Reverses Duchenne Progression in 1 Year

Newly announced data from the EXPLORE44 (NCT05670730) and EXPLORE44-open label extension (OLE) trials showed that treatment with Avidity’s del-zota led to reversal of disease progression and improvements in a number of efficacy-related outcomes in patients with Duchenne muscular dystrophy (DMD) treated for up to 1 year. The company remains on track to submit a biologics license application (BLA) at the end of the year for accelerated approval.1

EXPLORE44 was a placebo-controlled, double-blind, phase 1/2 trial of 26 patients with DMD with mutations amenable to exon 44 skipping (DMD44). Of these, 17 directly enrolled into the EXPLORE44-OLE, where both ambulatory and non-ambulatory patients received 5 mg/kg of del-zota every 6 weeks over a 24-month period. While not all patients completed all the assessments, 1-year functional data from the pooled dosing cohorts for del-zota-treated patients showed improvement relative to DMD44 natural history cohorts.

Overall, patients on the investigational antisense oligonucleotide improved by 2.1 seconds on 4-Stair Climb 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).

"For the first time, we have data showing that sustained muscle protection leads to meaningful improvements across multiple key functional measures in DMD," Sarah Boyce, president and chief executive officer at Avidity, said in a statement. "These unprecedented data underscore the impact of our revolutionary targeted approach to deliver RNA directly to muscle."

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Among the released data, findings showed stable North Star Ambulatory Assessment scores, whereas those in the natural history cohort declined by 2.4 points. In addition, patients on the investigational agent improved by 1.5 points on Performance of Upper Limb (PUL2) while natural history cohorts declined by 0.7 points. Notably, the improvements in PUL were similar across both ambulatory and non-ambulatory patients on treatment.

Boyce added, "We are acting with urgency to rapidly advance the del-zota development program and remain on track to submit a Biologics License Application (BLA) to FDA at year end 2025 for accelerated approval. We extend our deepest appreciation for the continued dedication of the investigators and their teams and, most importantly, the participants in our clinical trials and their families as we pursue a new treatment option for this relentless and devastating disease."

In the original double-blind period, trial participants on del-zota experienced significant increases of approximately 25% of normal dystrophin production and restored total dystrophin up to 58% normal. Creatine kinase (CK) levels were rapidly reduced by over 80% from baseline and sustained near normal for up to 16 months, with 50% of participants reaching normal CK levels at 1 year of treatment.

In August 2024, Avidity announced positive data from EXPLORE44, showcasing del-zota’s impact on dystrophin production and CK changes. Among those treated with 5 mg/kg doses, investigators reported a statistically significant increase of 37% in exon 44 skipping in studied patients, which had DMD mutations amenable to exon 44 skipping. At 4 months, those in this lower dose group had a 66% exon 44 skipping and a greater than 80% reduction in CK levels relative to baseline.2