Ataluren (1) – Translarna®

• Clinical trials
  • The basis for the assessment of the extent of the additional benefit is the marketing authorisation trial PTC124-GD-007-DMD, hereinafter referred to as Trial 007.
  • Study 007 is a multicentre, randomised, placebo-controlled, blinded Phase 2b dose-finding study with a parallel-group design (1:1:1) comprising three treatment arms (placebo, ataluren 10/10/20 mg/kg body weight (BW) daily, ataluren 20/20/40 mg/kg BW daily).

Ataluren for the treatment of Duchenne muscular dystrophy (DMD) resulting from a nonsense mutation in the dystrophin gene (nmDMD) in ambulatory patients aged 5 years and over

• In summary, the extent of the additional benefit of ataluren is assessed as follows: there is a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of ataluren as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in treating the condition.
• In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a previously unachieved moderate improvement in treatment-related benefit, as, in particular, a reduction in the proportion of patients experiencing at least a 10% deterioration and a statistically significant prolongation of the time to at least a 10% deterioration in walking distance in the 6MWT are achieved.
• mortality
  • No deaths were observed in the study; mortality was not an efficacy endpoint of the registration trial 007.
  • With regard to mortality, no conclusions can be drawn from the available results regarding the extent of the additional benefit.
• Morbidity – Change in the 6-minute walk test
  • The estimated treatment difference between the ataluren and placebo arms of 26.4 m in favour of ataluren was not statistically significant in the primary (pre-specified) analysis.
  • It was only in the potentially highly biased post-hoc analysis that a statistically significant effect, considered clinically relevant, was demonstrated, with an absolute difference in walking distance of 31.7 m (95% CI 5.1; 58.3), p=0.0367.
  • There is currently no evidence regarding a ‘minimal clinically important difference’ (MCID) for the 6MWT in DMD patients.
  • Pre-specified exploratory analyses were conducted for the proportion of patients with at least a 10% change in the 6MWT, as well as for the time to a change of at least 10%. These revealed a statistically significantly higher proportion of so-called ‘progressors’ in the placebo arm, i.e. patients with a deterioration of at least 10%.
  • The results for the time to deterioration were consistent with those for the proportion of deteriorations and were also statistically significant.
  • No statistically significant results were observed for so-called ‘responders’, i.e. patients with an improvement of at least 10%.
  • In the patient population analysis, which was carried out using a post hoc modified analysis model and was therefore potentially highly biased, significant results were observed for differences in walking distance in the 6MWT at 48 weeks for those aged < 9 years (mean difference 38 m, 95% CI 1; 76, p = 0.045), for patients on corticosteroid therapy (mean difference 36 m, 95% CI 2; 70, p = 0.036) and for patients with a baseline 6MWT distance of <350 m (mean difference 50 m, 95% CI 6; 94, p = 0.026).
• Morbidity – changes in proximal muscle function
  • The so-called Timed Function Tests (TFTs) enable the measurement of muscle function and may be considered relevant to disease progression.
  • The results for the TFTs ‘Rising from a supine position’, ‘Climbing or descending 4 steps’ and ‘Walking/running 10 metres’ showed no statistically significant effects in favour of ataluren.
  • The analyses of the kITT population for the TFT ‘time taken to climb 4 steps’, submitted during the commenting procedure, were statistically significant in favour of ataluren; however, the high potential for bias in post-hoc analyses must be taken into account here.
• quality of life
  • The Generic Core Scales package of the PedsQL Inventory, comprising the domains of physical, emotional, social and school functioning, was used to assess quality of life.
  • The PedsQL Fatigue Instrument was used in addition to the PedsQL.
  • No statistically significant difference was found between the treatment groups for any of the domains assessed, including the Fatigue Scale.
  • The total score differed only minimally and was not statistically significant between the treatment groups.
  • Taken together, the available results do not allow any conclusions to be drawn regarding the extent of the additional benefit in terms of quality of life.
• 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).
  • The adverse event profile was comparable between the ataluren and placebo groups.
  • No patients experienced therapy discontinuation due to AEs, and there were no deaths.
  • The most common AEs in the placebo and ataluren groups, respectively, were vomiting (38.6% vs. 56.1%), headache (24.6% vs. 38.6%), diarrhoea (24.6% vs. 19.3%), nasopharyngitis (22.8% in both groups), fever (21.1% vs. 24.6%), cough (19.3% vs. 15.8%) and upper abdominal pain (15.8% in both groups).
  • The frequency of side effects did not differ significantly between the groups.
  • No notable differences between the groups were observed with regard to dose interruptions or dose reductions.
  • The subgroup analysis revealed that patients taking corticosteroids were more likely to experience headaches, back pain, influenza, pain in the extremities and hypertension, but less likely to experience fever, disease progression, rhinitis, viral gastroenteritis, rhinorrhoea, lymphadenopathy, sinusitis, viral infections, skin lesions and seasonal allergies.
  • No relevant differences between the treatment groups were observed.
  • The adverse reaction profile showed no discernible dependence on age or on the 6MWT at baseline.
  • The European Medicines Agency (EMA) provides an indication of interactions with potentially nephrotoxic substances, in particular intravenously administered aminoglycosides; consequently, these medicines were not permitted in the study.
  • Furthermore, no studies have been conducted in patients with impaired renal or hepatic function, meaning that safety in these patient populations has not been investigated.
  • Taken together, no conclusions regarding the extent of the additional benefit can be drawn from the available results with regard to side effects.

Courtesy translation only, please refer to the German original.