Duchenne Muscular Dystrophy: Advances, Challenges, and the Future of Treatment

“Research is the only hope for families affected by Duchenne muscular dystrophy, and every step forward is a step closer to a cure.”

Duchenne Muscular Dystrophy (DMD) is a severe form of muscular dystrophy characterized by progressive muscle degeneration and weakness. It is a rare disorder, but it is one of the most common genetic conditions, affecting roughly 1 in every 3,500 male births worldwide. Recent advancements in research and treatment have significantly improved the outlook for patients with DMD. In 2023, the total number of prevalent Duchenne Muscular Dystrophy cases across the 7MM (the US, EU5, and Japan) was approximately 31K. The United States had the highest prevalence, with around 17K cases. Within the US, the 5-9 year age group had the highest number of cases, followed by the 10-14 year age group. Regardless of whether the numbers rise or fall, this article offers a comprehensive examination of the latest advancements in DMD therapies, encompassing gene therapies, pharmacological treatments, and emerging therapies, along with insights into current market trends and patient-focused strategies.

Advancements in Duchenne Muscular Dystrophy Treatment

Sarepta Therapeutics, a leader in precision genetic medicine for rare diseases, has recently made significant strides in the Duchenne muscular dystrophy (DMD) market with the FDA’s approval of AMONDYS 45 (casimersen). Developed using Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform, this antisense oligonucleotide is now approved for the treatment of Duchenne muscular dystrophy in patients with a confirmed mutation amenable to exon 45 skipping. The approval was granted following the demonstration of a statistically significant increase in dystrophin production in skeletal muscle, which is anticipated to offer therapeutic benefits for exon 45-amenable DMD patients. Continued approval of AMONDYS 45 may hinge on the outcomes of ongoing confirmatory trials.

The ESSENCE trial, a placebo-controlled study designed to bolster AMONDYS 45’s approval, is currently ongoing and expected to conclude in 2024. While clinical studies have not shown kidney toxicity, there is a risk of kidney toxicity, including potentially fatal glomerulonephritis, linked to some antisense oligonucleotides. Therefore, regular monitoring of kidney function is recommended for patients receiving AMONDYS 45. The most common adverse reactions, reported in at least 20% of patients, included upper respiratory tract infections, cough, fever, headache, joint pain, and pain in the mouth and throat.

On June 22, 2023, the FDA approved Sarepta’s ELEVIDYS, the first gene therapy for Duchenne muscular dystrophy treatment. Sarepta and Roche entered into a collaboration in December 2019, with Roche paying $1.15 billion upfront for exclusive rights to SRP-9001. It has been the FDA’s 13th gene therapy approval since 2017, and it is the first to address a prevalent genetic disease in ambulatory pediatric patients aged 4 through 5 years. ELEVIDYS, a one-time treatment, will cost $3.2 million. In April 2024, Sarepta forecasted flat sales for its new gene therapy, ELEVIDYS, leading to a first-quarter sales estimate of $131 million. 

In June 2024, Sarepta Therapeutics further expanded its impact on the Duchenne muscular dystrophy treatment landscape with the FDA’s approval to broaden the use of ELEVIDYS (delandistrogene moxeparvovec) for ambulatory DMD patients aged 4 and older. The company also received accelerated approval for non-ambulatory patients. This expansion led to a notable 40% surge in Sarepta’s stock. 

This series of approvals and ongoing developments highlights Sarepta’s pivotal role in advancing Duchenne muscular dystrophy therapies, contributing to the evolving landscape of drugs and treatment options.

The Future of Duchenne Muscular Dystrophy Gene Therapy

Gene therapy for Duchenne Muscular Dystrophy is set to transform the Duchenne Muscular Dystrophy treatment landscape by addressing the underlying genetic cause rather than merely managing symptoms. DMD results from mutations in the DMD gene, which encodes the dystrophin protein crucial for muscle cell integrity. The absence or dysfunction of dystrophin leads to progressive muscle degeneration, severe complications, and, ultimately, cardiomyopathy and respiratory failure. Gene therapy aims to introduce a functional version of the dystrophin gene or a microdystrophin gene—an engineered, smaller version retaining essential functions—into patients’ muscle cells. Early trials have shown promise, restoring partial dystrophin production and potentially slowing disease progression.

