<h3>Objective:</h3> To evaluate the safety and tolerability of single and multiple ascending doses of AOC 1020 in participants with FSHD. <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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. <h3>Results:</h3> N/A <h3>Conclusions:</h3> N/A <b>Disclosure:</b> Dr. Halseth has received personal compensation for serving as an employee of Avidity Biosciences. Dr. Halseth has stock in Avidity Biosciences. Dr. Ackermann has received personal compensation for serving as an employee of Avidity Biosciences. Teresa Brandt has received personal compensation for serving as an employee of Avidity Biosciences. Teresa Brandt has received personal compensation for serving as an employee of Acadia Pharmaceuticals. Teresa Brandt has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Acadia Pharmaceuticals. Teresa Brandt has stock in Avidity Biosciences. Dr. Chen has received personal compensation for serving as an employee of Avidity Biosciences. Dr. Stahl has received personal compensation for serving as an employee of Avidity Biosciences. Dr. Stahl has stock in Avidity Biosciences. Kelly Ditrapani has received personal compensation for serving as an employee of Avidity Biosciences. Kelly Ditrapani has received personal compensation for serving as an employee of Iovance Biotherapeutics. An immediate family member of Kelly Ditrapani has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Kelly Ditrapani has stock in Iovance Biotherapeutics. Kelly Ditrapani has stock in Avidity Biosciences. Kelly Ditrapani has stock in Aravive Inc.. An immediate family member of Kelly Ditrapani has stock in Jazz Pharmaceuticals. Kelly Ditrapani has stock in Abbvie. Dr. Hughes has received personal compensation for serving as an employee of Avidity Biosciences – Feb 2022-Present. Dr. Hughes has received personal compensation for serving as an employee of Arcturus Therapeutics – Jan 2020-Feb 2022. Dr. Hughes has received personal compensation for serving as an employee of Iatrogenic Solutions – Aug 2019-Present. Dr. Hughes has received personal compensation in the range of $500,000-$999,999 for serving as an officer or member of the Board of Directors for Arcturus Therapeutics. Dr. Hughes has stock in Avidity Biosciences. Dr. Hughes has stock in Arcturus Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for DYNE Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead Pharma. Dr. Tawil has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fulcrum Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acceleron Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MT Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for miRecule. The institution of Dr. Tawil has received research support from Friends of FSH Research. The institution of Dr. Tawil has received research support from FSH Society. The institution of Dr. Tawil has received research support from NIH. The institution of Dr. Tawil has received research support from Fulcrum. Dr. Tawil has received intellectual property interests from a discovery or technology relating to health care. Dr. Tawil has received publishing royalties from a publication relating to health care. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ML Bio. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MT Pharma. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Epic Bio. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Armatus . Dr. Statland has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Dyne Therapeutics. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avidity . Dr. Statland has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fulcrum Therapeutics. Dr. Statland has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Dr. Statland has received research support from NIH. The institution of Dr. Statland has received research support from FSHD Society. The institution of Dr. Statland has received research support from Friends of FSH Research. The institution of Dr. Statland has received research support from FSHD Canada. The institution of Dr. Statland has received research support from MDA.