obes 2017; 10:375-383. 
2. Diker-Cohen T, Cochran E, Gorden P,Brown RJ. Partial and generalized lipodystrophy: 
comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol 
Metab 2015; 100(5):1802-1810. 
3. Gonzaga-Jauregui C, Ge W, Staples J, Van Hout C, Yadav A, Colonie R, et al. Clinical 
and Molecular Prevalence of Lipodystrophy in an Unascertained Large Clinical Care 
Cohort. Diabetes 2020; 69(2):249-258. 
4. Herrmann C. International experiences with the Hospital Anxiety and Depression Scale--
a review of validation data and clinical results. J Psychosom Res 1997; 42(1):17-41. 
5. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
6. WHO Multicenter Growth Reference Study Group. WHO Child Growth Standards: 
Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body 
mass index-for-age: Methods and development. Geneva: World Health Organization; 
2006. 
7. Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The 
prevention and treatment of missing data in clinical trials. N Engl J Med. 2012 Oct 
4;367(14):1355-60. doi: 10.1056/NEJMsr1203730. 
8. FDA. Briefing Document: BLA 125390, Myalept (metreleptin for injection).  2013;  
Research CfDEa, editorFDA Maryland.  
9. Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data 
using multiple imputation in conjunction with robust regression. Biometrics. 2012 
Dec;68(4):1250-9. doi: 10.1111/j.1541-0420.2012.01780.x. 
10. Zigmond AS,Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 
1983; 67(6):361-370. 
 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Primary Efficacy Analysis: 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
• Change in HbA1c 
from baseline to 
week 12 in patients 
with elevated 
baseline HbA1c 
(ie, screening 
HbA1C > 7%). 
 
Glycemic 
Analysis 
Set – 
Cohort A 
 
 
 
 
 
MMRM 
 
No 
 
• Percent change in 
fasting triglyceride 
(TG) from baseline 
to week 12 in 
patients with 
elevated screening 
baseline fasting TG 
(ie, fasting TG ≥ 
200 mg/dL). 
 
Triglyceride 
Analysis 
Set – 
Cohort A 
MMRM  
Ranked 
ANCOVA 
No 
 
10.2. 
Windows for Analysis Time Points 
Below are the definitions for the visit windows programmatically imposed on measures 
repeatedly collected over the course of the study.  These visit windows reflect the study schedule 
of assessments as described in the protocol.  
The visit windows are constructed using ranges applied to the number of days in study (study 
days) when the measure is collected. Below are the relevant definitions for the analysis visit 
windows:  
1. Study day is defined as the number of days since the first study treatment administration 
+1. The first study treatment occurs on Day 1. 
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2. Single-blind study day is defined as the number of days since the first single-blind study 
treatment administration+1. Especially, Single-blind Study Day 1 (SB Day 1) is defined 
as the day for the first single-blind study treatment administration. 
3. Since the protocol specifies that measurements be collected before study treatment is 
administered on a given day, it is appropriate that baseline include Day 1. 
4. For randomized but not treated patients, Day 1 is the day of randomization.   
 
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Table 8: General Global Analysis Windows 
Visit Label 
 
Targeted DBTP 
Study Day 
Targeted SBTP 
Study Day 
Analysis Window in 
DBTP Study Days 
Analysis Window in 
SBTP Study Days 
Screening 
 
< Day -28 
N/A 
Measurement 
obtained prior to 1st 
study trt, and not 
defined as baseline 
visit 
N/A 
Baseline 
 
Day 1 
N/A 
Measurement 
obtained closest to 1st 
study trt, while 
remaining prior to 1st 
study trt.admin 
N/A 
Week 1 
 
8 
N/A 
Day 2 to Day 15 
N/A 
Week 3 
 
22 
N/A 
16 to 32 
N/A 
Week 6 
 
43 
N/A 
33 to 50 
N/A 
Week 8 
 
57 
N/A 
51 to 64 
N/A 
Week 10 
 
71 
N/A 
65 to 78 
N/A 
Week 12 
 
85 
N/A 
79 to SB Day 1 
N/A 
Week 13 
 
N/A 
SB Day 8 
N/A 
SB Day 2 to 15 
Week 15 
 
N/A 
22 
N/A 
16 to 29 
Week 17 
 
N/A 
36 
N/A 
30 to 39  
Week 18 
 
N/A 
43 
N/A 
40 to 50 
Week 20 
 
N/A 
57 
N/A 
51 to 64 
Week 22 
 
N/A 
71 
N/A 
65 to 78 
Week 24 
 
N/A 
85 
N/A 
79 to 92 
FU- W5 
Last study trt admin 
day + 35 days  
 Last study trt admin day +15 days TO last study trt admin day + 49 
days 
FU-W9 
Last study trt admin 
day + 63 days 
Last study trt admin day + 50 days TO last study trt admin day + 77 
days 
FU-W13 
Last study trt admin 
day + 91 days 
Last study trt admin day + 78 days TO last study trt admin day + 
105 days 
FU-W17 
Last study trt admin 
day + 119 days 
Last study trt admin day + 106 days TO last study trt admin day + 
126 days 
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Table 9: Analysis Windows for Vital Sign 
Visit 
Label 
 
Targeted DBTP 
Study Day 
Targeted SBTP 
Study Day 
Analysis Window in DBTP 
Study Days 
Analysis Window in 
SBTP Study Days 
Screening  
< Day 1 
N/A 
Measurement obtained prior to 
1st study trt, and not defined as 
baseline visit 
N/A 
Baseline  
Day 1 
N/A 
Measurement obtained closest to 
1st study trt, while remaining 
prior to 1st study trt.admin 
N/A 
Week 1 
 
