Ataluren (2) – Translarna®

• Clinical trials
  • In the multicentre, randomised, placebo-controlled, double-blind study 020, patients were stratified according to the factors of age, duration of corticosteroid use and distance walked in the 6-minute walk test (6MWT) at baseline, and were treated for 48 weeks.
  • In addition, the results of Study 007 are used for the benefit assessment. In this multicentre, three-arm, randomised, placebo-controlled, double-blind study, patients were stratified according to age, corticosteroid use and 6MWT at baseline, enrolled and treated for 48 weeks.

ambulatory patients aged 5 years and over with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene (nMDMD)

• For ambulatory patients aged 5 years and over with nMDMD, there is a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of ataluren as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in the treatment of the condition.
• mortality
  • No deaths occurred in either Study 020 or Study 007. Due to the lack of mortality data, it is not possible to assess the extent of the additional benefit.
• Morbidity – Change in the 6MWT
  • The 6-minute walk test is a standardised assessment of the distance patients can cover within 6 minutes. The 6MWT endpoint is patient-relevant for patients with Duchenne muscular dystrophy.
  • In Study 020, a statistically significant minor reduction in the decline in walking distance was observed only in the patient population with a baseline walking distance of ≥ 300 to < 400 metres; the difference between the placebo and ataluren groups was 42.89 metres (95% CI 11.75 m to 74.03 m; p=0.007). The lower confidence interval was therefore below the relevance threshold of 30 metres specified in the dossier.
  • In Study 007, there was no statistically significant difference in the 6MWT for the overall population. No separate analysis was available for the subpopulation of patients with a baseline walking distance of ≥ 300 to < 400 metres.
  • In the meta-analysis of the subpopulation of patients with a 6MWT of ≥ 300 to < 400 metres at baseline, a statistically significant minor decline was found over the study period.
  • In Study 020, a statistically significant minor deterioration in the ‘time to at least a 10% deterioration in the 6MWT’ was observed only in the patient population with a baseline 6MWT of < 300 metres. The median time was 56 days in the placebo group and 164 days in the intervention group (HR 0.48 [95% CI 0.24 m to 0.93 m], p = 0.031).
  • In Study 007, a statistically significant difference was observed between the groups. (HR 0.52 [95% CI 0.28 to 0.966], p = 0.039), but not for the time to a 10% improvement in the 6MWT, which was also assessed.
  • The proportion of patients with a ≥ 10% deterioration in the 6MWT was significantly higher in Study 007 for ataluren (43.9%) than for placebo (26.3%); in Study 020, these proportions—45.6% and 43.0% respectively—differed only slightly and not significantly.
  • In the meta-analysis of the subpopulation of patients with a baseline 6MWT of ≥ 300 to < 400 metres, no statistically significant difference was found for the endpoint ‘time to at least a 10% deterioration’.
• Morbidity – Timed Function Test (TFT) – Time taken to run/walk 10 metres
  • In studies 007 and 020, no statistically significant change was found in the time taken to run or walk 10 metres.
  • In the meta-analysis of studies 007 and 020, a statistically significant minor reduction in the time taken to run/walk 10 metres was found for ataluren in the 6MWT patient population with baseline values of ≥ 300 to < 400 metres.
• quality of life
  • In study 020, quality of life was assessed using the Paediatric Outcomes Data Collection Instrument (PODCI). No significant differences were observed.
  • No results are available for Study 007 regarding the measurement of quality of life using the PODCI; the data collected in that study using the Paediatric Quality of Life Inventory (PedsQL) showed no significant differences.
  • Based on the available results on quality of life, it is not possible to draw any conclusions regarding the extent of the additional benefit.
• Side effects
  • Adverse events (AEs) and serious adverse events (SAEs) were recorded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA), using the System Organ Class (SOC) and the Preferred Term (PT).
  • In Study 020, the adverse event profile was comparable between the ataluren and placebo groups. The proportion of patients with SAEs, as well as the proportion with severe and life-threatening AEs, differed only slightly between the ataluren and placebo groups. There were no therapy discontinuations due to AEs, and there were no deaths. The most common AEs classified by SOC/PT for the placebo and ataluren groups, respectively, were infections (43.5% vs. 54.8%) or those affecting the gastrointestinal tract (41.7% vs. 45.2%). The frequency of side effects differed only slightly between the groups.
  • No studies are available in patients with impaired renal or hepatic function. As ataluren is excreted via these organs, accumulation of the active ingredient (INN) and its metabolites may occur in the presence of such functional impairments. A higher proportion of patients with renal or hepatic impairment was observed in the ataluren group (13.0% for ataluren vs. 7.8% for placebo).
  • In Study 007, the proportion of patients with SAEs differed only slightly between the ataluren and placebo groups. There were no therapy discontinuations due to AEs, and no deaths occurred. The most common AEs in the placebo and ataluren groups were vomiting (38.6% vs. 56.1%), headache (24.6% vs. 38.6%) and diarrhoea (24.6% vs. 19.3%). The frequency of side effects differed only slightly between the groups.
  • Based on the available results regarding side effects, it is not possible to draw any conclusions regarding the extent of the additional benefit.
• Conclusion
  • The G-BA classifies the extent of the additional benefit of ataluren as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in the treatment of the condition. In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this represents a moderate improvement in therapy-relevant benefit, as, in addition to the positive results of the previously assessed Study 007, the study submitted after the limitation demonstrated a minor improvement in the ‘time taken to descend 4 steps’ and, for one patient population each, in the ‘distance walked in the 6MWT’ and‘time to 10% deterioration in the 6MWT’. The results on quality of life and side effects do not allow for any quantification of the additional benefit.

Courtesy translation only, please refer to the German original.