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With BridgeBio Pharma Inc. expecting to complete a regulatory submission prior to the close of 2023, the 30-month results of ATTRibute-CM provide the most comprehensive overview yet of the benefit-risk profile for acoramidis in ATTR-CM.
The 30-month results of the phase 3 ATTRibute-CM trial provide the latest insight into the effects of acoramidis in people with transthyretin amyloid cardiomyopathy (ATTR-CM) ahead of a potential regulatory submission for the agent.
Presented during a hot line session at the European Society of Cardiology (ESC) Congress 2023, results of the trial suggest the acoramidis cohort experienced an 81% survival rate at 30 months, with additional analysis suggesting use of acoramidis was associated with a 30% reduction in risk of cardiovascular death relative to placebo therapy.1
“The results of the ATTRibute-CM study of acoramidis in ATTR cardiomyopathy stand out for me as a clinician, not only for the highly significant outcome on the primary endpoint but for the consistency of treatment benefit across components of the primary and key secondary endpoints,” said principal investigator Julian Gillmore, MBBS, MD, PhD, professor at the University College London Centre for Amyloidosis.2 “These results contribute to my anticipation that acoramidis will provide patients and their providers with an attractive new treatment option that will surely be welcomed across the community.”
ATTRibute-CM trial was a randomized, double-blind, placebo-controlled phase 3 trial launched in 2019 as a 2-part trial with the intent of exploring the ability acoramidis, an investigational, next-generation, orally administered, highly potent, small molecule stabilizer of transthyretin, ability to reduce mortality, morbidity, and the decline in both effort tolerance and quality of life in patients with wild-type or variant transthyretin ATTR-CM. For inclusion, patients needed to have symptoms meeting criteria for New York Heart Association (NYHA) class I-III heart failure and have an ATTR-positive biopsy or 99mTc scan.1
Patients included in the trial underwent randomization to 800 mg acoramidis twice daily or placebo therapy. Part A of the trial was aimed at examining 12-month endpoints and part B examined 30-month endpoints.1
In December 2021, BridgeBio announced topline results from part A of the ATTRibute-CM trial, which had a primary endpoint of interest of change in 6-minute walking distance at month 12. Results of the analysis performed for part A of the trial indicated the mean observed decline in 6-minute walking distance at 12 months was 9 meters among those in the acoramidis group and 7 meters among the placebo group, respectively. Just 41 before the ESC Congress 2023 presentation, BridgeBio announced topline results of part B of the trial on July 17, 2023. In this release, the company announced plans to present further data at ESC Congress 2023 and to file a New Drug Application with the US Food and Drug Administration by end of 2023.3
The 30-month primary endpoint of interest was a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, change from baseline in NT-proBNP, and change from baseline in 6-minute walking distance. The primary outcome analysis presented at ESC Congress 2023 included 611 patients.1
Results demonstrated use of acoramidis was associated with statistically significant improvement in the primary outcome of interest, with a Win Ratio of 1.8 (95% confidence interval [CI] 1.4-2.2; P < .0001). Further analysis demonstrated results consistently favored acoramidis treatment across key subgroups, including across both variant and wild-type ATTR patients as well as across NYHA Class I-III patients. When assessing all-cause mortality, a 6.4% absolute risk reduction and 25% relative risk reduction were observed in favor of the acoramidis arm (Hazard ratio, 0.772; 95% CI, 0.542-1.102; P =.15).1
The observed survival rates at 30 months were 81% and 74% in the acoramidis and placebo groups, respectively, which correlates to an absolute risk reduction of 6.4% and a relative risk reduction of 25%. Investigators noted this was despite the rate of tafamidis use being approximately 50% greater among the placebo arm. Additionally, a 30% relative risk reduction was noted among the acoramidis arm, with the treatment group experiencing a cardiovascular mortality rate of 14.9% compared to 21.3% in the placebo group.1
Investigators also highlighted a statistically significant treatment effects at 30 months were observed for change from baseline for NT-proBNP and 6-minute walk distance (P for all < .001). For NT-proBNP, reductions were observed in 45% of the acoramidis group compared to 9% of the placebo group. For 6-minute walk distance, an improvement from baseline was observed in 40% of the acoramidis arm compared to 22% of the placebo arm.1
“The positive treatment effect was consistent across components of the primary endpoint, amongst key clinical subgroups, and across key secondary endpoints,” Gillmore said.4 “Acoramidis was more effective in preserving both functional capacity and quality of life, and increased circulating transthyretin levels, compared with placebo. Acoramidis has the potential to be an effective and safe alternative to tafamidis for the treatment of ATTR-CM.”