SAFARI44™: Design of a Phase 3 global study to evaluate the efficacy and safety of delpacibart zotadirsen (del-zota; AOC 1044) in treating DMD44

Topic:

Clinical Trials

Poster Number: 165 M

Author(s):

Laurent Servais, MD PhD, University of Oxford, Eugenio M. Mercuri, MD, Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Rome, Italy, Francesco Muntoni, MD, Dubowitz Neuromuscular Centre, UCL and Great Ormond Street Hospital Trust, London, UK, Carmen Castrillo, MD, Avidity Biosciences, Inc., Julie Coats, PT, DPT, Avidity Biosciences, Inc., Tara Carmack, MS, Avidity Biosciences, Inc., Yvonne Tami, BS, Avidity Biosciences, Inc., Joshua Lilienstein, MD, Avidity Biosciences, Marc Morris, MD, JD, Avidity Biosciences, Inc., Elizabeth Ackermann, PhD, Avidity Biosciences, Inc.

Background: Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene that result in absent or near-absent levels of dystrophin protein expression, is characterized by severe muscle damage, inflammation, progressive loss of muscle function throughout childhood and adolescence, and reduced life expectancy. There are no approved mutation-specific exon skipping therapies for the ~6-7% of individuals with DMD who are amenable to exon 44 skipping (DMD44). Delpacibart zotadirsen, or del-zota (AOC 1044), is an antibody-oligonucleotide conjugate (AOC™) comprised of an anti-transferrin receptor 1 antibody conjugated to exon 44-skipping phosphorodiamidate morpholino oligonucleotides (PMOs) designed to restore the dystrophin reading frame and produce shortened but functional dystrophin protein in muscle. Del-zota has demonstrated acceptable safety and tolerability, as well as efficacy in promoting dystrophin expression and reducing biomarkers of muscle damage to near normal levels in the completed Phase 1/2 EXPLORE44® (NCT05670730) and ongoing Phase 2 EXPLORE44-OLE™ (NCT06244082) trials.

Objectives: The upcoming SAFARI44™ trial will further evaluate the efficacy and safety of del-zota in individuals with DMD44.

Design: SAFARI44™ is a Phase 3, double-blind, placebo-controlled, study with a 54-week randomized treatment period, 54-week open-label extension period, and 6-week follow-up period. Approximately 70 ambulatory participants aged 7–16 years will be enrolled globally (ex-US). Participants will be randomized (1:1) to receive del-zota (5 mg/kg PMO component, 28 mg/kg total AOC weight) or placebo every 6 weeks by intravenous infusion for a total of 9 doses during the randomized portion, after which all participants will receive del-zota at the above dose every 6 weeks. The primary objective is to assess muscle function using change from baseline to Week 54 in time-to-rise velocity. Key secondary endpoints are change from baseline to Week 54 in creatine kinase (biomarker of muscle injury), 4-stair climb velocity, 10-meter walk/run velocity, stride velocity (SV95C), and North Star Ambulatory Assessment. Safety and additional exploratory efficacy endpoints will also be evaluated throughout the study.

Conclusions: SAFARI44™ is a pivotal Phase 3 trial designed to evaluate the efficacy and safety of del-zota over 54 weeks of treatment compared to placebo.