Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL
cholesterol. N Engl J Med. DOI: 10.1056/NEJMoa1912387
 Supplementary Appendix

Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

Kausik K Ray MD MPhil*, R Scott-Wright MD*,
David Kallend MD, Wolfgang Koenig MD, Lawrence A. Leiter MD, Frederick J
Raal PhD, Jenna A Bisch BA, Tara Richardson, B.A., Mark Jaros, Ph.D., Peter LJ
Wijngaard PhD, John JP Kastelein MD PhD for the ORION-10 and ORION-11
Investigators**
*
KKR and RSW contributed equally to this manuscript
**The ORION-10 and ORION-11 investigators are listed in section 2 of this
appendix

2
Supplementary Appendix Table of Contents

1. Study Oversight .................................................................................................................. 4

1.1 Executive Committee ........................................................................................................ 4
1.2 Independent Data Monitoring Committee.......................................................................... 5
2. List of Investigators and Study Sites ................................................................................... 6
3. Trial Registration ................................................................................................................13
4. Study Methods ...................................................................................................................14
4.1 Inclusion Criteria ..............................................................................................................14
4.2 Exclusion Criteria.............................................................................................................14
4.3 Baseline Statin Dose Categories .....................................................................................16
4.4 Randomization Strata ......................................................................................................16
4.5 Clinical End Point Adjudication ........................................................................................16
4.6 Laboratory Analytical Methods.........................................................................................16
4.7 Sample Size ....................................................................................................................18
4.8 Statistical Analyses – Efficacy End Points .......................................................................19
5. Supplementary Figures ......................................................................................................20
6. Supplementary Tables .......................................................................................................25
7. References ........................................................................................................................31

3
1. Study Oversight
The Principal Investigators and academic executive committee in collaboration with the sponsor
(The Medicines Company) designed the protocols of the ORION-10 and ORION-11 trials, which
were also agreed with Regulators, and also selected the countries and sites. Site monitoring
was performed by a CRO (PPD) and overseen by the sponsor. Data was collected on an eCRF
and reviewed and databased by the sponsor. At the end of the study, after unblinding data
analysis was performed by the sponsor. The manuscript was drafted by the Principal
Investigators with all co-authors contributing. The executive committee acted as the academic
steering group overseeing trial conduct.
Some sites were part of a site network that came under the umbrella of the CRO. All PIs at the
sites were physicians with experience in clinical trials and employed by the site. All CROs in any
study are paid by the sponsor for work performed and there was no difference in this study.
The independent Data Monitoring Committee (DMC) reviewed unblinded safety data beginning
after the first 40 subjects received the first injection of inclisiran or placebo and completed the
day 30 day follow-up visit. Thereafter the DMC reviewed safety data every 3 months until end of
study.
The Institutional review boards at each participating site approved the study protocol and each
patient provided written informed consent.

1.1 Executive Committee

Member
Kausik K. Ray, M.D., M.Phil.
(Principal Investigator ORION-11)
R Scott Wright, M.D.
(Principal Investigator ORION-10)
Wolfgang Koenig, M.D.
Lawrence A. Leiter, M.D.
John JP Kastelein, M.D, PhD
Frederick J Raal, PhD.
Peter LJ Wijngaard, PhD
David G Kallend, MBBS
Affiliation
Imperial College London, London, UK
Mayo Clinic, Rochester, Minnesota, USA
Deutsches Herzzentrum München, Germany
Li Ka Shinn=g Knowledge Institute, St. Michael’s
Hospital, University of Toronto, Toronto, Canada
Academic Medical Center, University of Amsterdam,
Amsterdam
University of the Witwatersrand, South Africa
The Medicines Company, Parsippany, USA
The Medicines Company, Zurich, Switzerland

4
1.2 Independent Data Monitoring Committee

Name/Credentials
David Waters, M.D. (Chair)
Terje Pedersen, M.D.
Eva Lonn, M.D, MSc, FRCP, FACC
Ian Ford
Address
UCSF, San Francisco, USA
Ulleval University Hospital, Oslo, Norway
McMaster University, Hamilton, Ontario, Canada
University of Glasgow, Glasgow, UK

5
2. List of Investigators and Study Sites
ORION-10 was conducted in the USA

Investigator Name Institution

James Kopp Synexus - Radiant Research, Inc. - Anderson
Michael Adams Synexus Clinical Research US, Inc. - Salt Lake City
Linda Murray Synexus Clinical Research - St. Petersburg
Charles Michieli Synexus Clinical Research US, Inc. – Orange Grove Family Practice
Jeffery DeGrauw Synexus Clinical Research US, Inc. - Wasatch Peak Family Practice
William Ellison Synexus - Radiant Research, Inc. - Greer
Leslie Tharenos Synexus Clinical Research US, Inc. - St. Louis
Stephen Halpern Synexus Clinical Research Inc
Michele Reynolds Synexus Clinical Research US, Inc. – Dallas- Greenville
Michael Noss Synexus Clinical Research US, Inc
Gary Korff Synexus - Clinical Research Advantage, Inc. - Carlsbad
Stephen Canowitz Synexus - Clinical Research Advantage, Inc. -Canyon Medical Center, Inc.
Randall Severance Synexus Clinical Research US, Inc. - Phoenix SE
Douglas Schumacher Synexus Clinical Research
William Kirby Synexus - Clinical Research Advantage, Inc. - Simon Williamson Clinic, PC
Jeffrey Klein Synexus Clinical Research - Akron
Rickie Conrady Synexus Clinical Research US, Inc. –Oklahoma City Clinic
Tami Wahlin Synexus Clinical Research US, Inc. - Minneapolis
Robert Lending Synexus Clinical Research US, Inc. - Tucson
Michael Harper Synexus Clinical Research US, Inc.
Jennifer Kay Synexus Clinical Research US, Inc - Omaha
Mehrdad Ariani Valley Clinical Trials, Inc
John Scott National Clinical Research Inc
Ahmed Arif AA MRC LLC
Mohammad Shoukfeh Caprock Cardiac Center Research Institute
Bogdan Gheorghiu BG Neurology
Matthew Teltser A & R Research Group, LLC
Timothy Crater Hutchinson Clinic
David Ramstad Suffolk Multispecialty Research, LLC
Sara Llerena Columbus Clinical Services LLC

