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The Duchenne Muscular Dystrophy (DMD) Continuum: The Case for Early Intervention and Long-term Treatment

Sponsored by PTC Therapeutics.

Duchenne muscular dystrophy (DMD) is a rare genetic disease that occurs when a mutation in the dystrophin gene prevents the cell from making a functional dystrophin protein.1,2 Dystrophin is a muscle membrane-associated protein and is critical to muscle fibers' structural and membrane stability in the skeletal, diaphragm and heart muscle—the absence of normally functioning dystrophin results in muscle fragility.3

The natural history of disease follows a relentless, progressive course that begins in infancy leading to muscle deterioration and ongoing decline in physical function.1,2

Early intervention is key to improving patients long term outcomes

The onset of symptoms of DMD occurs in early childhood, and some of the most noticeable signs can include difficulty walking and climbing stairs, a waddling gait, frequent falls, delayed speech and cognitive delay.1

As the disease progresses, loss of earlier milestones is predictive of future declines.6-8 Without adequate care and treatment, patients with DMD typically lose walking ability by their early teens, require ventilation support in their late teens and eventually experience premature death due to heart and lung failure.9 Early intervention is therefore crucial to increase the potential for slowing down the disease progression and to help preserve muscle function for as long as possible.1,10

Intervention with corticosteroid treatment has been a mainstay treatment option for DMD, regardless of disease-causing genetic mutation.1 The DMD standard of care (SoC) guidelines recommend starting corticosteroid treatment in younger children with DMD before a substantial physical decline.1 Emerging evidence confirming early and long-term corticosteroid treatment benefits have shown to slow disease progression and reduce disease complications, including preserving muscle strength and motor function, delaying loss of ambulation (LoA) and improving survival, among other benefits.1

Based on the associated benefits and clinical data, in 2017 the FDA approved EMFLAZA® (deflazacort), the first and only corticosteroid treatment for boys with DMD. Initially approved for children 5 years of age, it received an expanded indication in 2019 to treat children as early as 2 years and older which provided a treatment option for early intervention. The accumulative body of clinical and real-world evidence of deflazacort continue to demonstrate early and long-term treatment benefits across a number of key disease milestones throughout the DMD continuum, and show important differences when compared to an older generation corticosteroid prednisone, including;

Improved muscle strength and function: In a phase 3, double-blind, randomized, placebo-controlled, multicenter study evaluating muscle strength among 196 boys with DMD aged 5 to 15 during a 52-week period, deflazacort demonstrated a significant improvement in muscle strength versus prednisone from weeks 12 to 52.11

Delayed LoA: In two real-world studies, deflazacort prolonged ambulation by more than 2 years when compared with prednisone. In a 10-year follow up natural history observational prospective study conducted by the Cooperative International Neuromuscular Research Group (CINRG) evaluating age at LoA and side-effect profiles associated with different corticosteroid regimens in DMD, deflazacort demonstrated significant improvements in motor function versus prednisone over time. Boys taking deflazacort maintained the ability to walk (with no assistance) by 2.7 years longer than boys on prednisone.12 In a second real-world retrospective study at Cincinnati Children’s Hospital Medical Center (CCHMC) assessing outcomes among 435 boys with DMD receiving long-term treatment with deflazacort versus prednisone in real-world practice, median ages at LoA were 15.6 and 13.5 years among deflazacort and prednisone-initiated patients, respectively.13

Delayed onset of scoliosis and preserved lung function for longer: In the real-world retrospective study at CCHMC, onset of scoliosis was developed later in patients taking deflazacort than those taking prednisone. Over 11.9 years, 17.9% of patients developed scoliosis taking prednisone vs 7.9% taking deflazacort.13 Deflazacort also showed better preservation of pulmonary function with higher FVC %-predicted compared with patients receiving prednisone.13 Greater preservation of pulmonary function with deflazacort was also observed in a prospective natural history observational cohort study utilizing the CINRG database, which estimated a delay in median age at FVC <1L by approximately 2 years compared with treatment with prednisone.14

Overall, the totality of clinical evidence and treatment experience reinforce the clinical benefits of early intervention and foundational role of corticosteroids in the standard of care in DMD.

Importance of continuous treatment and care throughout the disease spectrum

In the context of the proven benefit of early intervention on patient long term outcomes, it’s important to continue to facilitate ongoing patient care to address the evolving needs of patients across the disease spectrum, including the transition from childhood to adulthood.

