An Open-label Study to Evaluate Safety, Efficacy and Pharmacokinetics (PK) of Patisiran-LNP in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) With Disease Progression Post-Orthotopic Liver Transplant
Phase: PHASE3
Conditions: Amyloidosis, Familial, Transthyretin Amyloidosis
Sponsor: Alnylam Pharmaceuticals

 
 
Official Title:  
An Open-label Study to Evaluate Safety, Efficacy and Pharmacokinetics (PK) 
of Patisiran-LNP in Patients With Hereditary Transthyretin-mediated 
Amyloidosis (hATTR Amyloidosis) With Disease Progression Post-
Orthotopic Liver Transplant 
 
NCT Number:   
NCT03862807 
 
Document Date:   
Clinical Study Protocol, 07 Oct 2018 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
1 
 
CLINICAL STUDY PROTOCOL 
ALN-TTR02-008 
DATED 07 OCTOBER 2018 
 
Protocol Title: 
An Open-label Study to Evaluate Safety, Efficacy 
and Pharmacokinetics (PK) of Patisiran-LNP in 
Patients with Hereditary Transthyretin-mediated 
Amyloidosis (hATTR amyloidosis) with Disease 
Progression Post-Orthotopic Liver Transplant 
Short Title: 
Patisiran-LNP in Patients with hATTR 
Amyloidosis Disease Progression Post-Liver 
Transplant  
Study Drug: 
patisiran-LNP (ALN-TTR02)  
EudraCT Number: 
2018-003519-24 
Protocol Date: 
07 October 2018 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone:  
 
Sponsor Contact: 
 
 
The concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without expressed written authorization of 
Alnylam Pharmaceuticals, Inc. 
 
PPD
PPD

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTR02-008 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
6 
to lower the corticosteroid dose may be made to the premedication regimen as described further 
in the protocol.  
Non-Alnylam Investigational Product, Dose, and Mode of Administration 
Not applicable, open-label study. 
Reference Treatment, Dose, and Mode of Administration 
Not applicable, open-label study 
Duration of Treatment and Study Participation 
The duration of treatment with patisiran-LNP is 12 months.  The estimated total time on study, 
inclusive of screening is up to 14.5 months, due to the requirement for an additional 4 weeks of 
follow-up. 
Statistical Methods 
Sample size assumptions included normally distributed true TTR percent reduction from baseline 
of 80% with a standard deviation of 18%.  Given these assumptions, a sample size of 16 patients 
will yield a 95% confidence interval with a half-width of approximately 10%.  Assuming a 20% 
premature discontinuation rate, approximately 20 patients will be enrolled in the study. 
The populations (analysis sets) are defined as follows:  
 Safety Analysis Set: All patients who received patisiran-LNP.  The Safety Analysis 
Set will be used for the analysis of efficacy and safety assessments.   
 Pharmacokinetic Analysis Set: All patients in the Safety Analysis Set who have 
provided at least one valid post-dose PK concentration value. 
The median TTR percent reduction and 95% confidence interval will be estimated using the 
Hodges-Lehmann method; the TTR percent reduction will also be assessed using the Wilcoxon 
signed-rank test.  Secondary endpoints will be analyzed using summary statistics of observed 
values and changes from baseline for the neuropathy impairment score (NIS) total score and 
component scores.  Patient reported quality of life and disease burden will be assessed by 
summary statistics for the Norfolk QOL-DN and R-ODS.  Patient reported autonomic 
neuropathy symptoms will be assessed by descriptive statistics for the COMPASS 31.  Summary 
statistics will be provided for observed values and changes from baseline.  
Safety data will be summarized with descriptive statistics.  Adverse events will be summarized 
by System Organ Class (SOC) and preferred term (PT) (all events, related events, and serious 
events), in addition to being summarized by severity (all events).  In addition, summaries will be 
provided for any AEs leading to discontinuation of study drug or death. 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
7 
Figure 1: 
Study Design  
Screening Period 
42 days 
Open Label Treatment 
Period 
12 months 
Follow Up Period 
4 weeks 
 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
8 
Table 1: 
Schedule of Assessments 
 
Screening 
Baselinea 
Dosing 
6-Month 
Efficacy
Dosing 
12-Month 
Efficacy
Early 
Termination
Safety 
Follow Up
Study Day  
(±Visit 
Window) 
Notes 
D-42 to -1 
Pre-Dose Day 1 
D1 
W1-2 
W3 ±3D 
W6 & 9 ±3D 
W12 ±3D 
W15 to 21 ±3D 
W24 ±3D 
W25  to WK 
26±3D
W27 to W33 
±3D
W36 ±3D 
W39 to W51 
±3D
W54 ±3D 
W55 to W56 
W57 
Not applicable 
W58 ±3D 
Informed 
Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
See Section 
6.1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Status 
Review 
Section 6.1.3  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NYHA 
Classification 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky 
Performance 
Status 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
PND Score and 
FAP Stage 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
NIS 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Norfolk-DN 
QoL 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
R-ODS 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
COMPASS-31 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
9 
Table 1: 
Schedule of Assessments 
 
Screening 
Baselinea 
Dosing 
6-Month 
Efficacy
Dosing 
12-Month 
Efficacy
Early 
Termination
Safety 
Follow Up
Study Day  
(±Visit 
Window) 
Notes 
D-42 to -1 
Pre-Dose Day 1 
D1 
W1-2 
W3 ±3D 
W6 & 9 ±3D 
W12 ±3D 
W15 to 21 ±3D 
W24 ±3D 
W25  to WK 
26±3D
W27 to W33 
±3D
W36 ±3D 
W39 to W51 
±3D
W54 ±3D 
W55 to W56 
W57 
Not applicable 
W58 ±3D 
Echocardiogra
m with Doppler 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
See 
Section 6.1.7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NT-proBNP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mBMI 
See Section 
6.2.6. 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Serum samples 
for TTR Protein 
See 
Section 6.2.1   
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
Serum samples 
for anti-drug 
antibody 
See 
Section 6.3.3.
1  
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Plasma samples 
for PK 
See 2 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
. 
 
Pregnancy Test 
See Section 
6.3.3.2, 
Section 
6.3.5.7, and 
Table 3 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Exploratory 
DNA  
Sample 
(optional) 
See 
Section 6.5  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
10 
Table 1: 
Schedule of Assessments 
 
Screening 
Baselinea 
Dosing 
6-Month 
Efficacy
Dosing 
12-Month 
Efficacy
Early 
Termination
Safety 
Follow Up
Study Day  
(±Visit 
Window) 
Notes 
D-42 to -1 
Pre-Dose Day 1 
D1 
W1-2 
W3 ±3D 
W6 & 9 ±3D 
W12 ±3D 
W15 to 21 ±3D 
W24 ±3D 
W25  to WK 
26±3D
W27 to W33 
±3D
W36 ±3D 
W39 to W51 
±3D
W54 ±3D 
W55 to W56 
W57 
Not applicable 
W58 ±3D 
Exploratory 
Biomarkers 
(plasma, serum) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Full Physical 
Exam 
See 
Section 6.3.2  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Symptom-
Directed 
Physical Exam 
See 
Section 6.3.2  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
See Section 
6.3.1 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum samples 
for Vitamin A 
See 
Section 6.1.1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
Chemistry,  
including LFTs 
See 
Section 5.2.4.
1  
X 
X 
(albumi
n only) 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
Hematology 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
Adverse Events 
See 
Section 6.3.5.
2  
 
 
 
Continuous 
Concomitant 
Medications 
and Procedures 
See Section 
5.3 
X 
 
 
Continuous 
Liver Allograft 
Status 
See 
Section 6.3.4  
X 
 
 
 
 
 
X 
 
 
 X 
 
X 
 
 
X 
 
X 
 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
11 
Table 1: 
Schedule of Assessments 
 
