HTAQ Summer 2017 Duchenne Muscular Dystrophy New and Revitalized Drugs Bring Hope to Patients

By Xcenda


Duchenne Muscular Dystrophy: New and Revitalized Drugs Bring Hope to Patients

Duchenne muscular dystrophy (DMD) is a devastating muscle-wasting disease that affects only a small number of mostly adolescent males, but the rare disease is making international headlines as new treatments are stimulating current discussions on evidentiary requirements, pricing, and access of pharmaceuticals. In this article, we review the burden of DMD, treatment, and disease management approaches in development, and we examine recent regulatory and health technology assessment (HTA) appraisals.

Burden of Disease

DMD is a progressive muscle disorder caused by the lack of functional dystrophin protein that is critical to the integrity of skeletal, lung, and cardiac muscles. The disease is caused by large deletions in genetic code in about 60%–70% of patients, large duplications in genetic code in about 10% of patients, and small changes, including nonsense mutations, in about 15%–30% of patients. The X-linked hereditary rare disease is estimated to occur in approximately 1 in every 3,600–6,000 males worldwide.
The impact of DMD is often evident from a young age, as most patients are diagnosed at 5 years when their physical disability is apparent. As early as age 10, patients with DMD lose the ability to walk and experience potentially life-threatening lung and heart complications as they enter their teens and early 20s.
Beyond the clinical burden, the debilitating disease has a significant economic burden on patients and family caregivers. Recent models estimated the lifetime direct medical costs with standard of care ranged between £217,510 and £284,640, with total costs between £624,240 and £713,840 in the United Kingdom (UK).

DMD Treatment Landscape

Unfortunately, there is no cure for DMD. Since patients with DMD are missing dystrophin—the essential structural protein—most treatments in development aim to replace dystrophin, promote muscle repair and regrowth, and/or protect muscle from injury and degeneration. A comprehensive list of treatment approaches is presented in Table 1. Currently, it is estimated that between about half and two-thirds of male patients (57%–69%) with DMD are treated with steroids. Of those treated with steroids, 64% took prednisone, 22% took deflazacort, and 14% took both prednisone and deflazacort at different times.
DMD Treatment Strategies Under Development
Table 1. DMD Treatment Strategies Under Development

DMD Treatment Spotlight

While there are many medicines in development for DMD, few treatments have reached advanced clinical development and garnered extensive media coverage related to appraisal and market access. In this section, we examine 3 treatments, eteplirsen, ataluren, and deflazacort, more closely.

Eteplirsen (EXONDYS™)

On September 19, 2016, eteplirsen became the first drug approved for the treatment of DMD by the United States (US) Food and Drug Administration (FDA). The gene therapy works in patients who have a mutation of the dystrophin gene that is amendable to exon 51 skipping. For this subset of patients, the manufacturer, Sarepta Therapeutics, has demonstrated improved 6-minute walk test (6MWT) and an increase in dystrophin-positive muscle fibers. However, gaining US approval was not without challenges. The clinical trial included only 12 patients, and it was unclear if the evidence would provide sufficient certainty in the safety and efficacy of treatment. The FDA considered the lack of treatment options and lethal nature of the disease in its controversial decision, where critics and regulators were divided. Under the accelerated approval provisions, the manufacturer will be required to confirm the drug’s clinical benefit in a study designed to assess motor function improvement. Treatment cost is weight dependent as the approved dosing for eteplirsen is 30 mg/kg once weekly. Eteplirsen has a wholesale acquisition cost (WAC) of $16 per mg, which for a 30 kg patient would result in a weekly treatment cost of $14,400 and an annual treatment cost of $748,800. Payers have responded by either not covering or placing restrictive management criteria on the drug. A report by a Jefferies analyst estimates 5 national and 8 of 15 regional managed care organizations (MCOs) have reported they will largely deny coverage of eteplirsen. Many payers have placed restrictions on medication access relating to patient age and degree of ambulation as measured by the 6MWT.
Since the US approval, the European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for eteplirsen in the treatment of DMD amendable to exon 51 skipping. Validation of the MAA confirms the submission is accepted and formal review by EMA’s Committee for Human Medicinal Products (CHMP) will begin. The standard review time by CHMP is 210 days, which suggests a decision should be communicated by mid-summer 2017.

