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

Approved TTR Stabilizer Therapies Beyond Tafamidis

Currently, tafamidis (Vyndamax/Vyndaqel) is the only FDA-approved TTR stabilizer therapy for transthyretin amyloid cardiomyopathy (ATTR-CM) 1. While other disease-modifying therapies exist, they work through different mechanisms or are approved for different indications.

Current Approved TTR-Targeting Therapies

TTR Stabilizers:

• Tafamidis: FDA-approved for ATTR-CM (both wild-type and variant forms) in patients with NYHA class I-III heart failure symptoms 1
  • Available in two formulations:
    • Tafamidis meglumine 80 mg (4 × 20 mg capsules) daily
    • Tafamidis 61 mg capsule daily

TTR Silencers (RNA-targeting therapies):

• Inotersen: FDA-approved only for ATTRv with polyneuropathy, not for cardiomyopathy 1
• Patisiran: FDA-approved only for ATTRv with polyneuropathy, not for cardiomyopathy 1
• Vutrisiran: FDA-approved for ATTRv polyneuropathy; may be forthcoming for ATTR-CM 2

Other TTR-Targeting Approaches (Not FDA-Approved for ATTR-CM)

Off-label TTR Stabilizers:

• Diflunisal: An NSAID with TTR-stabilizing properties
  • Not FDA-approved for ATTR-CM
  • Limited evidence of benefit on surrogate endpoints like LV mass 1
  • Not generally recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload due to potential adverse renal effects 1

TTR Disruptors (Investigational):

• Doxycycline plus TUDCA (tauroursodeoxycholic acid): Limited evidence on surrogate endpoints 1
• EGCG (epigallocatechin-3-gallate) in green tea: Limited evidence on surrogate endpoints 1

Clinical Considerations

• Efficacy of tafamidis: Reduces all-cause mortality (29.5% vs 42.9%) and cardiovascular-related hospitalizations (0.48 vs 0.70 per year) compared to placebo in ATTR-ACT trial 1, 3, 4
• Cost concerns: At 2020 list prices ($225,000 annually), tafamidis provides low economic value (>$180,000 per QALY gained) 1
• Patient selection: Most beneficial when started early in disease course; survival curves separated after 18 months in clinical trials 1
• Limitations: Not shown to be beneficial in NYHA class IV symptoms, severe aortic stenosis, or impaired renal function (eGFR <25 mL/min/1.73 m²) 1

Emerging Therapies

Several disease-modifying medications are in advanced stages of clinical development for ATTR-CM 2:

• Acoramidis: Recently approved TTR stabilizer for ATTR-CM 2
• Additional therapies in development include antisense oligonucleotides, gene editing therapies, and monoclonal antibodies 2

Key Takeaways

• Tafamidis and acoramidis are currently the only FDA-approved TTR stabilizers specifically for ATTR-CM 1, 2
• For ATTRv with polyneuropathy, inotersen and patisiran are approved but not specifically for cardiac manifestations
• Early diagnosis and treatment are critical for optimal outcomes
• Cost remains a significant barrier to treatment access