Simply Stated: Emerging Therapies to Treat DMD

The rare genetic disorder Duchenne muscular dystrophy (DMD) occurs in approximately 1 in every 3,500 to 5,000 male births. Boys affected by DMD experience progressive degeneration and weakness of the skeletal muscles that control movement. In later stages of disease, they may also experience complications of the heart and respiratory muscles, which can be life-threatening.

There are currently no therapies that can reverse the muscle degeneration caused by DMD, though eight US Food and Drug Administration (FDA) approved therapies have enabled improvements in muscle function and quality of life. To learn more about approved therapies for DMD see Simply Stated: Therapeutic Strategies to Treat DMD.

New therapeutics on the horizon also provide hope for people living with DMD. Research efforts to restore or replace dystrophin have taken center stage; these therapies work by increasing dystrophin levels in the body. Alternative therapeutic strategies that do not rely on modulating dystrophin levels are also under active investigation to treat DMD.

The causes and effects of DMD

DMD is caused by mutations of the dystrophin (DMD) gene, that lead to loss of dystrophin protein. Normally, dystrophin protein prevents muscle cell membranes from becoming damaged when muscles contract and relax and also holds other important proteins in place at the muscle cell membrane, helping to preserve the structure of muscle cells. The lack of dystrophin in people with DMD starts a cascade of damaging and degenerative events, including:

• Breakdown of muscle cell membranes, which allows calcium ions to enter the cells and signal for cell death (necrosis)
• Increase in damaging inflammation in the muscles
• Loss of the muscles’ ability to repair and regenerate over time
• Replacement of muscle tissue by connective and fat tissue (known as fibrosis or scarring)
• A type of heart disease (DMD-associated cardiomyopathy) that prevents the heart from pumping blood efficiently and can result in irregular heartbeats (arrhythmias) and heart failure

Understanding of the processes involved in DMD is prompting the development of new strategies to treat the disease. Researchers are testing new therapeutics to boost dystrophin levels, regulate the balance of calcium, target the inflammation that occurs in damaged muscles, boost regenerative capability of muscle cells, prevent fibrosis, and improve the function of heart muscle.

Evolving research and treatment landscape

Despite the availability of FDA-approved treatments for DMD, there are still unmet needs. More efficacious therapies would further improve the life of people with DMD and curative therapies have not yet been achieved. Here, we highlight some promising therapies in development that utilize dystrophin-modifying or alternative strategies to improve DMD symptoms. Most of the drug candidates listed below are being studied in clinical trials in the US.

Investigational therapies designed to increase dystrophin levels

Next generation exon skipping therapies

Exon skipping therapies are made of bits of genetic material, known as antisense oligonucleotides (AONs), that promote skipping over a section of genetic code (known as an “exon”) to avoid the DMD gene mutation, allowing the body to produce a truncated, but functional dystrophin protein. Four such therapies are already approved by the FDA. Next generation exon skipping therapies are being designed with modified genetic sequences, chemistry, and backbone structures to improve delivery into skeletal and cardiac muscles. Another approach involves the use of peptide- or antibody-based-delivery tags that enable the therapies (known as antibody oligonucleotide conjugates or AOCs) to get into specific cell types in the body. The goal is to better target the drugs so that they are more effective in boosting dystrophin levels in the muscle cells that need it.

• AOC 1044 (Avidity Biosciences) – An AOC indicated to treat DMD amenable to skipping exon 44. This therapy is being studied in a phase 2 trial (EXPLORE44OLE) that is currently enrolling patients with DMD.
• BMN 351 (Biomarin) – An AON indicated for treatment of DMD amenable to skipping exon 51. This therapy is being studied in a phase 1/2 trial that is currently enrolling patients with DMD.
• Dyne-251 (Dyne Therapeutics)- An AOC indicated to treat DMD amenable to skipping exon 51. This therapy is being studied in a phase 1/2 trial that is currently enrolling patients with DMD.
• ENTR-601-44 (Entrada Therapeutics) – An AON indicated for treatment of DMD amenable to exon 44 skipping. This therapy that uses a special Endosomal Escape Vehicle (EEV) technology to increase uptake by cells. Based on proof-of-concept findings in healthy volunteers in a phase 1 trial, the company is planning to initiate a phase 2 clinical trial.
• NS-050/​NCNP-03 (NS Pharma) – An AON indicated to treat DMD amenable to skipping exon 50. This therapy is being studied in a phase 1/2 trial that is not yet recruiting patients.
• NS-089/NCNP-02 (NS Pharma) – An AON indicated to treat DMD amenable to skipping exon 44. This therapy is being studied in a phase 2 trial that is currently enrolling patients with DMD.
• PGN-EDO51 (PepGen) – An AOC indicated to treat DMD amenable to skipping exon 51. This therapy is being studied in a phase 2 trial that is currently enrolling patients with DMD.
• SQY51 (Sqy Therapeutics) – An AON indicated to treat DMD amenable to skipping exon 51. This therapy is being studied in a phase 1/2a (AVANCE1) trial that is currently enrolling patients with DMD in France.
• WVE-N531 (Wave Life Sciences) – An AON indicated to treat DMD amenable to skipping exon 53. This therapy is being studied in a phase 1b/2a clinical trial that is active, but not recruiting patients.

