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MED-ALL-DMD-2200218 | November 2022
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Rare Disease Drug Development: Learnings From DMD

As you scroll through this timeline, you will learn about some of the key milestones in the history and evolution of our understanding in Duchenne muscular dystrophy (DMD). We begin with the initial description of DMD in 1861 and follow the evolution of the care and management of people living with DMD through to today. Let's take a look.

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1861
Guillaume-Benjamin-Amand Duchenne

DMD description

The French neurologist Guillaume-Benjamin-Amand Duchenne accurately describes in great detail a case of DMD in a young boy with a progressive muscle disease and significant physical-motor impairment linked to muscle hypertrophy in his book.

References

Parent A. Duchenne De Boulogne: a pioneer in neurology and medical photography. Can J Neurol Sci. 2005;32(3):369-377.

DMD description

The disorder that would eventually be called Duchenne muscular dystrophy was actually first described nearly 30 years earlier by two Italian physicians (Giovanni Semmola in 1834 and Gaetano Conte in 1836). Nonetheless, Duchenne describes and details the case of a boy who had this condition in the 1861 edition of his book Paraplegie hypertrophique de l'enfance de cause cerebrale, and he will present photos of his patient in his Album de photographies pathologiques a year later.

References

Bissonnette B, Luginbuehl I, Engelhardt T. Duchenne muscular dystrophy. In: Syndromes: Rapid Recognition and Perioperative Implications. 2nd ed. McGraw-Hill Education; 2019. https://accessanesthesiology.mhmedical.com/content.aspx?bookid=2674&sectionid=220528088. Accessed April 20, 2020.

DMD description
1974

Name: Jonny

Signs and symptoms at diagnosis

Waddling gait, difficulty climbing stairs, elevated creatine kinase

Age at diagnosis

5 years

Diagnostic method

Muscle biopsy characterization

Management/treatment options

Oral laevadosin for 3 years

Progression

Motor skill decline to non-ambulatory at 10 years of age

Outcome

Died at 18 years of age due to respiratory infections and cardiomyopathy

References

Bushby K, Connor E. Clinical outcome measures for trials in Duchenne muscular dystrophy: report from International Working Group meetings. Clin Investig (Lond). 2011;1(9):1217-1235.

Ciafaloni E, Fox DJ, Pandya S, et al. Delayed diagnosis in Duchenne muscular dystrophy: data from the muscular dystrophy surveillance, tracking, and research network (MD STARnet). J Pediatr. 2009;155(3):380-385

Gardner-Medwin. Duchenne muscular dystrophy: early diagnosis, and screening. Arch Dis Child. 1976;51(1):982-983.

Corticosteroid use

The first clinical trial evaluating the safety and efficacy of a corticosteroid (prednisone) in DMD is published, setting the stage for a potential palliative treatment option for some patients.

References

Drachman DB, Toyka KV, Myer E. Prednisone in Duchenne muscular dystrophy. Lancet. 1974;2(7894): 1409-1412.

1987
DMD cloning

American geneticist Louis M. Kunkel’s group clones the DMD cDNA, enabling him and others to begin to identify mutations from patients with DMD.

References

Koenig M, Hoffman EP, Bertelson CJ, et al. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell. 1987;50(3):509-517.

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Dystrophin description

Shortly after cloning the DMD gene, Dr Kunkel’s group describes the gene’s protein product, which they name dystrophin. This leads to the landmark discovery that boys with DMD lack dystrophin.

References

Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51(6):919-928.

1988
Dystrophin for DMD diagnosis

The discoveries by Kunkel and others lead to the use of muscle biopsies to characterize dystrophin levels and thereby diagnose patients with DMD.

References

Hoffman EP, Fischbeck KH, Brown RH, et al. Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne’s or Becker’s muscular dystrophy. N Engl J Med. 1988;318(21):1363-1368.

1990
DMD deletions for diagnosis

Advances in polymerase chain reaction (PCR) technology result in diagnostic tests that can detect 98% of deletions in DMD through blood samples.

References

Beggs AH, Koenig M, Boyce FM, et al. Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction. Hum Genet. 1990;86(1):45-48.

