Becker Muscular Dystrophy (BMD)

Research

MDA-supported investigators are actively pursuing several approaches to halt or reverse the muscle damage caused by Becker muscular dystrophy (BMD).

Flaws in the dystrophin gene cause Duchenne muscular dystrophy (DMD), BMD, and an intermediate form of the DMD, so many of the strategies being tried in DMD also apply to BMD.

Cardiac support

Researchers are pursuing strategies to sustain or improve heart function in BMD and DMD. They're testing existing medications for their possible benefits in the BMD/DMD-affected heart and conducting basic research to understand and find new approaches to treating the heart in these diseases.

Understanding and treating dystrophin-deficient cardiomyopathy (cardiac muscle abnormalities) is a priority for MDA. The MDA Clinical Research Network led by Dr. Forum Kamdar at The University of Minnesota, combines data from multiple centers that specialize in muscular dystrophy and heart failure. Treatments like heart transplants and heart pumps (ventricular assist devices) can greatly improve life quality and survival for people with advanced heart failure. However, there are concerns about how these treatments might impact other organs and the ability to do physical rehab, which has limited their use in muscular dystrophy patients. The goal is to better understand how these treatments work for muscular dystrophy patients. By gathering data from many centers, the study aims to fill gaps in heart care for muscular dystrophy patients and potentially improve their treatment options.

Because several cardiomyopathy drugs have been developed over the years to treat heart failure in older patients, doctors already have some tools at their disposal for treating the BMD/DMD heart. These therapies center on ways of reducing the burden on the pumping heart. To that end, doctors may prescribe angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) that make blood vessels open wide and thereby reduce the resistance to the heart’s pumping action. Doctors may also prescribe diuretics to remove extra water from the blood so that there is less volume for the heart to pump. Finally, doctors may prescribe beta blockers to slow the heart rate, giving the BMD/DMD heart sufficient time to empty and refill with each beat so that it can pump blood more efficiently.

Researchers are continuing to study existing drugs to determine the best regimen to preserve heart function in BMD/DMD. Researchers are continuing to study existing drugs to determine the best regimen to preserve heart function in BMD/DMD. Recently, several clinical studies aimed at determining the best combination and doses of medications to prevent decline of heart function. The clinical study led by Dr. Subha Raman at Ohio State University examined the relative efficacy of aldosterone receptor antagonists, including spironolactone and eplerenone, which are diuretics.¹ The results showed that both drugs were equally effective at preserving heart function, and neither caused major side effects. This suggests that starting either of these medications early can be a safe and effective way to protect the heart in BMD/DMD.

Recent guidelines for diagnosing and managing BMD offer patient-centered strategies for cardiac monitoring and treatments throughout the progression of the disease.^2,3

One promising and completely new therapy in development specifically for DMD is called CAP-1002 and is being developed by Capricor Therapeutics. CAP-1002 is a therapy based on cardiac stem cells derived from donor heart tissue. Researchers aim to transplant these therapeutic stem cells into people with DMD with the hope that the cells will promote muscle tissue regeneration. Capricor’s HOPE-2-OLE study showed improvements in several heart function measures, including how well the heart pumps blood (left ventricular ejection fraction, LVEF) and the size of the heart's chambers when it contracts and relaxes. These measures are important for predicting long-term health outcomes. Patients who had better heart function at the start of the study saw even greater improvements. The results highlight the importance of early treatment to help maintain heart function and slow down the progression of heart disease, a major cause of death in people with BMD and DMD. The study also showed that patients had significant improvements in upper body function, and the long-term use of CAP-1002 continues to be safe. The HOPE-3 study, a phase 3 trial, is currently ongoing, with the primary goal of evaluating how the treatment affects arm and hand function after one year. Secondary goals include assessing heart function and other physical abilities.

Myostatin inhibition

A strategy that has received considerable MDA support involves inhibiting the actions of a naturally occurring protein called myostatin, which limits muscle growth. Researchers hope that blocking myostatin may allow muscles to grow larger and stronger.

Myostatin inhibitors have received much attention from the neuromuscular disease research community since the discovery several years ago that people and animals with a genetic deficiency of myostatin appear to have large muscles and good strength without apparent ill effects.⁴

A unique strategy to block the action of myostatin uses gene therapy to introduce follistatin, a naturally occurring inhibitor of myostatin. Mice with a DMD-like disease that received genes for the follistatin protein showed an overall increase in body mass and weight of individual muscles. Preclinical studies of intramuscular delivery of the follistatin gene demonstrated safety and efficacy in enhancing muscle mass. A gene therapy delivering follistatin has been tested on BMD patients.^5,6 The study concluded that using follistatin early in the disease and focusing on specific muscle groups could boost muscle mass and strength. Because it promotes muscle growth, follistatin is a promising option to be used alongside other therapies and needs further investigation for BMD/DMD patients.

