An Extension Trial of Inclisiran Compared to Evolocumab in Participants With Cardiovascular Disease and High Cholesterol

ORION-3, an extension of study MDCO-PCS-15-01 (ORION-1) [NCT02597127], is a Phase II,
placebo-controlled, double-blind, randomized trial to evaluate the efficacy, safety, and
tolerability of inclisiran (ALN-PCSSC) injection(s). All participants who completed ORION-1
(at least up to and including Day 210) and meet the study criteria will be enrolled into this
study.

ORION-3 is a long-term extension trial with an active comparator (evolocumab) in participants
with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (diabetes,
familial hypercholesterolemia) and elevated LDL-C, despite maximum tolerated dose of LDL-C
lowering therapies.

Inclusion Criteria:

1. Completion of Study MDCO-PCS-15-01 and no contraindication to receiving inclisiran or
evolocumab.

2. Willing and able to give written and informed consent before initiation of any study
related procedures and willing to comply with all required study procedures.

3. Willing to self-inject.

Exclusion Criteria:

1. Any uncontrolled or serious disease, or any medical or surgical condition that may
either interfere with participation in the clinical study and/or put the participant
at significant risk (according to investigator's [or delegate's] judgment).

2. An underlying known disease or surgical, physical, or medical condition that, in the
opinion of the investigator (or delegate), might interfere with interpretation of the
clinical study results.

3. Serious comorbid disease in which the life expectancy of the participant is shorter
than the duration of the trial (for example, acute systemic infection, cancer, or
other serious illnesses).

4. Active liver disease defined as any known current infectious, neoplastic, or metabolic
pathology of the liver; unexplained alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) elevation greater than 2 times upper limit of normal (ULN); or
total bilirubin elevation greater than 1.5 times ULN at study entry visit.

5. Females who are pregnant or nursing, or who are of childbearing potential and
unwilling to use at least two methods of contraception (for example, oral
contraceptives, barrier methods, approved contraceptive implant, long-term injectable
contraception, intrauterine device) for the entire duration of the study. Exemptions
from this criterion are

- Women >2 years postmenopausal (defined as 1 year or longer since their last
menstrual period) AND more than 55 years of age

- Postmenopausal women (as defined above) and less than 55 years old with a
negative pregnancy test within 24 hours of enrollment

- Women who are surgically sterilized at least 3 months prior to enrollment

6. Males who are unwilling to use an acceptable method of birth control during the entire
study period (that is, condom with spermicide).

7. Treatment with investigational medicinal products other than inclisiran or devices
within 30 days or five half˗lives, whichever is longer.

8. Planned use of investigational medicinal products other than inclisiran or devices
during the course of the study.

9. Participants with a history of a serious hypersensitivity reaction to evolocumab or
any of the excipients

10. Previous or current treatment (within 90 days of study entry) with monoclonal
antibodies directed towards PCSK9.

11. Any condition that according to the investigator could interfere with the conduct of
the study, such as but not limited to:

- Inappropriate for this study, including participants who are unable to
communicate or to cooperate with the investigator.

- Unable to understand the protocol requirements, instructions and study-related
restrictions, the nature, scope, and possible consequences of the study
(including participants whose cooperation is doubtful due to drug abuse or
alcohol dependency).

- Unlikely to comply with the protocol requirements, instructions, and
study-related restrictions (for example, uncooperative attitude, inability to
return for follow-up visits, and improbability of completing the study).

- Involved with, or a relative of, someone directly involved in the conduct of the
study.

- Any known cognitive impairment (for example, Alzheimer's Disease).