As such, international care guidelines for DMD recommend a coordinated, multidisciplinary approach to care, and continuous treatment with corticosteroids even after loss of ambulation.1

A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of DMD.1 It includes neuromuscular, respiratory, cardiac, orthopedic, endocrine and rehabilitative disciplines that evolve throughout the disease.1 Utilizing a multidisciplinary treatment approach integrates skills and knowledge from experts from multiple disciplines and provides a comprehensive treatment plan for the patient.

Continuous treatment with corticosteroids is beneficial to delaying disease progression, while maintaining quality of life (QoL) and extending functional independence and survival.1,14

Consistent results were reported in a study conducted by the CINRG, which demonstrated delayed disease progression through a combination of extended functional capabilities and a reduction in loss of strength in patients receiving corticosteroid treatment into adolescence. The study, which enrolled 440 boys with DMD (ages 2-28 years), demonstrated that all disease progression milestones were significantly extended in patients treated with corticosteroids for 1 year or longer by 2.8 to 8.0 years compared with treatment for less than 1 month or never treated.14 The authors concluded that corticosteroid therapy used over the entire lifespan of patients with DMD is associated with improvements in strength and function, health-related QoL and survival.14

Even after the loss of ambulation, ongoing corticosteroid therapy is important to help maintain functional independence by extending upper limb function.1,9 In the above mentioned CINRG study, treatment with deflazacort showed a greater delay across three milestones (age at loss of ability to stand from supine, LoA, loss of hand-to-mouth function with retained hand function) by 2.1 to 2.7 years in comparison with prednisone.14

Further to the recommended care considerations for prolonged benefits, tracking the patients physical and emotional development can help inform ongoing management and treatment decisions, as such, optimize QoL across the lifespan.1 Given that children with DMD may be treated with corticosteroids long-term, it’s important to consider the effects of treatment in order to address the patient’s evolving needs.

Differentiated medicine, like deflazacort, has a well-established safety profile and is recommended by the standard of care guidelines for DMD as first-line therapy when there are pre-existing weight and/or behavioral issues or switching to deflazacort when weight gain and/or behavioral issues persist with prednisone.1 Based on clinical evidence, deflazacort treatment is associated with fewer side effects than prednisone, including abnormal behavior and weight gain.11

These differences may be meaningful considerations for choosing and/or switching a corticosteroid.

A recent study evaluated the effects of switching from prednisone to deflazacort in patients with DMD in the US. Physicians were asked to report the reasons for switching from prednisone to deflazacort for each patient as well as their impressions of the patients progress as measured by Clinical Global Impression (CGI). In total, 55 treating physicians responded to the study survey with the majority giving “a desire to slow disease progression” and “reducing tolerability issues” as the main reason for switching their DMD patients from prednisone to EMFLAZA. In total, 62 DMD boys with a mean age of 6.2 years old were switched. During an average of 6 months' follow-up after switching, the CGI outcomes were consistent, demonstrating that treatment with deflazacort addressed the physicians’ primary reason for switching.15

With the improved standards of care and therapeutic strategies contributing to prolonged patient lifespan, it’s important to continue to drive the potential for better patient outcomes and longevity.

INDICATION

EMFLAZA® is a corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older.

IMPORTANT SAFETY INFORMATION

Contraindication: EMFLAZA is contraindicated in patients with a hypersensitivity to deflazacort or any of the inactive ingredients in EMFLAZA.