Utrophin boosting

Laboratory evidence shows that raising levels of the muscle protein utrophin can, to some extent, compensate for a deficiency of dystrophin.

Utrophin closely resembles dystrophin but, unlike dystrophin, is normally produced and entirely functional in BMD. Therefore, raising utrophin levels is unlikely to provoke an unwanted immune response, while raising levels of dystrophin may do so. Increasing utrophin production has the potential to help compensate for dystrophin deficiency regardless of the specific dystrophin gene mutation. Some researchers claim that the combination of utrophin and dystrophin therapies might be even more beneficial for muscle function in patients. However, currently it has been tested only in animal models.⁷

Although utrophin is close to dystrophin in both structure and function, there’s at least one key difference between the two proteins. During fetal development and perhaps a little beyond, utrophin is present all around the muscle fiber, interacting with clusters of proteins stuck in its surrounding membrane. As an animal or person matures, utrophin is replaced almost entirely by dystrophin, with one exception. At the neuromuscular junction, utrophin remains throughout life.

Recently, Ractigen Therapeutics has received Orphan Drug Designation from the FDA for RAG-18, a leading small activating RNA (saRNA) product aimed at boosting utrophin production for the treatment of DMD and BMD. In early tests, RAG-18, delivered through a subcutaneous injection using Ractigen’s special delivery technology, has shown promise in reducing muscle damage. Increasing utrophin levels could potentially act as a substitute for the missing or decreased amount of dystrophin in muscle cells of DMD/BMD patients, offering a treatment option for both DMD and BMD patients, regardless of where their mutation occurs.

Reducing Fibrosis

DMD and BMD share similar underlying issues, including chronic muscle damage that leads to inflammation, muscle being replaced by fat and scar tissue (fibrosis), and impaired muscle repair. Givinostat, an HDAC inhibitor, has been shown to reduce fibrosis and slow down disease progression on a functional level in DMD.⁸ FDA approved givinostat (DUVYZATTM) for individuals diagnosed with DMD in March 2024. Building on the positive results from DMD trials, a separate study evaluated the efficacy and safety of givinostat in adults with BMD.⁹ After one year of treatment, givinostat had no effect on total muscle fibrosis in BMD patients. Although the trial did not meet its primary endpoint, it remains a crucial interventional study in BMD, providing insights into testing outcome measures and examining whether DMD results can be applied to BMD.

Active clinical trials for BMD

A Study to Assess Vamorolone in Becker Muscular Dystrophy (BMD)

ClinicalTrials.gov ID NCT05166109

This study by ReveraGen BioPharma is now looking into a new drug called vamorolone (a dissociative steroid) for BMD. Vamorolone works differently from traditional steroids and might be safer. Early studies show it could help with muscle strength and might be even better for BMD than DMD. This is because vamorolone might increase levels of dystrophin (a key protein missing in these diseases) in muscles and help with inflammation and heart health. The data from this study will help design a larger trial that could lead to vamorolone being approved for BMD.

Defining Endpoints in Becker Muscular Dystrophy (GRASP-01-002) (natural history)

ClinicalTrials.gov ID NCT05257473

This trial aims to assess the progression of BMD in individuals through functional measures and imaging endpoints. This global, multi-center study is spearheaded by the GRASP (General Resolution and Assessments Solving Phenotypes) consortium and Virginia Commonwealth University (VCU), in collaboration with ImagingDMD at the University of Florida (UF).

Approximately 150 individuals with BMD are expected to be recruited for this trial, which will gather data over a two-year period. The goal is to gain a more comprehensive understanding of the disease and support the development of potential future therapies. This natural history study will not test any investigational drugs but will instead monitor participants over time to track the progression of their disease.

Phase 2 Study of EDG-5506 in Becker Muscular Dystrophy (GRAND CANYON)

ClinicalTrials.gov ID NCT05291091

EDG-5506 is a therapy designed to reduce the activity of myosin, a protein crucial for muscle contractions. By making these contractions less forceful, the treatment aims to reduce muscle damage and help preserve muscle function over time.
In a phase 1 clinical trial (ARCH), most men with BMD who were treated with EDG-5506 either maintained or improved their motor function after a year, which is unusual since the disease typically leads to worsening motor function. The treatment also reduced markers of muscle damage.

