Pfizer Inc. announced the primary results from the Tafamidis phase 3 Transthyretin Cardiomyopathy (ATTR-ACT) study, which showed tafamidis significantly reduced the hierarchical combination of both all-cause mortality and frequency of cardiovascular-related hospitalizations compared to placebo over a 30-month period (P=0.0006) in patients with wild-type or variant (hereditary) transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is a rare, fatal, and underdiagnosed condition associated with progressive heart failure for which there are no approved pharmacologic treatments.

The late-breaking findings were presented during Hot Line Session 3 at the ESC Congress 2018 in Munich, Germany and simultaneously published online in the New England Journal of Medicine (NEJM).

“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,” said Brenda Cooperstone MD, senior vice president and chief development officer, rare disease, Pfizer Global Product Development. “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.”

The ATTR-ACT study showed 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 cardiovascular-related hospitalizations (0.48 vs 0.70 annualized rate; relative risk ratio = 0.68, 95% CI 0.56-0.81, P<0.0001), compared to placebo. This represents a 30% reduction in the risk of mortality and 32% reduction in the rate of cardiovascular-related hospitalization. The findings also showed a consistent directional mortality benefit of tafamidis across all sub-groups.

Secondary study endpoints also showed tafamidis reduced the decline in the six minute walk test distance (P<0.0001), a measure of functional capacity, and reduced the decline in aspects of quality of life measured by the Kansas City Cardiomyopathy Questionnaire – Overall Score (P<0.0001), compared with placebo at Month 30. Tafamidis was also well tolerated, with an observed safety profile comparable to placebo.

“ATTR-CM patients face a difficult diagnosis and treatment journey. By examining tafamidis in the ATTR-ACT trial, we were hoping the data for this oral agent would yield positive results for these patients and I am very pleased by the findings,” said Claudio Rapezzi MD, director, cardiology, School of Cardiovascular Diseases, University of Bologna, and ATTR-ACT study presenter at the ESC Congress 2018. “The ATTR-ACT data provide strong evidence that tafamidis improves survival, which could mean a significant advance for patients living with ATTR-CM today.”

In light of the seriousness of the disease and the lack of pharmacologic treatment options, Pfizer has established an expanded access treatment protocol to make tafamidis available to ATTR-CM patients who may benefit from treatment prior to regulatory approval. The expanded access treatment protocol is posted on clinicaltrials.gov (NCT02791230), and additional information about requesting access may be found at www.pfizercares.com. Access to these programs may vary by country; physicians may contact their local Pfizer Medical department for further information. Interested ATTR-CM patients should contact their local physician to discuss whether accessing tafamidis may be an appropriate option.

Tafamidis was granted Orphan Drug Designation for ATTR-CM in both the EU and US in 2012 and in Japan in 2018. In June 2017 and May 2018, respectively, the US Food and Drug Administration (FDA) granted tafamidis Fast Track and Breakthrough Therapy designations for ATTR-CM. Additionally, in March 2018, the Ministry of Labor Health and Welfare in Japan granted SAKIGAKE designation to tafamidis for this indication.

ATTR-ACT is a phase 3 international, multicenter, double-blind, placebo-controlled, randomized, 3-arm clinical study in 441 patients with ATTR-CM that investigated the efficacy, safety, and tolerability of an oral daily dose of 20 mg or 80 mg tafamidis meglumine capsules compared to placebo. The study included both patients with variant (ATTRm), or hereditary, form of the disease, and those with wild-type (ATTRwt) form, which is not hereditary and may occur as people age. The primary analysis of the study, which compared a pooled tafamidis (80 mg and 20 mg) treatment group to placebo, was the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalizations over a 30-month period in patients with transthyretin amyloid cardiomyopathy.

Tafamidis is an investigational treatment for transthyretin amyloid cardiomyopathy and is not approved for this indication.

ATTR-CM is a rare, progressive, and underdiagnosed disease caused by destabilization of a transport protein called transthyretin, which is composed of 4 identical sub units (a tetramer). In ATTR-CM, heart failure occurs when unstable tetramers dissociate, resulting in misfolded proteins that aggregate into amyloid fibrils and deposit predominantly in the heart.