6
Anwar Ahmad East Texas Cardiology
Krishnamoorthy
Northwest Houston Cardiology PA
Vivekananthan
Jeffrey Wayne Clinical Trials Research - Sacramento
Neil Fraser Arcturus Healthcare, PLC
Dennis Levinson Chicago Clinical Research Institute
Jeffrey Geohas Evanston Premier Healthcare Research LLC
Barry McLean Central Alabama Research
Sady Alpizar Clinical Research Trials of Florida, Inc
John Evans East Coast Institute for Research, LLC
Robert Buynak Buynak Clinical Research, P.C.
Michael Seep Centex Studies Inc
Sashi Makam Mid Hudson Medical Research PLLC
Ramachandra Patak California Medical Research Associates, Inc.
Matthew Budoff Los Angeles Biomedical Research Institute at Harbor-UCLA
Ahmad Aslam Northwest Houston Clinical Research, PLLC
Stephen Jones Carolina Research Center
Seth Baum Excel Medical Clinical Trials LLC
Alvaro Murcia DBC Research USA
Hessam Aazami Hope Clinical Research, LLC
Jalal Abbas Clinical Research Institute
Jeffrey Anderson Intermountain Medical Center
David Bouda Heartland Clinical Research Inc
Robert Busch Albany Medical College
Robert Falcone Amici Clinical Research
Leslie Forgosh HealthEast Medical Research Institute
Randal Jacks Hill Country Medical Associates
John LeDoux CB Flock Research Corporation
Steven Lupovitch Northwest Heart Clinical Research LLC
Sharan Mahal Advanced Heart Care
Joe Pouzar Centex Studies Inc
Priyavadan Shah Cary Research Group, LLC
Thomas Stuckey Moses H Cone Memorial Hospital
Suhail Zavaro Triwest Research Associates LLC

7
Jose Cardona Indago Research and Health Center
Mahesh Changlani Doctors Hospital at Renaissance
Winston Gandy Ellipsis Group
Bernard Garcia Invesclinic, LLC
William Jennings Synexus Clinical Research US, Inc. – San Antonio
Norman Lepor Westside Medical Associates of Los Angeles
James Lovell Iowa Clinic
Ronald Mayfield Mountain View Clinical Research Inc
Howard Rubenstein The Center for Clinical Trials
Gerald Shockey Synexus Clinical Research US, Inc.–Desert Clincial Research, Inc.
Stuart Stoller Tri-County Research, Inc.
Joseph Szcytowski Austin Heart, PA
Antonio Terrelonge Ocean Blue Medical Research Center Inc
Jorge Venereo Pharmax Research Clinic LLC
Phillip Toth Midwest Institute For Clinical Research
Laura Akright Northeast Clinical Research of San Antonio, LLC
Mahesh Amin BayCare Medical Group
Nabil Andrawis Manassas Clinical Research Center
Anthony Captain Global Research Partners and Consultants Inc
Anurekha Chadha ARC Clinical Research at Wilson Parke
Ankur Doshi Primecare Medical Group
Jonathan Fialkow Cardiovascular Research Center of South Florida
Ferris George East Coast Institute for Research, LLC
Timberly Gilford Associates In Medicine
Ashwini Gore East Coast Institute for Research, LLC
Tariq Haddad Virginia Heart
Aaron Hartman Virginia Research Center, LLC
Sandeep Khurana Healthy Heart Cardiology
Michael Koren Jacksonville Center For Clinical Research - ERN-PPDS
Srikanth Malempati Tampa Bay Medical Research Inc - MRA
Joaquin Martinez-Arraras Amarillo Heart Clinical Research Institute Inc
Mark Napoli Clinical Trials of America LA LLC
Brien Peirpont Advanced Medical Research Center
Drew Purdy Black Hills Cardiovascular Research, a department of Rapid City Regional Hospital, Inc

8
Erich Schramm St John's Center For Clinical Research - ERN-PPDS
Alfred Tan West Coast Research LLC
Charles Treasure Cardiovascular Research of Knoxville
Kishor Vora Research Integrity LLC
Jonathan Waltman KentuckyOne Health Cardiology Associates
Andrew Waxler Penn State Health Medical Group - Berks Cardiology
James Wild Upstate Clinical Research Associates LLC
Jonathan Bornfreund Family Medicine of Sayebrook
Atoya Adams AB Clinical Trials
Saadat Ansari Longwood Research
Sabrina Benjamin Universal Research Group LLC
Kenneth Blaze South Broward Research
Cristian Breton International Research Associates LLC
Thomas Carlson Austin Heart, PA
Evelyne Davidson New Phase Research & Development
William Davila Fleming Island Center For Clinical Research
Philip Diller Sterling Research Group, Ltd.
Frank Eder United Medical Associates
Mahfouz El-Shahawy Cardiovascular Center of Sarasota
Roger Estevez Clinical Research of South Nevada
Neil Farris Research Group of Lexington LLC
David Henderson Cardiology Associates Research Company
James Holler Regional Clinical Research Inc
Mumtazuddin Zubair Jafar Hudson Valley Cardiovascular Practice, PC
Curtis Jantzi Holston Medical Group PC
Vicki Kalen Eclipse Clinical Research
Daniel Koontz Palmetto Institute of Clinical Research Inc
Padma Mangu Sterling Research Group, Ltd.
Brock Merritt Phoenix Clinical LLC
Alan Miller Alta Pharmaceutical Research Center Inc
Nidal Morrar G & L Research, LLC
Edward Pereira East Coast Institute for Research, LLC
Jorge Posada Veritas Research Corporation
William Randall PriMed Clinical Research

9
Lilia Rodriguez Ables Finlay Medical Research Corporation
Saihari Sadanandan Comprehensive Research Institute
Satinder Saini Avant Research Associates, LLC
Bruce Seaton PMG of Piedmont Healthcare
Charles Sharpe Athens Medical Group
Pamela Stearns South Florida Research Solutions, LLC
Sanjay Vora SV Research LLC
Michelle Welch Consano Clinical Research LLC
Mohamed El-Shahawy Academic Medical Research Institute
Robert Lipetz Encompass Clinical Research
Traci Turner Metabolic and Atherosclerosis Research Center
Jorge Navas Clearwater Cardiovascular and Interventional Consultants
George Kichura St. Louis Heart and Vascular
Phyllis Marx Synexus - Radiant Research, Inc. - Chicago

ORION-11 was conducted in the Czech Republic, Germany, Hungary, Poland, South
Africa, Ukraine and the United Kingdom.

