By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration (FDA) has approved acoramidis, an oral drug for the treatment of transthyretin (TTR)-related amyloid cardiomyopathy (ATTR-CM). Acoramidis is a selective TTR stabilizer and mimics the action of the T119M variant (stabilizing TTR mutation). It is the second TTR stabilizer to be approved — after tafamidis (Vyndamax) and tafamidis meglumine (Vyndaqel), which were approved in 2019. Acoramidis was given an orphan designation and is distributed by BridgeBio Pharma, Inc. as Attruby.
Indications
Acoramidis is indicated for the treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis in adults to reduce cardiovascular death and cardiovascular-related hospitalization.1
Dosage
The recommended dose is 712 mg (800 mg of acoramidis HCl) taken orally twice daily with or without food.1 It is available as 356-mg tablets.
Potential Advantages
In vitro data suggest acoramidis is a more efficient stabilizer of TTR with high affinity and superior TTR occupancy compared to tafamidis.2,3
Potential Disadvantages
The most frequent adverse reactions were diarrhea and upper abdominal pain that were considered mild and generally resolved without drug discontinuation.4 Discontinuation rates because of adverse effects were 9.3% in the treatment group vs. 8.5% in the placebo group. Acoramidis does not appear to benefit patients who are ≥ 78 years of age, have an estimated glomerular filtration rate (eGFR) of < 45 mL/min/1.73 m2, or who are New York Heart Association class III.1 Concomitant use of acoramidis with UDP-glucuronosyltransferases and CYP3A inducers should be avoided, since these interactions can decrease the systemic exposure of acoramidis.1
Comments
ATTR-CM is caused by destabilization of transthyretin, mainly produced by hepatocytes, into unstable monomers. This results in deposition of amyloid fibrils in the myocardium, resulting in heart failure.3 Acoramidis binds to TTR at transthyretin binding sites and slows conversion to monomers, which is the rate-limiting step in amyloidogensis.1 Its efficacy was demonstrated in a randomized, double-blind, placebo-controlled study in adult participants with wild-type or variant (hereditary or de novo) ATTR-CM.1,5 Participants were randomized to acoramidis (n = 107) or placebo (n = 61) for 30 months and stratified by ATTR-CM type, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and eGFR. Participants had a mean age of 77 years, 91% were male, and 88% were white.
The primary composite endpoint included all-cause mortality (ACM) and cumulative frequency of cardiovascular-related hospitalizations (CVH) over 30 months. Key secondary functional outcomes were the change from baseline in the six-minute walk distance (6-MWD) and Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS.) score. ACM was 19% in the acoramidis group vs. 26% in the placebo group (35.5% decrease), CVH rates were 27% and 43%, respectively, mainly because of heart failure hospitalization. There were significantly slower declines in 6-MWD (mean difference of 40 meters) and KCCQ-OS (mean difference 10 points). The four-step primary hierarchical analysis, using the Finkelstein-Schoenfeld method, (including ACM, CVH, change from baseline in 6-MWD, and NT-probNP) proved to be better for the acoramidis group vs. the placebo group.5 Early and continuous use of acoramidis in an open-label extension, through month 42, was associated with sustained clinical benefits.6 Adverse reactions were similar between the two groups.5
Clinical Implications
ATTR-CM is a rare but serious condition with no cure comprising two types: hereditary and wild-type, with the latter being more common.3 There are currently two TTR stabilizers approved by the FDA for ATTR-CM. Both drugs reduce ACM and CVH and improve 6-MWD and KCCQ-OS scores. Currently, there are no comparisons between acoramidis and tafamidis. Tolcapone and diflunisal also are used off-label for this indication. Two silencers of hepatic transthyretin production, vutrisiran (a small interfering ribonucleic acid) and eplontersen (an antisense oligonucleotide) are being evaluated for ATTR-CM.7 Both currently are FDA-approved for polyneuropathy of hereditary TTR-mediated amyloidosis. The cost for a 28-day supply of acoramidis is $18,759 ($243,867 per year). The cost for a 30-day supply tafamidis is $22,332 ($271,780 per year).
REFERENCES
- BridgeBio Pharma, Inc. Attruby prescribing information. Published November 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216540s000lbl.pdf
- Miller M, Pal A, Albusairi W, et al. Enthalpy-driven stabilization of transthyretin by AG10 mimics a naturally occurring genetic variant that protects from transthyretin amyloidosis. J Med Chem 2018;61:7862-7876.
- Nuvolone M, Girelli M, Merlini G. Oral therapy for the treatment of transthyretin-related amyloid cardiomyopathy. Int J Mol Sci 2022;23:16145.
- U.S. Food and Drug Administration. FDA Approves drug for heart disorder caused by transthyretin-mediated amyloidosis. Nov. 25, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-heart-disorder-caused-transthyretin-mediated-amyloidosis#:~:text=The%20U.S.%20Food%20and%20Drug,hospitalization%20related%20to%20heart%20problems
- Gillmore JD, Judge DP, Cappelli F, et al. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. N Engl J Med 2024;390:132-142.
- Judge DP, Gillmore JD, Alexander KM, et al. Long-term efficacy and safety of acoramidis in ATTR-CM: Initial report from the open-label extension of the ATTRibute-CM Trial. Circulation 2024; doi:10.1161/circulationaha.124.072771. [Online ahead of print].
- Bampatsias D, Wardhere A, Mauerer MS. Treatment of transthyretin cardiac amyloidosis. Curr Opin Cardiol 2024:39:407-416.
The U.S. Food and Drug Administration has approved acoramidis, an oral drug for the treatment of transthyretin-related amyloid cardiomyopathy.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content