ro studies and modelpredictions show that tafamidis has a low potential to inhibit organic anion transporters OAT1 and OAT3 atclinically relevant concentrations. Tafamidis did not show a potential to inhibit Multi-Drug Resistant Protein
(MDR1) (also known as P-glycoprotein; P-gp), organic cation transporter OCT2, multidrug and toxin extrusiontransporters MATE1 and MATE2K and, organic anion transporting polypeptide OATP1B1 and OATP1B3.
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There was no evidence of an increased incidence of neoplasia in the transgenic (Tg)-rasH2 mouse followingrepeated daily administration for 26 weeks at daily doses of 0, 10, 30 or 90 mg/kg. There was no evidence ofincreased incidence of neoplasia in a 2-year carcinogenicity study in rats at exposures up to 18 times the AUCat the MRHD.
Mutagenesis
There was no evidence of mutagenicity or clastogenicity in vitro, and an in vivo rat micronucleus study wasnegative.
Impairment of Fertility
There were no effects of tafamidis meglumine on fertility, reproductive performance, or mating behavior in therat at any dose. Rats were dosed daily (0, 5, 15, and 30 mg/kg/day) prior to cohabitation (for at least 15 days forfemales and 28 days for males), throughout the cohabitation period to the day prior to termination of males andthrough to implantation of females (Gestation Day 7). No adverse effects were noted on male and female rats intoxicity, fertility, and mating behavior at any dose. The paternal and maternal no observed adverse effect levelfor reproductive toxicity of tafamidis meglumine is 30 mg/kg/day, approximately 4 times the MRHD on amg/m2
basis.
14. CLINICAL STUDIES
Efficacy was demonstrated in a multicenter, international, randomized, double-blind, placebo-controlled studyin 441 patients with wild type or hereditary ATTR-CM (NCT01994889).
Patients were randomized in a 1:2:2 ratio to receive VYNDAQEL 20 mg (n=88), VYNDAQEL 80 mg(administered as four 20-mg VYNDAQEL capsules) (n=176), or matching placebo (n=177) once daily for30 months, in addition to standard of care (e.g., diuretics). Treatment assignment was stratified by the presenceor absence of a variant TTR genotype as well as baseline disease severity (NYHA Class).
Transplant patientswere excluded from this study. Table 1 describes the patient demographics and baseline characteristics.
Table 1: Patient Demographics and Baseline Characteristics
Characteristic Pooled Tafamidis
N=264
Placebo
N=177
Age — years
Mean (standard deviation) 74.5 (7.2) 74.1 (6.7)
Median (minimum, maximum) 75 (46, 88) 74 (51, 89)
Sex — number (%)
Male 241 (91.3) 157 (88.7)
Female 23 (8.7) 20 (11.3)
TTR Genotype — number (%)
ATTRm 63 (23.9) 43 (24.3)
ATTRwt 201 (76.1) 134 (75.7)
NYHA Class — number (%)
NYHA Class I 24 (9.1) 13 (7.3)
NYHA Class II 162 (61.4) 101 (57.1)
NYHA Class III 78 (29.5) 63 (35.6)
Abbreviations: ATTRm = variant transthyretin amyloid, ATTRwt = wild type transthyretin amyloidThe primary analysis used a hierarchical combination applying the method of Finkelstein-Schoenfeld (F-S) toall-cause mortality and frequency of cardiovascular-related hospitalizations, which was defined as the numberof times a subject was hospitalized (i.e., admitted to a hospital) for cardiovascular-related morbidity.
Themethod compared each patient to every ot |
