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. Author manuscript; available in PMC: 2022 May 14.
Published in final edited form as: Circ Res. 2021 May 13;128(10):1554–1575. doi: 10.1161/CIRCRESAHA.121.318187

Table 3:

Therapies for Transthyretin Cardiac Amyloidosis

Drug Phase of study Indication by Amyloid Type Mechanism of action Dose Adverse Effects Concomitant Therapy & Monitoring Annual Cost Primary Endpoints
KNOCK-DOWN Inotersen (Tegsedi) Phase 2
NCT03702829 		ATTRv & ATTRwt-CA
NYHA I-III		 2’-O-methoxyethyl-modified ASO, binds to nuclear target mRNA in the liver and via RNase H2 initiates mRNA degradation 300 mg SC per week

  1. Glomerulonephritis

  2. Thrombocytopenia

  3. Vitamin A deficiency

 Vitamin A supplementation
CBC, BMP & UA every 2 weeks		 ~$450,000 Systolic strain imaging on echo compared to baseline at month 6
Patisiran (Onpattro) Phase 3
APOLLO-B
NCT03997383 		ATTRv & ATTRwt-CA
NYHA I-III		 siRNA which targets the 3’ untranslated region of the TTR mRNA, forming the RISC and subsequent mRNA degradation 0.3 mg/kg IV infusion q 3 weeks (max dose 30mg)

  1. Infusion reactions.

  2. Vitamin A deficiency

 Steroid IV, APAP, H1 & H2 blocker IV & Vitamin A Supplement ~$450,000 Change from baseline at month 12 in 6-MWT
Vutrisirian Phase 3
HELIOS-B
NCT04153149 		ATTRv & ATTRwt-CA
NYHA I-III		 siRNA conjugated to GalNAc, binds to TTR mRNA in the nucleus and initiates mRNA degradation via RNase H2 25mg SC every 3 months Unknown Vitamin A supplement Unknown Composite outcome of all-cause mortality and recurrent CV hospitalizations at 30–36 months
AKCEA-TTR-LRx / ION 682884 Phase 3
Cardio- TTRansform
NCT04136171 		ATTRv & ATTRwt-CA
NYHA I-III		 ASO conjugated to GalNAc, ASO portion shares the same base sequence as Inotersen, thus same mechanism of action 45mg SC every 4 weeks Unknown Vitamin A supplement
Platelets every week
BMP, LFTs and UPCR every 2 weeks		 Unknown Composite of CV mortality and frequency of CV clinical events at 120 weeks
CRISPR (NTLA-2001) Phase 1
Open label and Single Dose Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics		 ATTRv-FAP Cas9/CRISPR genome editing IV dose escalation study Unknown None Unknown

  1. Adverse events

  2. Change from baseline in serum TTR

  3. Change from baseline in prealbumin

  4. Pharmacokinetics

  5. Pharmacodynamics

  6. Change from baseline in anti-drug antibody and anti-Cas9 antibody levels
STABILIZERS Tafamidis meglumine60 (Vyndaqel)
Tafamidis free salt (Vyndamax) 		Approved ATTRv & ATTRwt-CA
NYHA I-III		 Benzoxazole derivative without NSAID activity which binds to T4 site on TTR 80mg po daily
61mg po daily		 No safety signals of potential clinical concern None $225,000

  1. All-cause mortality lower with tafamidis (29.5% vs 42.9%)

  2. Frequency of CV related hospitalizations lower with tafamidis (RRR 0.68)
AG-10 (Acoramidis) Phase 3
ATTRIBUTE-CM
NCT03860935 		ATTRv & ATTRwt-CA
NYHA I-III		 Mimics super-stabilizing activity of T119M, forms hydrogen bonds between neighboring serine residues at position 117 of each monomer 800 mg po twice daily Unknown None Unknown

  1. Change in 6MWT at 12 months

  2. All-cause mortality and CV-related hospitalizations at 30 months
Diflunisal57 Phase 2 ATTRv & ATTRwt-CA (off-label use) NSAID, binds to T4 binding site on serum TTR 250mg BID po

  1. Bleeding

  2. Hypertension,

  3. Fluid retention,

  4. Renal dysfunction

 Proton pump inhibitor
Monitor CBC and BMP q 3–6 months		 $420 Safety and efficacy
Tolcapone66 Phase 1
In-vitro and ex-vivo		 ATTRv & ATTRwt-CA (V122I & V30M) Cathecol-O-methyltransferase (COMT) inhibitor with a high affinity for T4 binding site on serum TTR Unknown Acute liver failure LFTs at baseline and q 2–4 weeks for the first 6 months, Unknown No phase 3 trial to date
DEGRADATION / EXTRACTION Doxycycline +/− TUDCA Phase 2 AL-CA*111 & ATTR-CA112 Doxycycline – inhibition of MMP
TUDCA – antiamyloid fibril activity
Synergistic activity to reduce amyloid fiber burden		 Oral Dermatologic Gastrointestinal None Unknown AL-CA: 20% 1-yr mortality and 60% ASCT utilization with CyBorD (no comparison arm)111
ATTR-CA: No significant changes in NYHA class, cardiac biomarkers or echocardiographic parameters over 22 months112
ANTI-SEEDING Tab FH2 Pre-clinical ATTRv Peptide inhibitor which binds to the amyloid driving F- and H-stands of fragmented fibrils, thereby impeding self-recognition and seeding. Pre-clinical Unknown Unknown Unknown Pre-clinical

ASO, antisense oligonucleotide; ATTRv, variant transthyretin amyloid; ATTRwt, wild-type ATTR; ATTR-FAP, ATTR familial amyloid polyneuropathy; BMP, basic metabolic panel; CRISPR, clustered regularly interspaced short palindromic repeats; CV, cardiovascular; LFT, liver function test; MMP, matrix metalloproteinase; NSAID, non-steroidal anti-inflammatory; NYHA, New York Heart Association heart failure class; RISC, RNA-induced silencing complex; TUDCA, tauroursodeoxycholic acid; UPCR, urine protein-creatinine ratio.

*

doxycycline alone