8 
N/A 
Day 2 to Day 11 
N/A 
Week 2 
 
15 
N/A 
12 to 18 
N/A 
Week 3 
 
22 
N/A 
19 to 25 
N/A 
Week 4 
 
29 
N/A 
26 to 32 
N/A 
Week 5 
 
36 
N/A 
33 to 39 
N/A 
Week 6 
 
43 
N/A 
40 to 46 
N/A 
Week 7 
 
50 
N/A 
47 to 53 
N/A 
Week 8 
 
57 
N/A 
54 to 60 
N/A 
Week 9 
 
64 
N/A 
61 to 67 
N/A 
Week 10  
71 
N/A 
68 to 74 
N/A 
Week 11  
78 
N/A 
75 to 81 
N/A 
Week 12  
85 
N/A 
82 to SB Day 1 
N/A 
Week 13  
N/A 
SB Day 8 
N/A 
SB Day 2 to 11 
Week 14  
N/A 
15 
N/A 
12 to 18 
Week 15  
N/A 
22 
N/A 
19 to 25 
Week 16  
N/A 
29 
N/A 
26 to 32 
Week 17  
N/A 
36 
N/A 
33 to 39 
Week 18  
N/A 
43 
N/A 
40 to 46 
Week 19  
N/A 
50 
N/A 
47 to 53 
Week 20  
N/A 
57 
N/A 
54 to 60 
Week 21  
N/A 
64 
N/A 
61 to 67 
Week 22  
N/A 
71 
N/A 
68 to 74 
Week 23  
N/A 
78 
N/A 
75 to 81 
Week 24  
N/A 
85 
N/A 
82 to 92 
FU- W5 
Last study trt admin 
day + 35 days  
 Last study trt admin day +15 days TO last study trt admin day + 49 days 
FU-W9 
Last study trt admin 
day + 63 days 
Last study trt admin day + 50 days TO last study trt admin day + 77 days 
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Visit 
Label 
 
Targeted DBTP 
Study Day 
Targeted SBTP 
Study Day 
Analysis Window in DBTP 
Study Days 
Analysis Window in 
SBTP Study Days 
FU-W13 
Last study trt admin 
day + 91 days 
Last study trt admin day + 78 days TO last study trt admin day + 105 days 
FU-W17 
Last study trt admin 
day + 119 days 
Last study trt admin day + 106 days TO last study trt admin day + 126 days 
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Table 10: Analysis Windows for Body Weight 
Visit 
Label 
 
Targeted DBTP 
Study Day 
Targeted SBTP 
Study Day 
Analysis Window in Study Days 
SBTP Analysis 
Window in Study 
Days 
Screening  
< Day 1 
N/A 
Measurement obtained prior to 1st 
study trt, and not defined as baseline 
visit 
N/A 
Baseline  
Day 1 
N/A 
Measurement obtained closest to 1st 
study trt 
N/A 
Week 1 
 
8 
N/A 
Day 2 to 15 
N/A 
Week 3 
 
22 
N/A 
16 to 29 
N/A 
Week 5 
 
36 
N/A 
30 to 39 
N/A 
Week 6 
 
43 
N/A 
40 to 50 
N/A 
Week 8 
 
57 
N/A 
51 to 64 
N/A 
Week 10  
71 
N/A 
65 to 78 
N/A 
Week 12 
 
 
85 
N/A 
82 to SB Day 1 
N/A  
Week 14  
N/A 
SB Day 15 
N/A 
SB Day 2 to 22 
Week 16  
N/A 
29 
N/A 
23 to 36 
Week 18  
N/A 
43 
N/A 
37 to 50 
Week 20  
N/A 
57 
N/A 
51 to 64 
Week 22  
N/A 
71 
N/A 
65 to 78 
Week 24  
N/A 
85 
N/A 
79 to 92 
FU- W5 
Last study trt admin 
day + 35 days  
 Last study trt admin day +15 days TO last study trt admin day + 49 days 
FU-W9 
Last study trt admin 
day + 63 days 
Last study trt admin day + 50 days TO last study trt admin day + 77 days 
FU-W13 
Last study trt admin 
day + 91 days 
Last study trt admin day + 78 days TO last study trt admin day + 105 days 
FU-W17 
Last study trt admin 
day + 119 days 
Last study trt admin day + 106 days TO last study trt admin day + 126 days 
 
 
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Table 11: Efficacy Analysis Windows for Fasting Triglycerides and Fasting Glucose 
Visit 
Label 
 Targeted DBTP 
Study Day 
Targeted SBTP 
Study Day 
Analysis Window in Study 
Days 
SBTP Analysis Window in 
Study Days 
Screenin
g 
 
< Day 1 
N/A 
Measurement obtained prior to 
1st study trt, and not defined as 
baseline visit 
N/A 
Baseline   
Day 1 
N/A 
Measurement obtained closest 
to 1st study trt while remaining 
prior to 1st study trt admin 
N/A 
Week 2  
15 
N/A 
Day 2 to 22 
N/A 
Week 4  
29 
N/A 
23 to 36  
N/A 
Week 6  
43 
N/A 
37 to 50 
N/A 
Week 8  
57 
N/A 
51 to 64  
N/A 
Week 10  
71 
N/A 
65 to 74 
N/A 
Week 11  
78 
N/A 
75 to 81 
N/A 
Week 12   
85 
N/A 
82 to SB Day 1 
N/A 
Week 14  
N/A 
SB Day 15 
N/A 
SB Day 2 to 22 
Week 16  
N/A 
29 
N/A 
23 to 36  
Week 18   
N/A 
43 
N/A 
37 to 50 
Week 20  
N/A 
57 
N/A 
51 to 64  
Week 22  
N/A 
71 
N/A 
65 to 74 
Week 23  
N/A 
78 
N/A 
75 to 81 
Week 24  
N/A 
85 
N/A 
82 to 92 
FU- W5 
Last study trt admin day + 35 days  
 Last study trt admin day +15 days TO last study trt admin 
day + 49 days 
FU- W9 
Last study trt admin day + 63 days 
Last study trt admin day + 50 days TO last study trt admin 
day + 77 days 
FU- W13 
Last study trt admin day + 91 days 
Last study trt admin day + 78 days TO last study trt admin 
day + 105 days 
FU- W17 
Last study trt admin day + 119 days 
Last study trt admin day + 106 days TO last study trt admin 
day + 126 days 
 
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Table 12: Efficacy Analysis Windows for HbA1c 
Visit 
Label 
 
Targeted Study 
DBTP Day 
Targeted SBTP 
Study Day 
Analysis Window in 
DBTP Study Days 
Analysis Window in SBTP 
Study Days 
Screening  
< Day 1 
N/A 
Measurement obtained 
prior to 1st study trt, and 
not defined as baseline 
visit 
N/A 
Baseline   
Day 1 
N/A 
Measurement obtained 
closest to 1st study trt 
while remaining prior to 
1st study trt admin 
N/A 
Week 4 
 
