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

With TTR Mediated Familial Amyloidotic Cardiomyopathy (ENDEAVOUR) trial of revusiran was
terminated early due to increased mortality in the treatment arm at a pre-specified interim analysis at 6.7
[15]
months . The majority of deaths were cardiovascular in etiology, but no clear causative mechanism was
identified.

The latest generation of small interfering RNA, vutrisiran (ALN-TTRSC02, Alnylam Pharmaceuticals) is
also a GalNAc ligand that targets the same site of the 3’ untranslated region of the TTR mRNA as revusiran.
However, vutrisiran potentially has fewer off-target effects through two modifications at the 5’ terminus of
the siRNA and a reduction in the number of 2’-fluoro-modified sugar residues, which increases the stability
of the molecule and decreases the amount of 2’-fluoro nucleoside metabolites. The recently completed
Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy and Safety of ALN-TTRSC02 in
Patients with Hereditary Transthyretin Amyloidosis (HELIOS-A) clinical trial investigated the efficacy of
vutrisiran in the treatment of patients with hereditary ATTR polyneuropathy. A total of 164 patients were
randomized in a 3:1 fashion to receive vutrisiran 25mg SQ once every 12 weeks or patisiran 0.3 mg/kg IV
once every 3 weeks. For efficacy analysis, the vutrisiran arm was compared to the placebo arm of the
APOLLO trial. The results of the trial will be presented on April 19, 2021 at the American Academy of
Neurology Virtual Annual Meeting 2021. However, a press release from the trial’s sponsor states that
vutrisiran demonstrated improvements in the progression of the modified Neurologic Impairment Score +
7 (mNIS + 7), the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) score, and the timed 10-
[16]
meter walk test compared to the historical control . The ongoing Phase 3, Randomized, Double-blind,
Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Vutrisiran in Patients with
Transthyretin Amyloidosis with Cardiomyopathy (HELIOS-B) clinical trial is investigating the efficacy of
vutrisiran in reducing a composite of all-cause mortality and recurrent cardiovascular hospitalizations in
patients with hereditary ATTR amyloidosis with cardiomyopathy.

Antisense oligonucleotides
TTR protein synthesis in the hepatocytes can also be downregulated by antisense oligonucleotides (ASOs),
which bind the gene’s transcribed mRNA and prevent translation. ASOs are short 20 nucleotide-long
chimeric RNA sequences that complementarily bind a target mRNA, leading to its rapid degradation
through RNaseH and effective gene expression inhibition . ASOs have a 5-10-5 structure of five 2’-O-
[10]
methoxyethyl modified ribonucleotides at each terminus and a central region of ten 2’-deoxynucleotide
residues.

Inotersen (TEGSEDI®, Akcea Therapeutics) is a chimeric 2’-O-methoxyethyl-modified antisense
oligodeoxynucleotide that binds to a 3’ untranslated region of the TTR mRNA, allowing for complementary
binding to the mRNA of both wild-type gene and all known hereditary variants of the gene . Inotersen
[17]
reduces hepatic TTR mRNA and protein concentrations by approximately 70%, with peak reduction
occurring 2-3 days after drug administration. There is gradual recovery to pre-treatment levels after 1-2
weeks and near-complete recovery after approximately 28 days. Because inotersen does not cross the blood-
brain barrier, TTR production in the choroid plexus in the central nervous system remains unaffected.

The Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of
ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (NEURO-TTR) compared inotersen vs.
placebo in patients with hereditary ATTR polyneuropathy. A total of 172 patients were randomized in a 2:1
fashion to treatment vs. placebo, 63% of the enrolled patients had cardiomyopathy, and it was more
prevalent in the treatment arm than placebo at the time of trial entry. Inotersen was dosed at 300 mg
subcutaneously injection three times weekly for the first week of treatment, followed by weekly injections