SAN DIEGO, California—Lately, much of the buzz around Duchenne muscular dystrophy (DMD) has been focused on gene therapy—specifically Sarepta’s delandistrogene moxeparvovec (Elevidys), which was recently approved by the US Food and Drug Administration (FDA).
But gene therapy isn’t the only game in town, and a rush of companies is eagerly pursuing various ways to treat the degenerative neuromuscular disease.
One such company is Edgewise Therapeutics, a biotech firm based in Boulder, Colorado, that employs around 50 people. Its small-molecule investigational therapy, EDG-5506, is based on the idea that “modulation of fast skeletal muscle contraction protects against muscle injury, degeneration and fibrosis in models of DMD,” the company’s chief scientific officer, Alan Russell, PhD, said in a recent press release.
Abby Bronson, vice president for patient advocacy at Edgewise, spoke to Rare Disease Advisor during this year’s CureDuchenne Futures conference here.
“We were founded in 2017 with the sole purpose of developing novel therapies for Becker and Duchenne muscular dystrophy,” she said. “Duchenne is a disease of muscles falling apart. We’re not aiming to restore dystrophin.”
Edgewise was established by Dr. Russell and cofounder Kevin Koch, PhD, she said, based on Dr. Russell’s observation that fast muscle fibers break down more quickly, “and that if we could protect them, we could preserve muscle function.”
“It happens at the point of contraction where the damage takes place. It doesn’t matter what mutation you have,” Bronson said.
Bronson, a veteran pharmaceutical industry executive, is well-versed in Duchenne. A former manager of special projects at Children’s National Medical Center in Washington, DC, she also worked for the nonprofit group Parent Project Muscular Dystrophy and the National Center for Advancing Translational Studies (NCATS)—a division of the National Institutes of Health—before coming to Edgewise.
“It’s such an elegant, and simple and novel approach to the problem of Duchenne,” she said. “Everyone defines the disease as a lack of dystrophin. But the lack of dystrophin causes the muscles to break down. You still have all the elements in your muscles, but over time, your body can’t keep up with that generation and regeneration.”
Edgewise is now recruiting patients for a phase 2 trial of EDG-5506. Seven sites are currently open, and the company is looking to open 7 more, according to Bronson. She explained that 1 group will receive steroids—the current DMD standard of care—while the other group will receive 3 doses of EDG-5506. After 3 months, all participants will receive EDG-5506 for 9 months.
“We’re considering running a cohort of boys previously treated with gene therapy and put EDG-5506 on top of that. We need to get that safety data,” she said. “Companies are going to have to start doing things like that. Patients will have had to be on gene therapy for a certain amount of time. There’s a benefit, yes, but it’s not as much of a benefit as promised.”
Using snRNA Technology to Induce Exon Skipping
Meanwhile, San Diego, California-based biotech firm Locanabio hopes to develop a small nuclear RNA (snRNA) to treat Duchenne patients amenable to exon 51 skipping.
Ranjan Batra, PhD, Locanabio’s senior vice president of research and development, presented data at CureDuchenne Futures on the company’s investigational therapy, LBIO-115. In a mouse model of DMD, intramuscular injection of LBIO-115 resulted in greater than 80% exon skipping in skeletal muscle, with more than half of muscle fibers positive for dystrophin protein after only 4 weeks.
In addition, exon 51 skipping levels in heart, diaphragm, and skeletal muscle were down more than 95%, 70% and 60% respectively, resulting in greater than 50% of muscle fibers positive for dystrophin protein, only 4 weeks after intravenous administration of LBIO-115.
Researchers also observed improvements in muscle pathology and a drop in creatine kinase (CK), a key marker of muscle damage in Duchenne.
“We’re pretty excited,” Locanabio CEO Jim Burns, PhD, told Rare Disease Advisor. “We believe our technology could help 35% to 40% of all Duchenne patients. I think 80% of DMD patients have an exon skippable disease, so we’re starting with the first 35% of them.”
Dr. Burns, a biomedical engineer who started his career at Genzyme, joined Locanabio in December 2019. The company, which, like Edgewise, has around 50 employees, has so far raised $159 million in capital, “the majority of which is going into DMD now,” he said.
“We didn’t start out with DMD. We were working on [amyotrophic lateral sclerosis (ALS)] as well as myotonic dystrophy type 1,” he said, adding that at the moment, “we’re the only one working on small nuclear RNAs” for Duchenne.
“What’s cool about that is that somewhat similar to [clustered regularly interspaced short palindromic repeats (CRISPR)], there’s a sequence you can design to target a specific nucleotide. It’s small, we can put a lot of these into a single [adeno-associated virus (AAV)] vector. It can also target multiple sites within an exon so it can induce skipping,” Dr. Burns said. “That’s different from an [antisense oligonucleotide (ASO)], which can only target a single site. And if you can target multiple sites, you could amplify the potency and the effect.”
He said Locanabio plans to file an Investigational New Drug application for LBIO-115 by mid-2024, adding that “one of the advantages we have is through manufacturing. It’s difficult to make these constructs, and we think we’ve cracked that nut.”
CureDuchenne: Research Has Come a Long Way
Debra Miller, founder and CEO of CureDuchenne, said her nonprofit has come a long way since she and her husband Paul formed it 20 years ago, following the DMD diagnosis of their son, Hawken, who’s now 26.
“When we started, I was working out of the corner of Hawken’s playroom, and today we have almost 30 staff members,” she said.
“Back in 2003, we were talking to lots of scientists, and they all had wonderful ideas. Our vision was to take those ideas and get them out of academic labs and into the hands of people who actually develop drugs and market them.”
A cure to the disease still remains to be discovered—and getting there will take more than science and luck, Miller said.
“When Hawken was diagnosed, we were helpless, so we turned to our faith and started praying,” she said. “I can’t tell you how much that has helped us.”