Gene therapy is emerging as the most promising candidate in the DMD pipeline. Sarepta Therapeutics, a market leader, has successfully launched three of the five DMD drugs currently marketed in the U.S. Sarepta and Pfizer are both in late-stage trials for their DMD gene therapy candidates. However, Pfizer faces higher stakes, as it lacks additional candidates to fall back on if its therapy fails to gain approval. Recent delays for Pfizer’s candidate, PF-06939926, due to a death in its Phase Ib trial, could give Sarepta’s SRP-9001 a competitive edge. Despite these challenges, Pfizer could still capture a significant share of the DMD market before more gene therapies become available.

Beyond Exon-Skipping: The Expanding DMD Treatment Landscape

Exon-skipping therapies are a form of genetic treatment designed to “skip” over faulty or mutated exons in the DNA sequence, allowing the production of a shorter but functional version of the dystrophin protein in patients with Duchenne muscular dystrophy . By targeting specific exons, these therapies help restore some of the dystrophin production, which is crucial for maintaining muscle strength and function, thereby slowing the progression of the disease. According to a recent analysis by DelveInsight, the Duchenne Muscular Dystrophy market in the 7MM (The United States, Germany, France, Italy, Spain, UK, and Japan) was valued at USD 2,150 million in 2023 and is projected to experience significant growth during the forecast period from 2024 to 2034. This growth is anticipated due to the launch of new exon-skipping therapies and the expected approvals of emerging treatments.

Sarepta Therapeutics currently dominates the Duchenne Muscular Dystrophy treatment landscape with a robust pipeline and four approved antisense oligonucleotide therapies: EXONDYS 51 (eteplirsen), approved in September 2016, VYONDYS 53 (golodirsen), AMONDYS 45 (casimersen), and ELEVIDYS, which received approval in June 2023. These therapies target specific mutations in exon 51, exon 53, exon 45, and exon 8 and/or exon 9, respectively, collectively addressing approximately 30% of all DMD cases. In June 2024, Sarepta further expanded its market presence by obtaining FDA approval to extend ELEVIDYS to ambulatory DMD patients aged 4 and older, along with accelerated approval for non-ambulatory patients. This approval significantly boosted Sarepta’s market position, leading to a 40% increase in the company’s stock. For those interested in understanding more about the available treatment options for DMD, these developments in exon-skipping therapy highlight the ongoing advancements in managing this challenging condition.

The Next Generation of Neuromuscular Disorder Therapies

Neuromuscular disorders (NMD) encompass a wide range of conditions affecting the peripheral nervous system, which links the brain and spinal cord to the body. These include muscular dystrophies, myopathies, motor neuron diseases, ion channel diseases, mitochondrial diseases, neuromuscular diseases, and peripheral nerve diseases. Prominent examples include Duchenne muscular dystrophy, spinal muscular atrophy (SMA), and multiple sclerosis. The prevalence of these disorders is increasingly recognized, highlighting the complex interplay between the nervous system and muscles, and the need for comprehensive management strategies.

According to DelveInsight, the diagnosed prevalence of multiple sclerosis in the 7MM was 1.2 million in 2023, with 723K cases in the U.S. The prevalence of DMD in the 7MM was 31,000 in 2023, with the highest proportion of cases in the U.S. observed in the 5-9 year age group. Current research focuses on genetic therapies, novel medications, and nucleic acids such as DNA and RNA, aiming to discover a cure. Meanwhile, management involves symptom control, disease progression slowing, and quality of life improvements through medications, physical therapy, occupational therapy, and surgery.

