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Emerging Therapies for Transthyretin Cardiac Amyloidosis

  • Heart Failure (W Tang, Section Editor)
  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Abstract

Purpose of review

Transthyretin cardiac amyloidosis is an underdiagnosed, undertreated disease which is associated with significant morbidity and mortality. This review will discuss the recent advancements in novel therapies for transthyretin amyloidosis.

Recent findings

In recent phase 3 clinical trials, transthyretin stabilizers (tafamidis) and transthyretin silencers (patisiran and inotersen) have proven to be effective therapies for various forms of transthyretin amyloidosis.

Summary

Understanding the recent and upcoming clinical trials for transthyretin amyloidosis will be important for improving the management of this challenging disease.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Alexander KM, Orav J, Singh A, Jacob SA, Menon A, Padera RF, et al. Geographic disparities in reported US amyloidosis mortality from 1979 to 2015: potential underdetection of cardiac amyloidosis. JAMA Cardiol. 2018;3(9):865–70.

    Article  Google Scholar 

  2. Falk RH, Alexander KM, Liao R, Dorbala S. AL (light-chain) cardiac amyloidosis: a review of diagnosis and therapy. J Am Coll Cardiol. 2016;68(12):1323–41.

    Article  Google Scholar 

  3. Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, et al. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015;126(5):612–5.

    Article  CAS  Google Scholar 

  4. Sperry BW, Ikram A, Hachamovitch R, Valent J, Vranian MN, Phelan D, et al. Efficacy of chemotherapy for light-chain amyloidosis in patients presenting with symptomatic heart failure. J Am Coll Cardiol. 2016;67(25):2941–8.

    Article  CAS  Google Scholar 

  5. Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017;130(7):900–2.

    Article  CAS  Google Scholar 

  6. Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585–94.

    Article  CAS  Google Scholar 

  7. Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, et al. The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. 2015;372(1):21–9.

    Article  Google Scholar 

  8. Dungu JN, Papadopoulou SA, Wykes K, Mahmood I, Marshall J, Valencia O, et al. Afro-Caribbean heart failure in the United Kingdom: cause, outcomes, and ATTR V122I cardiac amyloidosis. Circ Heart Fail. 2016;9(9). https://doi.org/10.1161/CIRCHEARTFAILURE.116.003352.

  9. Razavi H, Palaninathan SK, Powers ET, Wiseman RL, Purkey HE, Mohamedmohaideen NN, et al. Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action. Angew Chem Int Ed Engl. 2003;42(24):2758–61.

    Article  CAS  Google Scholar 

  10. Bulawa CE, Connelly S, Devit M, Wang L, Weigel C, Fleming JA, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A. 2012;109(24):9629–34.

    Article  CAS  Google Scholar 

  11. Scott LJ. Tafamidis: a review of its use in familial amyloid polyneuropathy. Drugs. 2014;74(12):1371–8.

    Article  CAS  Google Scholar 

  12. •• Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007–16. This large phase 3 trial showed that tafamidis improved survival and reduce cardiovascular-related hospitalizations in ATTR cardiomyopathy patients. This led to tafamidis being approved as the first drug for ATTR cardiomyopathy.

  13. Alhamadsheh MM, Connelly S, Cho A, Reixach N, Powers ET, Pan DW, et al. Potent kinetic stabilizers that prevent transthyretin-mediated cardiomyocyte proteotoxicity. Sci Transl Med. 2011;3(97):97ra81.

    Article  Google Scholar 

  14. Penchala SC, Connelly S, Wang Y, Park MS, Zhao L, Baranczak A, et al. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci. 2013;110(24):9992–7.

    Article  CAS  Google Scholar 

  15. Judge DP, Falk RH, Maurer MS, Shah SJ, Witteles RM, Grogan M, et al. Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy. J Am Coll Cardiol. 2019. https://doi.org/10.1016/j.jacc.2019.03.012.

    Article  CAS  Google Scholar 

  16. Hanson JLS, Arvanitis M, Koch CM, Berk JL, Ruberg FL, Prokaeva T, et al. Use of serum transthyretin as a prognostic Indicator and predictor of outcome in cardiac amyloid disease associated with wild-type transthyretin. Circ Heart Fail. 2018;11(2):e004000.

  17. Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the transthyretin amyloidosis cardiac study (TRACS). Am Heart J. 2012;164(2):222–8 e1.

    Article  Google Scholar 

  18. Efficacy and safety of AG10 in subjects with transthyretin amyloid cardiomyopathy. https://ClinicalTrials.gov/show/NCT03860935. Accessed 15 May 2019.

  19. Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW. Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis. J Med Chem. 2004;47(2):355–74.

    Article  CAS  Google Scholar 

  20. Sekijima Y, Dendle MA, Kelly JW. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid. 2006;13(4):236–49.

    Article  CAS  Google Scholar 

  21. Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658–67.

    Article  CAS  Google Scholar 

  22. Castano A, Helmke S, Alvarez J, Delisle S, Maurer MS. Diflunisal for ATTR cardiac amyloidosis. Congest Heart Fail. 2012;18(6):315–9.

    Article  CAS  Google Scholar 

  23. Ikram A, Donnelly JP, Sperry BW, Samaras C, Valent J, Hanna M. Diflunisal tolerability in transthyretin cardiac amyloidosis: a single center’s experience. Amyloid. 2018;25(3):197–202.

