A randomized, double-blind, placebo controlled, first in human study to investigate the safety, tolerability, and pharmacokinetic and pharmacodynamic response of SLN360 in subjects with elevated lipoprotein (a)

Completed

Conditions: atherosclerosis
elevated lipoprotein (a)
10011082
10027664
10014523

Registration Number: NL-OMON55119

Lead Sponsor: Silence Therapeutics plc

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 18

Inclusion Criteria

i. Male and female subjects aged 18 years to 70 years.
ii. Body mass index of >= 18 kg/m2 and <= 45 kg/m2.
iii. Women of childbearing potential (WOCBP) must have a negative serum
pregnancy test at screening and a negative pregnancy test (serum or urine) on
Day -1.
iv. All subjects must agree to adhere to appropriate contraception requirements
(acceptable methods of contraception are summarized below and described in
detail in the protocol), as follows:
a. WOCBP must agree to use 1 highly effective method of contraception, from the
beginning of the screening period until 3 months after the last administration
of study drug.
b. Male subjects must use a male condom (with or without spermicide) if
sexually active with a female of child-bearing potential from the start of the
screening period until 3 months after the last administration of study drug.
v. Male subjects are not allowed to donate sperm and female subjects are not
allowed to donate eggs from the beginning of the screening period until 3
months following the last administration of SLN360.
vi. Subjects must provide written informed consent and be willing and able to
comply with all study requirements.
vii. Elevated plasma Lp(a) = 150nmol/L
viii. For the MD part only: confirmed history of stable atherosclerortic
cardiovascular disease (including, but not limited to, coronary artery disease
with or without myocardial infarction, previous coronary revascularization with
percutaneous coronary intervention (PCI) or coronary artery bypass grafting
(CABG), ischaemic stroke, clinically important carotid artery stenosis,
peripheral arterial disease). 'Stable' is defined as the absence of acute
cardiovascular disease events within 6 months of screening (including, but not
limited to, acute myocardial infarction, unstable angina, acute stroke, acute
limb ischaemia).

Exclusion Criteria

i. Comorbidity;
a. For the SAD part only: any history of clinically overt cardiovascular
disease, defined as acute coronary syndromes, myocardial infarction, stable
angina, coronary or other revascularization, ischemic stroke or transient
ischemic attack and atherosclerotic peripheral arterial disease.
b. For the MD part only: recent history of acute cardiovascular disease events
within 6 months of screening (including, but not limited to, acute myocardial
infarction, unstable angina, acute stroke and acute limb ischemia).
c. Any uncontrolled or serious disease, or any medical or surgical condition
including evidence of unstable cardiovascular disease, that may interfere with
participation in the clinical study, significantly interfere with the
interpretation of the results and/or put the subject at significant risk
(according to Investigator*s judgement) if he/she participates in the clinical
study.
d. Moderate or severe hepatic cirrhosis with Child-Pugh grade B or C, or other
current or previous liver disease that may increase the risk of drug-induced
liver injury or influence the pharmacology of SLN360.
e. Active serious mental illness or psychiatric disorder, including but not
limited to schizophrenia, bipolar disorder, or severe depression requiring
current pharmacological intervention.
f. Clinically significant illness within 7 days before the first dose of study
drug.
g. Any conditions which, in the opinion of the Investigator, would make the
subject unsuitable for enrolment in the study or could interfere with the
subject*s participation in, or completion of the study.
h. Positive nucleic acid test for SARS-CoV-2 (the virus causing Covid-19)
during screening.
i. Positive test for hepatitis B surface antigen (HBsAg), hepatitis B core
antibody (anti HBC), hepatitis C virus antibody (HCV Ab) or human
immunodeficiency virus (HIV).

ii. Biochemical and hematological parameters:
a. Clinically significant abnormalities in screening blood tests (excluding
lipid profile) that are judged to affect the suitability for inclusion,
including:
i. ALT or AST >1.5 × ULN.
ii. Total bilirubin > ULN, except in previously confirmed cases of Gilbert*s
syndrome.
iii. Platelet count < lower limit of the normal range.
iv. Significant renal impairment before randomization, defined as estimated
glomerular filtration rate (using the Chronic Kidney Disease Epidemiology
Collaboration equation) <60 mL/min/1.73 m.
v. Haemoglobin A1c greater than 6.5% (47.5mmol/mol) in subjects without
diabetes mellitus, or haemoglobin A1c greater than 8.5% (69.4mmol/mol) in
subjects with diabetes mellitus and on appropriate diabetes treatment.

iii. Concomitant medication:
Subjects with previous or current use of the following therapies are not
eligible for participation:
a. Medication or therapies significantly affecting Lp(a) level (including but
not restricted to PCSK9 inhibitors, prescription dose niacin, fibrates or
anti-estrogen therapy), unless on a stable dose or off treatment for >= 8 weeks
prior to screening and no planned medication or dose adjustment during the
study.
b. Statins and/or ezetimibe unless on a stable dose or off treatment for at
least 8 weeks prior to screening and no planned medication or dose adjustment
during the study.
c. Lipid or lipoprote

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Safety and tolerability parameters of single or multiple doses SLN360 in<br /><br>subjects with elevated Lp(a) levels.<br /><br><br /><br>Please see Appendices 2 and 3 of the protocol for detailed information on<br /><br>safety and laboratory parameters. </p><br>

Secondary Outcome Measures

Name	Time	Method
<p>PD and PK parameters of single and multiple doses of SLN360 on Lp(a).<br /><br><br /><br>Extent and duration of reduction in Lp(a) following single and multiple doses<br /><br>of SLN360.<br /><br><br /><br>Impact of dose schedule of SLN360 on extent and duration of reduction in Lp(a).<br /><br><br /><br>Impact of single and multiple doses of SLN360 on lipid profile including apoB,<br /><br>OxPLs, inflammatory markers, and plasminogen.<br /><br><br /><br>Please see Appendices 2 and 3 of the protocol for detailed information on<br /><br>safety and laboratory parameters.</p><br>