Efficacy and Safety Profile

Approval of VYNDAMAX was based on ATTR-ACT, a phase 3, multicenter, international, randomized, double-blind, placebo-controlled study, which evaluated pooled VYNDAQEL® (tafamidis meglumine) doses of 20 mg and 80 mg in 441 patients with wild-type or hereditary ATTR-CM—a single VYNDAMAX 61-mg capsule is bioequivalent* to VYNDAQEL 80 mg (four 20-mg capsules) and is not interchangeable on a per-mg basis.

Primary analysis

VYNDAQEL® (tafamidis meglumine) significantly reduced the combination of all-cause mortality and CV-related hospitalizations vs placebo over 30 months, p=0.0006
Primary analysis determined by the Finkelstein-Schoenfeld method, a hierarchical combination of both components, prioritizing all-cause mortality
*As determined by the predefined 90% confidence interval criteria of 80%-125% bioequivalence limits for tafamidis area under curve (AUC) and peak plasma concentration (Cmax) after repeated oral daily dosing for 7 days.1
Heart transplantation, combined heart and liver transplantation, and cardiac mechanical assist device implantation are treated as equivalent to death in this analysis.2
 
REFERENCES
1. Tankisheva E. A phase 1, open-label, randomized, crossover, multiple dose, pivotal bioequivalence study to compare PF-06291826 4 × 20 mg tafamidis meglumine and 61 mg: tafamidis free acid soft gelatin capsules administered under fasted conditions to healthy volunteers. Full Clinical Study Report [protocol B3461056]. July 23, 2018.
2. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016.

Individual components of the primary analysis

VYNDAQEL® (tafamidis meglumine) significantly reduced the risk of mortality and frequency of CV-related hospitalizations vs placebo
*As determined by the predefined 90% confidence interval criteria of 80%-125% bioequivalence limits for tafamidis area under curve (AUC) and peak plasma concentration (Cmax) after repeated oral daily dosing for 7 days.2
Heart transplantation, combined heart and liver transplantation, and cardiac mechanical assist device implantation are treated as equivalent to death in this analysis.1
Study Endpoints Overview
Statistical analysis of individual components of the primary analysis overview1:
The components of the primary analysis, all-cause mortality and CV-related hospitalizations, were evaluated individually. All-cause mortality was analyzed with the use of a Cox proportional-hazards model, with treatment and the stratification factors treated as covariates. The CV-related hospitalization analysis was based on a Poisson regression model with treatment, transthyretin (TTR) status (hereditary and wild-type), New York Heart Association (NYHA) baseline class (NYHA Classes I and II combined versus NYHA Class III), treatment-by-TTR genotype interaction, and treatment-by-NYHA baseline classification interaction terms as factors.
 
REFERENCES
1. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016.
2. Tankisheva E. A phase 1, open-label, randomized, crossover, multiple dose, pivotal bioequivalence study to compare PF-06291826 4 × 20 mg tafamidis meglumine and 61 mg: tafamidis free acid soft gelatin capsules administered under fasted conditions to healthy volunteers. Full Clinical Study Report [protocol B3461056]. July 23, 2018.

Key secondary endpoints

The treatment effect significantly favored VYNDAQEL® (tafamidis meglumine) vs placebo
A significant treatment effect favoring VYNDAQEL was first observed at month 6 and remained consistent through month 30 on both 6MWT distance and KCCQ-OS score.
*As determined by the predefined 90% confidence interval criteria of 80%-125% bioequivalence limits for tafamidis area under curve (AUC) and peak plasma concentration (Cmax) after repeated oral daily dosing for 7 days.1
KCCQ-OS=Kansas City Cardiomyopathy Questionnaire-Overall Summary.
6MWT=6-minute walk test; LS=least squares; SE=standard error.
Study Endpoints Overview
Key secondary endpoints overview2:
The treatment effect of tafamidis on functional capacity and health status was assessed by the 6-minute walk test (6MWT) and the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, respectively. Both key secondary endpoints evaluated change from baseline to month 30. The 6MWT is a measure of functional capacity. KCCQ-OS score assesses health status through scores from 0 to 100, with lower scores denoting poorer health status. Vital status at month 30 was assessed for all enrolled patients.
 
REFERENCES
1. Tankisheva E. A phase 1, open-label, randomized, crossover, multiple dose, pivotal bioequivalence study to compare PF-06291826 4 × 20 mg tafamidis meglumine and 61 mg: tafamidis free acid soft gelatin capsules administered under fasted conditions to healthy volunteers. Full Clinical Study Report [protocol B3461056]. July 23, 2018.
2. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016.

Safety profile

VYNDAMAX and VYNDAQEL® (tafamidis meglumine) safety profile
Adverse reactions
  • The frequency of adverse events (AEs) in clinical trials in patients treated with VYNDAQEL was similar to placebo
Specific populations
  • Pregnancy
    Based on findings from animal studies, VYNDAQEL and VYNDAMAX may cause fetal harm when administered to a pregnant woman
  • Lactation
    There are no available data on the presence of tafamidis in human milk, the effect on the breastfed infant, or the effect on milk production. Tafamidis is present in rat milk. When a drug is present in animal milk, it is likely the drug will be present in human milk. Breastfeeding is not recommended during treatment with VYNDAQEL and VYNDAMAX
 
ATTR-ACT
  • VYNDAQEL was well tolerated, with a safety profile similar to placebo
  • VYNDAQEL showed similar rates of discontinuation due to AEs vs placebo
*As determined by the predefined 90% confidence interval criteria of 80%-125% bioequivalence limits for tafamidis area under curve (AUC) and peak plasma concentration (Cmax) after repeated oral daily dosing for 7 days.1
 
REFERENCE
1. Tankisheva E. A phase 1, open-label, randomized, crossover, multiple dose, pivotal bioequivalence study to compare PF-06291826 4 × 20 mg tafamidis meglumine and 61 mg: tafamidis free acid soft gelatin capsules administered under fasted conditions to healthy volunteers. Full Clinical Study Report [protocol B3461056]. July 23, 2018.