Analysis of Duchenne Muscular Dystrophy (DMD) clinical trials to inform trial design for a potential new treatment called DYNE-251

Duchenne muscular dystrophy (DMD) is a rare, inherited disease that causes progressive muscle weakness and loss of movement. It primarily affects boys, with symptoms often beginning around age 3. In the United States, it is estimated that DMD affects around 15,000 people. The disease is caused by changes (mutations) in a gene responsible for making dystrophin, a protein that helps keep muscle cells healthy. Without enough dystrophin, muscles gradually weaken, including the heart and breathing muscles.

We are studying a new treatment called DYNE-251 for boys with DMD who have a specific type of genetic change that may respond to a method called "exon 51 skipping." This technique helps muscle cells make a shortened but working form of dystrophin protein. DYNE-251 is designed to reach muscle cells more effectively than current treatments by attaching to a molecule called transferrin receptor 1, which is found in high amounts in muscles.

Our earlier study, called the DELIVER trial, tested DYNE-251 in boys aged 4 to 16 years and showed encouraging early results. Participants treated with DYNE-251 had increased levels of dystrophin protein in their muscles and showed some improvements in movement-related tests, such as how quickly they could walk or rise from the floor.
Now, we will use real-world data, past clinical trials, and natural history studies (which track how the disease progresses without treatment) to help us design the next large trial—called a phase 3 trial. This next step is crucial for confirming whether DYNE-251 is effective and safe.

In our project, we will study how boys with DMD perform over time on various physical and health tests, including:

⦁ North Star Ambulatory Assessment (a test of walking ability),
⦁ Timed function tests (like walking or getting up from the floor),
⦁ Stride speed,
⦁ Breathing strength,
⦁ Quality of life for children with muscle disease,
⦁ Kidney and liver function.

We will also look at factors such as age, genetic mutation type, steroid treatment (a common DMD therapy), height, weight, and baseline muscle and heart function. This information will help us decide who should be included in the phase 3 trial, how long the trial should last, and which outcomes we should measure.

By using existing data from real patients, we aim to design a trial that is both effective and efficient. Ultimately, this will help us determine whether DYNE-251 could become a future treatment option for boys with DMD.