Patients With DMD Treated With Avidity Biosciences’ Antibody-Oligonucleotide Conjugate Del-Zota Show Functional Improvements

Patients with Duchenne muscular dystrophy (DMD) treated with Avidity Biosciences' antibody-oligonucleotide conjugate delpacibart zotadirsen (also known as del-zota), which consists of an anti–transferrin receptor 1 (TfR1) antibody conjugated to an exon 44–skipping phosphorodiamidate-morpholino conjugate (PMO), have shown functional improvements.¹

The findings come from patients with DMD with exon 44 skipping (DMD44) treated in the phase 1/2 EXPLORE44 clinical trial (NCT05670730) and the phase 2 EXPLORE44OLE trial (NCT06244082). The group includes 12 ambulatory and 5 nonambulatory patients who have at least 1 year of follow-up. Results were compared with baseline and natural history data.

On the Performance of Upper Limb 2.0 (PUL2) test, patients treated with del-zota (n = 17) showed a 1.5-point improvement from baseline whereas natural history patients (n = 27) showed a 0.7-point decline from baseline. Avidity noted that for the patients treated with del-zota, similar improvements on PUL2 were seen for ambulatory and nonambulatory patients.

Furthermore, patients treated with del-zota (n = 10) showed a 2.1-second improvement from baseline on 4-stair climb whereas a natural history group (n = 22) showed a 2.7-second decline from baseline. In addition, patients treated with del-zota (n = 10) demonstrated a 0.7-second improvement from baseline on the 10-m walk/run test whereas a natural history group (n = 22) showed a 1.5-second decline from baseline. Patients treated with del-zota (n = 6) showed a 3.2-second improvement from baseline on the time to rise from floor test, whereas a natural history group (n = 19) showed a 1.6-second decline from baseline. Avidity also pointed out that patients who received del-zota (n = 10) maintained stability on the North Star Ambulatory Assessment (NSAA) whereas a natural history group (n = 20) showed a decline of 2.4 points from baseline. The company noted that all the aforementioned tests other than PUL2 were conducted only in patients who were ambulatory and that some participants could not complete all the tests.

Some patients treated in EXPLORE44 trial began on a dose of 5 mg/kg of del-zota every 6 weeks, and some began on a dose of 10 mg/kg every 8 weeks. However, in EXPLORE44OLE, all patients were shifted into the regimen of 5 mg/kg every 6 weeks.

Avidity stated that statistically significant increases in dystrophin production of approximately 25% from normal level were observed in patients treated with del-zota and that total dystrophin was restored to up to 58% of normal level. In addition, a rapid decrease of more than 80% vs baseline was seen in creatine kinase (CK) levels; the decrease was sustained at close to normal levels through the latest follow-up period, which was up to 16 months for some patients. At 1 year after the start of treatment, 50% of the treated patients showed CK levels in the normal range.

"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, the president and CEO of Avidity, said in a statement.¹ "These unprecedented data underscore the impact of our revolutionary targeted approach to deliver RNA directly to muscle. We are acting with urgency to rapidly advance the del-zota development program and remain on track to submit a biologics license application to [the] 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."

With regard to safety, Avidity noted that most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. Upper respiratory tract symptoms, diarrhea, fall, back pain, and headache constituted the most common TEAEs, which were defined as those observed in more than 3 patients. Notably, a single patient discontinued participation in EXPLORE44OLE after a case of hypersensitivity occurred. Avidity characterized del-zota's long-term safety and tolerability profile as “favorable.” The safety set included all patients evaluated in EXPLORE44OLE.

CGTLive's sister site Neurology Live® interviewed Michael Flanagan, PhD, the chief scientific officer at Avidity, about del-zota and the EXPLORE44 trial earlier this year at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, which was held March 16 to 19 in Dallas, Texas.² Flanagan explained the mechanism behind del-zota and the design of EXPLORE44.

“In exon 44, which we're targeting, it's defective in the sense that it doesn't make a full-length dystrophin,” Flanagan told Neurology Live. “What we can do is bind to that exon 44, skip the mutation, and bring it back into reading frame. Now we've only skipped a small portion of the full-length protein, and now we make a near full-length protein, and then that protein can go back and do what it's supposed to naturally do. That's the mechanism. We include a delivery reagent; that's basically the antibody. It acts like an address and finds the receptor of interest in muscle. It also binds to smooth muscle as well as cardiac muscle, so it delivers to all 3 muscles. Then we have the PMO that really does the exon skipping that you're probably more familiar with.”