DMD deletions for diagnosis

During the late 1980s and early 1990s, diagnosis of DMD typically requires a muscle biopsy. This biopsy is used to evaluate dystrophin protein expression. With the progress made in technology enabling the analysis of DNA, the recommended stepwise process for diagnosis of DMD was muscle biopsy, PCR, and then Southern Blotting. PCR and Southern blotting enabled evaluation of molecular changes in the DMD gene. Furthermore, with the continuing development of assays to detect genetic mutations from peripheral blood, the hope is that diagnosis of DMD would be performed by PCR without the need for muscle biopsy.

References

Beggs AH, Koenig M, Boyce FM, et al. Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction. Hum Genet. 1990;86(1):45-48.

Beggs AH, Kunkel LM. Improved diagnosis of Duchenne/Becker muscular dystrophy. J Clin Invest. 1990;85(3):613-619.

1991
Corticosteroid use

Corticosteroids are studied to evaluate efficacy and safety in patients with DMD.

References

Griggs RC, Moxley RT 3rd, Mendell JR, et al. Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol. 1991;48(4):383-388.
Mendell JR, Moxley RT, Griggs RC, et al. Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. N Engl Med. 1989;320(24):1592-1597.
Mesa LE, Dubrovsky AL, Corderi J, et al. Steroids in Duchenne muscular dystrophy--deflazacort trial. Neuromuscul Disord. 1991;1(4):261-266.

1992
mutations in DMD
Nonsense mutations in DMD

David Bentley’s group identifies nonsense mutations in the dystrophin gene of 4 out of 7 patients with DMD or intermediate muscular dystrophy, in whom no deletion was detected by multiple PCR. A nonsense mutation is a point mutation that changes a codon into an in-frame premature stop codon, resulting in premature termination of dystrophin translation and disease pathogenesis.

References

Roberts RG, Bobrow M, Bentley DR. Points mutations in the dystrophin gene. Proc Natl Acad Sci U S A. 1992; 89(6):2331-2335.

Nonsense mutations in DMD

The diagram below highlights mutations identified in the dystrophin gene in 3 of 4 these patients with nonsense mutations. The results of these analyses suggest that truncation of the dystrophin protein negatively impacts its function and contributes to disease pathogenesis. Since this discovery, over 4700 mutations have been linked to DMD, with roughly 10% to 15% making up small nonsense mutations in the DMD gene (nmDMD).

References

Pichavant C, Aartsma-Rus A, Clemens PR, et al. Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Mol Ther. 2011;19(5):830-840.

Roberts RG, Bobrow M, Bentley DR. Points mutations in the dystrophin gene. Proc Natl Acad Sci U S A. 1992; 89(6):2331-2335.

Winnard AV, Jia-Hsu Y, Gibbs RA, et al. Identification of a 2 base pair nonsense mutation causing a cryptic splice site in a DMD patient. Hum Mol Genet. 1992;1(8):645-646.

chart

Name: Benjamin

Signs and symptoms at diagnosis

Muscle weakness with Gower’s maneuver, family history (a brother with DMD)

Age at diagnosis

5 years

Diagnostic method

Muscle biopsy followed by molecular testing
(Southern blotting) for dystrophin

Management/treatment options

Oral daily prednisone

Progression

Becomes non-ambulatory at 10 years of age and receives spinal surgery for scoliosis at 14 years of age

Outcome

Died at 21 years of age due to cardiac and respiratory complications

References

Beggs AH, Kunkel LM. Improved diagnosis of Duchenne/Becker muscular dystrophy. J Clin Invest. 1990;85(3):613-619.

Bushby K, Connor E. Clinical outcome measures for trials in Duchenne muscular dystrophy: report from International Working Group meetings. Clin Investig (Lond). 2011;1(9):1217-1235.

Bushby K, Finkel R, Birnkrant DJ, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9(1):77-93.

DeSilva S, Drachman DB, Mellits D, et al. Prednisone treatment in Duchenne muscular dystrophy. Arch Neurol. 1987;44(8):818-822.

