An Open-label Study to Evaluate the Efficacy and Safety of Revusiran in Patients With Transthyretin-mediated Familial Amyloidotic Polyneuropathy With Disease Progression Post-Orthotopic Liver Transplant
Phase: PHASE2
Conditions: Transthyretin (TTR)-Mediated Amyloidosis, Familial Amyloidotic Polyneuropathy (FAP), ATTR Amyloidosis, Familial Amyloid Neuropathies
Sponsor: Alnylam Pharmaceuticals

Revusiran (ALN-TTRSC)                                                     Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
1 
 
REVUSIRAN 
ALN-TTRSC-005 
AN OPEN-LABEL STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF REVUSIRAN IN PATIENTS WITH 
TRANSTHYRETIN-MEDIATED FAMILIAL AMYLOIDOTIC 
POLYNEUROPATHY WITH DISEASE PROGRESSION POST-
ORTHOTOPIC LIVER TRANSPLANT 
 
Original Protocol: 
12 June 2015 
Protocol Amendment 1 (Sweden): 
19 August 2015 
Protocol Amendment 2: 
09 March 2016 
 
 
EUDRACT Number: 
2015-002603-29 
 
 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
Telephone:  +1-617-551-8200 
Fax:  +1-617-551-8101 
 
 
Sponsor Contact: 
 
Senior Vice President, Clinical Development 
 
 
 
 
 
Signature 
 
 
 
Date 
 
 
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. 
The study will be completed according to guidelines of Good Clinical Practice.  Compliance with this 
practice 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. 

Revusiran (ALN-TTRSC)                                                     Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
2 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-TTRSC-005 protocol and agree to conduct the study as outlined.  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 

Revusiran (ALN-TTRSC)                                                     Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
3 
STUDY SYNOPSIS 
Name of Sponsor:  Alnylam Pharmaceuticals, Inc. 
Name of Investigational Product:  Revusiran (ALN-TTRSC) 
Name of Active Ingredient:  ALN- 51547 
Title of Study:  An Open-label Study to Evaluate the Efficacy and Safety of Revusiran in Patients with 
Transthyretin-mediated Familial Amyloidotic Polyneuropathy with Disease Progression 
Post-Orthotopic Liver Transplant 
Study center(s):  It is anticipated that approximately 5 clinical study centers will participate in this 
study. 
Objectives:   
Primary: 
 
Assess the efficacy of revusiran in patients with Transthyretin (TTR) -mediated Familial 
Amyloidotic Polyneuropathy (FAP) with disease progression post-orthotopic liver 
transplant (OLT) by evaluating the reduction in serum TTR level compared to baseline 
Secondary: 
 
Evaluate the safety and tolerability of revusiran when administered to TTR-mediated FAP 
patients with disease progression post-OLT 
 
Characterize the pharmacokinetics (PK) of revusiran  
 
Describe the effect of revusiran on neurologic impairment  
Exploratory: 
 
Evaluate the effect of revusiran on various clinical activity parameters including quality of 
life, disease stage, modified body mass index (mBMI), and cardiac function 
Methodology:   
This is a multicenter, multinational, open-label study designed to evaluate the efficacy, safety, and PK 
of subcutaneously administered revusiran in patients with FAP with disease progression post-OLT.   
Eligible, consenting patients will receive 5 daily doses of revusiran (Days 0 through 4) and a dose at 
Day 7, followed by once weekly doses for the duration of the study.   
Visits will be held at the clinical study center for Screening, Screening/Baseline, and Baseline, and 
Daily Dosing (Days 0 through 4) as well as each month for the first 3 months, and approximately every 
3 months through Month 18 (or Early Termination), and at the End of Study (approximately 28 days 
after last dose).  The remaining study visits may be conducted at the clinical study center or in the 
patient’s home. 
The primary objective of the study will be evaluated by the collection of serum samples for the 
measurement of total TTR levels.  After screening and baseline measurements, TTR will be assessed 
on a monthly basis for 3 months, approximately every 3 months, thereafter, and at ET. 
Adverse events will be collected throughout the treatment period and at the End of Study visit.   
An independent Data Monitoring Committee will be implemented for the study and will operate under 
a prespecified charter. 

Revusiran (ALN-TTRSC)                                                     Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
4 
Number of Patients (planned):  Approximately 12 patients will be enrolled in the study 
Diagnosis and eligibility criteria:   
Each patient must meet all of the following inclusion criteria to be eligible for enrollment in the study: 
1. Male or female ≥18 years of age 
2. Diagnosis of FAP with documented TTR mutation 
3. Received an OLT ≥12 months before the date of informed consent 
4. An increase in polyneuropathy disability (PND) score (eg, a PND change from 1 to 2 or 3a to 
3b) compared to a preliver transplant assessment OR increase in PND score between any 
2 assessments postliver transplant, which in the opinion of the Investigator is due to underlying 
FAP progression  
5. On stable immunosuppressive regimen with ≤10 mg/day of prednisone for at least 3 months 
before the date of informed consent  
6. Neurological impairment score (NIS) of 5 to 130 (inclusive) 
7. Polyneuropathy Disability score of ≤3b 
8. Karnofsky Performance Status ≥60% 
9. No liver allograft rejection episodes (chronic, acute, or subacute) in the past 6 months before 
the date of informed consent 
10. Normal liver function, including aspartate transaminase, alanine transaminase,  and total 
bilirubin (≤ upper limit of normal), unless elevation in total bilirubin is due to Gilbert’s 
Syndrome based on central laboratory evaluation 
11. Adequate renal function demonstrated by estimated glomerular filtration rate  
≥45 mL/min/1.73 m2 (calculated by a central laboratory using the Modification of Diet in 
Renal Disease formula) 
12. Women of child-bearing potential must have a negative pregnancy test, cannot be 
breastfeeding, and use 1 highly effective method of contraception in combination with a barrier 
method throughout study participation, and for 28 days after last dose of study drug 
13. Males with partners of child-bearing potential, must agree to use a condom, accompanied with 
spermicidal foam, gel, film, cream, or suppository, except in countries where spermicide is not 
available for use in combination with condom, throughout study participation and for 28 days 
after the last dose of study drug; males must also abstain from sperm donation after the first 
dose of study drug through study participation and for 28 days after the last dose of study drug 
14. Patient, or patient’s legal representative, is able and willing to provide written informed 
consent and the patient is willing to comply with the study requirements 
Each patient must not meet any of the following exclusion criteria to be eligible for enrollment in the 
study:   
1. Untreated hypo- or hyperthyroidism 
2. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of study drug administration 

Revusiran (ALN-TTRSC)                                                     Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
5 
3. Active infection with hepatitis B or hepatitis C (based on serology)  
4. Known human immunodeficiency virus infection 
5. New York Heart Association (NYHA) classification of >2 
6. Known leptomeningeal amyloidosis 
7. Other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune disease) 
8. Known type I diabetes  
9. Type II diabetes mellitus for ≥5 years from the time of informed consent 
10. Vitamin B12 levels below the lower limit of normal 
11. Current, heavy alcohol use, defined as regular consumption of greater than 2 to 3 units/day for 
women and 3 to 4 units/day for men (a unit of alcohol equals 1 glass of wine [125 mL], 
1 measure of spirits, or ½ pint of beer), or a known history of alcohol abuse within the last 
2 years from the time of informed consent 
12. Received an investigational agent or device within 30 days of anticipated study drug 
administration or 5 half-lives of the study drug, whichever is longer 
13. Currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid; if previously 
on any of these agents, must have completed a 14-day washout before start of study drug 
administration in this study 
14. Malignancy within the last 2 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 
15. History of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc) 
16. History of intolerance to subcutaneous (SC) injection 
17. Other medical conditions or comorbidities which, in the opinion of the Investigator, would 
interfere with study compliance or data interpretation 
Investigational product, dosage, and mode of administration:   
Revusiran is comprised of a small interfering RNA targeting mutant and wild-type TTR messenger 
ribonucleic acid with a covalently-attached triantennary GalNAc ligand formulated in water for 
injection.   
Beginning on Day 0, patients will receive 5 daily SC doses of 500 mg of revusiran administered as 
2 injections.  The same dose will be administered at Day 7 and then weekly from Week 2 through 
18 months.  Study drug will be administered at the clinical study center on Days 0 through 4 by 
qualified clinical study center staff under the supervision of the Investigator or designee.  After Day 4, 
study drug may be administered at home by a healthcare professional trained in the administration of 
study drug or at the clinical study center.  At the discretion of the Investigator, after the Month 6 dosing 
visit, patients/caregivers may be trained by the Investigator or qualified clinical study center staff in the 
administration of the study drug, according to the protocol dosing requirements.   
Duration of treatment:  The time on study for each patient is approximately 21 months (inclusive of a 
42-day screening period and a follow-up visit 28 days after the last dose of study drug).  The duration 
of treatment is 18 months. 

Revusiran (ALN-TTRSC)                                                     Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
6 
Reference therapy, dosage, and mode of administration:  N/A 
Efficacy and Clinical Activity Endpoints: 
Primary Endpoint 
The primary endpoint is the percent reduction from baseline in serum TTR level at 6 months. 
Secondary Endpoints 
The secondary endpoints of the study are the change from baseline over 18 months for the following: 
 
Serum TTR 
 
Modified (m)NIS+7  
 
Norfolk Quality of Life-Diabetic Neuropathy questionnaire 
 
PND Score 
Pharmacokinetic Assessments: 
Blood samples will be obtained for the assessment of plasma levels of revusiran.  Exploratory analyses 
may also be conducted on plasma samples to evaluate metabolites of revusiran. 
Safety Assessments 
The safety of revusiran will be evaluated by: 
 
Adverse events (AEs), including liver allograft rejection 
 
Vital sign measurements  
 
Clinical laboratory Evaluations 
 
12-lead electrocardiogram (ECG) 
 
Physical examinations 
 
Ophthalmology examinations 
 
Concomitant medications, including immunosuppressive agent monitoring 
Exploratory Endpoints: 
The exploratory endpoints of the study are to assess the change from baseline over 18 months for the 
following: 
 
mBMI 
 
FAP Stage 
 
NIS 
 
Grip Strength Test 
 
NYHA classification 
 
Karnofsky Performance Status 
 
Echocardiogram (ECHO) parameters 
 
Cardiac biomarkers 
 
EuroQoL questionnaire in 5-dimensions (EQ-5D)  

Revusiran (ALN-TTRSC)                                                     Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
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 
Composite Autonomic Symptom Score (COMPASS) 31 questionnaire 
 
Columbia Suicide Severity Rating Scale Questionnaire 
 
Pharmacoeconomics questionnaire 
 
Optional exploratory residual liver tissue evaluation 
Statistical methods: 
The primary population used to evaluate efficacy will be the Evaluable Analysis Set.  Safety will be 
analyzed using the Safety Analysis Set.  The PK Analysis Set will be used to conduct PK analyses. 
The primary endpoint is the percent reduction from baseline in serum TTR level at 6 months.  The 
primary efficacy analysis will be a 2-sided 95% confidence interval (CI) for the mean of the primary 
endpoint.  A t-test, in which the null hypothesis of no reduction is compared against the alternative 
hypothesis of a change, will also be performed.   
For secondary endpoints with continuous parameters, measurements will be summarized using 
descriptive statistics.  For secondary endpoints with categorical parameters, frequencies and 
percentages will be presented. The mean change (for continuous variables) from baseline to 18 months 
with the associated 80% and 95% CIs will also be presented.  For categorical variables, frequencies and 
percentages will be presented.  To understand the effect of revusiran from baseline, the frequency and 
percentage of patients at each of the category shifts from baseline at 18 months will be summarized.   
The exploratory endpoints will be analyzed in a similar fashion as the secondary endpoints.   
Adverse event summaries will include tabulations of all treatment-emergent AEs, treatment-related 
AEs, serious AEs, discontinuations due to AEs, and AEs graded according to maximum severity and 
will be primarily descriptive in nature.  Clinical laboratory data, vital signs data, and ECG interval data 
will also be presented as both actual values and changes from baseline relative to each on-study 
evaluation.   
For categorical safety variables, summary tabulations of the frequency and percentage of patients will 
be presented.  For continuous safety variables, the mean, median, standard deviation, minimum, and 
maximum values will be presented. 
 
