Regulatory Decision Summary for Vyndaqel

The efficacy and safety of Vyndaqel (tafamidis meglumine) were assessed in a single double-blind, placebo-controlled Phase 3 trial (B3461028). The study enrolled 441 patients with cardiomyopathy due to hereditary or wild type transthyretin associated amyloidosis (ATTR-CM). Patients were randomized in a 1:2:2 ratio to receive Vyndaqel 20 mg, 80 mg, or placebo (88, 176, 177 patients, respectively) for 30 months. Patients were stratified by Transthyretin (TTR) status (wild type or variant) and New York Heart Association (NYHA) class at baseline.

The Vyndaqel 80 mg/day dose was emphasized in the study design based on greater TTR stabilization observed at this dose compared to the 20 mg dose in pharmacokinetic (PK) studies. However, the clinical relevance of a higher TTR tetramer stabilization with respect to cardiovascular outcomes is not known.

The primary efficacy endpoint was a comparison between the pooled Vyndaqel groups and placebo of a hierarchical combination of all-cause mortality followed by frequency of cardiovascular-related (CV) hospitalizations, calculated according to the Finkelstein-Schoenfeld method.

All-cause mortality and CV hospitalizations were lower in the pooled Vyndaqel group than in placebo-treated patients, at 29.5% versus 42.9% and 52.3% vs. 60.5%, respectively.

The difference in mortality between groups was attributable to CV related deaths, and this was reflected in the final approved Vyndaqel indication. Non CV-related deaths were seen in 5.3% of the pooled Vyndaqel group patients versus 4.7% of the placebo patients.

Statistically and clinically significant differences favouring Vyndaqel were seen for the key secondary endpoints, distance walked during the 6-minute walk test (6MWT), and scores on the Kansas City Cardiomyopathy Questionnaire-Overall Summary score (KCCQ-OS).

Overall, efficacy was similar between Vyndaqel doses. Results were also comparable between doses for the key secondary endpoints.

Potential benefit of the 80 mg dose over the 20 mg dose was suggested based on post-hoc exploratory subgroup analyses, which showed a greater reduction in the rate of increase in the cardiac biomarker N-terminal pro b-type natriuretic peptide (NT-proBNP) in the 80 mg group compared to the 20 mg group.

Consistent with the overall study population, a reduction in combined all-cause mortality and CV-related hospitalization was seen with Vyndaqel treatment for NYHA Class I, II, and III patients, as well as individual reductions in all-cause mortality, CV mortality, and CV-related hospitalization. An exception was an increased rate of CV-related hospitalizations in Class III patients, with 76.9% of pooled Vyndaqel treated patients hospitalized compared to 58.7% of placebo patients. For Class III patients, the rate of CV-related deaths was 47.4% vs 49.2% for the Vyndaqel and placebo groups, respectively. In light of the benefit seen across functional classes for all endpoints other than cardiovascular-related hospitalization, an indication was granted for Class I-III patients. There are no data in patients with NYHA Class IV.

Vyndaqel has not been studied in patients with severe hepatic impairment, and data are limited in patients with severe renal impairment.

The safety profile of Vyndaqel was comparable to placebo, and did not differ significantly according to dose. Potential risks include falls, pneumonia, changes in thyroid function and elevated liver function tests.

The most frequently reported events leading to discontinuation in any treatment group were cardiac failure, congestive cardiac failure, and cardiac amyloidosis.

Based on animal data, tafamidis is associated with a potential risk of reproductive and developmental toxicity. Limited clinical data are available and a risk to children born to women exposed to tafamidis during pregnancy cannot be excluded. Vyndaqel should not be used during pregnancy and use is not recommended in nursing women.

A Risk Management Plan (RMP) was submitted and considered acceptable.

Overall, the benefit risk assessment of Vyndaqel is considered favourable for the treatment of transthyretin amyloidosis in adult patients with wild-type or hereditary cardiomyopathy to reduce cardiovascular mortality and cardiovascular-related hospitalization.