Are there any other approved Transthyretin (TTR) stabilizer therapies besides tafamidis (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 stabilizers besides tafamidis (Vyndaqel/Vyndamax) have received regulatory approval for the treatment of ATTR-CM.

Current Approved Therapies for ATTR

TTR Stabilizers:

• Tafamidis: The only approved TTR stabilizer therapy for ATTR-CM
  • Available in two formulations 1:
    • Tafamidis meglumine (Vyndaqel): 20 mg capsules, dosed at 80 mg (4 capsules) once daily
    • Tafamidis (Vyndamax): 61 mg capsules, dosed at 61 mg once daily

Other Disease-Modifying Therapies (Not TTR Stabilizers):

• TTR Silencers (approved only for ATTRv with polyneuropathy, not for ATTR-CM):
  • Inotersen
  • Patisiran
  • Vutrisiran

Mechanism of Action of Tafamidis

Tafamidis works by binding to the thyroxine-binding sites of the TTR tetramer, preventing its dissociation into monomers 2, 3. This stabilization:

• Inhibits the formation of TTR amyloid fibrils
• Prevents the rate-limiting step in TTR amyloidogenesis
• Works on both wild-type and mutant TTR

Clinical Efficacy of Tafamidis

In the ATTR-ACT trial, tafamidis demonstrated significant benefits 1, 2:

• Reduced all-cause mortality (29.5% vs 42.9% with placebo)
• Decreased cardiovascular-related hospitalizations (0.48 vs 0.70 per year)
• Slowed deterioration in 6-minute walk test distance
• Improved quality of life
• Benefits were consistent across both wild-type and variant TTR genotypes

Unapproved Agents with Limited Evidence

Several other agents have been investigated as potential TTR stabilizers but lack FDA approval 1:

1. Diflunisal: An NSAID with TTR stabilizing properties

   • Limited evidence of benefit on surrogate endpoints like LV mass
   • Not recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²)
   • No proven impact on cardiovascular morbidity or mortality

2. TTR Disruptors (targeting tissue clearance):

   • Doxycycline plus tauroursodeoxycholic acid (TUDCA)
   • Epigallocatechin-3-gallate (EGCG) found in green tea
   • Limited evidence of benefit on surrogate endpoints
   • No proven impact on cardiovascular morbidity or mortality

Important Clinical Considerations

• Tafamidis is indicated for NYHA class I-III symptoms; benefit has not been observed in NYHA class IV 1
• Tafamidis prevents but does not reverse amyloid deposition, so earlier treatment is likely more beneficial 1
• The cost of tafamidis is substantial (approximately $225,000 annually), providing low economic value (>$180,000 per QALY gained) 1
• Patients with severe aortic stenosis or impaired renal function (eGFR <25 mL/min/1.73 m²) have not shown benefit with tafamidis 1

Conclusion

For patients with ATTR-CM requiring TTR stabilization, tafamidis remains the only approved option with proven mortality and morbidity benefits. Other investigational agents lack sufficient evidence or regulatory approval for clinical use in ATTR-CM.