Ataluren Delays Loss of Ambulation in Patients With Nonsense Mutation DMD

Panayiota Trifillis, PhD

Data from a recent study suggest that ataluren (Translarna; PTC Therapeutics) delays loss of ambulation in patients with nonsense mutation Duchenne muscular dystrophy (DMD).

In Study 019, patients received ataluren for a mean of 988 days (2.7 years) before loss of ambulation (LoA). These patients had a median age of 15.5 years at LoA, compared to 13.3 years in those receiving standard of care (SoC; P = .0006). Ataluren with SoC was associated with a delay in loss of ambulation of around 2.2 years compared to SoC alone. 

These findings were presented virtually at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference 2021, March 15-18, by study co-author Panayiota Trifillis, PhD, vice president and head, Global Scientific Affairs, Global Medical Affairs, PTC Therapeutics.

Trifillis and colleagues wrote that “approximately 10% [to] 15% of patients have a nonsense mutation (nm) in the DMD gene, resulting in the generation of a premature stop codon, which prevents translation of a full-length, functional dystrophin protein. Ataluren promotes readthrough of the in-frame premature stop codon, enabling production of full-length dystrophin.”

Ataluren 40 mg/kg per day is currently indicated for the treatment of nmDMD in ambulatory patients over the age of 2 years in member states of the European Union, Iceland, Israel, Kazakhstan, Liechtenstein, Norway, and South Korea, as well as in patients over 5 years of age in Brazil and Chile.

READ MORE: Muscular Dystrophy Association Virtual Conference to Feature Latest Advances in Neuromuscular Therapy and Clinical Care

Trifillis and colleagues conducted a post-hoc analysis of Study 019 (NCT01557400), a phase 3, international, multicenter, open-label, long-term safety study of 94 male patients with nmDMD that received ataluren plus SoC (corticosteroid and palliative therapies) for up to 240 weeks. Most patients were previously enrolled in either the ataluren phase 2b study (Study 007) and/or the subsequent open-label extension study (Study 007e); other patients participated in the phase 2a study (Study 004).

They compared the patients in Study 019 to patients in The Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS; NCT00468832), who received SoC. The CINRG DNHS was a prospective, longitudinal study of 440 patients with DMD followed up between 2006 and 2016 at international 20 centers as part of CINRG.

Trifillis and colleagues used propensity score matching (PSM) to match 60 patients from each study. The CINRG DNHS patients had an average of onset of 3.9 years (standard deviation [SD], 1.7), while age of onset data was unavailable in Study 019. Study 019 patients had an average age of initiating corticosteroid use of 8.6 years (SD, 3.6) and CINRG DNHS patients had an average age of initiation of 7.4 years (SD, 2.2).

Of the PSM patients in Study 019, 24 (40.0%) were either treatment-naïve or treated for less than 1 month with deflazacort, 1 (1.7%) was treated with deflazacort for over a month but less than a year, and 35 (58.3%) were treated with deflazacort for at least a year.

Of the PSM patients in CINRG DNHS, 27 (45.0%) were either treatment-naïve or treated for less than 1 month with deflazacort, 2 (3.3%) were treated for over a month but less than a year, and 31 (51.7%) were treated with deflazacort for at least a year (P = 0.6865). Treatment durations with other corticosteroids were also similar (P = 0.6816).

Trifillis and colleagues also assessed pulmonary function in PSM non-ambulatory patients (n = 45), as measured by forced vital capacity (FVC), with the use of Kaplan-Meier analysis to predict decline. They found that ataluren with SoC was associated with a delay in the age at predicted FVC less than 60% by approximately 2.3 years compared to SoC alone.

The median age at FVC less than 1L was 23.8 years for non-ambulatory patients in the CINRG DNHS study. One (2.2%) non-ambulatory patient from Study 019 and 7 (15.6%) non-ambulatory patients from the CINRG DNHS experienced a decline to an FVC of less than 1L. Predicted endpoints could not be calculated due to a low number of events.

“It is premature to draw conclusions about differences in pulmonary function as measured by FVC<1L between non-ambulatory patients in these 2 cohorts, because too few patients in Study 019 reached this pulmonary endpoint,” Trifillis and colleagues wrote.

Study 019 patients had a median age of 18.1 years at predicted FVC less than 60%, while CINRG DNHS patients had a median age of 15.8 years at predicted FVC less than 60% (P = .0180). Study 019 patients had a median age at predicted FVC less than 50% of 19.1 years, while CINRG DNHS patients had a median age of 17.9 years at this predicted endpoint (P = .01116).

Overall, 23 (51.1%) non-ambulatory patients from Study 019 and 32 (71.1%) from CINRG DNHS experienced a decline to predicted FVC less than 60%. Fourteen (31.1%) from Study 019 and 23 (51.1%) from CINRG DNHS experienced a decline to predicted FVC less than 50%.

“Our data show that long-term treatment with ataluren in addition to SoC delayed LoA and may delay pulmonary function decline in patients with nmDMD. Longer follow-up will be required to assess the clinical efficacy of ataluren in terms of pulmonary function more comprehensively,” Trifillis and colleagues concluded.

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REFERENCE

McDonald CM, Muntoni F, Rance M, et al. Ataluren delays loss of ambulation and decline in pulmonary function in patients with nonsense mutation Duchenne muscular dystrophy. Presented at: MDA Clinical and Scientific Conference 2021; March 15-18.