Diagnosing and Managing Duchenne Muscular Dystrophy: Tips for Practicing Clinicians
New Pharmacotherapeutic Options: Exon-Skipping Agents
Today’s treatments have expanded beyond corticosteroids, with newer therapeutic options that include targeted exon-skipping therapies and, more recently, gene therapies. “These new treatment paradigms have changed the face of DMD treatment,” Dr. Brandsema said.
“Exon-skipping drugs in their current form have only a modest effect, but at least they’re a step in the right direction and a breakthrough, in terms of slowing disease progression,” Dr. Brandsema said.
Current exon-skipping agents use antisense phosphorodiamidate morpholino oligomers (PMOs) to restore a DMD open reading frame. Next-generation drugs called cell-penetrating peptide-conjugated PMOs (PPMOs) are being actively researched, Dr. Brandsema said. These agents have shown enhanced cellular uptake and more efficient dystrophin restoration, compared with unconjugated PMOs.15
There are currently four FDA-approved exon-skipping agents for DMD, all of which are administered via a weekly intravenous infusion: Casimersen (Amondys-45, SRP-4045), approved by the FDA in 2021; Eteplirsen (Exondys 51), approved in 2016; Golodirsen (Vyondys 53,SRP-4053), approved in 2019; and Vitolarsen (Viltepso), approved in 2020. They can be associated with multiple side effects, depending on the drug, including upper respiratory infection, fever, cough, rash, and gastrointestinal issues.16 These agents have the potential to help 30% of DMD patients, restoring low levels of dystrophin.16
Gene Transfer Therapies
Gene transfer therapies, a new class of agents, utilize a nonpathogenic viral vector (adeno-associated virus) to transfer specific genes to patients with DMD. Gene therapy involves overexpressing the micro-dystrophin gene to restore functional dystrophin expression.16
Multiple clinical trials of gene therapy are currently in progress. In 2023, delandistrogene moxeparvovec-rokl (Elevidys, Serepta) was granted accelerated FDA approval for ambulatory individuals with DMD between the ages of 4 and 5 years of age and a confirmed mutation in the DMD gene. It received expanded approval in June 2024 to include ambulatory and nonambulatory individuals aged 4 years and older with DMD and a confirmed mutation in the DMD gene (with the exception of exon 8 or 9 mutations).
The approval was based on preliminary data from two double-blind, placebo-controlled studies and two open-label studies, which enrolled a total of 218 male patients (including those who received placebo) with a confirmed disease-causing mutation in the DMD gene.
Delandistrogene moxeparvovec-rokl is delivered as a one-time infusion and has been associated with side effects and “a lot of potential issues,” Dr. Brandsema said. “We’ve seen cardiac effects, immune system effects, increased muscle inflammation and hepatic complications, and some people who became quite unwell were hospitalized for a long time.”
Fortunately, he added, “these seem to be rare but they do happen. Once the medication has been delivered, it’s permanently in the body, so you’re managing the side effects potentially on a long-term basis.”
It is critical to discuss the risks and benefits of this treatment with the family and caregivers and with the patient as well, if he old enough and able to participate in the decision-making progress. “We don’t want to give unrealistic expectations and we want people to be aware of the potential downside of this treatment,” he said. “This is a very complex discussion because the trajectory of the disease is so devastating and this treatment does hold out hope that other therapies don’t necessarily have.”
