Clinical trial NCT05537571
Conditions: Cardiovascular Diseases Atherosclerosis Lipoprotein(a)
Keywords: Cardiovascular Diseases Atherosclerosis Lipoprotein(a)
Sponsor: Silence Therapeutics plc
Start date: 2022-12-13; Completion date: 2024-07-01
Enrollment: 180 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 2 study to evaluate the efficacy, safety and tolerability of SLN360 administered subcutaneously (SC) compared with placebo in adult participants with elevated lipoprotein(a) at high risk of atherosclerotic cardiovascular disease events

Detailed description:

Arms: arm 1: SLN360 300 mg administered subcutaneously at Weeks 0, 16 and 32 (Q16W) arm 2: SLN360 300 mg administered subcutaneously at Weeks 0 and 24 (Q24W) arm 3: SLN360 450 mg administered subcutaneously at Weeks 0 and 24 (Q24W) arm 4: Placebo administered subcutaneously at Weeks 0, 16 and 32 (Q16W) arm 5: Placebo administered subcutaneously at Weeks 0 and 24 (Q24W). This group was stratified so that half of participants were dosed to match the SLN360 300 mg Q24W group and half were dosed to match the SLN360 450 mg Q24W group (with respect to injected volume)
Interventions: intervention 1: SLN360 intervention 2: Placebo
Intervention descriptions: intervention 1: SLN360 is a double-stranded small interfering ribonucleic acid (siRNA) targeting LPA messenger RNA (mRNA) intervention 2: Sodium chloride, solution for injection

Protocol documents:
Prot_000.pdf: 
Study Number: SLN360-002
Compound No.: SLN360
Protocol
Version: 1.0
Page 1 of 87
Title:
A multi-centre, randomised, double-blind, placebo-controlled, 
Phase 2 study to investigate efficacy, safety and tolerability of 
SLN360 in participants with elevated lipoprotein(a) at high risk 
of atherosclerotic cardiovascular disease events.
Effective Date:
09-AUG-2022
EudraCT number:
2022-001876-32
Short Title: Efficacy, safety and tolerability study of SLN360 in participants with 
elevated lipoprotein(a) and cardiovascular disease.
Abstract: Despite lipoprotein(a) (Lp[a]) being a prevalent genetic risk factor for onset 
and progression of several manifestations of cardiovascular disease, there are no 
approved therapeutics designed to specifically lower Lp(a). SLN360 is a 19-mer 
double-stranded small interfering RNA targeting LPA messenger RNA. LPA encodes 
apolipoprotein(a), the protein specific to the Lp(a) particle, and it is the dominant and 
rate-limiting element in the synthesis of Lp(a). SLN360 is being developed for reducing 
the risk of Lp(a)-mediated atherosclerotic cardiovascular disease (ASCVD) by decreasing
circulating Lp(a) levels.
This Phase 2 study will evaluate the efficacy, safety and tolerability of SLN360 in 
participants with elevated Lp(a) at high risk of ASCVD events. Eligible participants will 
be randomised in a 1:1:2:2:2 ratio into one of five treatment groups and will receive 
either placebo or SLN360 (300 mg or 450 mg doses) every 16 weeks or 24 weeks.
Participation will include a screening period of up to 4 weeks, a treatment period of up to 
36 weeks and a follow-up period of up to 24 weeks, reaching the end-of-study visit at 
Week 60.
The results of the study should further characterise the SLN360 dosing regimen that 
displays favourable safety and tolerability and has the greatest magnitude and duration of 
Lp(a) reduction with the lowest dosing frequency. Optimising the combination of 
magnitude and duration of Lp(a) lowering is likely to confer the greatest clinical benefit 
with respect to ASCVD risk reduction.
NCT Number: NCT05537571


Study Number: SLN360-002
Compound No.: SLN360
Protocol
Version: 1.0
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Silence Therapeutics plc
72 Hammersmith Road
London
W14 8TH
UK


Study Number: SLN360-002
Compound No.: SLN360
Protocol
Version: 1.0
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SPONSOR SIGNATURE PAGE
Sponsor Signatory:
Silence Therapeutics plc
72 Hammersmith Road
London
W14 8TH
UK
Date


Study Number: SLN360-002
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INVESTIGATOR SIGNATURE PAGE
I agree to conduct this Study in accordance with the requirements of this Clinical Study
Protocol and associated study documents and also in accordance with the following:
Declaration of Helsinki (revised version of Fortaleza, Brazil, 2013)
The International Council on Harmonisation harmonised tripartite guideline 
regarding Good Clinical Practice (E6 R2, November 2016)
Local laws and regulations
Any amendments to these regulations
Investigator Name and Qualifications: _____________________________________
Investigator Signature
Date
Investigator Affiliation:
Institution:
Address:
Phone number:


Study Number: SLN360-002
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS................................................................................................................9
PROTOCOL SUMMARY ...................................................................................................11
1.
INTRODUCTION ........................................................................................................18
1.1.
Background.................................................................................................... 18
1.1.1.
Name and Description of the Investigational Product................... 19
1.1.2.
Nonclinical Studies......................................................................... 19
1.1.2.1.
Nonclinical Pharmacology............................................ 19
1.1.2.2.
Nonclinical Pharmacokinetics, Toxicokinetics 
and Absorption, Distribution, Metabolism and 
Excretion ...................................................................... 20
1.1.2.3.
Toxicology .................................................................... 21
1.1.2.4.
Immunogenicity ............................................................ 22
1.1.3.
Clinical Studies............................................................................... 22
1.1.3.1.
Demographics .............................................................. 22
1.1.3.2.
Pharmacokinetics......................................................... 23
1.1.3.3.
Pharmacology .............................................................. 23
1.1.3.4.
Safety ........................................................................... 25
1.1.4.
Study Conduct................................................................................ 27
1.2.
Rationale........................................................................................................ 28
1.3.
Potential Risks and Benefits to Human Participants..................................... 28
2.
OBJECTIVES..............................................................................................................29
2.1.
Primary Objective .......................................................................................... 29
2.2.
Secondary Objectives.................................................................................... 29
2.3.
Exploratory Objective .................................................................................... 30
3.
ENDPOINTS...............................................................................................................30
3.1.
Primary Endpoint ........................................................................................... 30
3.2.
Secondary Endpoints .................................................................................... 30
3.2.1.
Safety ............................................................................................. 30
3.2.2.
Pharmacodynamics and Efficacy................................................... 30
3.3.
Exploratory Endpoints ................................................................................... 31
4.
STUDY DESIGN.........................................................................................................31
4.1.
Summary of Study Design............................................................................. 31
4.1.1.
Study Design.................................................................................. 31
4.1.2.
Randomisation and Blinding .......................................................... 32
4.1.3.
Duration of Participant Participation .............................................. 33
4.2.
Study and Participant Termination ................................................................ 33
5.
STUDY POPULATION ...............................................................................................34
5.1.
Participants .................................................................................................... 34
5.2.
Eligibility Criteria ............................................................................................ 34


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5.2.1.
Inclusion Criteria ............................................................................ 34
5.2.2.
Exclusion Criteria ........................................................................... 35
6.
STUDY ASSESSMENTS AND PROCEDURES........................................................38
6.1.
Screening....................................................................................................... 38
6.2.
Medical History .............................................................................................. 38
6.3.
Demographics................................................................................................ 39
6.4.
Pharmacodynamic and Efficacy Procedures ................................................ 39
6.5.
Safety Procedures ......................................................................................... 40
6.5.1.
Adverse Event Assessments......................................................... 40
6.5.2.
Injection Site Reaction Assessment .............................................. 40
6.5.3.
Twelve-Lead Electrocardiogram.................................................... 41
6.5.4.
Vital Signs ...................................................................................... 41
6.5.5.
Physical Examination..................................................................... 42
6.5.6.
Laboratory Assessments ............................................................... 42
6.5.6.1.
Haematology and Coagulation .................................... 42
6.5.6.2.
Clinical Chemistry ........................................................ 43
6.5.6.3.
Viral serology................................................................ 44
6.5.6.4.
Anti-drug antibodies ..................................................... 44
6.5.6.5.
Urinalysis...................................................................... 44
6.5.7.
Pregnancy Testing and Reporting ................................................. 45
6.6.
Pharmacogenetic Procedures....................................................................... 45
6.6.1.
Genotyping..................................................................................... 46
6.7.
Independent Data Monitoring Committee ..................................................... 46
6.7.1.
Role of the Independent Data Monitoring Committee................... 46
6.7.2.
Independent Data Monitoring Committee Composition ................ 46
6.7.3.
Data Available for Independent Data Monitoring 
Committee Review......................................................................... 46
6.7.4.
Independent Data Monitoring Committee 
Recommendations and Meeting Schedule.................................... 46
7.
LIFESTYLE AND/OR DIETARY RESTRICTIONS ....................................................47
7.1.
Lifestyle and Dietary ...................................................................................... 47
7.2.
Contraception................................................................................................. 47
7.2.1.
Female Participants ....................................................................... 47
7.2.2.
Male Participants............................................................................ 48
8.
INVESTIGATIONAL PRODUCT(S) ...........................................................................48
8.1.
Dosage and Administration ........................................................................... 48
8.2.
Dose Rationale .............................................................................................. 49
8.2.1.
Pharmacokinetic-pharmacodynamic Modelling for Dose 
Selection......................................................................................... 49
8.3.
Maintaining the Blind ..................................................................................... 54
8.3.1.
Emergency Unblinding................................................................... 54
8.4.
Treatment Assignment .................................................................................. 55
8.5.
Packaging and Labelling ............................................................................... 55
8.6.
Preparation .................................................................................................... 56
8.7.
Handling and Storage.................................................................................... 56
8.8.
Product Accountability and Assessment of Compliance .............................. 56


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8.9.
Treatment of Investigational Product Overdose............................................ 56
8.10.
Occupational Safety....................................................................................... 57
9.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES...........................57
9.1.
Recording Prior and Concomitant Medication .............................................. 57
9.2.
Permitted Medications ................................................................................... 57
9.3.
Prohibited Medications and Procedures ....................................................... 57
10. PARTICIPANT COMPLETION AND WITHDRAWAL................................................58
10.1.
Participant Completion .................................................................................. 58
10.2.
Participant Withdrawal................................................................................... 58
10.2.1.
Participant Withdrawal of Consent................................................. 58
10.2.2.
Participant Withdrawal from Study................................................. 59
10.2.3.
Participant Withdrawal from Investigational Product..................... 59
10.3.
Long-term Follow-up...................................................................................... 59
10.4.
Treatment after the End of the Study............................................................ 60
10.5.
Screening and Baseline Failures................................................................... 60
10.6.
Testing for SARS-CoV-2 ............................................................................... 60
11. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.......................................61
11.1.
Definitions ...................................................................................................... 61
11.1.1.
Adverse Events.............................................................................. 61
11.1.2.
Adverse Events of Special Interest................................................ 61
11.1.3.
Serious Adverse Events................................................................. 61
11.1.4.
Adverse Drug Reactions................................................................ 62
11.2.
Assessment of Adverse Events..................................................................... 63
11.2.1.
Adverse Event Severity.................................................................. 63
11.2.2.
Adverse Event Causality................................................................ 63
11.2.3.
Structured Causality Assessment for Suspected Drug-
induced Liver Injury........................................................................ 64
11.3.
Safety Reporting............................................................................................ 65
11.3.1.
Reporting Adverse Events ............................................................. 65
11.3.2.
Reporting Serious Adverse Events................................................ 65
11.4.
Follow-up of Adverse Events......................................................................... 66
11.5.
Pregnancy...................................................................................................... 66
12. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.....................................66
12.1.
Hypotheses.................................................................................................... 67
12.2.
Estimands ...................................................................................................... 67
12.2.1.
Primary Estimand........................................................................... 67
12.2.2.
Secondary Estimands.................................................................... 68
12.3.
Study Design Considerations........................................................................ 68
12.3.1.
Sample Size Assumptions ............................................................. 68
12.3.2.
Sample Size Sensitivity.................................................................. 68
12.3.3.
Sample Size Re-estimation............................................................ 68
12.4.
Data Analysis Considerations ....................................................................... 68
12.4.1.
Analysis Populations...................................................................... 69
12.4.2.
Treatment Comparisons ................................................................ 69
12.4.3.
Interim Analysis.............................................................................. 69


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12.4.4.
Key Elements of Analysis Plan...................................................... 70
12.4.4.1.
Efficacy Analyses......................................................... 70
12.4.4.1.1.
Primary endpoint ..................................... 70
12.4.4.1.2.
Secondary endpoints............................... 70
12.4.4.2.
Safety Analyses ........................................................... 70
12.4.4.2.1.
Adverse events........................................ 70
12.4.5.
Missing, Unused and Spurious Data ............................................. 71
12.4.6.
Reporting Deviations from the Statistical Plan .............................. 71
13. STUDY ADMINISTRATION........................................................................................71
13.1.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................... 71
13.2.
Study Monitoring............................................................................................ 72
13.2.1.
Access to Source Data .................................................................. 72
13.2.2.
Data Handling and Record Keeping.............................................. 72
13.3.
Provision of Study Results and Information to Investigators ........................ 73
13.4.
Data Management ......................................................................................... 73
13.5.
Insurance, Indemnity and Finance................................................................ 74
14. REFERENCES ...........................................................................................................75
15. APPENDICES PROVIDED FOR STUDY SLN360-002.............................................79
15.1.
Appendix: Time and Events Table – Groups 1 and 3 (Dosing Every 
16 Weeks)...................................................................................................... 79
15.2.
Appendix: Time and Events Table – Groups 2, 4 and 5 (Dosing 
Every 24 Weeks) ........................................................................................... 82
15.3.
Appendix: Study Reports – Internal .............................................................. 85
15.4.
Appendix: Study Reports – External ............................................................. 86


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ABBREVIATIONS
ADL
Activities of daily living
AE
Adverse event
ALT
Alanine aminotransferase
apo(a)
Apolipoprotein(a)
apoB
Apolipoprotein B
ASCVD
Atherosclerotic cardiovascular disease
AST
Aspartate aminotransferase
AUC0–last
Area under the concentration curve to last measurable 
concentration
CAD
Coronary artery disease
CI
Confidential Interval
COVID-19
Coronavirus disease 2019
CRO
Contract Research Organisation
CSR
Clinical Study Report
CVD
Cardiovascular disease
CYP
Cytochrome P450
ECG
Electrocardiogram
eCRF
Electronic case report form
EoS
End-of-study
FIH
First-in-human
GalNAc
N-acetyl-galactosamine
GLP
Good Laboratory Practice
IB
Investigator’s Brochure
ICF
Informed consent form
ICH-GCP
International Council for Harmonisation – Good Clinical Practice
IDMC
Independent Data Monitoring Committee
IMP
Investigational medicinal product
IRT
Interactive response technology
ISR
Injection site reaction
LDL-C
Low-density lipoprotein cholesterol
Lp(a)
Lipoprotein(a)
MD
Multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
mRNA
Messenger RNA
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
QTcF
QT interval corrected using Fridericia’s formula
PCSK9
Proprotein convertase subtilisin/kexin type 9
PD
Pharmacodynamic
PK
Pharmacokinetic
Q3M
Dosing every 3 months


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Q4M
Dosing every 4 months
Q6M
Dosing every 6 months
Q16W
Dosing every 16 weeks
Q24W
Dosing every 24 weeks
SAD
Single ascending dose
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
siRNA
Small interfering RNA
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
Tmax
Time to reach peak plasma concentration
ULN
Upper limit of the normal range


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PROTOCOL SUMMARY
Rationale
Given the weight of evidence from genetic and observational epidemiology and findings 
from large outcomes trials of low-density lipoprotein cholesterol (LDL-C)-lowering 
drugs, pharmacological lowering of lipoprotein(a) (Lp[a]) has the potential to reduce risk 
of atherosclerotic cardiovascular disease (ASCVD) events. The independence of Lp(a) 
from established ASCVD risk factors, such as LDL-C, further strengthens the likely 
benefit of Lp(a)-lowering therapy for individuals whose atherosclerotic disease is driven 
predominantly by Lp(a). SLN360 is anticipated to offer a clinically important reduction 
in risk in those who have had a previous ASCVD event and those at high risk of a first 
event, i.e., with both secondary and primary preventive intent.
Data from the United Kingdom Biobank, a longitudinal study of 500,000 adults, 
demonstrated a strong prospective association of elevated Lp(a) (equal to or greater than 
150 nmol/L) with risk of ASCVD events. Elevated Lp(a) was present in 12.2% of those 
without and 20.3% of those with pre-existing ASCVD and associated with hazard ratios 
of 1.50 (95% confidence interval [CI], 1.44–1.56) and 1.16 (95% CI, 1.05–1.27),
respectively. Furthermore, in the Multi-Ethnic Study of Atherosclerosis (MESA)
(n = 4512) and Dallas Heart Study (n = 2078) cohorts, presence of coronary artery 
calcification (as determined by computed tomography coronary imaging) in individuals 
with elevated Lp(a) were strongly predictive of incident ASCVD events (hazard ratio 
4.71; 95% CI 3.01 to 7.40 with the highest degree of calcification). Subjects with the 
lowest level of calcification (score of 1-99) had at least x 2-fold increase in risk. In 
summary, elevated Lp(a) is a likely risk amplifier both in subjects with a prior history of 
ASCVD and those without established ASCVD. Lowering of elevated Lp(a) is 
anticipated to be beneficial to both these groups.
No data are yet available from an outcome trial of a specific Lp(a)-lowering therapy, and 
the absolute or relative reduction in Lp(a) required to achieve a given reduction in 
ASCVD risk is unknown. The aim of the proposed Phase 2 study is to characterise the 
dosing regimen that displays favourable safety and tolerability and has the greatest 
magnitude and duration of Lp(a) reduction with the lowest dosing frequency in a patient 
population at high risk of ASCVD events. The weight of observational and genetic 
epidemiological evidence suggests that optimising the combination of magnitude and 
duration of Lp(a) lowering is likely to confer the greatest clinical benefit with respect to 
ASCVD risk reduction.