Investigator Name Institution

Czech Republic
Jan Malecha Synexus Affiliate - Ordinace pro choroby srdce s.r.o
Antonin Dufka Synexus Affiliate - Clinical Trial Service s.r.o
Germany
Katrin Arelin Synexus - Leipzig
Suresh Yadav Synexus - Bochum
Christel Contzen Synexus - Frankfurt
Liana Vismane Synexus - Berlin
Manuela Licka University Clinic Heidelberg - PPDS
Hungary
Károly Nagy Synexus (DRS) - Synexus Magyarország Kft. Budapest
Csaba Hajdú Synexus Affiliate - BKS Research Kft. Hatvan
Karoly Wittmann Synexus (DRS) - Synexus Magyarország Kft. Zalaegerszeg
Csilla Nemeti Synexus Affiliate - Synexus Magyarorszag Kft. Debrecen
Poland
Malgorzata Duszynska Synexus – Poznan

10
 Anna Sidorowicz-Bialynicka Synexus – Wroclaw
Piotr Rozpondek Synexus Affiliate - Krakowskie Centrum Medyczne
Malgorzata Jagielska-Plata Synexus – Gdansk
Jolanta Krzykowska Synexus – Gdynia
Dorota Knychas Synexus – Warsaw
Elzbieta Blach Synexus – Katowice
Robert Glowka Synexus Affiliate - Clinical Best Solutions - Lublin
Instytut Kardiologii im Prymasa Tysiaclecia Kardynala Stefana
Jerzy Pregowski
Wyszynskiego
Donald Drozdz Zdrowie s.c. Agnieszka i Donald Drozdz
Renata Bijata-Bronisz Medical Center Kermed
Danuta Wronska Pro Familia Altera Sp. z o.o.
Rafal Sztembis Medical Center MEDYK
Jaroslaw Trebacz Centrum Medyczne Zdrowa
Boguslaw Derlaga Specjalistyczny Gabinet Lekarski Internistyczno-Kardiologiczny
Marek Styczkiewicz Szpital Specjalistyczny w Brzozowie
Bozena Zieba Gdanskie Centrum Zdrowia
Teresa Rusicka Niepubliczny Zaklad Opieki Zdrowotnej VITAMED
Janusz Spyra Specjalistyczna Praktyka Lekarska
South Africa
Lesley Burgess Synexus Affiliate - Tread Research Cc
Nyda Fourie Synexus Affiliate - Iatros International
Dorothea Urbach Synexus - Helderberg Clinical Research Centre
Thomas Coetzer Synexus Affiliate - CLINRESCO, ARWYP Medical Suites
Elane Nieuwenhuizen Synexus - Watermeyer Clinical Research Centre
Landman Lombard Synexus Affiliate - Cape Town Medical Centre
Yacoob Vahed Synexus Affiliate - Welkom Clinical Trial Centre
Suzanne Blignaut Synexus Affiliate - Paarl Research Centre
Ukraine
Synexus Affiliate - Medical Center of PHEI Institute of General
Inna Sorokina
Practice - Family Medicine
Synexus Aff - MC of SC Medical Scientific and Practical Association
Oleksandra Donets
Medbud of the PJS HC Kyivmiskbud
Synexus Aff - Kyiv Railway Clinical Hospital No2 of Branch Health
Halyna Myshanych
Center of the JSC Ukrainian Rail
Synexus Affiliate - State Institution Research Centre For Radiation
Oleksandr Kovalov
Medicine of NAMS of Ukraine

11
 Communal Nonprofit Enterprise Cherkasy Regional Onсology
Anna Kulyk
Dispensary of Cherkasy Oblast Council
Synexus Affiliate - Transcarpathian Regional Clinical Cardiological
Myroslava Vayda
Dispensary
Communal noncommercial enterprise of Lviv Regional Council Lviv
Orest Abrahamovych
Regional Clinical Hospital
Сommunal nonprofit enterprise Kharkiv City Clinical Hospital #8 of
Vira Tseluyko
Kharkiv city council
Communal Nonprofit Enterprise City Hospital #6 of Zaporizhzhia City
Roman Stets
Council
United Kingdom
Imrozia Arif Synexus - Scotland Clinical Research Centre
Nicoletta Sulli Synexus - North Tees Clinical Research Centre
Devina Weeraratne Synexus - Thames Valley Clinical Research Centre
Yieng Huong Synexus - Merseyside Clinical Research Centre
Madhu Venkate Gowda Synexus - Manchester Clinical Research Centre
Christina Kyriakidou Synexus - Midlands Clinical Research Centre
Hawys Thomas Synexus - Wales Clinical Research Centre
Nicoletta Sulli Synexus - Hexham Clinical Research Centre
Adrian Renouf Adrian Royal Devon and Exeter Hospital NHS Trust
Mark Blagden Ashgate Medical Practice
Rehan Symonds Oak Tree Surgery
Mahadev Ramjee Synexus - Lancashire Clinical Research Centre
Timothy Hall Knowle House Surgery
Ian Collyer Waters Green Medical Centre
Philip Stratford-Smith West Timperley Medical Centre
Paul Jackson Boundary House Medical Centre
Grainne Breen Firsway Health Centre
Keith Richardson Bridge House Medical Centre
Stephen Tomkinson Bodey Medical Centre
Simon De Vial Moorgate Primary Care Centre
Samina Ashraf Davyhulme Medical Centre
Peter Wilson The Waterhouse
Damian Allcock Barlow Medical Centre

12
3. Trial Registration
ORION-10
Registration for study MDCO-PCS-17-04 was submitted to ClinicalTrials.gov on 03 Jan 2018.

 The first patient was screened on Decr 15 2017, and was randomized on Dec 21 2017.

ORION-11
Registration for study MDCO-PCS-17-08 was submitted to ClinicalTrials.gov on 09 Jan 2018.

