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Shah et al. Vessel Plus 2021;5:53 https://dx.doi.org/10.20517/2574-1209.2021.76 Page 9 of 11

MisTTR (PRX004, Prothena Corporation) is a monoclonal antibody that binds residues 89-97 of the TTR
tetramer, resulting in inhibition of fibrillogenesis of misfolded TTR monomers. The misTTR antibody binds
[28]
to the F-strand of the protein at the dimer interface of TTR, which is inaccessible in the native tetramer .
Without amyloid fibrillin formation, the misfolded transthyretin monomers are targeted for degradation by
the immune system. In preclinical studies, the antibody was able to inhibit amyloid fibril formation and
promote clearance of insoluble amyloid fibrils through antibody-mediated phagocytosis. A Phase I clinical
study was completed recently and showed improvement in neuropathy progression and improvement in
left ventricular systolic function. Publication of the data is still pending.

Doxycycline and tauroursodeoxycholic acid
It had been hypothesized that TTR tetramers could be disrupted, and the resultant amyloid fibrils are
cleared by macrophages and giant cells in the innate immune system, by doxycycline plus
[29]
tauroursodeoxycholic acid (TUDCA) . Tetracycline antibiotics, such as doxycycline, had been shown to
disrupt TTR fibrillin structure. TUDCA was then shown to have a synergistic effect in disrupting the
fibrillin structure, and also in marking ATTR molecules for degradation. An initial phase II clinical trial,
where patients were given doxycycline 100 mg twice daily and TUDCA 250 mg three times daily for a total
of 12 months, showed promise in halting disease progression. However, a subsequent study showed
[29]
conflicting efficacy results, and raised concerns about high rates of serious adverse effects .
Naturally-derived compounds
Naturally-occurring compounds in green tea have been purported to decrease amyloid fibril monomer
formation. It has been hypothesized that epigallocatechin-3-gallate (EGCG), the most abundant catechin in
green tea, may inhibit amyloid fibril formation and reduce the incidence of clinical amyloidosis. This was
further supported by a study in mice that showed a decrease in left ventricular mass following daily
administration of EGCG to transgenic mice carrying the human Val30Met TTR variant. It was followed by
a series of small prospective cohort studies in humans examining the effect of voluntary daily green tea
consumption on the development of wild-type TTR amyloid cardiomyopathy. Daily consumption of 1200
mg of green tea extract containing 600 mg EGCG for a total of 12 months may be associated with a decrease
in left ventricular mass by 6%-13% on cardiac MRI; however, the results do not appear to be consistently
demonstrated . A single-center retrospective study examining patients treated for a minimum of 9 months
[30]
with EGCG did not demonstrate a survival improvement compared to guideline-directed medical therapy
[31]
alone .
CONCLUSION
The pharmacotherapeutic armamentarium in the treatment of transthyretin amyloid cardiomyopathy
(ATTR-CM) has expanded greatly in the last several years, as has our understanding of the prevalence of the
disease. It is now commonly accepted that ATTR-CM is not a so-called orphan disease but may, in fact,
afflict up to 10%-30% of all elderly patients with heart failure. Recognition of the disease has been aided by
rapid advances in technologies to diagnose ATTR-CM more accurately. The treating cardiologist may also
be faced with confusion in choosing an optimal pharmacotherapy regimen for treatment out of several
options in the coming years. While newer agents are being developed, attention should also be given to a
better understanding of the disease process, optimal screening strategies, developing treatment regimens
that effectively reverse the disease process, and assessing the efficacy of treatment. Consensus is needed on
identifying patient populations that warrant screening for ATTR-CM, and the imaging modalities and
biomarkers to be used for efficient screening. Consensus definitions on assessing treatment response and
disease progression are also needed. Finally, approaches to tailoring specific disease-modifying agents to
various stages of disease severity, and consideration for combination therapy, are still being developed. It
remains an exciting time for the diagnosis and treatment of ATTR-CM because of the expectation of