Finder JD, Birnkrant D, Carl J, et al; American Thoracic Society. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med. 2004;170(4):456-465.

Pandya S, James KA, Westfield C, et al. Health profile of a cohort of adults with Duchenne muscular dystrophy. Muscle Nerve. 2018;58(2):219-223.

PTC therapeutic
1998
Founding of PTC Therapeutics

Under the leadership of Dr Stuart Peltz, PTC Therapeutics is founded in New Jersey, USA. The PTC readthrough program is initiated to help identify small molecules that can read through nonsense mutations.

References

About PTC: Our history. PTC Therapeutics website. https://www.ptcbio.com/about/our-history/. Accessed April 21, 2020.

Our Science: Nonsense Readthrough. PTC Therapeutics website. https://www.ptcbio.com/our-science/expertise/nonsense-readthrough/. Accessed April 21, 2020.

This point denotes when PTC Therapeutics was founded based on their readthrough program. We will begin exploring the process of rare disease drug development through this lowerleft hand timeline.

Swipe to switch between the two timeline views

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Respiratory care guidelines
2004
Respiratory care guidelines

As respiratory disease in DMD is a major cause of morbidity and mortality, the American Thoracic Society (ATS) creates respiratory care guidelines for patients with DMD, highlighting:

  • Evaluation and anticipatory guidance for patients with DMD
  • Management options for respiratory complications related to DMD
References

Finder JD, Birnkrant D, Carl J, et al; American Thoracic Society. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med. 2004;170(4):456-465.

2005
American Academy of Neurology
Corticosteroid use

The American Academy of Neurology (AAN) develops the first practice parameter document recommending the use of corticosteroids in patients with DMD.

References

Moxley RT III, Ashwal S, Pandya S, et al; Quality Standards Subcommittee of the American Academy of Neurology; Practice Committee of the Child Neurology Society. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2005;64(1):13-20.

Genetics for DMD diagnosis

Genetic analysis techniques continue to evolve and can detect most mutations in patients with a clinical diagnosis of muscular dystrophy (e.g., DMD or Becker muscular dystrophy).

References

Flanigan KM, von Niederhausern A, Dunn DM, et al. Rapid direct sequence analysis of the dystrophin gene. Am J Hum Genet. 2003;72(4):931-939.

Gatta V, Scarciolla O, Gaspari AR, et al. Identification of deletions and duplications of the DMD gene in affected males and carrier females by multiple ligation probe amplification (MLPA). Hum Genet. 2005;117(1):92-98.

2007
Life expectancy

With the current standard of care, the average life expectancy for patients is in the third decade of life.

References

Bushby K, Connor E. Clinical outcome measures for trials in Duchenne muscular dystrophy: report from International Working Group meetings. Clin Investig (Lond). 2011;1(9):1217-1235.

Nonsense readthrough agent

Identification of a nonsense readthrough agent that may have broad clinical potential for certain genetic diseases is published in Nature.

References

Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447(7140):87-91.

2007
Nonsense readthrough agent

Identification of a nonsense readthrough agent that may have broad clinical potential for certain genetic diseases is published in Nature.

References

Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447(7140):87-91.

2010
DMD guidelines

Comprehensive, international guidance for the diagnosis and management of patients with DMD is developed. This guidance aims to:

  • Raise awareness of DMD
  • Help improve the quality and standardization of care for patients with DMD
References

Ward LM, Birnkrant DJ. An introduction to the Duchenne muscular dystrophy care considerations. Pediatrics. 2018;142(suppl 2):S1-S4.

Name: Eric

Signs and symptoms at diagnosis

Muscle weakness, Gower’s maneuver, differences in motor skills compared with peers, elevated serum creatine kinase

Age at diagnosis

5 years

Diagnostic method

Multiplex PCR for DMD mutation, which identified a deletion in DMD

Management/treatment options

Prednisone and physical therapy

Progression

Becomes non-ambulatory at 13 years of age; no surgery needed for scoliosis

Outcome

Died at 29 years of age due to cardiac and respiratory complications

References

Bushby K, Connor E. Clinical outcome measures for trials in Duchenne muscular dystrophy: report from International Working Group meetings. Clin Investig (Lond). 2011;1(9):1217-1235.

