Table 3.
Focus on available treatments in TTR-AC and novel drugs under investigation.
| Drugs | Mechanism | Design | Dose | Population | Results in TTR-AC | Approved indications (FDA/EMA; June 2020) |
|---|---|---|---|---|---|---|
| Tafamidis (ATTR-ACT, 2018) [26] | TTR stabilizer | Multicentre, double-blind, placebo controlled 2:1:2 randomization |
80 mg vs. 20 mg vs. placebo for 30 months | TTR cardiomyopathy (TTRv and TTRwt) (n = 441) | Reduced all-cause mortality (HR 0.70) and CV hospitalization (RR 0.68); Less decline in 6MWT and KCCQ-OS score (both p <0.001) |
FDA: not approved EMA: Stage I TTRv-related polyneuropathy |
| AG-10 (2019) [44] | TTR stabilizer | Multicentre, double-blind, placebo controlled 1:1:1 randomization |
1600 mg vs. 800 mg vs. placebo for 28 days | TTR cardiomyopathy (TTRv and TTRwt) (n = 49) | Near-complete stabilization of TTR with restoration of normal serum levels. More effective at higher doses (average increase of 36±21% and 51±38% at 400 and 800 mg (both p<0.001) | FDA: not approved. EMA: not approved. |
| Patisiran (APOLLO, 2018) [45] | SiRNA | Multicentre, double-blind, placebo controlled 2:1 randomization |
0.3 mg/kg iv vs. placebo once every 3 weeks for 18 months | TTRv-related polyneuropathy Subgroup with cardiomyopathy (n = 126, 56%) |
Slower LV functional deterioration and promotion of favourable remodelling: decreased LV volumes, wall thickness, RWT, mass and NT-proBNP. | FDA: TTRv-related polyneuropathy EMA: Stages I–II TTRv-related polyneuropathy |
| Inotersen (2018) [46] | ASO | Multicentre, double-blind, placebo controlled 2:1 randomization |
300 mg sc vs. placebo for 64 weeks | TTRv-related polyneuropathy – Stages I–II Subgroup with cardiomyopathy (n = 108, 63%) |
Slower progression in neuropathy, no effect on echocardiographic parameters (including GLS) | FDA: TTRv-related polyneuropathy EMA: Stages I–II TTRv-related polyneuropathy |
| PRX004 (NCT03336580) | mAb | Phase I, single centre, open-label, dose escalation | 0.1 mg/kg iv once every 28 days | TTRv amyloidosis (estimated n = 36) | Aim: determine the safety, tolerability, PK, PD and MTD | Prematurely terminated because of COVID 19 pandemic |
| Ab-A (2020) [47] | mAb | Single centre, open label, murine model | 10 mg/kg vs. 5 mg/kg vs. 0.1 mg/kg vs. sham | TTRwt amyloidosis | Promoting clearance and degradation of aggregated TTR by cardiac macrophages Protecting cardiomyocytes from aggregated TTR- mediated toxicity |
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Legend: 6MWT, Six Minute Walking Test; AC, Amyloid Cardiomyopathy; ASO, Antisense Oligonucleotide; CV, Cardiovascular; EMA, European Medicine Agency; FDA, Food and Drug Administration; GLS, Global Longitudinal, Strain; KCCQ-OS, Kansas City Cardiomyopathy Questionnaire Overall Summary; LV, Left Ventricular; mAb, Monoclonal Antibody; MTD, Maximum Tolerated Dose; NT-proBNP, N- terminal Brain Natriuretic Peptide; PD, Pharmacodynamics; PK, Pharmacokinetics; RWT, Relative Wall Thickness, siRNA, small interfering RNA; TTR, Transthyretin; TTRv, mutated Transthyretin; TTRwt, wild-type Transthyretin.