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Page 4 of 11 Shah et al. Vessel Plus 2021;5:53 https://dx.doi.org/10.20517/2574-1209.2021.76

EGCG Catechin 600 mg PO, daily No Naturally-occurring compound in green tea and turmeric, Unknown
[30]
limited data in humans

TTR: Transthyretin; COMT: catechol-O-methyltransferase; EGCG: epigallocatechin-3-gallate; TUDCA: tauroursodeoxycholic acid; ASO: antisense oligonucleotide.

expression of the TTR gene can be downregulated through an endogenous cellular mechanism. The siRNA molecules are selectively delivered to the
hepatocytes where TTR gene expression is most avid via a lipid nanoparticle vehicle .
[10]

Patisiran (ONPATTRO®, Alnylam Pharmaceuticals) binds to the 3’ untranslated region of the TTR mRNA, resulting in impaired transcription of the protein
and enzymatic degradation of the mRNA molecule . Because it targets a conserved region of the RNA sequence, patisiran is effective in both ATTRwt and
[11]
ATTRv and can reduce circulating TTR protein levels by up to 90% . In the Phase 3 Multicenter, Multinational, Randomized, Double-blind, Placebo-
[12]
controlled Study to Evaluate the Efficacy and Safety of Patisiran in TTR-Mediated Polyneuropathy (APOLLO) trial, 225 patients with ATTRv polyneuropathy
and New York Heart Association (NYHA) functional class I or II symptoms received patisiran vs. placebo in 2:1 randomized fashion. Patisiran was

administered at a dose of 0.3 mg/kg every 3 weeks intravenously for 18 months following pre-medication with steroids, antihistamines, and acetaminophen.
Treatment with patisiran showed statistically significant improvement in both morbidity and mortality compared to placebo . Patisiran-treated patients had
[13]
improvements in the modified neuropathy impairment score + 7 at 18 months, the Norfolk quality of life score, 10-min walk distance, and modified body mass
index. Adverse reactions consisted primarily of mild or moderate infusion-related reactions and occurred in approximately 20% of patients in the patisiran
arm compared to 10% in the placebo arm.

Because concomitant cardiac involvement is seen in over half of the patients with hereditary transthyretin-mediated polyneuropathy, a subgroup analysis on a

pre-specified subpopulation of patients with evidence of cardiac amyloid involvement, determined by left ventricular wall thickness ≥ 13 mm with no history of
[14]
hypertension and no aortic valve disease, was conducted . At 18 months, patisiran resulted in a decrease in left ventricular wall thickness by an average of 0.9
mm, an improvement in the global longitudinal strain by 1.4%, increase in end-diastolic volume by 8.3 mL, increase in cardiac output by 0.38 L/min, and

reduction in circulating NT-pro-BNP levels by 65%. A post-hoc exploratory analysis, though insufficiently powered for statistical comparison, found that the
rates of both all-cause and cardiac-specific hospitalizations and deaths were lower with patisiran compared to placebo. All-cause deaths were 7 vs. 6 (4.7% vs.

7.8%), and cardiac hospitalizations and/or deaths per 100-years were 10.1 vs. 18.7 with patisiran vs. placebo. Rates of cardiac arrhythmias were also lower in the
patisiran group compared to placebo; however, atrioventricular block requiring pacemaker support was seen more frequently with patisiran, in 4 vs. 0 (2.7%
vs. 0%) patients.

Another siRNA molecule, revusiran (ALN-TTRSC, Alnylam Pharmaceuticals), has also been developed. It is comprised of a siRNA directed against a

conserved region of the TTR mRNA that is conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand that delivers it directly to the liver. Recently,
the Phase 3 Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ALN TTRSC in Patients