Del-Zota Produced Statistically Significant Increases in Exon-Skipping and Dystrophin Levels in EXPLORE44, a Phase 1/2 Study in Individuals With DMD44M

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EP: 1.Del-Zota Produced Statistically Significant Increases in Exon-Skipping and Dystrophin Levels in EXPLORE44, a Phase 1/2 Study in Individuals With DMD44M

Summary of Del-Zota (Exon 44 Skipping Agent) Clinical Trial for Duchenne Muscular Dystrophy

Background

• Duchenne muscular dystrophy (DMD) is an X-linked recessive condition primarily affecting males
• Presents at ages 2-4 with muscle weakness; loss of ambulation typically occurs between ages 8-14
• Approximately 7% of DMD patients have genetic variants amenable to exon 44 skipping

Del-Zota Therapy

• A second-generation exon 44 skipping agent using Avidity technology
• Comprised of humanized antitransferrin antibody conjugated to multiple PMO (phosphorodiamidate morpholino oligomer) copies
• Designed to restore dystrophin reading frame and produce near full-length dystrophin

Phase 1/2 EXPLORE 44 Trial Design

• Randomized, placebo-controlled, double-blinded trial
• 24 participants with DMD44 (ages 7-27, both ambulatory and nonambulatory)
• Treatment arms: 5 mg/kg every 6 weeks vs 10 mg/kg every 8 weeks vs placebo (3:1 randomization)
• Muscle biopsies performed at baseline and one month after third dose

Key Results

Safety and Tolerability

• Favorable safety profile with most adverse events mild to moderate
• Most common adverse events: procedural pain and headache
• Two participants discontinued: 1 due to anaphylaxis, 1 due to moderate infusion-related reaction
• No symptomatic hemoglobin changes, no hypomagnesemia, no deaths

Biomarker Outcomes

• Consistent and high PMO muscle concentration in both dosing groups
• Significant exon 44 skipping: 37% in 5 mg/kg group, 43% in 10 mg/kg group
• Dystrophin production increased to approximately 25% of normal levels on average
• Up to 58% of normal dystrophin levels observed across all exon 44 amenable genotypes

Creatine Kinase (CK) Levels

• Consistently decreased CK levels to near normal in treated participants
• CK reductions sustained near upper limit of normal from day 70-140 in the 5 mg/kg group and day 84-140 in the 10 mg/kg group
• Greater than 80% reduction in CK levels compared to baseline
• Reductions sustained for up to 1 year in the open-label extension

Clinical Implications

• The dramatic reduction of CK levels to near-normal is unprecedented in DMD therapeutics
• Normalization of CK suggests significant reduction in muscle damage
• The 5 mg/kg every 6 weeks regimen is advancing as the pivotal dose for further trials
• Results support continued evaluation of del-zota in the ongoing open-label extension study

This represents the first patient experience using Avidity’s antibody-oligonucleotide conjugate technology to deliver PMOs specifically to muscle tissue in patients with DMD.