Recent advances in the pharmacotherapy of TTR amyloidosis of the heart

Abstract

Transthyretin amyloidosis of the heart, or transthyretin amyloid cardiomyopathy (ATTR-CM), once thought to be a rare disease, is now increasingly recognized as a common causing of restrictive cardiomyopathy, particularly in elderly patients and patients with heart failure with preserved ejection fraction. ATTR-CM is caused by an aggregation of misfolded transthyretin (TTR) protein amyloid fibrils in the myocardium. The TTR protein itself can be either wild-type (ATTRwt) or one of many pathologic variants (ATTRv). Recognition of ATTR-CM has been aided by rapid advances in technologies to diagnose the disease more accurately. Several advances in pharmacotherapeutic treatments have significantly reduced the morbidity and mortality of the disease. Treatments broadly fall into three categories: (1) TTR silencing through mRNA knockdown or silencing; (2) TTR stabilization; and (3) TTR resorption or extraction. This review article provides a survey of the pharmacokinetic and clinical data on all currently available treatments.

Keywords

Transthyretin amyloid cardiomyopathy / TTR silencing / TTR stabilization / TTR resorption / small interfering RNA / antisense oligonucleotides / carboxylic acid derivate / salicylic acid derivative

References

[1] Koike H.Transthyretin amyloidosis: update on the clinical spectrum, pathogenesis, and disease-modifying therapies.Neurol Ther2020;9:317-33 PMCID:PMC7500251

[2] Giorgetti A,Milan E.Italian Group of Nuclear Cardiology (GICN)Cardiac amyloidosis.Clin Transl Imaging2019;7:21-32

[3] Lane T,Martinez-Naharro A.Natural history, quality of life, and outcome in cardiac transythretin amyloidosis.Circulation2019;140:16-26

[4] Tanskanen M,Polvikoski T.Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study.Ann Med2008;40:232-9

[5] Coelho T,Suhr OB.THAOS - The transythretin amyloidosis outcome survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis.Curr Med Res Opin2013;29:63-76

[6] Jacobson DR,Tagoe C.Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans.Amyloid2015;22:171-4

[7] Kittleson MM,Ambardekar AA.American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the american heart association.Circulation2020;142:e7-22

[8] Gillmore JD,Falk RH.Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.Circulation2016;133:2404-12

[9] Ruberg FL,Hanna M,Maurer MS.Transthyretin amyloid cardiomyopathy: JACC State-of-the-Art review.J Am Coll Cardiol2019;73:2872-91 PMCID:PMC6724183

[10] Castaño A.Cardiac amyloidosis. Heart failure: a companion to Braunwald's heart disease. 4th ed. Elsevier; 2020. p. 301-10.e3.

[11] Siddiqi OK.Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment.Trends Cardiovasc Med2018;28:10-21 PMCID:PMC5741539

[12] Suhr OB,Buades J.Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study.Orphanet J Rare Dis2015;10:109 PMCID:PMC4559363

[13] Adams D,O'Riordan WD.Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis.N Engl J Med2018;379:11-21

[14] Solomon SD,Kristen A.Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis.Circulation2019;139:431-43

[15] Judge DP,Grogan M.Phase 3 multicenter study of revusiran in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with cardiomyopathy (ENDEAVOUR).Cardiovasc Drugs Ther2020;34:357-70 PMCID:PMC7242280

[16] Businesswire. Alnylam reports positive topline results from HELIOS-A phase 3 study of vutrisiran in patients with HATTR amyloidosis with polyneuropathy. Available from: https://www.businesswire.com/news/home/20210107005224/en/Alnylam-Reports-Positive-Topline-Results-from-HELIOS-A-Phase-3-Study-of-Vutrisiran-in-Patients-with-hATTR-Amyloidosis-with-Polyneuropathy [Last accessed on 24 Aug 2021]

[17] Ackermann EJ,Benson MD.Suppressing transthyretin production in mice, monkeys and humans using 2nd-Generation antisense oligonucleotides.Amyloid2016;23:148-57

[18] Benson MD,Berk JL.Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.N Engl J Med2018;379:22-31

[19] Benson MD,Rissing SM,Feigenbaum H.Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy.Amyloid2017;24:219-25

[20] Maurer MS,Gundapaneni B.ATTR-ACT Study InvestigatorsTafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med2018;379:1007-16

[21] Nativi-Nicolau J,Gundapaneni B.Abstract 15528: tafamidis free acid 61 Mg in patients with transthyretin amyloid cardiomyopathy.Circulation2020;142:A15528

[22] Ikram A,Sperry BW,Valent J.Diflunisal tolerability in transthyretin cardiac amyloidosis: a single center's experience.Amyloid2018;25:197-202

[23] Rosenblum H,Alvarez J,Helmke S.TTR (Transthyretin) stabilizers are associated with improved survival in patients with TTR cardiac amyloidosis.Circ Heart Fail2018;11:e004769 PMCID:PMC5886729

[24] Judge DP,Falk RH.Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy.J Am Coll Cardiol2019;74:285-95

[25] Sant'Anna R,Robinson LZ.Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity.Nat Commun2016;7:10787 PMCID:PMC4766415

[26] Richards DB,Berges AC.Therapeutic clearance of amyloid by antibodies to serum amyloid P component.N Engl J Med2015;373:1106-14

[27] Richards DB,Barton SV.Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis.Sci Transl Med2018;10:eaan3128

[28] Galant NJ,Rakhit R.Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses.Sci Rep2016;6:25080 PMCID:PMC4848561

[29] Wixner J,Lundgren HE,Anan I.Effect of doxycycline and ursodeoxycholic acid on transthyretin amyloidosis.Amyloid2017;24:78-9

[30] aus dem Siepen F,Aurich M.Green tea extract as a treatment for patients with wild-type transthyretin amyloidosis: an observational study.Drug Des Devel Ther2015;9:6319-25 PMCID:PMC4675646

[31] Cappelli F,Taborchi G.Epigallocatechin-3-gallate tolerability and impact on survival in a cohort of patients with transthyretin-related cardiac amyloidosis. A single-center retrospective study.Intern Emerg Med2018;13:873-80