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Objective(s)
Primary Objective
The primary objective is to evaluate the effect of SLN360 on circulating levels of Lp(a) 
in participants with elevated Lp(a) at high risk of ASCVD events.
Secondary Objectives
The secondary objectives are to:
Evaluate safety and tolerability of SLN360 in participants with elevated Lp(a) at 
high risk of ASCVD events
Evaluate the effects of SLN360 on LDL-C and apolipoprotein B (apoB) in this
population
Exploratory Objective
The exploratory objective is to evaluate the pharmacogenetic effects of germline genetic 
variation(s) in response to SLN360.
Endpoints
Primary Endpoint
The primary endpoint is the time-averaged change in Lp(a) from baseline to Week 36.
Secondary Endpoints
Safety
The secondary safety endpoint is the safety and tolerability of SLN360, as assessed by:
Adverse event reports
Physical examination findings
Twelve-lead electrocardiograms
Vital signs
Laboratory safety evaluations
Pharmacodynamics and Efficacy
The secondary pharmacodynamic and efficacy endpoints are:


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The change (time-averaged and by visit) in Lp(a) from the Day 1 pre-dose 
assessment to Week 48
The change (time-averaged and by visit) in Lp(a) from the Day 1 pre-dose 
assessment to Week 60
The change (time-averaged and by visit) in other lipids/lipoproteins, including 
LDL-C and apoB, from the Day 1 pre-dose assessment to Week 36
The change (time-averaged and by visit) in other lipids/lipoproteins, including
LDL-C and apoB, from the Day 1 pre-dose assessment to Week 48
The change (time-averaged and by visit) in other lipids/lipoproteins, including 
LDL-C and apoB, from the Day 1 pre-dose assessment to Week 60
Exploratory Endpoints
The exploratory endpoints are the pharmacogenetic effects of germline genetic variation 
on response to SLN360, measured by association analysis of genetic variants with 
markers of SLN360 efficacy, including change in Lp(a).
Study Design
This is a multi-centre, randomised, double-blind, placebo-controlled Phase 2 study to 
investigate the efficacy, safety and tolerability of SLN360 in participants with elevated 
Lp(a) at high risk of ASCVD.
The study will be divided into three study periods, comprising screening, treatment and 
follow-up. An end-of-study visit will be conducted to perform final safety and efficacy 
assessments.
Eligible participants will receive either placebo or SLN360 and will be randomised in the 
ratio 1:1:2:2:2 into five treatment groups:
Group 1: Placebo administered subcutaneously at Weeks 0, 16 and 32 (dosing every 
16 weeks [Q16W])
Group 2: Placebo administered subcutaneously at Weeks 0 and 24 (dosing every 
24 weeks [Q24W])
o
This group will be stratified so that half of participants are dosed to match the 
300 mg Q24W SLN360 group and half are dosed to match the 450 mg Q24W 
SLN360 group (with respect to injected volume)
Group 3: SLN360 300 mg administered subcutaneously at Weeks 0, 16 and 32
(Q16W)
Group 4: SLN360 300 mg administered subcutaneously at Weeks 0 and 24 (Q24W)
Group 5: SLN360 450 mg administered subcutaneously at Weeks 0 and 24 (Q24W)


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Placebo
The placebo has been chosen as the control treatment to assess whether any observed 
effects are treatment-related. The placebo is used since no appropriate active comparator 
is available; notably, there being no approved pharmacotherapy available that has been 
shown to yield a clinically meaningful lowering of Lp(a) in people with elevated levels.
Study Population
Inclusion Criteria
A participant will be eligible for inclusion in this study only if all of the following criteria 
are met:
1.
Male or female
2.
Aged 18 to 80 years inclusive at screening
3.
Lipoprotein(a) at screening equal to or greater than 125 nmol/L
4.
At high risk of ASCVD, i.e., at least one of the following conditions:
a.
Previous myocardial infarction (MI)
b.
Coronary angiographic diagnosis of coronary artery disease with or without 
previous MI
c.
Computerised tomography/magnetic resonance imaging diagnosis of coronary 
artery disease with or without previous MI
d.
Previous coronary revascularisation (percutaneous coronary intervention or 
coronary artery bypass graft)
e.
Prior ischeamic stroke as previously confirmed by a documented brain imaging 
study (e.g. computed tomography or magnetic resonance imaging brain), and 
considered not to be caused by thromboembolic phenomena associated with 
atrial fibrillation, valvular heart disease or mural thrombus
f.
Peripheral arterial disease
g.
Existing evidence of coronary artery calcium on computerised tomography 
(
AU)
5.
A body mass index at screening in the range 18.0 to 32.0 kg/m2, inclusive
6.
Participants must be able to provide valid informed consent and to comply with all 
study requirements
7.
Participants receiving lipid-modifying therapy (including statins, proprotein 
convertase subtilisin/kexin type 9 [PCSK9] inhibitors, ezetimibe) must be on a 
stable, maximum tolerated regimen, according to the clinical judgement of the 
Investigator, at screening (i.e., receiving therapy for a minimum of 8 weeks) with no 


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changes to existing regimens or introduction of new regimens made after screening.
For monoclonal antibody PCSK9 inhibitors, a stable dose is defined as at least 
four doses at a consistent dose level
Exclusion Criteria
A participant will not be eligible for inclusion in this study if any of the following criteria 
are met:
1.
Cardiovascular disease-related:
a.
Acute cardiovascular event within the 12 weeks before screening (including but 
not limited to acute MI, unstable angina, percutaneous coronary intervention, 
coronary artery bypass graft, stroke, acute limb ischaemia, limb 
revascularisation)
b.
Planned or expected cardiac surgery or coronary or other revascularisation 
within 12 weeks of screening or planned major non-cardiac surgery during the 
study period
2.
Medical history:
a.
Renal dysfunction with estimated glomerular filtration rate less than 
30 mL/min/1.73 m2 (according to the Chronic Kidney Disease Epidemiology 
Collaboration equation) at screening
b.
Acute, chronic or historical liver disease, including viral hepatitis (hepatitis A, B
or C virus) at screening. Participants with positive hepatitis B virus surface 
antibody titre reflecting hepatitis B virus immunisation are permitted to 
participate
c.
Hepatic dysfunction based on liver function markers at screening: aspartate 
aminotransferase, alanine aminotransferase or total bilirubin >2 × the upper limit 
of the normal range (ULN)
d.
Established diagnosis of Gilbert syndrome
e.
Inherited or other bleeding disorders
f.
Malignancy (except non-melanoma skin cancers, cervical in situ carcinoma, 
breast ductal carcinoma in situ, stage 1 prostate carcinoma, or benign tumours) 
within the 5 years before screening
g.
Current or previous history of moderate to severe heart failure (New York Heart 
Association Functional Classification grade III or IV at screening) or last known 
left ventricular ejection fraction less than 30% at screening
h.
Ventricular tachycardia, atrial fibrillation with rapid ventricular response or 
supraventricular tachycardia that are not controlled by medications in the 
12 weeks before screening
i.
Fasting triglycerides >400 mg/dL (4.5 mmol/L) at screening


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j.
Uncontrolled hypertension at screening, defined as an average sitting systolic 
blood pressure > 160 mmHg or an average diastolic blood pressure >110 mmHg 
after a minimum of three measurements
k.
Type 1 diabetes mellitus or poorly controlled (glycated haemoglobin 10% or
86 mmol/mol) type 2 diabetes mellitus at screening
l.
Known active infection or major haematological, renal, metabolic, 
gastrointestinal or endocrine dysfunction in the judgment of the Investigator at 
screening or Day 1
3.
Concomitant medication:
a.
Currently receiving or <12 weeks at Day 1 since receiving >200 mg/day niacin 
or niacin derivative drugs (e.g., niceritrol, nicomol)
b.
Treatment with lipid/lipoprotein apheresis within the 12 weeks before screening
c.
Treatment with a cholesteryl ester transfer protein inhibitor (e.g., anacetrapib, 
dalcetrapib, evacetrapib, obicetrapib) or lomitapide within the 52 weeks before 
screening
d.
Treatment with aspirin, clopidogrel, ticagrelor or other antiplatelet agent unless 
prescribed at a low maintenance dose for the purpose of cardiovascular risk 
reduction (i.e., aspirin up to 325 mg daily, clopidogrel 75 mg daily, ticagrelor 
180 mg daily)
e.
Participation in another clinical trial including an investigational medicinal 
product within 12 weeks, or within five half-lives of that investigational 
medicinal product, before screening
f.
Any previous use of approved or experimental small interfering RNA therapy
(e.g., inclisiran). NB: use of messenger RNAbased vaccines for infectious 
diseases is permitted
g.
Use of approved or experimental antisense oligonucleotide therapy within the 
24 weeks before screening. NB: use of messenger RNA-based vaccines for 
infectious diseases is permitted
h.
Use of experimental Lp(a)-reducing therapy within the 52 weeks before 
screening
i.
Use of herbal or complementary medicines, dietary supplements or vitamins 
known to substantially influence lipid metabolism or blood lipid or lipoprotein 
levels (e.g., fish oil, turmeric, red yeast rice) within the 4 weeks before Day 1
4.
Alcohol and illegal drugs:
a.
History or clinical evidence of alcohol misuse within the 26 weeks before 
screening
b.
History or clinical evidence of recreational drug use within the 26 weeks before 
screening


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5.
Other exclusions:
a.
Female participants of childbearing potential with a positive serum pregnancy 
test assessed at screening or positive urine pregnancy test on Day 1
b.
Female participants of childbearing potential planning to become pregnant or 
breastfeed during treatment and for an additional 12 weeks after the last dose of 
study treatment
c.
Female participants of childbearing potential unwilling to use a highly effective 
method of contraception during treatment and for an additional 12 weeks after 
the last dose of study treatment
d.
Male participants must be surgically sterile or, if engaged in sexual relations 
with a female of childbearing potential, the participant must be using a highly 
effective contraception method from the time of signing the informed consent 
form until at least 12 weeks after the last dose of study treatment
e.
Known sensitivity to any of the products to be administered during dosing
f.
Likely to be unavailable to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
participant and Investigator’s knowledge
g.
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
Investigator or Sponsor, if consulted, would pose a risk to the participant’s safety 
or interfere with the study evaluation, procedures or completion.
Study Assessments
Study assessments will be performed as detailed in the Time and Events tables in 
Appendix 15.1 (Groups 1 and 3; Q16W dosing) and Appendix 15.2 (Groups 2, 4 and 5; 
Q24W dosing).


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1.
INTRODUCTION
1.1.
Background
Elevated baseline levels of lipoprotein(a) (Lp[a]), a genetically determined low-density 
lipoprotein-like particle linked to apolipoprotein(a) (apo[a]), have been associated with 
increased risk of cardiovascular events in epidemiological studies [Emerging Risk 
Factors Collaboration, 2009] and Mendelian randomisation analyses [Larsson et al,
2020]. These studies showed that a genetically determined doubling of Lp(a) plasma 
levels resulted in a 22% increased risk of myocardial infarction (MI), consistent with a 
causal relationship between lifelong elevation in Lp(a) levels and MI risk [Kamstrup et 
al, 2009]. The LPA gene encodes apo(a), and it genetically determines increased plasma 
Lp(a) levels and apo(a) isoform size. LPA risk alleles (i.e., those determining elevated 
Lp[a] levels) have been linked with other atherosclerotic adverse outcomes, including 
ischaemic stroke, peripheral artery disease, abdominal aortic aneurysm, obstructed 
coronary vessels (and therefore increased coronary atherosclerotic burden) and earlier 
onset of coronary artery disease (CAD) [Helgadottir et al, 2012; Larsson et al, 2020]. In 
addition, elevated Lp(a) and the presence of coronary artery calcification detected on
computed tomography imaging identifies individuals at high risk of atherosclerotic 
cardiovascular disease (ASCVD) events [Mehta et al, 2022].
Lipoprotein(a) is the major carrier of oxidised phospholipid in human plasma [Zheng et 
al, 2019]. Oxidised phospholipids are mediators of potent proatherogenic and 
proinflammatory effects that account for a significant proportion of the cardiovascular 
risk attributable to Lp(a) [Que et al, 2018]. Critically, variants in LPA strongly associate 
with oxidised phospholipid-apolipoprotein B (apoB) concentration [Saleheen et al, 2017].
Large-scale population data suggest that low levels of Lp(a) are not detrimental to human 
health, rather they associate strongly with lower risk of cardiovascular diseases (CVDs)
[Emdin et al, 2016]. Notably, the complete absence of circulating Lp(a) has no effect on 
increasing morbidity or mortality [Emdin et al, 2016; Lim et al, 2014]. Additionally, 
direct pharmacological reduction of Lp(a) through gene silencing has been evaluated 
clinically and it did not associate with any safety concerns due to Lp(a) reduction 
[Tsimikas et al, 2015; Viney et al, 2016; Tsimikas et al, 2020; Koren et al, 2022].
SLN360 is a 19-mer double-stranded small interfering RNA (siRNA) targeting LPA
messenger RNA (mRNA). LPA encodes apo(a), the protein specific to the Lp(a) particle,
and it is the dominant and rate-limiting element in the synthesis of Lp(a). SLN360 
covalently links to a tri-antennary N-acetyl-galactosamine (GalNAc) moiety. The 
GalNAc residues of SLN360 specifically bind the asialoglycoprotein receptor that is
expressed on hepatocytes. Therefore, these modifications ensure that SLN360 is targeted 
to hepatocytes, as demonstrated by nonclinical tissue distribution studies where SLN360 
is found in meaningful concentrations only in the liver (the target organ) and the kidneys 


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(the organs of excretion). Following binding and receptor-mediated cellular uptake by 
endocytosis, LPA mRNA is targeted for degradation via RNA interference through the 
antisense strand of the siRNA. Through its highly specific silencing of LPA in 
hepatocytes, SLN360 is designed to reduce apo(a) levels, thereby reducing plasma Lp(a) 
levels.
SLN360 is being developed for reducing the risk of Lp(a)-mediated ASCVD by 
decreasing circulating Lp(a) levels. This study aims to evaluate doses and dosing
regimens of SLN360 in participants at high risk of ASCVD events.
1.1.1.
Name and Description of the Investigational Product
Silence Therapeutics is developing SLN360 to reduce the risk of major cardiovascular 
events in adults with elevated Lp(a) and at high risk of a first ASCVD event. SLN360 is a 
19-mer double-stranded siRNA oligonucleotide that is chemically stabilised and 
covalently linked to a tri-antennary GalNAc delivery moiety.
SLN360 will be provided as a solution for injection for subcutaneous use in glass vials. A 
2 mL injection vial contains 0.5 mL (extractable volume) of an aqueous sterile solution of 
SLN360 drug substance with a concentration of 200 mg/mL (as free acid form). The vials 
are intended for single use. The concentration of 200 mg/mL refers to 200 mg SLN360 
drug substance expressed as free anhydrous oligonucleotide (acid form) corrected for 
duplex purity.
1.1.2.
Nonclinical Studies
Full details of the nonclinical development of SLN360 can be found in the Investigator’s 
Brochure (IB).
1.1.2.1.
Nonclinical Pharmacology
A range of in vitro and in vivo studies have been performed to characterise the 
pharmacodynamic (PD) effects of SLN360.
In vitro, SLN360 potently reduces LPA mRNA levels in cynomolgus monkey and human 
primary hepatocytes. 
Adequate in vivo delivery and potency of SLN360 was investigated initially in healthy 
naïve animals. The first studies (DD-0001, DD-0004 and STEPS-0069; see IB) were 
performed with STS20041L6, which has an identical siRNA sequence and carries the 
same GalNAc ligand as SLN360; however, SLN360 has a different pattern of 
2’-O-Methyl and 2’Fluoro on the sense strand. No difference in the pharmacological 
potency of the two agents was observed (DD-0001, STEPS-0069 and STEPS-0099). The 
in vivo studies in naïve animals (STEPS-0069 and STEPS-0099) confirmed the intended 
prolonged reduction in serum Lp(a) levels (greater than 80%) after a single subcutaneous 


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injection of 3 mg/kg STS20041L6 and SLN360, with a sustained reduction greater than 
50% from baseline observed after 2 months. STS20041L6 and SLN360 were well 
tolerated, and no adverse clinical effects were observed.
No adverse clinical observations, injection site reactions (ISRs) or changes in clinical 
chemistry or coagulation parameters were observed in the in vivo studies at 
pharmacological doses. 
The in vivo studies in naïve animals confirmed the anticipated PD changes that were
expected from specific inhibition of LPA mRNA expression.
Safety pharmacology parameters were assessed during the course of the 29-day and 
13-week Good Laboratory Practice (GLP) studies. In rats (STEPS-0105), SLN360 did 
not cause any behavioural or motor reflex changes in the Irwin assessments. In 
cynomolgus monkeys (STEPS-0106), no test-article related findings for 
electrocardiogram (ECG), blood pressure or respiration were observed.
1.1.2.2.
Nonclinical Pharmacokinetics, Toxicokinetics and Absorption, 
Distribution, Metabolism and Excretion
Repeat-dose studies have been conducted for SLN360. LPA gene expression is restricted 
to humans, great apes and old-world monkeys. The basis for selecting a non-human 
primate primarily lies with the expression of the target LPA sequence, which is 
specifically expressed in non-human primates and in humans, and thus provides the only 
possibility to investigate target specific toxicological effects of SLN360. SLN360 is 
pharmacologically active in the cynomolgus monkey.
Extensive nonclinical safety and pharmacokinetic (PK) evaluation data of SLN360 has 
been accumulated, including studies on in vitro metabolism, biodistribution, protein 
plasma binding, repeat dose toxicity in two animal species (rat & cynomolgus monkey), 
safety pharmacology, antigenicity and genetic toxicity. Drug-drug interaction studies 
(cytochrome P450 [CYP] inhibition and induction studies, transporter substrate and 
inhibition tests) have also been carried out (STEPS-0120, STEPS-0124, STEPS-0125 and 
STEPS-0126).
Toxicological studies with SLN360 were conducted using exaggerated dosing regimens,
which contrasted markedly with the doses projected for clinical therapeutic evaluation. 
Biodistribution in the rat was affected by liver and renal changes at high doses; however, 
SLN360 in the liver declined to tissue levels less than or equal to 1% of peak levels 
3 weeks after dosing. Therefore, significant tissue accumulation is not expected in 
clinical trials with less frequent dosing.
In a rat biodistribution study, SLN360 was detected at significant concentrations in the 
liver and kidney, but it remained limited in other organs (including reproductive organs).
This distribution pattern was consistent with the specificity of the GalNAc hepatic 
delivery system and the main renal route of elimination [Janas et al, 2018].


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SLN360 plasma protein binding was comparable in rats (96.2% to 97.0%), monkeys
(97.5% to 97.9%) and human plasma (94.0% to 96.4%; STEPS-0120). SLN360 was 
chemically and metabolically stable in rat, monkey and human hepatic 
post-mitochondrial supernatant fractions (S9) and monkey and human hepatic lysosomes
(STEPS-0121 and STEPS-0122). SLN360 impacts CYP enzymes CYP2C8, CYP2C9, 
CYP2C9, CYP1A2, CYP2B6 and CYP3A4/5 at concentrations considerably higher than 
concentrations expected following clinical exposure to SLN360; subsequently, the effect 
of SLN360 on CYP expression is not considered to be of clinical significance. The liver 
and kidneys are the toxicological target organs identified in the nonclinical safety 
evaluations of SLN360 and are amenable to routine monitoring in clinical studies. 
Therefore, the associated risk at pharmacological dose levels of SLN360 is considered 
minimal.
1.1.2.3.
Toxicology
SLN360 was well tolerated in a 29-day rat GLP toxicity study, with no test article-related 
mortality. In a similar 29-day cynomolgus monkey GLP study, SLN360 was well
tolerated, with non-adverse reversible findings in the liver (increased weight with diffuse 
hepatocyte hypertrophy) and lymph nodes (macrophage vacuolation; STEPS-0106).
Similarly, in an extended 13-week cynomolgus monkey study using 30 mg/kg or
100 mg/kg SLN360, both doses did not elicit any adverse effects; moreover, there were 
non-adverse reversible liver findings as well as granular macrophages in the lymph nodes 
of at least one animal. An increased SLN360 dose of 200 mg/kg was also tolerated, but it 
was also associated with mortality (one animal during the recovery phase), body weight 
loss, hair loss, impaired menstrual cycling, increased liver enzymes (with correlating 
hepatocellular hypertrophy, degeneration and single cell necrosis), hepatic sinusoidal 
pigmented macrophages, granular macrophages in the lymph nodes and slight renal 
tubular vacuolation (STEPS-0128). This was considered mainly related to a dysmetabolic 
and diabetic status in concert with cardiomyopathy of an uncertain origin, but a role for 
SLN360 could not be ruled out. Based on these findings, the no-observed-adverse-effect 
level of SLN360 was established at 100 mg/kg.
Nonclinical safety evaluations of SLN360 have not revealed any unexpected findings. 
Supra-pharmacological doses of SLN360 in rat studies have highlighted the potential for 
liver and kidney pathology. Cynomolgus monkey studies have revealed adaptive changes 
in the draining lymph nodes and liver. These changes were generally observed with the 
siRNA drug class of molecules, are independent of the sequence-directed target 
specificity of siRNA and are reversible effects related to temporary drug accumulation in 
tissues [Janas et al, 2018]. No genotoxicity of SLN360 was observed in any of the in 
vitro (STEPS-0118 and STEPS-0119) or in vivo (in STEPS-0105) studies conducted, 
which is in accordance with other siRNAs of this class [Berman et al, 2016].
Overall, the toxicological data obtained thus far are regarded as adequate to support 
single and repeated intermittent treatment with SLN360. The highest dose of SLN360 to 


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be used in the proposed clinical study is 450 mg, which is lower than the highest dose 
that has been administered to date in an ongoing first-in-human (FIH) study of SLN360
(600 mg) [Nissen et al, 2022].
1.1.2.4.
Immunogenicity
To assess the potential for anti-drug antibodies against SLN360, SLN360 was coupled to 
a carrier protein (haemocyanin from Limulus polyphemus haemolymph), formulated in 
adjuvant and injected into rabbits intramuscularly on six separate occasions (1 mg/kg 
[Dose 1], 0.5 mg/kg [Doses 2 to 5] and 0.25 mg/kg [Dose 6]) over a 16-week period
(STEPS-0100). No antibodies specific to SLN360 were generated, suggesting that the 
risk of anti-drug antibody formation is minimal.
1.1.3.
Clinical Studies
One ongoing clinical study of SLN360 has been conducted to date. This FIH study is a 
Phase 1 randomised, double-blind, placebo-controlled, single ascending dose (SAD) and 
multiple dose (MD) study to assess preliminary safety, tolerability, PK and PD 
parameters of SLN360 administered subcutaneously to participants with elevated Lp(a) 
equal to or greater than 150 nmol/L (APOLLO; ClinicalTrials.gov identifier 
NCT04606602; EudraCT identifier 2020-002471-35). The SAD part of the study locked 
in January 2022 and results are published, with the MD part currently planned to be 
completed in 2023.
The SAD part of the study evaluated subcutaneous placebo (0.9% sodium chloride) and 
single doses of 30 mg, 100 mg, 300 mg and 600 mg SLN360 in healthy adults with an 
Lp(a) level equal to or greater than 150 nmol/L at screening. Four cohorts, each 
consisting of eight participants (two placebo, six active), were dosed with either placebo 
or SLN360 administered subcutaneously in the abdomen on Day 1 and followed up to 
Day 150. On the recommendation of the Safety Review Committee, follow-up of Lp(a) 
levels for participants in the 300 mg and 600 mg cohorts was extended from 150 to 365 
days.
1.1.3.1.
Demographics
In the SAD part of the APOLLO FIH trial, a total of 32 participants were included. The 
mean age of the study participants was 49.6 years, with 15 males and 17 females (one
female was of childbearing potential). Enrolled participants were Caucasian (62.5%), 
African American/Black (34.4%) and Asian (3.1%). Although none of the participants
had known pre-existing clinically overt CVD, hypertension was present in three (9.4%)
participants and diabetes in one (3.1%) participant. Of the 32 participants, 13 (41%)
participants were taking statins as concomitant medication (participants were in the 
placebo, 100 mg, 300 mg and 600 mg treatment groups). 


