Cardiovascular · Clinical trials
ATTR Cardiac Amyloidosis Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About attr cardiac amyloidosis — and why its trials are hard
Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of transthyretin (TTR), a liver-produced tetrameric transport protein, into amyloid fibrils that deposit in the myocardium and stiffen the heart, producing a restrictive cardiomyopathy and progressive heart failure with preserved ejection fraction. It occurs in a wild-type form (age-related, predominantly older men) and a hereditary form from TTR gene mutations. Once considered rare and untreatable, ATTR-CM is now increasingly diagnosed noninvasively using technetium pyrophosphate scintigraphy with exclusion of a plasma cell dyscrasia. Disease-modifying therapy targets the TTR protein through two strategies: stabilizers that hold the tetramer together to prevent fibril formation, and gene silencers (siRNA) that reduce hepatic TTR production. Tafamidis was the first approved stabilizer, followed by acoramidis, a near-complete stabilizer. The RNA-interference agents vutrisiran and patisiran suppress TTR synthesis; vutrisiran gained an ATTR-CM indication after the HELIOS-B trial. These therapies reduce cardiovascular death and hospitalization and slow functional decline, though they do not clear existing amyloid deposits, making early diagnosis and treatment critical.
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Tafamidis (Vyndaqel / Vyndamax) | 2019 | Wild-type or hereditary ATTR-CM (first-approved TTR stabilizer) | ATTR-ACT (NEJM 2018) | Hierarchical composite of all-cause mortality and frequency of cardiovascular-related hospitalizations over 30 months | All-cause mortality 29.5% vs 42.9% with placebo (HR 0.70); reduced CV hospitalizations (0.48 vs 0.70 per year) and slowed decline in 6MWD and KCCQ |
| Acoramidis (Attruby) | 2024 | Wild-type or hereditary ATTR-CM (near-complete TTR stabilizer, >=90%) | ATTRibute-CM (NEJM 2024) | Hierarchical outcome of all-cause death, cardiovascular hospitalization, change in NT-proBNP, and change in 6-minute walk distance at 30 months | Win ratio 1.8 favoring acoramidis (p<0.001); reduced cumulative CV-related hospitalizations and NT-proBNP versus placebo |
| Vutrisiran (Amvuttra) | 2025 (ATTR-CM indication; earlier approved 2022 for hATTR polyneuropathy) | ATTR-CM to reduce cardiovascular death and events (RNAi TTR silencer) | HELIOS-B (NEJM 2025) | Composite of all-cause mortality and recurrent cardiovascular events | Significant reduction in the composite (HR approximately 0.72 in the overall population) with reductions in all-cause mortality and CV events; first RNAi therapeutic with an ATTR-CM cardiovascular outcome benefit |
| Patisiran (Onpattro) | 2018 (hATTR polyneuropathy; NOT approved for ATTR-CM) | Hereditary ATTR with polyneuropathy (RNAi TTR silencer) | APOLLO (NEJM 2018); APOLLO-B (cardiomyopathy, 2023) | APOLLO: modified Neuropathy Impairment Score +7 (mNIS+7); APOLLO-B: 6-minute walk distance | APOLLO: significant improvement in neuropathy vs placebo; APOLLO-B showed a 6MWD benefit but FDA declined a cardiomyopathy indication (see failed) |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in attr cardiac amyloidosis development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| Patisiran (for the cardiomyopathy indication) — APOLLO-B (2023) | Although APOLLO-B met its primary 6-minute walk distance endpoint, the FDA declined to approve patisiran for ATTR-CM, concluding the demonstrated effect was not clinically meaningful enough for a cardiomyopathy indication | Modest functional benefit without a convincing mortality/CV outcome signal at review; the ATTR-CM indication went to stabilizers and later to vutrisiran |
| Revusiran — ENDEAVOUR | The first-generation RNAi agent revusiran was discontinued in 2016 after an imbalance in deaths in the treatment arm | Safety/mortality signal halted development; the program pivoted to the enhanced-stabilization chemistry siRNAs patisiran and vutrisiran |
Choosing the right endpoint
Primary endpoints that matter in attr cardiac amyloidosis trials
- All-cause mortality — Hard outcome and the top tier of the hierarchical composites in ATTR-ACT and ATTRibute-CM
- Cardiovascular hospitalization — Frequency of CV-related admissions; second tier of the pivotal stabilizer composites
- Composite of death and recurrent CV events — Primary endpoint in HELIOS-B for vutrisiran
- 6-minute walk distance (6MWD) — Functional capacity measure used across ATTR-CM trials, including the APOLLO-B primary endpoint
- NT-proBNP and KCCQ — Biomarker of cardiac stress and quality-of-life instrument used as key secondary/hierarchical endpoints
How iNGENū runs attr cardiac amyloidosis trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
Request a fixed-milestone proposal and a tailored endpoint & feasibility summary for this indication.
Frequently asked questions
ATTR Cardiac Amyloidosis clinical trials — FAQs
Do ATTR-CM drugs remove amyloid already in the heart?
What is the difference between a TTR stabilizer and a TTR silencer?
Why is tafamidis considered a landmark therapy?
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