MED-ALL-DMD-2200218 | October 2023

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

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.

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.

1974

Waddling gait, difficulty climbing stairs, elevated creatine kinase

5 years

Muscle biopsy characterization

Oral laevadosin for 3 years

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

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

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.

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.

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.

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.

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.

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.

1991

Corticosteroid use

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

1992

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.

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

5 years

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

Oral daily prednisone

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

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

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.

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

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

2005

Corticosteroid use

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

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).

2007

Life expectancy

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

Nonsense readthrough agent

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

2007

Nonsense readthrough agent

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

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

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

5 years

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

Prednisone and physical therapy

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

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

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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

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

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.

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

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

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.

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

4.5 years

Genetic sequencing for DMD,
which identified a nonsense mutation

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

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

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

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).

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.

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.”

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.

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.

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.

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

2024+

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.

Nonsense readthrough agent for DMD in the US

Identification and development of biomarkers to facilitate earlier detection of DMD and its impact on multiple organ systems (e.g., cardiac function)

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.