Not for promotional use. For educational purposes only. MED-ALL-DMD-2100060. September 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. In parallel to the evolution of our understanding DMD, you will also have the chance to learn about a drug development process and clinical trial program that may help to bring an investigational therapy closer to patients. 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

2003

2003

Ataluren clinical development program

Small molecule discovery

Through PTC's readthrough program, PTC124, later called ataluren, is discovered as a small molecule.

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

2004

A phase 1 study of ataluren is initiated to evaluate the safety, tolerability, and pharmacokinetic profile in healthy adult volunteers (n=62).

2005

Corticosteroid use

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

2005

As a proof of concept study, a phase 2a, open-label, dose-ranging study (study 004) for patients with nmDMD aged ≥5 years (n=38) within the United States is started to determine whether ataluren can elicit an increase in dystrophin expression on muscle biopsy in patients with nmDMD.

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).

Orphan designation

The FDA grants orphan drug designation for ataluren to treat patients with DMD caused by nonsense mutations. Around the same time, the European Medicines Agency (EMA) designates ataluren as an orphan medicine for DMD.

Orphan designation

Orphan drug designations may help support the development of therapies for patients with rare diseases.

The FDA grants orphan designation for drugs or biological products that treat, prevent, or diagnose a rare disease or condition, upon request of a sponsor
Rare disease=a disease that affects fewer than 200,000 people per year in the US or where the drug is unlikely to recover sales to justify the research and development costs.

Orphan medicine=a medicine for the diagnosis, prevention, or treatment of a condition that affects no more than 5 in 10,000 people in the European Union or where the medicine is unlikely to generate sufficient profit to justify research and development costs

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.

2008

As further studies are needed to better understand the efficacy and safety of ataluren in patients with nmDMD, a phase 2b, international, randomized, placebo-controlled study (study 007) is initiated to assess physical functioning in patients with nmDMD aged ≥5 years treated with ataluren.

The primary endpoint is the change in 6-minute walk distance (6MWD) from baseline after 48 weeks of treatment
Other assessments include time to persistent 10% 6MWD worsening relative to baseline

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

2010

After establishing short-term proof of concept, a study is initiated (study 016) to evaluate the long-term (up to 8 years) safety of ataluren in nmDMD among patients who were previously treated with ataluren in phase 2 studies in the United States.

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

To further understand the effects of therapy in a larger population, a randomized controlled trial (ACT DMD; study 020) is started to evaluate the effect of ataluren on motor function, specifically change in 6MWD at week 48 in patients with nmDMD aged 7 to 16 years (n=228).

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.

2014

EMA Conditional marketing authorization

EMA grants conditional marketing authorization for ataluren in ambulatory patients with nmDMD aged ≥5 years.

Milestone

This is the first instance of ataluren being approved by a regulatory agency for use in patients with nmDMD. The EMA will review and renew the conditional marketing authorization annually.

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.

2015

The Strategic Targeting of Registries and International Database of Excellence (STRIDE) Registry (study 025) is formed to provide real-world evidence of the effectiveness and safety of ataluren in patients with nmDMD.

This is a postapproval safety study (PASS) commitment to the EMA through a partnership with TREAT-NMD, Cooperative International Neuromuscular Research Group, and PTC Therapeutics.

Long-term registry study

The STRIDE registry is a multicenter observational study of ataluren in patients with nmDMD that evaluates the long-term safety and effectiveness of ataluren use. As of July 2018, 217 patients with nmDMD from 11 countries were enrolled in STRIDE, making this the first drug registry for patients with DMD and the largest real-world study in nmDMD to date.

Milestone

Approval in Israel & South Korea: Ataluren receives regulatory approval in Israel and South Korea for ambulatory patients with nmDMD aged ≥5 years.

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.

Treatment for patients’ siblings

PTC expands access to ataluren for siblings of patients in certain open-label PTC clinical trials for nmDMD, allowing individuals who may not have been eligible to participate in trials to have similar access.

2016

Eteplirsen approval

Eteplirsen becomes the first drug approved to treat patients with DMD in the US who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.

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

2016

Until now, all patients enrolled in ataluren trials were aged ≥5 years. To investigate the use of ataluren in younger patients, a phase 2 study (study 030) is started to evaluate the safety and pharmacokinetic and pharmacodynamic profile of ataluren in patients aged 2 to 5 years (n=14).

NICE guidance

The National Institute for Health and Care Excellence (NICE) provides Highly Specialized Technologies Evaluation guidance related to ataluren use for treating nmDMD.