 
 
 
 

Revusiran (ALN-TTRSC) 
 
Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
8 
Table 1: 
Schedule of Assessments 
Procedure 
 
Month 
Screening 
Screening
a/ 
Baseline 
Baselinea 
Predosed 
Daily Dosing 
Weekly Dosing 
(After D7±1, study drug will be administered weekly ±2 days) 
Early Termination
b 
EOS 
D7/W1 
W2 
M1 
W4-6 
M2 
W8-11 
M3 
W13-25 
M6 
W27-38 
M9 
W40-51 
M12 
W53-65 
M15 
W67-77 
M18 
M19 
Days/Weeks 
D-42 
to D -1 
D0 
D0 
D1 
D2 
D3 
D4 
W3 
W7 
W12 
W26 
W39 
W52 
W66 
W78 
W82 
Visit Window  
(Days)
c 
NA 
±1D 
±2D 
±7D 
±2D 
±7D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±7D 
Clinical Procedures and Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria
d 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History
e 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Status Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Body Weight 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs
f 
X 
 
 
X 
X X X X X 
 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
PND score 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
NYHA Classification 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Karnofsky Performance 
Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
FAP Stage 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Study Drug 
Administration
g 
 
 
 
 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
mBMI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 

Revusiran (ALN-TTRSC) 
 
Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
9 
Procedure 
 
Month 
Screening 
Screening
a/ 
Baseline 
Baselinea 
Predosed 
Daily Dosing 
Weekly Dosing 
(After D7±1, study drug will be administered weekly ±2 days) 
Early Termination
b 
EOS 
D7/W1 
W2 
M1 
W4-6 
M2 
W8-11 
M3 
W13-25 
M6 
W27-38 
M9 
W40-51 
M12 
W53-65 
M15 
W67-77 
M18 
M19 
Days/Weeks 
D-42 
to D -1 
D0 
D0 
D1 
D2 
D3 
D4 
W3 
W7 
W12 
W26 
W39 
W52 
W66 
W78 
W82 
Visit Window  
(Days)
c 
NA 
±1D 
±2D 
±7D 
±2D 
±7D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±7D 
Prior and Concomitant 
Medications
h 
X 
X 
X 
X 
 
X 
Adverse Events 
ONGOING THROUGHOUT THE DURATION OF THE STUDY 
Laboratory Assessments 
Serum Chemistry, 
including LFTs 
X 
Xa 
Xd 
 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
Xw 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Hematology and 
Urinalysis 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
Pregnancy Test
i 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
HBsAg, HBsAb, and 
HCVAb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
Assessments
j 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Xw 
X 
 
 
 
X 
 
 
 
 
X 
X 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Antidrug Antibodies
k 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
TTR Protein
l 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X
m 
X 
 
X 
 
X 
X
n 
X 
 
X 
X 
 
Blood samples for long-
term storage
o 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Vitamin A 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for 
plasma PK analysis
p 
 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 

Revusiran (ALN-TTRSC) 
 
Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
10 
Procedure 
 
Month 
Screening 
Screening
a/ 
Baseline 
Baselinea 
Predosed 
Daily Dosing 
Weekly Dosing 
(After D7±1, study drug will be administered weekly ±2 days) 
Early Termination
b 
EOS 
D7/W1 
W2 
M1 
W4-6 
M2 
W8-11 
M3 
W13-25 
M6 
W27-38 
M9 
W40-51 
M12 
W53-65 
M15 
W67-77 
M18 
M19 
Days/Weeks 
D-42 
to D -1 
D0 
D0 
D1 
D2 
D3 
D4 
W3 
W7 
W12 
W26 
W39 
W52 
W66 
W78 
W82 
Visit Window  
(Days)
c 
NA 
±1D 
±2D 
±7D 
±2D 
±7D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±7D 
NT-proBNP, BNP, and 
Troponin T and I 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Immunosuppressive 
agent monitoring
q 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Cardiac, Ophthalmologic, and Neurological Assessments 
NIS
r 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
mNIS+7
s 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Grip Strength Tests 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
ECHO with Doppler
t 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Ophthalmology Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
12-Lead ECG
u 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Questionnaires 
Norfolk QOL-DN 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
EQ-5D Questionnaire 
 
Xv 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
COMPASS 31 
Questionnaire 
 
X
v 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Pharmacoeconomics 
Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Columbia Suicide 
Severity Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Abbreviations:  aPTT=activated partial thromboplastin time; BNP=brain natriuretic peptide; COMPASS=Composite Autonomic Symptom Score; D=day; ECG=electrocardiogram; 
ECHO=echocardiogram; EOS=End of Study; EQ-5D= EuroQol 5 dimensions questionnaire; FAP=familial amyloidotic polyneuropathy; HBsAg=hepatitis B surface antigen; 

Revusiran (ALN-TTRSC) 
 
Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
11 
Procedure 
 
Month 
Screening 
Screening
a/ 
Baseline 
Baselinea 
Predosed 
Daily Dosing 
Weekly Dosing 
(After D7±1, study drug will be administered weekly ±2 days) 
Early Termination
b 
EOS 
D7/W1 
W2 
M1 
W4-6 
M2 
W8-11 
M3 
W13-25 
M6 
W27-38 
M9 
W40-51 
M12 
W53-65 
M15 
W67-77 
M18 
M19 
Days/Weeks 
D-42 
to D -1 
D0 
D0 
D1 
D2 
D3 
D4 
W3 
W7 
W12 
W26 
W39 
W52 
W66 
W78 
W82 
Visit Window  
(Days)
c 
NA 
±1D 
±2D 
±7D 
±2D 
±7D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±2D 
±14D 
±7D 
HBsAb=hepatitis B virus antibodies; HCVAb=hepatitis C virus antibodies; HIV=human immunodeficiency virus; HP=heat pain; IEC=Independent Ethics Committee; INR=international 
normalized ratio; IRB=Institutional Review Board; LFT=liver function test; mBMI=modified body mass index; mNIS=Modified Neurological Impairment Score; M=month; NA=not 
applicable; NIS=Neurological Impairment Score; NT-proBNP=N-terminal prohormone of B-type natriuretic peptide; OLT=orthotopic liver transplant; PK=pharmacokinetic; 
PND=polyneuropathy disability; NYHA=New York Heart Association; PT=prothrombin time; QOL-DN=Quality of Life-Diabetic Neuropathy; QTcB=Bazett corrected QT; 
QTcF=Fredericia-corrected QT interval; TP=touch pressure; TSH=thyroid stimulating hormone; TTR=transthyretin; W=week; WOCBP=women of child-bearing potential. 
Note:  White boxes are visits to the clinical study centers; whereas, grey boxes are for dosing procedures that may be conducted at home.  If, at any time 
during the study, a liver biopsy is performed per standard of care procedures, an optional evaluation of residual liver tissue may also be performed.  
Additionally, patients will be monitored for possible liver allograft rejection; any biopsies performed to rule out allograft rejection will be evaluated 
according to the Banff Working Group on Liver Allograft Pathology criteria, a set of consensus criteria for the causes of liver allograft dysfunction. 
a The Screening/Baseline visit must be performed within 21 days before the first dose of study drug (Day 0).  The Baseline visit must be conducted at least 
24 hours, but not more than 7 days, after the Screening/Baseline visit.  In consultation with the Medical Monitor(s), the Investigator may re-screen a patient 
after a minimum of 5 days have elapsed from the last screening assessment. 
b The withdrawn patient will be asked to consent to either be contacted by telephone or to allow non-patient contact follow-up (eg, medical record check) for up 
to 18 months after enrolling in the study to document overall health status. 
c Dosing on Days 1, 2, 3, and 4 must be performed 24±4 hours after the preceding dose of study drug.  After Day 7±1, study drug will be administered weekly 
(±2 days).  A 14-day window is permitted for study visits after Month 2 (excluding study drug administration). 
d LFTs must be assessed within 14 days of Day 0 (Predose) and results must be known before the first dose of study drug.  Other results from the clinical 
laboratory samples collected on Day 0 are not needed before dosing.  
e A complete medical history of FAP and OLT will be collected.  An interval medical history will be collected during the Screening/Baseline and Baseline visits 
and only changes in medical history will be recorded.  As part of the complete medical history, if available, the prior 6 months of LFTs will also be collected. 
f Vital signs include blood pressure, heart rate, oral body temperature, and respiratory rate.  Vital signs will be measured in the seated or supine position (should 
be consistent for each patient), after the patient has rested comfortably for 10 minutes.  Vital signs should be collected at each clinical study center visit. 
g The preferred region of SC injection is the abdomen; optional additional regions include the upper arm or thigh.  The site of injection within a given region will 
be rotated and recorded.  Refer to Section 6.5 for details on study drug administration, including administration at home by a healthcare professional or self or 
caregiver administration.  Patients (or caregivers) administering study drug will be contacted at least once per month by the clinical study center staff to assess 
AEs, concomitant medications, and to confirm pregnancy testing is being performed. 
h Prior immunosuppressive agent administration and blood levels from the 6 months before signing of the ICF will be collected, if available. 

Revusiran (ALN-TTRSC) 
 
Clinical Study Protocol Amendment 2 ALN-TTRSC-005 
 
 
09 March 2016 
Alnylam Pharmaceuticals 
Confidential 
12 
i A pregnancy test will be performed for WOCBP only.  A serum pregnancy test will be performed at Screening and urine pregnancy tests at all study visits 
thereafter (W4, W8, W12, W16, W20, W24, W28, W32, W36, W40, W44, W48, W52, W56, W60, W64, W68, W72, and W76) and any time pregnancy is 
suspected.  The results of the pregnancy test must be known before study drug administration. 
j Coagulation assessments include PT, aPTT, and INR. 
k Blood samples for antidrug antibody testing must be collected before study drug administration.  A sample will be collected at the Early Termination visit, if 
applicable. 
l Blood samples for TTR analysis should be obtained within 1 hour predose. 
m Blood sample for TTR analysis should be collected at Week 18 and Week 24 only. 
n Blood sample for TTR analysis should be collected at Week 57 only. 
o Where permitted per local regulations and IRB/IEC approval, blood samples for long-term storage to permit testing of additional proteins related to FAP will 
be collected. 
p Blood samples for plasma PK analysis will be collected predose and 2.5±1 hours postdose. 
q Immunosuppressive agent monitoring will be analyzed locally.  Unscheduled assessments may be performed if clinically indicated per local standard of care. 
r The NIS (weakness, reflexes, and sensation) will be assessed at Screening to determine the likelihood that a patient will meet NIS eligibility criteria at the 
Screening/Baseline visit; a NIS of 5-130 [inclusive] must be met at the Screening/Baseline visit.  The documented results of previously performed NIS 
assessments may be used at Screening if these tests were performed within 60 days before the date of informed consent. 
s The mNIS+7 consists of the modified NIS tool (weakness and reflexes), NCS 5 attributes (∑5), quantitative sensory testing by body surface area including TP 
and HP, and postural blood pressure.  At each time point, 2 independent assessments will be performed for the mNIS+7 and the Grip Strength Test.  The 
clinical study center will make every effort to have these assessments performed by the same study staff.  Assessments are to be performed ≥24 hours, but 
≤7 days apart. 
t ECHO assessments will be evaluated by a central laboratory. 
u A triplicate 12-lead ECG will be recorded at baseline; thereafter, single 12-lead ECGs will be recorded.  Additional ECGs may be collected at the discretion of 
the Investigator.  When an ECG is scheduled at the same time as a blood sample collection, the ECG will be obtained before the scheduled blood sample. 
v Assessment must be completed at a single time point during 1 of the specified visits, at the discretion of the Investigator. 
w Serum chemistry, including LFTs, and coagulation assessments must be collected at Week 15, Week 18, and Week 22. 
 

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TABLE OF CONTENTS  
STUDY SYNOPSIS ........................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................18 
1. 
INTRODUCTION ......................................................................................................20 
1.1. 
Background and Rationale ..........................................................................................20 
1.1.1. 
Transthyretin Biology .................................................................................................20 
1.1.2. 
Disease Overview .......................................................................................................20 
1.1.2.1. 
Transthyretin-mediated Amyloidosis and Familial Amyloidotic 
Polyneuropathy ...........................................................................................................20 
1.1.2.2. 
Familial Amyloidotic Polyneuropathy After Orthotopic Liver Transplant ................21 
1.1.3. 
RNA Interference ........................................................................................................21 
1.2. 
Overview of Revusiran ...............................................................................................22 
1.2.1. 
Summary of Revusiran Nonclinical Data ...................................................................22 
1.2.2. 
Summary of Revusiran Clinical Data .........................................................................23 
1.3. 
Study Design Rationale ..............................................................................................24 
1.4. 
Dose Selection Rationale ............................................................................................25 
1.5. 
Risk-Benefit Assessment ............................................................................................25 
1.5.1. 
Injection Site Reactions ..............................................................................................26 
1.5.2. 
Abnormal Liver Function Tests ..................................................................................26 
1.5.3. 
Vitamin A Reduction ..................................................................................................26 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................27 
2.1. 
Primary Objective .......................................................................................................27 
2.2. 
Secondary Objectives .................................................................................................27 
2.3. 
Exploratory Objective .................................................................................................27 
3. 
INVESTIGATIONAL PLAN .....................................................................................28 
3.1. 
Overall Study Design ..................................................................................................28 
3.2. 
Number of Patients .....................................................................................................28 
3.3. 
Treatment Assignment ................................................................................................28 
3.4. 
Efficacy and Clinical Activity Endpoints: ..................................................................28 
3.4.1. 
Primary Endpoint ........................................................................................................28 
3.4.2. 
Secondary Endpoints ..................................................................................................28 

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3.4.3. 
Pharmacokinetic Assessments: ...................................................................................29 
3.4.4. 
Safety Assessments .....................................................................................................29 
3.4.5. 
Exploratory Endpoints ................................................................................................29 
3.5. 
Dose Adjustment Criteria ...........................................................................................30 
3.5.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................30 
3.5.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses ....................................30 
3.6. 
Criteria for Study Termination ...................................................................................30 
3.6.1. 
Data Monitoring Committee .......................................................................................30 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................32 
4.1. 
Inclusion Criteria ........................................................................................................32 
4.2. 
Exclusion Criteria .......................................................................................................33 
4.3. 
Study Drug Discontinuation .......................................................................................33 
4.4. 
Withdrawal Criteria ....................................................................................................34 
5. 
TREATMENT OF PATIENTS ..................................................................................35 
5.1. 
Description of Study Drug ..........................................................................................35 
5.2. 
Concomitant Medications ...........................................................................................35 
5.3. 
Contraceptive Requirements .......................................................................................35 
5.3.1. 
Contraceptive Requirements for Female Patients .......................................................35 
5.3.2. 
Contraceptive Requirements for Male Patients ..........................................................36 
5.4. 
Treatment Compliance ................................................................................................36 
5.5. 
Randomization and Blinding ......................................................................................37 
5.6. 
Patient Numbering ......................................................................................................37 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
6.1. 
Study Drug ..................................................................................................................38 
6.2. 
Study Drug Packaging and Labeling ..........................................................................38 
6.3. 
Study Drug Storage .....................................................................................................38 
6.4. 
Study Drug Preparation ..............................................................................................38 
6.5. 
Administration ............................................................................................................38 
6.6. 
Study Drug Accountability .........................................................................................39 
6.7. 
Study Drug Handling and Disposal ............................................................................39 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................................40 
7.1. 
Blood Sample Collection ............................................................................................40 
7.2. 
Sample Analysis .........................................................................................................40 

