Treatment of Cardiac Transthyretin Amyloidosis: An Update

Michele Emdin; Alberto Aimo; Claudio Rapezzi; Marianna Fontana; Federico Perfetto; Petar M. Seferović; Andrea Barison; Vincenzo Castiglione; Giuseppe Vergaro; Alberto Giannoni; Claudio Passino; Giampaolo Merlini


Eur Heart J. 2019;40(45):3699-3706. 

In This Article

Degradation and Reabsorption of Amyloid Fibres

Doxycycline-tauroursodeoxycholic Acid (TUDCA)

Several hydrophobic molecules are effective in destabilizing and disaggregating amyloid fibres, which promote the reabsorption of amyloid deposits by tissue macrophages.[34] Tetracyclines, including doxycycline, proved able to cause complete disaggregation of amyloid fibres in vitro, generating non-toxic molecular species.[34] The combination of doxycycline and tauroursodeoxycholic acid (TUDCA) has a more pronounced effect, causing even complete amyloid clearance from tissues in animal models.[34]

In a small phase 2 trial, 28 patients with ATTR received doxycycline and TUDCA for 12 months followed by a 6-month withdrawal period. The results were modest and difficult to interpret because of a very high dropout rate (86%) due to treatment failure (expressed as >30% NT-proBNP increase), side effects and voluntary dropouts.[35] In a phase 2, open-label study, the treatment was well tolerated, and no progression of cardiac involvement and neuropathy was found in a preliminary analysis on 20 patients.[36]

Antibodies Targeting Serum Amyloid P Protein or Amyloid Fibrils

Serum amyloid P (SAP) is a normal plasma glycoprotein synthetized by the liver, which stabilizes and protects amyloid fibrils from proteolytic degradation.[37] Miridesap is a small molecule that binds circulating SAP and promotes its hepatic clearance.[38] In 2002, Pepys et al.[37] administered miridesap to 7 patients with systemic amyloidosis, obtaining more than 90% reduction of circulating SAP. These results were confirmed by an open label study on 31 patients with advanced systemic amyloidosis, including 4 with ATTR, receiving subcutaneous miridesap injections b.i.d. The histological analysis demonstrated a significant, though incomplete, depletion of SAP within amyloid deposits.[38] In an open-label, single-dose-escalation, phase 1 trial, 15 patients with systemic amyloidosis received miridesap and then a dose of anti-SAP antibodies proportionate to their amyloid load, showing an improvement in liver function and a reduction in visceral amyloid deposits at 6 weeks; patients with cardiac disease were excluded.[39] In an extension phase of the same trial, miridesap therapy was assessed on 6 patients with cardiac amyloidosis (3 with ATTR). Neither cardiac adverse events nor improvements in cardiac involvement were reported.[40] These results led to a phase 2 study assessing whether monthly repeated courses of miridesap followed by anti-SAP antibodies is associated with a reduction in cardiac amyloid load and improvement in cardiac function in patients with ATTR cardiomyopathy.[41] Patient enrolment was suspended on 22 August 2018, and a phase 1 trial was simultaneously stopped.[42] Therefore, the development of anti-SAP antibody therapy has stopped and this approach is no longer evaluated. In contrast, a monoclonal antibody designed to specifically target TTR amyloid deposits (PRX004) has entered clinical evaluation with an ongoing phase 1 study on ATTRv.[43]