Ataluren (TRANSLARNA™)

On December 6, 2012, ataluren had its MAA validated by the EMA and on August 4, 2014 was granted conditional marketing authorization for the treatment of nonsense mutation DMD (nmDMD) in ambulatory patients aged 5 years and older. It is estimated that nonsense mutations account for approximately 13% of DMD cases. The EMA decision was based on positive phase 2b data, which demonstrated improved 6-minute walk distance (6MWD) compared to placebo. Patients taking ataluren walked on average 31.3 meters further, and only 26% of patients had a ≥10% decline in 6MWD compared to 44% of patients in the placebo group. As part of this conditional approval, the manufacturer PTC Therapeutics (PTC) was obligated to conduct additional studies of ataluren in nmDMD. Reflecting a continued positive risk-benefit assessment, the conditional marketing authorization was renewed on January 9, 2017.
Ataluren obtained early access cohort approval in Italy in November 2014, which is an early access program for orphan drugs already approved by EMA or in the late stage of a centralized approval process. In December 2014, Germany became the first country to have the treatment commercially available. However, access and reimbursement of ataluren have not been easily obtained. The Federal Joint Committee (G-BA) of Germany rated ataluren as a 3 – minor additional benefit (eg, reduction in symptoms), and, in 2016 following long negotiations, PTC reported that pricing recommendations following arbitration in Germany had resulted in an unsatisfactory amount, and the company had to consider withdrawal from the market. The dossier on the benefit assessment of ataluren published by the Institute for Quality and Efficiency in Healthcare (IQWiG) estimates the annual treatment cost per patient to be €169,474, which is variable based on average patient age and weight assumptions.
In the summer of 2016, ataluren was approved by the National Institute for Health and Care Excellence (NICE) for patients in the UK under a 5-year Managed Access Agreement that limits the financial risk to the National Health Service (NHS) as the manufacturer collects additional data. Under the Managed Access Agreement, use of ataluren would be reserved for patients aged 5 years and older with confirmed DMD resulting from a nonsense mutation who are able to walk 10 steps unaided. Additionally, guidance states that patients should only start treatment after a full set of standard baseline criteria have been obtained and that treatment should be discontinued no later than 6 months after the patient becomes fully non-ambulant. Under conditions of the Managed Access Agreement, PTC estimates an incremental quality-adjusted life year (QALY) gain of 8.562 and 4.561 by linear and stepped cost-consequence models, respectively. Based on the recommended dosage of 40 mg/kg of body weight per day, the total cost per person per year of treatment with ataluren in the UK is £246,448. Based on list price (before confidential discounts), PTC estimates that, based on the treatment of 35 patients, the total cost of treatment with ataluren will be £8.6 million in the first year, rising to £16 million after 5 years.
In the US, discussions for regulatory approval have extended for years. PTC submitted a rolling new drug application (NDA) in December 2014. Under the rolling NDA submission, data can be submitted and reviewed by the FDA as they become available, which may facilitate a quicker decision and earlier patient access. PTC anticipated the application would be finalized and approval obtained following completion of a confirmatory phase 3 clinical trial around the fourth quarter of 2015. In October 2015, phase 3 data showed patients had a 15-meter benefit in the 6MWT (P=0.213) and a significant benefit of 47 meters (P=0.007) in the prespecified patient population that had a 300–400 6MWT at baseline. Ultimately, PTC received a Refuse to File letter in February 2016, indicating the data submitted to the FDA would not be sufficient to complete a substantive review. Rather than continue appeal, PTC plans to submit an NDA over protest to the FDA. This pathway may be utilized by manufacturers when there is a disagreement with the FDA over the acceptability of the NDA submission. As part of this submission, PTC plans to submit additional efficacy analyses and data from its recent EMA renewal recommendation. The FDA has notified PTC that a Peripheral and Central Nervous Systems Drugs Advisory Committee meeting has been scheduled for September 28 to review the NDA for the treatment of nmDMD.

Deflazacort (EMFLAZA™)

