‘Across the board’ benefits seen with acoramidis for transthyretin amyloid cardiomyopathy
Key takeaways:
- Acoramidis reduced risk for all-cause mortality and CV-related hospitalizations in symptomatic transthyretin amyloid cardiomyopathy.
- Researchers noted improvements in functional and quality of life measures.
Acoramidis, an investigational treatment for symptomatic transthyretin amyloid cardiomyopathy, was associated with marked improvements in all-cause mortality and CV-related hospitalizations compared with placebo, data show.
“Acoramidis was associated with benefits across the board — patient survival, hospitalizations, functional capacity, cardiac biomarkers and quality of life — in contemporary patients with transthyretin amyloid cardiomyopathy (ATTR-CM), and there were no safety signals of concern with the drug,” Julian Gillmore, MD, PhD, head of the University College London Centre for Amyloidosis incorporating the U.K. National Amyloidosis Centre, told Healio. “Acoramidis represents a new effective and safe therapy for ATTR-CM that will hopefully soon become widely available to patients.”
Image: Adobe Stock
Need for TTR stabilization therapy
As Healio previously reported, an early report on the phase 3 ATTRibute-CM trial, released by BridgeBio Pharma, showed that acoramidis, an investigational, next-generation, small molecule stabilizer of transthyretin (TTR), demonstrated consistent benefits on survival, hospitalization and other measures of illness severity.
“Pathogenic TTR variants that show greater destabilization are associated with increased penetrance, earlier disease onset and increased clinical severity,” the researchers wrote in The New England Journal of Medicine. “Thus, TTR stabilization represents a logical therapeutic strategy that has been shown to be effective for the treatment of ATTR-CM.”
Gillmore and colleagues analyzed data from 632 adults with symptomatic hereditary or wild-type ATTR-CM and NYHA class I, II or III HF who were randomly assigned acoramidis hydrochloride 800 mg twice daily (n = 421) or placebo (n = 211) for 30 months. Within the cohort, 21 participants with stage 4 chronic kidney disease (12 in the acoramidis group and nine in the placebo group) were excluded. The mean age of participants was 77 years; 90.2% were men and 90.3% had wild-type TTR. A four-step primary hierarchical analysis included all-cause death, CV hospitalization, change from baseline in N-terminal pro-B-type natriuretic peptide level, and change from baseline in 6-minute walk distance.
“One advantage of the hierarchical-analysis design is that all possible paired comparisons are made only at the initial step (ie, death from any cause in this trial),” the researchers wrote. “At each subsequent step, only those ties remaining after the previous step are subject to a paired comparison. This approach places greater weight on the steps at the top of the hierarchy, a weighting that diminishes in the lower steps in the hierarchy. This design can be compared with the use of a time-to-first-event clinical outcome, in which an equal weight is assigned to each component.”
Secondary outcomes included all-cause death, 6-minute walk test distance, Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score and the serum TTR level.
Improvements for all outcomes
Researchers found that the primary hierarchical analysis showed a better outcome in the acoramidis group compared with placebo, with a corresponding win ratio of 1.8 (95% CI, 1.4-2.2; P < .001), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Results persisted in a sensitivity analysis in the intention-to-treat population (P < .001).
All-cause death and CV-related hospitalizations contributed more than half the wins and losses to the win ratio (58%), according to the researchers, whereas NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses.
The RR ratio for frequency of CV-related hospitalization per year was 0.496 in favor of acoramidis (95% CI, 0.355-0.695). The 30-month change from baseline in the NT-proBNP level, defined as the ratio of adjusted geometric mean factor change, was 0.529 in favor of acoramidis (95% CI, 0.463-0.604).
The study design allowed for tafamidis (Vyndamax, Pfizer) drop-in after at least 12 months for the placebo and the acoramidis arms, and the researchers assessed differences in stabilizer performance as measured by serum TTR and NT-proBNP in an exploratory, post hoc analyses. In those analyses, 30-month findings demonstrated that acoramidis showed a 42% greater increase in serum TTR levels vs. tafamidis and acoramidis showed a 92% improvement in median NT-proBNP relative to placebo and tafamidis.
Adverse events were similar in the two groups, with fewer serious adverse events observed in the acoramidis group vs. placebo (54.6% vs. 64.9%).
Gillmore said there is a great need for improvements in ATTR-CM diagnosis, particularly in diagnosing the disease earlier.
“We also must determine which patients benefit most from therapy and which are failing to respond and might be switched between different disease-modifying therapies,” Gillmore told Healio. “Lastly, therapies which accelerate natural clearance of existing amyloid deposits are desperately needed.”
For more information:
Julian Gillmore, MD, PhD, can be reached at j.gillmore@ucl.ac.uk.
Collapse