Michael Flanagan, PhD, on Del-zota’s Breakthrough Potential for Duchenne Muscular Dystrophy

Michael Flanagan, PhD

The treatment landscape for Duchenne muscular dystrophy (DMD) is rapidly evolving, driven by advances in gene therapy, exon skipping, and steroid-sparing strategies. While corticosteroids have long served as the mainstay of care, newer therapies, like Del-zota (Avidity Biosciences), aim to more directly target the underlying defects responsible for the progressive muscle degeneration seen in DMD.

Del-zota, designed to restore dystrophin reading frame and produce functional, internally truncated dystrophin protein, is being tested in the phase 1/2 EXPLORE44 trial (NCT05670730). Results from this randomized, double-blind, placebo-controlled study were recently presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19, in Dallas, Texas. The findings, demonstrated Del-zota’s ability to increase dystrophin production and exon skipping and reduce creatine kinase (CK) levels.

During the meeting, NeurologyLive^® sat down with Michael Flanagan, PhD, chief scientific officer at Avidity, to provide a deep dive into Del-zota and the phase 1/2 findings. He spoke about the novel delivery mechanism targeting exon 44 and how it differs from previously approved therapies and what’s currently in the pipeline. Furthermore, Flanagan previewed what’s next for the therapy, including an open-label extension, a potential biologics license application, and the initiation of a confirmatory phase 3 trial.

NeurologyLive: Regarding the mechanism of Del-zota, why do we believe it can be successful in treating DMD?

Michael Flanagan, PhD: Our AOC technology stands for antibody oligonucleotide conjugates. What that means is there's an antibody portion linked to an oligo—in this case, a phosphorodiamidate morpholino oligomer, or PMO. Let’s just call it PMO from here.

Del-zota is composed of an antibody linked to a PMO. The antibody portion binds to the transferrin receptor, which is a professional transporter that carries iron into muscle cells. We use that natural mechanism to gain entry into the cell. Once inside, the PMO is released and traffics to the nucleus, where it binds pre-mRNA.

For example, in patients with an exon 44 mutation—which we’re targeting—the gene is defective and doesn’t produce full-length dystrophin. The PMO skips the faulty exon, bringing the gene back into frame. That results in a near full-length dystrophin protein that can then function more normally.

The delivery mechanism acts like an address label. It targets skeletal, cardiac, and smooth muscle, ensuring broad delivery. And then the PMO is responsible for the exon skipping—which you’re probably more familiar with.

What went into the phase 1/2 EXPLORE44 study? Can you discuss the goals, demographics, and patient population?

It’s a phase 1/2 trial using a 3-to-1 randomization, double-blind, placebo-controlled design—so a very rigorous, traditional clinical trial structure. The age range spans from 7 to 27 years, covering both ambulatory and non-ambulatory patients. We wanted to be inclusive and patient-centered in our design.

The key endpoints are safety, pharmacokinetics (PK), and pharmacodynamics (PD), including measures of exon skipping and dystrophin expression. We also included exploratory endpoints like muscle function, quality of life, and patient-reported outcomes.

The trial duration runs from roughly three to four months, with two dose arms: 5 mg/kg every six weeks and 10 mg/kg every eight weeks. After that, eligible patients can continue in the ongoing open-label extension.

What were the greatest takeaways from the study findings?

It’s incredibly exciting to be working on this—not just Del-zota, but our whole neuromuscular portfolio. For Del-zota specifically, we’re seeing what we believe is game-changing delivery to muscle tissue: about 200 nanomolar concentrations of PMO.

That delivery results in around 40% exon 44 skipping, which is remarkable. That skipping translates into dystrophin restoration—we’re seeing about a 25% increase, which brings patients up to roughly 30% of normal dystrophin levels.

Most excitingly, we’re seeing dramatic reductions in creatine kinase (CK) levels—more than 80% decreases, especially in younger ambulatory boys. CK levels drop near the upper limit of normal and stay there for nearly a year. That suggests improved membrane integrity and reduced muscle damage, which we hope translates to long-term functional benefit.

What does a potential phase 2 or phase 3 trial look like for this agent?

Looking forward, patients can continue into the open-label extension, which provides long-term safety data and continued access to treatment. Importantly, the FDA has confirmed that the accelerated approval pathway remains open. We’re planning to file a BLA based on dystrophin levels this year.

In parallel, we’ll launch a phase 3 trial to confirm the early signs of activity. It’s a really exciting time. You don’t get to work on a therapy like this very often in your career, and it’s incredibly motivating to potentially help people living with DMD and their families.

Transcript edited for clarity. Click here for more MDA 2025 coverage.