Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin (hATTR) amyloidosis is an inherited disease in which misfolded transthyretin (TTR) protein accumulates in tissues and organs, including the peripheral nerves, heart, eyes, and gastrointestinal tract.1,2 

Various therapeutic approaches are used to manage hATTR amyloidosis, including the inhibition of TTR synthesis and TTR stabilization.1 Currently, several interventional as well as non-interventional studies are addressing treatment, specifically treatment of hATTR amyloidosis with polyneuropathy (hATTR-PN) and of hATTR amyloidosis with cardiomyopathy (hATTR-CM). 

Interventional Clinical Trials in hATTR

HELIOS-A (NCTNCT03759379) is studying the safety and efficacy of vutrisiran (Amvuttra™) in approximately 160 patients with hATTR amyloidosis.3 In this randomized, open-label trial, patients receive either vutrisiran or a reference comparator, patisiran (Onpattro®), during the treatment period, after which the participants receive the other drug. This study is expected to be completed by October 2026.3 HELIOS-B (NCT04153149) is focused on determining the safety and efficacy of 25 mg of vutrisiran in patients with hATTR-CM.4 This randomized, double-blind, placebo-controlled, multicenter trial has currently enrolled 655 participants. The medication is administered subcutaneously every 3 months, and data will be compared with data from a placebo group. The expected date of completion is June 2025.4

The long-term safety of tafamidis meglumine (Vyndamax®) in ATTR-CM is being evaluated in an open-label extension trial (NCT02791230) that currently includes 1637 participants and is expected to end by February 2027.5

ATTribute-CM (NCT03860935), a randomized, double-blind, placebo-controlled trial, is currently evaluating the safety and efficacy of 800 mg of the experimental TTR stabilizer acoramidis (AG10) administered orally twice daily to patients with cardiomyopathy.6,7 ATTribute-CM trial will be conducted over 30 months; currently, 510 participants are enrolled. At completion of this trial, participants may be eligible to enter into an open-label extension trial to receive acoramidis.6

The efficacy of the experimental drug eplontersen, developed by Ionis Pharmaceuticals, is being evaluated in 2 different phase 3 trials. Eplontersen has a nucleotide sequence similar to that of inotersen (Tegsedi®), an antisense oligonucleotide inhibitor that interferes with TTR synthesis and is approved for the treatment of hATTR-PN.8 CARDIO-TTRansform (NCT04136171) is currently recruiting participants to study eplontersen in patients with hATTR-CM who are receiving standard of care9 and will last for 120 weeks (until June 2024). The experimental drug will be compared with placebo in approximately 750 participants.9 The efficacy and safety of eplontersen are also being evaluated in patients with hATTR-PN in NEURO-TTRansform (NCT04136184), an open-label, randomized study in which patients will be followed for 65 weeks.10 Currently, 168 participants are enrolled, who will receive a subcutaneous injection of either eplontersen every 4 weeks or inotersen once a week.10

Adverse events (AEs) occurring within 1 day following the administration of inotersen in patients with hATTR-PN will be reported in a phase 4 clinical trial sponsored by Akcea Therapeutics (NCT04306510).11 Approximately 75 participants are expected to be enrolled, and the timing of the onset of AEs, changes in vital signs, and required treatment will be recorded.11

Non-interventional Studies in hATTR

Participants are currently being recruited for 2 non-interventional studies. A prospective, multinational study sponsored by Akcea Therapeutics is underway to characterize the long-term safety profile of inotersen in real-world conditions in patients with hATTR-PN (NCT04850105).12 The goal of ConTTRibute (NCT04561518) is to elucidate the natural history, epidemiology, clinical characteristics, and real-world management of ATTR.13 Disease progression in presymptomatic carriers of mutations will be described. This study will also evaluate the safety and efficacy of patisiran when taken routinely in real-world conditions.13 

The real-world effectiveness of tafamidis (Vindamax®) in delaying the progression of neurological disease will be characterized in patients with mixed-phenotype hATTR-CM who have received high-dose tafamidis (80 or 61 mg) for at least 12 months. Approximately 150 participants are expected to be recruited in this study (NCT05139680).14

A worldwide safety surveillance study is currently recruiting participants to characterize outcomes in women with hATTR-PN who have been exposed to Tegsedi during pregnancy, as well as the outcomes of their offspring until 1 year of age (NCT04270058). This prospective study expects to enroll 20 participants.15 


1. Ando Y, Adams D, Benson MD, et al. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022:1-13. doi:10.1080/13506129.2022.2052838

2. Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. doi:10.2147/TCRM.S219979

3. HELIOS-A: A study of vutrisiran (ALN-TTRSC02) in patients with hereditary transthyretin amyloidosis (hATTR amyloidosis) (NCTT03759379). Updated June 6, 2022. Accessed July 17, 2022.

4. HELIOS-B: a study to evaluate vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy (NCT04153149). Updated June 16, 2022. Accessed July 17, 2022.

5. Long-term safety of tafamidis in subjects with transthyretin cardiomyopathy (NCT02791230). Updated December 7, 2021. Accessed July 17, 2022.

6. Efficacy and safety of AG10 in subjects with transthyretin amyloid cardiomyopathy (ATTRibute-CM) (NCT03860935). Updated December 30, 2021. Accessed July 17, 2022. 

7. Fox JC, Hellawell JL, Rao S, et al. First-in-human study of AG10, a novel, oral, specific, selective, and potent transthyretin stabilizer for the treatment of transthyretin amyloidosis: a phase 1 safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy adult volunteers. Clin Pharmacol Drug Dev. 2020;9(1):115-129. doi:10.1002/cpdd.700

8. Coelho T, Ando Y, Benson MD, et al. Design and rationale of the global phase 3 NEURO-TTRansform study of antisense oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in hereditary transthyretin-mediated amyloid polyneuropathy. Neurol Ther. 2021;10(1):375-389. doi:10.1007/s40120-021-00235-6

9. CARDIO-TTRansform: a study to evaluate the efficacy and safety of eplontersen (formerly known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in participants with transthyretin-mediated amyloid cardiomyopathy (ATTR CM) (NCT 04136171). Updated April 5, 2022. Accessed July 17, 2022. 

10. NEURO-TTRansform: a study to evaluate the efficacy and safety of eplontersen (formerly known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in participants with hereditary transthyretin-mediated amyloid polyneuropathy (NCT04136184). Updated June 10, 2022. Accessed July 17, 2022. 

11. A clinical study to characterize adverse events occurring within one day of TEGSEDI administration to adult patients with hATTR-PN (NCT 04306510). Updated December 17, 2021. Accessed July 17, 2022.

12. A non-interventional cohort safety study of patients with hATTR-PN (NCT04850105). Updated May 11, 2022. Accessed July 17, 2022.

13. ConTTRibute: a global observational study of patients with transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) (ConTTRibute) (NCT04561518). Updated June 3, 2022. Accessed July 17, 2022. 

14. Real-world effectiveness of tafamidis on neurologic disease progression in patients with mixed phenotype hereditary transthyretin amyloidosis cardiomyopathy (NCT05139680). Updated July 14, 2022. Accessed July 17, 2022.

15. TEGSEDI Pregnancy Surveillance Program (NCT04270058). Updated December 17, 2021. Accessed July 17, 2022

Reviewed by Hasan Avcu, MD, on 7/26/2022.