New ATTR amyloidosis treatment

March 29, 2019

Amyloidosis is a disease of protein misfolding leading to amyloid fibril deposition in organs and tissues throughout the body. Once considered rare, amyloidosis is increasingly recognized as an important cause of disease, especially heart failure. Intramyocardial deposition of amyloid fibrils leads to increased wall thickness and ventricular dysfunction. Patient outcomes depend on amyloid type and severity of cardiac dysfunction.

AL and ATTR amyloidosis

More than 30 different precursor proteins may form amyloid, but only two types of amyloidosis commonly affect the heart: immunoglobulin light chain amyloidosis (AL) due to a plasma cell dyscrasia, and transthyretin amyloidosis (ATTR) due to misfolding of transthyretin (prealbumin), which transports thyroxine and retinol binding protein.

AL amyloidosis is rare. Approximately 3,000 new cases, with and without cardiac involvement, are diagnosed in the U.S. yearly. But ATTR cardiac amyloidosis is increasingly recognized as an important cause of heart failure, atrial arrhythmias and conduction system disease. Medical therapy for ATTR cardiac amyloidosis has only recently been proved effective, and treatment options are now rapidly evolving.

Two types of ATTR amyloidosis

There are two types of ATTR amyloidosis: ATTRv, the hereditary form caused by pathogenic mutations of the transthyretin gene, and ATTRwt, previously known as senile systemic amyloidosis, in which a pathogenic mutation is not present. The inheritance pattern in ATTRv amyloidosis is autosomal dominant with variable penetrance. Although most forms of ATTRv amyloidosis are rare, approximately 4 percent of the black population in the U.S. carries the Val142Ile variant (legacy nomenclature VAL122Ile).

Patients with ATTRv amyloidosis may present with a predominant neuropathic or cardiac phenotype or with an overlap of manifestations. Those with ATTRwt amyloidosis have mostly cardiac manifestations — with the exception of spinal stenosis, ruptured biceps tendon and carpal tunnel syndrome — or an overlapping phenotype. ATTRwt amyloidosis typically presents after the age of 60 and is more common in males, with symptoms of right heart failure, arrhythmias and conduction system disease. Carpal tunnel syndrome is present in 30 to 40 percent of patients at diagnosis and usually precedes cardiac manifestations by six to 10 years, offering an opportunity for early diagnosis and treatment.

ATTR amyloidosis treatment options

Treatment options for ATTR amyloidosis are rapidly expanding. Diflunisal is a transthyretin stabilizer shown to slow progression of neuropathy in patients with ATTRv amyloidosis. However, the nonsteroidal anti-inflammatory effects of diflunisal limit the ability to use this medication in patients with moderate or advanced heart failure.

A new drug, tafamidis, is a benzoxazole derivative without nonsteroidal anti-inflammatory properties. The drug binds to the thyroxine-binding sites and inhibits the dissociation of tetramers into monomers. Prior studies demonstrated that tafamidis slows the progression of peripheral amyloid polyneuropathy in patients with ATTRv amyloidosis.

ATTR-ACT trial

This observation led to the design and implementation of the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), a phase 3, multicenter parallel-design, double-blind, placebo-controlled, randomized clinical trial comparing tafamidis 80 mg and tafamidis 20 mg against placebo in patients with heart failure due to ATTR amyloidosis, NYHA Class I to III. Of the 548 patients screened, 441 were eventually randomized in a 2:2:1 scheme; 264 patients received the active drug, and 177 received placebo. There were no significant differences in clinical characteristics such as age, sex, race, TTR genotype, NYHA class or baseline NT-proBNP levels among the groups. Approximately 76 percent of the patients in both the treated and placebo groups had ATTRwt amyloidosis. Patients were followed for 30 months.

Trial results

Results of the trial, published in the Sept. 13, 2018, New England Journal of Medicine, are very encouraging. In the analysis of primary endpoints, all-cause mortality (29.5 percent vs. 42.9 percent) and the incidence of cardiovascular hospitalizations (0.48/year vs. 0.70/year) were lower in patients who received tafamidis compared with those who did not. Additionally, patients who received tafamidis had a slower decline in performance on both the six-minute walk and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score, with statistically significant benefit seen after six months.

Martha Grogan, M.D., study author and director of the Cardiac Amyloid Clinic at Mayo Clinic in Rochester, Minnesota, points out that the trial also raised intriguing questions. "Patients with less severe heart failure at the beginning of the trial had more benefit from treatment, suggesting that early diagnosis and treatment may be key to influencing the course of the disease," she says.

Additionally, reductions in all-cause mortality were not seen until 18 months, and reductions in cardiovascular hospitalizations were not seen until nine months after initiation of treatment. "This delay in benefit may be due to the treatment time needed to affect disease progression," says Dr. Grogan. Additional studies evaluating the efficacy of blocking production of transthyretin are in progress.

For more information

Mauer MS, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. New England Journal of Medicine. 2018;379:1007.