Rare & Genetic · Clinical trials
Hereditary ATTR 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 hereditary attr amyloidosis — and why its trials are hard
Hereditary transthyretin (ATTRv) amyloidosis is an autosomal-dominant disease caused by mutations in the TTR gene, destabilizing the transthyretin tetramer so it misfolds and deposits as amyloid in peripheral nerves and the heart. It presents as a progressive, length-dependent polyneuropathy (sensorimotor and autonomic) and/or cardiomyopathy, and is relentlessly progressive and fatal untreated. Two therapeutic strategies dominate: gene-silencing (RNAi and antisense oligonucleotides) that lowers hepatic TTR production, and TTR stabilizers that prevent tetramer dissociation. For polyneuropathy, patisiran (Onpattro, RNAi, 2018) was validated in APOLLO; inotersen (Tegsedi, antisense) and later vutrisiran (Amvuttra, RNAi, HELIOS-A) and eplontersen (Wainua, antisense, 2023) expanded the options, several with convenient subcutaneous dosing. For the cardiomyopathy phenotype, the oral stabilizer tafamidis reduced mortality and hospitalizations. These agents dramatically slow or halt neuropathy progression and improve quality of life, marking one of the most successful applications of RNA-targeted medicine in a rare disease.
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 |
|---|---|---|---|---|---|
| patisiran (Onpattro) | 2018 | Polyneuropathy of hereditary ATTR amyloidosis (RNAi therapeutic) | APOLLO (Phase 3, vs placebo) | Change in mNIS+7 (modified Neuropathy Impairment Score +7) at 18 months | mNIS+7 improved with patisiran (~-6 points) vs worsening with placebo (~+28 points); between-group difference ~-34 points (p<0.001) |
| inotersen (Tegsedi) | 2018 | Polyneuropathy of hereditary ATTR amyloidosis (antisense oligonucleotide) | NEURO-TTR (Phase 3, vs placebo) | Change in mNIS+7 and Norfolk QoL-DN at ~66 weeks | Significant benefit vs placebo on both co-primary endpoints (neuropathy progression and quality of life); requires platelet and renal monitoring |
| vutrisiran (Amvuttra) | 2022 | Polyneuropathy of hereditary ATTR amyloidosis (subcutaneous RNAi, quarterly) | HELIOS-A (Phase 3, vs external placebo from APOLLO) | Change in mNIS+7 at 9 months (and 18 months) | Significant improvement vs placebo comparator on mNIS+7 and Norfolk QoL-DN, consistent with patisiran-level efficacy |
| eplontersen (Wainua) | 2023 | Polyneuropathy of hereditary ATTR amyloidosis (subcutaneous ligand-conjugated antisense) | NEURO-TTRansform (Phase 3) | Change in serum TTR, mNIS+7, and Norfolk QoL-DN | Significant TTR reduction and improvement/stabilization of neuropathy and quality of life vs placebo comparator |
Choosing the right endpoint
Primary endpoints that matter in hereditary attr amyloidosis trials
- mNIS+7 (modified Neuropathy Impairment Score +7) — Composite of motor, sensory, autonomic, and nerve-conduction measures; primary neuropathy endpoint across ATTRv polyneuropathy trials
- Norfolk QoL-DN — Patient-reported quality-of-life measure specific to diabetic/amyloid neuropathy; standard co-primary or key secondary endpoint
- Serum transthyretin (TTR) reduction — Pharmacodynamic biomarker demonstrating target engagement of gene-silencing agents
- Cardiac outcomes (mortality/CV hospitalization) — Key endpoints for the cardiomyopathy phenotype, e.g., stabilizer trials
How iNGENū runs hereditary attr 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
Hereditary ATTR Amyloidosis clinical trials — FAQs
How do the main ATTRv therapies work?
What is the primary endpoint in polyneuropathy trials?
Is the polyneuropathy or cardiomyopathy form treated the same way?
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