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1.1.3.2.
Pharmacokinetics
To assess PK parameters, plasma SLN360 concentration was measured, as well as
maximum plasma concentration, time to reach peak plasma concentration (Tmax) and area 
under the concentration curve to last measurable concentration (AUC0–last).
SLN360 plasma concentration increased in a dose-dependent manner among the dosing 
groups. Median Tmax was 4.0 hours for the 30 mg group and 6.0 hours for the 100 mg, 
300 mg and 600 mg groups. The AUC0–last measurements followed a similar increasing 
trend that depended on dose. Insufficient datapoints were available after Tmax in the SAD 
cohorts to reliably estimate the plasma apparent terminal elimination half-life; 
subsequently, plasma elimination half-life will be evaluated in the MD cohorts after 
denser PK sampling. The PK parameters obtained in the SAD cohorts are detailed in 
Table 1.
Table 1
Pharmacokinetic parameters of SLN360 for the single ascending 
dose cohorts in the first-in-human study of SLN360 (SLN360-001)
PK Parameter
SLN360 Dose Groups
(N=24)
30 mg
(N=6)
100 mg
(N=6)
300 mg
(N=6)
600 mg
(N=6)
Cmax (ng/mL)
115.8 ± 32.6
265.7 ± 125.5
979.2 ± 386.6
3035.0 ± 1131.4
Tmax (h)
4.0 (0.5 to 6.3)
6.0 (4.0 to 12.0)
6.0 (6.0 to 12.0)
6.0 (4.0 to 12.1)
AUC0–last (h*ng/mL)
898.0 ± 219.4
3229.8 ± 809.9
13166.1 ± 
4295.8
36719.9 ± 
9530.9
AUC0–last=area under the concentration curve to the last measurable concentration; Cmax=maximum plasma 
concentration; PK=pharmacokinetic; Tmax=time to reach peak plasma concentration
Note: Measurements of Cmax and AUC are presented as mean ± standard deviation and Tmax is presented as 
median (minimum to maximum).
1.1.3.3.
Pharmacology
SLN360 PD was evaluated by measuring serum Lp(a) concentration and the effects of
SLN360 on concentrations of other lipids and lipoproteins. The lipid profile included 
high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), total 
cholesterol, triglycerides and apoB.
The maximal total and percent changes in Lp(a) following administration of placebo or 
SLN360 across the four dose groups (30 mg, 100 mg, 300 mg and 600 mg) are presented 
in Table 2. Reductions in Lp(a) were dose proportional and reached a maximal median 
(interquartile range) percent change of -98% (-98%, -97%) following administration of 
600 mg SLN360. The greatest percent change in Lp(a) level concentration was achieved 
between 30 days and 60 days after dosing for all treatment groups. Subsequently, 
concentrations gradually rose, but they had not returned to baseline values 150 days 
post-dose for the 100 mg, 300 mg and 600 mg treatment groups. Median Lp(a) 




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Figure 1
Percent change in lipoprotein(a) concentration from baseline to 
Day 150 post-dose
Lp(a)=lipoprotein A
Note: ranges presented depict minimum and maximum values.
SLN360 produced a moderate, dose-dependent reduction in apoB-containing lipoproteins 
(i.e., Lp[a] and LDL, and reflected by total cholesterol). Mean levels were reduced by a 
maximum of 18% for total cholesterol and 26% for LDL-C, both following 
administration of the 600 mg dose. Smaller reductions were observed at lower doses. The 
maximum reduction in the mean level of apoB was 24% at 30 days after the 600 mg dose 
and 19% at 14 days after the 300 mg dose. The maximal mean percent reduction of
oxidised LDL was 20% in the 600 mg dose group at Day 30 and 11% in the 300 mg dose 
group at Day 90. There was no evidence of an SLN360-mediated effect on triglycerides 
or high-density lipoprotein cholesterol.
1.1.3.4.
Safety
Safety and tolerability were evaluated by dose-limiting toxicities, adverse events (AEs), 
physical examination, 12-lead ECGs, vital signs and laboratory safety parameters. 
Injection site AEs potentially meeting the criteria for dose-limiting toxicities were 


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designated as AEs of special interest. The positions of the injection sites were recorded at 
the time of dosing and ISRs were monitored intensively for 7 days after dosing and 
thereafter as AEs, if indicated. 
Treatment-emergent AEs (TEAEs) were generally mild and the most commonly reported 
TEAEs were low-grade injection site events (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0; Grades 1 and 2) 
and headache (CTCAE Grades 1 to 3, of which a single event was Grade 3 and was 
ascribed to the effects of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]
vaccination), none of which resulted in participant withdrawal. At Day 45, a single 
participant in the lowest dose group (30 mg) was admitted to hospital for fever and a 
severe headache, which were ascribed by the Investigator as effects from the 
SARS-CoV-2 vaccine that they had received on Day 38. Brain imaging showed no 
evidence of an intracranial thrombotic or embolic event. The subsequent planned Day 45 
visit was conducted on Day 49 and the participant was found to have values of alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) >3 × upper limit of the 
normal range (ULN), with no elevation in bilirubin. The participant’s AST and ALT 
values returned to the normal range at Day 60. The changes in AST and ALT levels were 
judged to be unrelated to SLN360 by the Investigator and were assessed as effects of the 
SARS-CoV-2 vaccine.
Serious AEs (SAEs) were experienced by one (3.1%) participant who received SLN360 
30 mg, assessed by the Investigator to be unrelated to study drug.
Transient, dose-dependent increases in C-reactive protein occurred at 12 hours and 
24 hours, with the greatest increase occurring in the 600 mg dose group. Neutrophil count 
also increased during the first 24 hours. These changes were observed predominantly at 
the higher doses.
The safety assessments for the SAD cohorts are detailed in Table 3.


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Table 3
Treatment-emergent and serious adverse events in the single 
ascending dose part of the first-in-human study of SLN360
(SLN360-001)
Adverse Events by 
Type
SLN360
30 mg
(N=6)
SLN360
100 mg
(N=6)
SLN360
300 mg
(N=6)
SLN360
600 mg
(N=6)
Placebo
(N=8)
Number (%) of 
participants with any 
TEAE
6 (100.0)
6 (100.0)
6 (100.0)
6 (100.0)
6 (75.0)
TEAE occurring in >3 participants, n (%)
Headache
2 (33.3)
1 (16.7)
0 (0)
5 (83.3)
1 (12.5)
Diarrhoea
1 (16.7)
0 (0)
0 (0)
1 (16.7)
1 (12.5)
Arthralgia
1 (16.7)
0 (0)
1 (6.7)
1 (16.7)
0 (0)
Neutrophil count 
increased
0 (0)
0 (0)
0 (0)
3 (50.0)
0 (0)
CRP increased
0 (0)
0 (0)
0 (0)
4 (66.7)
0 (0)
Injection site TEAEs, 
n (%) Ea
5 (83.3) 5
6 (100.0) 6
5 (83.3) 5
6 (100.0) 11
1 (12.5) 1
Grade 1
5 (83.3) 5
6 (100.0) 6
4 (66.7) 4
2 (33.3) 3
1 (12.5) 1
Grade 2
0 (0)
0 (0)
1 (16.7) 1
4 (66.7) 8
0 (0)
Grade 3
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Any SAEs, n (%)b
1 (16.7)
0 (0)
0 (0)
0 (0)
0 (0)
CRP=C-reactive protein; E=events; n=number of participants, percentages are based on N; SAE=serious adverse 
event; TEAE=treatment-emergent adverse event
a.
Summary by grade using the Common Terminology Criteria for Adverse Events version 5.0
b.
Participant visited the Accident and Emergency department for headache following the SARS-CoV-2
vaccine on Day 45 and the participant was hospitalised for cholecystitis and associated signs/symptoms on 
Day 110
Note: SAE cases were considered unrelated to study treatment.
Longer exposure and repeat dosing will be required to assess the duration of changes to 
PD parameters and to evaluate the safety of SLN360 further. The MD portion of the 
study is ongoing.
1.1.4.
Study Conduct
This study will be conducted in accordance with the requirements of this Clinical Study 
Protocol and associated study documents and also in accordance with the following:
Declaration of Helsinki (revised version of Fortaleza, Brazil, 2013)
The International Council on Harmonisation harmonised tripartite guideline 
regarding Good Clinical Practice (E6 R2, November 2016)
Local laws and regulations
Any amendments to these regulations


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1.2.
Rationale
Given the weight of evidence from genetic and observational epidemiology and findings 
from large outcomes trials of LDL-C-lowering drugs [Schwartz et al, 2018; Robinson et 
al, 2015], pharmacological lowering of Lp(a) has the potential to reduce risk of ASCVD 
events. The independence of Lp(a) from established ASCVD risk factors, such as 
LDL-C, further strengthens the likely benefit of Lp(a)-lowering therapy for individuals
whose atherosclerotic disease is driven predominantly by Lp(a). SLN360 is anticipated to 
offer a clinically important reduction in ASCVD risk in those who have had a previous 
ASCVD event and those at high risk of a first event, i.e., with both secondary and 
primary preventive intent.
Data from the United Kingdom Biobank, a longitudinal study of 500,000 adults, 
demonstrated a strong prospective association of elevated Lp(a) (equal to or greater than 
150 nmol/L) with risk of ASCVD events. Elevated Lp(a) was present in 12.2% of those 
without and 20.3% of those with pre-existing ASCVD and associated with hazard ratios 
of 1.50 (95% CI, 1.44–1.56) and 1.16 (95% CI, 1.05–1.27), respectively [Patel et al,
2021]. Furthermore, in the Multi-Ethnic Study of Atherosclerosis (MESA) (n = 4512) 
and Dallas Heart Study (n = 2078) cohorts, presence of coronary artery calcification (as 
determined by computed tomography coronary imaging) in individuals with elevated 
Lp(a) were strongly predictive of incident ASCVD events (hazard ratio 4.71; 95% CI 
3.01 to 7.40 with the highest degree of calcification). Subjects with the lowest level of 
calcification (score of 1-99) had at least x 2-fold increase in risk [Mehta et al, 2022]. In 
summary, elevated Lp(a) is a likely risk amplifier both in subjects with a prior history of 
ASCVD and those without established ASCVD. Pharmacological lowering of elevated
Lp(a) is anticipated to be beneficial to both these groups.
No data are yet available from an outcome trial of a specific Lp(a)-lowering therapy and 
the absolute or relative reduction in Lp(a) required to achieve a given reduction in 
ASCVD risk is unknown. The aim of the proposed Phase 2 study is to characterise the 
dosing regimen that displays favourable safety and tolerability and has the greatest 
magnitude and duration of Lp(a) reduction with the lowest dosing frequency in a patient 
population at high risk of ASCVD events. The weight of observational and genetic 
epidemiological evidence suggests that optimising the combination of magnitude and 
duration of Lp(a) lowering is likely to confer the greatest clinical benefit with respect to 
ASCVD risk reduction.
1.3.
Potential Risks and Benefits to Human Participants
Despite Lp(a) being a prevalent genetic risk factor for onset and progression of several 
manifestations of CVD [Tsimikas et al, 2018], there are no approved therapeutics 
designed to specifically lower Lp(a). Existing lipid-lowering therapies either have limited 
(proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors), neutral or even an 
adverse impact (statins) on circulating Lp(a) concentration [Arsenault et al, 2018; Raal et 
al, 2016].


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The eligibility threshold in this study of 125 nmol/L for Lp(a) has been selected to 
optimise the benefit: risk balance for participants enrolled in the proposed study. In 
observational cohorts, the inflection in risk of major adverse cardiovascular events 
appears at Lp(a) concentrations of approximately 30 mg/dL (75 nmol/L) [Emerging Risk 
Factors Collaboration, 2009]. European [Cegla et al, 2019] and United States clinical 
guidelines [Grundy et al, 2019] state that Lp(a) levels over approximately 50 mg/dL 
(circa 125 nmol/L) as conferring increased CVD risk. European guidance also notes that 
Lp(a) greater than 150 nmol/L is used as the threshold for offering plasma apheresis in 
countries where this procedure is available. Data from contemporary trials with PCSK9 
inhibitors data suggest that the risk of major adverse cardiovascular events and major 
adverse limb events is favourably modified above median Lp(a) levels of approximately 
15 mg/dL (38 nmol/L) (FOURIER) or 21 mg/dL (52 nmol/L) (ODYSSEY) studies
[Szarek et al, 2020; O'Donoghue et al, 2019]. In addition, to date there is no known
adverse phenotype associated with low Lp(a) levels. Therefore, 125 nmol/L has been
selected as the eligibility threshold in this study to enrol those participants with the
greatest potential to benefit from Lp(a)-lowering treatment with SLN360 and to include a 
broader population than that studied in the Phase 1 study.
Early safety, PK and pharmacology data from the SAD portion of the ongoing FIH study 
on SLN360 indicate that TEAEs were generally mild, and the most commonly reported 
TEAEs were low grade injection site events. Participants were administered a single dose
of SLN360 up to 600 mg. Contrastingly, the maximum dose of SLN360 in the proposed 
study is lower (450 mg) and participants will receive study treatment with at least a 
16-week gap between the two doses. Therefore, there are no expected risks to participants
in terms of treatment doses or dose scheduling.
The promising early safety results from the ongoing FIH study of SLN360 suggest that 
the clinical benefits of SLN360 outweigh the anticipated risks. Subsequently, SLN360 
could be a safe and effective treatment to lower Lp(a) and its associated cardiovascular 
risks in individuals with limited alternative treatment options.
2.
OBJECTIVES
2.1.
Primary Objective
The primary objective is to evaluate the effect of SLN360 on circulating levels of Lp(a) 
in participants with elevated Lp(a) at high risk of ASCVD events.
2.2.
Secondary Objectives
The secondary objectives are to:
Evaluate safety and tolerability of SLN360 in participants with elevated Lp(a) at 
high risk of ASCVD events


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Evaluate the effects of SLN360 on LDL-C and apoB in this population
2.3.
Exploratory Objective
The exploratory objective is to evaluate the pharmacogenetic effects of germline genetic 
variation(s) in response to SLN360.
3.
ENDPOINTS
3.1.
Primary Endpoint
The primary endpoint is the time-averaged change in Lp(a) from baseline to Week 36.
3.2.
Secondary Endpoints
3.2.1.
Safety
The secondary safety endpoint is the safety and tolerability of SLN360, as assessed by:
Adverse event reports
Physical examination findings
Twelve-lead ECGs
Vital signs
Laboratory safety evaluations
3.2.2.
Pharmacodynamics and Efficacy
The secondary PD and efficacy endpoints are:
The change (time-averaged and by visit) in Lp(a) from the Day 1 pre-dose 
assessment to Week 48
The change (time-averaged and by visit) in Lp(a) from the Day 1 pre-dose 
assessment to Week 60
The change (time-averaged and by visit) in other lipids/lipoproteins, including 
LDL-C and apoB, from the Day 1 pre-dose assessment to Week 36
The change (time-averaged and by visit) in other lipids/lipoproteins, including
LDL-C and apoB, from the Day 1 pre-dose assessment to Week 48
The change (time-averaged and by visit) in other lipids/lipoproteins, including 
LDL-C and apoB, from the Day 1 pre-dose assessment to Week 60


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3.3.
Exploratory Endpoints
The exploratory endpoints are the pharmacogenetic effects of germline genetic variation 
on response to SLN360, measured by association analysis of genetic variants with 
markers of SLN360 efficacy, including change in Lp(a).
4.
STUDY DESIGN
4.1.
Summary of Study Design
4.1.1.
Study Design
This is a multi-centre, randomised, double-blind, placebo-controlled Phase 2 study to 
investigate the efficacy, safety and tolerability of SLN360 in participants with elevated 
Lp(a) at high risk of ASCVD.
The study will be divided into three study periods, comprising screening, treatment and 
follow-up. An end-of-study (EoS) visit will be conducted to perform final safety and 
efficacy assessments.
Eligible participants will receive either placebo or SLN360 and will be randomised in the 
ratio 1:1:2:2:2 into five treatment groups:
Group 1: Placebo administered subcutaneously at Weeks 0, 16 and 32 (dosing every 
16 weeks [Q16W])
Group 2: Placebo administered subcutaneously at Weeks 0 and 24 (dosing every 
24 weeks [Q24W])
o
This group will be stratified so that half of participants are dosed to match the 
300 mg Q24W SLN360 group and half are dosed to match the 450 mg Q24W 
SLN360 group) with respect to injected volume
Group 3: SLN360 300 mg administered subcutaneously at Weeks 0, 16 and 32
(Q16W)
Group 4: SLN360 300 mg administered subcutaneously at Weeks 0 and 24 (Q24W)
Group 5: SLN360 450 mg administered subcutaneously at Weeks 0 and 24 (Q24W)
Placebo
The placebo has been chosen as the control treatment to assess whether any observed 
effects are treatment-related. The placebo is used since no appropriate active comparator 
is available; notably, there being no approved pharmacotherapy available that has been 
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Dose groups and treatment regimens are summarised in Table 4.
Table 4
Dose groups and treatment regimens for the proposed Phase 2 
study
Group
Regimen
No. of SLN360 doses
Total cumulative SLN360 
administered
1
Placebo Q16W
-
-
2
Placebo Q24W
-
-
3
SLN360 300 mg Q16W
3
900 mg
4
SLN360 300 mg Q24W
2
600 mg
5
SLN360 450 mg Q24W
2
900 mg
Q16W=dosing every 16 weeks; Q24W=dosing every 24 weeks
An overview of the trial is presented in Figure 2.
Figure 2
Overview of the Phase 2 study
Q16W=dosing every 16 weeks; Q24W=dosing every 24 weeks
Details of all dosing and assessment timepoints are outlined in the Time and Events 
tables (Appendix 15.1 and Appendix 15.2).
4.1.2.
Randomisation and Blinding
All participants will be centrally randomised using interactive response technology (IRT).


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This will be a double-blind study, i.e., participants, investigators and specific academic 
personnel and the Contract Research Organisation (CRO) along with Sponsor staff will 
be blinded to treatment group allocation. The nature of the treatment supply means that 
the Pharmacist will be unblinded with appropriate unblinded oversight in place; details 
will be provided in the Study Blinding Plan.
This design is appropriate since the principal marker of efficacy (serum Lp[a]
concentration) is an objective laboratory measure that is negligibly susceptible to bias and 
not influenced by potential confounders such as diet and physical activity. Blinding 
participants and investigators will ensure the robustness of the safety and tolerability 
assessments of SLN360.
4.1.3.
Duration of Participant Participation
There are a planned minimum of 15 visits for each participant, including screening. The 
maximum expected duration of participation for an individual participant will be up to 
64 weeks. This includes a screening period of up to 4 weeks, a treatment period of up to 
36 weeks and a follow-up period of up to 24 weeks, reaching EoS at Week 60.
Primary analysis will be performed once all participants have completed 36 weeks of 
treatment.
4.2.
Study and Participant Termination
Changes in the health status of the participant since the screening visit, including 
laboratory results, will be checked prior to administration of the study treatment.
Participation of a participant in this clinical study will be discontinued for any of the 
following reasons:
Withdrawal of consent
Termination of the study by the Sponsor or a regulatory authority
Participants are free to withdraw consent from the study (which means permanent 
discontinuation of study drug administration and all follow-up assessments) at any time 
without prejudice. Note that discontinuation of study drug in and of itself is not 
considered withdrawal of consent.
The Investigator must temporally interrupt or permanently discontinue study treatment
for the participant if administration is believed to be contrary to the best interests of the 
participant; further details are provided in Section 10.2.3.




