New Phase 3 SAFARI44 Trial To Confirm Benefit of Del-Zota in Duchenne Muscular Dystrophy

At the 2026 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 8-11 in Orlando, Florida, investigators presented the design of a new phase 3 study, dubbed SAFARI44, that evaluates the efficacy and safety of del-zota (Avidity Biosciences), an antibody-oligonucleotide conjugate (AOC), in patients with Duchenne muscular dystrophy amenable to exon 44 skipping (DMD44). This 54-week study is the latest and most advanced trial for this agent, which hopes to become the next pivotal option for the DMD44 community.

Del-zota, designed to restore dystrophin reading frame and produce functional, internally truncated dystrophin protein, aims to target skeletal, cardiac, and smooth muscle, ensuring broad delivery. SAFARI44, a newly announced trial, is a double-blind, placebo-controlled study in design, aimed to enroll approximately 70 ambulatory participants with DMD44 aged 7-16 years. The study includes a 54-week randomized treatment period, 54-week open-label extension, and 6-week follow-up safety period.

The phase 3 study will use change in time-to-rise velocity, a measure of muscle function, as the primary end point, with other secondary end points that include changes in creatine kinase, 4-stair climb velocity, 10-meter walk/run velocity, stride velocity (SV95C), and North Star Ambulatory Assessment (NSAA). In addition, study authors will also collect data on safety and other exploratory efficacy end points throughout the 54-week study period.

Led by Laurent Servais, MD, PhD, a professor of pediatric neuromuscular diseases at the University of Oxford, patients in the study will be randomly assigned 1:1 to either 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. Following this, all participants will receive the investigational drug at above dose every 6 weeks.

EXPLORE44 & OLE

Prior to SAFARI44, del-zota was previously assessed in EXPLORE44 (NCT05670730), a phase 1/2, placebo-controlled, double-blind trial comprising 26 participants with DMD44 and an open-label extension (OLE; NCT). Of these, 17 enrolled into the OLE, where both ambulatory and nonambulatory patients received 5 mg/kg of del-zota every 6 weeks over a 24-month period.²

Data from the OLE released in late 2025 showed that patients on del-zota improved by 2.1 seconds on the 4-stair climb test at 1 year whereas natural history cohorts declined by 2.7 seconds. Within the investigational group, the 10-meter walk/run test improved from baseline by 0.7 seconds compared with a 1.5-second decline in the natural history group (DMD44 Nat Hx N=22; del-zota n = 10) and time to rise from floor improved from baseline by 3.2 seconds compared with a 1.6-second decline in the natural history group (DMD Nat Hx: n = 19; del-zota: n = 6).

Among the reported data, North Star Ambulatory Assessment scores remained stable in treated patients, while those in the natural history cohort declined by 2.4 points. Patients receiving the investigational agent improved by 1.5 points on the Performance of Upper Limb (PUL) measure, whereas the natural history cohort declined by 0.7 points. These PUL improvements were observed in both ambulatory and nonambulatory patients receiving treatment.

In the original EXPLORE44 trial, del-zota at a 5 mg/kg dose demonstrated robust delivery of phosphorodiamidate morpholino oligomers (PMO) to skeletal muscle, reaching concentrations of 200 nM. Among patients with DMD44, treatment with the agent produced a statistically significant increase of 25% of normal dystrophin production along with a 37% increase in exon 44 skipping, highlighting the therapy’s ability to drive meaningful molecular changes in muscle tissue.³

At the 4-month assessment, participants in the 5 mg/kg cohort received three doses administered every 6 weeks, with biomarker and functional analyses conducted in 10 patients. Investigators observed up to 66% exon 44 skipping and a greater than 80% reduction in creatine kinase levels compared with baseline, with CK levels approaching normal in treated individuals. The therapy was also considered generally safe and well tolerated, with most adverse events reported as mild or moderate in severity.

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REFERENCE
1. Servais L, Mercuri EM, Muntoni F, et al. SAFARI44™: Design of a Phase 3 global study to evaluate the efficacy and safety of delpacibart zotadirsen (del-zota; AOC 1044) in treating DMD44. Presented at: 2026 MDA Conference; March 8-11; Orlando, FL. ABSTRACT 165M
2. Avidity Biosciences' del-zota demonstrated reversal of disease progression across key functional endpoints in EXPLORE44 and EXPLORE44-OLE phase 1/2 trial in people living with DMD44. News release. Avidity Biosciences. September 10, 2025. Accessed March 10, 2026. https://www.prnewswire.com/news-releases/avidity-biosciences-del-zota-demonstrated-reversal-of-disease-progression-across-key-functional-endpoints-in-explore44-and-explore44-ole-phase-12-trial-in-people-living-with-dmd44-302552339.html
3. Avidity Biosciences Announces Positive AOC 1044 Data Demonstrated Significant Increase of 25% in Dystrophin Production and Reduction of Creatine Kinase Levels to Near Normal in People Living with Duchenne Muscular Dystrophy Amenable to Exon 44 Skipping in the Phase 1/2 EXPLORE44™ Trial. News release. Avidity Biosciences. August 9, 2024. Accessed March 10, 2026. https://www.prnewswire.com/news-releases/avidity-biosciences-announces-positive-aoc-1044-data-demonstrated-significant-increase-of-25-in-dystrophin-production-and-reduction-of-creatine-kinase-levels-to-near-normal-in-people-living-with-duchenne-muscular-dystrophy-amenab-302218647.html