Page 36 - Read Online

Page 6 of 11 Shah et al. Vessel Plus 2021;5:53 https://dx.doi.org/10.20517/2574-1209.2021.76

for a total of 64 weeks. All patients were empirically given vitamin A supplementation due to TTR’s role as a
transport protein for retinol. At 66 weeks, inotersen compared to placebo showed a significant decrease in
the modified Neuropathy Impairment Score + 7 (mNIS + 7) score by an average of 19.7 points and a
decrease in the Norfolk QOL-DN score by an average of 11.7 points. There were five deaths in the inotersen
arm and zero in the placebo arm. The majority of the deaths in the inotersen arm were from the progression
of underlying disease. Serious adverse reactions in the inotersen arm included glomerulonephritis (3%) and
thrombocytopenia (3%), with 1 death associated with severe thrombocytopenia . Inotersen was granted
[18]
Food and Drug Administration (FDA) approval for hereditary ATTR polyneuropathy with the requirement
for weekly monitoring of platelet counts and biweekly monitoring of renal function and urinary protein.

A small open-label study of inotersen in 15 patients with either hereditary or wild-type ATTR
cardiomyopathy showed disease stabilization after 12 months of treatment. Inotersen use resulted in
improved 6-min walk distance by an average of 29.2 meters, reduction in left ventricular mass by an average
of 27 grams, change in global longitudinal strain by an average of -1.6, and reduction in circulating BNP
levels by an average of 61 pg/mL .
[19]
Similar to siRNA therapy, ASO therapy showed cardiovascular benefit after an average of 15-18 months of
use, later than the 9 months to see differences in neurologic outcomes in patients with hereditary TTR
amyloidosis.

A next-generation of ASO, AKCEA-TTR-L (ION-682884, Ionis Pharmaceuticals) is now being studied,
RX
targeting the same sequence as inotersen but also conjugated to a triantennary N-acetylgalactosamine
(GalNAc) ligand, to allow increased delivery to the liver and decrease the total dose required with hopes of
alleviating some of the safety concerns with inotersen. The Phase 3 Global, Double-Blind, Randomized,
Placebo-Controlled Study to Evaluate the Efficacy and Safety of ION-682884 in Patients with Transthyretin-
Mediated Amyloid Cardiomyopathy (CARDIO-TTRansform) and Phase 3 Global, Open-Label,
Randomized Study to Evaluate the Efficacy and Safety of ION-682884 in Patients with Hereditary
Transthyretin-Mediated Amyloid Polyneuropathy (NEURO-TTRansform) clinical trials are currently
underway.

Both siRNAs and ASOs can be effectively used to silence TTR gene expression and protein production.
They have therapeutic potential in the treatment of TTR cardiomyopathy when present with neuropathy;
the role of TTR silencing in the treatment of isolated cardiomyopathy is still under investigation. Several
randomized clinical trials, including APOLLO-B, HELIOS-B, CARDIO-TTRansform, and NEURO-
[7]
TTRansform, are ongoing .

TTR STABILIZATION
Tafamidis
The most well-known and widely available treatment for transthyretin amyloid cardiomyopathy is tafamidis
(Vyndaqel®, Pfizer Inc), a TTR protein stabilizer. Tafamidis is a benzoxazole derivative that binds TTR
protein molecules at the thyroxine-binding site with high affinity. Hydrogen bonding stabilizes the TTR
tetramer and prevents the creation of monomers that would pathologically aggregate into amyloid fibrils
subsequently. Tafamidis is a carboxylic acid derivate; however, it does not have anti-inflammatory
properties.

The Multicenter, International, Phase 3, Double-Blind, Placebo-Controlled, Randomized Study to Evaluate
the Efficacy, Safety, and Tolerability of Daily Oral Dosing of Tafadmis Meglumine PF-06291826 20 MG or