With three FDA approvals in the past 10 months, there is a lot of momentum in the Duchenne muscular dystrophy space. Here are five companies looking to keep it going.
The March approval of ITF Therapeutics’ Duvyzat marked the third new FDA-approved treatment in 10 months for Duchenne muscular dystrophy (DMD), a genetic disorder that causes progressive muscle weakness and degeneration. In June 2023, the regulator greenlit Sarepta’s Elevidys as the first-ever gene therapy for DMD. That approval was followed by Santhera Pharmaceuticals’ novel corticosteroid Agamree in October.
And the momentum isn’t slowing down. The DMD pipeline is flush with investigational treatments making their way through mid- and late-stage clinical trials, with several companies expecting data readouts in 2024.
“Where we are this year has been built upon activity, investments and trials over the past two, three and four years,” Michael Kelly, chief scientific advisor at CureDuchenne, told BioSpace in an email. “I think this could end up being the year where we become really informed on some of the long-term efficacy and safety data from ongoing trials and approved drugs.” Kelly said he is particularly interested in the clinical readouts from Pfizer, REGENXBIO and Solid Biosciences’ gene therapy programs and what he called the next-generation of exon-skipping programs from Avidity Biosciences, Dyne Therapeutics, PepGen and Entrada Therapeutics.
“There’s a lot of unmet needs, unfortunately,” Jeff Chamberlain, president of the American Society for Gene and Cell Therapy and the McCaw Chair in Muscular Dystrophy at the University of Washington School of Medicine, recently told BioSpace, but “we’re certainly moving in the right direction.”
BioSpace takes a closer look at five investigational therapies for which results are expected this year.
Pfizer’s fordadistrogene movaparvovec
Gene therapy
Pfizer is anticipating data from a Phase III trial of fordadistrogene movaparvovec in the second half of 2024, according to CureDuchenne. A mini-dystrophin gene therapy, fordadistrogene movaparvovec is being studied in this trial for use in ambulatory DMD patients.
DMD is caused by the absence of the dystrophin protein, which helps keep muscle cells intact. Fordadistrogene movaparvovec is an investigational recombinant adeno-associated virus serotype 9 (AAV9) capsid carrying a shortened version of this gene, according to Pfizer.
“The whole purpose of gene therapy in Duchenne, particularly micro-dystrophin gene therapy, is to transform the patient’s phenotype from Duchenne to the less severe Becker muscular dystrophy,” Kelly said. “It’s not a cure because we’re not putting in full-length dystrophin, so the question is, which type of Becker muscular dystrophy should we expect?”
Pfizer’s path with fordadistrogene movaparvovec has not been without its challenges. In 2021, the company paused screening and dosing in a Phase Ib study of the gene therapy after the death of a patient in the non-ambulatory cohort of the trial. By April 2022, Pfizer was back on track, opening the first U.S. sites in the Phase III trial.
The current gene therapies in development for DMD are “partially effective,” Chamberlain said, but “far from a cure.”
Dyne Therapeutics’ DYNE-251
Exon-skipping biologic
Also during the second half of this year, Waltham, Mass.–based Dyne Therapeutics is expecting data from the higher dose cohort of the Phase I/II DELIVER trial of DYNE-251.
DYNE-251 comprises a phosphorodiamidate morpholino oligomer conjugated to a fragment antibody that binds to the transferrin receptor 1, which is highly expressed in muscle. It was designed to promote skipping of exon 51 to create a truncated, functional dystrophin protein, according to Dyne. It is being developed for patients with mutations in exon 51.
In January, Dyne reported six-month data from six male patients in the 5 mg/kg cohort of the trial. Administration of DYNE-251 once every four weeks elicited levels of dystrophin expression, exon skipping and dystrophin positive fibers that exceeded levels seen in a clinical trial for eteplirsen, the current weekly standard of care for exon 51 DMD patients. The candidate also demonstrated a favorable safety profile, which a Dyne representative said positions the company to focus on optimizing dose and dose regimen in the DELIVER trial “with the goal of initiating registrational cohorts by the end of 2024.”
Edgewise Therapeutics’ EDG-5506
Small molecule
Edgewise Therapeutics plans to report three-month controlled dose-ranging data from the Phase II LYNX trial of its DMD candidate EDG-5506 this quarter.
EDG-5506 is designed to reduce injurious mechanical stress caused by the absence of functional dystrophin in order to enable a normal, healthy range of muscle contraction. The candidate was granted the FDA’s Fast Track designation in DMD in February.
The Boulder, Colorado–based company is also running the Phase II FOX trial in children and adolescents with DMD who have been treated with gene therapy. Regardless of the modality, Kelly said, a “combination of therapies targeting dystrophin restoration . . . with other approaches . . . is going to be the preferred route of treatment for Duchenne’s patients.”
Capricor Therapeutics’ CAP-1002
Cell therapy
On that note, Kelly said he is carefully watching Capricor Therapeutics’ CAP-1002. The cell therapy is currently in a pivotal Phase III study, from which the company expects topline data by the end of this year. In addition to evaluating CAP 1002 as a standalone therapy, Capricor is investigating the drug in patients who have previously been treated with gene therapy, Kelly said.
CAP-1002 is composed of cardiosphere-derived cells (CDCs) derived from healthy human hearts. The CDCs secrete exosomes containing bioactive cargo, including microRNAs, that alter gene expression in macrophages and other target cells, dialing down generalized inflammation and stimulating tissue regeneration, Capricor explains on its website.
The company additionally notes that CAP-1002 may be able to “work synergistically with emerging disease-modifying therapies.”
Avidity Biosciences’ AOC 1044
Exon skipping biologic
San Diego–based Avidity Biosciences is developing AOC 1044 on its proprietary antibody oligonucleotide conjugates (AOC) platform. The therapy is intended for patients with exon 44 mutations, a version of DMD for which there are currently no disease-modifying treatments, according to Avidity.
AOC 1044 is designed to deliver phosphorodiamidate morpholino oligomers to the skeletal muscle and heart tissue to specifically skip exon 44 of dystrophin mRNA in order to enable dystrophin production. In December 2023, Avidity reported positive data from the Phase I/II EXPLORE44 trial of AOC 1044 in healthy volunteers showing “statistically significant exon 44 skipping compared to placebo” of up to 1.5% after a single dose. The therapy was well-tolerated.
The company plans to provide a first look at data from DMD patients during the second half of 2024.
Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.