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8. 
ASSESSMENT OF EFFICACY ................................................................................41 
8.1. 
Primary Efficacy Assessment .....................................................................................41 
8.2. 
Secondary Efficacy Assessments ...............................................................................41 
8.2.1. 
Modified Neurological Impairment Score +7.............................................................41 
8.2.2. 
Norfolk Quality of Life – Diabetic Neuropathy Questionnaire ..................................41 
8.2.3. 
Polyneuropathy Disability Score ................................................................................41 
8.3. 
Exploratory Assessments ............................................................................................42 
8.3.1. 
Modified Body Mass Index ........................................................................................42 
8.3.2. 
Familial Amyloidotic Polyneuropathy Stage ..............................................................42 
8.3.3. 
Neurological Impairment Score ..................................................................................42 
8.3.4. 
Grip Strength Test .......................................................................................................42 
8.3.5. 
New York Heart Association Classification ...............................................................42 
8.3.6. 
Karnofsky Performance Status ...................................................................................42 
8.3.7. 
Echocardiogram ..........................................................................................................42 
8.3.8. 
Cardiac Biomarkers ....................................................................................................43 
8.3.9. 
EuroQOL Questionnaire in 5 Dimensions ..................................................................43 
8.3.10. 
Composite Autonomic Symptom Score .....................................................................43 
8.3.11. 
Columbia Suicide Severity Rating Scale Questionnaire ............................................43 
8.3.12. 
Pharmacoeconomics Questionnaire ............................................................................43 
8.3.13. 
Optional Exploratory Assessment ..............................................................................43 
8.3.13.1. 
Optional Residual Liver Tissue Evaluation ................................................................43 
9. 
ASSESSMENT OF SAFETY .....................................................................................44 
9.1. 
Safety Parameters .......................................................................................................44 
9.1.1. 
Demographic and Medical History .............................................................................44 
9.1.2. 
Vital Signs ..................................................................................................................44 
9.1.3. 
Weight and Height ......................................................................................................44 
9.1.4. 
Physical Examination .................................................................................................44 
9.1.5. 
Ophthalmologic examination......................................................................................44 
9.1.6. 
Immunosuppressive Agent Monitoring ......................................................................45 
9.1.7. 
Liver Allograft Status .................................................................................................45 
9.1.8. 
Electrocardiogram .......................................................................................................45 
9.1.9. 
Laboratory Assessments .............................................................................................45 
9.1.9.1. 
Pregnancy Screening ..................................................................................................47 

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9.1.9.2. 
Exploratory Biomarkers ..............................................................................................47 
9.1.9.3. 
Antidrug Antibodies ...................................................................................................47 
9.2. 
Adverse and Serious Adverse Events .........................................................................47 
9.2.1. 
Definition of Adverse Events .....................................................................................47 
9.2.1.1. 
Adverse Event .............................................................................................................47 
9.2.1.2. 
Serious Adverse Event ................................................................................................47 
9.2.1.3. 
Adverse Events of Clinical Interest ............................................................................48 
9.2.2. 
Eliciting Adverse Event Information ..........................................................................48 
9.3. 
Adverse Event Reporting ............................................................................................48 
9.4. 
Assessment of Causality .............................................................................................49 
9.5. 
Assessment of Severity ...............................................................................................49 
9.6. 
Coding of Adverse Events ..........................................................................................49 
9.7. 
Serious Adverse Event Reporting ...............................................................................50 
9.7.1. 
Notifying the Institutional Review Board/Independent Ethics Committee ................50 
9.7.2. 
Sponsor Reporting:  Notifying Regulatory Authorities ..............................................50 
9.7.3. 
Sponsor Notification of Participating Investigators ...................................................51 
9.8. 
Pregnancy Reporting ..................................................................................................51 
10. 
STATISTICS ..............................................................................................................52 
10.1. 
Sample Size ................................................................................................................52 
10.2. 
Statistical Methodology ..............................................................................................52 
10.2.1. 
Populations to be Analyzed ........................................................................................52 
10.2.2. 
Baseline Evaluations ...................................................................................................52 
10.2.3. 
Efficacy Analyses .......................................................................................................52 
10.2.3.1. 
Primary Efficacy Endpoint .........................................................................................52 
10.2.3.2. 
Secondary Efficacy Endpoints ....................................................................................53 
10.2.3.3. 
Exploratory Endpoints ................................................................................................53 
10.2.4. 
Safety Analyses ..........................................................................................................53 
10.2.4.1. 
Adverse Events ...........................................................................................................53 
10.2.4.2. 
Vital Signs, Clinical Laboratory Safety Tests, 12-lead Electrocardiograms, 
Physical and Ophthalmologic Examinations ..............................................................53 
10.2.4.3. 
Concomitant Medications ...........................................................................................54 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................55 
11.1. 
Study Monitoring ........................................................................................................55 

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11.2. 
Audits and Inspections ................................................................................................55 
11.3. 
Institutional Review Board .........................................................................................55 
11.4. 
Quality Control and Quality Assurance ......................................................................55 
12. 
ETHICS ......................................................................................................................57 
12.1. 
Ethics Review .............................................................................................................57 
12.2. 
Ethical Conduct of the Study ......................................................................................57 
12.3. 
Written Informed Consent ..........................................................................................57 
13. 
DATA HANDLING AND RECORD KEEPING ......................................................58 
13.1. 
Inspection of Records .................................................................................................58 
13.2. 
Retention of Records ..................................................................................................58 
14. 
PUBLICATION POLICY ..........................................................................................59 
15. 
LIST OF REFERENCES ............................................................................................60 
16. 
APPENDICES ............................................................................................................63 
16.1. 
Modified Neurological Impairment Score +7 Components .......................................63 
16.2. 
Polyneuropathy Disability Score ................................................................................64 
16.3. 
Familial Amyloidotic Polyneuropathy Stage ..............................................................65 
16.4. 
New York Heart Association Classification of Heart Failure ....................................66 
16.5. 
Karnofsky Performance Status ...................................................................................67 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ..............................................................................................8 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ATTR 
Transthyretin-mediated amyloidosis 
BNP 
B-type natriuretic peptide 
COMPASS 
Composite Autonomic Symptom Score 
CI 
Confidence interval 
CRO 
Contract research organization 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram  
ECHO 
Echocardiogram  
eCRF 
Electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
EQ-5D 
European quality of life questionnaire – 5 dimensions 
EU 
European Union 
FAC 
Familial amyloidotic cardiomyopathy 
FAP 
Familial amyloidotic polyneuropathy 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous (ly) 
LFT 
Liver function test 
mBMI 
Modified body mass index 
MedDRA® 
Medical Dictionary for Regulatory Activities 

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Abbreviation 
Definition 
mNIS 
Modified neurological impairment score 
mRNA 
Messenger ribonucleic acid 
NCS 
Nerve conduction studies 
NHP 
Non-human primate 
NIS 
Neurological impairment score 
NOAEL 
No-observed-adverse-effect-level 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide 
NYHA 
New York Heart Association 
OLT 
Orthotopic liver transplant 
OTC 
Over-the-counter 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PND 
Polyneuropathy disability 
QOL-DN 
(Norfolk) Quality of Life Diabetic Neuropathy 
QST 
Quantitative sensory testing 
QTcB 
Bazett-corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
RBP 
Retinol binding protein 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SC 
Subcutaneous(ly) 
siRNA 
Small interfering ribonucleic acid 
SSA 
Senile systemic amyloidosis 
T4 
Thyroxine  
TEAE 
treatment-emergent adverse event 
TTR 
Transthyretin  
ULN 
Upper limit of normal 
WOCBP 
Women of child-bearing potential 
WT 
Wild-type 
US 
United States 

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1. 
INTRODUCTION 
1.1. 
Background and Rationale 
1.1.1. 
Transthyretin Biology 
Transthyretin (TTR), also known as prealbumin, is a tetrameric protein produced predominantly 
by hepatocytes (>95% of TTR is liver-derived), with small fractions produced in the choroid 
plexus and retina.[1]  The primary physiological role of TTR is to serve as a carrier of retinol 
(also known as vitamin A) through its interaction with retinol binding protein (RBP); it also 
plays a minor role as a carrier for thyroxine (T4).  In humans, approximately 15% of T4 
circulating in the plasma is bound to TTR; the remainder is predominantly bound to 
thyroxine-binding globulin. 
Mutations in the TTR protein lead to destabilization of the tetrameric form and dissociation into 
dimers and monomers.  The misfolding of mutated monomers results in tissue deposition of 
oligomers and amyloid fibrils, which lead to significant tissue injury. 
1.1.2. 
Disease Overview 
1.1.2.1. 
Transthyretin-mediated Amyloidosis and Familial Amyloidotic Polyneuropathy 
Transthyretin-mediated amyloidosis (ATTR) is caused by deposition of TTR amyloid fibrils in 
various tissues.  The hereditary form of ATTR amyloidosis is caused by an autosomal dominant 
mutation in the TTR gene.  There are over 100 reported TTR genetic mutations[2,3] that 
phenotypically result in at least 2 clinical syndromes:  familial amyloidotic cardiomyopathy 
(FAC) and familial amyloidotic polyneuropathy (FAP), both of which are characterized by 
amyloid deposits of mutant and wild-type (WT) TTR.[4] 
The estimated worldwide prevalence of FAP is 5,000 to 10,000, with the majority of cases in 
Portugal, Sweden, France, Mallorca, Japan, Brazil, and the United States (US).[5,6,17]  The most 
common causative mutation of FAP is TTR valine substitution for methionine at position 30, 
with the onset of symptoms typically occurring between 30 and 55 years of age.[7]  Amyloid 
deposition occurs largely in the peripheral nerves, starting as a nerve length-dependent sensory 
polyneuropathy in the feet causing numbness and pain and progressing to painful dysesthesias.  
Disabling motor neuropathy follows, characterized by leg weakness and eventual inability to 
walk.  Autonomic neuropathy is another common feature of the disease, resulting in severe 
gastrointestinal pathology (including diarrhea or constipation and malabsorption, leading to 
severe malnutrition), orthostatic hypotension, and bladder dysfunction with recurring urinary 
tract infections.[8,9,10,11]  Several mutations, also manifest with cardiac pathology during later 
stages of disease due to amyloid infiltration of the sinus node, the atrioventricular conduction 
system, and infiltration of the myocardium.[12,13]  Involvement of the conduction system can 
lead to sudden death due to dysrhythmias, and myocardial infiltration can lead to diastolic 
dysfunction and biventricular heart failure.[14]  Death typically occurs within 10 years of 
diagnosis of FAP.[15]  A TTR tetramer stabilizer, tafamidis, was approved in the European 
Union (EU) in 2011 for use in the treatment of symptomatic FAP patients with Stage 1 disease.  
Diflunisal is a generic, nonsteroidal anti-inflammatory agent that has been demonstrated in in 

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vitro assays to bind to and stabilize the TTR tetramer in a manner similar to tafamidis.  A 
recently published National Institutes of Health-sponsored study showed that diflunisal slowed 
neuropathy progression in FAP,[16] and its use is contraindicated in patients with severe 
congestive heart failure (New York Heart Association [NYHA] class IV), renal insufficiency 
(estimated creatinine clearance <30 mL/min), or those undergoing anticoagulation therapy.  
Diflunisal is not currently licensed for use in the treatment of FAP in the US or EU, and there is 
limited evidence for its effectiveness in the treatment of patients with FAP.  However, there are 
no approved treatments for patients with later stages of FAP or for patients with disease 
progression post-orthotopic liver transplant (OLT). 
1.1.2.2. 
Familial Amyloidotic Polyneuropathy After Orthotopic Liver Transplant 
Since the liver is the primary source of WT and mutant TTR, OLT has been used since 1990 as a 
potential approach for the treatment of FAP [1] and is the current standard of care in select 
patients who are eligible for transplant.  More than 2000 patients have been transplanted in the 
world since 1990.  However, OLT carries significant risks:  life-threatening complications due to 
allograft rejection, hepatic artery thrombosis, or infections.  The 1-year mortality rate post-OLT 
in FAP patients is approximately 10%.[23]  Additionally, disease progression occurs in at least 
one third of patients post-OLT, presumably due to continued deposition of WT TTR protein 
from the transplanted liver.[17,18]  Amyloid deposits before liver transplant consist of both 
mutant and WT TTR.[19,20]  However, postliver transplant nerve and cardiac tissue contains 
increased amounts of WT TTR in patients with disease progression despite removal of mutant 
TTR with liver transplant.[21,36,22]  Disease progression may occur as early as 1 year 
post-transplant leading to loss of ambulation in 20% of patients.[18]  Additionally, as with 
disease progression in FAP patients who have not undergone liver transplant, progression 
post-OLT most commonly manifests as worsening of polyneuropathy and/or cardiac disease.  
Neurological progression is marked by an increase in Neurological Impairment Score (NIS) of 
8.84 per year and reduction in strength by 22% per year as assessed by the handgrip test.  Thirty 
percent of patients with clear progression of neuropathy died in follow-up.  Even in FAP patients 
where both the liver and heart have been transplanted, neuropathy progression continues, leaving 
the patient with marked disability.[36]  Causes of death after liver transplant include cardiac 
impairment (22%), liver-related complications (14%), and septicemia (22%).[18] 
None of the available therapeutic agents are considered truly disease modifying, nor has any 
treatment demonstrated the ability to halt disease progression in a majority of patients, which is 
particularly important in a setting where continued disease progression ultimately leads to 
marked disability and death.  Importantly, there are no approved treatment options for FAP 
patients whose disease continues to progress post-OLT, and this subset of patients is not eligible 
for ongoing clinical trials in FAP. 
1.1.3. 
RNA Interference 
Ribonucleic acid interference (RNAi) is a naturally occurring cellular mechanism for regulating 
gene expression that is mediated by small interfering ribonucleic acids (siRNAs).[24]  Typically, 
synthetic siRNAs are 19 to 23 base pair double-stranded oligonucleotides in a staggered duplex 
with a 2-nucleotide overhang at 1 or both of the 3' ends.  Such siRNAs can be designed to target 
endogenous or exogenous (infectious organisms) disease causing genes.  When introduced into 
cells, the net effect of an RNAi-based pharmacological approach is the binding of the siRNA to 