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

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.

2017

In an effort to obtain additional data on long-term safety of ataluren, an open-label study evaluating safety in patients who were previously treated with ataluren in phase 2 studies from Europe, Israel, Australia, and Canada is initiated (study 019).

To evaluate the long-term outcomes of ataluren, a large, randomized, double-blind, placebo-controlled 72-week study, followed by a 72-week open-label period, of patients with nmDMD aged ≥5 years is initiated (study 041).

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.

2018

To evaluate whether dystrophin can be used as a biomarker to assess treatment outcomes, a phase 2 study (study 045) is initiated in patients with nmDMD who were previously treated with ataluren in the United States.

Milestones

EMA label expansion: EMA approves the expansion of ataluren’s indication allowing ambulatory patients with nmDMD aged ≥2 years to be treated, broadening the current indication to include younger patients aged 2-5 years of age with nmDMD.
Approval in Chile and Ukraine: Ataluren receives regulatory approval in Chile for ambulatory patients with nmDMD aged ≥5 years of age. Ataluren also receives approval in specific UNDP program (government supplies only) in the Ukraine for ambulatory patients with nmDMD aged ≥5 years of age.

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).

Milestones

EMA label expansion: EMA approves the expansion of ataluren’s indication allowing ambulatory patients with nmDMD aged ≥2 years to be treated, broadening the current indication to include younger patients aged 2-5 years of age with nmDMD.
Approval in Chile and Ukraine: Ataluren receives regulatory approval in Chile for ambulatory patients with nmDMD aged ≥5 years of age. Ataluren also receives approval in specific UNDP program (government supplies only) in Ukraine for ambulatory patients with nmDMD aged ≥5 years of age.

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.

2019

A new biomarker study (study 046) is initiated evaluating changes in dystrophin expression in patients with nmDMD who have been receiving ataluren for
≥9 months within the United States.

STRIDE initial demographics

Initial baseline demographics from 213 male patients in STRIDE, the first drug registry for patients with DMD, to evaluate long-term outcomes for patients with nmDMD receiving ataluren are published.

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.

STRIDE initial demographics

Initial baseline demographics from 213 male patients in STRIDE, the first drug registry for patients with DMD, to evaluate long-term outcomes for patients with nmDMD receiving ataluren are published.

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.

Milestone

Approval in Brazil: Under the rare diseases procedure, ataluren is approved in Brazil for male paediatric ambulatory nmDMD patients aged 5 years and older.

Approval in Brazil

The Brazilian Health Authorities (ANVISA) created a protocol in 2017 to approve clinical trials and register investigational products for rare diseases and to help streamline and accelerate drug approval for patients with unmet needs
Rare disease=a condition affecting fewer than 65 of every 100,000 individuals

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

2020

STRIDE safety and efficacy

Safety and efficacy of ataluren treatment in patients with nmDMD enrolled in the STRIDE Registry is published, providing initial real-world evidence on long-term outcomes of ataluren.

EMA label update

The Committee for Medicinal Products for Human Use (CHMP) recommends removal of “efficacy has not been demonstrated in non-ambulatory patients” from the SmPC for ataluren.

Milestones

Ataluren approval: Ataluren receives regulatory approval in Kazakhstan, Israel and Republic of Korea for ambulatory patients with nmDMD aged ≥2 years of age. In the Russian Federation, ataluren is indicated for congenital malignant DMD resulting from a nonsense mutation in the dystrophin gene in adults and children over the age of 2 years.
Regulatory review: Ataluren is currently under review for regulatory approval for ambulatory patients with nmDMD in Colombia, Kuwait, Egypt and Ukraine.

2021

Milestone

Ataluren approval: Ataluren is indicated for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older in the European Member States and Iceland, Liechtenstein, Norway, Great Britain, Northern Ireland, Belarus, Russia and Brazil. In Brazil, the indication is specific to male paediatric patients.

2022

Milestone

Ataluren approval: Ataluren is indicated for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older in Peru and aged 5 years and older in the Kingdom of Saudi Arabia.

2023

Milestone

Ataluren approval: Ataluren is indicated for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older in Chile, Macedonia and Uruguay.

2024+

Milestones

Ataluren approval in Ukraine: A decision from the GMP is pending on ataluren approval for ambulatory patients with nmDMD aged 2 years and older.

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

PTC Therapeutics hopes to seek FDA approval for the use of ataluren in ambulatory patients with nmDMD, thereby bringing a disease-modifying therapy for patients with nmDMD to the United States.

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.