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b.
Coronary angiographic diagnosis of CAD with or without previous MI
c.
Computerised tomography/magnetic resonance imaging diagnosis of CAD with 
or without previous MI
d.
Previous coronary revascularisation (percutaneous coronary intervention or 
coronary artery bypass graft)
e.
Prior ischeamic stroke as previously confirmed by a documented brain imaging 
study (e.g. computed tomography or magnetic resonance imaging brain), and 
considered not to be caused by thromboembolic phenomena associated with 
atrial fibrillation, valvular heart disease or mural thrombus
f.
Peripheral arterial disease
g.
Existing evidence of coronary artery calcium on computerised tomography 
AU)
5.
A body mass index at screening in the range 18.0 to 32.0 kg/m2, inclusive
6.
Participants must be able to provide valid informed consent and to comply with all 
study requirements
7.
Participants receiving lipid-modifying therapy (including statins, proprotein 
convertase subtilisin/kexin type 9 [PCSK9] inhibitors, ezetimibe) must be on a 
stable, maximum tolerated regimen, according to the clinical judgement of the 
Investigator, at screening (i.e., receiving therapy for a minimum of 8 weeks) with no 
changes to existing regimens or introduction of new regimens made after screening. 
For monoclonal antibody PCSK9 inhibitors, a stable dose is defined as at least 
four doses at a consistent dose level
5.2.2.
Exclusion Criteria
A participant will not be eligible for inclusion in this study if any of the following criteria 
are met:
1.
Cardiovascular disease-related:
a.
Acute cardiovascular event within the 12 weeks before screening (including but 
not limited to acute MI, unstable angina, percutaneous coronary intervention,
coronary artery bypass graft, stroke, acute limb ischaemia, limb 
revascularisation)
b.
Planned or expected cardiac surgery or coronary or other revascularisation 
within 12 weeks of screening or planned major non-cardiac surgery during the 
study period
2.
Medical history:
a.
Renal dysfunction with estimated glomerular filtration rate less than 
30 mL/min/1.73 m2 (according to the Chronic Kidney Disease Epidemiology 
Collaboration equation) at screening


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b.
Acute, chronic or historical liver disease, including viral hepatitis (hepatitis A, B
or C virus) at screening. Participants with positive hepatitis B virus surface 
antibody titre reflecting hepatitis B virus immunisation are permitted to 
participate
c.
Hepatic dysfunction based on liver function markers at screening: AST, ALT or
total bilirubin >2 × ULN
d.
Established diagnosis of Gilbert syndrome
e.
Inherited or other bleeding disorders
f.
Malignancy (except non-melanoma skin cancers, cervical in situ carcinoma, 
breast ductal carcinoma in situ, stage 1 prostate carcinoma, or benign tumours) 
within the 5 years before screening
g.
Current or previous history of moderate to severe heart failure (New York Heart 
Association Functional Classification grade III or IV at screening) or last known 
left ventricular ejection fraction less than 30% at screening
h.
Ventricular tachycardia, atrial fibrillation with rapid ventricular response or 
supraventricular tachycardia that are not controlled by medications in the 
12 weeks before screening
i.
Fasting triglycerides >400 mg/dL (4.5 mmol/L) at screening
j.
Uncontrolled hypertension at screening, defined as an average sitting systolic 
blood pressure >160 mmHg or an average diastolic blood pressure >110 mmHg 
after a minimum of three measurements
k.
Type 1 diabetes mellitus or poorly controlled (glycated haemoglobin 10% or
86 mmol/mol) type 2 diabetes mellitus at screening
l.
Known active infection or major haematological, renal, metabolic, 
gastrointestinal or endocrine dysfunction in the judgment of the Investigator at 
screening or Day 1
3.
Concomitant medication:
a.
Currently receiving or <12 weeks at Day 1 since receiving >200 mg/day niacin 
or niacin derivative drugs (e.g., niceritrol, nicomol)
b.
Treatment with lipid/lipoprotein apheresis within the 12 weeks before screening
c.
Treatment with a cholesteryl ester transfer protein inhibitor (e.g., anacetrapib, 
dalcetrapib, evacetrapib, obicetrapib) or lomitapide within the 52 weeks before 
screening
d.
Treatment with aspirin, clopidogrel, ticagrelor or other antiplatelet agent unless 
prescribed at a low maintenance dose for the purpose of cardiovascular risk 
reduction (i.e., aspirin up to 325 mg daily, clopidogrel 75 mg daily, ticagrelor 
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e.
Participation in another clinical trial including an investigational medicinal 
product (IMP) within 12 weeks, or within five half-lives of that IMP, before
screening
f.
Any previous use of approved or experimental siRNA therapy (e.g., inclisiran).
NB: use of mRNA-based vaccines for infectious diseases is permitted
g.
Use of approved or experimental antisense oligonucleotide therapy within the 
24 weeks before screening. NB: use of mRNA-based vaccines for infectious 
diseases is permitted
h.
Use of experimental Lp(a)-reducing therapy within the 52 weeks before 
screening
i.
Use of herbal or complementary medicines, dietary supplements or vitamins 
known to substantially influence lipid metabolism or blood lipid or lipoprotein 
levels (e.g., fish oil, turmeric, red yeast rice) within the 4 weeks before Day 1
4.
Alcohol and illegal drugs:
a.
History or clinical evidence of alcohol misuse within the 26 weeks before 
screening
b.
History or clinical evidence of recreational drug use within the 26 weeks before 
screening
5.
Other exclusions:
a.
Female participants of childbearing potential with a positive serum pregnancy 
test assessed at screening or positive urine pregnancy test on Day 1
b.
Female participants of childbearing potential planning to become pregnant or 
breastfeed during treatment and for an additional 12 weeks after the last dose of 
study treatment
c.
Female participants of childbearing potential unwilling to use a highly effective 
method of contraception during treatment and for an additional 12 weeks after 
the last dose of study treatment
d.
Male participants must be surgically sterile or, if engaged in sexual relations 
with a female of childbearing potential, the participant must be using a highly 
effective contraception method from the time of signing the informed consent 
form (ICF) until at least 12 weeks after the last dose of study treatment
e.
Known sensitivity to any of the products to be administered during dosing
f.
Likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of 
the participant and Investigator’s knowledge
g.
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 


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Investigator or Sponsor, if consulted, would pose a risk to participant safety or 
interfere with the study evaluation, procedures or completion
6.
STUDY ASSESSMENTS AND PROCEDURES
6.1.
Screening
Once informed consent has been obtained, participants will undergo a screening 
assessment to see if they are suitable to be enrolled in the study. Screening visits will be 
conducted by the Investigator or their appropriately qualified designee. Screening may be 
performed up to 28 days before first treatment administration. 
For clinical sites without access to existing Lp(a) data for potentially eligible participants, 
participants may complete an optional pre-screening visit to evaluate Lp(a) levels. At this 
optional pre-screening visit, sites may send blood samples to a local laboratory to 
measure Lp(a) levels, thereby supporting the identification of eligible participants that 
may proceed into screening. The optional pre-screening visit may be conducted up to 
14 days prior to the screening visit. A separate pre-screening ICF is available for this 
purpose. Participants may choose to forego the optional pre-screening ICF and only sign 
the main study ICF. All patients will need to sign the main study ICF before proceeding
with study-related screening assessments.
6.2.
Medical History
The participant’s medical history will be collected by the Investigator or suitably 
qualified designee. The information will be collected from the participant and/or their 
medical records and should include all ongoing and past diseases or conditions identified 
as relevant by the Investigator. The participant should be excluded from the trial if any 
disease or condition listed in the exclusion criteria is detected. Particular attention should 
be paid to the following conditions/diagnoses:
Renal dysfunction
Acute, chronic or historical liver disease
Hepatic dysfunction
Inherited or other bleeding disorders
Malignancy
Heart failure or heart abnormalities
Hypertension
Diabetes mellitus
Active infection


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Other haematological, renal, metabolic, gastrointestinal or endocrine dysfunction
The Investigator or designee should record the date in which comorbidities began (where 
known).
Any relevant diagnostic, therapeutic or surgical procedures or those performed in the 
10 years before screening must be recorded in the electronic case report form (eCRF),
including the dates, indication, description of the procedure(s) and any clinical findings, 
if applicable. Other procedures performed greater than 10 years before screening but 
relevant to eligibility criteria, safety considerations or otherwise clinically relevant should 
also be recorded. 
6.3.
Demographics
The following demographic information should be recorded:
Age
Sex
Race
Ethnicity
Information that could identify the participant, such as name, initials, social security 
number (if applicable), (national) insurance number, etc., should not be recorded in the 
eCRF and should not be transmitted from the site to the Sponsor.
6.4.
Pharmacodynamic and Efficacy Procedures
SLN360 PD will evaluate Lp(a) levels as the most proximal measurable marker reflecting 
target engagement. Lipoprotein(a) will be measured centrally using a molar assay. On 
dosing days, blood samples for PD biomarkers should be collected pre-dose. Of note, the 
full set of parameters listed may not be assessed at every timepoint described in the Time 
and Events tables (Appendix 15.1 and Appendix 15.2).
Biomarkers to be measured include:
Serum lipids and lipoproteins
o
Lipoprotein(a)
o
Apolipoprotein B
o
Low-density lipoprotein cholesterol
o
High-density lipoprotein cholesterol
o
Total cholesterol
o
Triglycerides


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o
Oxidised phospholipids
o
C-reactive protein
All biomarkers will be measured centrally. Blood samples will be collected for biomarker 
evaluations at the times indicated in the Time and Events tables (Appendix 15.1 and 
Appendix 15.2).
6.5.
Safety Procedures
6.5.1.
Adverse Event Assessments
Information regarding the occurrence of AEs for each participant will be collected from 
the time a signed and dated ICF for the main study is obtained until completion of the 
participant's last study-related procedure, which may include contact to follow-up for
safety. Adverse events that start from the time the participant signs the main study ICF
until treatment administration on Day 1 will be assigned as non-treatment emergent AEs; 
AEs starting or worsening after treatment administration will be recorded as TEAEs. See 
the Time and Events tables (Appendix 15.1 and Appendix 15.2) for detailed timing of 
assessments. Grading of AEs is outlined in Section 11.2.
6.5.2.
Injection Site Reaction Assessment
The monitoring of AEs will include special attention paid to potential ISRs. The position 
of the injection sites should be marked at the time of dosing and injection sites monitored 
throughout the study. Inspection of the site of administration and surrounding area will be 
performed at timepoints specified in the Time and Events tables (Appendix 15.1 and 
Appendix 15.2). Injection site reactions should be followed up until resolution. Should an 
ISR not be resolved at the end of a study visit, the Investigator should maintain frequent 
contact, either in person or remotely, with the patient to confirm the course and the date 
of resolution. Additional evaluations of the injection site may be performed if a reaction 
is observed, at the discretion of the Investigator. The following information will be 
collected at all ISR assessments: 
Pain: Yes/No
Tenderness: Yes/No
Redness/erythema: Yes/No
o
If ‘Yes’, measurement of the largest dimension to be recorded in centimetres
Swelling/induration: Yes/No
o
If ‘Yes’, measurement of the largest dimension to be recorded in centimetres


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All ISRs are to be recorded as an AE if they meet AE criteria and an overall rating for 
each ISR will be recorded using the specific scale described in NCI-CTCAE v5 
(Table 6).
Table 6
Injection site reaction grading scale
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Injection site 
reaction (ISR)
Tenderness 
with or without 
associated 
symptoms 
(e.g., warmth, 
erythema,
itching)
Pain; 
lipodystrophy; 
oedema;
phlebitis
Ulceration or 
necrosis; 
severe tissue 
damage; 
operative 
intervention 
indicated
Life-threatening 
consequences:
urgent 
intervention 
indicated
Death
6.5.3.
Twelve-Lead Electrocardiogram
Twelve-lead ECGs should be performed at the times outlined in the Time and Events 
tables (Appendix 15.1 and Appendix 15.2) in a standardised manner, that is, after the 
participant has rested in the semi-supine position for at least 10 minutes. Measurements 
will be made using an ECG machine that automatically calculates the heart rate, PR 
interval, QRS interval, RR interval and QT interval. All ECG traces will be reviewed and 
signed by the Investigator or designee, and any abnormalities will be marked as clinically 
significant or not clinically significant. If the average QT interval corrected using 
Fridericia’s formula (QTcF) is 500 milliseconds, then an additional ECG should be 
repeated after at least a 5minute interval. If the participant has a permanent pacemaker in 
situ, the effects of pacing on the QTcF should be taken into account.
6.5.4.
Vital Signs
Vital signs (temperature, respiratory rate, heart rate and systolic and diastolic blood 
pressure) will be assessed at the times outlined in the Time and Events tables 
(Appendix 15.1 and Appendix 15.2). Participants should rest in a supine position for 
10 minutes before the vital signs are assessed. Vital signs may be repeated once after at 
least a 5-minute interval if obtained values are abnormal or outside the normal range at 
first measurement.
The participant’s weight will be measured at each timepoint (without shoes or heavy 
garments [e.g., coats, jumpers]). The participant’s height will only be measured at the 
screening visit.


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6.5.5.
Physical Examination
Full or abbreviated physical examinations will be performed by a qualified clinician at 
the times outlined in the Time and Events tables (Appendix 15.1 and Appendix 15.2), as 
described below.
Full physical examination at screening, pre-dose on Day 1 and EoS: the Investigator
or appropriately qualified designee will examine and/or measure height and weight 
and the skin, eyes, ears, mouth, lymph nodes, respiratory, cardiovascular, 
gastrointestinal, neurological and musculoskeletal systems
Abbreviated physical examination at subsequent visits: the assessment will be 
focused and guided by symptoms reported by the participant, other physical signs 
detected and findings from laboratory assessments. It should be conducted by the 
Investigator or appropriately qualified designee. The examination may include the 
skin, lymph nodes, respiratory, cardiovascular, gastrointestinal and musculoskeletal 
systems, and any ad hoc examinations based on signs and symptoms reported during 
or prior to the visit
6.5.6.
Laboratory Assessments
6.5.6.1.
Haematology and Coagulation
Blood for the assessment of haematology parameters will be collected at the times 
outlined in the Time and Events tables (Appendix 15.1 and Appendix 15.2). Of note, the 
full set of parameters listed may not be assessed at every timepoint described in the Time 
and Events tables.
The following parameters will be assessed during the study:
Red blood cell count
Haematocrit
Mean corpuscular volume
Haemoglobin concentration
Platelet count
White blood cell count
Neutrophil count and percentage
Lymphocyte count and percentage
Monocyte count and percentage
Eosinophil count and percentage
Basophil count and percentage


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Prothrombin time
Activated partial thromboplastin time
International normalised ratio
Fibrinogen concentration
Plasminogen activity
Plasminogen concentration
Haemoglobin A1C
Blood samples will be analysed centrally, and some samples will be retained for further 
analysis. Further details on processing can be found in the Laboratory Manual.
6.5.6.2.
Clinical Chemistry
Blood for the assessment of clinical chemistry parameters will be collected at the times 
outlined in the Time and Events tables (Appendix 15.1 and Appendix 15.2). Of note, the 
full set of parameters listed may not be assessed at every timepoint described in the Time 
and Events tables.
The following parameters will be assessed:
Creatinine
Urea
Estimated glomerular filtration rate (using Chronic Kidney Disease Epidemiology 
Collaboration equation) 
Sodium
Potassium
Calcium
Chloride 
Inorganic phosphate
Creatine kinase
Alanine aminotransferase
Aspartate aminotransferase
Alkaline phosphatase
Gamma-glutamyl transferase
Total bilirubin
Direct bilirubin


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Total protein
Albumin
Glucose
C-reactive protein
Beta-human chorionic gonadotrophin
Thyroid stimulating hormone
Triiodothyronine
Thyroxine
Blood samples will be analysed centrally, and some samples will be retained for further 
analysis. Further details on processing can be found in the Laboratory Manual.
6.5.6.3.
Viral serology
Blood samples will be collected at screening for detection of hepatitis A, B and C and 
human immunodeficiency virus. The following parameters will be assessed:
Hepatitis A serology
Hepatitis B surface antigen
Hepatitis B core antibody
Hepatitis C antibody
Human immunodeficiency virus 1 and 2 serology
6.5.6.4.
Anti-drug antibodies
Blood samples will be collected for assessment of SLN360 anti-drug antibodies at the 
times outlined in the Time and Events tables (Appendix 15.1 and Appendix 15.2).
6.5.6.5.
Urinalysis
Urine samples will be collected at the times outlined in the Time and Events tables 
(Appendix 15.1 and Appendix 15.2).
The following parameters will be assessed at each timepoint:
Leukocytes
Glucose
Ketones
Nitrite


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Bilirubin
Specific gravity
Blood
pH
Protein
Urobilinogen
Urine samples will be analysed locally using a dipstick but may also be analysed 
centrally if indicated and deemed appropriate by the Investigator.
6.5.7.
Pregnancy Testing and Reporting
Women of child-bearing potential must have a negative pregnancy test at screening. A 
pregnancy test will be performed at the times indicated in the Time and Events tables 
(Appendix 15.1 and Appendix 15.2). Following administration of study drug, any known 
cases of pregnancy in female patients or in pregnant partners of male patients will be 
reported until 3 months after study completion. It is the responsibility of the Investigator,
or designee, to report any pregnancy and anticipated date of birth that occurs while a 
patient is receiving the study drug via the in utero exposure form. If the pregnancy is to 
be terminated, the anticipated date of termination should be provided.
The pregnancy will be reported immediately by faxing/emailing a completed pregnancy 
report to the Sponsor (or designee) within 24 hours. The pregnancy must be followed up 
within 30 days regardless of the outcome (including spontaneous miscarriage, elective 
termination, normal birth or congenital abnormality) and status of mother and child, even 
if the patient was discontinued form the study. The Investigator should notify the Sponsor
(or designee) of the pregnancy outcome by submitting a follow-up pregnancy report. 
If the Investigator becomes aware of a pregnancy occurring in the partner of a patient 
participating in the study, the pregnancy should be reported to the Sponsor (or designee) 
within 24 hours. Information regarding the pregnancy must only be submitted after 
obtaining written consent from the pregnant partner. If consent is provided, the pregnancy 
of the partner should be followed by the Investigator until completion of the pregnancy.
6.6.
Pharmacogenetic Procedures
Pharmacogenetic effects of germline genetic variation on Lp(a) response to SLN360 will 
be measured from a blood sample by association analysis of genetic variants with 
markers of SLN360 efficacy at times indicated in the Time and Events tables 
(Appendix 15.1 and Appendix 15.2).