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its complementary messenger ribonucleic acid (mRNA) sequence, cleavage of this target mRNA, 
and suppression of the target protein.[25]  The ability to selectively and potently degrade the 
mRNA encoding the TTR protein using a siRNA offers a potent and specific approach for the 
treatment of ATTR. 
Unformulated siRNAs, and those without chemical modification, are rapidly degraded and 
eliminated upon systemic administration, and thus do not achieve significant tissue 
distribution.[26] As a result, various formulations and/or chemical modifications of the siRNAs 
have been used to increase distribution to tissues, and to facilitate their uptake into the relevant 
cell type. 
One approach that has been used successfully in humans for delivery of siRNAs to the liver 
employs intravenous (IV) administration of siRNAs formulated in lipid nanoparticles.[26,27,28]  
Another approach for liver-specific gene silencing has been to use subcutaneously (SC) 
administered siRNA conjugated to an N-acetylgalactosamine (GalNAc) ligand.  It has been 
shown that conjugation of a triantennary GalNAc ligand to the 3’ end of the sense strand of 
siRNA results in high affinity (ie, nM) binding to the hepatic expressed asialoglycoprotein 
receptor and subsequent receptor-mediated uptake into hepatocytes.  Single and multiple doses 
of SC administered siRNA-GalNAc conjugates have achieved sustained suppression of multiple 
different hepatocyte-expressed targets in rodents, nonhuman primates (NHPs), and humans, 
including TTR (see the revusiran Investigator’s Brochure [IB] for further details).   
1.2. 
Overview of Revusiran 
Alnylam Pharmaceuticals, Inc. (the Sponsor), in collaboration with Genzyme Corporation, has a 
synthetic RNAi therapeutic targeting liver TTR mRNA in clinical development for the treatment 
of ATTR amyloidosis (revusiran), which has received orphan drug designation in the EU.  
Revusiran is comprised of a siRNA targeting mutant and WT TTR mRNA with a 
covalently-attached triantennary GalNAc ligand formulated in water for injection.  The siRNA 
consists of a 21-mer duplex oligonucleotide targeting the 3’UTR of the TTR mRNA, thereby 
conferring homology to WT TTR and all reported TTR mutations.  Once delivered to 
hepatocytes, revusiran targets TTR mRNA for degradation, resulting in reduction of mutant and 
WT TTR protein via the RNAi mechanism.  Therefore, revusiran is expected to directly address 
the etiology of ATTR amyloidosis and improve the disease course of patients.  This is consistent 
with results in other systemic amyloidoses (eg, amyloid light chain and secondary amyloidosis) 
where reduction in circulating pathogenic protein levels is associated with attenuation in 
end-organ damage.[29,30,31,32]   
1.2.1. 
Summary of Revusiran Nonclinical Data 
A series of nonclinical studies were conducted to elucidate the pharmacology, pharmacokinetics 
(PK), and toxicology of revusiran. 
A cardiovascular/respiratory safety pharmacology study conducted in NHPs demonstrated no 
functional cardiovascular or respiratory effects, with a no-observed-effect-level of ≥100 mg/kg.  
In addition, genetic toxicity studies were negative. 
The toxicity of revusiran was evaluated in 6-month chronic toxicity studies in rats and NHPs (the 
pharmacologically relevant species).  In the 6-month rat study the 

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no-observed-adverse-event-level (NOAEL) was 30 mg/kg based on histopathological findings in 
the liver in conjunction with transient mild liver function test (LFT) changes.  In the 9-month 
NHP study, there were no dose-limiting findings and the NOAEL was greater than the highest 
dose tested (>200 mg/kg).   
Further nonclinical information can be found in the revusiran IB. 
1.2.2. 
Summary of Revusiran Clinical Data 
Study ALN-TTRSC-001 was a Phase 1 randomized, double -blind, placebo-controlled study of 
revusiran administration in healthy subjects.  Subjects received single ascending doses or 
multiple ascending doses of up to 10 mg/kg or fixed doses of up to 600 mg of revusiran, or 
placebo.  In the multiple dose cohorts, subjects received a total of 10 doses over a 35 day period 
administered as 5 daily SC doses followed by 5 weekly doses.  
In this study, revusiran was generally well-tolerated.  The majority of treatment-emergent 
adverse events (AEs) were mild or moderate in severity and considered unrelated to study 
treatment.  There were no serious adverse events (SAEs).  Injection site reactions (ISRs) were 
the most common AEs related to study treatment.  All ISRs were mild or moderate in severity 
and resolved without sequelae.  Overall, the incidence of alanine transaminase (ALT) and 
aspartate transaminase (AST) elevation >1× upper limit of normal (ULN) was similar in placebo 
and revusiran-treated subjects.  One subject who received 600 mg revusiran developed an 
asymptomatic elevation of ALT (4.3×ULN) and AST (1.9×ULN), which was defined in the 
protocol as a dose limiting toxicity and resulted in study discontinuation.  There were no other 
AEs leading to dose interruption or dose reduction.  No elevations in cytokines, C-reactive 
protein, or other abnormal clinical findings were noted.  The pharmacodynamic (PD) effect of 
revusiran was dose-dependent and resulted in >85% reduction of TTR at ≥5 mg/kg of revusiran 
and was accompanied by reduction of RBP and vitamin A.  Fixed doses of 500 mg and 600 mg 
revusiran also demonstrated similar safety and PD effect over a wide range of body weights 
compared to that observed in cohorts with weight based dosing.  
ALN-TTRSC-002 was an open-label, multiple-dose Phase 2 study of revusiran administered to 
patients with ATTR cardiac amyloidosis.  Patients received revusiran 5 mg/kg or 7.5 mg/kg for 
10 doses over a 35 day period administered as 5 daily SC doses followed by 5 weekly doses.  
Multiple doses of revusiran were generally well-tolerated.  The majority of AEs were mild or 
moderate in severity, not related to study drug and expected for the population under study.  
Three patients experienced 1 SAE each, 2 of which were unrelated to study drug (non-cardiac 
chest pain and implantable defibrillator insertion).  The third SAE was asymptomatic elevation 
of ALT (4.2×ULN) and AST (3.2×ULN) after administration of 6 doses of 5 mg/kg revusiran 
and was considered mild in severity and possibly related to study drug.  Study drug was 
interrupted for 1 dose and then resumed with subsequent normalization of ALT and AST during 
the remaining period of dosing.  The most common AEs related to study treatment were ISRs 
which were localized, mild in severity, self-limiting and did not result in interruption or 
discontinuation of treatment.  There were no other AEs leading to dose interruption or dose 
reduction.  A PD effect of >85% TTR reduction with 5 mg/kg or 7.5 mg/kg revusiran dosing was 
observed. 
ALN-TTRSC-003 is an ongoing, Phase 2 open-label extension study to evaluate long-term 
treatment with revusiran for patients who completed the ALN-TTRSC-002 study.  Patients 

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receive revusiran 500 mg administered as 5 daily SC doses, followed by weekly SC doses for 
approximately 2 years.  As of 05 January 2016, 25 patients have been treated with revusiran for 
approximately 8 months (range 1-13 months).  Multiple doses of revusiran have been generally 
well-tolerated.  The majority of AEs were mild or moderate in severity.  The most common AEs 
related to study drug have been ISRs, usually characterized by transient erythema, pruritus, pain, 
or swelling at or around the injection site.  Occasionally, these reactions have been recurrent, of 
longer duration and increased intensity.  In some cases, ISRs have led to interruption or 
discontinuation of study drug.  Elevations of ALT and AST have been observed, the majority of 
which have been mild, transient, <3×ULN and not associated with any changes in total bilirubin 
or clinical symptoms.  In several subjects, the elevations may have led to interruption and/or 
dose reduction of study treatment.  There were no serious hepatic AEs. 
ALN-TTRSC-004 is an ongoing, Phase 3 randomized, double-blind, placebo-controlled study of 
revusiran in patients with FAC.  Patients receive revusiran 500 mg or placebo administered as 5 
daily SC doses, followed by weekly SC doses for 18 months.  As of 14 January 2016, 83 patients 
have been treated with blinded study drug for approximately 3 months (range 0-13 months).  The 
majority of AEs were mild or moderate in severity.  The most common AEs considered related 
to blinded study treatment have been ISRs.  One patient developed symptoms of anorexia, 
weight loss, and a cholestatic liver enzyme profile.  The patient was hospitalized and an 
evaluation was consistent with drug-induced acute hepatitis and cholestasis.  The event was 
considered possibly related to study treatment and a contributory role could not be excluded.  
The subject also had a number of other potential contributory factors.   
Further details on these clinical studies can be found in the revusiran IB. 
1.3. 
Study Design Rationale 
There is a high unmet medical need for treatment alternatives in FAP.  Very few treatment 
options exist once a patient has progressed after receiving an OLT.  Post-OLT patients no longer 
have mutant TTR circulating or depositing into tissues; however, those with disease progression 
after transplant suffer from continued WT TTR amyloid deposition in a variety of tissues 
including the peripheral nervous system.[33,36]   
Preliminary Phase 2 open-label extension study data with patisiran, a liquid 
nanoparticle-formulated siRNA targeting hepatic TTR production, has shown stabilization of 
neuropathy after 1 year in FAP patients associated with >80% TTR reduction.  Given the IV 
route, shared mechanism of action, and similar magnitude of TTR reduction (both WT and 
mutant) with both revusiran and patisiran to date, it is anticipated that revusiran will lead to a 
similar degree of TTR reduction in FAP patients, and thus have the potential to affect neuropathy 
in FAP patients who are progressing post-OLT. 
In this study, patients will receive 5 daily SC injections of 500 mg revusiran during the first week 
(Day 0 to Day 4) and then SC injections of 500 mg revusiran once every week for approximately 
18 months.  This dose and schedule maximizes TTR reduction (>85%) in healthy volunteers and 
FAC patients at the lowest revusiran exposure with a favorable safety profile, and is being used 
in the ongoing revusiran Phase 2 open-label extension study and Phase 3 study in FAC patients.  
Furthermore, the level of TTR reduction obtained with this regimen of revusiran is comparable 
to the TTR reduction observed with patisiran in the Phase 2 open-label extension study where 
TTR reduction was associated with clinical stabilization of neuropathy in patients with FAP. 

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The primary endpoint is the percent reduction from baseline in serum TTR level at 6 months.  In 
healthy volunteers, mean reduction of 88% in serum TTR has been observed from baseline to 
Day 35 with a standard deviation of 6%.  If this study yields a mean reduction of 80% at 6-
months with a standard deviation of 6%, 12 patients would yield a 95% confidence interval (CI) 
of approximately 77% to 83%. 
The primary endpoint of the percent reduction from baseline in serum TTR level at 6 months 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.  
Secondary endpoints include TTR reduction over 18 months compared to baseline, modified 
Neurological Impairment Score (mNIS+7), NIS, Norfolk Quality of Life Diabetic Neuropathy 
(QOL-DN) questionnaire, and polyneuropathy disability (PND) score. 
1.4. 
Dose Selection Rationale 
Dose selection for this trial is based on the fundamental role of TTR in the pathogenesis of the 
disease, data from liver transplantation in FAP, and the therapeutic hypothesis that maximal TTR 
reduction is required to fully realize clinical benefit with revusiran.  Clinical data demonstrate 
that administration of multiple doses of revusiran in healthy volunteers resulted in >85% mean 
TTR reduction at nadir with doses of 5.0 to 10.0 mg/kg or with fixed doses of 500 and 600 mg; 
these doses were well tolerated.  The fixed dose of 500 mg had a wide PD and safety window 
across both heavy and light patients, with a TTR reduction effect that matched 5.0 and 
10.0 mg/kg (ALN-TTRSC-001).  In the Phase 2 study in patients with FAC and SSA, doses of 
5.0 and 7.5 mg/kg have resulted in similar degrees of TTR reduction as were seen in healthy 
volunteers.  Based on these consistent PD data in both healthy volunteers and FAC/SSA patients 
showing maximization of TTR reduction with either fixed or mg/kg dosing at a total dose of 
≥500 mg, along with the favorable safety profile observed with the 500 mg fixed dose, 500 mg is 
the planned dose for this study.  The dose selection is also supported by the absence of findings 
in the long-term toxicology studies in rats and monkeys.   
1.5. 
Risk-Benefit Assessment 
Familial amyloidotic polyneuropathy and FAC are diseases with significant morbidity and 
mortality and limited treatment options.  Orthotopic liver transplantation has been considered the 
standard treatment for early stage FAP patients; however, approximately one-third of patients 
demonstrate neuropathy progression post-transplant, with progression marked by a reduction of 
ambulation in which 20% of patients become bedridden.[18]  Once a patient continues to 
progress post-OLT overall outcome is very poor and treatment options are limited.  The potential 
benefit of treatment with revusiran is that reduction of wild-type and mutant TTR deposition may 
result in clinical benefit in these patients.  Based on the mechanism of action of siRNAs and the 
lack of effect of revusiran in nonclinical in vitro cytochrome P450 (CYP) inhibition, induction, 
and phenotyping studies, as well as transporter studies, an interaction between revusiran and 
concomitantly administered immunosuppressive agents is not expected.  The main risks 
associated with revusiran treatment and TTR reduction are summarized below and support a 
favorable risk/benefit assessment. 
Refer to the IB for additional information. 