 The first patient was screened on 27 Oct 2017, and was randomized on 01 Nov 2017.

13
4. Study Methods
4.1 Inclusion Criteria
The inclusion criteria for ORION-10 and ORION-11 were identical except that ORION-11 also
included some patients without ASCVD into a risk-equivalent category for whom there was a
higher LDL-C entry criteria.
1. Male or female subjects ≥18 years of age
2. History of ASCVD (CHD, CVD or PAD; see APPENDIX A) or in ORION-11 ASCVD-risk
equivalents (type 2 diabetes, familial hypercholesterolemia (FH), and including subjects
whose 10-year risk of a CV event assessed by Framingham Risk Score for Cardiovascular
Disease or equivalent has a target LDL-C of <100 mg/dL). FH was defined using standard
clinical criteria used in the region. These include Dutch Lipid Clinic Network (DLCN) criteria,
Simon Broome criteria and Make Early Diagnosis to Prevent Early Deaths (MEDPED
criteria.
3. Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL) for ASCVD subjects or ≥2.6 mmol/L (≥100 mg/dL)
for ASCVD-risk equivalent subjects at screening
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening
5. Calculated glomerular filtration rate >30 mL/min/ 1.73 m2 by estimated glomerular filtration
rate (eGFR) using Cockcroft Gault methodology.
6. Subjects on statins should be receiving a maximally tolerated dose. Maximum tolerated
dose is defined as the maximum dose of statin that can be taken on a regular basis without
intolerable adverse events. Intolerance to any dose of any statin must be documented as
historical AEs attributed to the statin in question in the source documentation and on the
Medical History page of the electronic case report form (eCRF) (see APPENDIX B).
7. Subjects not receiving statin must have documented evidence of intolerance to all doses of
at least two different statins (see APPENDIX B).
8. Subjects on lipid-lowering therapies (such as a statin and/or ezetimibe) should be on a
stable dose for ≥30 days before screening with no planned medication or dose change
during study participation.
9. Subjects must be willing and able to give informed consent before initiation of any study-
related procedures and willing to comply with all required study procedures.

4.2 Exclusion Criteria

1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either
interfere with participation in the clinical study, and/or put the subject at significant risk
(according to investigator’s [or delegate] judgment) if he/she participates in the clinical study.
2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion
of the investigator (or delegate) might interfere with interpretation of the clinical study
results.
3. New York Heart Association (NYHA) class IV heart failure or last known left ventricular
ejection fraction <25%.
4. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by
medication or via ablation.
5. Major adverse cardiovascular event within 3 months prior to randomization.

14
6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood
pressure >110 mmHg prior to randomization despite anti-hypertensive therapy.
7. Active liver disease defined as any known current infectious, neoplastic, or metabolic
pathology of the liver or unexplained elevations in ALT, aspartate aminotransferase (AST),
>3x the ULN, or total bilirubin >2x ULN at screening confirmed by a repeat abnormal
measurement at least 1 week apart.
8. Severe concomitant non-cardiovascular disease that carries the risk of reducing life
expectancy to less than 2 years.
9. History of malignancy that required surgery (excluding local and wide-local excision),
radiation therapy and/or systemic therapy during the three years prior to randomization.
10. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to
use at least two methods of highly effective contraception (failure rate less than 1% per
year) (eg combined oral contraceptives, barrier methods, approved contraceptive implant,
long- term injectable contraception, or intrauterine device) for the entire duration of the
study. Exemptions from this criterion:
a. Women >2 years postmenopausal (defined as 1 year or longer since last menstrual
period) AND more than 55 years of age.
b. Postmenopausal women (as defined above) and less than 55 years of age with a
negative pregnancy test within 24 hours of randomization.
c. Women who are surgically sterilized at least 3 months prior to enrollment.
11. Males who are unwilling to use an acceptable method of birth control during the entire study
period (ie, condom with spermicide).
12. Known history of alcohol and/or drug abuse within the last 5 years.
13. Treatment with other investigational products or devices within 30 days or five half˗lives of
the screening visit, whichever is longer.
14. Planned use of other investigational products or devices during the course of the study.
15. Any condition that according to the investigator could interfere with the conduct of the study,
such as but not limited to:
d. Subjects who are unable to communicate or to cooperate with the investigator.
e. Unable to understand the protocol requirements, instructions and study-related
restrictions, the nature, scope, and possible consequences of the study (including
subjects whose cooperation is doubtful due to drug abuse or alcohol dependency).
f. Unlikely to comply with the protocol requirements, instructions, and study-related
restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and
improbability of completing the study).
g. Have any medical or surgical condition, which in the opinion of the investigator would put
the subject at increased risk from participating in the study.
h. Persons directly involved in the conduct of the study.
16. Treatment (within 90 days of screening) with monoclonal antibodies directed towards
PCSK9.
Subjects excluded for any of the above reasons may not be re-screened for participation at any
time even if the exclusion characteristic has changed.

15
4.3 Baseline Statin Dose Categories

High-intensity Statins Moderate-intensity Statins Low-intensity Statins*

Atorvastatin 40 – 80 mg Atorvastatin 10 – 20 mg Simvastatin 10 mg
Rosuvastatin 20 – 40 mg Rosuvastatin 5 – 10 mg Pravastatin 10 – 20 mg
Simvastatin 80mg Simvastatin 20 – 40 mg Lovastatin 20 mg
Pravastatin 40 – 80 mg Fluvastatin 20 – 40 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg twice daily
Pitavastatin 2 – 4 mg
*Low-intensity statins also include those patients taking low-dose statins using an alternate regimen (i.e., every
other day or for a specified number of times per week).