Screening 
Baselinea 
Dosing 
6-Month 
Efficacy
Dosing 
12-Month 
Efficacy
Early 
Termination
Safety 
Follow Up
Study Day  
(±Visit 
Window) 
Notes 
D-42 to -1 
Pre-Dose Day 1 
D1 
W1-2 
W3 ±3D 
W6 & 9 ±3D 
W12 ±3D 
W15 to 21 ±3D 
W24 ±3D 
W25  to WK 
26±3D
W27 to W33 
±3D
W36 ±3D 
W39 to W51 
±3D
W54 ±3D 
W55 to W56 
W57 
Not applicable 
W58 ±3D 
Weight 
See 
Section 6.1.4 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Premedication 
and Study  
Drug 
Administration 
Phone contact 
for home 
infusions only 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Abbreviations:  COMPASS=Composite Autonomic Symptom Score; DNA=deoxyribonucleic acid; ECG=electrocardiogram; FAP=familial amyloidotic 
polyneuropathy; HIV=human immunodeficiency virus; LFT=liver function test; M=month; mBMI=modified body mass index; NIS=neurological impairment 
scale; NYHA=New York Heart Association; NT-proBNP=N-terminal prohormone of B-type natriuretic peptide; PK=pharmacokinetic; PND=paroxysmal 
nocturnal dyspnea; QoL= quality of life; R-ODS=Rasch-built Overall Disability Scale; TTR=transthyretin; W=week. 
Notes: The Screening visit must be performed within 42 days before the first dose of study drug (Day 1). 
Early termination visit should occur within 7 days of the decision to stop participating in the study. 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
13 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................13 
LIST OF TABLES .........................................................................................................................16 
LIST OF FIGURES .......................................................................................................................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................17 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
Disease Overview .......................................................................................................19 
1.2. 
Patisiran-LNP (ALN-TTR02) .....................................................................................20 
1.3. 
Study Design Rationale ..............................................................................................20 
1.4. 
Dose Rationale ............................................................................................................21 
1.5. 
Benefit-Risk Assessment ............................................................................................21 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
3. 
INVESTIGATIONAL PLAN .....................................................................................23 
3.1. 
Summary of Study Design ..........................................................................................23 
3.2. 
Duration of Treatment ................................................................................................24 
3.3. 
Duration of Study Participants ....................................................................................24 
3.4. 
Number of Planned Patients .......................................................................................24 
3.5. 
Safety Review Committee ..........................................................................................24 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................24 
4.1. 
Inclusion Criteria ........................................................................................................24 
4.2. 
Exclusion Criteria .......................................................................................................25 
4.3. 
Removal from Study Drug or Assessment .................................................................27 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................27 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................28 
4.3.2.1. 
Patient Stops Participation in the Study ......................................................................28 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................28 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................28 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................28 
4.3.3. 
Lost to Follow-Up.......................................................................................................29 
4.3.4. 
Replacement of Study Patients ...................................................................................29 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................29 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
14 
5.1. 
Treatments Administered ............................................................................................29 
5.2. 
Study Drug ..................................................................................................................29 
5.2.1. 
Description ..................................................................................................................29 
5.2.2. 
Dose and Administration ............................................................................................30 
5.2.2.1. 
Home infusion ............................................................................................................31 
5.2.3. 
Suggested Guidelines for Management of Infusion-Related Reactions .....................31 
5.2.4. 
Dose Modifications .....................................................................................................31 
5.2.4.1. 
Liver Function Test Criteria for Withholding, Monitoring and Stopping 
patisiran-LNP Dosing .................................................................................................32 
5.2.5. 
Preparation, Handling, and Storage ............................................................................32 
5.2.6. 
Packaging and Labeling ..............................................................................................32 
5.2.7. 
Accountability .............................................................................................................32 
5.3. 
Concomitant Medications and Procedures .................................................................33 
5.4. 
Treatment Compliance ................................................................................................33 
5.5. 
Other Requirements ....................................................................................................33 
5.5.1. 
Contraception ..............................................................................................................33 
5.5.2. 
Alcohol Restrictions ...................................................................................................34 
6. 
STUDY ASSESSMENTS ..........................................................................................35 
6.1. 
Screening and Baseline Assessments .........................................................................35 
6.1.1. 
Patient Demographic and Medical History/Disease History ......................................35 
6.1.2. 
Vitamin A ...................................................................................................................35 
6.1.3. 
HIV Status Review .....................................................................................................35 
6.1.4. 
Weight and Height ......................................................................................................35 
6.1.5. 
NYHA Classification ..................................................................................................36 
6.1.6. 
Electrocardiogram .......................................................................................................36 
6.1.7. 
Echocardiogram and Biomarkers of Cardiac Function ..............................................36 
6.2. 
Efficacy Assessments .................................................................................................36 
6.2.1. 
TTR Serum Samples ...................................................................................................36 
6.2.2. 
Neurological Testing ..................................................................................................36 
6.2.3. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire ..................................37 
6.2.4. 
Rasch-built Overall Disability Scale ..........................................................................37 
6.2.5. 
Composite Autonomic Symptom Score .....................................................................37 
6.2.6. 
Modified Body Mass Index ........................................................................................37 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
15 
6.2.7. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score ...........................................................................................................................37 
6.2.8. 
Karnofsky Scale ..........................................................................................................37 
6.3. 
Safety Assessments .....................................................................................................38 
6.3.1. 
Vital Signs ..................................................................................................................38 
6.3.2. 
Physical Examination .................................................................................................38 
6.3.3. 
Clinical Laboratory Assessments ...............................................................................38 
6.3.3.1. 
Immunogenicity ..........................................................................................................40 
6.3.3.2. 
Pregnancy Testing ......................................................................................................41 
6.3.3.3. 
Additional Liver Function Assessments .....................................................................41 
6.3.4. 
Liver Allograft Status .................................................................................................41 
6.3.5. 
Adverse Events ...........................................................................................................41 
6.3.5.1. 
Definitions ..................................................................................................................41 
6.3.5.2. 
Eliciting and Recording Adverse Events ....................................................................43 
6.3.5.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................43 
6.3.5.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........44 
6.3.5.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................44 
6.3.5.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................44 
6.3.5.7. 
Pregnancy Reporting ..................................................................................................44 
6.3.5.8. 
Overdose Reporting ....................................................................................................45 
6.4. 
Pharmacokinetic Assessments ....................................................................................45 
6.5. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................45 
7. 
STATISTICS ..............................................................................................................46 
7.1. 
Determination of Sample Size ....................................................................................46 
7.2. 
Statistical Methodology ..............................................................................................46 
7.2.1. 
Populations to be Analyzed ........................................................................................46 
7.2.2. 
Examination of Subgroups .........................................................................................46 
7.2.3. 
Handling of Missing Data ...........................................................................................46 
7.2.4. 
Baseline Evaluations ...................................................................................................47 
7.2.5. 
Safety Analyses ..........................................................................................................47 
7.2.6. 
Efficacy Analyses .......................................................................................................47 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................47 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
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Alnylam Pharmaceuticals 
Confidential 
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7.2.8. 
Immunogenicity Analyses ..........................................................................................48 
7.2.9. 
Optional Additional Research .....................................................................................48 
8. 
STUDY ADMINISTRATION ...................................................................................48 
8.1. 
Ethical and Regulatory Considerations ......................................................................48 
8.1.1. 
Informed Consent .......................................................................................................48 
8.1.2. 
Ethical Review ............................................................................................................48 
8.1.3. 
Serious Breach of Protocol .........................................................................................49 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................49 
8.1.5. 
End of Study ...............................................................................................................50 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................50 
8.2. 
Data Quality Control and Quality Assurance .............................................................50 
8.2.1. 
Data Handling .............................................................................................................50 
8.2.2. 
Study Monitoring ........................................................................................................50 
8.2.3. 
Audits and Inspections ................................................................................................50 
8.3. 
Publication Policy .......................................................................................................51 
9. 
LIST OF REFERENCES ............................................................................................52 
10. 
APPENDICES ............................................................................................................54 
10.1. 
New York Heart Association Classification of Heart Failure ....................................54 
10.2. 
Karnofsky Scale ..........................................................................................................54 
10.3. 
Polyneuropathy Disability Score ................................................................................55 
10.4. 
Familial Amyloidotic Polyneuropathy Stage ..............................................................55 
10.5. 
Categorization of Infusion-Related Reactions ............................................................56 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ..............................................................................................8 
Table 2: 
Pharmacokinetic Time Points .....................................................................................12 
Table 3: 
Clinical Laboratory Assessments ...............................................................................40 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................7 
 

Clinical Study Protocol ALN-TTR02-008 
patisiran-LNP 
Original, 07 October 2018 
Alnylam Pharmaceuticals 
Confidential 
17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibodies 
AE  
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
AUCτ 
Area under the plasma concentration-time curve from time zero to 
infinity 
CLss 
Systemic clearance at steady state 
Cmax 
Maximum (peak) plasma drug concentration 
CRF 
Case report form 
DLin-MC3-DMA 
(6Z, 9Z, 28Z, 31Z)-heptatriaconta-6, 9, 28, 31-tetraen-19-yl-
4(dimethylamino) butanoate 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice 
hATTR 
Hereditary transthyretin 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IB 
Investigational Brochure 
INR 
International normalized ratio  
IRB 
Institutional Review Board 
IRR 
Infusion related reaction 
IV 
Intravenous 
LFT 
Liver function test 
LNP 
Lipid nanoparticle 
MedDRA 
Medical Dictionary for Regulatory Activities 
mBMI 
Modified body mass index 
NIS 
Neuropathy impairment score 
NYHA 
New York Heart Association 
OLT 
Orthotopic liver transplantation 
os 
Oral suspension 

Clinical Study Protocol ALN-TTR02-008 
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Alnylam Pharmaceuticals 
Confidential 
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Abbreviation  
Definition 
PEG2000-C-DMG 
(R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride 
PK 
Pharmacokinetic 
PND 
Paroxysmal nocturnal dyspnoea 
PO 
By mouth 
RNAi 
Ribonucleic acid interference 
ULN 
Upper limit of normal 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
siRNA 
Small interfering RNA 
SmPC 
Summary of product characteristics 
TTR 
Transthyretin 
wt 
Wild type 
 

