The primary objective is:i. To determine the safety and tolerability of single or multiple doses SLN360 in subjects with elevated Lp(a) levels. The secondary objectives include assessment of the following:i. PD effects of single and multiple doses…
ID
Source
Brief title
Condition
- Coronary artery disorders
- Congenital and hereditary disorders NEC
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability parameters of single or multiple doses SLN360 in
subjects with elevated Lp(a) levels.
Please see Appendices 2 and 3 of the protocol for detailed information on
safety and laboratory parameters.
Secondary outcome
PD and PK parameters of single and multiple doses of SLN360 on Lp(a).
Extent and duration of reduction in Lp(a) following single and multiple doses
of SLN360.
Impact of dose schedule of SLN360 on extent and duration of reduction in Lp(a).
Impact of single and multiple doses of SLN360 on lipid profile including apoB,
OxPLs, inflammatory markers, and plasminogen.
Please see Appendices 2 and 3 of the protocol for detailed information on
safety and laboratory parameters.
Background summary
The investigational medicinal product (IMP) SLN360 is a candidate siRNA
medicine for the treatment of patients with conditions associated with raised
Lp(a). SLN360 has the potential to address a major unmet medical need in this
target subject population through targeted reduction of apo(a), a key component
of the atherogenic Lp(a) particle. The preclinical pharmacology data support
the use of SLN360 in subjects with raised Lp(a).
Study objective
The primary objective is:
i. To determine the safety and tolerability of single or multiple doses SLN360
in subjects with elevated Lp(a) levels.
The secondary objectives include assessment of the following:
i. PD effects of single and multiple doses of SLN360 on Lp(a).
ii. PK of SLN360 after a single and multiple dose administration.
iii. Extent and duration of reduction in Lp(a) following single and multiple
doses of SLN360.
iv. Impact of dose schedule of SLN360 on extent and duration of reduction in
Lp(a).
The exploratory objectives include assessment of the following:
i. Impact of single and multiple doses of SLN360 on lipid profile including
apoB, OxPLs, inflammatory markers, and plasminogen.
Study design
Sentinel dosing will be employed for each cohort in the SAD: the first 2
subjects in each cohort will be randomised for 1 subject to receive active
SLN360 and 1 subject to receive placebo. These two subjects will be dosed a
minimum of 24 hours in advance of the rest of the subjects in the cohort.
For each cohort, safety and, where available, PK data will be reviewed and
assessed by the SRC before recommending progression to the to the next dose
escalation.
SAD:
Up to 5 cohorts, each consisting of of 8 subjects (6 active: 2 placebo) with
elevated Lp(a) levels will be dosed at the appropriate dose level of SLN360 or
placebo administered subcutaneously on Day 1. Subjects will be admitted as
inpatients for dosing and for at least 24 hours of post-dose monitoring and
assessment. The PD effects of SLN360 will be evaluated by measuring plasma
Lp(a) levels as the most proximal measurable marker of target engagement.
Effects on a broader lipid profile, including high density lipoprotein
(HDL)-cholesterol, LDL-cholesterol and total cholesterol, triglyceride and apoB
will also be measured. PK parameters will also be assessed at several
timepoints for up to 36 hours after dosing. The SRC may recommend increasing
the duration of follow-up beyond the currently planned 150 days, up to a
maximum of 365 days.
MD:
Up to 3 cohorts, each consisting of 12 subjects (9 active: 3 placebo) with
elevated Lp(a) levels will be treated with doses and at dose frequencies of
SLN360 informed by data from the SAD part. Subjects will be admitted as
inpatients for dosing and at least 24 hours of post-dose monitoring and
assessment. Subjects will be followed for up to 201 days (duration informed by
data from the SAD part) from the first dose to understand the magnitude and
durability of the Lp(a) response to multiple dose administration of SLN360. As
for the SAD cohorts, the PD effect of SLN360 will be evaluated by measuring
plasma levels of Lp(a) and a range of other lipid fractions (LDL-cholesterol,
HDLcholesterol, total cholesterol, triglyceride, and apoB). PK parameters will
also be assessed at several timepoints after dosing. The final dose levels and
dosing frequency of the MD cohorts will be dependent on safety, tolerability,
PD and PK findings from the SAD part of the study
Please also refer to protocol section 3.
Intervention
SLN360 is a GalNAc conjugated 19-mer double stranded fully modified short
interfering RNA (siRNA) targeting LPA messenger RNA (mRNA).
SLN360 will be provided as a solution for injection for s.c. use (200 mg/mL [as
free acid form], presented as 0.5 mL extractable volume per vial).
Individual injection volume at each injection site will not exceed 1.5 mL, and
up to 3 injection sites may be used to achieve the required dose.
Study burden and risks
physical examinations, hart monitoring, venapunctions, and subcutaneous
injections are required for participants in this study. The venapunctions and
injections have a risk of creating swelling or irritations. Unknown risks due
to and allergic reactions to the study treatment are possible. Participants
will have to spent additional time undergoing assessments and being monitored
in the hospital.
Opposed to these additional burdens are the potential benefit of the study
treatment to participants and the gained scientific insights. Participants are
drawn, and participate on an informed voluntary basis, from an applicable
patient group with elevated Lp(a).
Hammersmith Road 72
London W14 8TH
GB
Hammersmith Road 72
London W14 8TH
GB
Listed location countries
Age
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 lipoprotein apheresis.
d. An investigational agent other than SLN360 within 90 days (or 10 half lives,
whichever is longer) before the first dose of study drug.
e. Oligonucleotide therapy, including antisense oligonucleotides and siRNA,
other than SLN360, within 12 months of screening.
f. Current use of hormone replacement therapy unless on a stable regimen or off
treatment for at least 8 weeks prior to screening and no planned adjustment to
the regimen during the study.
g. Current use of anti-estrogen or estrogen receptor modulator (e.g. tamoxifen).
iv. Alcohol and illegal drugs:
a. History or clinical evidence of alcohol misuse within the 6 months before
screening.
b. History or clinical evidence of illegal drug use within the 6 months before
screening.
v. Drug intolerance:
a. History of multiple drug allergies or history of allergic reaction to an
oligonucleotide or GalNAc.
b. History of intolerance to s.c. injections or scarring (e.g. from surgical
procedures or burns) in skin areas where s.c. doses may need to be
administered.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-002471-35-NL |
| ClinicalTrials.gov | NCT04606602 |
| CCMO | NL74573.000.20 |