4.4 Randomization Strata

ORION-10

Statin use

ORION-11

Statin use Country

4.5 Clinical End Point Adjudication

No clinical endpoint adjudication was performed in this study

4.6 Laboratory Analytical Methods

All analyses were performed by Medpace Reference laboratories (MRL) who are certified in the
CDC-NHLBI Lipid Standardization Part III Program.
PCSK9 analysis was performed using Quantikine ELISA from R&D Systems according to the
manufacturer’s instructions using a Tecan Sunrise reader and EDTA-plasma. Intra- and inter-
assay coefficients of variation were observed to be 4.7% and 5.4%. Completed subject sets
were analyzed on the same plate to eliminate inter-assay variability when comparing results
within a subject.
LDL cholesterol was determined by both the Friedewald formula, and additionally by preparative
ultracentrifugation (PUC). LDL cholesterol methods remained the same throughout the trial,
including both calibration and reagent systems. MRL does not change methods during the
course of a study. Reflexive testing for LDL-C with ultracentrifugation was performed if LDL-C

16
was < 40mg/dl or TG was greater than 400mg/dl. Baseline samples were not reanalysed if LDL-
C fell below 40mg/dl during the trial.
Analytical methods (includes all methods required to derive LDL cholesterol by
Friedewald and PUC)
Analysis of total cholesterol (TC) and triglycerides (TG) were by enzymatic methods on a
Beckman Coulter AU Series automatic analyzer with in-house developed serum calibrators
directly traceable to CDC-NHLBI reference procedures. (Ref: Myers GL, Cooper GR, et al. The
Centers for Disease Control-National Heart, Lung and Blood Institute Lipid Standardization
Program. An approach to accurate and precise lipid measurements. Clin Lab Med 1989;9:105-
35).
HDL cholesterol was performed by precipitation with 50 kDa dextran sulfate with magnesium
ions (MgCl2), followed by analysis of the supernatant for cholesterol by enzymatic methods on a
Beckman Coulter AU Series automatic analyzer with in-house developed serum calibrators
directly traceable to CDC-NHLBI reference procedures (same methodology as TC).
PUC was performed using the method outlined in the Lipid Research Clinics methods manual.
(Ref: US Department of Health and Human Services. Manual of laboratory operations: lipid and
lipoprotein analysis (revised). Washington, DC: US Government Printing Office; 1982. Report
No.: (NIH) 75-67815).
Serum or plasma was overlaid with normal saline (density 1.006 g/mL) and centrifuged
(Beckman Ultracentrifuge Model # L-90K and rotor, Type 50.4) at 40,000 rpm for 18–22 hours at
10°C to separate very low-density lipoprotein (VLDL) in the supernatant (‘top’ fraction) from LDL
and HDL in the infranatant or ‘bottom’ fraction. The cholesterol concentration of the infranatant
was measured. All apolipoprotein B-containing lipoproteins, VLDL, LDL and Lp(a), were
precipitated from serum using 50 kDa dextran sulfate with magnesium ions (MgCl2), and the
cholesterol in the remaining HDL fraction was measured. The HDL cholesterol concentration
was subtracted from the infranatant cholesterol to provide the PUC LDL cholesterol value.

Calculated LDL cholesterol was derived from the Friedewald formula where:
LDL cholesterol = TC – (HDL cholesterol + TG/5)
[for mmol/L, LDL cholesterol = TC – HDL cholesterol – (TG/2.2)].

Lp(a): MRL uses an automated monoclonal antibody immunoturbidometric “isoform-

independent” method, meaning independent of Lp(a) particle size. The calibrators for this kit are
referenced against WHO SRM 2B. Since there is significant heterogeneity in Lp(a) particles, the
assay used should be insensitive to the size of apo(a)─the protein bound to apo B-100. Results
are reported in nmol/L of Lp(a) protein, rather than mass units, due to the varying mass ratio of
apo(a) to apoB in different sized Lp(a) particles. The Polymedco Lp(a) method in use at MRL is
analyzed on a Beckman Coulter AU Series analyzer, and is referenced to an International
Reference Material (SRM 2B) developed by the International Federation of Clinical Chemistry
(IFCC), and approved by National Heart, Lung, and Blood Institute (NHLBI). This allows
accurate measurement of Lp(a) levels irrespective of isoform size.

17
Apolipoproteins B were measured using nephelometric methodology on a Siemens BNII
analyzer.

4.7 Sample size in each trial

The sample size calculation was performed with the assumption (which was based on the
observed results from a Phase II study) that the difference in change from baseline between the
active dose group and the placebo group for LDL-C will be no less than 30 mg/dL, with a
standard deviation of 20 mg/dL.
Assuming about a 5% drop out rate, the sample size will be approximately 1425 subjects that
are evaluable for efficacy across the placebo and inclisiran dose groups. This sample size of at
least 1425 evaluable subjects, will provide more than 90% power to detect a 30% reduction of
LDL-C levels in the inclisiran group compared to the placebo group at one-sided significance
level of 0.025. This sample size will also contribute additional sufficient safety data.

4.8 Efficacy Endpoints

Co-primary endpoints:
-- Percentage change in LDL-C from baseline to Day 510
-- Time adjusted percentage change in LDL-C from baseline after Day 90 and up to
Day 540. This is the average percentage change in LDL-C from baseline over the
period after Day 90 and up to Day 540.

Key secondary endpoints:

-- Absolute change in LDL-C from baseline to Day 510
-- Time adjusted absolute change in LDL-C from baseline after Day 90 and up to
Day 540
-- Percentage change from baseline to Day 510 in PCSK9, total cholesterol, apoB, and
non-HDL-C

Other secondary endpoints of this study:

-- Mean maximum percentage change in LDL-C
-- Absolute change from baseline to Day 510 in PCSK9, total cholesterol, apoB and
non-HDL-C
-- Absolute change and percentage change in LDL-C from baseline to each assessment
time up to Day 540
-- Individual responsiveness defined as the number of subjects reaching on treatment
LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at Day 510
-- Proportion of subjects in each group with greater or equal to 50% LDL-C reduction
from baseline
-- Absolute change and percentage change in other lipids, lipoproteins, apolipoproteins,
and PCSK9 from baseline at each subsequent visit to Day 540
-- Proportion of subjects in each group who attain global lipid targets for their level of
ASCVD risk
-- Safety and tolerability profile of inclisiran as measured by adverse events (AEs), serious
adverse events (SAEs), vital signs,
clinical laboratory values, ECG measurements and formation of anti-drug antibody (ADA) and
subsequent characterization of ADA