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1.5.1. 
Injection Site Reactions 
ISRs have been observed in subjects receiving revusiran in completed and ongoing clinical 
studies.  The majority have been mild or moderate in severity.  Typically, the reactions consist of 
localized erythema, pain, swelling, pruritus, or rash at or around the injection site, and are 
transient in nature.  Occasionally, these reactions have been of longer duration, more severe in 
nature and/or recurrent.  In some subjects, this resulted in discontinuation of revusiran.  If such 
reactions occur, rotation of the injection site (eg, to the extremities) is recommended as a 
potential mitigation strategy (see Section 6.5).  Dose reduction may be considered in some cases 
after consultation with the Medical Monitor (see Section 3.5). 
1.5.2. 
Abnormal Liver Function Tests 
Elevations of ALT and/or AST have been seen in subjects receiving revusiran in completed and 
ongoing clinical studies.  The majority of abnormalities have been mild and transient elevations 
of ALT and/or AST <3×ULN, and are not associated with changes in total bilirubin or clinical 
symptoms.  In some subjects, higher ALT and/or AST elevations have been observed and led to 
interruption or discontinuation of study treatment.  Serious hepatic adverse events have also been 
reported, including a case of possible drug-induced hepatitis and cholestasis; in this case a 
contributory role of study drug could not be excluded. 
In this study, patients will be required to have normal liver function at study entry, and regular 
monitoring of LFTs will be performed throughout study participation.  If a patient develops 
clinical signs or symptoms such as unexplained anorexia, fatigue, jaundice, or dark urine, the 
Investigator should consider liver injury as a potential etiology.  Patients receiving revusiran 
after OLT will be a minimum of 12 months from transplant with no recent rejection episodes and 
on stable immunosuppressive medication to ensure that complications secondary to liver 
transplant are minimized.  Dose reduction may be considered in some cases after consultation 
with the Medical Monitor (see Section 3.5). 
1.5.3. 
Vitamin A Reduction 
The reduction of serum levels of TTR and RBP is expected to result in reduced circulating 
vitamin A levels.  Preclinical and clinical data have shown that reducing circulating vitamin A 
associated with reduction of RBP does not result in severe vitamin A deficiency.  Individuals 
with RBP/TTR mutations have life-long reduced levels of circulating vitamin A with good 
health, suggesting that compensatory transport mechanisms for vitamin A exist.  Furthermore, 
reducing vitamin A has not been associated with any vitamin A deficiency-related AEs in 
healthy volunteers, and patients with FAP, treated with patisiran (another RNAi therapeutic with 
an siRNA targeting TTR formulated in a lipid nanoparticle) who experienced >80% reduction of 
both TTR and vitamin A.  Periodic eye exams are planned for patients in this study to assess any 
potential impact of vitamin A reduction on visual function.  Additionally, all patients on the 
study will be asked to take a daily supplement containing the recommended daily allowance of 
vitamin A.   

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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. 
Primary Objective 
 Assess the efficacy of revusiran in patients with TTR-mediated FAP with disease 
progression post-OLT by evaluating the reduction in serum TTR level compared to 
baseline 
2.2. 
Secondary Objectives 
 Evaluate the safety and tolerability of revusiran when administered to TTR-mediated 
FAP patients with disease progression post-OLT 
 Characterize PK of revusiran  
 Describe the effect of revusiran on neurologic impairment  
2.3. 
Exploratory Objective 
 Evaluate the effect of revusiran on various clinical activity parameters including 
quality of life, disease stage, modified body mass index (mBMI), and cardiac function 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, multinational, open-label study designed to evaluate the efficacy, safety, 
and PK of SC administered revusiran in patients with TTR-mediated FAP with disease 
progression post-OLT.  It is anticipated that patients from approximately 5 clinical study centers 
will participate in this study.   
Eligible, consenting patients will receive 5 daily doses of revusiran (Days 0 through 4) and a 
dose at Day 7, followed by once weekly doses for the duration of the study.   
Visits will be held at the clinical study center for Screening, Screening/Baseline, and Baseline, 
and Daily Dosing (Days 0 through 4) as well as each month for the first 3 months, and 
approximately every 3 months through Month 18 (or Early Termination), and at the End of Study 
(approximately 28 days after last dose).  The remaining study visits may be conducted at the 
clinical study center or in the patient’s home. 
The primary objective of the study will be evaluated by the collection of serum samples for the 
measurement of total TTR levels.  After screening and baseline measurements, TTR will be 
assessed on a monthly basis for 3 months, approximately every 3 months, thereafter, and at ET. 
Adverse events will be collected throughout the treatment period and at the End of Study visit. 
Patients will participate in the study for approximately 21 months (inclusive of a 42-day 
screening period and a follow-up visit 28 days after the last dose of study drug) and will be 
treated with study drug for 18 months. 
An independent Data Monitoring Committee will be implemented for the study and will operate 
under a prespecified charter. 
3.2. 
Number of Patients 
Approximately 12 patients are planned for enrollment in this study. 
3.3. 
Treatment Assignment 
This is an open-label study. 
3.4. 
Efficacy and Clinical Activity Endpoints: 
3.4.1. 
Primary Endpoint 
The primary endpoint is the percent reduction from baseline in serum TTR level at 6 months. 
3.4.2. 
Secondary Endpoints 
The secondary endpoints of the study are the change from baseline over 18 months for the 
following: 
 Serum TTR 

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 mNIS+7  
 Norfolk Quality of Life-Diabetic Neuropathy questionnaire 
 PND Score 
3.4.3. 
Pharmacokinetic Assessments: 
Blood samples will be obtained for the assessment of plasma levels of revusiran.  Exploratory 
analyses may also be conducted on plasma samples to evaluate metabolites of revusiran. 
3.4.4. 
Safety Assessments 
The safety of revusiran will be evaluated by: 
 Adverse events (AEs), including liver allograft rejection 
 Vital sign measurements 
 Clinical laboratory evaluations 
 12-lead ECG 
 Physical examinations 
 Ophthalmology examinations 
 Concomitant medications, including immunosuppressive agent monitoring 
3.4.5. 
Exploratory Endpoints 
The exploratory endpoints of the study are to assess the change from baseline over 18 months for 
the following: 
 mBMI 
 FAP Stage 
 NIS 
 Grip Strength Test 
 NYHA classification 
 Karnofsky Performance Status 
 Echocardiogram (ECHO) parameters 
 Cardiac biomarkers 
 EuroQoL questionnaire in 5-dimensions (EQ-5D)  
 Composite Autonomic Symptom Score (COMPASS) 31 questionnaire 
 Columbia Suicide Severity Rating Scale Questionnaire 
 Pharmacoeconomics questionnaire 
 Optional exploratory residual liver tissue evaluation 

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3.5. 
Dose Adjustment Criteria 
3.5.1. 
Safety Criteria for Adjustment or Stopping Doses 
If, after study drug administration, AST, ALT, or total bilirubin (unless due to Gilbert’s 
Syndrome) >2×ULN, repeat AST, ALT, and total bilirubin within 72 hours and implement close 
monitoring with continued study drug dosing.  Close monitoring consists of AST, ALT, and total 
bilirubin measurement twice weekly.  Close monitoring can be stopped when ALT, AST, and 
total bilirubin return to ≤2×ULN.  Additional and repeat testing may be performed at the 
discretion of the Investigator. 
Dosing will be held for the following LFT abnormalities: 
 AST or ALT elevation of ≥3×ULN in association with either total bilirubin elevation 
of ≥1.5×ULN or gastrointestinal symptoms including nausea, vomiting, and/or 
abdominal pain 
 AST or ALT elevation of ≥5×ULN 
Under these circumstances, the contract research organization (CRO) Medical Monitor and 
Investigator, in consultation with the Alnylam Medical Monitor and/or a hepatologist, as deemed 
necessary, will decide on appropriate action regarding frequency of repeat LFTs and resumption 
of dosing. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the Medical Monitor and Investigator will review 
all available safety data for that patient and for all other patients enrolled in the study.  Based on 
the judgment of the Investigator and the Medical Monitor, it may be decided that further 
revusiran administration be discontinued, or that the patient may continue or resume revusiran 
dosing at the same dose or at a lower dose of 250 mg weekly. 
3.5.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
No formal PK criteria have been established for adjusting or stopping dosing of revusiran for this 
study. 
3.6. 
Criteria for Study Termination 
The Sponsor reserves the right to terminate the study for clinical or administrative reasons at any 
time.  If the clinical study center does not recruit at a reasonable rate, the study may be closed for 
recruitment and/or terminated at that center.  Should the study be terminated and/or the clinical 
study center 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, Independent Ethics 
Committee (IEC)/Institutional Review Board (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. 
3.6.1. 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be involved in the conduct of this study.  The DMC 
has the responsibility for monitoring the progress of the clinical study and the safety of the study 

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participants.  The DMC will perform periodic reviews of data and study conduct during the 
course of the clinical trial, as defined in the DMC Charter for this clinical trial.  The membership 
of the DMC and reporting structure are defined in the DMC Charter. 

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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be eligible for enrollment in the 
study: 
1. Male or female ≥18 years of age 
2. Diagnosis of FAP with documented TTR mutation 
3. Received an OLT ≥12 months before the date of informed consent 
4. An increase in polyneuropathy disability (PND) score (eg, a PND change from 1 to 2 or 
3a to 3b) compared to a preliver transplant assessment OR increase in PND score 
between any 2 assessments postliver transplant, which in the opinion of the Investigator 
is due to underlying FAP progression  
5. On stable immunosuppressive regimen with ≤10 mg/day of prednisone for at least 
3 months before the date of informed consent  
6. Neurological impairment score of 5 to 130 (inclusive) 
7. Polyneuropathy Disability score of ≤3b 
8. Karnofsky Performance Status ≥60% 
9. No liver allograft rejection episodes (chronic, acute, or subacute) in the past 6 months 
before the date of informed consent 
10. Normal liver function, including AST, ALT, and total bilirubin (≤ULN), unless elevation 
in total bilirubin is due to Gilbert’s Syndrome, based on central laboratory evaluation 
11. Adequate renal function demonstrated by estimated glomerular filtration rate (eGFR) 
≥45 mL/min/1.73 m2 (calculated by a central laboratory using the Modification of Diet in 
Renal Disease formula, where eGFR in mL/min/1.73m2 = 175 × [serum creatinine 
in mg/dL-1.154] × [Age-0.203] × [1.212 if Black] × [0.742 if female]). 
12. Women of child-bearing potential (WOCBP) must have a negative pregnancy test, cannot 
be breastfeeding, and use 1 highly effective method of contraception in combination with 
a barrier method throughout study participation, and for 28 days after last dose of study 
drug 
13. Males with partners of child-bearing potential, must agree to use a condom, accompanied 
with spermicidal foam, gel, film, cream, or suppository, except in countries where 
spermicide is not available for use in combination with condom, throughout study 
participation and for 28 days after the last dose of study drug; males must also abstain 
from sperm donation after the first dose of study drug through study participation and for 
28 days after the last dose of study drug 
14. Patient, or patient’s legal representative, is able and willing to provide written informed 
consent and the patient is willing to comply with the study requirements 

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4.2. 
Exclusion Criteria 
Each patient must not meet any of the following exclusion criteria to be eligible for enrollment in 
the study: 
1. Untreated hypo- or hyperthyroidism 
2. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed before the first dose of study drug administration 
3. Active infection with hepatitis B or hepatitis C (based on serology) 
4. Known human immunodeficiency virus infection 
5. NYHA classification of >2 
6. Known leptomeningeal amyloidosis 
7. Other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune disease) 
8. Known type I diabetes  
9. Type II diabetes mellitus for ≥5 years from the time of informed consent 
10. Vitamin B12 levels below the lower limit of normal 
11. Current, heavy alcohol use, defined as regular consumption of greater than 2 to 
3 units/day for women and 3 to 4 units/day for men (a unit of alcohol equals 1 glass of 
wine [125 mL], 1 measure of spirits, or ½ pint of beer), or a known history of alcohol 
abuse within the last 2 years from the time of informed consent 
12. Received an investigational agent or device within 30 days of anticipated study drug 
administration or 5 half-lives of the study drug, whichever is longer 
13. Currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid; if 
previously on any of these agents, must have completed a 14-day washout before start of 
study drug administration in this study 
14. Malignancy within the last 2 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 
15. History of allergic reaction to an oligonucleotide or GalNAc 
16. History of intolerance to SC injection 
17. Other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation 
4.3. 
Study Drug Discontinuation 
Patients are free to discontinue treatment at any time and for any reason, without penalty to their 
continuing medical care.   
The Investigator or designee may discontinue dosing in a patient if the patient: 
 Is in violation of the protocol 

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 Experiences a serious or intolerable AE 
 Requires a prohibited medication 
 Is found to be considerably noncompliant with the protocol-required visits 
The Investigator will confer with the Sponsor or CRO Medical Monitor before discontinuing 
dosing in the patient.  Patients who are pregnant will be discontinued from dosing immediately.  
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 18-month visit so that 
their experience is captured in the final analyses; however, a patient may withdraw consent to 
participate in the study at any time.  Patients who discontinue study drug may receive local 
standard of care treatment for their disease. 
4.4. 
Withdrawal Criteria 
While patients who discontinue drug are encouraged to remain in the study to complete study 
assessments (Section 4.3), they are free to withdraw from the study at any time and for any 
reason, without penalty to their continuing medical care.  Patients who withdraw or have a dose 
reduction before 6 months of study participation may be replaced.  Patients will also be 
withdrawn if the study is terminated. 
If a patient chooses to withdraw from the study, every effort should be made to conduct the Early 
Termination visit.  When a patient withdraws from the study, the primary reason for 
discontinuation must be recorded in the appropriate section of the electronic case report form 
(eCRF) and all efforts will be made to complete and report the observations as thoroughly as 
possible. 
The withdrawn patient will be asked to consent to either be contacted by telephone or to allow 
nonpatient contact follow-up (eg, medical record check) for up to 18 months after enrolling onto 
the study to document their overall health status. 