Clinical Study Protocol ALN-TTR02-008 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a rare autosomal 
dominant, systemic disease caused by a mutation in the transthyretin (TTR) gene leading to the 
extracellular deposition of amyloid fibrils containing both mutant and wild type (wt) TT [Yazaki 
2000; Gillmore 2006]  There are more than 120 reported TTR genetic mutations associated with 
hATTR amyloidosis, and almost all patients are heterozygous for the mutated TTR 
allele [Connors 2003; Ando 2013].  The most common genotype is the valine to methionine 
mutation at position 30 (V30M), accounting for approximately 50% of cases worldwide, and 
occurring primarily in families with heritage from Portugal, Sweden, Japan, and Brazil [Ando 
2013; Ando 2005; Gertz 2015]. 
The cardinal manifestations of hATTR amyloidosis are polyneuropathy and cardiomyopathy.  
The clinical manifestations of the length-dependent, symmetrical polyneuropathy are the result 
of amyloid-mediated injury to large and small peripheral nerve fibers [Ando 2013; Plante-
Bordeneuve 2011; Benson 2007].  Sensory abnormalities include painful dysesthesias in the feet 
and hands, and loss of sensation leading to thermal burns involving the feet and hands and to 
joint injury in the lower limbs.  Progressive muscle atrophy and motor weakness in both lower 
and upper limbs lead to impaired ambulation and inability to perform other activities of daily 
living, such as being able to hold eating utensils or a drinking glass, or button a shirt or zip up a 
coat.  Autonomic dysfunction results in debilitating orthostatic hypotension, severe 
gastrointestinal symptoms (including early satiety, chronic nausea/vomiting, and both diarrhea 
and constipation), bladder dysfunction with recurrent urinary tract infections, and cardiac 
arrhythmias.  Cardiac infiltration with amyloid leads to heart wall thickening and 
cardiomyopathy characterized by heart failure due to diastolic and systolic dysfunction, and 
conduction disturbances and arrhythmias[Ando 2013; Benson 2007; Carvalho 1992; Soares 
2005; Connors 2004].  This constellation of progressive morbidity from amyloid infiltration 
results in severe disability, and wasting due to gastrointestinal malabsorption, malnutrition, and 
cardiac cachexia.  Death usually results from heart failure (including sudden death caused by 
ventricular arrhythmias or electromechanical dissociation) or infection.  The median survival is 
4.7 years following diagnosis[Yazaki 2000; Plante-Bordeneuve 2011] with a reduced survival 
(3.4 years) for patients presenting with cardiomyopathy[Yazaki 2000; Gertz 1992; 
Sattianayagam 2012].  
The liver is the primary source of TTR, and liver transplantation is used in some patients for 
treatment of hATTR amyloidosis [Stangou 2004].  More than 2000 patients have been 
transplanted in the world since 1990, however, morbidity and mortality are substantial.  Patients 
require life-long immunosuppressive medications, with their attendant risks of infection and 
renal injury.  One-year mortality rates of up to 10% have been reported [Okamoto 2009; Bispo 
2009; Herlenius 2004]. 
Liver transplantation eliminates mutant TTR from the circulation, however, wt TTR is produced 
by the liver allograft.  Disease progression occurs in at least one third of hATTR amyloidosis 
patients after a liver transplant, presumably due to continued deposition of wt TTR protein from 
the transplanted liver [Reines 2014; Adams 2013]. 

Clinical Study Protocol ALN-TTR02-008 
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Alnylam Pharmaceuticals 
Confidential 
20 
There is a need for a safe and effective treatment for patients who have disease progression 
following liver transplantation.  By reducing mutant and wt TTR, patisiran-lipid nanoparticle 
(LNP) is anticipated to prevent disease progression in patients with hATTR amyloidosis who 
have progressive disease following orthotopic liver transplant (OLT). 
1.2. 
Patisiran-LNP (ALN-TTR02) 
Patisiran-LNP comprises a small interfering ribonucleic acid (siRNA) which is specific for TTR, 
and is formulated in a lipid nanoparticle (LNP) for the hepatic delivery following an intravenous 
(IV) administration [Akinc 2010; Coelho 2013].  It is designed to significantly suppress liver 
production of both wt and mutant forms of TTR, thereby having the potential to reduce amyloid 
formation and provide clinical benefit to patients with hATTR amyloidosis. 
The nonclinical pharmacology, pharmacokinetics (PK), and toxicology of patisiran-LNP were 
evaluated in a series of in vitro and in vivo studies that have enabled chronic dosing in clinical 
studies.  A summary of the nonclinical data can be found in the patisiran-LNP Investigator’s 
Brochure (IB).  The clinical development program for patisiran-LNP consists of 6 studies 
including 2 Phase 1 studies in healthy volunteers (Studies ALN-TTR02-001 and 
ALN-TTR02-005) and 4 studies in patients with hATTR amyloidosis with polyneuropathy 
(Studies ALN-TTR02-002, ALN-TTR02-003, ALN-TTR02-004, and ALN-TTR02-006).  All of 
the studies have been completed, with the exception of the ongoing, global open-label extension 
Study 006 which is evaluating the long-term safety and efficacy of patisiran-LNP in patients with 
hATTR amyloidosis.  Patisiran-LNP reduced or halted neuropathy progression across motor, 
sensory and autonomic domains, with association with degree of TTR reduction, and provided 
evidence of favorable changes on exploratory cardiac endpoints. 
On 10 August 2018, US FDA approval was granted for the treatment of the polyneuropathy of 
hATTR amyloidosis in adults.  The Committee for Medicinal Products for Human Use adopted a 
positive opinion for the treatment of hATTR amyloidosis in adult patients with Stage 1 or 
Stage 2 polyneuropathy, and the European Commission Decision was granted on 
27 August 2018.  
1.3. 
Study Design Rationale 
This is a global Phase 3b open-label study designed to evaluate the safety, efficacy, and PK of 
patisiran-LNP in patients with hATTR amyloidosis with disease progression after liver 
transplant.  The primary endpoint for the study is the average TTR percent reduction at Month 6 
and Month 12. 
The open-label design is supported by previous studies, including a pivotal Phase 3 double-blind, 
placebo-controlled study.  The clinical benefits seen in the pivotal Phase 3 Study 
ALN-TTR02-004 (APOLLO) were observed in association with an 80% reduction of TTR with 
patisiran within 10 to 14 days after a single dose, which was maintained over the duration of the 
18-month study compared to no change with placebo.  The primary efficacy endpoint in the 
current study, TTR reduction, is an objective measurement and not susceptible to bias of clinical 
study center staff or study patients and therefore does not require a blinded placebo group for 
accurate interpretation. 

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All patients in this study will receive patisiran-LNP treatment.  The study will consist of a 
12 -month treatment period and a 4-week follow up period after the last dose.  The 12-month 
treatment duration will enable collection of safety and efficacy data in patients with hATTR 
amyloidosis with disease progression after liver transplant.  Previous trials support the 12-month 
duration, since beneficial effect on TTR reduction and efficacy endpoints including neuropathy 
impairment score and Norfolk QoL-DN score are evident by 9 months[Adams 2018]. 
1.4. 
Dose Rationale 
The patisiran drug substance is a novel siRNA that is delivered by a LNP.  The LNP facilitates 
siRNA delivery into hepatocytes via an ApoE dependent process.  Upon internalization into 
hepatocytes via endocytosis, the LNP disintegrates, releasing the TTR-targeting siRNA ALN-
18328 into the cytoplasm, where it reduces the production of wt and mutant TTR mRNA via the 
endogenous mechanism of ribonucleic acid interference (RNAi).  A transplanted liver is 
anticipated to have a similar mechanism of LNP uptake and subsequent TTR mRNA gene 
silencing as native liver in hATTR patients. 
The 0.3 mg/kg dose of patisiran-LNP once every 3 weeks was selected based on dose-response 
analysis for TTR reduction from 3 Phase 1 and Phase 2 studies.  This dose was confirmed by the 
pivotal Phase 3 Study ALN-TTR02-004. 
To minimize the risk of IRRs, patients must receive premedication prior to dosing with patisiran. 
Patients will receive the following premedications at least 60 minutes before the start of the 
patisiran-LNP infusion: 
 Intravenous dexamethasone (10 mg) or equivalent 
 Oral paracetamol/acetaminophen (500 mg) or equivalent 
 Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other H2 
blocker dose) 
 Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the study site).  Hydroxyzine 25 mg per oral suspension (os) by 
mouth(PO) or fexofenadine 30 mg or 60 mg PO or cetirizine 10 mg PO may be 
substituted for any patient who does not tolerate IV diphenhydramine or other IV H1 
blocker  
These are the same premedications that were used in previous clinical trials. 
1.5. 
Benefit-Risk Assessment 
Patisiran-LNP obtained marketing approval in the US and EU based on the overall favorable 
risk-benefit profile in previous clinical studies, demonstrating improvement in outcomes of 
neuropathy, quality of life, activities of daily living, and nutritional status in hATTR patients 
with polyneuropathy.  Previous clinical trials have shown a sustained mean serum TTR reduction 
of approximately 80% and a reduction of toxic misfolded TTR oligomers.  The Phase 2 open 
label extension study showed evidence of improvement of neurologic impairment at 24 months, 
as assessed by the mNIS+7 [Adams D 2017].  The randomized, placebo-controlled Phase 3 study 
met its primary efficacy endpoint (change from baseline in mNIS+7 at 18 months) and all 

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secondary endpoints.  Both studies had an acceptable safety profile with similar risks.  Similar 
benefits are expected in patients who have disease progression post liver transplant. 
Infusion-related reactions (IRRs) have been observed in patients treated with patisiran-LNP.  To 
minimize the risk of IRRs, all patients must receive premedication before dosing with 
patisiran-LNP (Section 5).  The infusion may be interrupted or slowed if an infusion related 
reaction (IRR) occurs (Section 5.2.2).   
Patisiran-LNP is contraindicated in patients with a history of severe hypersensitivity 
(eg, anaphylaxis) to patisiran-LNP or any of the excipients. 
Adverse drug reactions reported at a frequency of ≥1/10 (very common) in clinical trial were 
IRR and peripheral edema.  
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of patisiran-LNP may be found in the current edition of the IB.  The IB is to be 
used as the reference safety information for this study.  It will be supplemented by the summary 
of product characteristics (SmPC) in regions where there is an approved label. 