18
A summary of endpoints reported in this this manuscript are shown below

Endpoint Reported within the

present manuscript
and/or
supplementary
appendix
All co-primary endpoints Yes
Key secondary endpoints Yes
Individual responsiveness defined as the number (proportion) of Yes
subjects reaching on treatment LDL-C levels of <25 mg/dL, <50
mg/dL, <70 mg/dL, and <100 mg/dL at Day 510
Proportion of subjects in each group with greater or equal to 50% Yes
LDL-C reduction from baseline
Changes in Lipoprotein (a), Triglycerides and HDL-C at Day 510 Yes
Safety and tolerability profile of inclisiran as measured by AEs, Yes
SAEs, vital signs, clinical laboratory values, ECG measurements and
formation of ADA and subsequent characterization of ADA

4.8 Statistical Analyses – Efficacy End Points

Please refer to full Statistical Analysis Plan available at NEJM
Treatments were compared utilizing two sample t-tests, analysis of covariance models
(ANCOVA), and mixed models for repeated measures (MMRM). Imputed data using multiple
imputation techniques were utilized for all quantitative analyses presented. Multiple imputation
techniques were utilized to explore the possibility that missing data were missing not at random
(MNAR). The first was a control-based pattern mixture model (CB-PMM) (Ratitch and O’Kelly
(2011), the second was a washout model which is a variation of the CB-PMM, and a 2% return
to baseline model. The 2% return to baseline model assumes that inclisiran subjects have the
LDL-C values return to baseline at a rate of 2% per month. For each multiple imputation
technique 100 imputed datasets were created with analysis results combined using Rubin’s
method (Rubin, 1987). For the analysis of time adjusted percent change (after Day 90 up to
Day 540), the LDL-C values were imputed first using CB-PMM and then the average from 90 to
540 was calculated from the MMRM using linear combinations of the estimated means. The
averages were based on fully imputed data from the model for each visit and not on a per
subject basis. Multiple imputation was also used to account for missing data for analyses of
other lipid parameters at Day 510 for the secondary endpoints presented. Refer to full Statistical
Analysis Plan available at NEJM.org

19
5. Supplementary Figures

Figure S1. Study Design ORION-10 and ORION-11

20
Figure S2. Patient Disposition (Consort Diagram)

ORION-10

ORION-11

21
Figure S3. Inter-Individual Variation in PCSK9 and LDL Cholesterol from Baseline to Day
510 (Observed data).

Panel (A) and (B) show individual response in proprotein convertase subtilisin–kexin type 9
(PCSK9) and low-density lipoprotein (LDL) cholesterol in ORION-10 and Panel (C) and (D)
show corresponding data in ORION-11. The waterfall plot shown represents the change in
PCSK9 and LDL Cholesterol between two specified time points in individuals with observed
data both at baseline and day 510. Data are presented in the following order; patients with the
greatest increase to patients with the greatest decrease for each parameter. The ordering of
panel A with panel B and panel C with panel D do not necessarily reflect the same patient.

ORION-10

Panel A

22
Panel B

ORION-11
Panel C

23
Panel D

24
6. Supplementary Tables
The tables in this section quantify the amount of missing data for different biological variables
included in the primary and secondary endpoints. Reasons for missing data included subject
discontinued study, a sample issue, or a missed visit. Unless a subject discontinued the study,
an individual with missing data at one-time point had data available at other time-points.
However, all analyses of the primary and key secondary endpoints were imputed using multiple
imputation methods.
Table S1. Missing LDL-C measurements at specific time points.
Number of participants with missing data

Time points ORION-10 ORION-11

Inclisiran Placebo Inclisiran Placebo
Baseline 0 0 0 0
Day 90 23 (2.9) 18 (2.3) 20 (2.5) 10 (1.2)
Day 150 24 (3.1) 35 (4.5) 14 (1.7) 22 (2.7)
Day 270 44 (5.6) 56 (7.2) 32 (4.0) 33 (4.1)
Day 330 50 (6.4) 65 (8.3) 37 (4.6) 34 (4.2)
Day 450 60 (7.7) 82 (10.5) 42 (5.2) 43 (5.3)
Day 510 90 (11.5) 114 (14.6) 86 (10.6) 68 (8.4)
Day 540 70 (9.0) 110 (14.1) 68 (8.4) 58 (7.2)
Absolute numbers and percentage of cohort in each treatment group within each trial

Table S2. Missing PCSK9 measurements at specific time points.

Number of participants with missing data

Time points ORION-10 ORION-11

Inclisiran Placebo Inclisiran Placebo
Baseline 5 (0.6) 1 (0.1) 1 (0.1) 4 (0.5)
Day 150 27 (3.5) 35 (4.5) 19 (2.3) 26 (3.2)
Day 330 53 (6.8) 65 (8.3) 43 (5.3) 40 (5.0)
Day 510 93 (11.9) 117 (15.0) 89 (11.0) 69 (8.6)
Day 540 80 (10.2) 110 (14.1) 72 (8.9) 61 (7.6)
Absolute numbers and percentage of cohort in each treatment group within each trial

Table S3. Missing lipid measurements at Day 510.

Number of participants with missing data

Parameter ORION-10 ORION-11

Inclisiran Placebo Inclisiran Placebo
Total Cholesterol 90 (11.5) 114 (14.6) 86 (10.6) 67 (8.3)
Apo B 91(11.7) 116 (14.9) 86 (10.6) 67 (8.3)
Non HDL-C 90 (11.5) 114 (14.6) 86 (10.6) 67 (8.3)
HDL-C 90 (11.5) 114 (14.6) 86 (10.6) 67 (8.3)
Triglycerides 90 (11.5) 114 (14.6) 86 (10.6) 67 (8.3)
Lipoprotein (a)* 78 (10.0) 110 (14.1) 68 (8.4) 58 (7.2)
*Day 540 sampling time point

Absolute numbers and percentage of cohort in each treatment group within each trial

25
Tables S4A and S4B. Changes in Lipid Parameters at Day 510 (multiple imputation, ITT
population)
S4A-ORION-10

Parameter Inclisiran Placebo Placebo P value

(n=781) (n=780) adjusted
Total cholesterol -33.6% +0.4% -33.1% < 0.001
ApoB -44.8% -1.7% -43.1% < 0.001
Non-HDL-C -47.4% -0.1% -47.4% < 0.001
Triglyceride (median) -14.9% -2.3% -12.6%
Lp (a)* (median) -21.9% +3.7% -25.6%
HDL-C +7.5% +2.4% +5.1%

*Day 540 sampling time point

Note P values are not shown for TG, HDL-C and Lp(a) as these did not take into account the
multiplicity of testing and the Hochberg procedure. Thus only those key-secondary endpoints
which corrected for multiple testing have P values shown.

