Del-Zota for Duchenne Muscular Dystrophy

Michael Flanagan, PhD

Avidity Biosciences' antibody-oligonucleotide conjugate (AOC) 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), is currently being evaluated in the phase 1/2 EXPLORE44 clinical trial (NCT05670730). At the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific conference, held March 16 to 19, in Dallas, Texas, findings were presented from part B of the randomized, double-blind, placebo-controlled study.

CGTLive®'s sister site NeurologyLive® interviewed Michael Flanagan, PhD, the chief scientific officer at Avidity, about the trial at the conference. Flanagan spoke on the key end points of the study, the flexibility of the trial, and its open-label extension that will be used for ongoing evaluation.

NeurologyLive: Can you give some background info about del-zota?

Michael Flanagan, PhD: Our AOC technology stands for antibody-oligonucleotide conjugates. So what does that mean? It's an antibody portion married to an oligo, and in this case, for del-zota, it's a phosphorodiamidate morpholino oligo (PMO). It's linked to a PMO, and that PMO, the antibody portion, binds to the transferrin receptor. The transferrin receptor is a professional transporter. It transports iron into muscle cells, so we use it and piggyback onto this natural mechanism to get inside the cell. Once we're inside the cell, it releases the PMO and the PMO then traffics to the nucleus, where it then binds the pre-mRNA. For instance, in exon 44 which we're targeting, it's defective in the sense that it doesn't make a full-length dystrophin. 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 kind of 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.

Can you discuss the trial?

It's a phase 1/2 trial, with a 3:1 randomization, and is double-blind and placebo controlled, so it's a very rigorous traditional clinical trial. The age ranges from 7 to 27 so we have a broad age range. It includes both ambulatory and nonambulatory patients. So it's really trying to focus on patients, their needs, and trying to be as encompassing as possible. The key end points include of course, safety. We'll then look at the pharmacokinetic and pharmacodynamic responses, we'll look at exon skipping and dystrophin. More exploratory end points would be muscle function, quality of life, and patient-reported outcomes. Just to remember, this is a relatively short trial, so we have 2 doses, basically 5 mg/kg every 6 weeks, or 10 mg/kg every 8 weeks. The trial basically runs from anywhere from 3 to 4 months and then we follow patients longer. Those patients that elect can then go on to the open-label extension that is ongoing right now.

This transcript has been edited for clarity.