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100 kg or more, patisiran-LNP will be administered at a total dose of 30 mg IV once every 
3 weeks.  Eligibility for this study will be confirmed before administration of the first dose on 
Day 1. 
Patisiran-LNP will be administered as an approximately 80-minute IV infusion (approximately 
1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder 
of the infusion).  In order to reduce the potential for an IRR with patisiran-LNP, all patients on 
this study will receive premedications at least 60 minutes before the start of the patisiran-LNP 
infusion.  Patients who are tolerating their infusions well may be eligible to have a stepwise taper 
of the dose of corticosteroid premedication from 10 mg dexamethasone (or equivalent) to 5 mg 
during the study. 
After the Day 1 visit, patients should return to the clinical site for patisiran-LNP dosing once 
every 3 weeks.  Where applicable country and local regulations allow, eligible patients may 
receive the patisiran-LNP infusions at home by a healthcare professional trained on the protocol 
and delivery of premedications and patisiran-LNP.  
Safety will be assessed throughout the study.  Patients will return to the clinical site for safety 
evaluations at Week 12, 6 month efficacy visit, and 12 month efficacy visit.  Patients will be 
continually assessed throughout the study for adverse events (AEs).  Unscheduled visits for study 
assessments may occur if deemed necessary by the study personnel. 
Efficacy assessments will be performed at baseline, 6 and 12 months. 
3.2. 
Duration of Treatment  
The duration of treatment with patisiran-LNP is 12 months. 
3.3. 
Duration of Study Participants 
It is anticipated that the duration of study participation for a subject or patient will be 
14.5 months (inclusive of a 42-day screening period, 12-month treatment period, and a follow-up 
visit 4 weeks after the last dose of study drug.)   
A patient is considered to have reached the end of the study when they have completed the 
follow up visit (4 weeks) after the last dose of patisiran-LNP.  
3.4. 
Number of Planned Patients 
The planned enrollment for this study is 20 patients. 
3.5. 
Safety Review Committee 
A safety review committee will not be utilized for this study; however, a transplant hepatologist 
will be available for consultation on an as needed basis.   
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 

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Age 
1. Age 18 years (or age of legal consent, whichever is older) or older at the time of informed 
consent. 
Patient and Disease Characteristics 
2. Received an OLT for treatment of documented hATTR amyloidosis ≥12 months before 
the date of informed consent 
3. A documented increase in polyneuropathy disability (PND) score (eg, a PND change 
from I to II, II to IIIA, or IIIA to IIIB) compared to a pre-liver transplant assessment OR 
a documented increase in PND score between any 2 assessments post-liver transplant, 
which in the opinion of the Investigator is due to underlying disease progression 
4. On stable immunosuppressive regimen with ≤10 mg/day of prednisone for at least 
3 months before the date of informed consent 
5. Karnofsky performance status of ≥70% at the time of consent 
6. Vitamin A level greater than or equal to lower limit of normal at Screening Visit  
Informed Consent 
7. Willing and able to comply with the study requirements and to provide written informed 
consent, per local and national requirements. 
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Prior/Concomitant Therapy 
1. Currently taking tafamidis, doxycycline, or tauroursodeoxycholic acid; if previously on 
any of these agents, must have completed a 14-day wash-out before dosing (Day 1) 
2. Currently taking diflunisal; if previously on this agent, must have completed a 3-day 
wash-out before dosing (Day 1) 
3. Received an investigational agent within the last 30 days of anticipated study drug 
administration or 5 half-lives of the study drug, whichever is longer, or are in follow-up 
of another clinical study before study enrollment 
4. Current or past use of inotersen or patisiran-LNP  
Medical Conditions 
5. Liver allograft rejection episodes (chronic, acute, or subacute) or abnormal LFTs 
suggestive of possible allograft rejection in the past 6 months before the date of informed 
consent  
6. Liver function test (including aspartate transaminase, alanine transaminase, and total 
bilirubin) results greater than upper limit of normal at the screening visit based on central 
laboratory evaluation.  International normalized ratio (INR) >1.2 for patients not on 
anticoagulant therapy; INR >3.5 for patients receiving anticoagulant therapy 
7. Known portal hypertension with ascites 

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8. Estimated glomerular filtration rate ≤30 mL/min/1.73 m2 (calculated by a central 
laboratory using the Modification of Diet in Renal Disease formula) at screening visit 
9. Other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune disease) 
10. Known leptomeningeal amyloidosis 
11. Uncontrolled diabetes (episodes of diabetic ketoacidosis or hyperglycemic, hyperosmolar 
nonketotic coma within the prior 9 months) 
12. Active infection with hepatitis B or hepatitis C at screening visit (based on serology at 
central laboratory) 
13. Known human immunodeficiency virus (HIV) infection based on patient’s medical 
history 
14. Hospitalizations for infections in prior 3 months from the time of informed consent, and 
no active infections at screening or baseline 
15. New York Heart Association (NYHA) classification of >2 at screening visit 
16. PND score IV (wheelchair bound or bedridden) 
17. Hospitalizations for congestive heart failure or arrhythmia in the past 3 months before the 
date of informed consent 
18. Malignancy within the last 5 years from the time of informed consent, except for basal or 
squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been 
successfully treated 
19. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation 
20. Unable to comply with requirements of study including premedications required prior to 
patisiran-LNP infusions 
21.  Exclude patients with organ transplants other than liver transplant 
Contraception, Pregnancy, and Breastfeeding 
22. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.5.1.  (NOTE: Contraception is not required in males.) 
23. Female patient is pregnant or breastfeeding. 
Alcohol Use 
24. Unwilling or unable to limit alcohol consumption throughout the course of the study. 
Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine, 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer, approximately 284 mL).  
25. History of alcohol abuse, within the last 12 months before screening, in the opinion of the 
Investigator. 

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4.3. 
Removal from Study Drug or Assessment 
Patients are free to discontinue study drug and/or stop protocol procedural assessments, or 
participation in the study as a whole at any time and for any reason, without penalty to their 
continuing medical care.  The Investigator or the Sponsor may discontinue study drug or stop a 
patient’s participation in the study at any time if this is considered to be in the patient’s best 
interest.  Any discontinuation of treatment or the stopping of the patient’s participation in the 
study must be fully documented in the electronic case report form (eCRF), and should be 
followed up by the Investigator.   
Discontinuation of study drug or declining procedural assessments is described in Section 4.3.1 
while the stopping of a patient’s participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
 Significant violation of the protocol 
 Adverse event (AE) 
 Non-adherence to treatment regimen 
 Pregnancy 
 Lost to follow-up 
 Other reason (non-AE) 
 Or, study is terminated by the Sponsor 
The Investigator will confer with the Sponsor or Medical Monitor before discontinuing dosing in 
the patient.  Patients who are pregnant will be discontinued from study drug dosing immediately 
(see Section 6.3.5.7  for reporting and follow-up of pregnancy).  A positive urine pregnancy test 
should be confirmed by a serum pregnancy test before discontinuing the study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study.  In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments 
through the 12-month efficacy visit and approximately 4 weeks after the last dose so that their 
experience is captured in the final analyses.   
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 1), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, through family or friends, or from options not 
involving patient contact, such as communication with other treating physicians or from review 
of medical records), including endpoints and AEs, and must document this decision in the 
patient’s medical records. 
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.3.5.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the appropriate section of the eCRF.  Patients who discontinue study drug 

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and remain on study may receive treatment consistent with local standard practice for their 
disease per Investigator judgment, as applicable.  Safety will be captured for the entire duration 
of study for patients who discontinue study drug. 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient Stops Participation in the Study 
A patient may stop participation in the study at any time.  A patient considering stopping 
participation in the study should be informed that they can discontinue study drug and/or decline 
procedural assessments and remain in the study for the collection of important study data as 
described in Section 4.3.1.  If a patient still chooses to discontinue study drug and stop 
participation in all follow-up, every effort should be made to conduct the end of study 
assessments within 4 weeks of the last dose (see Table 1).   
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study.  Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data 
Where allowed by local law, the patient may decide to withdraw consent to collect, store, and 
use biological samples and, as applicable, other personal data, informing the study doctor at any 
time in writing or in any other form that may be locally required.  The Sponsor will continue to 
keep and use the patient’s study information (including any data resulting from the analysis of 
the patient’s biological samples until the time of withdrawal) according to applicable law.  The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements.  
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible.  If a patient’s study participation is stopped due to an AE, 
including SAEs, the event should be followed as described in Section 6.3.5. 

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4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center.  The following actions 
must be taken if a patient fails to return to the clinic for a required study visit: 
 The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes to continue in the study, and/or should 
continue in the study.  
 Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, 
if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the patient’s 
medical record. 
 Should the patient continue to be unreachable, the patient will be considered to have 
stopped participation in the study. 
 For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status.  This 
ensures that the outcome of the study is as comprehensive as possible. 
4.3.4. 
Replacement of Study Patients 
Patients who discontinue the study drug or stop participation in the study will not be replaced.  
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of patisiran-LNP is 
provided in the Pharmacy Manual. 
5.2.1. 
Description 
Patisiran Solution for IV infusion is RNAi therapeutic consisting siRNA targeting TTR 
messenger RNA (mRNA) in the liver formulated in a LNP.  The patisiran drug product is a 
sterile formulation of siRNA (ALN-18328), formulated as LNPs with lipid 4 excipients (DLin-
MC3-DMA, 1,2-Distearoyl-sn-glycero-3-phosphocholine [DSPC], cholesterol, and PEG2000-C-
DMG) in isotonic phosphate buffered saline.  Patisiran Solution for intravenous infusion contains 
2 mg/mL of patisiran. 

