Duchenne Muscular Dystrophy as a Model Disease for PDUFA-V

Posted by: Carlo Rago on November 04, 2012

Duchenne Muscular Dystrophy as a Model Disease for PDUFA-V

Submitted to FDA November 1st 2012

Re: Docket No. FDA–2012–N–0967, Prescription Drug User Fee Act Patient-Focused Drug Development; Public Meeting and Request for Comments

Carlo Rago, PhD

  • Scientific Advisor and Founder, Duchenne Alliance

  • Founder, OpenOnward

  • Received a PhD from the Cellular and Molecular Medicine Program, Johns Hopkins Medical Institute

  • Post-doctoral Fellowship from the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins

  • Co-authored over 30 high-impact scientific papers

Christine McSherry, RN

  • Founder, Duchenne Alliance

  • Founder and President, Jett Foundation

  • Parent of a son with Duchenne muscular dystrophy


The Food and Drug Administration (FDA) drug approval process is designed to understand safety and efficacy for each drug asset in each disease subcategory and, increasingly, for each genetic alteration – appropriateness for each indication must be carefully considered.  The FDA routinely seeks ways to optimize the review process and the fifth enactment of the prescription drug user fee act (PDUFA-V) encourages all stakeholders (FDA, drug sponsor, and patients) to collaborate and define permissible risk for each regulatory decision (e.g. IND, NDA, AA, FT, post market etc).  Patient perspectives on disease severity and current treatment options are particularly helpful to reviewers as they assess risk and benefit.  In PDUFA-V, the FDA is designing a framework to best integrate patient perspectives and is seeking 20 model diseases.  Duchenne muscular dystrophy (DMD) is severe and progressive with no substantially useful therapies but a burgeoning, innovative drug pipeline that will require close collaboration between stakeholders to make well-informed decisions - DMD, therefore, serves as an excellent disease model for PDFUA-V.

The Patient Perspective is Essential to Understanding Permissible Risk

The FDA is tasked with ensuring safety and efficacy.  Drug sponsors intend to produce useful drugs and often seek financial gain in return.  Patients need viable therapies.  In an ideal review process, these stakeholders will collaborate to achieve the greatest understanding to identify appropriate indications.  Risk does not have to be tolerated - instead, risk can be vigilantly monitored and continuously minimized.  MedWatch and confirmatory trials were designed to mitigate risk, for example.  While we consider permissible risk for each prospective indication in Duchenne, let’s keep in mind that there is also risk in not treating, as progressive decline and premature death is imminent.

On October 10th, the FDA invited patient advocacy groups to help define a framework for capturing patient perspectives.  On the 25th, the FDA took public statements to nominate diseases and make recommendations about the process.  I attended both meetings on behalf of DMD patients and believe strongly that DMD should be included in PDUFA-V.  November 1st is the deadline to submit recommendations to the FDA docket.

Recommendations to the FDA for PDUFA-V:

1.  In the criteria for consideration of the 20 diseases, please also consider the impact of the disease on the family and caregivers.

2.  Publish the updated review process.  Patients and advocates would benefit from a road map to understand how to best assist the FDA.  Please describe the way in which patient perspectives will be used by reviewers as they assess permissible risk of each drug asset.  Ideally, the FDA would provide an infographic as well as a detailed description.

3.  Invite patients to the review process.  The FDA notes that patient perspectives can assist drug benefit risk assessment by providing an analysis of severity of disease condition and current treatment options.  However, expert summaries or patient testimonials that are documented by text or video may not be enough to thoroughly inform reviewers, particularly where there are unexpected, nuanced decisions in the balance.  A simple solution is to invite patients (and scientific advisors, advocates, and parents) to provide perspective precisely at the moment it is needed and precisely for the critical, nuanced decisions during the review process that determine the fate of a drug asset.  Well-informed patients with no conflicts of interest will be most valuable.  Patients would benefit from some background information or details prior to participation in the review process.  New therapy opportunities are infrequent for each disease subset and sufficient participation is likely since patients have a direct stake in the outcome.