Deflazacort is a corticosteroid that works by reducing inflammation and suppressing the activity of the immune system, which is overactivated in DMD. Until recently, the drug was not approved by the US FDA but was available in other countries. Since first being introduced in 1969, deflazacort has been marketed under various trade names, in Europe since the 1990s as a corticosteroid for the treatment of a variety of inflammatory conditions including asthma, arthritis, nephritic syndrome, systemic lupus erythematosus, and transplantation. Its marketing authorization in key markets pre-dates the current HTA processes, so little information is available on the cost-effectiveness of the treatment for DMD.
As with other treatments not approved in the US but deemed necessary for a particular patient, the drug was being imported by many patients for approximately $1,200 per year of treatment. On February 9, 2017, deflazacort was approved by the FDA for DMD patients 5 years of age and older. The decision was based on the safety and efficacy data from 2 key trials. In a study of 196 DMD patients between ages 5 and 15 who had symptom onset before age 5, patients taking deflazacort demonstrated improvements in a clinical assessment of muscle strength across a number of muscles compared to those taking placebo. Muscle strength was maintained in the deflazacort arm through the 52-week trial. In a separate study of 29 patients that lasted 104 weeks, deflazacort demonstrated a numerical advantage over placebo on an assessment of average muscle strength.
FDA approval may allow for increased patient access to deflazacort in the US. The initial list price set at $89,000 (before rebates and discounts) triggered criticism from patients, prescribers, and payers who sought greater transparency in price setting. Shortly after initial pricing was announced, Marathon Pharmaceuticals (Marathon), which had led commercial development, released an open letter to the Duchenne community as it placed commercialization plans on hold. The letter highlighted that Marathon-sponsored research increased understanding on proper dosing, potential side effects, and drug-to-drug interactions associated with deflazacort. While the company maintained its goal was to expand access to deflazacort, it noted that several factors influenced its price-setting decision making, including research and development (R&D) investment, resources needed to complete phase 4 studies, ability to fund future R&D, and ability to ensure broad patient access through insurer reimbursement and its patient assistance program. While the letter emphasizes that Marathon anticipates patients will only be responsible for a standard $20 out-of-pocket copay, there were access concerns across stakeholders. While commercial development plans for deflazacort were on hold, it was announced that the medicine’s licensing rights were sold to PTC as part of a $140 million+ deal. PTC has announced deflazacort will be launched at a new reduced annual net price of $35,000.


While recent drug approvals mark advances in clinical management, DMD remains a devastating disease in need of continued research. Examining the limited number of recent HTA and reimbursement decisions illustrates some of the common challenges in evidence generation and reimbursement experienced by rare disease manufacturers. However, with few formal appraisals complete, much remains unknown. To sustain investment in innovation that improves outcomes, there must be affordability for all stakeholders including patients, prescribers, payers, and society.


  • Barber BJ, Andrews JG, Lu Z, et al. Oral corticosteroids and onset of cardiomyopathy in Duchenne muscular dystrophy. J Pediatr. 2013 Oct;163(4):1080-1084.e1.
  •  Behind the Sarepta drug approval was intense FDA bickering. STAT. September 19, 2016. Accessed April 2017.
  • 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 Jan;9(1):77-93.
  • Bushby KM, Hill A, Steele JG. Failure of early diagnosis in symptomatic Duchenne muscular dystrophy. Lancet. 1999;353:55-78.
  • Castro AM. Drug Approvals International. Deflazacort. Accessed May 2017.
  • Did the FDA set ‘a dangerous precedent’ with its latest drug approval? STAT. September 19, 2016. Accessed April 2017.
  • FDA approves drug to treat Duchenne muscular dystrophy. Reuters. February 9 2017. Accessed February 2017.
  • Federal Joint Committee. Ataluren pharmaceutical directive. May 21, 2015. Accessed April 2017.
  • Gatlin A. Investor’s Business Daily. Anthem, Humana, United Push Back on Sarepta’s FDA-Approved DMD Drug. Accessed May 2017.
  • IQWiG. Ataluren dossier on the benefit assessment according to § 35a SGB V. 2016 (Aug)30. (2).pdf. Accessed May 2017.
  • Kim S, Campbell KA, Fox DJ, Matthews DJ, Valdez R; MD STARnet. Corticosteroid treatments in males with Duchenne muscular dystrophy: treatment duration and time to loss of ambulation. J Child Neurol. 2015 Sept;30(10):1275-1280.
  • Kole R, Krieg AM. Exon skipping therapy for Duchenne muscular dystrophy. Adv Drug Deliv Rev. 2015;87:104-107.
  • Landfeldt E, Alfredsson L, Straub V, Lochmüller H, Bushby K, Lindgren P. Economic evaluation in Duchenne muscular dystrophy: model frameworks for cost-effectiveness analysis. Pharmacoeconomics. 2017 Feb;35(2):249-258.
  • Marathon Pharmaceuticals. An Open Letter to the Duchenne Community. February 13, 2017. Accessed April 2017.
  • Mendell JR, Rodino-Klapac LR, Sahenk Z, et al; Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74(5):637-647.
  • NICE. Ataluren for treating Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene. July 20, 2016. Accessed April 2017.
  • PTC Therapeutics. Press releases. Accessed April 2017.
  • US Food and Drug Administration. FDA approves drug to treat Duchenne muscular dystrophy. February 9, 2017. Accessed April 2017.
  • US Food and Drug Administration. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. FDA: Silver Spring, MD. September 19, 2016. Accessed April 2017.