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5.2.2. 
Dose and Administration 
Patients will receive 0.3 mg/kg patisiran-LNP IV once every 3 weeks for 12 months.  Dosing is 
based on actual body weight.  For patients weighing 100 kg or more, patisiran-LNP will be 
administered at a total dose of 30 mg IV once every 3 weeks.  Patisiran-LNP will be 
administered as an approximately 80 minute IV infusion (approximately 1 mL/minute for the 
first 15 minutes followed by approximately 3 mL/minute for the remainder of the infusion). 
Prior to each dose of patisiran-LNP, patients will receive the following premedications in order 
to reduce the risk of experiencing an IRR at least 60 minutes before the infusion:  
 Intravenous dexamethasone (10 mg) or equivalent 
 Oral paracetamol/acetaminophen (500 mg) or equivalent 
 Intravenous H2 blocker (ranitidine 50 mg, famotidine 20 mg, or equivalent other 
H2 blocker dose) 
 Intravenous H1 blocker: diphenhydramine 50 mg (or equivalent other IV H1 blocker 
available at the clinical site).  Hydroxyzine 25 mg per os (PO) or fexofenadine 30 mg 
or 60 mg PO or cetirizine 10 mg PO may be substituted for any patient who does not 
tolerate IV diphenhydramine or other IV H1 blocker. 
Patients will be started on the above premedication regimen.  However, modifications to lower 
the corticosteroid dose may be made to the premedication regimen for either of the following 2 
reasons: 
 If a patient is having difficulty tolerating the corticosteroid premedication regimen 
(eg, patient develops uncontrolled hyperglycemia, altered mental status, or other 
complication), then lowering of the corticosteroid premedication may be allowed for 
that patient after consultation with the Medical Monitor.  
 If a patient has tolerated 3 or more infusions of patisiran-LNP with the current steroid 
premedication regimen (ie, patient has not had any IRRs), then lowering of the steroid 
premedication is recommended. 
Corticosteroid tapering should be performed in the clinic.  If an individual patient’s steroid 
premedication will be lowered, then the following steps must be followed: 
1. If the current corticosteroid dose is 10 mg or less of intravenous dexamethasone or 
equivalent, then subsequent doses will be lowered in steps of no greater than 2.5 mg each 
time. 
2. After each lowering of intravenous dexamethasone or equivalent, the patient must receive 
3 consecutive intravenous doses of patisiran-LNP at that corticosteroid dose without 
experiencing an IRR and before further reductions in corticosteroid premedications.   
3. The premedication corticosteroid dose will not be reduced below 5 mg intravenous 
dexamethasone or equivalent. 
If a patient experiences an IRR, then proceed to Section 5.2.3. 

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5.2.2.1. 
Home infusion 
Home infusion will be allowed if approved by local regulatory authorities.  Home infusions are 
allowed if the patient has tolerated at least 3 infusions well in the clinic. 
Patients who are receiving patisiran-LNP infusions at home will have a phone contact with the 
site at least every 30 (±5) days.  Patients will also have visits at the clinical site at Weeks 12, 26 
and 52.  
5.2.3. 
Suggested Guidelines for Management of Infusion-Related Reactions 
In the event of an IRR, the infusion of patisiran-LNP may be slowed or stopped and the patient 
closely monitored until resolution of the reaction.  Drugs that may be used to facilitate resolution 
and permit resumption of patisiran-LNP administration include, but are not limited to: 
paracetamol/acetaminophen (or equivalent), additional histamine H1/H2 receptor antagonists 
(eg, ranitidine), NSAIDs, adrenaline, supplemental oxygen, IV fluids, and/or corticosteroids. 
Following resolution of a mild or moderate IRR that required interruption of the patisiran-LNP 
infusion, resumption of administration may occur at the Investigator’s discretion at a slower 
infusion rate for that dose and for all subsequent doses of patisiran.  If the infusion is delayed, the 
infusion should be completed no more than 16 hours after preparation of the solution for 
infusion.   
Patisiran-LNP administration should not be resumed for any patient following a severe IRR until 
the case is discussed with the Medical Monitor. 
If after consultation with the Medical Monitor it is agreed that an individual patient’s steroid 
premedication should be increased then the following steps are recommended: 
 If the IRR occurred while the patient received 10 mg intravenous dexamethasone or 
equivalent at least 60 minutes before the infusion and did not resolve with slowing of 
the infusion rate, then the patient should be increased by multiples of 5 mg 
intravenous dexamethasone or equivalent at least 60 minutes before the infusion 
and/or 5 mg oral dexamethasone or equivalent the night before the intravenous 
infusion.  
 Increased dose of premedication steroids should NOT exceed the combination of 
20 mg intravenous dexamethasone or equivalent on the day of infusion and 8 mg oral 
dexamethasone or equivalent taken the night before the infusion.  
 If the IRR occurred while the patient received less than 10 mg intravenous 
dexamethasone or equivalent, then the patient should return to the prior dose of 
intravenous dexamethasone or equivalent that did not result in an IRR. 
Patients will be instructed to call the Investigator if they experience symptoms such as fever, 
chills, myalgia, or nausea/vomiting after discharge from the site.  For categorization of IRRs, see 
Section 10.5. 
5.2.4. 
Dose Modifications 
Dose modifications are not permitted.  

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5.2.4.1. 
Liver Function Test Criteria for Withholding, Monitoring and Stopping 
patisiran-LNP Dosing  
Liver function tests (LFT) will be evaluated throughout the study.  
For any alanine transaminase (ALT) or aspartate transaminase (AST) elevation >3× upper limit 
of normal (ULN):  
a. Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but 
no later than 7 days. 
b. Contact the patient's liver transplant doctor to discuss and agree on appropriate work-
up which can include repeat lab testing (central lab), immunosuppressive drug levels, 
and/or liver biopsy if allograft rejection is suspected. 
c. Contact the medical monitor as soon as possible and optimally within 72 hours to 
discuss appropriate work-up and whether patisiran administration should be 
continued, temporarily held or permanently discontinued. 
d. If the patient has ALT or AST elevation 3×ULN or potential or confirmed event of 
liver transplant rejection, the Sponsor (or designee) should be notified using  a 
supplemental AEs of Clinical Interest eCRF or serious adverse event (SAE) eCRF 
(Section 6.3.5). 
5.2.5. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of patisiran-LNP doses, according to procedures detailed in the Pharmacy Manual.  
No special procedures for the safe handling of study drug are required. 
Study drug will be stored upright and refrigerated at approximately 2 to 8°C.  Deviations from 
the recommended storage conditions should be reported to the Sponsor and use of the study drug 
halted until authorization for its continued use has been provided by the Sponsor or designee, as 
described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual. 
5.2.6. 
Packaging and Labeling 
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practice specifications, and applicable local regulations.  Study drug labels and 
external packaging will include all appropriate information as per local labeling requirements.  
Additional details are available in the Pharmacy Manual. 
5.2.7. 
Accountability 
The Investigator or designee according to local regulations will maintain accurate records of 
receipt and the condition of the study drug supplied for this study, including dates of receipt.  In 
addition, accurate records will be kept of when and how much study drug is dispensed and 
administered to each patient in the study.  Any reasons for departure from the protocol 
dispensing regimen must also be recorded. 

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At the completion of the study, there will be a final reconciliation of all study drug.  Used, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study center according to applicable regulations. 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s case report 
form (CRF) as specified in the Schedule of Assessments (see Table 1).  Concomitant 
medications include all prescription medications, herbal preparations, over the counter 
medications, vitamins, and minerals.  Any changes in medications during the study will also be 
recorded on the CRF.   
Use of the medications/treatments listed below is not permitted during the study: 
 Tafamidis 
 Diflunisal 
 Doxycycline/TUDCA 
All patients will be asked to continue to take the recommended daily allowance of vitamin A 
during the study.  If required by local regulations, clinical sites will provide patients with a 
prescription for vitamin A. 
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated.   
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  It is the responsibility of the Investigator to ensure that details regarding the 
medication are recorded on the CRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
If available, information from a cardiac technetium scan or liver biopsy before study enrollment 
or during the study (as part of standard of care) should be collected and recorded as part of 
concomitant procedure information. 
Patients will be monitored for possible liver allograft rejection; any biopsies performed to rule 
out allograft rejection will be evaluated and recorded as a concomitant procedure.  Liver allograft 
status will include checking and recording immunosuppressive drug levels. 
5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals.  
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 90 days 

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after last dose administration or until study completion.  Pediatric/adolescent female patients 
must initiate contraception at menarche or must discontinue study drug.   
Birth control methods which are considered acceptable highly effective include: 
 Placement of an intrauterine device 
 Placement of an intrauterine hormone-releasing system 
 Bilateral tubal occlusion 
 Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
 Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception. 
 True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods, if they 
start heterosexual relationships during the study and for up to 90 days after the last 
dose of study drug. 
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of childbearing potential include female patients who have experienced menarche or 
begin menarche over the course of the study, and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required.  However, contraception use by males should be 
consistent with local regulations as described in the corresponding patient informed consent 
forms.  
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study.   
5.5.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine, approximately 125 mL = 1 measure of 
spirits, approximately 1 fluid ounce = ½ pint of beer, approximately 284 mL) for the duration of 
the study. 