4.  Include Duchenne muscular dystrophy in PDUFA-V as an optimal disease model.  DMD is severe (high morbidity and mortality), progressive, lacks meaningful therapies, is complicated by a disparate presumed standard of care, and serves as a model for many other muscular dystrophies.  Duchenne shares much of the same pathophysiology as many other muscular dystrophies, though the burden is more severe in Duchenne patients.  In fact, many of the therapies in the Duchenne pipeline will likely be tested in many other muscular disorders and other diseases.  There is a vast pipeline of drugs for Duchenne and many nuances will arise in the review process due to novel drug strategies and the many patient subcategories found in Duchenne – the reviewers will need assistance.

The FDA has indicated that patient perspectives can be particularly helpful as reviewers assess the severity of condition and the available treatment options.  We have made a preliminary attempt to compile this information in the sections below.  We also offer a specific example where collaboration between FDA, drug sponsor, and patient advocates can help determine the best course for patients.

Analysis of Condition - Duchenne muscular dystrophy

FDA requested the following information about the severity of the condition to assist the review process:

  • What clinical manifestations of the disease have the greatest impact on patients?

  • Are there other aspects of the disease that have a significant impact on a patient’s daily life? (e.g. impaired mobility, sleep problems, etc.)

  • How do the clinical manifestations change with disease progression?

  • How do the other aspects of the disease change with disease progression?

Duchenne muscular dystrophy is caused by inactivating mutations in Dystrophin.  Dystrophin is located on the X chromosome and is the second largest gene in the human genome.  Approximately 1:3600 males are affected.  There are known genetic modifiers and variable penetrance in some female carriers.  Some mutations in Dystrophin result in a less severe muscular dystrophy called Becker.

Duchenne is the most severe form of pediatric muscular dystrophy.  Duchenne patients are, on average, in a wheel chair by 11, require a respirator as the disease progresses and die from respiratory and cardiac complications by 20 years old.  Becker patients have a mutation in the same gene as DMD patients, Dystrophin, but have a less severe clinical course.  Notably, 80% of all muscular dystrophy deaths under 30 years old are from Duchenne or Becker muscular dystrophy (Kenneson 2012).  Women and non-ambulatory patients are under-served in clinical trials.  Also, there is a rich preclinical drug pipeline that includes innovative drug platforms that will further complicate the FDA review process for Duchenne therapies.

Christine McSherry, RN and other parents helped to provide extensive perspective below:

What clinical manifestations of the disease have the greatest impact on patients? 

Duchenne muscular dystrophy is a catastrophic, progressive muscle wasting condition that can affect any family.  Children lose their ability to walk, breathe, eat and speak, eventually they die an agonizing death in their early 20s - however, many patients die in their early to late teens.  The symptoms manifest before the age of 5, the earliest signs of Duchenne can include developmental delays in talking and walking.  This is followed by progressive weakening and muscle wasting, more specifically muscles of the thigh and pelvis.  The victim has trouble related to walking up stairs or rising from chairs and the floor.  With progressive involvement of the muscles the trunk, shoulder and back, and typical lordosis can be seen.  There is a progressive lack of grip strength that further impairs independence.

The child finds it difficult to balance and falls over a number of times.  The child soon begins to walk on his toes owing to contraction of the heel cords.  The elbows, knees, hips and spine are affected as the disease progresses, resulting in scoliosis (curvature of the spine).  The affected individual is confined to a wheelchair before 12 years of age.

Although most patients have normal levels of intelligence, signs of cognitive difficulties may be seen in a small percentage of the cases.  The muscle of the heart and lungs are also affected, leading to death from either respiratory or cardiac failure.  Once the muscles of the diaphragm become involved, the patient finds it difficult to breathe and is dependent on a ventilator/ respirator for breathing support.

Are there other aspects of the disease that have a significant impact on a patient’s daily life? (e.g. impaired mobility, sleep problems, etc.)

Activities of daily living are affected in numerous ways.  Once an individual who was nearly capable of performing most acts of daily living, is quickly robbed of this independence and physically dependent on parents, caregivers and support equipment for all acts daily life, including assistance with cardiac and respiratory functions.

The individual’s fatigue and subsequent weakness and immobility place the affected at high risk of injury.  Injury can result from frequent falls, skin breakdown, and impaired healing to name a few.

Impaired sleep related to the inability to reposition oneself in bed, discomfort due to pressure sores and/or impaired respiratory status due to airway clearance and respiratory muscle weakness.  Sleep can be further disrupted by the addition of a night-time breathing apparatus.