29 
N/A 
Day 2 to 36  
N/A 
Week 6 
 
43 
N/A 
37 to 57 
N/A 
Week 10  
71 
N/A 
58 to 78 
N/A 
Week 12   
85 
NA 
79 to SB Day 1 
N/A  
Week 16  
N/A 
SB Day 29 
N/A 
SB Day 2 to 36  
Week 18   
N/A 
43 
N/A 
37 to 57 
Week 22  
N/A 
71 
N/A 
58 to 78 
Week 24  
N/A 
85 
N/A 
79 to 92 
FU- W5 
Last study trt admin day + 35 days  
 Last study trt admin day +15 days TO last study trt 
admin day + 49 days 
FU- W9 
Last study trt admin day + 63 days 
Last study trt admin day + 50 days TO last study trt 
admin day + 77 days 
FU- W13 
Last study trt admin day + 91 days 
Last study trt admin day + 78 days TO last study trt 
admin day + 105 days 
FU- W17 
Last study trt admin day + 119 days 
Last study trt admin day + 106 days TO last study trt 
admin day + 126 days 
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Table 13: Efficacy Analysis Windows for Daily Lipodystrophy Hunger Questionnaire 
Visit 
Label 
 
Analysis Window in DBTP Study Days 
Analysis Window in SBTP Study Days 
Baseline   Day -27 to Day 1 while remaining prior to 1st 
DB study trt admin 
N/A 
Week 4 
 
Day 2 to 29 
N/A 
Week 8 
 
30 to 57 
N/A 
Week 12   
58 to SB Day 1 while remaining prior to 1st 
SB study trt admin or to last study trt admin 
day + 7 days if not entering SBTP 
N/A  
Week 16  
N/A 
SB Day 2 to 29  
Week 20   
N/A 
30 to 57 
Week 24  
N/A 
58 to Last study trt admin day + 7 days 
FU- W5 
 Last study trt admin day +8 days TO last study trt admin day + 35 days 
FU- W9 
Last study trt admin day + 36 days TO last study trt admin day + 63 days 
FU- W13 
Last study trt admin day + 64 days TO last study trt admin day + 91 days 
FU- W17 
Last study trt admin day + 92 days TO last study trt admin day + 119 days 
 
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Table 14: Efficacy Analysis Windows for DXA, MRI, NMR Lipid, and Bioimpedance 
Visit 
Label 
 
Targeted Study 
DBTP Day 
Targeted SBTP 
Study Day 
Analysis Window in DBTP 
Study Days 
Analysis Window in SBTP 
Study Days 
Baseline   
Day 1 
N/A 
Measurement obtained closest 
to 1st study trt while 
remaining prior to 1st study trt 
admin 
N/A 
Week 12   
85 
NA 
Day 43 to SB Day 1 or to last 
DB trt admin day + 28 days if 
not entering SBTP 
N/A  
Week 24  
N/A 
SB Day 85 
N/A 
SB Day 43 to last SB trt 
admin day + 28 days 
FU- W17 
Last study trt admin day + 119 days 
Last study trt admin day + 69 days TO last study trt admin 
day + 133 days 
 
 
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Table 15: Double-blind treatment period – Period Windows 
For those measurements that are collected over time (eg, IV and SC exposure), analyses 
performed within the 12-week double-blinded treatment period (DBTP) windows will use the 
following definitions to bin observations. Observations will be binned based on the start date of 
the measurement.  
• The DBTP is defined as from the starting time of the first DBTP study drug 
administration to the day of the last DBTP study drug administration + 14 days for 
those patients not proceeding into the single-blinded treatment period (SBTP). For 
those patients proceeding into the SBTP, the DBTP ends at the starting time of the 
first SBTP study drug administration. 
•  
Table 16: Single-blind treatment period – Period Windows 
For those measurements that are collected over time (eg, IV and SC exposure), analyses 
performed within the 12-week single-blinded treatment period (SBTP) windows will use the 
following definitions to bin observations. Observations will be binned based on the start date of 
the measurement.  
• The SBTP is defined from the time of the first SBTP study drug administration to the 
day of the last SBTP study drug administration + 14 days. 
•  
Table 17: Double-blind treatment-emergent adverse event period – Period Windows 
• The double-blind treatment-emergent adverse event (TEAE) period is defined from 
the starting time of the first dose of double-blind study treatment administration to the 
day of the last dose of double-blind study treatment administration + 112 days (16 
weeks) for those patients not proceeding into SBTP, or up to the starting time of the 
first dose of SBTP study treatment administration for those patients proceeding into 
the SBTP. 
•  
Table 18: Single-blind treatment-emergent adverse event period – Period Windows 
• The single-blind treatment-emergent adverse event (TEAE) period is defined from the 
starting time of the first single-blind study treatment administration to the day of the 
last single-blind study treatment administration + 112 days (16 weeks).  
•  
•  
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10.3. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ 
Table 19: Summary of AESIs and the Methods of Data Collections and Derivations 
AESI 
Using an e-CRF specific 
tick box on AE page 
Using Standard MedDRA Query 
(SMQ)/company MedDRA 
Query (CMQ) or Laboratory 
data criteria 
Hypoglycemia 
Yes 
• Blood glucose <54 mg/dL 
New onset diabetes mellitus 
(NODM) 
Yes 
For patients with no diabetes at 
baseline: 
• Two values of fasting (≥8 hr) 
plasma glucose ≥126 mg/dL 
(7.0 mmol) during treatment 
period 
OR 
• Two values of HbA1c ≥6.5% 
(48 mmol/mol) during 
treatment period 
Note: Patients who meet either of 
these criteria during the PBO run-
in period will be considered to 
have diabetes at baseline. 
Hyperglycemia requiring 
treatment 
Yes  
HbA1c ≥10.5% AND increase in 
HbA1c of ≥1.5% from baseline 
value 
OR 
b. Fasting glucose ≥250 mg/dL on 
2 occasions AND increase in 
fasting glucose >50 mg/dL above 
baseline 
Development of new or 
worsening of autoimmune 
disease 
Yes 
N/A 
Moderate and severe 
Hypersensitivity reactions 
  