Bushby K, Finkel R, Birnkrant DJ, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9(1):77-93.

Ciafaloni E, Fox DJ, Pandya S, et al. Delayed diagnosis in Duchenne muscular dystrophy: data from the muscular dystrophy surveillance, tracking, and research network (MD STARnet). J Pediatr. 2009;155(3):380-385.

Henricson EK, Abresch RT, Cnaan A, et al.; CINRG Investigators. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. 2013;48(1):55-67.

Pandya S, James KA, Westfield C, et al. Health profile of a cohort of adults with Duchenne muscular dystrophy. Muscle Nerve. 2018;58(2):219-223.

2011
Developing therapies for DMD

A review article highlights potential therapeutic options in development for DMD, including a nonsense readthrough agent and antisense oligonucleotides that aims to increase endogenous dystrophin production.

References

Pichavant C, Aartsma-Rus A, Clemens PR, et al. Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Mol Ther. 2011;19(5):830-840.

2011
Natural history of DMD

On behalf of the International Working Group on DMD clinical outcomes, Dr Kate Bushby and Dr Edward Connor summarize discussions from a workshop, including a description of the natural history of DMD in the era of corticosteroids. This information and that of clinical trial control data sets are integral to help develop better end points for future clinical trials of investigative therapies for DMD.

References

Bushby K, Connor E. Clinical outcome measures for trials in Duchenne muscular dystrophy: report from International Working Group meetings. Clin Investig (Lond). 2011;1(9):1217-1235.

Natural history of DMD

Natural history studies for rare diseases are crucial to pave the way for improved disease understanding and better clinical trial end points. In addition, some of the natural history studies in DMD helped identify optimal baseline characteristics of patients for clinical trial enrollment using

  • Longitudinal observations of motor function
  • Longitudinal, multicenter, clinical history of patients with DMD

Over time, these studies also included characteristics of patients who received corticosteroids.

References

Bushby K, Connor E. Clinical outcome measures for trials in Duchenne muscular dystrophy: report from International Working Group meetings. Clin Investig (Lond). 2011;1(9):1217-1235.

Humbertclaude V, Hamroun D, Bezzou K, et al. Motor and respiratory heterogeneity in Duchenne patients: implication for clinical trials. Eur J Paediatr Neurol. 2012;16(2):149-160.

Mazzone E, Vasco G, Sormani MP, et al. Functional changes in Duchenne muscular dystrophy: a 12-month longitudinal cohort study. Neurology. 2011;77(3):250-256.

2013
2013
Natural history of DMD

Several research groups publish natural history studies of patients with DMD to better understand the disease progression and to help improve clinical trial end points.

References

Bushby K, Finkel R, Wong B, et al; PTC124-GD-007-DMD Study Group. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014;50(4):477-487.

McDonald CM, Henricson EK, Abresch RT, et al. The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve. 2013;48(3):343-356.

Natural history of DMD

With the natural history studies that have been published, many factors have been investigated as potential end points for ambulatory DMD trials. Some of these end points include time to persistent 10% 6MWD worsening and the 6MWD test. Notably, baseline 6MWD has prognostic value, both for primary assessment of walking and secondary assessments of function, muscle strength, activity, and fall frequency. The results of these studies support a clinically meaningful change in 6MWD to be approximately 20 to 30 meters, which can be a target treatment effect among ambulatory patients with DMD.

References

Bushby K, Finkel R, Wong B, et al; PTC124-GD-007-DMD Study Group. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014;50(4):477-487.
McDonald CM, Henricson EK, Abresch RT, et al. The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve. 2013;48(3):343-356.

2015
CK-M in DMD

The discovery of elevated serum muscle-type creatine kinase (CK-M) in patients with DMD provides an opportunity for the use of a non-invasive biomarker to help monitor disease progression.

References

Burch PM, Pogoryelova O, Goldstein R, et al. Muscle-derived proteins as serum biomarkers for monitoring disease progression in three forms of muscular dystrophy. J Neuromuscul Dis. 2015;2(3):241-255.