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5. 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug 
As this is an open-label study, all patients will receive the same study treatments.  Beginning on 
Day 0, all patients will receive 5 daily SC doses of 500 mg of revusiran administered as 
2 injections.  The same dose will be administered at Day 7 and then weekly from Week 2 
through 18 months.  Dose reductions will be allowed during the study, see Section 3.5 for details.   
5.2. 
Concomitant Medications 
Use of tafamidis, diflunisal, doxycycline, or tauroursodeoxycholic acid within 14 days before the 
first dose of study medication in this protocol or use of any other investigational agent or device 
within 30 days (or 5 half-lives of the study drug, whichever is longer) before the first dose of 
study medication is prohibited for study entry and during study participation. 
Medications and treatments other than those specified previously, including palliative and 
supportive care approved by the Investigator for disease-related symptoms (eg, 
immunosuppressive agents) are permitted during the study and will be recorded.  Previous 
immunosuppressive agent administration and blood levels from the 6 months before signing of 
the ICF will be collected, if available, as part of prior concomitant medications.   
All patients on the study will be asked to take a daily supplement containing the recommended 
daily allowance of vitamin A. 
The Investigator should review over-the-counter (OTC) and or herbal preparations to ensure that 
these are not potentially disease modifying.   
During the study, patients are also advised not to consume alcohol over the levels stated in the 
eligibility criterion. 
Use of all concomitant medications from the Screening visit through the Follow-up visit will be 
recorded on the patient’s eCRF.  This will include all prescription drugs, herbal preparations, 
OTC medications, vitamins (including the supplemental vitamin A), and minerals.  Any changes 
in medications during the study will also be recorded on the eCRF. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator; however, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF. 
5.3. 
Contraceptive Requirements 
5.3.1. 
Contraceptive Requirements for Female Patients 
Women of child-bearing potential (WOCBP) may be included in this study and include any 
female who has experienced menarche and who is not postmenopausal or permanently sterilized 
(eg, tubal occlusion, hysterectomy, or bilateral salpingectomy). 
WOCBP must have a negative pregnancy test and must be using 1 highly effective method of 
contraception in combination with a barrier method from the signing of the informed consent 

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form (ICF), throughout study participation, and for 28 days after the last dose of the study drug.  
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year).  
Acceptable forms of effective contraception are defined as follows: 
 Hormonal:  established use of oral (except low-dose gestagens [eg, lynestrenol and 
norethisterone]), implantable or injectable methods of contraception in conjunction 
with spermicide, condom, or diaphragm 
 Placement of an intrauterine device (IUD) in conjunction with spermicide or condom 
 Placement of an intrauterine system (IUS) (for example, progestin-releasing coil) in 
conjunction with spermicide or condom 
 Bilateral tubal occlusion in conjunction with spermicide, condom, or diaphragm 
 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) in 
conjunction with spermicide, condom, or diaphragm 
 Sexual true abstinence:  when this is 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 
Interaction between revusiran and hormonal contraceptives is not anticipated; there were no 
effects of study drug on the reproductive organs (including histopathology) in any of the animal 
(rat and NHP) studies conducted to date.  Moreover, revusiran showed no inhibition in vitro of 
CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 (both testosterone and midazolam 
were used as substrates in human liver microsomes). 
5.3.2. 
Contraceptive Requirements for Male Patients 
Males with partners of child-bearing potential who agree to use appropriate means of 
contraception throughout study participation until 28 days after the last dose of study drug may 
be included in this study. 
It is unknown if revusiran poses any potential risk of drug exposure through the ejaculate.  Male 
patients (including men who have had vasectomies), particularly those with partners who are 
pregnant, must use a condom, accompanied with spermicidal foam, gel, film, cream, or 
suppository, except in countries where spermicide is not available for use in combination with 
condom, as the appropriate means of contraception for the duration of the study and until 28 days 
after the last administration of study drug. 
Males should also abstain from sperm donation after the first dose of study drug through study 
participation and for 28 days after the last dose of study drug. 
5.4. 
Treatment Compliance 
Treatment compliance with study drug administration is dependent on the proper preparation and 
administration of SC injections.  Patients will be permitted to miss an occasional dose of study 
drug.  However, if a patient misses 3 consecutive doses at any time during the study, the 
Investigator, in consultation with the CRO Medical Monitor, will discuss whether the patient will 

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be able to continue on the study.  If a patient misses a dose of study drug, and remembers before 
their next dose, they should receive the missed dose as soon as possible within the visit window, 
otherwise the missed dose will not be made up.  Patients should never receive more than 1 dose 
of study drug a day. 
5.5. 
Randomization and Blinding 
This is an open-label, single-arm study, therefore no randomization or blinding will be needed in 
this study. 
5.6. 
Patient Numbering 
Each patient will be uniquely identified in the study by a combination of the clinical study center 
number and screening number.  The clinical study center number will be assigned by the 
Sponsor.  A combination of the center number and screening number will create the unique 
patient identifier.  

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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug 
All study drugs may be dispensed only by the Investigator or trained individual as defined in the 
Pharmacy Manual and Homecare Nursing Manual. 
Revusiran Solution for Injection (SC use) is comprised of an siRNA targeting mutant and WT 
TTR mRNA with a covalently attached triantennary GalNAc ligand formulated in water for 
injection.   
Revusiran will be supplied as a sterile 200 mg/mL solution.   
6.2. 
Study Drug Packaging and Labeling 
All packaging and labeling as well as the preparation of revusiran will be in compliance with 
Good Manufacturing Practice specifications, and any other or local applicable regulations. 
6.3. 
Study Drug Storage 
All study drugs will be stored refrigerated at approximately 5°C±3°C, protected from light.  Any 
deviation from the recommended storage conditions should be reported to the Sponsor and/or the 
CRO. 
No special procedures for the safe handling of revusiran are required. 
The Sponsor will be permitted, upon request, to audit the supplies, storage, dispensing 
procedures, and records. 
No study drug may be administered to any person not enrolled in the study. 
Additional storage details are provided in the Pharmacy Manual. 
6.4. 
Study Drug Preparation 
The study drug will be prepared by clinical study center staff, a healthcare professional, the 
patient, or caregiver according to the procedures detailed in the Pharmacy Manual.   
6.5. 
Administration 
Beginning on Day 0, patients will receive 5 daily SC doses of 500 mg of revusiran administered 
as 2 injections.  The same dose will be administered at Day 7 and then weekly from Week 2 
through 18 months.  Study drug will be administered at the clinical study center on Days 0 
through 4 by qualified clinical study center staff under the supervision of the Investigator, or 
designee. 
After Day 4 study drug may be administered at home by a healthcare professional trained in the 
administration of study drug or at the clinic.  At the discretion of the Investigator, after the 
Month 6 dosing visit, and if the patient has not previously experienced any severe AE or SAEs 
considered related to the study drug within the previous 12 weeks, that the Investigator and 
Medical Monitor believe should preclude the patient from self-administration, patients/caregivers 

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may be trained by the Investigator or qualified clinical study center staff in the administration of 
the study drug, according to the protocol dosing requirements.  If a severe AE or related SAE 
occurs, patients should not self-administer study drug for a 12-week period, unless prior approval 
is obtained from the Medical Monitor.  The preferred region of SC injection is the abdomen.  
Optional additional regions include the upper arms and thighs.  The site of injection within a 
given region will be rotated and recorded. 
Detailed instructions can be found in the Pharmacy Manual. 
6.6. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of all 
study drugs including dates of receipt.  Accurate records will be kept detailing when and how 
much study drug is dispensed and used by each patient in the study.  Any reason for departure 
from the protocol dispensing regimen must also be recorded. 
Drug accountability records and inventory will be available for verification by the Sponsor 
Monitor or designee.  Periodically throughout the study, there will be a reconciliation of all study 
drug. 
Study drug must not be used for any purpose other than the present study.  Study drug which has 
been dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
Further instructions about study drug accountability are detailed in the Pharmacy Manual. 
6.7. 
Study Drug Handling and Disposal 
Remaining study drug (all used, partially used, and unused vials) will be returned to the Sponsor 
or its agent or destroyed at the clinical study center according to applicable regulations. 

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7. 
PHARMACOKINETIC ASSESSMENTS 
7.1. 
Blood Sample Collection 
Blood samples will be collected for the assessment of plasma levels of revusiran at the time 
points in the Schedule of Assessments (Table 1). 
Exploratory analyses may also be conducted on plasma samples to evaluate metabolites of 
revusiran. 
7.2. 
Sample Analysis 
Pharmacokinetic samples will be analyzed by a central laboratory.  Instructions for storage and 
handling of PK samples can be found in the Study Reference Manual. 

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8. 
ASSESSMENT OF EFFICACY 
The timing of assessments is in the Schedule of Assessments (Table 1). 
8.1. 
Primary Efficacy Assessment 
Serum samples will be collected within 1 hour predose for the measurement of total TTR levels.  
Samples will be analysed using an enzyme-linked immunosorbent assay method at a central 
laboratory. 
8.2. 
Secondary Efficacy Assessments 
8.2.1. 
Modified Neurological Impairment Score +7 
The mNIS+7 assessment tool is a composite measure of neurologic impairment which includes 
the following measures: 
 Clinical exam-based neurologic impairment score (including NIS weakness, reflexes, 
and sensation.  Note: sensation is not included in the mNIS+7 score) 
 Electrophysiologic measures of small and large nerve fiber function (+7) including: 
 Nerve conduction studies (NCS) 5 attributes (Σ5) 
 Quantitative sensory testing (QST) by body surface area including touch pressure 
and heat pain 
 Autonomic function (postural blood pressure) 
A summary of the scoring of the components of the mNIS+7 is in Appendix 16.1. 
At each time point, 2 independent assessments will be performed.  Each clinical study center will 
make every effort to have these assessments performed by the same study staff.  Assessments are 
to be performed at least 24 hours (approximately) apart from each other but no greater than 
7 days apart.  In order to limit potential intra-operator bias, the source documents and results 
from any of the prior assessments will not be available to the examiner when performing the 
second assessment. 
Every effort will be made to use the same devices for NCS and QST for a patient throughout the 
duration of the study. 
8.2.2. 
Norfolk Quality of Life – Diabetic Neuropathy Questionnaire 
Quality of life will be assessed through the Norfolk QOL-DN questionnaire, a standardized 
47-item patient-reported outcomes measure that is sensitive to the different features of diabetic 
neuropathy-small fiber, large fiber, and autonomic nerve function.[37 ] 
8.2.3. 
Polyneuropathy Disability Score 
Changes in ambulation will be evaluated through the PND score; the PND scale is in 
Appendix 16.2.[38,39] 

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8.3. 
Exploratory Assessments 
Additional details can be found in the revusiran Study Reference Manual. 
8.3.1. 
Modified Body Mass Index 
Using Body weight data, the mBMI will be calculated (body mass index × albumin).  This 
calculation will take place programmatically; the calculation will not be performed by the 
clinical study center staff. 
8.3.2. 
Familial Amyloidotic Polyneuropathy Stage 
Changes in ambulation will be evaluated through the FAP stage; the FAP stage scale is in 
Appendix 16.3.[38,39] 
8.3.3. 
Neurological Impairment Score 
The NIS includes measurements of weakness, sensation, and reflexes.  The NIS weakness and 
reflex sub-components are the same as the mNIS+7.  The sensory component in mNIS+7 uses 
QST a more quantitative approach to assessing a broader range of somatic sensory function than 
the sensory sub-score within the NIS.  At each time point, 2 independent assessments will be 
performed in the same manner as described for mNIS+7. 
8.3.4. 
Grip Strength Test 
Hand grip strength will be measured by dynamometer.  Clinical study center staff will be trained 
on the use of a dynamometer and testing for the study.  When performing the test, patients will 
stand, holding the dynamometer in their dominant hand, with their arm parallel to the body 
without squeezing the arm against the body.  Tests will be performed in triplicate on the same 
study visit day and 2 independent assessments will be performed ≥24 hours, but ≤7 days apart.  
Every effort will be made to use the same dynamometer for a patient throughout the duration of 
the study. 
8.3.5. 
New York Heart Association Classification  
New York Heart Association classification will be recorded.  The NYHA classification scale is 
provided in Appendix 16.4. 
8.3.6. 
Karnofsky Performance Status 
Performance status will be assessed according to the Karnofsky Performance Status scale; the 
scale is in Appendix 16.5. 
8.3.7. 
Echocardiogram 
An echocardiogram (ECHO) with Doppler will be used for assessment of cardiac structure and 
function and will be assessed by a central laboratory.   
Details for image acquisition and upload for central review can be found in the revusiran Study 
Reference Manual. 

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8.3.8. 
Cardiac Biomarkers 
Blood samples will be collected and analyzed for the quantification of troponin T, troponin I, 
N-terminal prohormone of B-type natriuretic peptide (NT-proBNP; biomarkers of cardiac 
status), and B-type natriuretic peptide (BNP).  Quantification of these biomarkers will be 
performed at a central laboratory. 
8.3.9. 
EuroQOL Questionnaire in 5 Dimensions 
Quality of life will be assessed through the use of the EuroQOL questionnaire in 5 dimensions 
(EQ-5D), a standardized 5-question instrument for use as a measure of health outcomes.[34] 
8.3.10. 
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).[35] 
8.3.11. 
Columbia Suicide Severity Rating Scale Questionnaire  
The Columbia Suicide Severity Rating Scale (C-SSRS) will be used to assess the mental status 
of the patient as it relates to suicidal ideation and behavior.  This questionnaire will be 
administered to the patient by trained study personnel.[41] 
8.3.12. 
Pharmacoeconomics Questionnaire 
Disease level and healthcare utilization will be assessed using a patient reported 
pharmacoeconomics questionnaire. 
8.3.13. 
Optional Exploratory Assessment 
8.3.13.1. Optional Residual Liver Tissue Evaluation 
If, at any time during the study, a liver biopsy is performed per standard of care procedures, an 
optional evaluation of residual liver tissue may also be performed; and, if allowed by local 
regulations, this evaluation will include measurement of the concentration of revusiran in 
residual tissue and a possible evaluation of the mechanism of action for revusiran. 
Details can be found in the revusiran Study Reference Manual. 
 

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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
9.1.1. 
Demographic and Medical History 
Patient demographic data will be obtained at the Screening visit.  A complete medical history 
will be obtained at Screening.  As part of the complete medical history, if available, the prior 6 
months of LFTs will also be collected.  An interval medical history will be collected during the 
Screening/Baseline and Baseline visits and only changes in medical history will be recorded. 
9.1.2. 
Vital Signs 
Vital sign measurements include blood pressure, heart rate, oral body temperature, and 
respiratory rate.  Vital signs will be measured in the seated or supine position (should be 
consistent for each patient), after the patient has rested comfortably for 10 minutes.  Blood 
pressure should be taken using the same arm.  Oral body temperature will be obtained in degrees 
Celsius, 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. 
When vital signs are scheduled at the same time as blood samples, vital signs should be obtained 
before the blood sample.  On dosing days, vital signs should be obtained before dosing. 
For the safety of the patient, additional vital sign assessments may be added at the discretion of 
the Investigator. 
9.1.3. 
Weight and Height 
Height will be measured only at the Screening visit.  Body weight will be measured in kilograms. 
9.1.4. 
Physical Examination 
Routine physical examinations will include the examination of the following:  general 
appearance, head, eyes, ears, nose and throat, chest/respiratory, heart/cardiovascular, 
gastrointestinal/liver, musculoskeletal/extremities, dermatological/skin, thyroid/neck, lymph 
nodes, and neurological/psychiatric. 
9.1.5. 
Ophthalmologic examination 
Visual acuity should be evaluated at the beginning of each specified visit (eg, before slit-lamp 
examination).  Manifest refraction will be performed at each specified visit, where possible, 
before visual acuity testing and will be used to obtain a correction for visual acuity evaluations.  
Visual acuity testing should be done with best (most recent) correction and be tested in bright 
and dim light conditions. 
Further details regarding the ophthalmologic examinations will be provided in the Study 
Reference Manual. 

