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AMSTERDAM -- Novel anti-amyloid agent acoramidis improved a composite of outcome endpoints in the pivotal ATTRibute-CM trial for transthyretin mediated amyloidosis (ATTR) cardiomyopathy, with suggestion of clinical normalization albeit no mortality reduction.

The drug met the 30-month primary endpoint, with a "win ratio" of 1.772 (P<0.0001) compared with placebo in a hierarchical analysis comprising all-cause mortality, cumulative cardiovascular hospitalization frequency, change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP), and change from baseline in 6-minute walk distance (6MWD).

Acoramidis also reduced the characteristically progressive increase in NT-proBNP as a biomarker of heart failure severity compared with placebo and 45% of patients actually saw improvement over baseline in that measure, while 40% had greater 6MWD at 30 months than at baseline, Julian Gillmore, MD, PhD, of the National Amyloidosis Centre at University College London, reported at the European Society of Cardiology (ESC) conference.

He emphasized that the 81% survival rate on acoramidis at 30 months in the trial approached the about 85% expected in an age-matched U.S. population, while the mean 0.29-per year cardiovascular hospitalization rate on acoramidis also came in similar to the about 0.26-per year rate in the U.S. Medicare population.

Together, the trial "suggests the tantalizing possibility of genuine clinical improvement," Gillmore said.

However, it was notable that the oral agent didn't result in the relative 30% all-cause mortality advantage seen at 30 months in the pivotal trial with the first TTR stabilizer, tafamidis (Vyndamax, Vyndaqel). Acoramidis yielded a nonsignificant 6.4% absolute reduction in all-cause mortality compared with placebo.

And, had missed its other primary endpoint, finding no less decline in 6MWD at month 12 on acoramidis than placebo. In those topline results, drug developer BridgeBio noted that the declines in both groups were "similar to healthy elderly adults and less than prior untreated ATTR-CM cohorts."

These findings come amid a rapidly changing landscape in ATTR-CM, noted ESC session study discussant Thibaud Damy, MD, PhD, of the Referral Center for Cardiac Amyloidosis and University Hospital Henri Mondor in Creteil, France.

"The rates of mortality in the placebo group between the two trials are quite different, and it's clear that the population is less sick in ATTRibute-CM," he told attendees at the hotline session.

"As ATTR-CM patients are getting diagnosed sooner and in better condition, and as the trial focused on less sick patients, we can question whether the ATTRibute-CM trial had enough power to show an impact on all-cause mortality and cardiovascular hospitalization," Damy added. But he concluded that "there is a place for acoramidis in the treatment of these patients," while noting that a number of novel agents that target amyloid in different ways are in the works.

Notably, while tafamidis is expected to be a competitor to acoramidis -- the small molecule drug has a unique approach (mimicking a protective mutation) but achieves a similar end in binding to and stabilizing TTR -- the ATTRibute-CM trial allowed open-label tafamidis after month 12 at the discretion of the treating clinician.

Indeed, 14.5% of the acoramidis-assigned patients and 21.8% in the placebo arm got tafamidis.

"The drop in of tafamidis would, if anything, have been expected to dilute the treatment effect in this study," Gillmore said at an ESC press conference. "So I think that the strongly positive results in the context of tafamidis drop-in only go to strengthen the results of the study."

The trial included 632 patients diagnosed with ATTR cardiomyopathy with New York Heart Association class I-III symptoms and a positive biopsy or positive 99mTc scan with exclusion of light chain amyloidosis. More than 90% carried wild-type ATTR while the rest had variant ATTR.

They were randomized 2:1 to 800-mg acoramidis or placebo twice daily for 30 months, with an open-label acoramidis extension thereafter.

Among the secondary findings, 58% of win ratio ties were broken by all-cause mortality and cardiovascular hospitalization. Separate analysis of those two components alone also significantly favored acoramidis. The 50% reduction in cardiovascular hospitalizations was significant compared with placebo. Findings were also favorable for functional status, NT-proBNP, quality of life, and serum TTR.

The findings were consistent across subgroups with few exceptions.

Acoramidis was associated with a "reassuring safety profile with no signals of potential clinical concern," Gillmore noted.

The drug developer has announced plans to file for FDA review of an indication for acoramidis toward the end of 2023.

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