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6.6.1.
Genotyping
Blood samples will be collected at the times outlined in the Time and Events tables 
(Appendix 15.1 and Appendix 15.2) for genotyping to enable generation of genetic data 
for exploratory pharmacogenetic analysis.
6.7.
Independent Data Monitoring Committee
6.7.1.
Role of the Independent Data Monitoring Committee
The Independent Data Monitoring Committee (IDMC) is responsible for review of data 
during the study. The IDMC will review accrued data on an ongoing basis and make 
relevant recommendations to the Sponsor. The IDMC is an independent group of experts 
in clinical trials, clinical medicine and drug safety. The details of the role, remit and 
responsibility of the IDMC, together with practical considerations for data review and 
IDMC meetings are provided in the IDMC Charter.
6.7.2.
Independent Data Monitoring Committee Composition
The IDMC is composed of experts who are independent of the Sponsor and CRO. The 
expertise of members will cover medical aspects of clinical trial conduct in CVD,
cardiovascular medicine, oligonucleotide therapeutics and drug safety.
6.7.3.
Data Available for Independent Data Monitoring Committee
Review
The IDMC will primarily review semi-blinded data from this Phase 2 study. Where 
necessary, to enable interpretation of the data and to make a recommendation to the 
Sponsor, the IDMC may review unblinded data; the minimum necessary amount of data 
to enable decision-making should be unblinded to maintain the scientific integrity of the 
study. The IDMC may also review accrued data from the ongoing Phase 1 (APOLLO) 
study. 
6.7.4.
Independent Data Monitoring Committee Recommendations and 
Meeting Schedule
The IDMC will provide recommendations on specific questions of study conduct deemed 
appropriate by the IDMC or Sponsor. The meeting schedule will be defined in the IDMC 
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7.
LIFESTYLE AND/OR DIETARY RESTRICTIONS
7.1.
Lifestyle and Dietary
The following lifestyle and dietary restrictions apply throughout the study:
Participants should not consume alcohol within the 48 hours before and until 
48 hours after each dose administration
Participants should not consume more than 14 units of alcohol per week. A unit is 
defined as one measure (25 mL) of spirits, half a pint (236 mL) of standard-strength 
beer or one small glass (125 mL) of wine
Participants should not use recreational drugs unless prescribed by a physician
Participants are required to refrain from strenuous exercise for 24 hours before and 
24 hours after each study visit, and will otherwise maintain their normal level of 
physical activity during this time (i.e., will not begin a new exercise programme nor
participate in any unusually strenuous physical exertion)
7.2.
Contraception
7.2.1.
Female Participants
Female participants who are of childbearing potential (who are heterosexually active) 
must agree to use a highly effective method of contraception from the start of the 
screening period until 12 weeks after the last administration of study drug.
Methods with a failure rate of less than 1% per year when used consistently and correctly 
are considered highly effective birth control methods, and include: 
Combined (oestrogen and progestogen containing) hormonal contraception 
association with inhibition of ovulation (including oral, intravaginal or transdermal 
formulations)
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(including oral, injectable or implantable formulations)
Intrauterine device
Intrauterine hormone-releasing system
Bilateral tubal occlusion
Vasectomised partner (provided that the partner is the sole sexual partner of the 
study participant and that the vasectomised partner has received medical 
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Complete sexual abstinence (defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments). The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the participant. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal and post-ovulation methods), declaration of 
abstinence for the duration of exposure to study treatment and withdrawal are not 
acceptable methods of contraception
All women are to be considered of childbearing potential unless they are permanently 
sterile or postmenopausal. A woman must only be considered permanently sterile if they 
have clear medical documentation confirming hysterectomy, bilateral salpingectomy or 
bilateral oophorectomy. A postmenopausal state is defined as no menses for at least 
12 months before the start of the screening period, without an alternative medical cause. 
A high follicle-stimulating hormone level in the postmenopausal range (as per local 
laboratory guidelines) should be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy.
7.2.2.
Male Participants
Male participants must use a male condom (with or without spermicide) if sexually active 
with a female of childbearing potential from the start of the screening period until 
12 weeks after the last administration of study drug. Male participants should be 
encouraged to inform their female sexual partners that they are participating in a Phase 2 
clinical study.
Male participants who have documented vasectomy with medical confirmation of success 
are not required to use contraception.
8.
INVESTIGATIONAL PRODUCT(S)
8.1.
Dosage and Administration
SLN360 is provided as a solution for injection for subcutaneous use in glass vials. A vial 
(2R vial) contains 0.5 mL (extractable volume) of an aqueous sterile solution of SLN360 
drug substance with a concentration of 200 mg/mL (as free acid form). The vials are 
intended for single use. SLN360 will be supplied by the Sponsor or designee, along with 
the batch/lot numbers and Certificates of Analysis.
Each dose of SLN360 or placebo will be administered via subcutaneous injection by 
appropriately qualified clinical study site staff. The injection will be delivered in the 
abdomen, avoiding areas where the skin is red, bruised, tender, indurated or in sites of 
previous scars. Where other medicinal products are required to be given by subcutaneous 
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Individual injection volume at each injection site will not exceed 1.5 mL, and up to 
two injection sites may be used to achieve the required dose. Please refer to the IMP
Handling Manual for further guidance.
Where multiple injections are required in one dosing session, injection sites ideally 
should be separated by a few centimetres, according to local practice. When multiple 
injections are given, injection sites should be rotated to a different location (i.e., not 
administered in precisely the same place for subsequent administrations) and a new 
quadrant of the abdomen should be used for each injection. It is recommended to proceed 
around the quadrants in a clockwise direction. Injection sites should be recorded in the 
eCRF.
Participants will be dosed at the timepoints outlined in the Time and Events tables 
(Appendix 15.1 and Appendix 15.2).
8.2.
Dose Rationale
Data from SAD administration in the FIH study and from modelling of nonclinical data 
(LYO-X Report No.: LYO-X-2022-06-0003) indicate that the safe, tolerable and 
effective doses of SLN360 for evaluation in this Phase 2 study are 300 mg and 450 mg. 
SLN360 and placebo will be administered via subcutaneous injection in multiple doses. 
Placebo and three SLN360 dosing regimens will be evaluated: 300 mg Q16W, 300 mg 
Q24W and 450 mg Q24W.
Efficacy is defined as a combination of magnitude of Lp(a) reduction and the duration 
over which that reduction persists. Data from the FIH study suggest that a reduction of 80
to 90% in Lp(a) levels from baseline sustained for more than 12 weeks is anticipated at 
these doses.
8.2.1.
Pharmacokinetic-pharmacodynamic Modelling for Dose Selection
Recommended Dose Range:
Safety data from the completed SAD part of the ongoing Phase 1 study support the dose 
range in this Phase 2 study of 300 to 450 mg based on the summarised data in 
Section 1.1.3. The 300 mg dose in the SAD part of the Phase 1 study was well tolerated 
with no concerning treatment-associated safety signals. The maximal dose, 600 mg, was 
associated with ISRs (up to CTCAE grade 2), all of which resolved. Plasma PK for these 
doses was broadly dose proportional. From an efficacy perspective, lowering of Lp(a) 
concentration from baseline by at least approximately 80% is the objective of the 
SLN360 programme; this magnitude of effect or greater was observed after single doses 
of 100 mg, 300 mg and 600 mg in the SAD part of the Phase 1 study. Exaggerated 
pharmacology is not a concern with Lp(a)-lowering as individuals have been identified 
with near-zero circulating concentrations of Lp(a) and with no reported adverse 


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consequences. Therefore, the benefit: risk balance based on the available clinical and 
nonclinical data supports a starting dose of 300 mg in this study.
Maximum Supported Dose:
Data from the SAD part of the Phase 1 study, suggest lower tolerability of the maximum 
evaluated dose of 600 mg. In brief, ISRs accompanied by transient leukocytosis and rises 
in C-reactive protein were observed at the 600 mg dose. Considering these findings, we 
do not intend to pursue the 600 mg dose further in development. However, the SAD 
Phase 1 data and PK-PD modelling appear to support a favourable benefit: risk when 
evaluating doses up to 450 mg based on predicted magnitude and duration of Lp(a) 
lowering for clinical benefit in patients with ASCVD.
Pharmacokinetic-pharmacodynamic Modelling:
The data from the SAD part of the Phase 1 study was used to construct a population PK-
PD-based SLN360 model. The model structure was based on modelling of preclinical 
studies in non-human primates and included a liver compartment and associated liver 
parameters. A small subset of parameters in the human model were fixed to values 
allometrically scaled from the non-human primate model, a choice justified by the lack of 
liver data in humans and the ability of the full non-human primate model predict the 
Phase 1 data after scaling to human. All model parameters not fixed to values 
allometrically scaled from non-human primates were estimated using the Phase 1 study 
PK and PD data.
Data used for the modelling included:
Non-human primate plasma and liver SLN360 concentrations, serum Lp(a) 
concentrations
Human plasma SLN360 and Lp(a) concentration from SAD part of the Phase 1 study 
for single doses of placebo and 30, 100, 300 and 600 mg of SLN360
Full details of the nonclinical studies are available in the IB. Modelling tested a range of 
covariates: age, body weight, sex, eGFR (PK estimates only), and baseline Lp(a) (PD 
estimates only). No covariates were included in the final model used for predictions of 
PK and PD in this Phase 2 study.
Simulations were prepared for a range of repeat dosing regimens, including but not 
limited to:
Three hundred mg dosing every 3, 4 and 6 months (Q3M, Q4M and Q6M,
respectively)
Four hundred and fifty mg Q3M, Q4M and Q6M


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Each simulation included 300 individuals, from which were derived the simulated liver 
concentrations of SLN360, longitudinal profile of Lp(a) change over 24 months and the 
time-averaged change in Lp(a) over a dosing interval after the final simulated dose. 
The simulated SLN360 liver exposure is shown in Figure 3. With repeated dosing, only 
modest increments in liver exposure are predicted, with the increment diminishing after 
the second dose.
Figure 3
Predicted liver SLN360 concentrations after repeat dosing with a 
range of doses and regimens
Note: simulated median (red line), 5th and 95th prediction interval (red area) from 300 simulated individual profiles.
The profiles for the dosing regimens proposed for the planned Phase 2 study are in 
Figure 4.


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Figure 4
Simulated serum Lp(a) levels for the dosing regimens planned in the 
proposed Phase 2 study
Note: simulated median serum Lp(a) (red line), 5th and 95th prediction interval (red area) from 300 simulated individual 
profiles. Baseline (dashed line). Target % lowering from baseline = 20% (dotted line).
The most clinically meaningful measure of SLN360 efficacy is a function of the 
magnitude and duration of Lp(a) lowering. This can be quantified by the time-averaged 
change in Lp(a) after dosing. Figure 5 illustrates the simulated time-averaged change in 
Lp(a), from 300 simulated individuals. The time period for the average is the change
from the last dose administered in each regimen to 12 months. For Q4M regimens this is 
the period after the third dose and for Q6M regimens it is the period after the second 
dose. In both cases, the time periods represent a single dosing interval.


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Figure 5
Simulated time-averaged change in serum Lp(a) for a range of 
dosing regimens, including those planned for the proposed Phase 2 
study
A
B
Lp(a)=lipoprotein(a); q4m=dosing every 4 months; q6m=dosing every 6 months
A) Serum Lp(a) predicted time-average % change from baseline for dosing interval (after final simulated dose). 
B) Illustration of sources of data for time-averaged change in Lp(a). Based on 300 simulated individual profiles. Trough 
refers to trough exposure for a continuous Q6M dosing interval.
The percentage of the simulated population with time-averaged reduction in Lp(a) >80% 
lower than baseline values are described in Table 7. The doses planned in the proposed 
Phase 2 study are highlighted.




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An email notification will be sent out immediately after the unblinding has occurred to 
the roles defined in the IRT requirements, including the Principal Investigator at the site, 
the Sponsor, the Safety Manager and the Medical Monitor. The notification of unblinding 
will be filed in the Investigator Site File and includes the following information:
Participant number
Site number
Study/protocol number
Date and time of unblinding
Reason for unblinding
The notification of unblinding will not contain the actual treatment assignment.
8.4.
Treatment Assignment
This is a randomised controlled study; participants will be assigned their treatment using 
IRT. Participants will be allocated to a treatment group in accordance with the 
randomisation schedule. The randomisation schedule will be computer generated.
Randomisation (allocation to treatment) will occur just before the participant receives 
their first dose of study drug. Once assigned, randomisation numbers shall not be 
reassigned. Randomisation numbers will be assigned and maintained using IRT. Each 
participant will be allocated a unique participant identifier at screening that will be used 
throughout the study.
Participants will be randomised in a 1:1:2:2:2 ratio to the groups described in 
Section 4.1.1 to receive either SLN360 or placebo.
Further details on the randomisation process will be provided in the IMP Handling 
Manual.
8.5.
Packaging and Labelling
Study treatment will be supplied in single-use, pre-filled glass vials that will have been 
labelled and packaged before distribution to the study sites. Study treatment will be 
labelled and packaged under the responsibility of the Sponsor. No medication can be 
re-labelled or repackaged without prior approval from the Sponsor.
Medication will be provided to the sites in an open-label format. The labels will contain 
all information required to meet the applicable local regulatory requirements. The syringe 
labels applied following dispensing will be blinded.
Further information on the study drug packaging, labelling and dispensing will be 
provided in the IMP Handling Manual.


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8.6.
Preparation
Details on the preparation of SLN360 will be provided in the IMP Handling Manual.
8.7.
Handling and Storage
SLN360 must be kept in an appropriate, secure, locked area and stored in accordance 
with the conditions specified on the labels. SLN360 will be stored between 2°C (35.6°F) 
and 8°C (46.4°F).
Placebo treatment (commercial NaCl injection, 0.9% weight/volume administered via 
subcutaneous injection) will be supplied by the Sponsor (or designee). Placebo will be 
stored in accordance with the conditions specified on the label. All study drug 
vials/ampoules are single-use and any unused portion remaining in the vial must be 
discarded.
8.8.
Product Accountability and Assessment of Compliance
The appropriate study personnel will maintain a log of all study drugs received, 
dispensed, destroyed and returned. Drug supplies will be inventoried and accounted for 
throughout the study. Local site drug destruction is acceptable, provided it is authorised 
by the Sponsor and a certificate of destruction is made available.
The Investigator’s unblinded designee will ensure that each participant receives the 
appropriate dose of the study drug. Only participants enrolled in the study may receive 
study treatment and only site staff, as outlined in the site accountability log, may 
administer study treatment.
8.9.
Treatment of Investigational Product Overdose
From a primary pharmacological perspective, participants are individuals who have 
elevated Lp(a) levels and are at high risk of a first ASCVD event. The majority of the 
general population has low (less than approximately 50 mg/dL) circulating Lp(a) levels 
[Kamstrup et al, 2009]. These low levels are not associated with adverse health 
outcomes; for instance, individuals with no detectable Lp(a) have been identified, and 
they display no substantial detrimental effects [Lim et al, 2014; Emdin et al, 2016].
Therefore, potential harmful effects of reduced Lp(a) levels are not expected to be a 
primary concern, and exaggerated primary pharmacology is not expected to occur. Since 
SLN360 is administered in a controlled clinical setting by healthcare professionals the 
potential for overdose is extremely low. The Sponsor will collect information pertinent to 
overdose across the clinical development program. Further information regarding 
overdose will be provided by the Sponsor to Investigators in the IB.


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8.10.
Occupational Safety
No specific risks have been identified for staff handling the study treatment. The Material 
Safety Data Sheets will be made available where required by local regulations.
9.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
9.1.
Recording Prior and Concomitant Medication
All concomitant medications, including medication given in the 30 days before study 
treatment administration and during the study, must be recorded in the eCRF along with 
the indication for which it was used. The generic name of the drug should be specified 
along with the dose, frequency, duration and route of administration of treatment. 
Any diagnostic, therapeutic or surgical procedure performed during the study period 
should be recorded in the eCRF, including the dates, indication, description of the 
procedure(s) and any clinical findings, if applicable.
9.2.
Permitted Medications
Other than the therapies listed in Section 9.3, the use of any concomitant 
medication/therapy, including over-the-counter medications that is deemed necessary for 
treating the participant is permitted during the study. Any medication used for the 
management of dyslipidaemia (including statins, ezetimibe, bempedoic acid, fibrates, 
omega-3 fatty acids, colesevelam and implitapide) must have been at a stable, maximum 
tolerated dose for at least 8 weeks prior to screening and expected to remain stable for the 
duration of the study (in the opinion of the Principal Investigator). Sex hormone 
replacement therapy for male or female participants will only be permitted if the therapy 
has been prescribed at a stable dose for at least 8 weeks prior to screening and is expected 
to remain stable for the duration of the study (in the opinion of the Principal Investigator). 
Acetaminophen (paracetamol), up to a maximum dose of 2 g/day, will be permitted for 
use as an antipyretic and/or analgesic. Aspirin (up to a maximum dose of 325 mg/day) 
will be permitted for use as an antipyretic and/or analgesic, and for primary or secondary 
prevention of CVD. Oral contraceptives are permitted.
9.3.
Prohibited Medications and Procedures
The following concomitant treatments are not permitted during the study:
Initiation of medication or therapies significantly affecting Lp(a) levels (including 
but not restricted to PCSK9 inhibitors, prescription dose niacin, fibrates and 
anti-oestrogen therapy)


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Initiation of statins and/or ezetimibe
Initiation of lipid or lipoprotein apheresis
Initiation of oligonucleotide therapy, including antisense oligonucleotides, and 
siRNA, other than SLN360. Vaccines using mRNA technology are permitted
Initiation of sex hormone replacement therapy for male or female participants
Initiation of anti-oestrogen or oestrogen receptor modulator (e.g., tamoxifen)
If during the course of the study, a participant needs additional medication, surgery or an 
investigation that affects participation in the study or otherwise compromises either the 
participant’s safety or the integrity of the data collected, this should be discussed with the 
Medical Monitor. The participant may be withdrawn from the study, if deemed 
necessary, and replaced if appropriate; all participants that have been dosed should 
complete follow-up assessments even if withdrawn. The participant’s treating 
physician(s) must be informed of the experimental therapy and the likely effects of 
SLN360 on Lp(a) levels, other plasma lipid fractions and markers of toxicity.
10.
PARTICIPANT COMPLETION AND WITHDRAWAL
10.1.
Participant Completion
The participant will be classed as having completed the study once they have completed 
the EoS visit, which will be up to 36 weeks after the last administration of treatment,
depending on group, or an early withdrawal visit.
10.2.
Participant Withdrawal
10.2.1.
Participant Withdrawal of Consent
A participant may withdraw consent for:
Treatment
Follow-up visits
Non-patient contact follow-up, e.g., medical records checks
Withdrawal of consent for follow-up should be accompanied by documentation of the 
reason for withdrawal.
Participants requesting withdrawal should be informed that withdrawal of consent for 
follow-up may jeopardise the public health value of the study. Patients who withdraw 
should also be explicitly asked about the contribution of possible AEs to their decision to 
withdraw consent, and any AE information elicited should be documented.


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The participant should withdraw consent preferably in writing and, if the participant
refuses or is physically unavailable, the site should document and sign the reason for the 
participant’s failure to withdraw consent in writing. 
10.2.2.
Participant Withdrawal from Study
Participants may withdraw from the study at any time and for any reason without the 
need for justification. Participants may also be withdrawn by the Investigator if, in the 
Investigator’s opinion, further participation in the study would be deleterious to the 
participant’s health. Reasons for withdrawal could include unacceptable adverse 
reactions, protocol violation or administrative reasons. To maintain the value and 
integrity of the study, excessive withdrawals should be avoided where possible.
Where consent remains, every effort must be made to follow-up participants and, other 
than re-dosing, the scheduled trial assessments should be performed if possible. A reason 
for withdrawal and an early withdrawal clinic assessments (consisting of assessments 
included in the Week 36 and EoS visit) as per the Time and Events tables (Appendix 15.1
and Appendix 15.2) are essential.
10.2.3.
Participant Withdrawal from Investigational Product
A participant will be withdrawn from treatment for any of the following reasons:
Withdrawal of consent to continue with treatment. The reason for this will be 
documented if provided
Lack of compliance, as assessed per the Investigator and/or the Sponsor
Adverse events that cannot be tolerated by the participant
The reason(s) for withdrawal must be recorded in the eCRF. If a participant is withdrawn 
from treatment, every effort must be made for the participant to attend scheduled trial 
assessments if possible. Where a participant withdrawn from treatment is unable to attend 
scheduled assessments, every effort must be made to have them return for the Week 36 
and EoS visits, if possible. Only if the participant is unable to attend scheduled 
assessments, follow-up may include contact with managing physicians or pharmacists, 
medical record review and limited phone call visits.
10.3.
Long-term Follow-up
Where participants are lost to follow-up, continued efforts to locate participants during 
long-term follow-up until the EoS visit will be conducted in accordance with local 
regulations including available public records to determine vital status. 


