ATTRibute trial
The randomized double-blind ATTRibute-CM trial included 632 patients with ATTR-CM and New York Heart Association class I-III heart failure.
They were randomly assigned 2:1 to acoramidis (800 mg twice daily) or placebo, with a follow-up of 30 months. After the first 12 months, tafamidis was permitted if available. This was more prevalent in the placebo arm (22% vs. 14%).
The trial met the primary endpoint – a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, and change from baseline in NT-proBNP and 6-minute walking distance – with a win ratio of 1.8, which was highly statistically significant (P < .0001).
Results were consistent across all components of the primary endpoint and across all subgroups, Dr. Gillmore reported.
“Importantly, 58% of the win ratio ties were broken by the first two components of the hierarchical analysis – all-cause mortality and cardiovascular hospitalizations – and a separate analysis of these two components alone was also statistically significant,” he noted.
A trend was seen toward a treatment effect on all-cause mortality favoring acoramidis, with an 81% survival rate in the treated group, representing an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 25%.
Of the deaths reported in the study, 78% were cardiovascular in nature. Cardiovascular death also showed a trend favoring treatment with the study drug (14.9% in the acoramidis group vs. 21.3% in the placebo group), giving an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 30%.
Acoramidis was also associated with 50% reduction in cardiovascular hospitalizations, which was highly significant (P < .0001).
A treatment effect was also seen in terms of functional status; at 30 months, the difference in 6-minute walk distance between the groups was 40 meters, a “highly statistically significant improvement and clinically important difference, Dr. Gillmore said. Improvement from baseline occurred in 40% of the acoramidis group versus 22% of the placebo group.
Acoramidis recipients showed a blunting of the progressive rise of NT-proBNP, which Dr. Gillmore noted has been shown to be strongly associated with outcomes, with 45% of the acoramidis treated patients showing an improvement in NT-proBNP levels, compared with 9% of placebo group.
There was also a relative preservation of quality of life in the acoramidis group consistent with the separation of NT-proBNP curves, he added.
“Consistent with the mechanism of action and preclinical data showing near-complete stabilization of TTR at therapeutic drug concentrations, serum TTR (an in vivo reflection of TTR stabilization) was promptly and persistently elevated in patients receiving acoramidis,” Dr. Gillmore said.
Safety data showed that treatment-related adverse events were equal between the two groups, and there were fewer treatment emergent serious adverse events in the acoramidis group. The drug was said to be “generally well tolerated, with no findings of potential clinical concern.”
Second primary endpoint not significant
Discussant of the study at the ESC Hotline session, Thibaud Damy, MD, Hospital Henri Mondor, Paris East Creteil University, pointed out that a second primary endpoint of the study, change from baseline to month 12 in the 6-minute walking test, did not significantly differ between acoramidis and placebo.
Dr. Damy also highlighted the significant all-cause mortality reduction seen with tafamidis in ATTR-ACT but not achieved with acoramidis in ATTRibute.
He agreed with Dr. Gillmore’s interpretation that this was probably stemmed from the ATTRibute trial recruiting lower-risk patients, pointing out that patients in this trial had lower levels of NT-proBNP and less severe heart failure.
“It is clear that there is a place for acoramidis in patients with ATTR-CM,” Dr. Damy concluded, adding that many other treatments are in development.
The ATTribute trial was supported by BridgeBio Pharma. Dr. Gillmore reported advisory/consultant roles with BridgeBio, Alnylam, Ionis, AstraZeneca, Intellia, Pfizer, ATTRalus, and Lycia.
A version of this article first appeared on Medscape.com.