S4B-ORION-11

Parameter Inclisiran Placebo Placebo P value

(n=810) (n=807) adjusted
Total cholesterol -28.0% +1.8% -29.8% < 0.001
ApoB -38.2% +0.8% -38.9% < 0.001
Non-HDL-C -41.2% +2.2% -43.3% < 0.001
Triglyceride (median) -12.0% _5.0% -7.0%
Lp(a)* (median) -18.6% +0.0 -18.6%
HDL-C +10.2% +4.1% +6.1%

*Day 540 sampling time point

Note P values are not shown for TG, HDL-C and Lp(a) as these did not take into account the
multiplicity of testing and the Hochberg procedure. Thus only those key-secondary endpoints
which corrected for multiple testing have P values shown.

26
Table S5. Proportion of patients achieving LDL cholesterol goals at Day 510 (ITT
Population)

Patients Achieving LDL Cholesterol Goals at Day 510 (ITT Population)

ORION-10 ORION-11

LDL-C target Inclisiran Placebo OR Inclisiran Placebo OR

level (N=781) (N=780) (95% CI) (N=810) (n=807) (95% CI)
Global goal
581 119 19.2 588 132 17.1
attainment for
(74.4) (15.3) (14.7 to 25.2) (81.2) (17.9) (13.2 to 22.0)
level of risk
160 4 39.1 95 1 78.3
<25 mg/dL
(20.5) (0.5) (15.0 to 101.6) (11.7) (0.1) (12.1 to 507.0)
483 19 53.6 420 19 42.7
<50 mg/dL
(61.8) (2.4) (34.0 to 84.7) (51.9) (2.4) (26.7 to 68.3)
581 119 19.2 564 104 18.5
<70 mg/dL
(74.4) (15.3) (14.7 to 25.2) (69.6) (12.9) (14.2 to 24.1)
651 387 9.6 661 425 6.8
<100mg/dL
(83.4) (49.6) (7.0 to 13.4) (81.6) (52.7) (5.1 to 9.0)
40 279 0.1 63 314 0.1
≥100 mg/dL
(5.1) (35.8) (0.1 to 0.1) (7.8) (38.9) (0.1 to 0.2)
≥ 50%
503 17 67.1 418 17 49.3
reduction
(72.8) (2.6) (41.8 to 107.6) (57.7) (2.3) (30.3 to 80.3)
from baseline

Missing 90 114 86 68
NA NA
data (11.5) (14.6) (10.6) (8.4)
Available 691 666 NA 724 739 NA
data (88.5) (85.4) (89.4) (91.6)

The table shows the number of individuals in the ITT population who attain LDL-C levels below
specific levels or goals. The number of individuals with missing values and the number of
individuals with evaluable data at Day 510 are also shown. The percentage of individuals
attaining goal reported (%) reflect the population with available data (the denominator), rather
than the whole ITT population and thus use observed values.
Data using multiple imputation rather than observed values, from 100 imputed datasets were
used to calculate odds ratios (OR) and 95% confidence intervals (CI) using a logistic regression
model and reflect the likelihood of goal attainment with inclisiran versus placebo. Reasons for
missing data included subject discontinued study, a sample issue, or a missed visit. However,
for all analyses of goal attainment we imputed using multiple imputation methods.

27
Table S6. Baseline and changes in hsCRP at Day 540 (Safety population)

ORION-10 ORION-11

Inclisiran Placebo Placebo Inclisiran Placebo Placebo

(n=781) (n=778) adjusted (n=810) (n=807) adjusted
difference difference

hsCRP
mg/L
2.2 2.0 1.5 1.6
median NA NA
(0.9 – 4.8) (1.0 – 5.5) (0.7, 3.6) (0.8, 3.7)
(IQR) at
baseline
Median
percent
0.0% -8.8% +8.8% 0.0% -8.9% +8.9%
change at
Day 540

28
Table S7. Most common treatment emergent adverse events (Safety population)
S7A ORION-10

Preferred Term Inclisiran Placebo Risk Ratio Total

n = 781 (%) n = 778 (%) and CI n= 1559
inclisiran vs (%)
placebo
Subjects with at least one
574 (73.5) 582 (74.8) 1.0 (0.9, 1.0) 1156 (74.2)
TEAE*

