A long term extension trial of the Phase III lipid-lowering trials to assess the effect of long term dosing of inclisiran given as subcutaneous injections in subjects with high cardiovascular risk and elevated LDL-C (ORION-8)

Despite advances in treatment, cardiovascular disease (CVD) is the leading
cause of death worldwide, resulting in over 17 million deaths annually [WHO,
2016]. Eighty percent of all CVD deaths are due to coronary heart disease (CHD)
or strokes. Elevated low-density lipoprotein associated cholesterol (LDL-C) is
a major risk factor for the development of CVD [Grundy et all 2004; Go et al,
2014]. Lowering LDL-C has been shown to reduce the risk of death or heart
attack and within the range of effects achieved so far, the clinical risk
reduction is linearly proportional to the absolute LDL-C reduction [Baigent et
al 20051
Recently developed and approved PCSK9-blocking monoclonal antibodies reduce
circulating PCSK9 levels and lower LDL-C levels. Preliminary reports indicate
that treatment with such antibodies can lead to reduction of cardiovascular
events compared with placebo
The data from PCSK9 blocking antibodies such as Repatha@ (evolocumab) and
Praluent@ (arilocumab) are very encouraging.
However, these products are dosed SC every 2 to 4 weeks necessitating up to 26
injections per year [Hooper et al, 2005; Navarese et al, 2015; Zhang et al,
2015]. In contrast, one injection of inclisiran is anticipated to be given
three times in the first year and every 6 months thereafter.

The primary objectives are to evaluate:
-The effect of inclisiran treatment on the proportion of subjects achieving
prespecified low density
lipoprotein cholesterol (LDL-C) targets at end of study (EOS)
-The safety and tolerability profile of long term use of inclisiran

Secondary:
The secondary objectives are to evaluate the effect of inclisiran on:
-LDL-C levels
-Other lipids and lipoproteins

This study will be a long-term extension study in up to 3300 subjects with
atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalents (eg,
diabetes and familial hypercholesterolemia), or heterozygous or homozygous
familial hypercholesterolemia (HeFH or HoFH) and elevated low density
lipoprotein cholesterol (LDL-C) despite treatment with LDL-C lowering
therapies who have completed the Phase II trial MDCO-PCS-16-01 (ORION-3, also
referred to as CKJX839A12201E1) or Phase III lipid lowering studies:
MDCO-PCS-17-03(ORION-9 also referred to as CKJX839A12303), MDCO-PCS-17-04
(ORION-10, also referred to as CKJX839A12304, or MDCO-PCS-17-08(ORION-11, also
referred to as CKJX839A12305) The purpose of this extension study is to
evaluate the efficacy, safety, and tolerability of long-term dosing of
inclisiran. Informed consent will be obtained from subjects before the
initiation of any study-specific procedures. The EOS visit in the previous
study will be Day 1 in ORION-8
Subjects who received placebo in the previous Phase III feeder study will
receive blinded inclisiran and subjects who received inclisiran in the previous
feeder study will receive blinded placebo at this visit, in order to maintain
the blinding of the feeder study until database lock of those studies
. This dosing regimen is to enable former placebo subjects to start ORION-8
with the same starting dosing-regimen as subjects in the inclisiran arms of the
feeder studies i.e. an initial dose, followed by a dose after 90 days and then
followed by doses every six months. Subjects who previously received inclisiran
only require dosing every six months. All subjects will return at Day 90 for
the next visit and will receive open label inclisiran sodium 300 mg which is
equivalent to 284 mg inclisiran. Subjects will then return for open label drug
administration of inclisiran sodium 300 mg every 180 days until EOS and be
observed for 30 minutes at each visit.
The study duration for each subject is expected to be a maximum of 3 years.

Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) will be administered
as a single SC injection on Day 1, Day 90, Day 270, Day 450, Day 630, Day 810,
Day 990.
Placebo will be administered as SC injections of saline solution. Placebo
volume will be matched to test product volume within each dose and injection
ie, the 300 mg dose will be administered as 1.5 mL of placebo.

Most drugs have side effects, which some people may experience, and others may
not. Since the study drug is investigational when taken alone or in combination
with other medications, not all of the possible side effects of the study
treatment are known at this time. It is very important that you tell the Study
Doctor if you have any complaints, side effects, or had other doctor visits or
hospitalizations outside of the study. Ask the study doctor if you have any
questions about the signs or symptoms of any side effects that you read about
in this consent form.
Inclisiran was safe and well tolerated in all previously completed studies.
Safety data from three large studies that included a total of 1833 patients
treated with inclisiran for up to 18 months (mean treatment duration on
inclisiran was 526 days) showed that patients treated with inclisiran had a
similar number of adverse events compared to patients receiving placebo.
Injection site reactions were found to be the only events related to inclisiran
treatment.

Injection Reactions
Inclisiran will be given under your skin in your abdomen and like with any
injection given under the skin, you could develop a reaction at the site of the
injection. You could develop pain, tenderness, redness, swelling, itching,
rash, formation of sores, skin color changes, or other reactions around an
injection site. If you have a reaction, you may undergo an examination by a
doctor or other health care professional. During the study, the study staff
will check the site of injection for any reactions. In the overall research
program, fewer than 1 in 10 people (8.2%) noticed reactions where the injection
was given.. These were usually mild, occasionally moderate and localized and
did not require any specific treatment, resolving usually within 1-2 weeks.

Allergic reactions
No general allergic reactions or signs or symptoms suggestive of general
allergic reactions have been seen following administration of inclisiran in any
of the completed clinical studies. However there is a remote chance that
inclisiran (like any investigational drug) may cause an allergic reaction,
which in some cases can be severe. This severe reaction may be characterized by
sudden shortness of breath, decreased consciousness, and rash, and may require
emergency treatment. If you think, you are having an allergic reaction, call
the study Doctor right away and/or seek medical attention.

Risks associated with blood draws
There is a risk of minor discomfort, bruising, bleeding, swelling, or (rarely)
infection at the site of needle insertion for blood drawing.

Fasting Risks
Fasting could cause dizziness, headache, stomach discomfort, or fainting
Reproductive risks
It is not known if the study treatment by inclisiran may affect an unborn child
or nursing infant. There is no information on the long-term effects of
inclisiran on fertility.
Benefit
If the patients are placed on inclisiran, they may benefit from treatment with
inclisiran and it may prove as safe or safer and as effective as or more
effective due to its unique effects on lowering the 'bad' cholesterol than
other treatment you might have previously received. In the future, other people
with elevated cholesterol may benefit from the information we learn from this
study