Tafamidis Reduces Mortality in Patients with Transthyretin Amyloid Cardiomyopathy

Primary results yielded from a phase 3 trial demonstrate that Pfizer's tafamidis significantly reduced the hierarchical combination of all-cause mortality and frequency of cardiovascular-associated hospitalizations compared with placebo over 30 months in patients with wild-type or hereditary transthyretin amyloid cardiomyopathy (ATTR-CM).

The results were published in the New England Journal of Medicine and presented at the European Society of Cardiology Congress 2018 held in Munich, Germany.

“ATTR-CM is a rare, progressive and universally fatal disease associated with progressive heart failure, and for which there are no approved pharmacologic treatments. We're committed to doing everything we can to help to educate and raise awareness for this rare disease and ultimately help patients in need of treatment,” a representative from Pfizer told Rare Disease Report^®. “Tafamidis, our investigational oral therapy for this condition, remains the only potential treatment that has been evaluated in a Phase 3 trial designed to assess the safety and efficacy, specifically in patients with ATTR-CM.”

For the multicenter, double-blind, placebo-controlled trial, investigators randomized 441 patients with ATTR-CM between the ages of 18 and 90 into a 2:1:2 ratio to receive either 80 mg of tafamidis, 20 mg of tafamidis, or placebo once-daily for the duration of 30 months. Upon completion, patients were offered enrollment in an extension study.

For their primary analysis, the investigators evaluated all-cause mortality and the frequency of cardiovascular-associated hospitalizations according to the Finkelstein-Schoenfeld method, the authors write. The change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) were the key secondary endpoints of the trial.

The investigators found that tafamidis significantly reduced all-cause mortality (29.5% vs. 42.9%; hazard ratio = 0.70, 95% confidence interval [CI] 0.51-0.96, P=0.0259) and rates of cardiovascular-associated hospitalizations (0.48 vs. 0.70 annualized rate; relative risk radio = 0.68, 95% CI 0.56-0.81, P<0.0001) in the 264 patients who received it as compared with the 177 patients who were given the placebo.

This represents a 30% total reduction in the risk of mortality and a 32% reduction in the rate of cardiovascular-associated hospitalizations.

Furthermore, a consistent directional mortality benefit of tafamidis has been demonstrated across all sub-groups.

Tafamidis was found to be associated with a lower rate of decline in distance for the 6-minute walk test (75.68 m [standard error, ±9.24, P<0.001]) compared with placebo with differences first observed at 6 months. Additionally, tafamidis resulted in a lower rate of decline in KCCQ-OS score, in which higher scores correlate with better health status, as compared with placebo (13.65 [standard error, ±2.13; P<0.001]).

The safety profiles of tafamidis and the placebo were found to be comparable. Furthermore, the investigators did not note a meaningful difference in the safety of the 2 different doses of the drug. The adverse events observed in the study ranged from mild to moderate in severity; permanent discontinuation of treatment to adverse events was less common in the group who received tafamidis, according to study authors.

The investigators concluded that treatment with tafamidis reduced all-cause mortality and cardiovascular-associated hospitalizations as well as the decline in functional capacity and quality of life.

“We believe the ATTR-ACT study findings bring us a significant step closer to our goal of providing an urgently needed therapy for a serious and often fatal disease,” Brenda Cooperstone, MD, senior vice president and chief development officer, Rare Disease, Pfizer Global Product Development, said in a recent statement. “We look forward to continuing discussions with global regulatory authorities about the potential of tafamidis as a treatment option for people living with ATTR-CM.”

Pfizer has established an expanded access treatment protocol which allows patients with ATTR-CM who could benefit from treatment to access the drug prior to regulatory approval; however, access can vary by country. As such, physicians should contact their local Pfizer Medical department for further information.