Hereditary Transthyretin Amyloidosis (hATTR)

The treatment of hereditary transthyretin (hATTR) amyloidosis focuses primarily on inhibiting the formation and deposition of amyloid protein aggregates, managing symptoms, and monitoring involved organ systems. Organ transplant is used in cases of advanced disease and organ failure.1

Anti-amyloid Therapies

Anti-amyloid therapies are divided into 2 main categories: transthyretin (TTR)-stabilizing therapies and gene-silencing therapies.1 

TTR Tetramer Stabilizers

TTR-stabilizing therapies are designed to prevent the dissociation of circulating TTR tetramers, thereby preventing the formation of amyloid fibrils. These treatments delay disease progression by preventing further tissue and organ damage due to amyloid aggregation and deposition.1 

The 2 pharmaceutical agents classified as TTR stabilizers are tafamidis and diflunisal

In a phase 3 clinical trial, tafamidis stabilized TTR protein in 98% of 128 patients with hATTR amyloidosis who had mild peripheral neuropathy at baseline. Peripheral neuropathy did not progress in 60% of the patients treated with tafamidis and in 38% of the placebo group.1,2 

The safety and short-term efficacy of tafamidis were shown in 3 open-label studies; however, tafamidis did not prevent the progression of neuropathy or disability after 1 year of treatment, demonstrating decreased long-term efficacy. Poorer outcomes in regard to progression of peripheral neuropathy correlated with a worse clinical status and older age at the initiation of tafamidis treatment.1,3-5

The US Food and Drug Administration (FDA) approved tafamidis to treat cardiomyopathy associated with hATTR amyloidosis following positive results of the ATTRACT trial. Tafamidis reduced all-cause mortality and hospitalizations for cardiovascular events, delayed functional decline, and maintained quality of life in patients who had hATTR amyloidosis-related cardiomyopathy.1,6 

Diflunisal, a nonsteroidal anti-inflammatory drug (NSAID), also stabilizes TTR tetramers. In a randomized, placebo-controlled phase 3 trial, patients with hATTR amyloidosis, including some with late-onset disease, responded well to the long-term use of diflunisal in comparison with placebo. Treatment with diflunisal reduced the progression of peripheral neuropathy and maintained the quality of life of patients with hATTR amyloidosis after 2 years, although half of the patients discontinued diflunisal after liver transplant. Diflunisal must be administered with caution because of the increased risk for side effects affecting the gastrointestinal system, kidneys, and heart, which are common with prolonged NSAID use.1,7

Gene-Silencing Therapies

Novel gene-silencing therapies target mutated genes associated with specific diseases like hATTR amyloidosis, blocking the faulty messaging that results in the manifestation of disease. Their effects are accomplished in several different ways, including RNA interference (RNAi) and preventing the translation of TTR messenger RNA (mRNA) into TTR protein via the use of antisense oligonucleotides.1,8

RNA Interference

The FDA has approved 2 RNAi drugs, patisiran and vutrisiran, to treat hATTR amyloidosis.9 RNA interference (iRNA) drugs use noncoding, small interfering RNAs (siRNAs) to mediate the degradation of targeted mRNA and inhibit the expression of specific genes that result in the production of TTR proteins.1 

A phase 1 study showed that maximum TTR reduction from baseline was generally reached approximately 10 days after single‐dose administration.10,11 A phase 2 multiple‐ascending‐dose (MAD) study showed maximum TTR reduction of 82.9% to 86.7% with the highest dose of 0.3 mg/kg administered intravenously once every 3 weeks.10,12 An open label extension (OLE) of the phase 2 study showed rapid and sustained reduction of 82% in mean serum TTR over 24 months, which resulted in disease stabilization.10,13

Vutrisiran, recently approved by the FDA in June of 2022, is an effective RNAi therapy. The drug is injected subcutaneously every 3 months to treat polyneuropathy in adults with hATTR amyloidosis. FDA approval was based on the positive results of a 9-month phase 3 clinical trial, HELIOS-A, in which vutrisiran either stopped or reversed the progression of neuropathic disease in more than 50% of patients with hATTR amyloidosis. To date, vutrisiran is the only known RNAi therapy that has demonstrated the ability to reverse neuropathic impairment in patients with hATTR amyloidosis.14   