Respiratory condition is further compromised through a variety of symptoms of Duchenne, but most prevalent is the weakening of the diaphragm, further compounded by impaired airway clearance, respiratory muscle weakness and lack of gas exchange at the cellular level.

The patient will typically show signs of nutritional compromise through their weight, many are overweight and others are underweight.  Corticosteroid dependence is often the blame for patients on the heavier side of the scale, while many other patients suffer from severe symptoms of GERD – and for that reason, unable to maintain a healthy weight.  GI and GU problems can also contribute to the overall nutritional health of the patient, with increased muscle weakness leading to an overall underactive GI and GU system.

Cardiomyopathy symptoms also impact the patients in life-altering and life-limiting examples.  Patients are easily fatigued, demonstrate significant shortness of breath and frequently treated for arrhythmias related to their disease.  Side effects of the more common ACE-Inhibitors and Beta Blockers are noted to be an interruption in the lives of those with Duchenne.

Several factors of the disease and dependent use of off-label corticosteroids will further impact the already aggressive osteoporosis.  The risk of a spontaneous break in young men non-ambulatory is significant, while the incidence of an fall/injury related break in the younger population is also significant and higher than average than that of a normal school-age boy.

As the child ages, loses the ability to walk, becomes more dependent on their power chair for postural support, decreasing trunk stability give signs to the inevitable scoliosis.  Symptoms of scoliosis further compound the already compromised respiratory state as well as add further discomfort to the trunk and extremities that use the trunk for stability.   Severe lower back and sacral discomfort become evident while the bones of the spine weaken, along with the muscles maintaining the integrity of the spine.  Spontaneous compression fractures are noted during this time of spinal instability.  It is common to witness seating and positioning intervention in their power-chair, it is also common to not find an option to alleviate the discomfort caused and many young men manage the chronic pain daily.  Chronic daily pain can also stem from the severe contractures that are often associated with Duchenne.

Other unwanted side effects of corticosteroids include the delay of puberty and growth, both can influence the individual’s psychosocial health.  There are also significant ophthalmic considerations, behavioral side effects, a hazardous increase in weight, and significant GI upsets leading to ulcerations of the stomach and esophagus and the risk of a GI bleed.

How do the clinical manifestations change with disease progression?

Duchenne starts with subtle muscle weakness in the torso, which manifests as the Gowers Maneuver and frequent falling.  As the patient ages, the weakness extends to limbs causing loss of ambulation, progresses to loss of grip strength, until they reach quadriplegic status and requiring alternate ventilation and cardiac support.  As the vital organs are affected, the disease progresses rapidly until end-of-life directives intervene generally in the patients early 20’s, often at a younger age.

How do the other aspects of the disease change with disease progression?

Duchenne affects the individual in a multi systemic breakdown of epic proportions and is not limited to the physical loss, but also the social loss and grievance of a normal school age and adolescent life.  Friendships are commonly weak amongst this population of boys due to the inability to participate because of physical limitations and health issues.  Patients are often left out of the traditional activities such as birthday parties, inclusion of recess and after school sports games, school lunch is affected when the affected teen can no longer eat without assistance.

Economic hardships are often felt on the family and individual.  Parents need to have a flexible schedule and be able to request many days off due to health and preventative health of a child with Duchenne.  There is often a lack of insurance coverage for equipment not deemed necessary by insurance companies.  Vehicles (generally $62,000) are not covered that transport individuals in 300lb plus power-chairs to appointments, therapies, vocations and activities of child or adolescent.  Therapy and counseling for parents, siblings, extended family members and affected individual also becomes the responsibility of the family.  Home modifications, specialty clothing and personal care assistants often become the financial burden of the family.

Emotional/Psychological – individuals with Duchenne are unable to participate in “normal” activities of childhood, adolescence, and young adulthood.  The individual with Duchenne continues to mount up numerous loses over their shortened lifetime.  Driving is typically an activity that a teenager holds near and dear to their heart and is the benchmark into adulthood and independence.  All young men with Duchenne are stripped of this right-of-passage.  They are also feeling the significant loss of being part of a sports group, participating in music or clubs.  For the younger child diagnosed with Duchenne, it could be the reduction of recess minutes, being reduced to prevent fatigue and injury.  The adolescent becomes the victim of being dependent on others to perform the simplest tasks: personal care, dressing, bathing, eating, hugging a parent.  Not being at eye level, once the child becomes dependent of using their chair for activities of daily living, looking parents, peers, siblings in the eye while communicating has a tremendous impact on an already bruised self esteem.  Managing the continuous physical discomfort becomes difficult on the individual and is often seen through a more demanding attitude and not typically managed through a pain management program or liaison.