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10.4.
Treatment after the End of the Study
Participants will not be provided with study treatment following the end of the study. 
Regular treatment that participants received before entering the study can be continued 
following study completion.
10.5.
Screening and Baseline Failures
If, after review pre-dose on Day -1 or Day 1, any eligibility criteria are found not to be 
met, the participant may be rescreened at the Investigator’s discretion, or should be 
deemed a baseline failure. If a patient has a positive SARS-CoV-2 antigen lateral flow 
test or active coronavirus disease 2019 (COVID-19) infection during screening, 
rescreening should take place at least 4 weeks after the initial screening. 
For participants who do not pass at screening or baseline, at least the ICF, demographics, 
inclusion and exclusion criteria, reason for screen failure and any AEs during screening 
will be collected in the eCRF. Information on screening and baseline failures will be 
collected and may be used for the final analysis.
10.6.
Testing for SARS-CoV-2
Testing for SARS-CoV-2 will be completed using an antigen-based point-of-care lateral 
flow test at each visit. A positive test result should be confirmed with a second test 
immediately after the first.
In the event of a confirmed positive test result on or shortly before a dosing day, that dose 
administration should be delayed until the participant has a negative test result and dose 
administration is deemed clinically appropriate by the Investigator. If the first dose is 
delayed because of a positive test result, all subsequent visits should also be delayed
accordingly. If a second or third dose is delayed because of a positive test result, the 
impacted visit will be delayed. All subsequent visits should be completed according to 
their original schedule as described in the Time and Events tables (Appendix 15.1 and 
Appendix 15.2), i.e., not delayed. 
Administration of doses outside the visit windows should not, per se, be grounds for 
withdrawing a participant unless this is deemed clinically appropriate by the Investigator.
A positive SARS-CoV-2 test result should be recorded as an AE, even if the participant is 
asymptomatic for COVID-19.


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11.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
11.1.
Definitions
11.1.1.
Adverse Events
An AE is any untoward medical occurrence associated with the use of a drug/
investigational drug in humans, whether or not considered drug related. An AE can 
therefore be any unfavourable and unintended sign, symptom or disease that either 
emerges during the study or, if present at screening, worsens during the study, regardless 
of the suspected cause of the event.
11.1.2.
Adverse Events of Special Interest
An AE of special interest, whether serious or non-serious, is one of scientific and medical 
concern specific to the Sponsor’s study drug/device or programme, which warrants
ongoing monitoring and rapid communication by the Investigator to the Sponsor. Such an 
event might warrant further investigation to characterise and understand it. Adverse 
events of special interest may include events noted in prior studies. No AEs have been 
determined, for reporting purposes, to be AEs of special interest in this study.
11.1.3.
Serious Adverse Events
An SAE is any untoward medical occurrence that, at any dose:
1.
Results in death
2.
Is life-threatening
NB: An AE is ‘life-threatening’ if the patient is at immediate risk of death from the event 
as it occurs (i.e., does not include a reaction that might have caused death if it had 
occurred in a more serious form). For instance, drug-induced hepatitis that resolves 
without evidence of hepatic failure would not be considered life-threatening, even though 
drug-induced hepatitis can be fatal. 
3.
Requires in-patient hospitalisation or prolongation of existing hospitalisation (see 
below)
4.
Results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions)
5.
Results in a congenital anomaly/birth defect
6.
Results in an important medical event 
NB: Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered SAEs when, based upon appropriate medical 


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judgement, they may jeopardise the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
events are invasive or malignant cancers, intensive treatment in an emergency department 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalisation.
Hospitalisation
Adverse events requiring hospitalisation or prolongation of hospitalisation should be 
considered serious. In the absence of an AE, the participating Investigator should not 
report hospitalisation or prolongation of hospitalisation. In general, hospitalisation 
signifies that the participant has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or intervention that would 
not have been appropriate in the treating physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfils any other seriousness criteria, the event is serious. When in 
doubt as to whether hospitalisation occurred or was necessary, the AE should be 
considered serious.
In the following situations, hospitalisation would not qualify as serious:
Hospitalisation or prolongation of hospitalisation is needed for a procedure required 
by the protocol
Hospitalisation or prolongation of hospitalisation is part of a routine procedure 
followed by the study centre. This should be recorded in the study file
Hospitalisation for survey visits or annual physicals fall into the same category 
Hospitalisation is required for an elective intervention of a pre-existing condition that 
has not worsened from study treatment
Hospitalisation for social reasons/circumstances 
11.1.4.
Adverse Drug Reactions
All noxious and unintended responses to an IMP (i.e., where a causal relationship 
between an IMP and an AE is at least a reasonable possibility) related to any dose should
be considered adverse drug reactions.
Suspected unexpected serious adverse reactions (SUSARs) are SAEs, classed as related, 
which are not specified as expected in the approved IB. An unexpected adverse drug 
reaction is defined as an adverse reaction, the nature and severity of which is not 
consistent with the applicable product information (e.g., the IB for an unapproved IMP).


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11.2.
Assessment of Adverse Events
11.2.1.
Adverse Event Severity
Intensity of all AEs will be graded according to NCI-CTCAE version 5 on a five-point 
scale (Grade 1 to 5) and reported in detail on the eCRF. Adverse events not listed on the 
CTCAE should be graded as follows:
Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
Grade 2: moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)*
Grade 3: severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-
care ADL**
Grade 4: life-threatening consequences; urgent intervention indicated
Grade 5: death related to AE
*NB: Instrumental ADL refers to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.
**NB: Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications and not being bedridden.
11.2.2.
Adverse Event Causality
The Investigator (or appropriately qualified designee) will determine the relationship of 
the AE to the study drug using all available data (including detailed history taking, 
comprehensive clinical and laboratory/imaging assessment, as appropriate), taking into 
account good clinical and scientific judgement and categorise as detailed in the following 
sections.
Related to Study Treatment
A ‘reasonable possibility’ of a relationship between an AE to the study treatment is 
considered if:
It follows a reasonable temporal sequence from administration of the drug, or
It could not readily have been produced by the patient’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to the patients; or it follows 
a known pattern of response to the test drug


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Not Related to Study Treatment
‘No reasonable possibility’ of a relationship between an AE to the study treatment is 
considered if:
It is clearly related to extraneous causes, or
It does not follow a reasonable temporal sequence from administration of the test 
drug, or
It could readily have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patients, or
It does not follow a known pattern of response to the test drug, or
It does not reappear when the drug is re-administered
Adverse events, medical history and concomitant procedures will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) according to the version 
specified in the Data Management Plan. Prior and concomitant medications will be coded 
using the World Health Organization Drug Dictionary according to the version specified 
in the Data Management Plan.
11.2.3.
Structured Causality Assessment for Suspected Drug-induced 
Liver Injury
In the specific case of causality assessment for possible drug-induced liver injury,
decision making is based on compatible clinical course, typical changes in hepatic 
biochemistry and careful, systematic exclusion of all other reasonable causes such as the 
following: viral hepatitis (including consideration of cytomegalovirus and Epstein-Barr 
virus), non-alcoholic or alcoholic fatty liver disease, autoimmune hepatitis, hypotension, 
heart failure, sepsis, biliary tract obstruction, including gallstone disease, portal vein 
thrombosis, metabolic or heredity liver diseases (e.g., Wilson’s disease), and other 
hepatotoxic drugs [Aithal et al, 2011].
Comprehensive causality assessment for possible drug-induced liver injury should utilise
expert opinion with formal hepatology or gastroenterology expertise as much as possible, 
particularly in any severe cases, ideally blinded to treatment assignment in line with 
published recommendations [Regev, 2014].
In all cases, structured causality assessment should consider the following: history and 
concomitant diseases, temporal relationship with study drug, including latency to time 
from first drug exposure to qualifying laboratory tests or compatible symptoms, which 
include the following: increasing fatigue; anorexia; nausea; vomiting; right upper 
quadrant pain; pattern of injury (hepatocellular, cholestatic, or mixed) based on the first 
set of laboratory tests that meet the threshold for possible drug-induced liver injury and 
using the R value; injury severity, including peak values and assessment of hepatic 
synthetic function (prothrombin time/international normalised ratio and albumin); 


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washout data, i.e., the resolution and time taken to reach a reduction in serum enzymes to 
nd return to baseline; exclusion of other potential causes of liver injury with 
appropriate diagnostic evaluation (e.g., viral hepatitis serology, autoimmune hepatitis 
serology, imaging, and histology, if available); and clinical outcome [Chalasani et al,
2014].
11.3.
Safety Reporting 
11.3.1.
Reporting Adverse Events 
All medical and psychiatric conditions (except those related to the indication under study) 
present at screening will be documented in the medical history eCRF. Changes in these 
conditions and new symptoms, physical signs, syndromes or diseases should be noted on 
the eCRF during the rest of the study. Clinically significant laboratory abnormalities 
should also be recorded as AEs.
Wherever possible, a specific disease or syndrome rather than associated signs, 
symptoms, or abnormal assessments or laboratory findings should be identified by the 
Investigator and recorded on the eCRF. However, if an observed or reported sign or 
symptom is not considered a component of a specific disease or syndrome by the 
Investigator, it should be recorded as a separate AE on the eCRF.
Surgical procedures not prohibited in the eligibility criteria that were planned before 
enrolment in the study are not considered AEs, if the conditions were known before study 
inclusion. The medical condition(s) necessitating the surgical procedure should be 
reported in the patient’s medical history.
Each AE is to be documented on the eCRF with reference to the date of onset, duration, 
frequency, severity, relationship to study drug, action taken with study drug, treatment of 
event and outcome. Furthermore, each AE is to be classified as being serious or non-
serious. Changes to AEs and resolution dates are to be documented on the eCRF.
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the event should be noted. If the intensity category changes over 
time, then those changes should be recorded separately (with distinct onset dates).
11.3.2.
Reporting Serious Adverse Events
In the event of an SAE, regardless of suspected causality, the Investigator must notify the 
Sponsor and/or its safety representative immediately, without undue delay, and under no 
circumstances later than 24 hours of becoming aware of the event using study specific 
SAE forms. The Investigator must provide detailed follow-up AE information, as 
necessary, to the Sponsor and/or its safety representative in a timely manner to meet 
regulatory reporting requirements. Serious AEs must also be reported to the Independent 
Ethics Committee/Institutional Review Board according to their policies and procedures. 


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Recruitment episodes, complications or progression of the initial SAE must be reported 
as follow-up to the original episode immediately, without undue delay, under no 
circumstances later than 24 hours of the Investigator receiving the follow-up information. 
An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previous reported one should be reported separately as a new event.
If an Investigator becomes aware of an SAE occurring after discontinuation but he or she 
considers it to be related to study drug, the Investigator should report the event to the 
Sponsor.
11.4.
Follow-up of Adverse Events
For the purposes of this study, the period of observation for collection of AEs extends 
from the time the patients provide informed consent until the last follow-up visit. Follow-
up of the AE, even after the date of therapy discontinuation, is required if the AE persists 
until the event resolves or stabilises at a level acceptable to the Investigator.
Every reasonable effort will be made to follow up with patients who have AEs. Any 
patient who has an ongoing AE that is related to the IMP or study procedures at the 
follow-up visit will be followed up, where possible, until resolution, or until the 
unresolved AE is judged by the Investigator (or designee) to have stabilised. This will be 
completed at the Investigator’s (or designee’s) discretion. Any patient who has an 
ongoing AE that is not related to the IMP or study procedures at the follow-up visit can 
be closed out as ongoing at the Investigator’s and Sponsor’s discretion.
Any SAE that is not resolved by the end of the study or upon discontinuation of the 
patient’s participation in the study is to be followed up until it either resolves, stabilises, 
returns to randomisation values (if a randomisation value is available) or is shown to not 
be attributable to the study drug or procedures.
11.5.
Pregnancy
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(e.g., postpartum complications, spontaneous miscarriage, still birth, or congenital 
anomaly [even of an aborted foetus]), the Investigator should follow the procedures for 
reporting an SAE (Sections 6.5.7 and 11.3.2). Note, elective termination of a pregnancy 
would not meet the criteria for an SAE, and in these cases, a follow-up pregnancy report 
should be provided by the Investigator.
12.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
The database will be locked and the main analysis will be performed after all participants 
have completed 36 weeks of treatment. All follow-up data collected up to Week 60 will 
be analysed subsequently and included in the final report.


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Prior to the database lock (either at main or final analysis), a detailed, finalised Statistical 
Analysis Plan (SAP) will be completed, approved and placed on file. The SAP will 
contain a more comprehensive description of the statistical analyses methodology for the 
study than outlined in this Protocol. The SAP will provide full details of the analyses, the 
data displays and the algorithms to be used for data derivations, database closure and 
unblinding of the randomisation code. The SAP will also contain the rules and data 
handling conventions that will be used to perform the analyses and the procedure(s) that 
will be used to account for missing data. Any change to the analysis methods described in 
the Protocol will be documented in the SAP and/or Clinical Study Report (CSR) along 
with the justification for making the change. Additional exploratory analyses performed 
after the database lock that are not described in the SAP can be conducted as deemed 
appropriate. These additional analyses will be fully identified as exploratory post-hoc 
analyses in the CSR.
12.1.
Hypotheses
To demonstrate the treatment effect of SLN360 compared with placebo, the following 
hypothesis:
H0: µT = µP
will, at the 5% significance level, be tested against the alternative hypothesis:
H1: µT > µP
wherein µ denotes the mean time-averaged change in Lp(a) from baseline to Week 36, T
denotes SLN360 and P denotes placebo. For estimating treatment effects, the difference 
between treatments and corresponding confidence intervals will be provided.
12.2.
Estimands
12.2.1.
Primary Estimand
The primary estimand for this study is defined by the following attributes:
Target population: participants with elevated Lp(a) at high risk of ASCVD events
Treatments: SLN360 versus placebo
Primary outcome measure: time-averaged change in Lp(a) from baseline to Week 36
Analysis set and handling of intercurrent events: All available values of Lp(a) will be 
included in the calculation of time-averaged change from baseline in Lp(a)
Population level summary: difference in mean time-averaged change in Lp(a) from 
baseline to Week 36 between treatment groups


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Further details will be included in the SAP.
12.2.2.
Secondary Estimands
Secondary estimands, if used, will be specified in the SAP.
12.3.
Study Design Considerations
12.3.1.
Sample Size Assumptions
A total of five treatment groups and approximately 160 participants are planned. Each 
placebo group will include 20 randomly allocated participants, and each SLN360 group 
will include 40 randomly allocated participants. This will result in a total of 
120 participants exposed to SLN360 and 40 participants exposed to placebo. The placebo 
groups will be analysed and reported both separately and in combination.
The treatment effect observed in the FIH Phase 1 study (APOLLO; ClinicalTrials.gov 
identifier NCT04606602; EudraCT identifier 2020-002471-35) between placebo and 
300 mg SLN360 at Day 150 (the smallest effect observed at the lowest dose to be used in 
the proposed study) was approximately 60% with a conservative pooled standard 
deviation of 40%. As few as 10 participants per arm would give approximately 90%
power to detect this magnitude of difference, at the 5% significance level (p <0.05).
The proposed sample size, even separating the placebo arms with a different dose 
frequency, is expected to be more than adequate to demonstrate the SLN360 effect on 
Lp(a). The larger sample size should allow a more robust evaluation of safety at these 
doses and dose frequencies than a smaller sample size that may be expected in a Phase 2
study.
12.3.2.
Sample Size Sensitivity
The sensitivity of the sample size will not be investigated because 40 participants per 
active arm are planned and as few as 10 participants per arm would provide adequate 
power.
12.3.3.
Sample Size Re-estimation
No sample size re-estimation will occur during the study.
12.4.
Data Analysis Considerations
Analysis of variance methodology will be used to test for differences between active 
treatment and placebo for the primary endpoint of time-averaged change from baseline in
Lp(a) and secondary endpoints including time-averaged, percent and absolute change 


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from baseline in Lp(a) and other lipids/lipoproteins including LDL-C, total cholesterol
and apoB. Multiplicity adjustment to the type 1 error will be applied for comparisons of 
active treatment arms versus placebo with similar dosing regimens and will be described 
in the SAP. Pairwise comparisons between active arms will be considered exploratory 
and multiplicity adjustments will not be applied.
The distribution of Lp(a) is expected to be positively skewed, but the percentage change 
from baseline Lp(a) value is not expected to have the same distribution; therefore, 
parametric testing is appropriate. Testing the assumption of normality will be performed 
before any formal analysis and sensitivity analyses will be undertaken, if required. Full 
details of this process will be included in the SAP.
Baseline will be defined as last non-missing observation/measurement before the start of 
study drug administration.
Descriptive statistics will be used to summarise safety and PD endpoints by treatment 
group.
Each SLN360 dosing regimen will be presented separately. 
12.4.1.
Analysis Populations
The following analysis populations will be included for this study:
Screened Population: all participants who signed an ICF
Safety Population: all participants who received at least one dose of study drug
Pharmacodynamic Population: all participants who received at least one dose of 
study drug and have evaluable PD data
12.4.2.
Treatment Comparisons
Treatment comparisons will be made between the active treatment arms and the placebo 
arms.
12.4.3.
Interim Analysis
There will not be a formal interim data analysis. The main analysis will be performed
after all participants have completed 36 weeks of treatment. All follow-up data collected 
up to Week 60 will also be analysed and reported.


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12.4.4.
Key Elements of Analysis Plan
12.4.4.1.
Efficacy Analyses
12.4.4.1.1. Primary endpoint
Analysis of variance methodology will be used to test for differences between active 
treatment and placebo for time-averaged change in serum Lp(a) for the PD population.
Individual and mean and/or median Lp(a) will also be presented graphically as per each 
scheduled visit by treatment group.
12.4.4.1.2. Secondary endpoints
Pharmacodynamic biomarker data will be listed and summarised using analysis of 
variance techniques based on the PD Population. Individual and mean and/or median PD 
biomarkers will also be presented graphically as per each scheduled visit by treatment 
group.
12.4.4.2.
Safety Analyses
Safety and tolerability will be evaluated in the Safety Population by means of AE reports, 
physical examination findings, 12-lead ECGs, vital signs and laboratory safety 
evaluations. Safety parameters will be listed and summarised using descriptive statistics. 
No formal statistical hypothesis testing is planned for safety data.
Descriptive statistics of vital signs, 12-lead ECGs and safety laboratory evaluations at 
each visit will be presented by treatment group. The changes from baseline will be 
similarly presented. Physical examination findings will be listed.
12.4.4.2.1. Adverse events
The verbatim terms used in the eCRF by Investigators to identify AEs will be coded 
using MedDRA. All reported AEs with onset during the treatment phase will be included 
in the analysis and will be summarised by treatment group, and these include the 
following: AEs that have worsened since study entry, TEAEs, study drug-related TEAEs, 
serious TEAEs, study drug-related serious TEAEs, TEAEs leading to study 
discontinuation, TEAEs leading to discontinuation of study treatment or TEAEs leading 
to death. All other AEs will be listed only.
For each AE, the number and percentage of participants who experience at least one 
occurrence of the given event will be summarised by treatment group. Summaries will be 
presented overall and also by system organ class and preferred term using MedDRA.
TEAEs will also be summarised by severity and relationship classified by System Organ 
Class and Preferred Term.


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The number and percentage of early withdrawals and the corresponding reasons will be 
tabulated presenting number and percentage of participants for each treatment group.
Summaries, listings, datasets or narratives may be provided, as appropriate, for those 
participants who die, discontinue treatment due to an AE or experience a severe or 
serious AE.
12.4.5.
Missing, Unused and Spurious Data
Missing data will be accounted for in all summaries by time, with reasons provided 
where possible (e.g., discontinuation). If any data are excluded from analyses, the reason 
for exclusion will be documented in the CSR.
Imputation of missing data will be described in the SAP.
12.4.6.
Reporting Deviations from the Statistical Plan
Any deviations from the planned analyses will be described and justified in the final 
CSR.
13.
STUDY ADMINISTRATION
13.1.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Before initiation of a study site, the Sponsor will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with the International Council for
Harmonisation – Good Clinical Practice (ICH-GCP) and applicable country-specific 
regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH-GCP, all applicable participant
privacy requirements and the ethical principles that are outlined in the Declaration of 
Helsinki 2013, including, but not limited to:
An Independent Ethics Committee/Institutional Review Board review and approval 
of study protocol and any subsequent amendments and all ICFs or other information 
given to the participant
Participant informed consent
Investigator reporting requirements
The Sponsor will provide full details of the above procedures, either verbally, in writing 
or both.