Yes 
• CMQ ‘Hypersensitivity, which 
is defined as Hypersensitivity 
SMQ (narrow) excluding the 
following PTs: 
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o Injection site 
dermatitis,  
o Injection site eczema, 
o  Injection site 
hypersensitivity, 
o  Injections site rash, 
o  injection site reaction,  
o Injection site recall 
reaction,  
o Injection site urticaria,  
o Injection site vasculitis 
Moderate and severe 
infusion reactions  
Yes 
N/A 
^ dedicated CRF for ISR captures event PT and associated symptoms  
10.4. 
Criteria for Potentially Clinically Significant Values (PCSV)  
Table 20: Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
Comments 
Clinical chemistry 
ALT 
By distribution analysis: 
>2 ULN and baseline ≤ 2 ULN 
>3 ULN and baseline ≤ 3 ULN 
>5 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
 
AST 
By distribution analysis: 
>2 ULN and baseline ≤ 2 ULN 
>3 ULN and baseline ≤ 3 ULN 
>5 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
 
Alkaline 
Phosphatase 
> 1.5 ULN and baseline ≤ 1.5 ULN 
 
Total Bilirubin 
> 1.5 ULN and baseline ≤ 1.5 ULN 
> 2 ULN and baseline ≤ 2 ULN 
 
ALT and Total 
Bilirubin 
ALT > 3 ULN and Total Bilirubin > 2 ULN 
and baseline ALT≤3 ULN or Total bilirubin 
≤ 2 ULN 
 
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Parameter 
PCSV 
Comments 
CPK 
> 3 ULN and ≤ 5 ULN and baseline ≤ 
3ULN 
>5 ULN and ≤ 10 ULN and baseline ≤ 5 
ULN 
>10 ULN and baseline ≤ 10 ULN 
  
Creatinine 
 30% increase from baseline 
 60% increase from baseline 
 
Creatinine 
Clearance 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
 
 
Uric Acid 
Hyperuricemia 
 
>408 μmol/L 
 
 
Blood Urea 
Nitrogen 
≥17 mmol/L 
 
Chloride 
Hypochloremia: 
Hyperchloremia: 
 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
129 mmol/L  
 150 mmol/L  
Must also be outside the normal 
range. 
 
Potassium 
< 3  mmol/L 
 5.5 mmol/L  
Must also be outside the normal 
range. 
 
Total Cholesterol 
>6.20 mmol/L (Under 18 yrs) 
>7.74 mmol/L (18 yrs +) 
Must also be outside the normal 
range. 
 
Triglycerides 
> 5.6 mmol/L if baseline < 5.6 mmol/L 
or 
>50% from baseline 
Must also be outside the normal 
range. 
Glucose 
  
  
Hypoglycemia <3.9 mmol/L or 70 mg/dL  
 
Hyperglycemia  
Fasting glucose ≥250 mg/dL or 13.9mmol/L 
and 
Increase in fasting glucose >50 mg/dL or 
2.8mmol/L above baseline 
Must also be outside the normal 
range. 
 
 
 
 
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Parameter 
PCSV 
Comments 
HbA1c  
HbA1c ≥10.5% AND increase in HbA1c of 
≥1.5% from baseline value  
 
 
Albumin 
≤25 g/L 
 
Hematology 
WBC 
< 3.0 Giga/L (3000/mm3)  
≥ 16.0 Giga/L (18 yrs +) 
Must also be outside the normal 
range. 
 
Lymphocytes 
>4.0 Giga/L 
<0.6 Giga/L 
 
Neutrophils 
< 1.5 Giga/L (1,500/mm3) 
Must also be outside the normal 
range. 
 
Eosinophils 
> 0.5 Giga/L (500/ mm3) 
or > ULN if ULN ≥ 0.5 Giga/L 
 
Monocytes 
>1.5 Giga/L 
 
Hemoglobin 
≤115 g/L (Male 18 yrs +) 
≤95 g/L (Female 18 yrs +) 
≥185 g/L (Male 18 yrs +) 
≥165 g/L (Female 18 yrs +) 
Decrease from Baseline ≥20 g/L (18 yrs +) 
Must also be outside the normal 
range. 
 
Platelets 
< 100 Giga/L (100,000/mm3) 
> 700 Giga/L (100,000/mm3) 
Must also be outside the normal 
range. 
 
Hematocrit  
 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
 
Vital Signs 
HR 
≤45 bpm and decrease from baseline ≥20 
bpm 
≥120 bpm and increase from baseline≥20 
bpm 
 
SBP 
 90 mmHg and decrease from baseline 
 20 mmHg (18 yrs +) 
 160 mmHg and increase from baseline 
 20 mmHg (18 yrs +) 
 
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Parameter 
PCSV 
Comments 
DBP 
 45 mmHg and decrease from baseline 
 10 mmHg (18 yrs +) 
 110 mmHg and increase from baseline 
 10 mmHg (18 yrs +) 
 
 
Weight 
 10% decrease versus baseline 
 
ECG parameters 
  
HR 
≤45 bpm and decrease from baseline ≥20 
bpm (18 yrs +) 
≥120 bpm and increase from baseline≥20 
bpm (18 yrs +) 
 
PR 
>220 ms and increase from baseline ≥20 ms 
(18 yrs +) 
 
 
QRS 
>110 ms and increase from baseline ≥20% 
(18 yrs +) 
>120 ms and increase from baseline ≥20% 
(18 yrs +) 
 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms)  
Borderline:  
431-450 ms (Male) 
451-470 ms (Female) 
 
Prolonged*:  
>450 ms (Male) 
> 470 ms (Female) 
QTc ≥500 ms 
 
Increase versus baseline (Males and 
Females) 
Borderline 30-60 ms 
Prolonged*: >60 ms  
 
To be applied to QTcF correction 
formulas  
 
 
 