    Article  CAS  Google Scholar 

  24. Ericzon BG, Wilczek HE, Larsson M, Wijayatunga P, Stangou A, Pena JR, et al. Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation. 2015;99(9):1847–54.

    Article  CAS  Google Scholar 

  25. Buxbaum JN. Oligonucleotide drugs for transthyretin amyloidosis. N Engl J Med. 2018;379(1):82–5.

    Article  Google Scholar 

  26. Dong Y, Siegwart DJ, Anderson DG. Strategies, design, and chemistry in siRNA delivery systems. Adv Drug Deliv Rev. 2019. https://doi.org/10.1016/j.addr.2019.05.004.

  27. Akinc A, Querbes W, De S, Qin J, Frank-Kamenetsky M, Jayaprakash KN, et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther. 2010;18(7):1357–64.

    Article  CAS  Google Scholar 

  28. Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819–29.

    Article  CAS  Google Scholar 

  29. Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I, Berk 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.

  30. •• Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11–21. This phase 3 study showed that patisiran improved neuropathy impairment in ATTR polyneuropathy patients and led to patisiran’s FDA approval.

    Article  CAS  Google Scholar 

  31. Solomon SD, Adams D, Kristen A, Grogan M, Gonzalez-Duarte A, Maurer MS, et al. Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis. Circulation. 2019;139(4):431–43.

    Article  CAS  Google Scholar 

  32. Minamisawa M, Claggett B, Adams D, Kristen AV, Merlini G, Slama MS, et al. Association of patisiran, an RNA interference therapeutic, with regional left ventricular myocardial strain in hereditary transthyretin amyloidosis: the APOLLO study. JAMA Cardiol. 2019;4:466.

    Article  Google Scholar 

  33. HELIOS-A: A study of vutrisiran (ALN-TTRSC02) in patients with hereditary transthyretin amyloidosis (hATTR Amyloidosis). https://ClinicalTrials.gov/show/NCT03759379. Accessed 15 May 2019.

  34. Ackermann EJ, Guo S, Benson MD, Booten S, Freier S, Hughes SG, et al. Suppressing transthyretin production in mice, monkeys and humans using 2nd-generation antisense oligonucleotides. Amyloid. 2016;23(3):148–57.

    Article  CAS  Google Scholar 

  35. •• Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22–31. This phase 3 study showed that inotersen slowed disease progression in ATTR polyneuropathy patients and led to inotersen’s FDA approval.

  36. A study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ION-TTR-LRx in healthy volunteers and patients with hereditary transthyretin-mediated amyloidosis. https://ClinicalTrials.gov/show/NCT03728634. Accessed 15 May 2019.

  37. Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature. 2002;417(6886):254–9.

    Article  CAS  Google Scholar 

  38. Gillmore JD, Tennent GA, Hutchinson WL, Gallimore JR, Lachmann HJ, Goodman HJ, et al. Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis. Br J Haematol. 2010;148(5):760–7.

    Article  CAS  Google Scholar 

  39. Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A, Gilbertson JA, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature. 2010;468(7320):93–7.

    Article  CAS  Google Scholar 

  40. Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, et al. Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N Engl J Med. 2015;373(12):1106–14.

    Article  CAS  Google Scholar 

  41. • Richards DB, Cookson LM, Barton SV, Liefaard L, Lane T, Hutt DF, et al. Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis. Sci Transl Med. 2018;10(422). This study examines the safety and efficacy of a novel monoclonal antibody, dezamizumab, that stimulates the removal of organ-deposited amyloid fibrils.

    Article  Google Scholar 

  42. Multiple treatment session study to assess GSK2398852 administered following and along with GSK2315698. https://ClinicalTrials.gov/show/NCT03044353. Accessed 15 May 2019.

  43. Higaki JN, Chakrabartty A, Galant NJ, Hadley KC, Hammerson B, Nijjar T, et al. Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin. Amyloid. 2016;23(2):86–97.

    Article  CAS  Google Scholar 

  44. A study of PRX004 in subjects with amyloid transthyretin (ATTR) amyloidosis. https://ClinicalTrials.gov/show/NCT03336580. Accessed 15 May 2019.

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Authors and Affiliations

  1. Stanford Amyloid Center, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Lane #158, Stanford, CA, 94305, USA

    Kevin M. Alexander MD, Alessandro Evangelisti BS & Ronald M. Witteles MD

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  1. Kevin M. Alexander MD
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  2. Alessandro Evangelisti BS
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  3. Ronald M. Witteles MD
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Corresponding author

Correspondence to Ronald M. Witteles MD.

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Conflict of Interest

Kevin M. Alexander has received an investigator-initiated research grant from Pfizer.

Alessandro Evangelisti declares no potential conflicts of interest.

Ronald M. Witteles has received consulting fees (modest) from Pfizer and Alnylam, and has received clinical trial support from Pfizer, Alnylam, and Eidos.

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The article does not contain any studies with human or animal subjects performed by any of the authors.

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Alexander, K.M., Evangelisti, A. & Witteles, R.M. Emerging Therapies for Transthyretin Cardiac Amyloidosis. Curr Treat Options Cardio Med 21, 40 (2019). https://doi.org/10.1007/s11936-019-0743-2

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