Work begins on first ATTR-CM study of its kind
The first asymptomatic patient with a known pathogenic transthyretin (TTR) variant have been dosed in the ACT-EARLY trial with the drug acoramidis (Attruby) to see if it can prevent progression to transthyretin amyloid disease.
It is the first trial to look at a drug to prevent the development of transthyretin amyloid disease. If successful, it may be the first prevention strategy for transthyretin amyloid cardiomyopathy (ATTR-CM), which leads to heart failure, and polyneuropathy (ATTR-PN), which causes damage to the peripheral nerve system.
ACT-EARLY is testing the hypothesis that the prophylactic treatment of asymptomatic carriers of a pathogenic TTR variant with acoramidis, a selective, small-molecule, orally administered, near-complete TTR stabilizer, could delay the disease onset of amyloidosis. It also may prevent the development of variant ATTR (ATTRv), which is also known as hereditary ATTR (hATTR). If the trial shows the drug can prevent amyloidosis, specialists believe it could be a game-changer for patients.
The drug, sold by BridgeBio, gained U.S. Food and Drug Administration (FDA) clearance in November 2024.
“Current approved therapies for ATTR amyloidosis are only approved to treat diagnosed disease and can only be expected to slow disease progression. There are still many people who carry a genetic variant which puts them at risk of this progressive and fatal disease, and who typically watched other family members suffer through it. Currently, there are no proven prevention treatment options,” Ahmad Masri, MD, MS, cardiomyopathy section head and director of the Cardiac Amyloidosis Program at Oregon Health and Science University, said in a statement. “By collaborating with BridgeBio on this groundbreaking study, I am hopeful that we can fill the significant gap in care for asymptomatic carriers of a genetic variant by providing potential preventative intervention early with resulting greater clinical benefit than addressing the disease at a later stage.”
Both ATTR-CM and ATTR-PN variations of the disease are fatal if they are not treated early. It is a progressive, hereditary disease that causes misfolded TTR protein to irreversibly deposit amyloid in organs that leads to degraded function that worsens over time.
“I have met many families of those diagnosed with hereditary ATTR and one question often asked is what can be done for asymptomatic carriers of the genetic variant causing ATTR. Since there is currently no approved therapy to delay or prevent disease onset, this underserved, at-risk population must wait for the development of symptoms before therapy can be prescribed,” said Muriel Finkel, President of non-profit Amyloidosis Support Groups, in a statement. “I am hopeful that with ACT-EARLY, loved ones of those with variant ATTR will be able to get genetic testing done, and if they meet the qualification criteria, can get started on a clinical trial that might identify whether prophylactic treatment will slow down or prevent ATTR at its genetic source.”
ACT-EARLY study details
The study aims to randomize approximately 600 asymptomatic carriers of a pathogenic TTR variant. The primary efficacy endpoint is time to development of ATTR-CM and/or ATTR-PN. Additional endpoints include the safety and tolerability of acoramidis as well as its effects on cardiac imaging parameters, plasma TTR concentration, nerve conduction and neurofilament light chain.
BridgeBio noted that the ATTRibute-CM Phase 3 trial showed separation at three months in time to first event, either all-cause mortality (ACM) or cardiovascular-related hospitalization (CVH) when comparing ATTR-CM patients treated with acoramidis or a placebo. In a post-hoc analysis, acoramidis led to a 42% reduction in composite ACM and recurrent CVH events relative to placebo at month 30. The drug also showed a 50% reduction in the cumulative frequency of CVH events relative to placebo at month 30.
Additional data announced during ACC.25, meanwhile, found that acoramidis achieved statistical significance in reducing the risk of ACM or first CVH versus placebo in the ATTRv-CM subgroup, with a 59.1% risk reduction. The company said the treatment effect represents the greatest observed benefit to date for ATTRv-CM patients. This established the mechanistic hypothesis that stabilization of tetrametric TTR with acoramidis could possibly delay or prevent ATTRv.
Dave Fornell has covered healthcare for more than 17 years, with a focus in cardiology and radiology. Fornell is a 5-time winner of a Jesse H. Neal Award, the most prestigious editorial honors in the field of specialized journalism. The wins included best technical content, best use of social media and best COVID-19 coverage. Fornell was also a three-time Neal finalist for best range of work by a single author. He produces more than 100 editorial videos each year, most of them interviews with key opinion leaders in medicine. He also writes technical articles, covers key trends, conducts video hospital site visits, and is very involved with social media. E-mail: [email protected]