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10.5. 
Biomarker-NMR Lipoprotein analysis 
The following data fields are reported in the Biomarker-Lipoprotein NMR.  
LP3 Data to be sent quarterly 
Abbreviation  
Parameter to be reported  
Unit  
VLDLCP3  
VLDL & Chylomicron Particles (total) 1  
nmol/L  
VLCP3  
Large VLDL & Chylomicrons Particles1  
nmol/L  
VMP3  
Medium VLDL Particles1  
nmol/L  
VSP3  
Small VLDL Particles1  
nmol/L  
LDLP3  
LDL Particles (total) 1  
nmol/L  
IDLP3  
IDL Particles1  
nmol/L  
LLP3  
Large LDL Particles1  
nmol/L  
LSP3  
Small LDL Particles (total) 1  
nmol/L  
HDLP3  
HDL Particles (total) 1  
μmol/L  
HLP3  
Large HDL Particles1  
μmol/L  
HMP3  
Medium HDL Particles1  
μmol/L  
HSP3  
Small HDL Particles1  
μmol/L  
VZ3  
VLDL Size  
nm  
LZ3  
LDL Size  
nm  
HZ3  
HDL Size  
nm  
LP-IR  
Lipoprotein Insulin Resistance Score  
N/A  
 
LP4 Data to be sent at the end of the study 
Abbreviation  
Analyte Description  
Units  
TRLP  
Triglyceride rich lipoprotein (TRL) particles 
(Total chylomicron & VLDL particles)  
nmol/L  
VL_TRLP  
Very large TRL particles  
nmol/L  
L_TRLP  
Large TRL particles  
nmol/L  
M_TRLP  
Medium TRL particles  
nmol/L  
S_TRLP  
Small TRL particles  
nmol/L  
VS_TRLP  
Very small TRL particles  
nmol/L  
LDLP  
Total low density lipoprotein (LDL) particles  
nmol/L  
L_LDLP  
Large LDL particles  
nmol/L  
M_LDLP  
Medium LDL particles  
nmol/L  
S_LDLP  
Small LDL particles  
nmol/L  
HDLP  
Total high density lipoprotein (HDL) particles  
μmol/L  
L_HDLP  
Large HDL particles  
μmol/L  
M_HDLP  
Medium HDL particles  
μmol/L  
S_HDLP  
Small HDL particles  
μmol/L  
H7P  
H7 subspecies of HDL  
μmol/L  
H6P  
H6 subspecies of HDL  
μmol/L  
H5P  
H5 subspecies of HDL  
μmol/L  
H4P  
H4 subspecies of HDL  
μmol/L  
H3P  
H3 subspecies of HDL  
μmol/L  
H2P  
H2 subspecies of HDL  
μmol/L  
H1P  
H1 subspecies of HDL  
μmol/L  
TRLZ  
Mean TRL size  
nm  
LDLZ  
Mean LDL size  
nm  
HDLZ  
Mean HDL size  
nm  
TRLTG  
TRL triglycerides  
mg/dL  
TRLC  
TRL cholesterol  
mg/dL  
LP-X  
Lipoprotein X  
mg/dL  
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LP-Z  
Lipoprotein Z  
nmol/L  
ApoAI  
Apolipoprotein A-I  
mg/dL  
BCAA  
Total branched chain amino acids  
μmol/L  
Val  
Valine  
μmol/L  
Leu  
Leucine  
μmol/L  
Ileu  
Isoleucine  
μmol/L  
Ala  
Alanine  
μmol/L  
 
LP4 Derived Lipids  
Abbreviation  
Analyte Description  
Units  
TC  
Total Cholesterol  
mg/dL  
HDLC  
HDL Cholesterol  
mg/dL  
LDLC  
TG 
LDL Cholesterol  
Total Triglycerides  
mg/dL  
mg/dL 
ApoB 
Apolipoprotein B  
mg/dL 
 
Inflammation Biomarker  
Abbreviation  
Analyte Description  
Units  
GlycA  
GlycA  
μmol/L  
 
Ketone Bodies  
Abbreviation  
Analyte Description  
Units  
KetBod  
Total Ketone Bodies  
μmol/L  
B-HB  
β-hydroxybutyrate  
μmol/L  
AcAc  
Acetoacetate  
μmol/L  
Acetone  
Acetone  
μmol/L  
 
Small Molecule Metabolites  
Abbreviation  
Analyte Description  Units  
Glu  
Glucose  
mg/dL  
Ctr  
Citrate  
mg/dL  
 
NMR Multimarker (score 1-100)  
Abbreviation  
Analyte Description  
LP-IR  
Lipoprotein Insulin Resistance Index  
DRI  
Diabetes Risk Index  
 
10.6. 
DXA Variable List 
LARM_AREA 
LARM_BMC 
LARM_BMD 
LARM_FAT 
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LARM_LEAN 
LARM_CR 
RARM_AREA 
RARM_BMC 
RARM_BMD 
RARM_FAT 
RARM_LEAN 
RARM_CR 
LLEG_AREA 
LLEG_BMC 
LLEG_BMD 
LLEG_FAT 
LLEG_LEAN 
LLEG_CR 
RLEG_AREA 
RLEG_BMC 
RLEG_BMD 
RLEG_FAT 
RLEG_LEAN 
RLEG_CR 
TRUNK_FAT 
TRUNK_LEAN 
ANDRD_FAT 
ANDRD_LEAN 
GYND_FAT 
GYND_LEAN 
HEAD_AREA 
HEAD_BMC 
HEAD_BMD 
HEAD_FAT 
HEAD_LEAN 
HEAD_CR 
LEG_AREA 
LEG_BMC 
LEG_BMD 
LEG_FAT 
LEG_LEAN 
LEG_CR 
ARM_AREA 
ARM_BMC 
ARM_BMD 
ARM_FAT 
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ARM_LEAN 
ARM_CR 
TOT_AREA 
TOT_BMC 
TOT_BMD 
TOT_FAT 
TOT_LEAN 
TOT_PFAT 
TOT_CR 
TOT_ZSCORE 
TOT_ZSCORE_CR 
ADJTOT_AREA 
ADJTOT_BMC 
ADJTOT_BMD 
ADJTOT_FAT 
ADJTOT_LEAN 
ADJTOT_PFAT 
ADJTOT_CR 
ADJTOT_ZSCORE 
ADJTOT_ZSCORE_CR 
VATMASS 
VATVOL 
10.7. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures in response to 
COVID-19 are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency. 
Study assessments and procedures are presented by study period and visit in Table 21 and 
Table 22. 
 
