Tafamidis (2) – Vyndaqel®

• Clinical trials
  • The benefit assessment is based on the randomised, placebo-controlled, double-blind, multicentre Phase III registration trial ATTR-ACT (B3461028), which investigated the efficacy and safety of tafamidis in patients with hereditary or wild-type ATTR-CM receiving standard therapy.

Adult patients with wild-type or hereditary transthyretin amyloidosis with cardiomyopathy (ATTR-CM)

• For adult patients with wild-type or hereditary transthyretin amyloidosis with cardiomyopathy (ATTR-CM), there is a hint of considerable additional benefit.
• In summary, for adult patients with wild-type or hereditary transthyretin amyloidosis with cardiomyopathy (ATTR-CM), a hint of a considerable additional benefit is derived from the statistically significant and clinically relevant advantages of tafamidis over placebo across three categories, taking into account the statistical power of the results for tafamidis.
• mortality
  • In the ATTR-ACT trial, all-cause mortality was defined as the time from randomisation to death from any cause.
  • Median survival was not reached in either study arm. A statistically significant advantage was observed for the endpoint of all-cause mortality in favour of tafamidis treatment.
• Morbidity – Hospitalisations
  • In the Tafamidis group, 71% of patients and 77% in the control group experienced at least one hospitalisation during the study.
  • The rates adjusted using Poisson regression showed a statistically significant rate ratio in favour of tafamidis for the frequency of any hospitalisations.
  • Overall, there was a statistically significant advantage for tafamidis in terms of hospitalisations at month 30; however, this is qualified by the effect modification observed according to the NYHA classification (Class I + II vs. Class III).
• Morbidity – Walking ability (6MWT)
  • By month 18, patients in the intervention group had, on average, a 39 m reduction in walking distance during the study, which was less pronounced than the 84 m reduction observed in patients in the control group.
  • There is a statistically significant advantage in favour of tafamidis for the mean change in walking distance compared with baseline (LS-MWD: 45.04 m), the extent of which cannot be conclusively assessed.
  • Overall, based on the ATTR-ACT study, there is a statistically significant effect in favour of treatment with tafamidis on walking ability at month 18, the extent of which cannot be conclusively assessed.
• Morbidity – Health status (EQ-5D-VAS)
  • Compared with baseline, health status as measured by the EQ-5D-VAS deteriorated by 2.21 points in the intervention group and by 9.96 points in the control group at month 30 in the ATTR-ACT study.
  • The difference according to LS-MWD at month 30, compared with baseline, is statistically significant between the treatment groups.
  • Based on Hedges’ g, the confidence interval for the effect lies entirely above the irrelevance threshold of 0.2, suggesting that at month 30 there is a clinically relevant, statistically significant advantage for tafamidis over placebo in terms of health status.
• Quality of life – Kansas City Cardiomyopathy Questionnaire (KCCQ)
  • The difference according to LS-MWD at month 30 is statistically significant between the treatment arms and, based on Hedges’ g, is also classified as clinically relevant.
  • Overall, a statistically significant, clinically relevant advantage for Tafamidis over placebo in terms of quality of life is observed at month 30.
• Side effects
  • 98.3% of patients in the tafamidis group experienced at least one AE, compared with 98.9% in the placebo group.
  • No statistically significant difference was observed between the treatment arms, either in the time to the first severe AE or in the incidence of severe AEs.
  • Among the Preferred Terms, statistically significant differences between the treatment arms in the hazard ratio were observed for ‘dyspnoea’ and ‘pleural effusion’ – also in favour of tafamidis.
• 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 over placebo was also observed for the additional endpoint ‘cardiovascular mortality’.
  • In the morbidity category, there is a statistically significant advantage for Tafamidis in the patient-relevant endpoint of walking ability (6MWT), the extent of which cannot be conclusively assessed. A statistically significant, clinically relevant advantage in favour of Tafamidis can also be inferred for health status (EQ-5D-VAS). 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 statistically significant and clinically relevant advantage over placebo.
  • In the ‘side effects’ endpoint category, there are no relevant differences in the overall rates between the treatment groups.
  • In summary, the statistically significant and clinically relevant advantages of Tafamidis over placebo, 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.

Courtesy translation only, please refer to the German original.