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9.1.6. 
Immunosuppressive Agent Monitoring 
Blood samples for immunosuppressant monitoring will be collected at the time points in the 
Schedule of Assessments and for any suspected episodes of allograft rejection.  Samples may 
also be collected at unscheduled time points when clinically indicated per local standard of care 
procedures.  Sample analysis will take place at a local laboratory.  
9.1.7. 
Liver Allograft Status 
Patients will be monitored for possible liver allograft rejection; any biopsies performed to rule 
out allograft rejection will be evaluated according to the Banff Working Group on Liver 
Allograft Pathology criteria, a set of consensus criteria for the causes of liver allograft 
dysfunction.[40] 
9.1.8. 
Electrocardiogram 
A triplicate 12-lead ECG will be recorded at baseline; thereafter, single 12-lead ECGs will be 
recorded.  Additional ECGs may be collected at the discretion of the Investigator.  Standard 
computerized 12-lead electrocardiogram (ECG) recordings will be obtained.  Each lead shall be 
recorded for at least 3 beats at a speed of 25 mm/s.  Recordings will be obtained before dosing, 
after the patient has rested comfortably for approximately 10 minutes.  The electrophysiological 
parameters assessed will be rhythm, ventricular rate, PR interval, QRS duration, QT interval, ST 
and T-waves, Bazett-corrected QT interval (QTcB) and Fredericia-corrected QT interval (QTcF). 
When an ECG is scheduled at the same time as a blood sample collection, the ECG will be 
obtained before the scheduled blood sample. 
The Investigator or designee is responsible for reviewing the ECGs to assess whether the results 
have changed since the Screening/Baseline visit and to determine the clinical significance of the 
results.  These assessments will be recorded on the eCRF.  For any clinically significant changes 
from the Screening/Baseline visit (eg, ischemic ECG changes, wave/interval changes, or 
arrhythmia), the Investigator must contact the CRO Medical Monitor to discuss continued 
participation of the patient in the study. 
9.1.9. 
Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  In the event of 
an 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. 
Hematology 
Hematocrit 
Neutrophils, absolute and % 
Hemoglobin 
Lymphocytes, absolute and % 
RBC count 
Monocytes, absolute and % 
WBC count 
Eosinophils, absolute and % 
Mean corpuscular volume 
Basophils, absolute and % 

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Mean corpuscular hemoglobin 
Platelet count 
Mean corpuscular hemoglobin concentration 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatininea 
Albumin 
Uric acid 
Calcium 
LDH 
Carbon dioxide 
Glucose 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Coagulation Assessments 
PT 
INR 
aPTT 
Thyroid Function Test 
TSH 
 
Serology Parameters 
HBsAg 
HBsAb 
HCV Ab 
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin 
Leukocytes 
Glucose 
Microscopy (if clinically indicated) 
Pregnancy Testing (WOCBP only) 
β-human chorionic gonadotropin 
Other 
Vitamin A 
Vitamin B12 
Abbreviations:  AST=aspartate transaminase; ALP=alkaline phosphatase; ALT=alanine transaminase; BUN=blood 
urea nitrogen; HBsAg=hepatitis B surface antigen; HBsAb=hepatitis B surface antibodies; HCVAb=antihepatitis 
C virus antibodies; INR=international normalized ratio; LDH=lactate dehydrogenase; PT=prothrombin time; 
aPTT=activated partial prothrombin time; RBC=red blood cells; TSH=thyroid stimulating hormone; WBC=white 
blood cell; WOCBP=women of child bearing potential. 

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a eGFR will be calculated by a central laboratory using the Modification of Diet in Renal Disease formula, where 
eGFR in mL/min/1.73m2 = 175 × [serum creatinine in mg/dL-1.154] × [Age-0.203] × [1.212 if Black] × [0.742 if 
female]. 
9.1.9.1. 
Pregnancy Screening 
A serum pregnancy test will be performed for WOCBP at screening.  A urinary pregnancy test 
will be performed monthly and at any time pregnancy is suspected.  The results of the pregnancy 
test must be known before administration of study drug.  Patients who are pregnant are not 
eligible for study participation.  Patients determined to be pregnant while on study will be 
followed until the pregnancy outcome is known (Section 9.8). 
9.1.9.2. 
Exploratory Biomarkers 
Where local regulations permit, predose blood samples will be collected.  Collection of blood 
samples for long-term storage to permit testing of additional proteins related to FAP and 
exploratory biomarker analysis will be subject to discretionary approval from the IRB/IEC at the 
clinical study centers.  Samples will be stored by the Sponsor or designee in a secure and 
controlled environment until analysis, and will be destroyed by the Sponsor or designee after all 
worldwide obligations have been met, or sooner if required by local regulations. 
9.1.9.3. 
Antidrug Antibodies 
Blood samples will be collected to evaluate antidrug antibodies.  Blood samples for antidrug 
antibody testing must be collected before study drug administration. 
9.2. 
Adverse and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is defined as any unfavorable and unintended change in structure, function, or chemistry 
of the body temporally associated with the use of the investigational product, whether or not it is 
considered related to the use of the product. 
Any medical condition that is present when a patient is screened and does not deteriorate should 
not be reported as an AE; however, if the medical condition does deteriorate at any time after 
administration of the first dose of study drug, it should be reported as an AE. 
9.2.1.2. 
Serious Adverse Event 
An 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 

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 Is a congenital abnormality or birth defect 
 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) 
9.2.1.3. 
Adverse Events of Clinical Interest 
The following events are considered to be AEs of clinical interest: 
 ISRs 
 Hepatic AEs, including LFT abnormalities considered clinically significant by the 
Investigator 
9.2.2. 
Eliciting Adverse Event Information 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC).  
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. 
9.3. 
Adverse Event Reporting 
The Investigator is responsible for reporting all AEs that are observed or reported after 
administration of the first dose of study drug regardless of their relationship to study drug 
through the end of study (28 days after administration of the last dose of study drug). 
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 investigational product, 
action taken, and outcome (including time and date of resolution, if applicable).   
For AEs that are considered AEs of clinical interest, additional clinical information may be 
collected based upon the severity or nature of the event.   
If a patient has ISRs meeting any of the following criteria, the Investigator or delegate should 
contact the Medical Monitor and submit a supplemental ISR eCRF: 
 ISRs that are recurrent and/or demonstrate a pattern of increasing severity 
 Any ISR that is determined to be severe and/or a cause for study drug discontinuation  
 Any ISR which, in the opinion of the Investigator, requires further medical evaluation or 
treatment 
In some cases, where it is medically appropriate, further evaluation may include photographs, 
referral to a dermatologist, skin biopsy, or other laboratory testing.  If a biopsy was obtained, the 

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Sponsor may request that the biopsy also be reviewed by a central dermatopathologist.  To better 
understand the safety profile of the study drug, additional analysis of biopsy tissue may be 
performed according to local regulations. 
For patients with hepatic AEs, additional information, including, clinical history, course of event, 
and local laboratory results to monitor LFT levels or other laboratory parameters, may be 
collected. 
9.4. 
Assessment of Causality 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in a plausible 
time relationship to the medication administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals.  The response to 
withdrawal of the drug should be clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to the medication administration, but which could also be explained 
by concurrent disease or other drugs or chemicals.  Information on the drug 
withdrawal may be lacking or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or no temporal 
relationship to medication administration, and which other drugs, chemicals, or 
underlying disease provide plausible explanations. 
Not Related: 
A clinical event, including laboratory test abnormality that has no temporal 
relationship to the medication or has more likely alternative etiology. 
9.5. 
Assessment of Severity 
Adverse events are to be graded according to the categories detailed below:   
Mild 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate 
Moderate events are those which cause sufficient discomfort to interfere with 
normal daily activities. 
Severe 
Severe events are those which incapacitate and prevent usual activity. 
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). 
9.6. 
Coding of Adverse Events 
The Medical Dictionary of Regulatory Activities (MedDRA) will be used to code AEs. 

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9.7. 
Serious Adverse Event Reporting 
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 9.2.1.2 must be reported to the 
CRO 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, and 
 Preliminary assignment of causality to study drug 
To report the SAE, complete the SAE form.  Within 24 hours of receipt of follow-up 
information, the Investigator must update the SAE form.  SAEs must be reported using the 
contact information provided below. 
SAE Reporting Contact Information 
Medpace, Inc. 
medpace-safetynotification@medpace.com 
Country-specific fax numbers will be included in the Study 
Reference 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. 
9.7.1. 
Notifying the Institutional Review Board/Independent Ethics Committee 
Serious adverse events 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. 
9.7.2. 
Sponsor Reporting:  Notifying Regulatory Authorities 
The Sponsor or its representative is required to 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. 
The following describes the safety reporting timeline requirements for suspected unexpected 
serious adverse reactions and other reportable events: 
Immediately and within 7 calendar days 

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 Any suspected adverse reaction that is:  associated with the use of the study drug, 
unexpected, and fatal or life threatening.  Follow-up information must be reported in 
the following 8 days. 
Immediately and within 15 calendar days 
 Any suspected adverse reaction that is:  associated with the use of the study drug, 
unexpected, and serious, but not fatal or life threatening, and there is evidence to 
suggest a causal relationship between the study drug and the reaction. 
 Any finding from tests in laboratory animals that:  suggest a significant risk for 
human patients including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 Any event in connection with the conduct of the study or the development of the 
study drug that may affect the safety of the trial patients. 
In addition, periodic safety reporting to regulatory authorities will be done by the Sponsor or its 
representative according to national and local regulations. 
9.7.3. 
Sponsor Notification of Participating Investigators 
All Investigators will be informed by the Sponsor or its representative of relevant clinical safety 
findings from this or other clinical studies, as well as any new findings from tests in laboratory 
animals that significantly impact the benefit/risk to patients in this study.  All reports should be 
transmitted to the IEC/IRB that approved the study. 
9.8. 
Pregnancy Reporting 
A female patient with a positive pregnancy test at screening is ineligible for this study.  If a 
female patient becomes pregnant during the course of this study (or during the first month 
following the last dose of study drug), the patient must be instructed to stop all study drug 
administration, and the Investigator must report the pregnancy to the CRO 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 and the possible effects on the fetus. 
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 meets the criteria for an SAE (ie, 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 9.7. 
If the female partner of a patient becomes pregnant during the course of this study, the 
Investigator must report the pregnancy to the CRO within 24 hours of being notified of the 
pregnancy.  The pregnancy should be followed by the Investigator until its conclusion. 

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10. 
STATISTICS 
10.1. 
Sample Size 
This is an open-label study to evaluate efficacy, safety, and PK of revusiran in patients with 
TTR-mediated FAP with disease progression post-OLT.  In healthy volunteers, mean reduction 
of 88% in serum TTR has been observed from baseline to Day 35 with a standard deviation of 
6%.  If this study yields a mean reduction of 80% at 6 months with a standard deviation of 6%, 
12 patients would yield a 95% confidence interval (CI) of approximately 77% to 83%. 
10.2. 
Statistical Methodology 
A full statistical plan will be finalized before database lock.   
The primary efficacy analysis will be performed after all patients have finished 6 months of 
treatment with study drug. 
Analyses will be performed using SAS® for Windows (version 9.2 or higher).  Descriptive 
statistics (mean, standard deviation, median, minimum, and maximum) will be presented for 
continuous variables, and frequencies and percentages will be presented for categorical and 
ordinal variables.  Percentages will be based on the number of nonmissing values in the dose 
group.  All study data will be presented in by-patient/patient data listings. 
10.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
Evaluable Analysis Set:  All patients who have received at least one dose of study drug and 
have a non-missing serum TTR result at the Month 6 (Week 26) visit. 
Safety Analysis Set:  All patients who received at least a single dose of study drug. 
PK Analysis Set:  All patients who received at least a single dose of study drug and have at least 
1 postdose blood sample for PK parameters and who have evaluable PK data. 
The primary population used to evaluate efficacy will be the Evaluable Analysis Set.  Safety will 
be analyzed using the Safety Analysis Set.  The PK Analysis Set will be used to conduct PK 
analyses. 
10.2.2. 
Baseline Evaluations 
Demographic and key disease characteristics data will be summarized.  Data to be tabulated 
consist of gender, age, ethnicity, and race, as well as other key disease characteristics. 
10.2.3. 
Efficacy Analyses 
10.2.3.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent reduction from baseline in serum TTR level at 6 
months.  This analysis will be a 2-sided 95% CI for the mean of the primary endpoint.  A t-test, 