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6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1.  Additional information on the 
collection of study assessments will be detailed in the Study Manual. 
6.1. 
Screening and Baseline Assessments 
An informed consent form (ICF) that has been approved by the appropriate Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) must be signed by the patient before the 
Screening procedures are initiated.  All patients will be given a copy of the signed and dated ICF.  
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Patient demographic data and medical history/disease history will be 
obtained.  Any changes to medical history occurring between the screening assessment and 
Day 1 will be updated before study drug administration.  An interval medical history will be 
collected at the Screening and Baseline visit.  Only changes since the Screening visit will be 
collected.  Medical history will capture transplant history and evidence for disease progression. 
6.1.1. 
Patient Demographic and Medical History/Disease History 
Patient demographic data and medical history/disease history will be obtained (including any 
cardiac disorders, any eye disorders or previous ophthalmology test results, and prior 
medications).  Any changes to medical history occurring between the screening assessment and 
Day 1 will be updated before study drug administration.  An interval medical history will be 
collected at the Screening and Baseline visit.  Only changes since the Screening visit will be 
collected.  Medical history will capture transplant history and evidence for disease progression. 
6.1.2. 
Vitamin A 
Vitamin A levels must be obtained and evaluated at Screening.  If vitamin A is not greater than 
or equal to lower limit of normal at Screening, it can be repleted and vitamin A level evaluation 
repeated during screening visit.   
The primary physiological role of TTR is to serve as a carrier of retinol (also known as vitamin 
A), which involves TTR binding to the retinol binding protein vitamin A complex.  By reducing 
serum TTR protein, patisiran-LNP treatment leads to a decrease in vitamin A levels measured in 
the serum.  Supplementation at the recommended daily amount of vitamin A is advised for 
patients taking patisiran-LNP.  Laboratory tests for serum vitamin A do not reflect the total 
amount of vitamin A in the body and should not be used to guide vitamin A supplementation 
beyond the recommended daily dose during treatment with patisiran-LNP.  Clinical sites may 
provide patients with a prescription for vitamin A depending on local requirements (Section 5.3). 
6.1.3. 
HIV Status Review 
At the Screening visit, Investigator will inquire into the patient’s HIV status and will record this 
information.  
6.1.4. 
Weight and Height 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 

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(Table 1) and will be recorded in the eCRF.  Weight from prior or current visit should be used 
for calculating dose. 
6.1.5. 
NYHA Classification 
All patients will be screened using the NYHA classification, as outlined in Table 1 . 
6.1.6. 
Electrocardiogram 
Twelve-lead electrocardiograms (ECGs) reporting rhythm, ventricular rate, RR interval, PR 
interval, QRS duration, and QT interval and Fridericia corrected QT interval (QTcF) will be 
obtained, as specified in the Schedule of Assessments (Table 1).  Patients should be supine for at 
least 5 minutes before each ECG is obtained.  All ECGs are to be obtained in triplicate and read 
locally by the PI or delegated physician. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
Recordings will be archived according to the Study Manual. 
6.1.7. 
Echocardiogram and Biomarkers of Cardiac Function 
Cardiac structure and function will be assessed through echocardiograms and measurement of 
serum levels of the cardiac biomarkers N-terminal prohormone of B-type natriuretic peptide 
(NT-proBNP) at the time points specified in Table 1. 
Echocardiograms will be performed and interpreted locally at the clinical trial center at baseline 
only.  Image acquisition, storage, and transfer guidelines will be provided in a Study Manual.  
Blood samples will be drawn to measure levels of NT-proBNP.  Details on sample collection, 
processing, and storage will be provided in a Study Laboratory Manual. 
6.2. 
Efficacy Assessments 
Efficacy will be assessed at Baseline, Month 6, and Month 12.  The specific timing for each 
assessment is presented in Table 1.  On days that study drug is administered, efficacy 
assessments will be performed predose. 
Further details on performing the efficacy assessments will be provided in the Study Reference 
Manual.  
6.2.1. 
TTR Serum Samples 
Blood for serum TTR levels will be collected at scheduled time points specified in Table 1 
before the administration of patisiran-LNP.  Serum TTR will be assessed using enzyme linked 
immunosorbent assay (ELISA).  Samples for TTR measurements will be taken pre-dose on 
infusion days.  Details regarding sample volumes to be collected, and the processing, shipping, 
and analysis of the samples will be provided in the Laboratory Manual. 
6.2.2. 
Neurological Testing 
Neurological testing will be performed by a neurologist and the results of these tests will be used 
to calculate the Neuropathy Impairment Score (NIS).  The NIS, a composite neurologic 

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impairment score, was developed at the Mayo Clinic initially for evaluation of diabetic 
polyneuropathy.  The NIS is an assessment of motor weakness (NIS-W), sensation (NIS-S) and 
reflexes (NIS-R) scored based on physical exam findings.  The score range is from 0 to 244 
points. 
The NIS will be performed at the time points specified in Table 1   
6.2.3. 
Norfolk Quality of Life - Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk Quality of Life-Diabetic Neuropathy 
(QOL-DN) questionnaire.  The Norfolk QoL-DN scale is a patient-reported assessment that 
evaluates the subjective experience of neuropathy in the following domains: physical 
functioning/large fiberneuropathy, activities of daily living, symptoms, small fiber neuropathy, 
and autonomic neuropathy.  The version of the Norfolk QoL-DN that was used in the trial had a 
total score range from -4 to 136, with higher scores representing greater impairment.  The 
questionnaire will be administered at the time points specified in Table 1 . 
6.2.4. 
Rasch-built Overall Disability Scale 
An assessment of the disability each patient experiences will be assessed through the Rasch-built 
Overall Disability Scale (R-ODS) at the time points specified in Table 1.  The R-ODS is a 
questionnaire completed by the patient that consists of a 24-item linearly weighted scale that 
specifically captures activity and social participation limitations in patients. 
6.2.5. 
Composite Autonomic Symptom Score 
To evaluate changes in autonomic symptoms, patients will complete the Composite Autonomic 
Symptom Score (COMPASS 31) questionnaire.  The questionnaire consists of 31 clinically 
selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, 
gastrointestinal, bladder, and pupillomotor). 
6.2.6. 
Modified Body Mass Index 
Sites will measure body weight on all dosing days.  Using that data, the modified body mass 
index (mBMI = BMI x albumin) will be calculated programmatically and does not need to be 
performed at the study center.   
6.2.7. 
Familial Amyloidotic Polyneuropathy Stage and Polyneuropathy Disability 
Score 
Changes in ambulation will be evaluated through the polyneuropathy disability (PND) score and 
familial amyloidotic polyneuropathy (FAP) stage as specified in Table 1 (see Section 10.3 and 
Section 10.4). 
6.2.8. 
Karnofsky Scale 
The Investigator will assess all patients according to the Karnofsky Scale as specified in Table 1 
(see Section 10.2). 

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6.3. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs 
including SAEs, recording of concomitant medication and measurements of vital signs, weight 
and height, and ECG findings and laboratory tests.  Clinically significant abnormalities observed 
during the physical examination are recorded.  
6.3.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include 
blood pressure, pulse rate, temperature, and respiratory rate.  Vital signs will be measured 
predose in the supine position using an automated instrument after the patient has rested 
comfortably for 10 minutes.  Blood pressure should be taken using the same arm throughout the 
study.  Body temperature in degrees Celsius will be obtained via oral, tympanic, or axillary 
methods.  Heart rate will be counted for a full minute and recorded in beats per minute, and 
respiration rate will be counted for a full minute and recorded in breaths per minute.  On Day 1, 
vital signs will also be collected post-dose. 
Additional vital sign assessments, as medially indicated, may be added at the discretion of the 
Investigator. 
6.3.2. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1).  If a physical examination is scheduled for a dosing visit, it should be 
conducted before dosing.  Full physical examinations will include the examination of the 
following:  general appearance; head, eyes, ears, nose, and throat; respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, and dermatological systems; thyroid; lymph nodes; and 
neurological status.   
Symptom-directed physical examinations will be guided by evaluation of changes in symptoms, 
or the onset of new symptoms, since the last visit. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.3.3. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  Specific 
instructions for transaminase elevations are provided in Section 5.2.4.1.  For any other 
unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the Investigator, 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality.  Additional safety laboratories and assessments as indicated by the 
clinical situation may be requested.  Clinical laboratory assessments are listed in Table 3 and 
assessments will be assessed as specified in the Schedule of Assessments (Table 1). 
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the clinic visit assessments, all laboratory assessments specified in Table 3 which are performed 
at the clinic should also be sent in parallel to the central laboratory.  In the case of discrepant 

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local and central laboratory results on samples drawn on the same day, central laboratory results 
will be relied upon for clinical and dosing decisions. 
Clinical laboratory assessments may be collected at the clinical study center or at home by a 
trained healthcare professional. 
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 
 

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Table 3: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
Neutrophils, absolute and % 
Hematocrit 
Lymphocytes, absolute and % 
Hemoglobin 
Monocytes, absolute and % 
RBC count 
Eosinophils, absolute and % 
White blood cell (WBC) count 
Basophils, absolute and % 
Mean corpuscular volume 
Platelet count 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Serum Chemistry 
Sodium 
Glucose 
Potassium 
Phosphate 
BUN 
Albumin 
Creatinine 
Calcium 
Bicarbonate 
Chloride 
Liver Function Tests 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Immunogenicity (see Section 6.3.3.1) 
Antidrug antibodies 
 
Pregnancy Testing (Females of childbearing potential only, Section 6.3.3.2) 
β-human chorionic gonadotropin 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; RBC=red blood cell; WBC=white 
blood cell. 
 