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Written informed consent must be obtained from each participant before participation in 
the study, ahead of the pre-screening optional visit and ahead of the screening visit as part 
of the main study (Section 6.1). Written informed consent will be collected following a 
review of the participant’s information leaflet by the potential participant and a 
discussion between the participant and the Investigator or suitably qualified designee.
The Investigator will cooperate with all regulatory inspections and will notify the 
Sponsor as soon as they are aware of an inspection which may involve this study. With 
the exception of statutory regulatory authority inspections, the Sponsor will be consulted 
in the event of inspection of the clinical site(s) by an outside authority before the 
Inspectors are permitted access to any of the study records or the study areas.
13.2.
Study Monitoring
In accordance with applicable regulations, ICH-GCP, the monitoring plan and the 
Sponsor’s and/or delegate procedures, monitors will contact the site before the start of the 
study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and the Sponsor’s requirements. When 
reviewing data collection procedures, the discussion will include identification, 
agreement and documentation of data items for which the eCRF will serve as the source 
document.
The Sponsor and or delegated monitors will perform monitoring during the conduct of 
the study to ensure that:
The data are authentic, accurate and complete
The participant’s safety and rights are being protected
The study is conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP and all applicable regulatory requirements
Taking into account recent limitations with on-site monitoring relating to the COVID-19
pandemic or other restrictions, remote monitoring visits may be performed.
13.2.1.
Access to Source Data
The Investigator and the head of the medical institution (where applicable) agrees to 
allow the Medical Monitor, Sponsor-appointed auditors, Sponsor-appointed delegates and 
regulatory inspectors direct access to all relevant documents.
13.2.2.
Data Handling and Record Keeping
Following closure of the study, the Investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location. The records must 


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be easily accessible when needed (e.g., for a Sponsor audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than a hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
Investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The Investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
The Sponsor will inform the Investigator of the time period for retaining the site records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, the Sponsor’s standard operating procedures and/or institutional 
requirements.
The Investigator must notify the Sponsor of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the Investigator is no longer associated with the 
site.
13.3.
Provision of Study Results and Information to Investigators
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the CSR.
The Sponsor will also provide the Investigator with the full summary of the study results. 
The Investigator is encouraged to share the summary results with the study participants, 
as appropriate.
13.4.
Data Management
For this study, participant data will be collected using an eCRF and combined with data 
provided from other sources in a validated data system.
Management of clinical data will be performed in accordance with the applicable Sponsor 
or designee standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data. Adverse events, medical history and 
concomitant procedures will be coded using MedDRA according to the version specified 
in the Data Management Plan. Prior and concomitant medications will be coded using the
World Health Organization Drug Dictionary according to the version specified in the 
Data Management Plan.


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When using electronic trial data handling and/or remote electronic trial data systems, the 
Sponsor or designee will: 
Ensure and document that the electronic data processing system(s) conforms to the 
Sponsor’s established requirements for completeness, accuracy, reliability and 
consistent intended performance (i.e., validation)
Maintain standard operating procedures for using these systems
Ensure that the systems are designed to permit data changes in such a way that the 
data changes are documented and that there is no deletion of entered data (i.e., 
maintain an audit trail, data trail, edit trail)
Maintain a security system that prevents unauthorised access to the data
Maintain a list of the individuals who are authorised to make data changes
Maintain adequate backup of the data
Safeguard the blinding, if any (e.g., maintain the blinding during data entry and 
processing)
Training on the use of the electronic data collection system will be provided to all 
relevant study site staff.
13.5.
Insurance, Indemnity and Finance
The Sponsor will maintain appropriate insurance coverage for the clinical studies and 
follow applicable local compensation laws.
The Sponsor will indemnify all Investigators participating in this study against future 
claims by study participants; the terms of this will be detailed within a separate letter of
indemnification. The indemnity will only apply where all study procedures have been 
carried out according to this protocol.
The financial aspects of the study are addressed in a separate agreement.


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New Insights from a Large National Biobank. Arterioscler Thromb Vasc Biol. 
2021;41(1):465-74.
Que X, Hung MY, Yeang C, Gonen A, Prohaska TA, Sun X, et al. Oxidized 
phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice 
[published correction appears in Nature. 2018;561(7724): E43]. Nature. 
2018;558(7709):301-6.
Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Blom D, Seidah NG, et al. PCSK9 
inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials 
and the LDL receptor’s role. J Lipid Res. 2016;57(6):1086-96.
Regev A. Drug-induced liver injury and drug development: industry perspective. Semin 
Liver Dis. 2014;34(2):227-39.
Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and 
safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 
2015;372(16):1489-99.
Saleheen D, Haycock PC, Zhao W, Rasheed A, Taleb A, Imran A, et al. 
Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: 
a mendelian randomisation analysis [published correction appears in Lancet Diabetes 
Endocrinol. 2017 Sep;5(9): e6]. Lancet Diabetes Endocrinol. 2017;5(7):524-33.
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and 
Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 
2018;379(22):2097-107.
Szarek M, Bittner VA, Aylward P, Baccara-Dinet M, Bhatt DL, Diaz R, et al. 
Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events 
independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES 
trial. Eur Heart J. 2020;41(44):4245-55.
Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, Baker BF, et al. Antisense 
therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled 
phase 1 study. Lancet. 2015;386(10002):1472-83.
Tsimikas S, Fazio S, Ferdinand KC, Ginsberg HN, Koschinsky ML, Marcovina SM, et al. 
NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of 
Cardiovascular Disease and Aortic Stenosis. J Am Coll Cardiol. 2018;71(2):177-92.
Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, 
Steinhagen-Thiessen E, et al. Lipoprotein(a) Reduction in Persons with Cardiovascular 
Disease. N Engl J Med. 2020;382(3):244-55.


Study Number: SLN360-002
Compound No.: SLN360
Protocol
Version: Final Version
Page 78 of 87
Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, et al. Antisense 
oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two 
randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet Lond Engl. 
2016;388(10057):2239-53.
Zheng KH, Tsimikas S, Pawade T, Kroon J, Jenkins WSA, Doris MK, et al. 
Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients with
Aortic Stenosis. J Am Coll Cardiol. 2019;73(17):2150-62.














Study Number: SLN360-002
Compound No.: SLN360
Protocol
Version: Final Version
Page 85 of 87
15.3.
Appendix: Study Reports – Internal
DD-0001: Schubert S. In vitro screening of siRNA sequences for inhibition of LPA 
mRNA expression in a human cell line and in primary hepatocytes. Silence Therapeutics 
GmbH, Berlin, Germany. February 2020.
DD-0004: Eisermann M. Measurement of PLG Messenger RNA in samples originating 
from Covance Study Number 8387516 “A 9-week Study on the Pharmacodynamic 
Monkeys”. Silence Therapeutics GmbH, Berlin, Germany. February 2020.
LYO-X-2022-06-0003: Wade J. Pharmacokinetics and pharmacodynamics of SLN360 in 
the Phase 1 single ascending dose study and PK/PD simulations to support Phase 2 
dosing selection. Silence Therapeutics GmbH, Berlin, Germany. June 2022.


Study Number: SLN360-002
Compound No.: SLN360
Protocol
Version: Final Version
Page 86 of 87
15.4.
Appendix: Study Reports – External
STEPS-0069: Schefchek J. A 9-week Study on the Pharmacodynamic Effects and Safety 
of Subcutaneous GalNAc-siRNA Administration in Cynomolgus Monkeys. Covance 
Laboratories Inc., Madison, WI, USA. May 2019.
STEPS-0099: McPhie G. 22-week Pharmacokinetic/Pharmacodynamic Study of SLN360 
Following Subcutaneous Administration to the Male Cynomolgus Monkey. Covance 
Laboratories Ltd, Harrogate, UK. May 2020.
STEPS-0100: Pressl J. Development of anti-X0619-specific antibodies in rabbit 
BioGenes GmbH, Berlin, Germany. September 2019.
STEPS-0105: Gibson L. SLN360: 29-day Subcutaneous Administration Toxicity Study 
in the Rat Followed by an 8 Week Recovery Period. Covance Laboratories Ltd, 
Harrogate, UK. December 2020.
STEPS-0106: McPhie G. SLN360: 29-day Subcutaneous Administration Toxicity Study 
in the Monkey Followed by an 8-week Recovery Period. Covance Laboratories Ltd, 
Harrogate, UK. December 2020.
STEPS-0118: Hargreaves V. SLN360: In Vitro L5178Y Gene Mutation Assay at the tk 
locus. Covance Laboratories Ltd, Harrogate, UK. May 2020.
STEPS-0119: Hargreaves V. SLN360: In Vitro Human Lymphocyte Micronucleus 
Assay. Covance Laboratories Ltd, Harrogate, UK. June 2020.
STEPS-0120: Luo G. In Vitro Plasma Protein Binding of SLN360 in Rat, Monkey and 
Human. Covance Laboratories Inc., Madison, WI, USA. March 2020.
STEPS-0121: Luo G. Metabolism of SLN360 in Rat, Monkey, and Human Hepatic 
Postmitochondrial Supernatant Fractions (S9). Covance Laboratories Inc., Madison, WI, 
USA. February 2020.
STEPS-0122: Luo G. Metabolism of SLN360 in Monkey and Human Hepatic 
Lysosomes. Covance Laboratories Inc., Madison, WI, USA. March 2020.
STEPS-0124: Campbell R. SLN360: Cytochrome P450 Induction in Cultured Human 
Hepatocytes. Sekisui XenoTech, LLC, Kansas City, KS, USA. April 2020.
STEPS-0125: Snyder R. SLN360: Cytochrome P450 Inhibition in Suspended and 
Cultured Cryopreserved Human Hepatocytes. Sekisui XenoTech, LLC, Kansas City, KS,
USA. May 2020.


Study Number: SLN360-002
Compound No.: SLN360
Protocol
Version: Final Version
Page 87 of 87
STEPS-0126: Takare R. SLN360: ABC and SLC Transport in Cells. Sekisui XenoTech, 
LLC, Kansas City, KS, USA. May 2020.
STEPS-0128: Niehoff M. SLN360: 13-week Subcutaneous Administration Toxicity 
Study with a 13-Week Recovery Period in Sexually Mature Cynomolgus Monkeys. 
LabCorp Muenster, Münster, Germany. March 2022.

SAP_001.pdf: 
APPENDIX 16.1.9: DOCUMENTATION OF STATISTICAL METHODS 
Statistical Analysis Plan, Version 2.0, 14 February 2024 ............................................................... 2 
Version 1.0, 06 February 2025
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Clinical Study Report SLN360-002
Page 1 of 18
Study Official Title: A Multi-centre, Randomised, Double-blind, Placebo-controlled, 
Phase 2 Study to Investigate Efficacy, Safety and Tolerability of
SLN360 in Participants With Elevated Lipoprotein(a) at High Risk of Atherosclerotic 
Cardiovascular Disease Events
NCT Number: NCT05537571


  
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Page 2 of 18
STATISTICALANALYSIS PLAN 
Protocol Title: 
Protocol Number: 
Protocol Version/Date: 
Investigational Product: 
Sponsor: 
SAP Version/Date: 
A multi-centre, randomised, double-blind, placebo-controlled, 
Phase 2 study to investigate efficacy, safety and tolerability of 
SLN360 in participants with elevated lipoprotein(a) at high risk 
of atherosclerotic cardiovascular disease events. 
SLN360-002 
l .0/09AUG2022 
SLN360 
Silence Therapeutics plc 
72 Hammersmith Road 
London 
W14 8TH 
UK 
2.0/14 February 2024 