Dystrophin mutations in DMD

With advances in disease understanding, genotype-phenotype correlations in muscular dystrophy are identified, which have implications for diagnosis, prediction of prognosis, and management. Different procedures and tools to identify these mutations become integral to the diagnosis of DMD and other dystrophies.

References

Falzarano MS, Scotton C, Passarelli C, et al. Duchenne muscular dystrophy: from diagnosis to therapy. Molecules. 2015;20(10):1816&zwj8-18184.

Dystrophin mutations in DMD

Amino acids, the building blocks of protein, are coded for by 3 nucleotide sequences in a gene. When a mutation is found within the gene sequence, it may lead to changes in the translated protein. For example, section B of the diagram shows how the deletion of exons 47-50 in the dystrophin gene shifts the nucleotide reading frame. This frameshift results in an incorrect sequence of amino acids being incorporated after the deletion during translation, leading to a non-functional protein and DMD. In contrast, section C of the diagram shows how the deletion of exons 46-54 in the dystrophin gene maintains the reading frame. The gene is transcribed and translated to produce a truncated but partially functional dystrophin protein, leading to Becker muscular dystrophy (BMD). Note that there are exceptions to this rule that mutations that disrupt the reading frame lead to DMD and mutations that maintain the reading frame lead to BMD.

The molecular tools to help diagnose DMD include

  • Multiplex ligation-dependent probe amplification, microarray-based comparative genomic hybridization, and next-generation sequencing to identify deletion/duplication of exons
  • Microarray-based comparative genomic hybridization, reverse transcription PCR, and fluidic card to identify complex mutations
  • Sanger sequencing and next-generation sequencing to identify point mutations, including nonsense mutations
References

Aartsma-Rus A, Ginjaar IB, Bushby K. The importance of genetic diagnosis for Duchenne muscular dystrophy. J Med Genet. 2016;53(3):145-151.

Berg JM, Tymoczko JL, Stryer L. Section 5.5 Amino acids are encoded by groups of three bases starting from a fixed point. Biochemistry. 5th edition. New York: W H Freeman; 2002.

Falzarano MS, Scotton C, Passarelli C, et al. Duchenne muscular dystrophy: from diagnosis to therapy. Molecules. 2015;20(10):181&zwj68-18184.

Pichavant C, Aartsma-Rus A, Clemens PR, et al. Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Mol Ther. 2011;19(5):830-840.

Wang L, Xu M, Li H, et al. Genotypes and phenotypes of DMD small mutations in Chinese patients with dystrophinopathies. Front Genet. 2019;10:114.

examples of genetic mutations examples of genetic mutations
STRIVE award

The Strategies to Realize Innovation, Vision and Empowerment (STRIVE) award is presented for the first time. The award provides grants to different organizations in recognition of their efforts to meet the needs of the Duchenne community around the world.

References

STRIVE Awards program. PTC Therapeutics website. https://www.ptcbio.com/about/strive-awards-program/all-recipients/. Accessed April 21, 2020.

2016
Revised North Star Ambulatory Assessment

The North Star Ambulatory Assessment (NSAA) is revised to be suitable for boys with DMD between the ages of 3 and 5 years, forming an age-appropriate outcome measure for these patients.

References

Mercuri E, Coratti G, Messina S, et al. Revised North Star Ambulatory Assessment for young boys with Duchenne muscular dystrophy. PLoS One. 2016;11(8):e0160195. doi: 10.1371/journal.pone.0160195.

Updated corticosteroid guidelines

About a decade after the first corticosteroid treatment guidelines are published, AAN updates their practice guidelines to address several key points:

  • Efficacy of corticosteroids for survival, quality of life, motor function, scoliosis, pulmonary function, and cardiac function
  • Comparison of prednisone and deflazacort
  • Adverse events associated with corticosteroids
  • Interventions to maximize bone health
References

Gloss D, Moxley RT 3rd, Ashwal S, et al. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(5):465-472.

