Exon-Skipping Drugs for Duchenne Shown to be Expensive, Rarely Used, With High Discontinuation Rates


Despite initial enthusiasm, novel treatments for Duchenne muscular dystrophy face discontinuation challenges and lack long-term clinical efficacy data.

Aaron S. Kesselheim, MD, MPH, a professor of medicine at Harvard Medical School

Aaron S. Kesselheim, MD, MPH

A recently published study assessing novel Duchenne muscular dystrophy (DMD) treatments in postapproval clinical settings showed that these therapies are expensive and often discontinued, raising questions about the translation of drug trial findings. The study authors noted that additional data is needed to determine whether these high costs are accompanied by corresponding clinical benefits.1

Published in JAMA Network Open, the cross-sectional study included 223 routine care patients from national claims databases and 106 patients from pivotal DMD trials who were identified for comparison. Patients were followed for 1 year after the date of first use of such novel DMD treatments, which encompassed eteplirsen (Exondys 51; Sarepta Therapeutics), golodirsen (Vyondys 53; Sarepta), viltolarsen (Viltepso; NS Pharma), and casimersen (Amondys 45; Sarepta), all FDA-approved exon-skipping agents.

Led by Aaron S. Kesselheim, MD, MPH, a professor of medicine at Harvard Medical School, 58 patients initiated novel DMD drugs in MarketScan, 35 patients in CDM, and 130 patients in Medicaid. Among those in pivotal trials, 90.6% (n = 90) were White and 9.4% (n = 10) were another race or ethnicity, which differed from the racial and ethnic distribution of DMD drug users covered by Medicaid (White: 76.2% [n = 48]; Other: 23.8% [n = 15]; P = .01). Patients in the pivotal trials were younger than those in clinical settings, with a mean age of 8.5 (SD, 2.0) years vs 13.7 (SD, 6.5) years in MarketScan (P <.001), 11.9 (SD, 5.7) years in CDM (P <.001), and 13.4 (SD, 6.5) years in Medicaid (P <.001).

Most patients in pivotal trials were categorized into stage 1 or 2 DMD, defined as stable cardiac function, stable pulmonary function, and excluding those receiving pharmacological treatment apart from corticosteroids. Patients in such trials were categorized into stage 3 DMD if they used other cardiac medications. In the postapproval clinical setting, slightly more than one-third of patients with DMD were in disease progression stage 3 or 4 when initiating novel DMD treatments (MarketScan: 36.2% [n = 17]; P <.001; CDM: 41.9% [n = 13]; P <.001; Medicaid: 47.0% [n = 54]; P <.001).

Study results showed that approximately one-third of patients discontinued novel DMD treatments after approximately 7 months. Kesselheim et al noted that various factors could contribute to this nonpersistence, including “lack of efficacy, financial challenges, safety concerns related to side effects, and the presence of other health issues. Although our study did not assess the specific reasons for discontinuation, the literature suggests the lack of data on any long-term benefits and cardiac function improvements may be a limitation of exon-skipping treatments, which could be the reason for discontinuation."

Nearly all patients initiated eteplirsen, while golodirsen and viltolarsen were less commonly initiated, with only 3 (5.2%) and 2 patients (3.5%) in MarketScan, respectively, initiating these treatments. There was no use of casimersen, which was approved in 2021.

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In addition to patients discontinuing DMD treatment, 12 patients (20.7%) in MarketScan, 8 (22.9%) in CDM, and less than 11 (<8.5%) in Medicaid disenrolled from their health insurance after receiving their treatments. In a sensitivity analysis, higher discontinuation rates of DMD treatments were observed among patients with later stages (stages 3 and 4) of DMD compared with earlier stages (stages 1 and 2). These therapies can be expensive as well, with higher payer costs observed in MarketScan (mean, $1,300,246 [SD, $466,298) and CDM (mean, $1,343,809 [SD, $945,606]) among patients with complete 1-year follow-up data compared with all patients initiating novel DMD treatments.

"Older patients and patients at later stages of disease may respond differently to these drugs than the relatively younger and healthier patients in the clinical trials, and whether these treatments have any clinical benefit for patients at later stages of DMD remains a question that has not yet been formally tested," Kesselheim et al wrote.

The study investigators noted several factors to improving postapproval studies, including incorporating patients with similar prognostic factors. In addition, more data are needed on the actual clinical effectiveness and safety of novel DMD treatments, including in individuals who are older, of minority race and ethnicity, and with more advanced stages of the disease. Notably, several of the postmarking confirmatory trials for the drugs observed in the study are still incomplete many years after these drugs’ FDA approval.

1. Hong D, Avorn J, Wyss R, Kesselheim AS. Characteristics of patients receiving novel muscular dystrophy drugs in trials vs routine care. JAMA Netw Open. 2024;7(1):e2353094. doi:10.1001/jamanetworkopen.2023.53094
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