Diabetes mellitus 120 ( 15.4) 108 ( 13.9) 1.1 (0.9, 1.4) 228 ( 14.6)
Hypertension 42 ( 5.4) 42 ( 5.4) 1.0 (0.7, 1.5) 84 ( 5.4)
Back pain 39 ( 5.0) 39 ( 5.0) 1.0 (0.6, 1.5) 78 ( 5.0)
Bronchitis 46 ( 5.9) 30 ( 3.9) 1.5 (1.0, 2.4) 76 ( 4.9)
URTI 37 ( 4.7) 38 ( 4.9) 1.0 (0.6, 1.5) 75 ( 4.8)
Dyspnoea 39 ( 5.0) 33 ( 4.2) 1.2 (0.7, 1.9) 72 ( 4.6)
Arthralgia 35 ( 4.5) 33 ( 4.2) 1.1 (0.7, 1.7) 68 ( 4.4)
Urinary tract infection 33 ( 4.2) 34 ( 4.4) 1.0 (0.6, 1.5) 67 ( 4.3)
Dizziness 34 ( 4.4) 32 ( 4.1) 1.1 (0.7, 1.7) 66 ( 4.2)
Sinusitis 27 ( 3.5) 36 ( 4.6) 0.7 (0.5, 1.2) 63 ( 4.0)
Non-cardiac chest pain 26 ( 3.3) 34 ( 4.4) 0.8 (0.5, 1.3) 60 ( 3.8)
Diarrhoea 29 ( 3.7) 25 ( 3.2) 1.2 (0.7, 2.0) 54 ( 3.5)
Coronary artery disease 23 ( 2.9) 28 ( 3.6) 0.8 (0.5, 1.4) 51 ( 3.3)
Fall 24 ( 3.1) 26 ( 3.3) 0.9 (0.5, 1.6) 50 ( 3.2)
Pain in extremity 28 ( 3.6) 21 ( 2.7) 1.3 (0.8, 2.3) 49 ( 3.1)
Oedema peripheral 27 ( 3.5) 22 ( 2.8) 1.2 (0.7, 2.1) 49 ( 3.1)
Pneumonia 26 ( 3.3) 22 ( 2.8) 1.2 (0.7, 2.1) 48 ( 3.1)
Headache 22 ( 2.8) 26 ( 3.3) 0.8 (0.5, 1.5) 48 ( 3.1)
Fatigue 20 ( 2.6) 26 ( 3.3) 0.8 (0.4, 1.4) 46 ( 3.0)
Nasopharyngitis 21 ( 2.7) 24 ( 3.1) 0.9 (0.5, 1.6) 45 ( 2.9)
Blood CK increased 17 ( 2.2) 27 ( 3.5) 0.6 (0.3, 1.1) 44 ( 2.8)
Angina pectoris 26 ( 3.3) 17 ( 2.2) 1.5 (0.8, 2.8) 43 ( 2.8)
Cough 18 ( 2.3) 25 ( 3.2) 0.7 (0.4, 1.3) 43 ( 2.8)
Cardiac failure congestive 15 ( 1.9) 27 ( 3.5) 0.6 (0.3, 1.0) 42 ( 2.7)
Atrial fibrillation 18 ( 2.3) 22 ( 2.8) 0.8 (0.4, 1.5) 40 ( 2.6)
Nausea 19 ( 2.4) 18 ( 2.3) 1.1 (0.6, 2.0) 37 ( 2.4)
COPD 17 ( 2.2) 19 ( 2.4) 0.9 (0.5, 1.7) 36 ( 2.3)
Anaemia 15 ( 1.9) 16 ( 2.1) 0.9 (0.5, 1.9) 31 ( 2.0)
Constipation 15 ( 1.9) 16 ( 2.1) 0.9 (0.5, 1.9) 31 ( 2.0)
*Treatment emergent adverse events that occurred in ≥2% of patients in total

29
S7B ORION-11

Preferred Term Inclisiran Placebo Risk Ratio Total

n = 811 (%) n =804 (%) and CI n=1615 (%)
I inclisiran vs
placebo
Subjects with at least one
671 (82.7) 655 (81.5) 1.0 (1.0, 1.1) 1326 (82.1)
TEAE*

Diabetes mellitus 88 (10.9) 94 (11.7) 0.9 (0.7, 1.2) 182 (11.3)

Nasopharyngitis 91 (11.2) 90 (11.2) 1.0 (0.7, 1.4) 181 (11.2)
Hypertension 53 (6.5) 54 (6.7) 1.0 (0.7, 1.4) 107 (6.7)
Upper respiratory tract 1.1 (0.7, 1.5)
52 (6.4) 49 (6.1) 101 (6.3)
infection
Arthralgia 47 (5.8) 32 (4.0) 1.5 (0.9, 2.3) 79 (4.9)
Osteoarthritis 32 (3.9) 40 (5.0) 0.8 (0.5, 1.2) 72 (4.5)
Diarrhea 33 (4.2) 33 (4.1) 1.0 (0.6, 1.6) 66 (4.1)
Angina Pectoris 30 (3.7) 36 (4.5) 0.8 (0.5, 1.2) 66 (4.1)
Urinary Tract Infection 39 (4.8) 25 (3.1) 1.5 (0.9. 2.5) 64 (4.0)
Cough 32 (3.9) 27 (3.4) 1.2 (0.7, 1.9) 59 (3.7)
Lower Respiratory Tract 1.3 (0.8, 2.1)
32 (3.9) 25 (3.1) 57 (3.5)
infection
Headache 31 (3.8) 24 (3.0) 1.3 (0.8, 2.2) 55 (3.4)
Back pain 27 (3.3) 28(3.5) 1.0 (0.6, 1.6) 55 (3.4)
Blood creatine 0.7 (0.4, 1.2)
22 (2.7) 30 (3.7) 52 (3.2)
phosphokinase increase
Pain in extremity 25 (3.1) 24 (3.0) 1.0 (0.6, 1.8) 49 (3.0)
Myalgia 21 (2.6) 23 (2.9) 0.9 (0.5, 1.6) 44 (2.7)
Musculoskeletal pain 23 (2.8)) 20 (2.5) 1.1 (0.6, 2.1) 43 (2.7)
Bronchitis 23 (2.8) 16 (2.0) 1.4 (0.8, 2.7) 39 (2.4)
Influenza 19 (2.3) 20 (2.5) 0.9 (0.5, 1.8) 39 (2.4)
Fall 17 (2.1) 21 (2.6) 0.8 (0.4, 1.5) 38 (2.4)
Dizziness 21 (2.6) 16 (2.0) 1.3 (0.7, 2.5) 37 (2.3)
Atrial fibrillation 18 (2.2) 18 (2.2) 1.0 (0.5, 1.9) 36 (2.2)
Anemia 20 (2.5) 15 (1.9) 1.3 (0.7, 2.6) 35 (2.2)
Non-cardiac chest pain 14 (1.7) 21 (2.6) 0.7 (0.3, 1.3) 35 (2.2)
Respiratory tract infection 18 (2.2) 16 (2.0) 1.1 (0.6, 2.2) 34 (2.1)
Fatigue 17 (2.1) 15 (1.9) 1.1 (0.6, 2.2) 32 (2.0)
Peripheral arterial occlusive 0.6 (0.3, 1.2)
12 (1.5) 20 (2.5) 32 (2.0)
disease
*Treatment emergent adverse events that occurred in ≥2% of patients in total

30
7. References
Ratitch B, O’Kelly M: Imputation of Pattern-Mixture Models Using Standard SAS/STAT
Procedures, PharmaSUG2011 - Paper SP04.

Rubin, D.B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John Wiley
& Sons, Inc.

31