Updated corticosteroid guidelines

About a decade after the first corticosteroid treatment guidelines are published, AAN updates their practice guidelines to address several key points:

  • Efficacy of corticosteroids for survival, quality of life, motor function, scoliosis, pulmonary function, and cardiac function
  • Adverse events associated with corticosteroids
  • Interventions to maximize bone health
References

Gloss D, Moxley RT 3rd, Ashwal S, et al. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(5):465-472.

2017
Corticosteroid treatment approval

The first and only corticosteroid treatment for patients with DMD who are aged ≥5 years is approved in the United States by the FDA.

References

FDA approves drug to treat Duchenne muscular dystrophy [news release]. US Food and Drug Administration; February 9, 2017. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-duchenne-muscular-dystrophy. Accessed April 21, 2020.

Slope of change in 6MWD

Slope of change in 6MWD from baseline to end of treatment is published as an alternate efficacy end point in trials for DMD and may more accurately estimate the rate of change in 6MWD than previously used methods.

  • This analysis accounts for the time to loss of ambulation, which is not accounted for in analyses of change from baseline
References

Riebling P, Souza M, Elfring GL, et al. Slope analysis of 6-minute walk distance as an alternative method to determine treatment effect in trials in Duchenne muscular dystrophy [abstract]. Eur J Paediatr Neurol. 2017;21(suppl 1):E94.

2018
Updated DMD guidelines

The updated DMD Care Considerations Guidelines are published in a 3-part series that includes:

  • Three new topics for discussion: primary care and emergency management, endocrine management, and transitions of care across the life span of a patient with DMD
  • Dystrophin restorative therapies (e.g., ataluren and eteplirsen) as emerging treatments for DMD
  • Behavioral considerations for patients who are living longer owing to better disease management options. Specifically, referral to a psychologist and/or speech-language pathologist is appropriate when patients exhibit intellectual disability, attention deficit hyperactivity disorder, or autism spectrum disorder
References

Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):251-267.

Colvin MK, Poysky J, Kinnett K, et al. Psychosocial management of the patient with Duchenne muscular dystrophy. Pediatrics. 2018;142 (suppl 2): S99-S109.

Updated DMD guidelines

The life expectancy of patients with DMD increases to 30 to 40 years of age; consequently, The DMD Care Considerations Guidelines to diagnose and manage patients with DMD are updated to address the evolving needs of older patients and potential disease-modifying therapies in development.

References

Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):251-267.

Henricson EK, Abresch RT, Cnaan A, et al.; CINRG Investigators. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. 2013;48(1):55-67.

Pandya S, James KA, Westfield C, et al. Health profile of a cohort of adults with Duchenne muscular dystrophy. Muscle Nerve. 2018;58(2):219-223.

Name: Alan

Signs and symptoms at diagnosis

Gower’s maneuver, general muscle weakness, clumsiness, toe-walking, elevated creatine kinase

Age at diagnosis

4.5 years

Diagnostic method

Genetic sequencing for DMD,
which identified a nonsense mutation

Management/treatment options

Daily prednisone with dose adjustments as needed; management care team involvement (e.g., physical therapist, occupational therapist, speech-language pathologist, orthotist, nutritionist)

Progression

Becomes non-ambulatory at 13 years of age;
no surgery needed for scoliosis

Outcome

Died at 32 years of age due to cardiac and respiratory complications

References

Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):251-267.

Bushby K, Connor E. Clinical outcome measures for trials in Duchenne muscular dystrophy: report from International Working Group meetings. Clin Investig (Lond). 2011;1(9):1217-1235.

Ciafaloni E, Fox DJ, Pandya S, et al. Delayed diagnosis in Duchenne muscular dystrophy: data from the muscular dystrophy surveillance, tracking, and research network (MD STARnet). J Pediatr. 2009;155(3):380-385.

Pandya S, James KA, Westfield C, et al. Health profile of a cohort of adults with Duchenne muscular dystrophy. Muscle Nerve. 2018;58(2):219-223.

Use of revised NSAA

The revised NSAA is employed as a clinical trial outcome measure to evaluate motor function according to age-appropriate outcomes in young (2-5 years of age) patients with DMD that is caused by nonsense mutations (nmDMD).