Antisense Oligonucleotides

Inotersen is a methoxyethyl-modified antisense oligonucleotide that prevents the liver from producing both mutant and wild-type TTR by degrading TTR mRNA, thereby interfering with the translation of mRNA into TTR protein. Treatment with inotersen reduces circulating plasma TTR concentrations in both animal and healthy human models by more than 80%.1 

In a phase 3 trial, 172 patients with stage 1 or 2 hATTR amyloidosis causing peripheral neuropathy received 300 mg of inotersen, administered subcutaneously 3 times in the first week and once weekly for 64 weeks. Disease progression was stabilized or reversed with inotersen in 36.6% of patients with hATTR amyloidosis independently of mutation type, presence of cardiomyopathy, and stage of disease, compared with 19.2% of patients in the placebo group.1,15

Organ Transplant

Liver transplant remains the gold standard treatment for hATTR because the abnormal TTR proteins are produced in the liver.1,9 Following liver transplant, which effectively replaces abnormal TTR proteins with wild-type TTR proteins, the 20-year survival rate of patients with hATTR was 55.3%.1,16 

Cardiovascular complications were the primary cause of death in patients with hATTR after liver transplant.1,16 Studies have found that liver transplant may not successfully prevent the progressive deposition of amyloid in the heart because preformed amyloid fibrils have been “seeded” in the organs of patients with hATTR before liver transplant. The “seeding” feature of hATTR may make it necessary for patients with hATTR progressively affecting the myocardium eventually to undergo cardiac transplant.17,18 Early referral for liver transplant is recommended for patients with stage I hATTR.9 

In addition to liver and cardiac transplant, patients with hATTR may also require kidney transplant depending on the extent of renal involvement.9


  1. 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
  2. Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785–792. doi:10.1212/WNL.0b013e3182661eb1
  3. Lozeron P, Théaudin M, Mincheva Z, et al. Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy. Eur J Neurol. 2013;20(12):1539–1545. doi:10.1111/ene.12225
  4. Cortese A, Vita G, Luigetti M, et al. Monitoring effectiveness and safety of tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area. J Neurol. 2016;263(5):916–924. doi:10.1007/s00415-016-8064-9
  5. Planté-Bordeneuve V, Gorram F, Salhi H, et al. Long-term treatment of transthyretin familial amyloid polyneuropathy with tafamidis: a clinical and neurophysiological study. J Neurol. 2017;264(2):268–276. doi: 10.1007/s00415-016-8337-3
  6. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.  N Engl J Med. 2018;379(11):1007–1016. doi:10.1056/NEJMoa1805689
  7. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658–2667. doi:10.1001/jama.2013.283815 
  8. Gene silencing: the basics. Silence Therapeutics. Accessed July 24, 2022.
  9. Roberts JR. Transthyretin-related amyloidosis treatment & management: approach considerations, medical care, surgical care. Medscape. Updated July 19, 2022. Accessed July 24, 2022.
  10. Zhang X, Goel V, Robbie GJ. Pharmacokinetics of patisiran, the first approved RNA interference therapy in patients with hereditary transthyretin‐mediated amyloidosis. J Clin Pharmacol. 2020;60(5):573-585. doi:10.1002/jcph.1553
  11. Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829. doi:10.1056/NEJMoa1208760
  12. Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109. doi:10.1186/s13023-015-0326-6
  13. Coelho T, Adams D, Conceição I, et al. A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. Orphanet J Rare Dis. 2020;15(1):179. doi:10.1186/s13023-020-01399-4
  14. Alnylam announces FDA approval of AMVUTTRA (vutrisiran), an RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. News release. Alnylam. June 13, 2022. Accessed July 24, 2022.
  15. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22-31. doi:10.1056/NEJMoa1716793
  16. Ericzon B-G, Wilczek HE, Larsson M, et al. Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation. 2015;99(9):1847-1854. doi:10.1097/TP.0000000000000574
  17. Saelices L, Chung K, Lee JH, et al. Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition. Proc Natl Acad Sci U S A. 2018;115(29):E6741–E6750. doi:10.1073/pnas.1805131115
  18. Saelices L, Nguyen BA, Chung K, et al. A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrils. J Biol Chem. 2019;294(15):6130-6141. doi:10.1074/jbc.RA118.005257

Reviewed by Hasan Avcu, MD, on 7/27/2022.