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CONFIDENTIAL 
Table 21: Schedule of Events: Screening and Placebo Run-In 
Study Period 
Screening 1,2 
Placebo Run-In 
  
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic Outpatient 
visit or Remote visit 3 
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic 
Outpatient visit or 
Remote visit 3 
Visit Number: 
1 
24 
(3)4  
4 
5 
6 
7 
Day: 
-98 to -63 
-91 to -
49 
-77 to -49 
-28 
-21 
-14 
-7 
±visit window (d): 
  
  
  
±3 
±3 
±3 
±3 
Week: 
week -14  
to -9 
week -13 
to -7 
week-11 
to -7 
week -4 
week 
-3 
week 
-2 
week 
-1 
Screening  
  
  
  
  
  
  
  
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
X 
 
 
 
Medical History 5 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Confirm partial lipodystrophy 
diagnosis 
X 
 
 
 
 
 
 
HIV serology and hepatitis 
testing (HBsAg,  HCV) 
X 
 
 
 
 
 
 
Treatment 
  
  
  
  
  
  
  
Placebo Administration for Run-
In IV 1  
  
  
  
X 
 
 
 
Placebo Administration for Run-
In SC 
 
 
 
 
X 
X 
X 
Concomitant Meds and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
Monitoring/dose adjustments for 
antidiabetic and lipid lowering 
medication 6 
  
  
  
X 
X 
X 
X 
Safety 7 
  
  
  
  
  
  
  
Vital Signs 8 
X 
  
  
X 
X 
X 
X 
Height 
X 
  
  
  
  
  
  
Weight 9 
X 
  
  
X 
  
  
X 
Physical Examination 
X 
  
  
X 
  
  
  
Waist and hip circumference 
X 
 
 
X 
 
 
 
Electrocardiogram 10 
X 
  
  
 
  
  
  
Adverse Events 
X 
 X 
X  
X 
X 
X 
X 
Menstrual history, pregnancy 
status reporting, and 
confirmation of contraception 
 X 
  
  
X 
  
X 
  
Laboratory Testing 11 
  
  
  
  
  
  
  
Hematology 
X 
  
  
X 
  
X 
  
Blood Chemistry 
X 
  
  
X 
  
X 
  
Pregnancy Test (WOCBP)12 
Serum 
  
  
Urine 
  
Urine 
  
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
Date: May 16, 2024 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 75 
 
CONFIDENTIAL 
Study Period 
Screening 1,2 
Placebo Run-In 
  
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic Outpatient 
visit or Remote visit 3 
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic 
Outpatient visit or 
Remote visit 3 
Visit Number: 
1 
24 
(3)4  
4 
5 
6 
7 
Day: 
-98 to -63 
-91 to -
49 
-77 to -49 
-28 
-21 
-14 
-7 
±visit window (d): 
  
  
  
±3 
±3 
±3 
±3 
Week: 
week -14  
to -9 
week -13 
to -7 
week-11 
to -7 
week -4 
week 
-3 
week 
-2 
week 
-1 
Urinalysis 
X 
  
   
  
  
  
  
Leptin13,14 
X 
X 
X 
  
X 
  
X 
Efficacy11 
  
  
  
  
  
  
  
Lipid panel14 
  
  
  
X 
  
  
  
Free Fatty Acids14 
 
 
 
X 
 
X 
 
Fasting Triglycerides13,14 
X 
X 
X 
X 
X 
X 
X 
Fasting Glucose 14 
X 
  
  
X 
X 
X 
X 
HbA1c 
X 
  
  
X 
  
  
  
Fructosamine  
X 
  
  
X 
  
X 
  
Insulin 14 
  
  
  
X 
  
X 
  
NMR Lipid panel LDL-C, 
HDL-C, total-Cholesterol 14 
  
  
  
X 
  
  
  
Urine Creatinine and Albumin 
  
  
  
X 
  
  
  
Patient eCOA Training15 
  
  
  
X 
  
  
  
Daily Lipodystrophy Hunger 
questionnaire  
  
  
  
 
BPI-SF questionnaire 
  
  
  
X 
  
  
  
PHQ-8 questionnaire 
  
  
  
X 
  
  
  
SF-36 questionnaire 
 
 
 
X 
 
 
 
HADS questionnaire 
  
  
  
X 
  
  
  
Patient Global Impression of 
Severity- Hunger 
  
  
  
X 
  
  
  
Patient Global Impression of 
Severity- Pain 
  
  
  
X 
  
  
  
Bioimpedance 
X 
 
 
X 
 
 
 
DXA 
X16 
  
X16 
Liver volume (MRI) and liver fat 
content (MRI-PDFF) 
  
  
  
X16 
Biomarkers 
Procedure/Samples  
  
  
  
  
  
  
  
Apolipoprotein C3 (ApoC3)11,14 
  
  
  
X 
  
  
  
ANGPTL311,14 
  
  
  
X 
  
  
  
X  
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
Date: May 16, 2024 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 76 
 
CONFIDENTIAL 
Study Period 
Screening 1,2 
Placebo Run-In 
  
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic Outpatient 
visit or Remote visit 3 
Mandatory 
In-Clinic 
Outpatient 
visit 
In-Clinic 
Outpatient visit or 
Remote visit 3 
Visit Number: 
1 
24 
(3)4  
4 
5 
6 
7 
Day: 
-98 to -63 
-91 to -
49 
-77 to -49 
-28 
-21 
-14 
-7 
±visit window (d): 
  
  
  
±3 
±3 
±3 
±3 
Week: 
week -14  
to -9 
week -13 
to -7 
week-11 
to -7 
week -4 
week 
-3 
week 
-2 
week 
-1 
Future biomedical research 
serum and plasma samples 
(Optional) 
  
  
  
X 
  
  
  
Pharmacogenomics Sub-study (Optional)   
  
  
  
  
  
  
Blood sample for DNA 
isolation17  
X  
  
  
 
  
  