Approved Therapies Available for Neuromuscular Disorders Treatment

ZOLGENSMA (Onasemnogene abeparvovec-xioi) is the only FDA-approved gene therapy for SMA. SPINRAZA (nusinersen) is an RNA-based antisense oligonucleotide for SMA, developed by Ionis Pharmaceuticals and approved by the FDA in December 2016. EVRYSDI (Risdiplam), the first oral medication for the treatment of SMA, was approved by the FDA in August 2020, showing significant long-term efficacy with 91% of patients alive and 59% able to sit independently for at least 30 seconds after five years of treatment. AMONDYS 45 is an antisense oligonucleotide for DMD, approved by the FDA in February 2021, targeting mutations amenable to exon 45 skipping. ZOLGENSMA was approved by the FDA on May 24, 2019, for the treatment of spinal muscular atrophy (SMA), while SPINRAZA received FDA approval on December 23, 2016. 

The Path to a Cure for Duchenne Muscular Dystrophy

For Duchenne muscular dystrophy, treatment has primarily focused on symptom management and improving the quality of life for patients. Duchenne Muscular Dystrophy therapies currently available in the market include corticosteroids, steroids, assistive devices, physical therapies, and more. Corticosteroids have been the standard DMD Treatment for strengthening muscles and enhancing lung function. Assistive devices aid patients with breathing difficulties, while orthopedic devices facilitate movement. Steroids, such as prednisone, deflazacort, and oxandrolone, have also proven effective, extending the ability to walk by 2–5 years. However, steroid use may lead to side effects, including weight gain, high blood pressure, behavioral changes, and delayed growth.

Some of the notable DMD drugs in the market include DEFLAZACORT, marketed by PTC Therapeutics, and Marathon Pharmaceuticals, which is FDA-approved for treating DMD in patients aged 5 years and older. In June 2024, Cranbury Pharmaceuticals received FDA approval for the generic version of EMFLAZA (deflazacort) for DMD. Eteplirsen, produced by Sarepta Therapeutics, is approved for patients with a confirmed mutation of the DMD gene amenable to exon 51 skipping. A March 2024 study titled “Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy” reported improved survival rates for eteplirsen-treated patients, with a median survival age of 32.8 years, compared to 27.4 years in natural history controls. Additionally, Ataluren is approved for use in ambulatory patients aged two years and older with nmDMD in the European Union, Iceland, Liechtenstein, Norway, Israel, and South Korea. The current US market features approved products like EMFLAZA (deflazacort), VYONDYS 53 (golodirsen), EXONDYS 51 (eteplirsen), AMONDYS 45 (casimersen), VILTEPSO (viltolarsen), and ELEVIDYS (delandistrogene moxeparvovec) for treating patients with DMD.

To address various unmet needs in the DMD therapeutical landscape, several randomized trials are being conducted by pharma and biotech companies. These trials are researching new drugs with novel mechanisms of action, such as those with a high-efficacy/toxicity ratio to improve outcomes in DMD. Companies like FibroGen, Santhera Pharmaceutical, Italfarmaco, ReveraGen BioPharma, Cumberland Pharmaceuticals, Sarepta Therapeutics, Antisense Therapeutics, and Capricor Therapeutics among others are working to accelerate advancements in the Duchenne Muscular Dystrophy landscape.

Although there is no cure for muscular dystrophy, treatments for conditions like DMD can extend mobility and improve muscle strength. Key strategies include gene replacement and genetic therapies to restore dystrophin production, stabilize membranes, upregulate compensatory proteins, and reduce inflammation. These advancements represent a significant path to cure, targeting the underlying genetic causes to enhance patient outcomes.

Conclusion

The Duchenne Muscular Dystrophy (DMD) treatment landscape is on the cusp of a transformative era, driven by groundbreaking advancements in gene therapy and precision medicine. With therapies like ELEVIDYS and AMONDYS 45 ushering in a new wave of targeted treatments, there is a tangible shift towards addressing the root genetic causes of DMD. These developments not only enhance the potential for improved patient outcomes but also signal a significant step towards a definitive cure. The relentless pursuit of innovation and the promising results from ongoing research highlight a future where DMD may be managed far more effectively, bringing a new level of hope to patients and their families. As the field advances, the integration of cutting-edge therapies promises to revolutionize the standard of care and bring us closer to overcoming this challenging condition.