Tafamidis (4) – Vyndaqel®

• Clinical trials
  • The benefit assessment is based on the randomised, placebo-controlled, double-blind, multicentre Phase III registration trial ATTR-ACT, which investigated the efficacy and safety of tafamidis in patients with hereditary or wild-type ATTR-CM receiving standard care.
  • The ATTR-ACT trial is a multicentre, double-blind, three-arm RCT in which two different doses of tafamidis, each administered as an add-on to best-standard care (BSC), are compared with placebo plus BSC.

Adult patients with wild-type or hereditary transthyretin amyloidosis with cardiomyopathy

• mortality
  • In the ATTR-ACT study, all-cause mortality was defined as the time from randomisation to death from any cause.
  • A statistically significant advantage was observed for the endpoint of all-cause mortality in favour of tafamidis treatment.
  • A statistically significant effect in favour of tafamidis can be inferred for cardiovascular mortality, which was also analysed.
• Morbidity – Hospitalisations (total)
  • In the tafamidis group, 71% of patients experienced at least one hospitalisation during the study, compared with 77% in the control group. The difference was not statistically significant.
  • The rates adjusted using Poisson regression yielded a statistically significant rate ratio in favour of tafamidis for the incidence of any hospitalisation.
  • Interaction tests revealed an effect modification by the NYHA classification (Class I + II vs. Class III) for the frequency of any hospitalisations. In the NYHA Class I + II patient population, a statistically significant treatment effect in favour of tafamidis was observed. This effect was reversed in the NYHA Class III patient population to the detriment of tafamidis; however, this disadvantage is not statistically significant.
  • Overall, there was a statistically significant advantage for tafamidis in terms of hospitalisations at month 30; however, this is qualified by the observed effect modification according to NYHA classification (Class I + II vs. Class III).
• Quality of life – Kansas City Cardiomyopathy Questionnaire (KCCQ)
  • For the health-related quality of life endpoint, a statistically significant advantage was observed for Tafamidis + BSC compared with placebo + BSC in terms of time to a deterioration of ≥ 5 points on the KCCQ-OSS.
  • The responder analysis at the 15% scale range (deterioration of ≥ 15 points on the KCCQ-OSS) also showed a clear, statistically significant advantage in favour of tafamidis compared with BSC.
• Side effects – overall rates of SAE, discontinuation due to AEs
  • For the endpoints of SAE and discontinuation due to AEs, there were no statistically significant advantages or disadvantages of Tafamidis + BSC compared with placebo + BSC at month 30 in the ATTR-ACT study.
• Overall assessment/Conclusion
  • In the mortality category, a statistically significant advantage in favour of treatment with tafamidis was observed for all-cause mortality. A statistically significant advantage for Tafamidis compared with BSC was also observed for the additional endpoint ‘cardiovascular mortality’.
  • In the morbidity category, there is a statistically significant advantage for Tafamidis in terms of the patient-relevant endpoint of walking ability (6MWT), although the extent of this advantage cannot be conclusively assessed. With regard to health status (EQ-5D-VAS), a statistically significant, clinically relevant advantage in favour of Tafamidis can be inferred. Furthermore, an overall advantage for Tafamidis is observed in the morbidity endpoint ‘hospitalisations’, although this is qualified by the effect modification observed with the NYHA classification (Class I + II vs. Class III).
  • In the quality of life category, Tafamidis shows a clear, statistically significant advantage over BSC, which is particularly evident in the responder analysis covering the 15% scale range. Overall, there is a significant advantage in terms of health-related quality of life.
  • In the side effects endpoint category, there were no relevant differences in the overall rates between the treatment groups. For the patient-relevant endpoint ‘dyspnoea’, the ATTR-ACT study shows a statistically significant overall advantage in favour of Tafamidis over BSC for the PT at month 30.
  • In summary, the statistically significant and clinically relevant advantages of tafamidis over BSC, which are evident across three categories, are, on balance and based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease, the written submissions and the oral hearing, are classified as considerable in their extent.
  • On balance, the uncertainties mentioned do not justify a downgrading of the certainty of the findings; consequently, there is an indication of additional benefit.
• Overall assessment/Conclusion
  • In the mortality category, a statistically significant advantage in favour of treatment with Tafamidis is evident for overall mortality. In the additional endpoint ‘cardiovascular mortality’, which was also taken into account, there is a statistically significant advantage for Tafamidis compared with best standard care (BSC).
  • In the morbidity category, there is a statistically significant advantage for Tafamidis in terms of the patient-relevant endpoint of walking ability (6MWT), although the extent of this advantage cannot be conclusively assessed. With regard to health status (EQ-5D-VAS), a statistically significant, clinically relevant advantage in favour of Tafamidis can be inferred. Furthermore, an overall advantage for Tafamidis is observed in the morbidity endpoint ‘hospitalisations’; however, this is qualified by the effect modification observed with the NYHA classification (Class I + II vs. Class III).
  • In the quality of life category, Tafamidis shows a clear, statistically significant advantage over BSC, which is particularly evident in the responder analysis covering the 15% scale range. Overall, there is a significant advantage in terms of health-related quality of life.
  • In the side effects endpoint category, there were no relevant differences in the overall rates between the treatment groups. For the patient-relevant endpoint ‘dyspnoea’, the ATTR-ACT study shows a statistically significant overall advantage in favour of Tafamidis over BSC for the PT at month 30.
  • In summary, the statistically significant and clinically relevant advantages of tafamidis over BSC, which are evident across three categories, are, on balance and based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease, the written submissions and the oral hearing, are classified as considerable in their extent.
  • On balance, the uncertainties mentioned do not justify a downgrading of the certainty of the findings; consequently, there is an indication of additional benefit.

Courtesy translation only, please refer to the German original.