Edgewise is now conducting a phase 2 trial (CANYON and GRAND CANYON) to compare EDG-5506 with a placebo in BMD patients aged 12 to 50. This trial will evaluate the safety and pharmacological properties of EDG-5506 along with biomarkers of muscle damage and functional performance. Positive results from this study could potentially support regulatory approval applications.

To get an overview on BMD and learn more about treatments on the horizon for BMD, see this MDA resource for clinicians, with accompanying webinar.

References

1. Raman SV, Hor KN, Mazur W, Cardona A, He X, Halnon N, Markham L, Soslow JH, Puchalski MD, Auerbach SR, Truong U, Smart S, McCarthy B, Saeed IM, Statland JM, Kissel JT, Cripe LH. Stabilization of Early Duchenne Cardiomyopathy With Aldosterone Inhibition: Results of the Multicenter AIDMD Trial. J Am Heart Assoc. 2019 Oct;8(19):e013501. doi: 10.1161/JAHA.119.013501. Epub 2019 Sep 24. PMID: 31549577; PMCID: PMC6806050.
2. Magot A, Wahbi K, Leturcq F, Jaffre S, Péréon Y, Sole G; French BMD working group. Diagnosis and management of Becker muscular dystrophy: the French guidelines. J Neurol. 2023 Oct;270(10):4763-4781. doi: 10.1007/s00415-023-11837-5. Epub 2023 Jul 9. PMID: 37422773.
3. Bourke JP, Bueser T, Quinlivan R. Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X-linked dilated cardiomyopathy. Cochrane Database Syst Rev. 2018 Oct 16;10(10):CD009068. doi: 10.1002/14651858.CD009068.pub3. PMID: 30326162; PMCID: PMC6517009.
4. Wagner, K. R. & Cohen, J. S. Myostatin-Related Muscle Hypertrophy. GeneReviews (2013).
5. Mendell JR, Sahenk Z, Malik V, Gomez AM, Flanigan KM, Lowes LP, Alfano LN, Berry K, Meadows E, Lewis S, Braun L, Shontz K, Rouhana M, Clark KR, Rosales XQ, Al-Zaidy S, Govoni A, Rodino-Klapac LR, Hogan MJ, Kaspar BK. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol Ther. 2015 Jan;23(1):192-201. doi: 10.1038/mt.2014.200. Epub 2014 Oct 17. PMID: 25322757; PMCID: PMC4426808.
6. Al-Zaidy SA, Sahenk Z, Rodino-Klapac LR, Kaspar B, Mendell JR. Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy. J Neuromuscul Dis. 2015 Sep 2;2(3):185-192. doi: 10.3233/JND-150083. PMID: 27858738; PMCID: PMC5240576.
7. Guiraud, S. et al. The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy. Hum. Mol. Genet. (2019). doi:10.1093/hmg/ddz049
8. Mercuri E, Vilchez JJ, Boespflug-Tanguy O, Zaidman CM, Mah JK, Goemans N, Müller-Felber W, Niks EH, Schara-Schmidt U, Bertini E, Comi GP, Mathews KD, Servais L, Vandenborne K, Johannsen J, Messina S, Spinty S, McAdam L, Selby K, Byrne B, Laverty CG, Carroll K, Zardi G, Cazzaniga S, Coceani N, Bettica P, McDonald CM; EPIDYS Study Group. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X. Erratum in: Lancet Neurol. 2024 Jun;23(6):e10. doi: 10.1016/S1474-4422(24)00172-8. Erratum in: Lancet Neurol. 2024 Aug;23(8):e12. doi: 10.1016/S1474-4422(24)00257-6. PMID: 38508835.
9. Comi GP, Niks EH, Vandenborne K, Cinnante CM, Kan HE, Willcocks RJ, Velardo D, Magri F, Ripolone M, van Benthem JJ, van de Velde NM, Nava S, Ambrosoli L, Cazzaniga S, Bettica PU. Givinostat for Becker muscular dystrophy: A randomized, placebo-controlled, double-blind study. Front Neurol. 2023 Jan 30;14:1095121. doi: 10.3389/fneur.2023.1095121. PMID: 36793492; PMCID: PMC9923355.

Last update: September 2024
Reviewed by Sumit Verma, MD; Emory University School of Medicine