Loss of normal relationships, friend, family and romantic are prevalent through out the community.  Navigating high school and college can be both frustrating and disconcerting for the young person and comes with its own list of problems.  Trying to navigate high school and college as a quadriplegic, add to the list of impactful Duchenne symptoms that many of these young men face daily.  There is the loss of normal relationship - marriage, finding alternate ways to start a family.  Patients can also suffer from physically inability to perform vocational wants and needs, such as  - driving a truck, becoming a landscaper, delivering the mail.

Furthermore, the impact can also affect parental depression and parental stress. Divorce has a higher rate in life limiting disorders of children.  Depression is common due to the feelings of helplessness.  And the lack of acceptable treatments in the community adds to the growing frustration and depression found commonly among parents.

Depression and anxiety is often seen in Duchenne and is evidenced by the following: irritability, moodiness, sad flat affect, guilty, low self esteem, loss of interest in fun, social withdrawal, crying spells, change in appetite, lethargy, problems sleeping.

Cognitive/behavioral - Absence of Dystrophin can have an effect on the brain.

  • disruption in ion channel localization

  • disrupts normal electrophysiology of neurons

  • downstream consequences for calcium homeostasis and synaptic plasticity.

Increased risk of behavior problems: ADHD, Autism spectrum disorders, obsessive compulsive disorder, depression, anxiety, sensory integration dysfunction, socially.


Current Treatment Options – Duchenne Muscular Dystrophy

FDA requested the patient perspective on current treatment options to assist the review process and they have asked the following questions:

  • What is the current standard of care?

  • What therapies are being used to treat the condition (including approved and indicated therapies, drugs used off-label, and non-pharmacological therapies)

  • How effective are the existing therapies at treating the clinical manifestations of the disease?

  • How well do they mitigate other aspects of the disease?

  • How well tolerated are the existing therapies?

  • How does the effectiveness of approved therapies change with progression of the disease?

  • Does therapy effectiveness vary by patient sub-population?

Corticosteroids are indicated by extensive clinical data to slow the decline of muscle strength and function in Duchenne muscular dystrophy, which also reduces scoliosis and stabilizes pulmonary function (ref 5).  While retrospective analyses are limited in power, the patient reported outcome data seems to suggest that steroid use results in up to a two-year delay in time to wheelchair, with an average shift from about 9 to 11 years old (ref 6).  Without marginalizing the benefits of steroids, it should be noted that they do not sufficiently treat DMD patients and there are associated side effects.

The use of corticosteroids or any new drug should be considered in the context of overall care for DMD.  In 2009, a panel of 84 experts recommended a multidisciplinary approach to management of DMD, which includes physiotherapy, rehabilitation, orthopedic, skeletal, respiratory, cardiac, nutritional, pain, surgical and emergency care considerations (ref 5).  Patient perspectives can assist review decisions here.

Many off-label drugs or supplement therapies are in use for DMD.  The lists below are intended to give an idea of the complexity that exists for the review process due to the wide range of drugs and non-uniform, presumed standard of care.  The lists are not meant to be exhaustive, nor do they represent medical advice of any sort – I am not a physician.  Please consult your physician for appropriate evidenced-based strategies and specific considerations that may apply to your specific situation.

Duchenne Treatments as Categories:

This list is not exhaustive, but provides a framework for understanding the complexity in treatment of Duchenne.

