Objective: To evaluate the safety and tolerability of single and multiple ascending doses of AOC 1020 in participants with FSHD. Background: FSHD is a rare, slowly progressive, often asymmetric, genetic skeletal muscle disease caused by aberrant expression of the transcription factor DUX4 in skeletal muscle, leading to a series of downstream events that result in skeletal muscle degeneration and wasting. Strategies targeting DUX4 expression in skeletal muscle of individuals with FSHD via oligonucleotides are promising therapeutic approaches. AOC 1020 is an antibody-oligonucleotide conjugate (AOC) comprised of a DUX4-targeting siRNA conjugated to a humanized antibody targeting transferrin receptor 1 (TfR1) to facilitate delivery to muscle. Methods: This phase 1/2 study is a randomized, placebo-controlled, double-blind trial conducted in three parts. The study will enroll 72 adults aged 18 to 65 years with a genetic diagnosis of FSHD1 or FSHD2. All participants will receive 5 doses of study medication administered quarterly with 1 booster at 6 weeks. Part A (N=12; 3:1 AOC 1020:placebo) utilizes a dose-titration design to evaluate the safety of AOC 1020 at two low doses. Part B (N=24; 2:1 AOC 1020:placebo) is a nested single-ascending dose/multiple-ascending dose design evaluating two presumed efficacious doses. Staggered cohorts will be initiated based on a safety data review of the preceding cohort(s). Part C (N=36; 1:1:1 AOC 1020 dose 1:AOC 1020 dose 2:placebo) is a parallel, multiple-dose design to be conducted with two presumed efficacious doses to evaluate clinical outcomes. After their final dose, participants enter a 3-month follow-up period. The total duration is 12 months. Eligible participants will have the option to enroll in an open-label extension study. The primary objective is safety and tolerability. Secondary objectives include pharmacokinetic measurements of AOC 1020. Exploratory measures of efficacy include pharmacodynamics, PROs, and measures of muscle function, strength, and composition by MRI.