Del-zota treatment is associated with near normalization of CK levels and improvements in key functional outcomes at 1 year in participants with DMD44

Topic:

Clinical Trials

Poster Number: 403 O

Author(s):

Craig McDonald, MD, University of California Davis Health, Diana Castro, MD, Neurology Rare Disease Center, Denton, Texas, USA, Stephen Chrzanowski, MD, PhD, UMass Chan Medical School, Jamie Eskuri, MD, Gillette Children’s Specialty Healthcare, Kevin Flanigan, MD, Nationwide Children's Hospital, Chamindra Laverty, MD, UC San Diego Health, Han Phan, MD, Rare Disease Research, Atlanta, Georgia, USA, Edward C. Smith, MD, Rare Disease Research North Carolina, Carolina Tesi Rocha, MD, Stanford University, Aravindhan Veerapandiyan, MD, Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US, Brenda Wong, MD, UMass Chan Medical School, James Signorovitch, PhD, Analysis Group, Inc., Boston, Massachusetts, USA , Gautam Sajeev, ScD, Analysis Group, Yvonne Tami, BS, Avidity Biosciences, Inc., Tara Carmack, MS, Avidity Biosciences, Inc., Carmen Castrillo, MD, Avidity Biosciences, Inc., Julie Coats, PT, DPT, Avidity Biosciences, Inc., Elizabeth Ackermann, PhD, Avidity Biosciences, Inc.

Background: Duchenne muscular dystrophy (DMD) arises from pathogenic variants in the dystrophin gene. Delpacibart zotadirsen (del-zota; AOC 1044), is an antibody-oligonucleotide conjugate (AOC™) comprised of an anti-transferrin receptor 1 (TfR1) antibody conjugated to exon 44-skipping phosphorodiamidate morpholino oligonucleotides. Del-zota is designed to restore the dystrophin reading frame and produce a shorter but functional dystrophin protein in individuals with DMD with mutations amenable to exon 44 skipping (DMD44).

Methods: Part B of the Phase 1/2 EXPLORE44® trial (NCT05670730) was a randomized, placebo-controlled, double-blind study that assessed safety, tolerability, pharmacokinetics, and exon skipping efficacy of multiple-ascending doses of del-zota. EXPLORE44-OLE™ (NCT06244082) is an ongoing open label extension study of EXPLORE44® evaluating the long-term safety and efficacy of del-zota in participants that completed EXPLORE44® and de novo-enrolled participants. Here, we present one-year change from baseline in serum creatine kinase (CK, a biomarker of muscle damage) and functional outcomes with del-zota relative to DMD44 external natural history comparators (PRO-DMD-01 database and Brogna et al. 2023).

Results: Forty-two ambulatory (n=28) and non-ambulatory (n=14) individuals aged 7–27 years with DMD44 were enrolled across EXPLORE44® and EXPLORE44-OLE™. All ongoing participants have received ~1 year of cumulative del-zota treatment. Median serum CK levels remained near the upper limit of normal over the 1-year period. Del-zota treatment is associated with improvements in key functional outcomes at 1 year compared to natural history data, which has not been previously reported following gene therapy or exon skipping treatment for DMD. Del-zota produced acceptable safety and tolerability results.

Conclusions: Earlier analyses in a subset of participants demonstrated reductions in CK and improvements in key measures of function. One year follow-up in the full cohort, including prior placebo-treated (from EXPLORE44®) and newly enrolled participants (from EXPLORE44-OLE™) confirms and extends these findings. These results support the potential of del-zota to improve the lives of participants with DMD44.