Version 1.0, 06 Febmary 2025 
Silence Therapeutics 
SLN360-002 
Protocol Title: 
Protocol Number: 
SAP Version/Date: 
SIGNATURE PAGE 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
A multi-centre, randomised, double-blind, placebo-controlled, 
Phase 2 study to investigate efficacy, safety and tolerability of 
SLN360 in participants with elevated lipoprotein(a) at high risk of 
atherosclerotic cardiovascular disease events. 
SLN360-002 
2.0/ 14 February 2024 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
Signature 
Date 
14-Feb-2024 
14-Feb-2024 
14-Feb-2024 
14FEB2024 
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Version 1.0, 06 Febmary 2025 
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VERSION IDSTORY 
Version 
Version Date 
1.0 
16SEP2022 
2.0 
14FEB2024 
Descriotion 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
Original signed version 
Section 2.1 clarifications of study primary and 
secondary objectives 
Section 2.3 clarifications of primary endpoint 
and secondary pharrnacodynamic and efficacy 
endpoints 
Section 3.1 laboratory values imputation rules 
above and below limits of quantification 
Section 3.2 Pharmacodynamic Per-Protocol 
(PDPP) Population is removed. 
Section 3.4 clarifications of time-averaged 
AUC calculation excluding Day 1 pre-dose 
value and using actual time instead of nominal 
time 
Section 3.4 clarifications ofusing pooled 
group in analysis of variance analysis 
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Silence Therapeutics 
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Statistical Analysis Plan 
Version 2.0, 14 February 2024 
TABLE OF CONTENTS 
1 
Introduction .......................................................................................................................... 7 
2 
Study Overview .................................................................................................................... 7 
2.1 
Study Objectives ............................................................................................................ 7 
2.1. l 
Primary Objective ................................................................................................... 7 
2.1.2 
Secondary Objectives .............................................................................................. 7 
2.1.3 
Exploratory Objective .............................................................................................. 7 
2.2 
Study Design ................................................................................................................. 7 
2.2.1 
Overview ............................................................................................................... 7 
2.2.2 
Randomization and Blinding ..................................................................................... 8 
2.2.3 
Study Drug ............................................................................................................. 8 
2.2.4 
Sample Size Determination ....................................................................................... 8 
2.3 
Study Endpoints ............................................................................................................. 8 
2.3. l 
Primary Endpoint .................................................................................................... 8 
2.3.2 
Secondary Endpoints ............................................................................................... 9 
2.3.3 
Exploratory Endpoints ............................................................................................. 9 
3 
Statistical Methodology .......................................................................................................... 9 
3.1 
General Considerations ................................................................................................... 9 
3.1.1 
3.1.2 
3.1.3 
3.1.4 
3.1.5 
3.1.6 
3.1.7 
3.1.8 
Analysis Day .......................................................................................................... 9 
Analysis Visits ........................................................................................................ 9 
Definition of Baseline ............................................................................................. 10 
Laboratory Values Above or Below Limits of Quantification ....................................... 10 
Summary Statistics ................................................................................................. 10 
Hypothesis Testing ................................................................................................. 10 
Evaluation of Site Effect ......................................................................................... 10 
Handling ofDropouts and Missing Data .................................................................... 11 
3.2 
Analysis Populations ..................................................................................................... 11 
3.2.1 
3.2.2 
3.2.3 
Screened Population ............................................................................................... 11 
Safety Population ................................................................................................... 11 
Pharmacodynamic Population .................................................................................. 11 
3.3 
Subject Data and Study Conduct ..................................................................................... 11 
3.3.l 
Subject Disposition ................................................................................................. 11 
3 .3 .2 
Protocol Deviations ................................................................................................ 12 
3 .3 .3 
Analysis Populations .............................................................................................. 12 
3.3.4 
Demographic and Baseline Characteristics ................................................................ 12 
3.3.5 
Medical History ..................................................................................................... 12 
3.3.6 
Concomitant Medications ........................................................................................ 12 
3.3.7 
Study Drug Exposure and Compliance ...................................................................... 13 
3 .4 
Efficacy Assessment ...................................................................................................... 13 
3.4.1 
Primary Endpoint ................................................................................................... 13 
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Statistical Analysis Plan 
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3.4.2 
3.4.3 
3.4.4 
Secondary Pharmacodynamics and Efficacy Endpoints ............................................... 14 
Exploratory Endpoints ............................................................................................ 14 
Subgroups ............................................................................................................. 14 
Safety Assessment ......................................................................................................... 15 
3.5 
3.5.1 
3.5.2 
3.5.3 
3.5.4 
3.5.5 
3.5.6 
3.5.7 
Adverse Events (AEs) ............................................................................................. 15 
Clinical Laboratory Tests ........................................................................................ 15 
Vital Signs ............................................................................................................. 16 
Electrocardiograms ................................................................................................. 16 
Injection Site Assessments ...................................................................................... 16 
Physical Examinations ............................................................................................ 16 
Other Safety Assessments ....................................................................................... 16 
4 
Independent Data Monitoring Committee ................................................................................ 16 
5 
Interim Analysis ................................................................................................................... 17 
6 
Changes from Protocol-Specified Statistical Analyses ............................................................... 17 
7 
Programming Specifications .................................................................................................. 17 
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Statistical Analysis Plan 
Version 2.0, 14 February 2024 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ASCVD 
atherosclerotic cardiovascular disease 
apoB 
aooliooprotein B 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline ohosohatase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC 
area under the curve 
BMI 
Body mass index 
COVID-1 9 
Coronavirus disease 2019 
CRF 
Case renort form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
FIH 
First-in-human 
HDL-C 
J-ligh-densitv linonrotein cholesterol 
ICF 
informed consent form 
IDMC 
Independent Data Monitorin2 Committee 
IRT 
interactive resoonse technolol!:Y 
LDL-C 
low-density liooprotein cholesterol 
LLO 
Lower limit of auantification 
Lo(a) 
Linonrotein( a) 
MedDRA 
Medical Dictionarv for Reo-nlatorv Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
PD 
Pharmacodynamics 
O16W 
Dosing every 16 weeks 
O24W 
Dosing every 24 weeks 
OTcF 
OT interval corrected usinl.! Fridericia's formula 
SAE 
Serious adverse event 
SAP 
Statistical Analvsis Plan 
TEAE 
Treatment-emergent adverse event 
ULO 
Uooer limit of ciuantification 
WHO 
World Health Organization 
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Version 1.0, 06 Febmary 2025 
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1 INTRODUCTION 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical methods to 
be implemented for the analysis of data from the study with protocol number SLN360-002. The SAP will 
be finalized prior to database lock and unblinding. Any deviations from the SAP after database lock will 
be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 
Primary Objective 
The primary objective is to evaluate the effect of SLN360 on circulating molar concentration of 
lipoprotein(a) (Lp(a)) in participants with elevated Lp(a) at high risk of ASCVD events. 
2.1.2 Secondary Objectives 
The secondary objectives are to: 
• 
Evaluate safety and tolerability ofSLN360 in participants with elevated Lp(a) at high risk of 
ASCVD events 
• 
Evaluate the effects of SLN360 on Lp(a) mass concentration, apolipoprotein B (apoB), low-
density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total 
cholesterol, and triglycerides in this population 
2.1. 3 Exploratory Objective 
The exploratory objective is to evaluate the pharmacogenetic effects of germline genetic variation(s) in 
response to SLN360. 
2.2 Study Design 
This is a multi-centre, randomised, double-blind, placebo-controlled Phase 2 study to investigate the 
efficacy, safety and tolerability ofSLN360 in participants with elevated Lp(a) at high risk of 
atherosclerotic cardiovascular disease (ASCVD). 
2.2.1 
Overview 
The study will be divided into three study periods, comprising screening, treatment and follow-up. An 
end-of-study visit will be conducted to perform final safety and efficacy assessments. 
Eligible participants will receive either placebo or SLN360 and will be randomised in the ratio 1: 1 :2:2:2 
into five treatment groups: 
Group I: Placebo administered subcutaneously at Weeks 0, 16 and 32 (dosing every 16 weeks 
[Ql6W]) 
Group 2: Placebo administered subcutaneously at Weeks O and 24 (dosing every 24 weeks 
[Q24W]) 
o 
This group will be stratified so that half of participants are dosed to match the 300 mg 
Q24W SLN360 group and half are dosed to match the 450 mg Q24W SLN360 group 
(with respect to injected volume) 
Group 3: SLN360 300 mg administered subcutaneously at Weeks 0, 16 and 32(Ql6W) 
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Statistical Analysis Plan 
Version 2.0, 14 February 2024 
Group 4: SLN360 300 mg administered subcutaneously at Weeks O and 24 (Q24W) 
Group 5: SLN360 450 mg administered subcutaneously at Weeks O and 24 (Q24W) 
2.2.2 Randomization and Blinding 
All participants will be centrally randomised using interactive response technology (IRT). This will be a 
double-blind study, i.e., participants, investigators and specific academic personnel and the Contract 
Research Organisation (CRO) along with Sponsor staff will be blinded to treatment group allocation. 
2.2.3 Study Drug 
SLN360 is provided as a solution for injection for subcutaneous use in glass vials. A vial (2R vial) 
contains 0.5 mL ( extractable volume) of an aqueous sterile solution of SLN360 drug substance with a 
concentration of200 mg/mL (as free acid form). Individual injection volume at each injection site will not 
exceed 1.5 mL, and up to two injection sites may be used to achieve the required dose. 
Dose groups and treatment regimens are summarised in Table I. 
Table 1 Dose groups and treatment regimens for the proposed Phase 2 study 
Group 
Regimen 
No. of doses of SLN360 
I 
Placebo O16W 
-
2 
Placebo O24W 
-
3 
SLN360 300 mg Q l6W 
3 
4 
SLN360 300 m2 O24W 
2 
5 
SLN360 450 m2 O24W 
2 
Ql6W=dosmg every 16 weeks; Q24W=dosmg every 24 weeks 
2.2.4 Sample Size Determination 
Total cumulative 
SLN360 administered 
--
900mg 
600 ml!: 
900 ml!: 
A total of five treatment groups and approximately 160 participants are planned. Each placebo group will 
include 20 randomly allocated participants, and each SLN360 group will include 40 randomly allocated 
participants. This will result in a total of 120 participants exposed to SLN360 and 40 participants exposed 
to placebo. The placebo groups will be analysed and reported both separately and in combination. 
The treatment effect observed in the first-in-human (FIH) Phase l study (APOLLO; Clinica!Trials.gov 
identifier NCT04606602; EudraCT identifier 2020-002471-35) between placebo and 300 mg SLN360 at 
Day 150 (the smallest effect observed at the lowest dose to be used in the proposed study) was 
approximately 60% with a conservative pooled standard deviation of 40%. As few as 10 participants per 
arm would give approximately 90% power to detect this magnitude of difference, at the 5% significance 
level (p <0.05). 
The proposed sample size, even separating the placebo arms with a different dose frequency, is expected 
to be more than adequate to demonstrate the SLN360 effect on Lp(a). The larger sample size should allow 
a more robust evaluation of safety at these doses and dose frequencies than a smaller sample size that may 
be expected in a Phase 2 study. 
2.3 Study Endpoints 
2.3.J 
Primary Endpoint 
The primary endpoint is the time-averaged percent change in Lp(a) molar concentration from baseline to 
Week 36. 
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2.3.2 Secondary Endpoints 
2.3.2.J 
Safety 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
The secondary safety endpoint is the safety and tolerability of SLN360, as assessed by: 
Adverse event reports 
Physical examination findings 
Twelve-lead Electrocardiogram (ECGs) 
Vital signs 
Laboratory safety evaluations 
2.3.2.2 
Pharmacodynamics and Efficacy 
The secondary pharrnacodynamic (PD) and efficacy endpoints are: 
Time-averaged percent change in Lp(a) molar concentration from baseline to Week 48 and Week 
60. 
Time-averaged absolute change in Lp(a) molar concentration from baseline to Week 36, Week 
48, and Week 60. 
Time-averaged percent and absolute change in Lp(a) mass concentration, ApoB, LDL-C, HDL-C, 
total cholesterol and triglycerides, from baseline to Week 36, Week 48, and Week 60. 
Percent and absolute change in Lp(a) molar concentration, Lp(a) mass concentration, ApoB, 
LDL-C, HDL-C, total cholesterol, triglycerides, oxidized phospholipids, and C-reactive protein, 
from baseline by visit (i.e., not time-averaged) 
2.3.3 Exploratory Endpoints 
The exploratory endpoints are the pharmacogenetic effects of germline genetic variation on response to 
SLN360, measured by association analysis of genetic variants with markers of SLN360 efficacy, 
including change in Lp(a). 
3 
STATISTICAL METHODOLOGY 
3.1 General Considerations 
3. 1. 1 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug. The day of the first dose of study 
drug will be Day 1, and the day immediately before Day 1 will be Day -1. There will be no Day 0. 
3.1.2 Analysis Visits 
For pharmacodynamics and efficacy parameters, visits will be assigned to analysis visits according to the 
following visit windows. Within each analysis visit window, scheduled visits will be assigned to analysis 
visits as recorded on the case report form (CRF). lfno scheduled visit is within the analysis visit window, 
measurement(s) taken at a visit close to the target analysis day will be used as the measurement for that 
specific visit. Unscheduled visits will not be used unless the scheduled result has not been reported. If 
samples are collected after the scheduled week 60 analysis these will not be included. 
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Analysis Visit 
Screening 
Baseline 
Week I 
Week4 
Week8 
Week 12 
Week 16 
Week20 
Week 24 
Week28 
Week32 
Week 36 
Week40 
Week48 
Week60 
Tare:et Analysis Day 
I 
8 
29 
57 
85 
113 
141 
169 
197 
225 
252 
281 
337 
421 
Low Analvsis Day 
2 
20 
44 
72 
100 
128 
156 
184 
212 
239 
268 
310 
380 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
Hie:b Analysis Day 
1 
19 
43 
71 
99 
127 
155 
183 
211 
238 
267 
309 
379 
No study visit window will be used for safety parameters. Analysis visits will be based on the nominal 
visits as captured on the CRFs. 
3.1. 3 Definition of Baseline 
Baseline is defined as the last measurement prior to the first dose of study drug. 
3.1.4 Laboratory Values Above or Below Limits of Quantification 
For laboratory values less than the lower limit of quantification (LLQ), half of the lower limit value (i.e., 
LLQ/2) will be used in the efficacy analyses described below. Likewise, for values greater than the upper 
limit of quantification (ULQ), the upper limit value (i.e., ULQ) will be used in the efficacy analyses. 
3.1.5 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of subjects. The denominator 
used for the percentage calculation will be clearly defined. Continuous data will generally be summarized 
with descriptive statistics including n (number of non-missing values), mean, median, 251h and 75th 
percentiles, standard deviation, minimum, maximum and 95% confidence intervals where appropriate. 
3.1.6 Hypothesis Testing 
To demonstrate the treatment effect of SLN360 compared with placebo, the following hypothesis: 
Ho: µr = µp 
will, at the 5% significance level, be tested against the alternative hypothesis: 
H1: µr > µp 
wherein µ denotes the mean time-averaged change in Lp(a) from Day I pre-dose to Week 36, T denotes 
SLN360 and P denotes placebo. For estimating treatment effects, the difference between treatments and 
corresponding confidence intervals will be provided. 
No formal statistical hypothesis testing is planned for safety data. 
3.1. 7 Evaluation of Site Effect 
It is not planned to perform a subgroup analysis on individual or groups of centres. 
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Statistical Analysis Plan 
Version 2.0, 14 February 2024 
3.1. 8 Handling of Dropouts and Missing Data 
Missing data will not be imputed unless otherwise specified. Only observed data will be used in the 
summaries and analyses. 
In all listings, missing or incomplete dates should be left as they have been recorded. However, for 
calculation / sorting/ assignation based on dates, the following methods will be used: 
1) The most conservative approach will be systematically considered (i.e. if the onset date of an AE 
is missing / incomplete, it is assumed to have occurred during the active phase (i.e. a TEAE for 
AEs) except if the partial onset date or other data [stop date, ... ) indicates differently). 
2) A missing/incomplete date of medical history or disease diagnosis will be assumed to have 
occurred before any study treatment. 
3) If a partial date and the associated information do not allow to state about the assignation to a 
group / category, all the possible groups / categories will be considered (i.e. an AE could be 
assigned to several possible doses at event onset according to its partial onset date and stop date. 
Particularly an AE with missing start date will be assigned to each dose received before its end 
date.). 
4) Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e.: for an AE started in FEB2004 after the administration performed on 
31JAN2004, the days since last dose will be '~2", similarly the duration of ongoing AEs or 
medication will be'~" according to the start and last visit dates). 
3.2 Analysis Populations 
3.2.J Screened Population 
Screened Population includes all participants who signed an informed consent form (ICF). 
3.2.2 Safety Population 
Safety Population includes all participants who received at least one dose of study drug. 
3.2.3 Pharmacodynamic Population 
Pharmacodynamic Population includes all participants who received at least one dose of study drug and 
have evaluable PD data. 
3.3 Subject Data and Study Conduct 
3.3.J Subject Disposition 
Counts and percentages of subjects who were screened (signed informed consent), discontinued early 
during screening (screen failures), and randomized will be summarized in total based on all screened 
subjects. Reasons for early discontinuation will also be summarized. 
Counts and percentages of subjects who were randomized, discontinued treatment early, completed study 
treatment, discontinued early from the study, and completed the study will be summarized by treatment 
and in total based on all randomized su~jects. Primary reasons for early discontinuation treatment and 
study will also be summarized. Early discontinuation treatment and study due to Coronavirus disease 
2019 (COVID-19) will be summarized. 
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Silence Therapeutics 
SLN360-002 
3.3.2 Protocol Deviations 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
Counts and percentages of subjects with protocol deviations by deviation category will be summarized by 
treatment and in total based on all randomized subjects. Protocol deviations related to COVID-19 will be 
summarized in the same manner. 
3.3.3 Analysis Populations 
Counts and percentages of subjects in each analysis population will be summarized by treatment and in 
total based on all randomized subjects. Reasons for exclusion from each analysis population will also be 
summarized. 
3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
• 
Age (years) and age categories (18-64 years, ~65 years) 
• 
Sex (male, female) 
• 
Childbearing potential (yes, no) 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, other) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, not reported, unknown) 
• 
Height ( cm) 
• 
Weight (kg) 
• 
Body mass index (BMI) (kg/m2) 
• 
Time from the initial date of elevated Lp(a) to randomization date (months) 
Demographic and baseline characteristics will be summarized with descriptive statistics or counts and 
percentages of subjects as appropriate by treatment and in total for the Safety Population. 
3.3.5 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA). Counts and percentages of subjects with medical history by system 
organ class and preferred term will be summarized by treatment and in total based on the Safety 
Population. 
Counts and percentages of subjects with high-risk conditions for ASCVD will be summarized by 
treatment and in total based on the Safety Population. 
3.3.6 Concomitant Medications 
Prior and concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and 
preferred term using the WHO Drug Dictionary. For summary purposes, medications will be considered 
prior medications if they stopped prior to the first dose of study drug and concomitant medications if they 
were taken at any time after the first dose of study drug (i.e., started prior to the first dose of study drug 
and were ongoing or started after the first dose of study drug). 
If a medication has a missing start date, the most conservative approach will be applied and the 
medication start date will be assumed to be during the active phase unless other data (e.g. stop date) 
indicates differently. For a missing stop date, the medication will be assumed to be ongoing. 
If a medication has incomplete start or stop dates, dates will be imputed to determine whether a 
medication should be considered prior or concomitant. If a medication start date is incomplete, the first 
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Silence Therapeutics 
SLN360-002 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
day of the month will be imputed for missing day and January will be imputed for missing month. If a 
medication stop date is incomplete, the last day of the month will be imputed for missing day and 
December will be imputed for missing month. Incomplete start and stop dates will be listed as collected 
without imputation. 
Counts and percentages of subjects taking prior and concomitant medications by ATC class and preferred 
term will be summarised by treatment and in total based on the Safety Population. 
3. 3. 7 Study Drug Exposure and Compliance 
Total dose administered (mg), total planned and actual volume administered (mL), number of doses and 
duration of exposure will be included in an overall summary by treatment based on the Safety Population 
with descriptive statistics. 
Duration (weeks)= (Date of last injection- Date of first injection +1))/7. 
For each dose, whether full dose was administered plus reason for not administering the full dose and 
number of injections will be summarized by treatment based on the Safety Population with descriptive 
statistics. 
All information collected on the eCRF related to study treatment will be listed. 
3.4 Efficacy Assessment 
Efficacy data will be summarized by randomized treatment based on Pharmacodynamic Population. 
3. 4.1 
Primary Endpoint 
Primary Estimand 
The primary estimand for this study is defined by the following attributes: 
• 
Target population: participants with elevated Lp(a) at high risk of ASCVD events 
Treatments: SLN360 versus placebo 
Primary outcome measure: time-averaged percent change in Lp(a) molar concentration from Day 
1 pre-dose to Week 36 
Analysis population: Pharrnacodynamic Population 
Intercurrent events: prohibited medications/procedures and permitted medications (defined in 
protocol section 9.2 and 9.3), death, early withdrawal from study drug, and early withdrawal from 
the study. 
• 
Analysis set and handling of intercurrent events: Treatment policy strategy will be used. All 
values ofLp(a) from scheduled assessments up to Week 36 will be included in the calculation of 
time-averaged percent change for each participant 
• 
Population level summary: difference in mean time-averaged percent change in Lp(a) from Day 1 
pre-dose to Week 36 between treatment groups 
Time-averaged percent change from Week 4 to Week 36 is calculated from Week 4 corrected area under 
the curve (AUC) using linear trapezoidal method from Week 4 to Week 36 divided by the per-patient 
total time interval. Note that the Day 1 pre -dose values will be excluded from the time-averaged 
calculations (i.e., for each participant, the initial value included in the calculation will be from their first 
scheduled post-baseline assessment). Furthermore, the actual analysis day of each assessment will be used 
in the AUC calculation. 
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Silence Therapeutics 
SLN360-002 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
If the last available measurement ofLp(a) is before Week 36, time-averaged percent change in Lp(a) from 
Day 1 pr~dose to Week 36 will be calculated by arithmetic mean of all percent changes in Lp(a) from 
Day 1 p~dose up to the last available time point before Week 36. 
Analysis of variance. will be used to test for differences between each active treatment group (i.e., Group 
3, 4, or 5 in Table 1) and the pooled placebo groups (i.e., Groups 1 and 2 in Table 1 combined) for time-
averaged percent change in Lp(a). Tim~averaged percent change from Day 1 pre-dose to Week 36 in 
Lp(a) will be the dependent variable and treatment will be included as a factor. The least squares means, 
standard errors, and 2-sided 95% confidence intervals for each treatment group and for the pairwise 
comparisons between the SLN360 and placebo groups will be provided. 
Holm's procedure will be used to control multiplicity of pairwise comparisons between each SLN360 
group and the pooled placebo group. p-values will be first ordered from the smallest to the largest. P(t) 
represents the smallest value, P <2) the next-smallest p-value, P(3) the third-smallest p-value. 
(1) The test begins by comparing the smallest p-value, Pol. to 0.05/3 or 0.0167. If this Pol is less than 
0.0167, the pairwise treatment comparison with this p-value is considered significant. 
(2) The test then compares the next-smallest p-value, P(2). to 0.05/2 or 0.025. If this P (2) is less than 
0.025, the pairwise treatment comparison with this p•value is also considered significant. 
(3) The test then compares the next ordered p-value, P(J), to 0.05. If this P(3) is less than 0.05, the 
pairwise treatment comparison with this p-value is also considered significant. 
Pairwise comparisons between SLN360 groups will be provided and considered exploratory and 
multiplicity adjustments will not be applied. 
P-values below 0.05 will still be considered nominally significant. 
3.4.2 Secondary Pharmacodynamics and Efficacy Endpoints 
Time averaged secondary endpoints will be calculated and analyzed using the same conventions as the 
primary endpoint. 
For each PD parameter, percent and absolute change from Day 1 pr~dose to each visit will be 
summarized descriptively. The least squares means, standard errors, and 2-sided 95% confidence intervals 
from analysis of variance will be provided for each treatment group and for the pairwise comparisons of 
each SLN360 group and placebo. Figures displaying mean(+/- standard deviation) by visit will be plotted 
for Lp(a), Apolipoprotein B, LDL Cholesterol, HDL Cholesterol, Total Cholesterol, Triglycerides, 
Oxidized Phospbolipids, and C Reactive Protein will be displayed at baseline and each post-baseline visit. 
Additionally, figures for mean change and percent change(+/- standard deviation) from baseline will be 
presented for Lp(a), Apolipoprotein B, LDL Cholesterol, and C Reactive Protein will be displayed for 
each post-baseline visit. 
3. 4. 3 Exploratory Endpoints 
Analysis of exploratory endpoints, the pharmacogenetic eJTects of germ line genetic variation on response 
to SLN360, measured by association analysis of genetic variants with markers of SLN360 efficacy, 
including change in Lp(a), will be described in a separate analysis plan. 
3.4.4 Subgroups 
There is no planned subgroup analysis. 
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Silence Therapeutics 
SLN360-002 
3.5 Safety Assessment 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
All safety data will be included in the subject data listings. Safety data will be summarised by actual 
treatment received (and in total for selected analyses) based on the Safety Population. 
3. 5. I Adverse Events (AEs) 
All AEs will be coded to system organ class and preferred term using MedDRA. Treatment emergent 
adverse events (TEAEs) are defined as AEs that start after the first dose of study drug. Severity will be 
graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) on a five-point scale (Grade 1 to 5). Study drug-related AEs are defined as AEs 
considered by the investigator as having a reasonable possibility of being related to study drug. 
An overview of TEAEs will be provided including counts and percentages of subjects (and event counts) 
with the following: 
• 
Any TEAEs (overall and by maximum severity) 
Any study drug-related TEAEs (overall and by maximum severity) 
Any serious adverse events (SAEs) 
Any serious TEAEs 
Any study drug-related serious TEAEs 
Any TEAEs leading to discontinuation of study drug 
Any TEAEs leading to discontinuation of study 
Any TEAEs leading to death 
Summary tables ofTEAEs, TEAEs by maximum severity, study drug-related TEAEs, serious TEAEs and 
TEAEs leading to discontinuation of study drug or study will be provided with the number and 
percentage of subjects with adverse events and the number of events classified by primary system organ 
class, and preferred term. 
System organ classes and preferred terms will be sorted alphabetically. 
For tabulations that include classification by relationship to study drug, TEAEs with missing relationship 
will be considered related to study drug. For tabulations that include classification by severity, missing 
severity will be considered as the most severe TEAEs that are not SAEs. 
Adverse event listings will be presented by subject, system organ class and preferred term. 
3.5.2 Clinical Laboratory Tests 
Blood samples for clinical laboratory tests will be collected at every scheduled visit and processed by a 
central laboratory. Urine samples will be analysed locally using a dipstick but may also be analysed 
centrally if indicated and deemed appropriate by the Investigator. A list of laboratory tests to be 
performed is specified in the protocol. 
Values and changes from baseline will be presented at each scheduled visit and baseline by laboratory 
test. 
Shift tables from baseline to scheduled post-baseline will be tabulated for all laboratory parameters, if 
applicable. 
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Silence Therapeutics 
SLN360-002 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
The number and percentage of subjects with the following potentially clinically significant abnormal liver 
function tests will be summarized: 
ALT>3xULN 
AST>3xULN 
ALP~xULN 
Total bilirubin >2xULN 
ALT or AST c::3xULN with total bilirubin >2xULN 
Both scheduled and unscheduled results will be considered in clinical abnormality laboratory tables. 
Listings will list results in Standard International units and conventional units and sort by test, date and 
time. 
3.5.3 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure, heart rate, temperature and respiratory rate. 
Descriptive statistics will be provided for vital sign values as well as change from baseline at each 
scheduled visit. 
3.5.4 Electrocardiograms 
For the continuous variables, descriptive statistics ofresults at each study visit, as well as the change from 
baseline to each study visit, will be presented in summary tables; for the categorical responses to overall 
interpretation (rhythm), results and the associated findings at each visit will be summarized by counts and 
percentages. 
Number and percentage of patients with QTcF interval in the categories below will be provided. 
Absolute QTcF interval >500 msec, 
Absolute QT interval >500 msec, 
Increase from baseline QTcF interval >60 msec. 
A shift table from baseline to scheduled post-baseline will be tabulated for overall interpretation (rhythm). 
3.5.5 Injection Site Assessments 
The number and percentage of subjects will be presented for any pain, tenderness, erythema/redness, and 
induration/swelling of injection site location at each visit and time point. 
3.5.6 Physical Examinations 
A listing of physical examination assessments will be provided. 
3. 5. 7 Other Safety Assessments 
All other safety assessments will be listed. 
4 
INDEPENDENT DATA MONITORING COMMITTEE 
The Independent Data Monitoring Committee (IDMC) is responsible for review of data during the study. 
The IDMC will review accrued data on an ongoing basis and make relevant recommendations to the 
Sponsor. The IDMC is an independent group of experts in clinical trials, clinical medicine and drug 
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Silence Therapeutics 
SLN360-002 
Silence Therapeutics plc 
Clinical Study Report SLN360-002 
Statistical Analysis Plan 
Version 2.0, 14 February 2024 
safety. The details of the role, remit and responsibility of the IDMC, together with practical 
considerations for data review and lDMC meetings are provided in the IDMC Charter. 
5 
INTERIM ANALYSIS 
There will not be a formal interim data analysis. The database will be locked and the primary analysis will 
be performed after all participants have completed 36 weeks of treatment. Similar analysis will also be 
performed after all participants have completed 48 weeks of treatment (end of treatment period). All 
follow-up data collected up to Week 60 will also be analysed and reported (final analysis). 
6 
CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL 
ANALYSES 
There are no changes from the protocol-specified statistical analyses. 
7 
PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.4 or higher. All available data will be presented in 
su~ject data listings which will be sorted by subject and visit date as applicable. Detailed Programming 
Specifications will be provided in a separate document. 
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