  
Abbreviations: 
ANGPTL3=angiopoietin-like 
protein 
3; 
BPI-SF=brief 
pain 
inventory 
– 
short 
form; 
DNA=deoxyribonucleic acid; DXA=dual-energy X-ray absorptiometry; eCOA=electronic clinical outcome 
assessment; HADS=hospital anxiety and depression scale; HbA1c=hemoglobin A1c; HBsAg=hepatitis B surface 
antigen; HCV=hepatitis C virus; ; MRI=magnetic resonance imaging; MRI-PDFF=MRI-derived proton density fat 
fraction; NMR=nuclear magnetic resonance; PHQ-8=8-item patient health questionnaire depression scale; 
SC=subcutaneous; SF-36=short form 36; WOCBP=women of child-bearing potential; HDL-C=high density 
lipoprotein cholesterol; LEPR=soluble leptin receptor; l; IV=intravenous; LDL-C=low density lipoprotein cholesterol  
10.7.1. 
Footnotes for the Schedule of Events Table 21: Screening and Placebo Run-in 
1. Patients may be re-screened if they fail the screening for reasons related to incidental or 
transitory conditions (eg, medication use, concomitant illness, medical condition). If 
patients are re-screened within the original 10-week screening period, only screening 
test(s) (eg, an out-of-range lab value) that resulted in initial screen failure should be 
repeated. All patients will be monitored for 4 hours following IV placebo infusion to 
maintain study blinding. For those patients screened and found eligible under the original 
protocol, HbA1c and triglycerides assessments will be repeated to reconfirm eligibility of 
the patient if the screening window of 10 weeks has been exceeded by the time the relevant 
approvals for Protocol Amendment 1 are in place. 
2. Procedures may be conducted on different days during the screening period, if needed. 
Blood draws for laboratory testing at the screening visit will be collected in a fasted state 
(after at least approximately a 12-hour fast). The duration of fasting may be shortened for 
patients with a documented clinical contraindication to fasting. 
3. Procedures may be conducted by trained study staff at a remote location (at home, work 
place, and/or school). 
4. Visit 2 has to occur at least 7 days after visit 1. Visit 3 is conditional upon the results of 
results from visit 1 and visit 2. Visit 3 may not be required in all patients depending on the 
results from visit 1 and visit 2.  
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
Date: May 16, 2024 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 77 
 
CONFIDENTIAL 
5. Medical history should include detailed lipodystrophy history including prior 
medication/IPs, genetic diagnosis (if known), and results of any previous anti-metreleptin 
antibody testing (if applicable). 
6. Monitoring by qualified study personnel may be performed as a telephone contact or an in-
clinic or inpatient assessment. A telephone contact may be converted to an in-person site 
visit if in the opinion of qualified study personnel that a direct, in-person assessment would 
aid assessment of safety or clarify concomitant medication use and adjustment. For diabetic 
patients, all monitoring assessments will include asking about symptoms of hypoglycemia 
(per local standards), a review of the patient’s home glucometer readings (if applicable), 
and patient education regarding the importance of blood glucose monitoring and how to 
recognize symptoms of hypoglycemia (per local standards). Diabetic patients should be 
reminded to call the site if any signs or symptoms of hypoglycemia occur. 
7. All safety assessment should be performed before study drug administration. 
8. Vital signs should be recorded prior to IV study drug infusion, and approximately 
120 minutes post-IV infusion or prior to SC study drug injection. 
9. Body weight should be measured with patient in a gown after voiding (empty bladder) 
using a calibrated scale. Patients should empty pockets and remove shoes, belts, outer-layer 
clothing, or any other heavy wearable prior to being weighed. 
10. The ECG can be performed up to 24 hours prior to study drug administration. 
11. Blood (for safety, efficacy and biomarkers) and urine samples are to be collected before 
study drug administration, unless otherwise indicated. For patients undergoing apheresis, 
study assessments are to be performed and blood samples are to be collected immediately 
before the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
12. If there is a positive urine pregnancy test, a confirmatory serum pregnancy test will be 
performed. Study treatment will not be administered until a negative serum pregnancy test 
is obtained. If the serum pregnancy test is negative the patient can continue in the study. A 
positive serum pregnancy test will result in permanent stopping of study drug 
administration. 
13. Please refer to Appendix 1 in the study protocol for actions based on Hb1Ac, TG, and 
leptin results.  
14. Patients must be in a fasted state (after at least approximately a 12-hour fast). The duration 
of fasting may be shortened for patients with a documented clinical contraindication to 
fasting.  
15. Patients must receive eCOA training at the time they receive the eCOA device.  
16. Two DXA scans will be performed as follows: Screening DXA will be performed at either 
visit 1 or visit 2. The second DXA will be performed during the run-in period and can be 
performed from day -28 to day 1 prior to dosing of study drug. Two baseline liver volume 
and liver fat content MRI-PDFF scans will be obtained from day -28 to day 1 prior to 
dosing. These 2 MRI-PDFF scans must be performed on separate days at least 24 hours 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
Date: May 16, 2024 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 78 
 
CONFIDENTIAL 
apart and up to a maximum of 28 days apart. Patients may be required to fast at least 5 hours 
prior to the scans. 
17. DNA should be collected at visit 1, but can be collected at any visit after obtaining consent. 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
     
 Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
 
 
    Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 79 
 
CONFIDENTIAL 
Table 22: Schedule of Events: TP1, TP2, and Off-Drug Follow up  
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Patient Disposition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
(Mibavademab/Placebo)2 
(IV) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
(Mibavademab/Placebo)2 
(SC) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
 
 
 
 
 
Concomitant 
Medications and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
     
 Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
 
 
    Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 80 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Monitoring dose 
adjustments for 
antidiabetic and lipid 
lowering medication 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
Safety4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
Weight6 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Waist and hip 
circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
     
 Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
 
 
    Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 81 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Menstrual history, 
pregnancy status 
reporting, and 
Confirmation of 
contraception 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Laboratory Testing7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy Test 
(WOCBP)8 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Leptin9 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Efficacy7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
     
 Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
 
 
    Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 82 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Fasting Triglycerides9 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X X 
X 
X 
X 
X 
Lipid Panel9 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Fasting Glucose9 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X X 
X 
X 
X 
X 
HbA1c 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Fructosamine 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Insulin9 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Free Fatty Acids9 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
NMR Lipid panel 
LDL-C, HDL-C, total-
Cholesterol9 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Urine  Creatinine and 
Albumin 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
     
 Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
 
 
    Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 83 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Daily Lipodystrophy 
Hunger questionnaire  
 
BPI-SF questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
SF-36 questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
PHQ-8 questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
HADS questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Patient Global 
Impression of Severity-
Hunger 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Patient Global 
Impression of Severity- 
Pain 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
     
 Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
 
 
    Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 84 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Patient Global 
Impression of Change- 
Hunger 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Patient Global 
Impression of Change- 
Pain 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Bioimpedance 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
DXA10 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Liver volume (MRI) and 
liver fat content (MRI-
PDFF)10 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
PK/Drug 
Concentration and 
ADA Samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
     
 Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
 
 
    Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 85 
 
CONFIDENTIAL 
Study Period 
Double Blind Treatment Period (TP1) 
Single Blind Treatment Period (TP2) 
E
O
T
/
E
T
12 
Off-Drug 
Safety 
Follow up 
Period 
E
O
S 
  
 In
-
Cli
nic 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
 I
n-
Cl
ini
c 
O
ut
pa
tie
nt 
vis
it 
In-Clinic Outpatient visit or Remote visit 
In-Clinic 
Outpatient visit 
Visit Number: 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Day: 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
197 
225 
253 
281 
±visit window (d): 
 
±3 
±3 
±3 
±3 
±3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
± 
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
Week: 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
28 
32 
36 
40 
Biomarkers 
Procedure/Samples7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
     
 Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
 
 
    Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 86 
 
CONFIDENTIAL 
Abbreviations: ADA=antidrug antibodies; ANGPTL3=angiopoietin-like protein 3; BPI-SF=brief pain inventory – short form; DNA=deoxyribonucleic acid; 
DXA=dual-energy X-ray absorptiometry; EOS=end of study; EOT=end of treatment; ET=early termination; HADS=hospital anxiety and depression scale; 
HbA1c=hemoglobin A1c; HDL-C=high density lipoprotein cholesterol; IV=intravenous; LDL-C=low density lipoprotein cholesterol; MRI=magnetic resonance 
imaging; NMR=nuclear magnetic resonance; PK=pharmacokinetic; SC=subcutaneous; sLEPR=soluble leptin receptor; WOCBP=women of childbearing 
potential  
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 87 of 88 
 
CONFIDENTIAL 
10.7.2. 
Footnotes for the Schedule of Events Table 22: TP1, TP2 and Off-Drug 
Follow-Up 
18. Randomization can occur within 24 hours prior to day 1 study drug administration if 
necessary.  
19. All patients will be monitored for 4 hours following infusion on day 1 and day 85.  For 
patients undergoing apheresis, study drug will be administered after the apheresis 
procedure. 
20. Monitoring by qualified study personnel may be performed as a telephone contact or an in-
clinic or inpatient assessment. A telephone contact may be converted to an in-person site 
visit if in the opinion of qualified study personnel a direct, in-person assessment would aid 
assessment of safety or clarify concomitant medication use and adjustment. For diabetic 
patients, all monitoring assessments will include asking about  symptoms of hypoglycemia 
(per local standards), a review of the patient’s home glucometer readings (if applicable), 
and patient education regarding the importance of blood glucose monitoring and how to 
recognize symptoms of hypoglycemia (per local standards). Diabetic patients should be 
reminded to call the site if any signs or symptoms of hypoglycemia occur. 
21. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
22. Vital signs should be recorded prior to IV study drug infusion, and approximately 
120 minutes post-IV infusion (on day 1 and day 85) and prior to SC study drug injection 
(on day 85).  
23. Body weight should be measured after voiding (empty bladder) using a calibrated scale. 
Patients should empty pockets and remove shoes, belts, outer-layer clothing, or any other 
heavy wearable prior to being weighed. 
24. Study assessments, urine, and blood (safety, efficacy and biomarkers) samples will be 
collected before study drug administration, unless otherwise indicated. For patients 
undergoing apheresis, study assessments, urine, and blood samples will be collected 
immediately before the lipid-apheresis procedure.  
25. If there is a positive urine pregnancy test, a confirmatory serum pregnancy test will be 
performed. Study treatment will not be administered until a negative serum pregnancy test 
is obtained. If the serum pregnancy test is negative, the patient can continue in the study. 
A positive serum pregnancy test will result in permanent stopping of study drug 
administration. 
26. Patients must be in a fasted state (after at least approximately a 12-hour fast). The duration 
of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
27. Liver volume (MRI) and liver fat content (MRI-PDFF) and whole body DXA scans may 
be performed up to14 days prior to visits 20 and 32. Patients may be required to fast at least 
5 hours prior to the scans. 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-PLD-20100 
Statistical Analysis Plan V1.0 
 
Date: May 16, 2024 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 88 of 88 
 
CONFIDENTIAL 
28. Collection of blood samples for drug concentration/sLEPR on days 1 and 85 will be 
pre-infusion and again at the end of infusion (0 to 15 mins after the end of the infusion). 
On other visits, drug concentration/sLEPR samples will be collected pre-dose.  
29. Early termination (ET)/End of treatment (EOT) visit consists of the end of study 
assessments. 
10.7.3. 
 Early Termination Visit 
Patients who withdraw from the study will be asked to return to the clinic for 2 visits: an EOT/ET 
visit and an end of study visit. The EOT/ET visit should take place within 5 days of treatment 
discontinuation, if possible. A final end of study visit should take place with assessments 17 weeks 
after the last dose of study drug as described in Table 22. 
Patients who have discontinued study drug but who remain in the study will enter the off-drug 
follow-up period (Table 22) after completing the early termination visit. In the off-drug follow-up 
period, patients will continue with monthly visits until 17 weeks after last dose of study drug. Each 
of these monthly visits will consist of safety assessments, including laboratory tests. 
Sexually active patients who discontinue the study prematurely should be reminded to maintain 
highly effective contraceptive measures for 17 weeks after the last dose of study drug.  
10.7.4. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. An unscheduled visit may be performed as a remote visit or an 
outpatient in-clinic visit. 
 
                                        VV-RIM-00351304-1.0 Approved - 20 May 2024 GMT-5:00


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