Are there any other approved Transthyretin (TTR) stabilizer therapies besides tafamidis (Vyndamax/Vyndaqel)?

Approved TTR Stabilizer Therapies Beyond Tafamidis

Tafamidis is currently the only FDA-approved TTR stabilizer therapy for transthyretin amyloid cardiomyopathy (ATTR-CM). No other TTR stabilizer therapies are currently approved for ATTR-CM besides tafamidis (Vyndamax/Vyndaqel).

Current Approved Disease-Modifying Therapies for ATTR

TTR Stabilizers:

• Tafamidis (Vyndamax/Vyndaqel): The only FDA-approved TTR stabilizer for ATTR-CM
  • Available in two formulations 1:
    • Tafamidis meglumine: 20-mg capsules (FDA-approved dose: 80 mg [4 capsules] once daily)
    • Tafamidis: 61-mg capsules (FDA-approved dose: 61 mg once daily)
  • Indication: Wild-type or variant ATTR-CM with NYHA class I-III heart failure symptoms
  • Mechanism: Binds to thyroxine-binding sites of TTR tetramer, preventing dissociation into amyloidogenic monomers 2, 3

TTR Silencers:

• Inotersen: FDA-approved for ATTRv polyneuropathy only (not approved for ATTR-CM) 1
• Patisiran: FDA-approved for ATTRv polyneuropathy only (not approved for ATTR-CM) 1
• Vutrisiran: FDA-approved for ATTRv polyneuropathy only (not approved for ATTR-CM) 1, 4

Investigational TTR Stabilizers

• Diflunisal: An NSAID with TTR-stabilizing properties, but not FDA-approved for ATTR-CM 1

  • Limitations: Not generally recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload due to NSAID-related adverse effects 1

• Acoramidis: Recently approved for ATTR-CM but not yet widely available 4

Other Investigational Approaches

• TTR Disruptors: Target tissue clearance (doxycycline, tauroursodeoxycholic acid [TUDCA], and epigallocatechin-3-gallate [EGCG] in green tea) 1

  • Limited evidence of benefit on surrogate endpoints like LV mass
  • No proven impact on cardiovascular morbidity and mortality

• Gene Editing Therapies and Monoclonal Antibodies: In development 4

Clinical Considerations

• For patients with ATTRv (variant) who have polyneuropathy, TTR silencers (inotersen, patisiran, vutrisiran) are approved options, but they are not approved for ATTR-CM 1

• Genetic testing is important to differentiate ATTRv from ATTRwt, as this affects treatment options and triggers genetic counseling and potential screening of family members 1

• Tafamidis is highly effective but extremely expensive (>$225,000 annually), providing low economic value (>$180,000 per QALY gained) 1

Pitfalls and Caveats

• Tafamidis has not shown benefit in patients with NYHA class IV symptoms, severe aortic stenosis, or impaired renal function (eGFR <25 mL/min/1.73 m²) 1

• Early initiation of tafamidis is crucial as it prevents but does not reverse amyloid deposition 1

• TTR silencers approved for polyneuropathy are being studied for ATTR-CM in ongoing trials, but currently lack FDA approval for cardiac indications 1

• Inotersen has been associated with crescentic glomerulonephritis in 3% of patients in clinical trials 1