References

PTC Therapeutics announces positive data from its TranslarnaTM phase II clinical trial in children as young as two years with nonsense mutation Duchenne muscular dystrophy [press release]. South Plainfield, NJ: PTC Therapeutics, Inc; July 9, 2018. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-positive-data-its-translarnatm-phase. Accessed April 21, 2020.

2019
CK-MM in newborn screening for DMD

The FDA authorizes the first newborn screening test for DMD, which measures creatine kinase MM (CK-MM) in dried blood spot samples, enabling diagnosis before symptom onset.

References

FDA authorizes first test to aid in newborn screening for Duchenne muscular dystrophy [news release]. US Food and Drug Administration; December 12, 2019. https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-test-aid-newborn-screening-duchenne-muscular-dystrophy. Accessed April 21, 2020.

CK-MM in newborn screening for DMD

Dr Tim Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health stated, “This authorization reflects our commitment to fostering innovation in devices to help inform and provide options to patients and their caregivers. Early screening can help identify individuals who need additional follow-up or treatment.”

References

FDA authorizes first test to aid in newborn screening for Duchenne muscular dystrophy [news release]. US Food and Drug Administration; December 12, 2019. https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-test-aid-newborn-screening-duchenne-muscular-dystrophy. Accessed April 21, 2020.

Golodirsen approval

Golodirsen is approved in the US for patients with DMD who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping.

References

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy [news release]. US Food and Drug Administration; December 12, 2019. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation. Accessed July 14, 2020.

Deflazacort label expansion
Expansion of indicated population for a corticosteroid treatment

The FDA expands the indicated population for an approved corticosteroid treatment to include patients with DMD aged 2 years of age and older, in line with clinical care guidelines supporting use of glucocorticoid treatment in the early ambulatory stage of the disease to slow disease progression.

References

Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):251-267.

PTC Therapeutics receives FDA approval for the expansion of the EMFLAZA® (deflazacort) labeling to include patients 2-5 years of age [press release]. South Plainfield, NJ: PTC Therapeutics, Inc; June 7, 2019. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-receives-fda-approval-expansion-emflazar. Accessed April 21, 2020.

2020
Management during COVID-19

An expert panel of physicians who treat Duchenne and Becker muscular dystrophies come together to provide guidance on treating people with muscular dystrophy during the COVID-19 pandemic.

References

Veerapandiyan A, Wagner KR, Apkon S, et al. The care of patients with Duchenne, Becker, and other muscular dystrophies in the COVID-19 pandemic. Muscle Nerve. 2020;62(1):41-45.

Management during COVID-19

Some of this guidance to treat patients with muscular dystrophy during COVID-19 includes:

  • Ensure timely, uninterrupted care using telemedicine, single-provider or multidisciplinary visits
  • Individual treatment decisions should be made between the multidisciplinary care team, and the patient/family after considering the policies and precautions for COVID-19
  • Conduct clinical trials in accordance with institution and sponsor-specific policies and implement site specific precautions for COVID-19 as required
References

Veerapandiyan A, Wagner KR, Apkon S, et al. The care of patients with Duchenne, Becker, and other muscular dystrophies in the COVID-19 pandemic. Muscle Nerve. 2020;62(1):41-45.

2022+
Looking ahead

Over the years, the field has made many advances in the understanding of DMD and management of patients with the disease. Ongoing and planned initiatives to further improve the lives of patients with DMD include:

  • Increased awareness and availability of newborn screening tests (e.g., CK-MM) for DMD in the United States and around the world to allow for timely diagnosis and improved preservation of motor function through available treatments.
References

Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):251-267.

Mendell JR, Shilling C, Leslie ND, et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012; 71(3):304-313.

Nonsense readthrough agent for DMD in the US
STRIVE continuation
  • Identification and development of biomarkers to facilitate earlier detection of DMD and its impact on multiple organ systems (e.g., cardiac function)
STRIVE continuation
STRIVE continuation

In an effort to recognize and support the rare disease community, PTC’s STRIVE program continues to award grants to nonprofit organizations that are serving patients with DMD.