Warnings & Precautions

  • Alterations in Endocrine Function: Corticosteroids, such as EMFLAZA, can cause serious and life-threatening alterations in endocrine function, especially with chronic use. Monitor patients receiving EMFLAZA for Cushing’s syndrome, hyperglycemia, and adrenal insufficiency after EMFLAZA withdrawal. In addition, patients with hypopituitarism, primary adrenal insufficiency or congenital adrenal hyperplasia, altered thyroid function, or pheochromocytoma may be at increased risk for adverse endocrine events. Acute adrenal insufficiency or “withdrawal syndrome” can occur if corticosteroids are withdrawn abruptly, and can be fatal. The risk is reduced by gradually tapering the corticosteroid dose when withdrawing treatment. During times of medical stress, corticosteroid dosage may need to be increased.
  • Immunosuppression and Increased Risk of Infection: Increased risk of new, exacerbation, dissemination, or reactivation of latent infections, which can be severe and at times fatal; Signs and symptoms of infection may be masked. Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Warn patients who are on corticosteroids who have not had chickenpox or measles to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed.
  • Alterations in Cardiovascular/Renal Function: Monitor for elevated blood pressure. Dietary salt restriction and potassium supplementation may be needed.
  • Gastrointestinal Perforation: Increased risk of gastrointestinal perforation during corticosteroid use in patients with certain gastrointestinal disorders such as active or latent peptic ulcers, diverticulitis, recent intestinal anastomoses, and inflammatory bowel disease. Signs and symptoms may be masked.
  • Behavioral and Mood Disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis. Encourage patients to seek medical attention if symptoms develop or worsen.
  • Effects on Bones: The risk of osteoporosis increases with prolonged use of EMFLAZA, which can predispose patients to vertebral and long bone fractures. Monitor for decreases in bone density with chronic use of EMFLAZA.
  • Ophthalmic Effects: May include cataract formation, ocular infections, and glaucoma. If treatment with corticosteroids, including EMFLAZA, are continued for more than 6 weeks, monitor intraocular pressure.
  • Vaccination: Do not administer live or live attenuated vaccines to patients receiving immunosuppressive doses of corticosteroids. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting EMFLAZA.
  • Serious Skin Rashes: Toxic epidermal necrolysis has been reported with the use of deflazacort. Discontinue at the first sign of rash, unless the rash is clearly not drug related.
  • Effects on Growth and Development: Long-term use of corticosteroids, including EMFLAZA, may slow growth and development in children.
  • Thromboembolic Events: Observational studies have shown an increased risk of thromboembolism. Use EMFLAZA with caution in patients who have or may be predisposed to thromboembolic disorders.

Adverse Reactions: The most common adverse reactions (≥10% for EMFLAZA and greater than placebo) are Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis.

Drug Interactions: Give one third of the recommended dose of EMFLAZA when EMFLAZA is administered with strong or moderate CYP3A4 inhibitors. Avoid use of strong or moderate CYP3A4 inducers with EMFLAZA, as they may reduce efficacy.

Please see the accompanying full Prescribing Information

For medical information, product complaints, or to report an adverse event, please call 1-866-562-4620 or email at usmedinfo@ptcbio.com.

You may report side effects to FDA at 1–800–FDA–1088 or www.fda.gov/medwatch.

To learn more, please visit https://hcp.emflaza.com/.

REFERENCES
1. Birnkrant DJ, et al. Lancet Neurol.2018;17:251–267
2. van Ruiten HJ,et al.Arch Dis Child. 2014;99:1074–1077
3. Blake DJ, Weir A, Newey SE, Davies KE et al. Muscle. Physiol Rev. 2002 Apr;82(2):291-329
4. Mendell JR, Lloyd-Puryear M. Muscle Nerve. 2013;48:21–26
5. van Dommelen P, et al. Dev med Child Neurol. 2020; doi: 10.1111/dmc
6. Henricson EK,et al.Muscle Nerve. 2013;48:55-67
7. HumbertclaudeV,et al.EurJPaediatrNeurol. 2012;16:149-160
8. McDonald CM,et al.Muscle Nerve. 2013;48:32-54
9. Bushby K, et al. Lancet Neurol.2010;9:177-189.
10. Aartsma-Rus A, et al. J Pediatr. 2019; 204:305–313.e4.
11. Griggs RC et al. Neurology. 2016;87.
12. Bello L, et al. Neurology. 2015;85(12):1048-1055
13. Marden JR, et al. J Comp Eff Res. 2020;9(3):177-189.
14. McDonald CM, et al. Lancet. 2018;391:451-461.
15. Marden JR, Steroid Switching in the Treatment of Dystrophinopathies in the US: a Nationwide Chart Review of Patient Characteristics and Clinical Outcomes. Poster presented at the 2021 MDA Virtual Clinical & Scientific Conference of the Muscular Dystrophy Association (MDA), March 15-18, 2021.

This article is contributed and sponsored by PTC Therapeutics.
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© 2021 PTC Therapeutics. All rights reserved.

US-EMF-0334 I 11/09/2021