6.3.3.1. 
Immunogenicity 
Serum blood samples will be collected to evaluate antidrug antibodies.  Blood samples for 
antidrug antibody testing must be collected before study drug administration as specified in the 
Schedule of Assessments (Table 1).  Anti-PEG2000-C-DMG antibody measurements will be taken 
predose on infusion days. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 

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6.3.3.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of childbearing potential.  A serum pregnancy 
test will be performed at Screening and Baseline, and urine pregnancy tests at all study visits 
thereafter per the Schedule of Assessments and any time pregnancy is suspected.  The results of 
the pregnancy test must be known before study drug administration.  Patients who are pregnant 
are not eligible for study participation.  Any woman with a positive pregnancy test during the 
study will be discontinued from study drug, but will continue to be followed for safety.  Patients 
determined to be pregnant while on study will be followed until the pregnancy outcome is known 
(see Section 6.3.5.7 for follow-up instructions).  
6.3.3.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.4.1.  Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 1 will 
be performed one time, and hematology, serum chemistry, LFT, and coagulation assessments 
from Table 3, and other assessments or evaluations per Investigator discretion, as appropriate. 
Monitoring and dose modification will also be performed as outlined in Section 5.2.4.1. 
6.3.4. 
Liver Allograft Status 
Patients will be monitored for possible liver allograft rejection; any biopsies performed to rule 
out allograft rejection will be recorded as a concomitant procedure.  Liver allograft status will 
include checking and recording immunosuppressive drug levels every 3 months. 
6.3.5. 
Adverse Events 
6.3.5.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an AE is any 
untoward medical occurrence in a patient or clinical investigational subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 

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 Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Events of Clinical Interest 
This study enrolls patients who have received a liver transplant.  Liver function abnormalities are 
not an identified risk of patisiran-LNP treatment; however, for purposes of this study given the 
patient population, the following events will be considered events of interest: ALT or AST 
elevations > 3 x ULN, or potential or confirmed events of liver transplant rejections. 
For information on recording and reporting of AEs of clinical interest, see Section 6.3.5.2 and 
Section 6.3.5.3, respectively. 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, shopping for 
groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living (ie, bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden); OR life-threatening consequences; urgent 
intervention indicated; OR death related to an adverse event. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of 
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” 

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6.3.5.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in the patient’s health since the 
last visit.  The patient should also be asked if the patient has been hospitalized, had any 
accidents, used any new medications, or changed concomitant medication routines (both 
prescription and over-the-counter).  In addition to patient observations, AEs will be documented 
from any clinically relevant laboratory findings, physical examination findings, ECG changes, or 
other findings that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
study drug through the end of study.  Non-serious AEs will be followed until the end of study.  
Events occurring after signing of the ICF and before study drug administration will be captured 
as medical history (see Section 6.1), while AEs that occur after study drug administration, and  
baseline events that worsen after study drug administration, must be recorded as AEs.   
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study drug 
through the end of study.  SAEs will be followed until satisfactory resolution, until baseline level 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
All IRRs will be recorded as AEs.  All information on IRRs is to be recorded on the applicable 
eCRF per the CRF completion guidelines. 
If patients develop ocular symptoms suggestive of vitamin A deficiency, for example, reduced 
night vision or night blindness, the Investigator should consult with the Medical Monitor to 
determine if an ophthalmological assessment is needed.  Any information collected during an 
ophthalmological assessment should be recorded in the AE eCRF and reports or images of 
ophthalmological assessments should be collected as well. 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form.  
For AEs that are considered AEs of clinical interest (Section 6.3.5.1), the Sponsor or its designee 
should complete the supplemental AEs of Clinical Interest eCRF.  Additional clinical and 
laboratory information may be collected.  Refer to CRF completion guidelines for details on 
reporting events in the supplemental AEs of Clinical Interest eCRF.   
6.3.5.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.3.5.1), the Sponsor or its designee 
should be notified within 24 hours using a supplemental AEs of Clinical Interest eCRF. 

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6.3.5.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.3.5.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
 Patient’s study number 
 Description and date of onset of the event 
 Criterion for serious 
 Preliminary assignment of relationship to study drug, and 
 Investigator/site information 
To report the SAE, complete the eCRF and, as applicable, the SAE form.  Within 24 hours of 
receipt of follow-up information, the Investigator must update the eCRF and, as applicable, the 
SAE form.  SAEs must be reported using the contact information provided in the Study Manual. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable.  Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.3.5.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Directive 2001/20/EC, and to all country regulatory authorities where the 
study is being conducted, according to local applicable regulations. 
6.3.5.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions will be reported to the IRB/IEC per their 
institutional policy by the Investigator or Sponsor (or Sponsor designee) according to country 
requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.3.5.7. 
Pregnancy Reporting 
If a patient becomes pregnant during the study through the first month following the last dose of 
study drug, the Investigator must report the pregnancy to the Sponsor or designee within 
24 hours of being notified of the pregnancy.  Details of the pregnancy will be recorded on the 
pregnancy reporting form.  The patient should receive any necessary counseling regarding the 
risks of continuing the pregnancy, the possible effects on the fetus, and be counseled to not 
breastfeed for 90 days after the last dose of study drug.  

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The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 
or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 6.3.5.4. 
6.3.5.8. 
Overdose Reporting 
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency, than included in the 
protocol.  The investigator will decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.  In the event of an overdose, the actual dose administered must be 
recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for evaluation of PK parameters for ALN-18328 and 2 novel 
lipids (DLin-MC3-DMA and PEG2000-C-DMG) at the visits in the Schedule of Assessments 
(Table 1).  A detailed schedule of PK time points for the collection of blood samples is in 
Table 3. 
Details regarding sample volumes to be collected, and the processing, shipping, and analysis of 
the samples will be provided in the Laboratory Manual. 
6.5. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect. 
More generally, genetic variations may account for the well-described heterogeneous 
manifestations of disease in patients with hATTR amyloidosis, and their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/EC) approval, and patient consent, 
samples will be collected as part of this study to permit exploratory investigations and the 
application of novel approaches to bioanalyses that may further elucidate the outcomes of this 
study, or potentially advance understanding of the safety, mechanism of action, and/or efficacy 
of patisiran-LNP.   
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
Table 1.  Potential exploratory investigations may include DNA, RNA, or biochemical 
metabolite assessments as they relate to disease progression, efficacy, or safety.  
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc.) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 

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Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principle features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
Assuming a normally distributed true TTR percent reduction from baseline of 80% with a 
standard deviation of 18%, a sample size of 16 patients will yield a 95% confidence interval with 
a half-width of approximately 10%.  Assuming a 20% premature discontinuation rate, 
approximately 20 patients will be enrolled in the study. 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the SAP.  Changes to the methods described in the final 
SAP will be described and justified as needed in the clinical study report.  For information on 
study endpoints, see Section 2  
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
 Safety Analysis Set: All patients who received patisiran-LNP.  The Safety Analysis 
Set will be used for the analysis of efficacy and safety assessments.   
 Pharmacokinetic Analysis Set: All patients in the Safety Analysis Set who have 
provided at least one valid post-dose PK concentration value. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 

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7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized.  Data to be 
tabulated will include gender, age, race, and disease-specific information. 
7.2.5. 
Safety Analyses 
A summary of exposure to patisiran, including the durations of the infusions and doses, will be 
produced. 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be summarized by the MedDRA system organ class and preferred term.  
Separate tabulations will be produced for all treatment emergent AEs, treatment-related AEs, 
(SAEs, discontinuations due to AEs, and AEs by severity.  By-patient listings will be provided 
for deaths, SAEs, and AEs leading to discontinuation of treatment. 
Prior and concomitant medications will be classified according to the World Health Organization 
drug dictionary.  Results will be tabulated by anatomic therapeutic class and preferred term. 
Descriptive statistics will be provided for clinical laboratory data, ECG, and vital signs data.  
Laboratory shift tables from baseline to worst values will be presented. 
7.2.6. 
Efficacy Analyses 
Summary tables and graphical displays of observed values and changes from baseline in serum 
TTR will be used to assess the durability of suppression over the course of the study.  The 
primary endpoint is the average TTR percent reduction across Month 6 and Month 12.  The 
median TTR percent reduction along with the 2-sided 95% confidence interval will be estimated 
using the Hodges-Lehmann method.  The p-value for the TTR percent reduction will be obtained 
using the Wilcoxon signed-rank test 
Summary statistics of observed values and changes from baseline will be provided for the NIS 
total score and component scores.   
Patient reported quality of life and disease burden will be assessed by summary statistics for the 
Norfolk QOL-DN and R-ODS.  Patient reported autonomic neuropathy symptoms will be 
assessed by descriptive statistics for the COMPASS 31.  Summary statistics will be provided for 
observed values and changes from baseline.   
Descriptive statistics will also be provided for observed values and changes from baseline in 
nutritional status (mBMI), functional impairment (Karnofsky Performance Status), and 
ambulation (FAP stage and PND score). 
Results of echocardiograms will be summarized.  
7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be performed using noncompartmental analysis methods.   
The following PK parameters will be estimated:  maximum plasma concentration (Cmax), time to 
maximum plasma concentration (tmax), terminal elimination half-life (t½β), area under the 
concentration-time curve during a dosing interval (AUCτ), systemic clearance at steady state 

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(CLss), and apparent volume of distribution at steady state (Vss), and accumulation ratio for PK 
exposure parameters (Rac).  Additional PK parameters may be calculated, if deemed necessary.  
7.2.8. 
Immunogenicity Analyses 
Number of patients with confirmed positive antidrug antibodies (ADA) results will be 
summarized by visit and overall.  Titer will be summarized by visit and overall.  Patients with 
both pre- and post- treatment ADA assay results will be used to calculate incidence of treatment 
emergent ADA. 
7.2.9. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the informed consent form 
(see Section 6.1).  
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP).  Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study.  Patients must also 
be notified that they are free to discontinue from the study at any time.  The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
tests or procedures that are not part of routine care.  
The Investigator must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the patient. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study.  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 

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Initial IRB approval of the protocol, and all materials approved by the IRB for this study 
including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.3.5.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB or IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug.  The Sponsor 
or designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a serious 
breach of the protocol.  A serious breach is a breach that is likely to affect to a significant degree 
the safety and rights of a study participant or the reliability and robustness of the data generated 
in the clinical trial. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for 2 years after the last approval in an 
ICH territory or as locally required, whichever is longer.  If it becomes necessary for the 
Sponsor, the Sponsor’s designees, applicable IRB/IEC, or applicable regulatory authorities to 
review or audit any documentation relating to the study, the Investigator must permit direct 
access to all source documents/data.  Records will not be destroyed without informing the 
Sponsor in writing and giving the Sponsor the opportunity to store the records for a longer period 
of time at the Sponsor’s expense.  
The Investigator must ensure that the patients’ confidentiality will be maintained.  On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document.  Documents not for submission to the Sponsor 
(eg, signed ICFs) should be maintained by the Investigator in strict confidence.  
The Investigator must treat all information related to the study and the complied data as 
confidential, whose use is for the purpose of conducting the study.  The Sponsor must approve 
any transfer of information not directly involved in the study. 