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in which the null hypothesis of no reduction is compared against the alternative hypothesis of a 
change, will also be performed.   
Sensitivity analyses, including different methods for handling the missing data, will assess the 
robustness of the primary endpoint for the Evaluable Analysis Set. 
10.2.3.2. Secondary Efficacy Endpoints 
The secondary endpoints of the study are the change from baseline over 18 months for the 
following:  serum TTR, mNIS+7, Norfolk QOL-DN, and PND score. 
For continuous parameters, measurements will be summarized using descriptive statistics.  
Actual measurement, change, and percentage change from baseline to each scheduled visit will 
be summarized.  To understand the effect of revusiran, the mean change from baseline at 
18 months with the associated 80% and 95% CIs will also be summarized.   
For categorical parameters, frequencies and percentages will be presented.  To understand the 
effect of revusiran from baseline, the frequency and percentage of patients at each of the 
category shifts from baseline at 18 months will be summarized. 
10.2.3.3. Exploratory Endpoints 
The exploratory endpoints of the study are to assess the change from baseline over 18 months for 
the following:  mBMI, FAP stage, NIS, a grip strength test, NYHA classification, Karnofsky 
Performance Status, ECHO parameters, cardiac biomarkers, EQ-5D and COMPASS 31 
questionnaires, and an optional exploratory residual liver tissue evaluation, if available.  
Analyses for these endpoints will be conducted in a similar fashion as specified for secondary 
efficacy endpoints.   
10.2.4. 
Safety Analyses 
Safety assessments include AEs (including liver allograft rejection), clinical laboratory 
parameters (hematology and serum chemistry, including liver function tests, renal function, 
thyroid function, coagulation, and urinalysis), vital signs (oral body temperature, blood pressure, 
heart rate, and respiration rate), 12-lead ECGs, physical and ophthalmologic examinations, and 
concomitant medications (including immunosuppressive agent monitoring). 
10.2.4.1. Adverse Events 
Adverse events will be summarized by MedDRA System Organ Class and Preferred Term.  
Separate tabulations will be generated for treatment-emergent AEs (TEAEs), TEAEs by 
maximum severity, treatment-related AEs, SAEs, and discontinuation of study drug due to AEs.  
A patient listing will be produced for all AEs, deaths, SAEs, and AES leading to discontinuation 
of study drug. 
10.2.4.2. Vital Signs, Clinical Laboratory Safety Tests, 12-lead Electrocardiograms, 
Physical and Ophthalmologic Examinations 
For each continuous laboratory safety parameter (including, but not limited to, hematology, 
serum chemistry, coagulation, and urinalysis) results will be categorized as low, normal, or high 
based on the laboratory normal ranges.  Shifts from baseline laboratory grade to the maximum 

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laboratory grades will be examined for key safety parameters.  All out-of-range and clinically 
significant laboratory results will be identified in data listings.  Descriptive statistics will also be 
provided as actual value and change from baseline over time. 
Descriptive statistics for vital signs and ECG interval data will be presented by actual values and 
changes over time from baseline.  Details of any abnormalities will be included in the data 
listings. 
For ophthalmologic examinations, descriptive statistics of changes in eye examinations from 
baseline over time will be presented.  Separate listings will be generated for any abnormalities 
noted during the eye examination. 
10.2.4.3. Concomitant Medications  
All concomitant medications collected from screening through the study period will be classified 
to preferred terms according to the World Health Organization (WHO) drug dictionary.  
Additional safety analyses will focus on therapy, frequency, and dose of immunosuppressive 
agents. 

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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The clinical monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the monitor will visit the Investigator and clinical study center periodically 
as well as 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.  All 
aspects of the study will be carefully monitored by the Sponsor or its designee for compliance 
with applicable government regulations in respect to Good Clinical Practice (GCP) and current 
standard operating procedures. 
11.2. 
Audits and Inspections 
Authorized representatives of Alnylam Pharmaceuticals, Inc., a regulatory authority, an IEC, or 
an IRB may visit the clinical study center to perform audits or inspections, including source data 
verification.  The purpose of an Alnylam Pharmaceuticals, Inc. audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines of the International Conference on 
Harmonization (ICH), and any applicable regulatory requirements.  The Investigator should 
contact Alnylam Pharmaceuticals, Inc. immediately if contacted by a regulatory agency about an 
inspection. 
11.3. 
Institutional Review Board 
The Principal Investigator must obtain IRB/IEC approval for the investigation.  Initial IRB/IEC 
approval and all materials approved by the IRB/IEC for this study including the patient ICF and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
11.4. 
Quality Control and Quality Assurance 
Study staff is expected to adhere to the following practices governed by GCP and all applicable 
regulatory requirements.  To ensure these practices are in place, the Sponsor may conduct a 
quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her 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. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections or other studies that 
impact this protocol or the qualifications of study staff should be promptly reported to the CRO. 

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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. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national and any local regulations. 

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12. 
ETHICS 
12.1. 
Ethics Review 
The final study protocol, including the final version of 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 to Alnylam Pharmaceuticals, Inc. before he or she can enroll any patient into 
the study. 
The Principal 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 
advertising used to recruit patients for the study.  The protocol must be reapproved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  Alnylam Pharmaceuticals, Inc. will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
12.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements, 
and Alnylam Pharmaceuticals, Inc.’s policy. 
12.3. 
Written Informed Consent 
The Principal Investigator(s) at each center 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 withdraw 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 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the patient. 

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13. 
DATA HANDLING AND RECORD KEEPING 
13.1. 
Inspection of Records 
Alnylam Pharmaceuticals, Inc. will be allowed to conduct clinical study center 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, and other records relative to 
study conduct. 
13.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
at least 2 years after the last marketing application approval, or if not approved 2 years following 
the discontinuance of the test article for investigation.  If it becomes necessary for Alnylam 
Pharmaceuticals, Inc. or the Regulatory Authority to review any documentation relating to the 
study, the Investigator must permit access to such records. 

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14. 
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 copy of any proposed manuscript 
must be provided and confirmed received at Alnylam at least 30 days before submission, and 
according to any additional publication details in the Investigator Agreement. 

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15. 
LIST OF REFERENCES 
1. Stangou, A.J., Hawkins, P.N. Liver transplantation in transthyretin-related familial 
amyloid polyneuropathy. Curr Opin Neurol. 2004;17(5):615-620. 
2. Connors LH, Lim A, Prokaeva T, Roskens VA, Costello CE. Tabulation of human 
transthyretin (TTR) variants. Amyloid. 2003;10:160-184. 
3. Tsuchiya A, Yazaki M, Kametani F, Takei Y-i, Ikeda S-i. Marked regression of 
abdominal fat amyloid in patients with familial amyloid polyneuropathy consists of 
abundant wild-type transthyretin. Liver Transplantation. 2008;14:702-706. 
4. 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;274(3):702-706. 
5. Suhr OB. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) 
patients' symptoms and complications. Amyloid. 2003;10(Suppl 1):77-83. 
6. Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic 
polyneuropathy. Arch Neurol. 2005;62(7):1057-1062. 
7. Coelho T, Adams D, Silva A, et al. Safety and Efficacy of an RNAi Therapeutic 
Targeting Transthyretin (TTR) for TTR Amyloidosis. NEJM. 2013, accepted for 
publication. 
8. Carvalho M, Alves M, Luis M. Octreotide--a new treatment for diarrhoea in familial 
amyloidotic polyneuropathy. J Neurol Neurosurg Psychiatry. 1992;55(9):860-861. 
9. Connors LH, Yamashita T, Yazaki M, Skinner M, Benson MD. A rare transthyretin 
mutation (Asp18Glu) associated with cardiomyopathy. Amyloid. 2004;11(1):61-66. 
10. 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;14(4):543-553. 
11. Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid 
neuropathy. Muscle Nerve. 2007;36(4):411-423. 
12. Eriksson P, Olofsson BO. Pacemaker treatment in familial amyloidosis with 
polyneuropathy. Pacing Clin Electrophysiol. 1984;7(4):702-706. 
13. Roberts WC, Waller BF. Cardiac amyloidosis causing cardiac dysfunction: analysis of 54 
necropsy patients. Am J Cardiol. 1983;52(1):137-146. 
14. Shah KB, Inoue Y, Mehra MR. Amyloidosis and the heart: a comprehensive review. 
Arch Intern Med. 2006;166(17):1805-1813. 
15. Plante-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 
2011;10(12):1086-1097. 
16. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid 
polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658-2667. 

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17. Reines JB, Vera TR, Martín MU, et al. Epidemiology of transthyretin-associated familial 
amyloid polyneuropathy in the Majorcan area: Son Llatzer Hospital descriptive study. 
Orphanet J Rare Dis. 2014;9:29. 
18. Adams D, Mincheva Z, Antonini T, et al. Worsening of familial amyloid polyneuropathy 
after liver transplant. J Peripheral Nervous System. 2013;18(Supplement): S2. 
19. Benson MD. Liver transplantation and transthyretin amyloidosis. Muscle Nerve. 
2013;47(2):157-162. 
20. Tsuchiya-Suzuki A, Yazaki M, Kametani F, Sekijima Y, Ikeda S. Wild-type transthyretin 
significantly contributes to the formation of amyloid fibrils in familial amyloid 
polyneuropathy patients with amyloidogenic transthyretin Val30Met. Hum Pathol. 
2011;42:236–43. 
21. Yazaki M, Mitsuhashi S, Tokuda T, et al. Progressive wild-type transthyretin deposition 
after liver transplantation preferentially occurs onto myocardium in FAP patients. Am J 
Transplantation. 2007;7(1):235-242. 
22. Ihse E, Suhr OB, Hellman U, Westermark P. Variation in amount of wild-type 
transthyretin in different fibril and tissue types in ATTR amyloidosis. J Mol Med (Berl). 
2011;89(2):171-180. 
23. Ericzon BG,Wilczek HE. Liver transplantation for hereditary transthyretin amyloidosis: 
After 20 years still the best therapeutic alternative? Transplantation. 2015. 
24. Vaishnaw AK, Gollob J, Gamba-Vitalo C, et al. A status report on RNAi therapeutics. 
Silence. 2010 Jul 8;1(1):14. 
25. Elbashir SM, Lendeckel W, Tuschi T. RNA interference is mediated by 21- and 22-
nucleotide RNAs. Genes Dev. 2001 Jan 15;15(2):188-200. 
26. Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous gene by 
systemic administration of modified siRNAs. Nature. 2004 Nov 11;432:173-178. 
27. Coelho T, Silva A, Suhr OB, et al. Final Phase 1 safety, pharmacokinetic and 
pharmacodynamics results for ALN-TTR01, a novel RNAi therapeutic for the treatment 
of transthyretin amyloidosis. 13th International Symposium of Amyloidosis, 2012 Oral 
Presentation. 
28. Fitzgerald K, Frank-Kamenetsky M, Mant T, et al. Phase I safety, pharmacokinetic and 
pharmacodynamics results for ALN PCS02, a novel RNAi therapeutic for the treatment 
of hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology 2012 
Scientific Sessions. Oral Presentation. 
29. Lachmann HJ, Gallimore R, Gillmore JD, et al. Outcome in systemic AL amyloidosis in 
relation to changes in concentration of circulating free immunoglobulin light chains 
following chemotherapy. Br J Haematol. 2003;122(1):78-84. 
30. Lachmann HJ, Goodman HJ, Gilbertson JA, et al. Natural history and outcome in 
systemic AA amyloidosis. N Engl J Med. 2007;356(23):2361-2371. 
31. Gillmore JD, Hawkins PN. Drug Insight: emerging therapies for amyloidosis. Nat Clin 
Pract Nephrol. 2006;2(5):263-270. 

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32. Stangou AJ, Banner NR, Hendry BM, et al. Hereditary fibrinogen A alpha-chain 
amyloidosis: phenotypic characterization of a systemic disease and the role of liver 
transplantation. Blood. 2010;115(15):2998-3007. 
33. Oshima T, Kawahara S, Ueda M, et al. Changes in pathological and biochemical findings 
of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver 
transplantation. J Neurol Neurosurg Psychiatry. 2014;85(7):740-6. 
34. The EuroQol Group. EuroQol-a new facility for the measurement of health-related 
quality of life. Health Policy.1990;16(3):199-208. 
35. Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS-31: a refined and 
abbreviated composite autonomic symptom score. Mayo Clin Proc. 2012;87:1196-1201. 
36. Liepnieks JJ, Zhang LQ, Benson MD. Progression of transthyretin amyloid neuropathy 
after liver transplantation. Neurology. 2010;75:324–327. 
37. Vinik EJ, Vinik AI, Paulson JF, Merkies ISJ, Packman J, Grogan DR, and CoelhoT.  
Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin 
familial amyloid polyneuropathy. Journal of the Peripheral Nervous System. 
2014;19:104–114. 
38. Yamamoto S, Wilczek HE, Nowak G, et al. Liver transplantation for familial amyloidotic 
polyneuropathy (FAP): a single-center experience over 16 years. Am J Transplant. 
2007;7:2597-604. 
39. Coutinho P, DeSilva AM, Lima JL, Barbosa AR. Forty years of experience with type I 
amyloid neuropathy:  review of 483 cases. In: Glenner GG, Pinho P, Costa E, Falcao de 
Freitas A, Eds. Amyloid and Amyloidosis. Amsterdam: Excerpta Medica;1980:88-98. 
40. Demetris AJ, Adeyi O, Bellamy CO, Clouston A, Charlotte F, et al. Banff Working 
Group.  Liver biopsy interpretation for causes of late liver allograft dysfunction. 
Hepatology 2006;44:489-501. 
41. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry. 2011 Dec;168:1266-77. 

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16. 
APPENDICES 
16.1. 
Modified Neurological Impairment Score +7 Components 
 
 
Assessment Tool 
Total Points 
Components (points) 
Modified NIS+7 
304 
 Neurologic exam of lower limbs, upper limbs, and cranial 
nerves (mNIS) 
 Weakness (192) 
 Reflexes (20) 
 Nerve conduction studies ∑5 (10) 
 Ulnar CMAP and SNAP, sural SNAP, tibial 
CMAP, peroneal CMAP 
 Quantitative sensory testing:  QST-BSATP+HP (80) 
 Postural blood pressure (2) 
Abbreviations: ∑5=5 attributes; CMAP=compound muscle action potential; QST-BSATP+HP=quantitative sensory 
testing, body surface area, touch pressure plus heat pain; SNAP=sensory nerve action potential. 

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16.2. 
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 1 stick or crutch 
Walking with the help of 2 sticks or crutches 
IV 
Confined to a wheelchair or bedridden 

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16.3. 
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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16.4. 
New York Heart Association Classification of Heart Failure 
Class 
Symptomology 
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 1 to 2 blocks on the level and 
climbing more than 1 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. 

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16.5. 
Karnofsky Performance Status 
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 is not imminent 
20 
Very sick; hospital admission necessary; active supportive 
treatment necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead