Trial evaluates drug’s potential to reverse ATTR-CM heart damage
Attruby post-marketing study now enrolling participants
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Enrollment is open in a post-marketing clinical trial designed to investigate whether long-term treatment with Attruby (acoramidis) can reverse heart disease-related changes in people with transthyretin amyloid cardiomyopathy (ATTR-CM).
The Phase 4 study, ASCEND-ATTR (NCT07695701), will evaluate the effects of the ATTR-CM-approved therapy on heart structure and function over three years, BridgeBio, the therapy’s developer and the company responsible for its commercialization in the U.S., said in a company press release.
The trial will enroll up to 150 participants. Recruitment of ATTR-CM patients, ages 18 to 80, with mild to moderate heart failure that’s been clinically stable for at least six weeks, is underway at one U.S. site.
In ATTR-CM, the transthyretin (TTR) protein becomes unstable, breaks apart, and misfolds, forming toxic clumps called amyloid deposits that accumulate in the heart muscle. This causes the muscle to thicken and stiffen, making it increasingly difficult for the heart to pump blood. This can lead to ATTR-CM symptoms such as shortness of breath and an irregular heartbeat, and ultimately to heart failure.
ATTR-CM can be caused by mutations in the TTR gene (hereditary) or can develop with age (wild-type).
Treatment improves survival, heart health
Attruby is an oral therapy designed to stabilize the TTR protein, preventing it from breaking apart. This is expected to reduce the formation of amyloid deposits, easing symptoms and slowing ATTR-CM progression. The drug is approved in the U.S., European Union, and elsewhere to reduce the risk of cardiovascular-related death and hospitalization in adults with either hereditary or wild-type ATTR-CM. In the EU, the medication is sold by Bayer under the brand name Beyonttra.
Regulatory approvals were based on data from the global Phase 3 ATTRibute-CM trial (NCT03860935), which showed that Attruby was superior to a placebo at prolonging survival and improving heart-related outcomes after about 2.5 years.
Patients completing the trial could enter its ongoing open-label extension (OLE) study (NCT04988386), in which all participants receive Attruby for up to five years. Pooled data from ATTRibute-CM and the OLE study showed that Attruby’s benefits were sustained for as long as 4.5 years. Starting Attruby earlier halved the risk of death or cardiovascular-related hospitalization compared with starting treatment later.
The ASCEND-ATTR study will look at whether long-term treatment can reverse some of the structural and functional changes ATTR-CM causes in the heart.
Evidence supporting that possibility came from an exploratory substudy of the ATTRibute-CM trial. Among participants with evaluable heart MRI scans after about 2.5 years, measures of heart structure and function generally improved or remained stable in those treated with Attruby, while tending to worsen or remain unchanged in those given the placebo.
Three of 24 evaluable Attruby-treated participants (12.5%) also showed evidence of amyloid regression in the heart, defined as at least a 5% reduction in extracellular volume — an MRI measure that can reflect how much of the heart tissue is occupied by amyloid deposits. No participants in the placebo group met this outcome.
Researchers have proposed that substantially slowing the formation of new amyloid deposits could allow the body’s natural mechanisms for removing existing clumps to begin outpacing the formation of new ones. However, the substudy’s exploratory nature and small sample size called for further studies to confirm this benefit.
In ASCEND-ATTR, participants will receive the approved Attruby dosage of 712 mg (two tablets), taken twice daily for 36 months (about three years).
The study’s main goal is to determine whether heart function improves, as assessed by heart MRI scans. Researchers will look for improvements in the percentage of blood pumped from the heart’s main pumping chamber with each contraction and in the amount of blood pumped per heartbeat relative to a person’s body size.
Secondary goals include changes in other aspects of heart function and structure, as well as the effect of treatment on heart amyloid burden. As an exploratory outcome, researchers will evaluate the therapy’s effect on several biomarkers and heart echocardiography, an ultrasound-based imaging test.
ASCEND-ATTR launch comes as additional analyses continue to explore Attruby’s effects beyond the main ATTRibute-CM findings. Recent data suggested the therapy may reduce the risk of outpatient worsening heart failure and potentially help preserve kidney function.
“I’m excited by the growing body of evidence continuing to demonstrate Attruby is the drug of choice for all ATTR-CM patients, … including the first-ever demonstration of early, sustained kidney-protective effects in ATTR-CM alongside the [heart] benefit we’ve established,” said Neil Kumar, PhD, cofounder and CEO of Bridgebio.
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