How effective is Attruby (acoramidis) in treating confirmed wild‑type or hereditary transthyretin cardiac amyloidosis (ATTR‑CM) in adults?

Efficacy of Attruby (Acoramidis) in ATTR-CM

Attruby (acoramidis) is highly effective for treating both wild-type and hereditary transthyretin cardiac amyloidosis (ATTR-CM), reducing cardiovascular death and hospitalizations by approximately 36% compared to placebo, with benefits emerging as early as 3 months and sustained through at least 42 months of treatment. 1, 2, 3

FDA-Approved Indication and Dosing

Attruby is FDA-approved specifically for the treatment of ATTR-CM cardiomyopathy in adults to reduce cardiovascular death and cardiovascular-related hospitalization. 1 The recommended dosage is 712 mg orally twice daily (administered as two 356 mg tablets), taken with or without food. 1

Clinical Efficacy Data

Primary Outcomes from ATTRibute-CM Trial

The pivotal phase 3 ATTRibute-CM trial randomized 632 patients with ATTR-CM (2:1 ratio) to receive acoramidis or placebo for 30 months. 2 The primary hierarchical analysis demonstrated significant superiority of acoramidis (P<0.001), with a win ratio of 1.8 (95% CI: 1.4-2.2), meaning 63.7% of pairwise comparisons favored acoramidis versus 35.9% favoring placebo. 2

Mortality and Hospitalization Benefits

Acoramidis reduced the composite endpoint of all-cause mortality or first cardiovascular-related hospitalization by 36% (HR: 0.64; 95% CI: 0.50-0.83; P=0.0008) at 30 months. 3 The Kaplan-Meier curves separated at month 3 and continued to diverge through month 30, indicating early and sustained benefit. 3

Breaking down the composite endpoint:

• First cardiovascular-related hospitalization alone was reduced by 40% (HR: 0.60; 95% CI: 0.45-0.80; P=0.0005) 3
• Annualized frequency of cardiovascular hospitalizations was reduced by 50% (relative risk ratio: 0.50; 95% CI: 0.36-0.70; P<0.0001) 3

Long-Term Efficacy Through 42 Months

In the ongoing open-label extension study, participants who received continuous acoramidis from baseline through 42 months maintained robust clinical benefits. 4 The hazard ratio for all-cause mortality or first cardiovascular-related hospitalization was 0.57 (95% CI: 0.46-0.72; P<0.0001) at month 42. 4 All-cause mortality alone showed a hazard ratio of 0.64 (95% CI: 0.47-0.88) at 42 months. 4

Efficacy Across Disease Subtypes

Acoramidis demonstrates consistent efficacy in both wild-type and hereditary ATTR-CM, including high-risk variant subgroups. 5

In wild-type ATTR-CM (552 participants):

• 31% reduction in all-cause mortality/first cardiovascular hospitalization at month 30 (HR: 0.69; 95% CI: 0.52-0.90; P=0.007) 5
• 30% reduction in all-cause mortality through month 42 (HR: 0.70; 95% CI: 0.50-0.98; P=0.04) 5

In hereditary ATTR-CM (59 participants):

• 59% reduction in all-cause mortality/first cardiovascular hospitalization at month 30 (HR: 0.41; 95% CI: 0.21-0.81; P=0.01) 5
• 59% reduction in all-cause mortality through month 42 (HR: 0.41; 95% CI: 0.19-0.93; P=0.03) 5

Notably, the p.Val142Ile variant subgroup, which is associated with rapid progression and increased mortality, showed consistent treatment benefits comparable to non-p.Val142Ile variants. 5

Functional and Quality of Life Outcomes

Acoramidis preserved functional capacity and quality of life compared to progressive decline with placebo. 2, 4 Treatment effects favored acoramidis for:

• 6-minute walk distance preservation 2, 4
• Kansas City Cardiomyopathy Questionnaire Overall Summary scores, which were well preserved through 42 months in continuous-acoramidis participants 4
• NT-proBNP levels, with pairwise comparisons yielding the highest ratio of wins to losses (23.3% vs. 7.0%) 2

Mechanism and Pharmacodynamic Marker

Acoramidis is a high-affinity transthyretin stabilizer that achieves ≥90% TTR stabilization across the dosing interval. 2, 6 Treatment results in a sharp and sustained rise in serum transthyretin levels (mean increase of 9.1 mg/dL) within 28 days. 6

The early increase in serum transthyretin at day 28 independently predicts improved survival. 6 For every 5 mg/dL increase in serum TTR levels, there is a 31.6% relative reduction in odds of all-cause mortality. 6 This pharmacodynamic effect fully mediates the treatment effect on mortality (P=0.002). 6

Safety Profile

The overall incidence of adverse events was similar between acoramidis (98.1%) and placebo (97.6%) groups. 2 Serious adverse events occurred in 54.6% of acoramidis-treated patients versus 64.9% of placebo patients. 2

Gastrointestinal adverse reactions were more common with acoramidis: diarrhea (11.6% vs. 7.6%) and upper abdominal pain (5.5% vs. 1.4%). 1 The majority were mild and resolved without drug discontinuation. 1 Discontinuation rates due to adverse events were similar (9.3% acoramidis vs. 8.5% placebo). 1

Acoramidis causes a reversible increase in serum creatinine and decrease in eGFR. 1 At day 28, mean serum creatinine increased by 0.2 mg/dL and eGFR decreased by 8.2 mL/min/1.73 m² in the acoramidis group versus 0.0 mg/dL and 0.7 mL/min/1.73 m² in placebo. 1 These changes stabilize and are reversible after discontinuation. 1

Through 42 months of the open-label extension, no new clinically important safety issues were identified. 4

Comparison to Other ATTR-CM Therapies

While the 2023 ACC Expert Consensus and 2020 Canadian guidelines recommend tafamidis for ATTR-CM with NYHA class I-III symptoms 7, 8 and TTR silencers (patisiran, inotersen, vutrisiran) for hereditary ATTR with polyneuropathy 7, 8, these guidelines predate acoramidis approval.

Tafamidis is not FDA-approved for neuropathy 7, whereas acoramidis is approved for both wild-type and variant ATTR-CM cardiomyopathy regardless of neuropathy status. 1

Network meta-analysis comparing TTR stabilizers shows that patisiran, tafamidis, vutrisiran, and acoramidis all improve global longitudinal strain versus placebo, with similar effect sizes. 9

Clinical Implications

Early diagnosis and treatment initiation is critical, as benefits emerge within 3 months and accumulate over time. 3, 4 Participants who switched from placebo to acoramidis in the open-label extension showed prompt increases in serum transthyretin but had already experienced irreversible disease progression during the placebo period. 4

Acoramidis offers several practical advantages:

• Oral administration twice daily (versus intravenous patisiran every 3 weeks) 1
• No requirement for vitamin A supplementation (unlike TTR silencers) 7
• No premedication required (unlike patisiran) 7
• No need for weekly platelet monitoring or biweekly renal monitoring (unlike inotersen) 7

Important Caveats

Avoid concomitant use with UGT inducers and strong CYP3A inducers, as these may decrease acoramidis exposure. 1 Acoramidis inhibits CYP2C9, requiring more frequent monitoring when co-administered with sensitive CYP2C9 substrates for signs of increased exposure or toxicity. 1

The ATTRibute-CM trial excluded patients with NYHA class IV symptoms or 6-minute walk distance <100 meters, and required baseline eGFR ≥30 mL/min/1.73 m². 1, 2 However, prespecified analyses confirmed efficacy in high-risk participants with stage 4 chronic kidney disease. 10