1.  ACE Inhibitor (lisinopril, losartan, captopril, enalipril, perindopril, or ramipril)

2.  Corticosteroids (deflazacourt or prednisone)

3.  PDE5 Inhibitor (Viagra or Cialis)

4.  Beta blockers (carvedilol)

5.  Antioxidant (idebenone, CoQ10, juven, protandim, green tea extract, grape seed extract)

6.  Vitamins and Supplements (glutamine, L-arginine, calcium, magnesium, vitamin D, vitamin C, vitamin E, creatine monohydrate, vitamin A, vitamin B complex, L-carnitine, Selenomax)

7.  Antiinflammatory

8.  Other (D3, Hmb, HGH, Fosamax)

9.  Antidepressant or Mood Stabilizers (Zoloft, melatonin, zonegran)

10.  Physical Therapy (stretch, massage, pool, etc)

Duchenne Treatments as “Inferred” Standard of Care

Retrospective analyses have serious limitations and there are many cases where the results have been contradicted by more rigorous prospective studies.  While the results may serve as a great source for clinical trial ideas, retrospective interpretation of patient reported outcomes should be approached with extreme caution.  With that important disclaimer in mind, a “standard of care” has been inferred from analyses of patient reported outcomes.  Outcomes considered in Stan Nelson’s analysis of patient reported information were time to wheelchair, fractures, and scoliosis (ref 6).  This list is provided for reviewers as an anecdotal reference only and readers are encouraged to reference any academic papers that may arise from this study.  This does not constitute medical advice.

1. ACE inhibitors

2. Corticosteroids

3. Calcium

4. Vitamin D

5. CoenzymeQ10 (or Idebenone)

6. Protandim

7. Vitamin C

8. Creatine


Exon-skipping as a Prescient Example for PDUFA-V

Sarepta’s exon-skipping drug, Eteplirsen, highlights the need (and value) that exists for inclusion of Duchenne in PDUFA-V.

Eteplirsen showed no serious safety issues for a large panel of parameters tested and is currently the only drug to show an increase in the distance covered in the 6-minute walk test – this is a remarkable reversal of the disease course.  The crossover study design allowed for a particularly striking result, as the initial decline in the “placebo/delayed treatment” group seems to have reversed after receiving drug.  Although the patient numbers are low, the results are statistically significant and dramatic.  The reversal of disease course has been referred to as “non-random” and the data “breathtaking.”  Many patients are anxiously awaiting their opportunity to use the drug.  These results need thorough, unbiased consideration such that the stakeholders can make the best decisions on behalf of the patients.


Eteplirsen was granted fast track status, which recognizes that Duchenne is a serious disease and the drug addresses an unmet need.  Many patients and parents are interested in the possibility of accelerated approval, which allows the use of a scientifically supported surrogate outcome or marker in place of a clinical outcome where the drug has been shown to modulate the surrogate marker under “adequate and well-controlled studies.”  Based on the recent clinical trial reports, it appears that Eteplirsen is able to increase Dystrophin (in all patients tested) and this increased Dystrophin seems to provide an improvement in the 6MWT (for many patients tested), which is a clinically meaningful outcome for these patients.  While the 6MWT may be sufficient to indicate expedited approval in ambulatory boys similar to the ones in the trial, it’s possible that expression of Dystrophin may serve as a useful surrogate marker for broader use.

There are recent examples where conditional approval has been granted with data from limited patients, including Genzyme’s Cerezyme and Myozyme with 12 and 18 patients, respectively.  If broad-label, conditional approval for Eteplirsen is granted, ongoing analysis to monitor safety and efficacy may benefit from additional outcome measurements including respiratory function, cardiac function using MRI, or scoliosis – these would be particularly useful for evaluating safety and efficacy in the non-ambulatory setting.  Of these outcomes, cardiac MRI may be most useful.  It’s possible that Dystrophin expression may serve as a scientifically legitimate surrogate marker in particular patient subsets.

The Duchenne Alliance consists of over 30 non-profit foundations globally.  Members of the Duchenne Alliance are interested in promoting a thorough understanding of the considerations needed to assess permissible risk.  Wherever appropriate, members of the Duchenne Alliance aim to collaborate with the FDA and drug sponsors so the best decisions are made for the patient population.  Scientific data serves as the basis for assessing risk, but patient perspectives are vital to understanding permissible risk.



1. Infographic:  Overview of FDA Drug Approval Process

2.  FDA – Fast Track, Accelerated Approval, and Priority Review

3.  Management and Care of DMD – Part 1

4.  Management and Care of DMD – Part 2

5.  Management and Care of DMD – Free versions

6.  Stan Nelson’s Analysis of Patient Reported Outcomes

7.  Forbes – Breathtaking Slide from Sarepta

8.  Forbes – “That’s not random”

9.  Forbes – Discussion of approval with small patient numbers



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