Gene replacement therapy

Most gene therapies for DMD use a viral vector to introduce microdystrophin into cells. Microdystrophin is a shortened dystrophin protein that may restore dystrophin functions in people with DMD. Gene therapies are usually designed to be administered as a single-dose.

• RGX-202 (REGENXBIO) – An AAV8-based gene therapy. This therapy is being studied in a phase 1/2 clinical trial that is currently enrolling patients with DMD.
• SGT-003 (Solid Biosciences) – An AAV-based gene therapy that uses a new viral capsid design and modified microdystrophin to improve delivery to and function in muscle cells. This therapy is being studied in a phase 1/2 clinical trial that is currently enrolling patients with DMD.

Exon skipping gene therapy

Instead of introducing new microdystrophin, some gene therapies are designed to restore dystrophin production in cells using methods such as exon skipping of DMD gene mutations.

• U7.ACCA (Nationwide Children’s Hospital) – An AAV9-based gene therapy that introduces a small piece of genetic material (snRNA) that promotes exon skipping over the mutations in exon 2 of the DMD gene, resulting in a shortened, but functional dystrophin protein. This therapy is being studied in a phase 1/2 clinical trial that is active, but not recruiting patients.

Surrogate gene therapy

Another gene therapy strategy under investigation introduces genes other than microdystrophin into cells to compensate for the loss of dystrophin and block changes that occur in DMD.

• MCK.GALGT2 (Sarepta/Nationwide Children’s Hospital) – A AAV-based gene therapy that introduces the GALGT2gene to promote production of proteins essential for muscle function. Preclinical studies and a first-in-human, phase 1/2a trial showed safety and potential efficacy of the therapy. The current status of therapeutic development is not known.

Investigational therapies designed to reduce inflammation

Muscle damage triggers inflammation and recruitment of immune cells to the sites of damage. In DMD, the muscles are chronically inflamed; some new therapies aim to reduce this level of inflammation.

• Satralizumab (Hoffmann-La Roche) – A monoclonal antibody that blocks a cell receptor in the immune system (IL-6 receptor) involved in promoting inflammation. This therapy is being studied in a phase 2 trial (SHIELD DMD) in children with DMD (ages 8-15 years old) who are also receiving corticosteroid therapy to reduce inflammation. The study is currently enrolling patients.
• ATL1102 (Percheron Therapeutics) – An ASO designed to block the function of a receptor (CD49d) on T cells in the immune system involved in the inflammatory response. This therapy is being studied in a phase 2 study in Europe and Australia that is active, but not recruiting patients.
• Canakinumab (Children’s Research Institute) – A monoclonal antibody that blocks an inflammatory protein of the immune system (IL1b). This therapy is used to treat autoinflammatory conditions in children, and is being studied as a possible treatment for DMD in a phase 1/2 trial that is active, but not recruiting patients.

Investigational therapies designed to promote muscle growth/protection

A number of new therapies are designed to encourage muscle growth and discourage muscle degeneration in people with DMD.

• CAP-1002 (Capricor Therapeutics) – A cell-based therapy derived from donated heart muscle that is believed to work by releasing signaling molecules that can stimulate muscle regeneration, reduce scarring, and modulate the immune response. This therapy is being studied in a phase 3 clinical trial (HOPE-3) that is currently enrolling patients with DMD.
• EDG-5506 (Edgewise Therapeutics) – An oral small molecule that may help to stabilize muscles. EDG-5506 is being studied in phase 2 clinical trials in children with DMD and children/adolescents with DMD who have previously been treated with gene therapy. Both studies are currently recruiting patients.
• MyoPAXon (Myogenica) – A cell-based therapy derived from induced pluripotent stem cells (iPSC). This therapy is designed to be injected into muscles affected by DMD so the healthy stem cells can contribute to generation of new muscle fibers. In July 2024, the FDA approved an Investigational New Drug (IND) application for MyoPAXon, allowing the company to start a clinical trial testing the stem cell therapy in people with DMD.
• SAT-3247 (Satellos) – An oral, small molecule drug that inhibits the enzyme AAK1 and is designed to regenerate skeletal muscle in DMD. This therapy is being studied in a first-in-human, phase 1 study in healthy volunteers and adult participants with DMD. The study is currently recruiting patients in Australia.

Investigational therapies designed to improve heart function

DMD almost always lead to DMD-associated cardiomyopathy in affected people, a condition that can worsen rapidly and become fatal. A number of therapies in development, therefore, are aimed at improving and protecting heart function.

• Oral Ifetroban (Cumberland Pharmaceuticals Inc.) – A small molecule inhibitor of a receptor involved in blood clotting (thromboxane receptor). This drug has been studied in other diseases and has been shown to protect the heart from scarring and to help maintain normal heart function. It is being studied for efficacy in people with DMD in a phase 2 clinical trial that is currently enrolling patients with DMD.
• SRD-003 (originally designated SRD-001) (Sardocor Corp.) – An AAV-mediated gene therapy designed to introduce a particular gene, the SERCA2a gene, into heart muscle. This therapy may help regulate calcium balance in the heart muscle cells and help the heart squeeze/contract better, thereby improving the ability to pump blood to the rest of the body. This therapy is in a phase 1 trial that is expected to begin recruitment of patients soon. A phase 2b trial is anticipated in the second half of 2025.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about Duchenne muscular dystrophy (DMD), open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.