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To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClincalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor reserves the right to terminate the study for clinical or administrative reasons at any 
time.  If the site does not recruit at a reasonable rate, or if there is insufficient adherence to the 
protocol requirements, the study may be closed at that site.  Should the study be terminated 
and/or the site closed for whatever reason, all documentation and study drug pertaining to the 
study must be returned to the Sponsor or its representative, and the Investigators, IEC/IRB, and 
regulatory authorities will be promptly informed of the termination and the reason for the 
decision.  The Investigator should promptly inform the patients and assure appropriate therapy 
and follow-up.  
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor.  Case report forms must be completed only by persons 
designated by the Investigator.  If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system.  All data entered into the eCRF must 
also be available in the source documents.  Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site.  The monitor will visit the Investigator and clinical study center periodically 
and will maintain frequent telephone and written contact.  The monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems, and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately.  The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study.  The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 

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were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The Investigator should contact the Sponsor, or its designee, immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A separate publication by 
Institution or Investigator may not be submitted for publication until after this primary 
manuscript is published, or following the period of 18 months after completion of the study at all 
centers.  A copy of any proposed publication (eg, manuscript, abstracts, oral/slide presentations, 
book chapters) based on this study, must be provided and confirmed received at the Sponsor at 
least 30 days before its submission.  The Clinical Trial Agreement among the institution, 
Investigator, and Alnylam will detail the procedures for Alnylam’s review of publications. 
Authorship of any publications resulting from this study will be determined basis on the Uniform 
Requirement for Manuscripts Submitted to Biomedical Journals (International Committee of 
Medical Journal Editors). 
 

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9. 
LIST OF REFERENCES 
Mutations in Hereditary Amyloidosis - Mutations in Transthyretin Gene(TTR). Available from: 
http://amyloidosismutations.com/mut-attr.php. 
Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv 
Neurol Disord. 2013 Mar;6(2):129-39. 
Adams D CT, Conceicao I, et al.  . Phase 2 Open-Label Extension Study (OLE) of Patisiran, an 
Investigational RNAi Therapeutic for the Treatment of Hereditary ATTR Amyloidosis with 
Polyneuropathy. Neuology. 2017 April 18;88(16 Supplemental: AAN Meeting 
Abstracts):S27.0004. 
Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi Therapeutic, for 
Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21. 
Akinc A, Querbes W, De S, et al. Targeted delivery of RNAi therapeutics with endogenous and 
exogenous ligand-based mechanisms. Mol Ther. 2010 Jul;18(7):1357-64. 
Ando Y, Coelho T, Berk J, et al. Guideline of transthyretin-related hereditary amyloidosis for 
clinicians. Orphanet J of Rare Dis. 2013;8(31). 
Ando Y, Nakamura M,Araki S. Transthyretin-related familial amyloidotic polyneuropathy. Arch 
Neurol. 2005;62(7):1057-62. 
Benson M,Kincaid J. The molecular biology and clinical features of amyloid neuropathy. Muscle 
Nerve. 2007;36(4):411-23. 
Bispo M, Marcelino P, Freire A, et al. High incidence of thrombotic complications early after 
liver transplantation for familial amyloidotic polyneuropathy. Transpl Int. 2009 Feb;22(2):165-
71. 
Carvalho M, Alves M,Luis ML. Octreotide--a new treatment for diarrhoea in familial 
amyloidotic polyneuropathy. J Neurol Neurosurg Psychiatry. 1992 Sep;55(9):860-1. 
Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin 
amyloidosis. N Engl J Med. 2013 Aug 29;369(9):819-29. 
Connors L, Yamashita T, Yazaki M, Skinner M,Benson M. A rare transthyretin mutation 
(Asp18Glu) associated with cardiomyopathy. Amyloid. 2004;11(1):61-6. 
Connors LH, Lim A, Prokaeva T, Roskens VA,Costello CE. Tabulation of human transthyretin 
(TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. 
Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, Prognosis, and Therapy of Transthyretin 
Amyloidosis. J Am Coll Cardiol. 2015 Dec 1;66(21):2451-66. 
Gertz MA, Kyle RA,Thibodeau SN. Familial amyloidosis: a study of 52 North American-born 
patients examined during a 30-year period. Mayo Clin Proc. 1992 May;67(5):428-40. 
Gillmore JD,Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin Pract 
Nephrol. 2006 May;2(5):263-70. 
Herlenius G, Wilczek HE, Larsson M,Ericzon BG. Ten years of international experience with 
liver transplantation for familial amyloidotic polyneuropathy: results from the Familial 

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Amyloidotic Polyneuropathy World Transplant Registry. Transplantation. 2004 Jan 15;77(1):64-
71. 
Okamoto S, Wixner J, Obayashi K, et al. Liver transplantation for familial amyloidotic 
polyneuropathy: impact on Swedish patients' survival. Liver Transpl. 2009;15:1229-35. 
Plante-Bordeneuve V,Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10(12):1086-
97. 
Reines JB, Vera TR, Martin MU, et al. Epidemiology of transthyretin-associated familial 
amyloid polyneuropathy in the Majorcan area: Son Llatzer Hospital descriptive study. Orphanet 
J Rare Dis. 2014 Feb 26;9:29. 
Sattianayagam PT, Hahn AF, Whelan CJ, et al. Cardiac phenotype and clinical outcome of 
familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 
2012 May;33(9):1120-7. 
Soares ML, Coelho T, Sousa A, et al. Susceptibility and modifier genes in Portuguese 
transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease. Hum Mol 
Genet. 2005 Feb 15;14(4):543-53. 
Stangou A,Hawkin P. Liver transplantation in transthyretin-related familial amyloid polyneuropathy. 
Current Opinion in Neurology. 2004;17(5):615-20. 
Yazaki M, Tokuda T, Nakamura A, et al. Cardiac amyloid in patients with familial amyloid 
polyneuropathy consists of abundant wild-type transthyretin. Biochem Biophys Res Commun. 
2000 Aug 11;274(3):702-6. 
 

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10. 
APPENDICES 
10.1. 
New York Heart Association Classification of Heart Failure  
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and 
climbing stairs does not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing 
stairs rapidly, walking uphill, walking or stair climbing after meals, 
in cold weather, in wind or when under emotional stress causes 
undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to 
two blocks on the level and climbing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without 
fatigue or dyspnea. 
 
10.2. 
Karnofsky Scale 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.   
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 

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10.3. 
Polyneuropathy Disability Score  
Stage 
Description 
0 
No symptoms 
I 
Sensory disturbances but preserved walking capability 
II 
Impaired walking capacity but ability to walk without a stick or crutches 
IIIA 
IIIB 
Walking with the help of one stick or crutch. 
Walking with the help of two sticks or crutches. 
IV 
Confined to a wheelchair or bedridden. 
 
 
10.4. 
Familial Amyloidotic Polyneuropathy Stage 
Stage 
Description 
0 
No symptoms 
I 
Unimpaired ambulation; mostly mild sensory, motor, and autonomic 
neuropathy in the lower limbs 
II 
Assistance with ambulation required, mostly moderate impairment 
progression to the lower limbs, upper limbs, and trunk. 
III 
Wheelchair-bound or bedridden; severe sensory, motor, and autonomic 
involvement of all limbs. 
 

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10.5. 
Categorization of Infusion-Related Reactions 
Signs and symptoms of an IRR usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  Signs/symptoms may 
include: allergic reaction/hypersensitivity (including drug fever), arthralgia (joint pain), 
bronchospasm, cough, dizziness, dyspnea (shortness of breath), fatigue (asthenia, lethargy, 
malaise), headache, hypertension, hypotension, myalgia (muscle pain), nausea, pruritus/itching, 
rash/desquamation, rigors/chills, sweating (diaphoresis), tachycardia, urticaria (hives, welts, 
wheals), vomiting. 
Categorization of IRRs is as follows: 
Categorization 
Description 
Mild 
Mild reaction:  infusion may be continued; if intervention is indicated 
it is minimal and additional treatment (other than paracetamol for 
delayed reactions) is not required. 
Moderate 
Moderate reaction:  requires treatment including more intensive 
therapy (eg, IV fluids, nonsteroidal anti-inflammatory drug 
[NSAIDs]) in addition to infusion interruption but responds promptly 
to medication.  Treatment is indicated for ≤24 hours. 
Severe 
More than moderate reaction:  not rapidly responsive to medication or 
to interruption of infusion; and/ or prolonged (treatment is indicated 
for >24 hours); recurrence of severe symptoms following initial 
improvement.