Table 3.
Therapies for the Treatment of Transthyretin Cardiac Amyloidosis
| Drug | Phase of Study | Mechanism | Dose/Route | Monitoring | Side effects | Efficacy/Primary Outcomes | Annual List Price |
|---|---|---|---|---|---|---|---|
| Stabilizers | |||||||
| Diflunisal | Phase 2/3 | Binds to T4-binding site | 250 mg oral twice daily | CBC and BMP every 3 mo | 1) Renal dysfunction; 2) Bleeding; 3) Hypertension; 4) Fluid retention | Safety and efficacy | $420 |
| Tafamidis meglumine (Vyndaqel); Tafamidis free acid (Vyndamax) |
Approved for ATTRwt and ATTRv | Benzoxazole derivative of NSAID, binds to T4-binding site on TTR | 80 mg (4 × 20 mg) oral daily (Vyndaqel); 61 mg oral daily (Vyndamax) |
No monitoring required | No known side-effects or interactions | Tafamidis superior to placebo: 1) lower all-cause mortality (29.5% vs 42.9%); NNT: 7.5; 2) lower CV-related hospitalizations; NNT: 4 | $225,000 |
| Acoramidis/AG10 | Phase 3 in ATTRwt and ATTRv (ATTRIBUTE-CM; NCT03860935) | Forms hydrogen bonds between neighboring serine residues at position 117 of each monomer, mimicking activity of Thr119Met | 800 mg oral twice daily | TBD | No known side-effects or interactions | 1) Change in 6MWT at 12 mo; 2) all-cause mortality and CV-related hospitalizations at 30 mo | TBD |
| Knockdown/silencing TTR | |||||||
| Inotersen (Tegsedi) | Phase 2 (NCT03702829); not being pursued for ATTR-CA | 2′-O-methoxyethyl-modified phosphorothioate antisense ASO, binds to target mRNA in liver and initiates mRNA degradation | 300 mg SC once weekly, plus 3,000 IU vitamin A daily | CBC, BMP, urinalysis every 2 wk | 1) 3% thrombocytopenia; 2) 3% glomerulonephritis; 3) Vitamin A deficiency |
Echocardiographic strain imaging compared with baseline at 6 mo | ∼$450,000 |
| Patisiran (Onpattro) | Phase 3 (APOLLO-B; NCT03997383) | siRNA, targets the 3′ untranslated region of TTR mRNA in the liver to form the RNA-induced silencing complex, initiating mRNA degradation | 0.3 mg/kg IV infusion every 3 wk (max dose 30 mg), plus 3,000 IU vitamin A daily; premedications for infusion: steroids IV, APAP, and H1- and H2-blockers | TBD | 1) Infusion reactions; 2) Vitamin A deficiency | Change in 6-MWT from baseline to 12 mo | ∼$450,000 |
| Vutrisiran | Phase 3 (HELIOS-B; NCT04153149) | siRNA conjugated to GalNAc, targets TTR mRNA in the nucleus and initiates degradation via RNaseH2 | 25 mg SC every 12 wk, Plus 3,000 IU vitamin A daily; no premedications required | TBD | Vitamin A deficiency | Composite outcome of all-cause mortality and recurrent CV hospitalizations at 30-36 mo | TBD |
| AKCEA-TTR-LRx/ION 682884 | Phase 3 (Cardio-TTRansform; NCT04136171) | ASO conjugated to GalNAc, same backbone as inotersen, similar mechanism of action, enhanced liver uptake, 51-fold greater potency, 27-fold lower exposure to drug than predecessor | 45 mg SC every 4 wk, plus 3,000 IU vitamin A daily; no premedications required | TBD | Vitamin A deficiency | Composite of CV mortality and frequency of CV clinical events at 120 wk | TBD |
| Emerging agents for degradation/extraction | |||||||
| PRX-004 | Phase 1 (NCT03336580) | Intravenous monoclonal antibody, clears amyloid deposits by binding to misfolded TTR, not to native TTR | IV every 28 d | n/a | n/a | Dose escalation study to determine safety, tolerability, PK, and PD | n/a |
| NI006 | Phase 1 (NCT04360434) | Recombinant IgG1 human monoclonal antibody, targets misfolded and aggregated form of TTR | IV every 28 d | n/a | n/a | Dose escalation study to determine safety, tolerability, PK, and PD | n/a |
| Anti-SAP monoclonal antibody and CPHPC (Dezamizumab) | Phase 2 (NCT03044353); failed to show improvement in cardiac amyloid burden | Synergism of CPHPC, which clears 90% of circulating SAP, and IgG anti-SAP antibody, which binds to SAP in amyloid deposits, initiating a complement-dependent phagocytic clearance of residual deposits | CPHPC IV daily for up to 3 d, then anti-SAP antibody IV on days 1 and 3, plus 60 mg CPHPC 3 times daily on days 1-11 | n/a | n/a | Safety and efficacy | n/a |
6MWT = 6-minute walk test; APAP = acetaminophen; ASO = antisense oligonucleotide; ATTRv = variant transthyretin cardiac amyloidosis; ATTRwt = wild-type transthyretin cardiac amyloidosis; BMP = basic metabolic panel; CBC = complete blood count; CPHPC = (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid; CV = cardiovascular; GalNAc = N-acetyl galactosamine; IV = intravenous; LFT = liver function test; NNT = number needed to treat; NSAID = nonsteroidal antiinflammatory drug; PD = pharmacodynamics; PK = pharmacokinetics; SAP = serum amyloid P component; SC = subcutaneous; siRNA = small interfering ribonucleic acid; TBD = to be determined.