The U.S. Food and Drug Administration (FDA) has granted approval to BridgeBio Pharma's Attruby (acoramidis) for the treatment of adult patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This rare and often fatal heart condition is characterized by the accumulation of misfolded transthyretin (TTR) protein in the heart, leading to heart failure and other severe complications. Attruby is the first and only approved therapy to demonstrate near-complete stabilization of TTR, addressing the underlying cause of ATTR-CM.
Clinical Efficacy and Safety
The FDA's decision was supported by data from the Phase 3 ATTRibute-CM trial, which enrolled 632 patients with symptomatic ATTR-CM. Participants were randomized in a 2:1 ratio to receive either Attruby or a placebo over a 30-month period. The results, published in The New England Journal of Medicine, demonstrated a statistically significant reduction in the combined endpoint of all-cause mortality and cardiovascular-related hospitalizations in the Attruby group compared to the placebo group.
Specifically, Attruby demonstrated a 42% reduction in the combined endpoint of all-cause mortality and cardiovascular events and a 50% reduction in cumulative cardiovascular events at 30 months compared with placebo. Additionally, patients treated with Attruby experienced improvements in quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire, and in functional capacity, as assessed by the six-minute walk test. The increase in N-terminal pro b-type natriuretic peptide (NT-proBNP) was only about half on Attruby as that of placebo.
In terms of safety, Attruby was generally well-tolerated in the clinical trial. Mild side effects such as diarrhea and upper abdominal pain were reported, but these were generally transient and resolved without intervention.
Mechanism of Action
Acoramidis, the active ingredient in Attruby, is an orally administered small molecule designed to stabilize the TTR protein. It mimics a naturally occurring "rescue mutation" of the TTR gene (T119M) that confers stability to the TTR tetramer, preventing its dissociation and subsequent misfolding and aggregation. By stabilizing TTR, Attruby preserves its native function as a transport protein for thyroxine and vitamin A, while also reducing the formation of amyloid fibrils in the heart.
Addressing an Unmet Need
ATTR-CM is a progressive and debilitating disease with a poor prognosis if left untreated. The prevalence of ATTR-CM is estimated to be higher than previously recognized, with recent estimates suggesting that it affects approximately 35 per 100,000 people. The condition results in stiffening of the heart walls, impairing its ability to pump blood effectively and leading to heart failure and increased risk of death.
Prior to the approval of Attruby, treatment options for ATTR-CM were limited. Pfizer's Vyndaqel (tafamidis) is another approved TTR stabilizer, but Attruby is the first to specify near-complete TTR stabilization on its label. Alnylam Pharmaceuticals' Amvuttra (vutrisiran), an RNA silencing therapy, is approved for treating nerve damage related to the disease.
Market and Availability
BridgeBio plans to price Attruby at $18,759.12 for a 28-day supply. While this is lower than the list price of Pfizer's Vyndaqel (approximately $268,000 per year), the twice-daily dosing regimen of Attruby may pose a challenge to patient adherence compared to the once-daily dosing of Vyndaqel.
BridgeBio has established partnerships to commercialize Attruby globally. Bayer holds exclusive rights to market the drug in Europe, while AstraZeneca's Alexion unit has rights in Japan. The company also offers a patient support program, ForgingBridges, to assist U.S. patients in accessing the therapy.
Expert Commentary
"Transthyretin cardiac amyloidosis is a progressive disease with a poor prognosis when left untreated. Having a new first line treatment option which provides excellent TTR stabilization and improves outcomes in this disease gives patients more options," said Martha Grogan, MD, consultant in the Department of Cardiovascular Diseases, and director of the Cardiac Amyloid Clinic of the Mayo Clinic.
"Encouraging data suggests Attruby reduces all-cause mortality and cardiovascular hospitalization as early as three months after initiation of therapy. With continued advances in therapy, this previously fatal disease is becoming a manageable chronic cardiovascular condition."
