Two part (double-blind inclisiran versus placebo [Year 1] followed by open-label inclisiran [Year 2]) randomized multicenter study to evaluate safety, tolerability, and efficacy of inclisiran in adolescents (12 to less than 18 years) with heterozygous familial hypercholesterolemia and elevated LDL-cholesterol (ORION-16)

Familial hypercholesterolemia (FH) is a genetic disorder that causes high
levels of LDL-C in the blood and is characterized by premature cardiovascular
(CV) disease. Current treatment options are still limited for children with FH,
and the known limitations of contemporary therapies are particularly relevant
among children with FH who are at the highest risk of future CV events, and
thus require the most intensive and aggressive management of
hypercholesterolemia. There remains a clear unmet medical need for treatments
that will lower LDL-C, especially in pediatric populations.
Inclisiran is a medication made to reduce the level of LDL-cholesterol in the
blood. Inclisiran works in a way that makes the liver produce less of a
substance called *PCSK9*. PCSK9 reduces the ability of the liver to remove
LDL-cholesterol from the blood. By lowering the production of PCSK9, inclisiran
leads to more LDL-cholesterol being removed by the liver from the blood. By
that, the level of LDL-cholesterol in the blood is reduced.
Inclisiran may improve the treatment of children/adolescents with HeFH, with a
low injection burden given the only twice yearly dosing.

Study CKJX839C12301 (ORION-16) is a pivotal phase III study designed to
evaluate safety, tolerability, and efficacy of inclisiran in adolescents (aged
12 to <18 years) with HeFH and LDL-C >130 mg/dL (3.4 mmol/L). The use of
inclisiran (as an adjunct to stable, optimal background lipid-lowering therapy)
for the treatment of HeFH in adolescent patients who require additional
lipid-lowering will be investigated in order to obtain needed pediatric
information on inclisiran. The follow-up period (Part 2/Year 2) serves to
collect longer-term data on inclisiran and also allows access of study
participants to a potentially effective treatment.

This study is a two-part (double-blind, placebo-controlled / open-label)
multicenter study in adolescents (aged 12 to <18 years) with HeFH and elevated
LDL-C (>130 mg/dL / 3.4 mmol/L) on stable, individualized, optimal SoC
background lipid-lowering therapy (including maximally tolerated statin
treatment).

- Part 1 (Year 1): 12 months double-blind, parallel group period in which
participants will be randomized to receive either inclisiran sodium 300 mg
(equivalent to 284 mg inclisiran*) s.c. or placebo (given at Days 1, 90 and
270).
- Part 2 (Year 2): 12 months single arm, open-label follow-up period with all
participants receiving inclisiran sodium 300 mg (equivalent to 284 mg
inclisiran*) s.c. Participants randomized to placebo in Part 1 will receive
inclisiran starting on Day 360 (*Switch* Day 360). Participants randomized to
inclisiran in Part 1 will receive placebo on Day 360. This dose of
inclisiran/placebo on Day 360 will remain blinded in order to maintain the
blind for Part 1 of the study. All participants will receive subsequent doses
of open-label inclisiran on Days 450 and 630.

Participants will be randomized 2:1 to double-blind s.c. injections of
inclisiran sodium 300 mg or placebo in Part 1 (Year 1) of the study, and
subsequently all participants will receive open-label s.c. injections of
inclisiran sodium 300 mg in Part 2 (Year 2) of the study.

- Injection site reactions: itching, pain, rash, redness, changes of the color
of the skin, ulcers, swelling, sensitive skin, or other reactions near the
injection site.
- Allergic reactions. Frequently seen allergic reactions are rash, itching,
skin problems, swelling of the face and throat and problems with breathing. So
far no general allergic reactions have been reported with inclisiran and no
symptoms have been seen which matches an allergic reaction.
- Blood sampling can cause some pain and/or bruising.