Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C)

Participants will be screened and 480 eligible participants will be randomized: 60 participants per each of six ALN-PCSSC dose groups plus 120 participants total across the placebo groups (20 participants each to match each of the six drug dose groups). Treatment allocation will be stratified by country and by current use of statins or other lipid-modifying therapies. Each participant will receive either one or two injections on Day 1 or a single injection on Day 1 and on Day 90 of blinded ALN-PCSSC or placebo. Formation of anti-drug antibodies (ADA) will be assessed on Day 1 (prior to and 4 hours after the injection) and on Days 30, 60, 90, 120, 150, 180 (Days 150 and 180 only in participants who receive a second dose of study drug), and 210 or until any ADA response becomes negative within the study duration. The independent Data Monitoring Committee (DMC) will review safety data beginning after the first 40 participants receive the first injection of ALN-PCSSC or placebo and complete the Day 14 follow-up visit. Thereafter, the DMC will review safety data every 2 months until the end of the trial. A recommendation may be taken to stop or amend the study at any of these reviews. On Day 1, all eligible participants will be randomized and receive the first subcutaneous (SC) administration of ALN-PCSSC or placebo. After the first study drug administration, the participant will be observed in the clinic for at least 4 hours post injection before being discharged. Participants will return at Day 14 and then at monthly intervals for 6 months. Participants randomized to receive a second dose of study drug will receive the second injection of ALN-PCSSC or placebo at the Day 90 visit. Efficacy assessments will include the measurement of the effects of ALN-PCSSC on levels of LDL-C lipids and lipoproteins including total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, very low-density lipoprotein (VLDL), apolipoprotein A1 (Apo-AI), apolipoprotein B (Apo-B), lipoprotein (a) \[Lp(a)\], C-reactive protein (CRP), and proprotein convertase subtilisin/kexin type 9 (PCSK9). End of study (EOS) evaluations will be conducted at the EOS visit (Day 210). The expected duration of the participants' involvement in the study will be approximately 374 days, which includes screening, study drug administration, the course of single or multiple injections, and the follow-up period to Day 360. Participants completing the study to Day 210 will be given the opportunity to enroll in a separate long-term extension study. Any participants in whom LDL-C levels have not returned to \>80% of baseline values will continue to be followed as part of this study until either this level has been reached or until a maximum of Day 360, at which point they will be given the opportunity to enroll in the long-term extension study. At each visit, LDL-C levels, adverse events, serious adverse events, concomitant medications, and safety laboratory assessments will be collected. Objectives: Primary: To evaluate the effect of ALN-PCSSC treatment on LDL-C levels at Day 180. Secondary: To evaluate the effect of ALN-PCSSC on the following: * LDL-C at Day 90 * LDL-C levels at other time points * PCSK9 levels over time * Other lipids, lipoproteins, apolipoproteins * Proportion of participants achieving pre-specified global lipid guidelines * Individual responsiveness to different doses * Duration of lipid-lowering effect of different doses * Safety and tolerability profile of ALN-PCSSC Exploratory: To collect/evaluate the effect of ALN-PCSSC on the following: * Cardiovascular (CV) events such as CV death, non-fatal myocardial infarction, resuscitated cardiac arrest and non-fatal stroke (ischemic and hemorrhagic) * Evaluation of ADA for the investigational product