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

Approved TTR Stabilizer Therapies Beyond Tafamidis

Tafamidis (Vyndaqel/Vyndamax) is currently the only FDA-approved TTR stabilizer therapy for transthyretin amyloid cardiomyopathy (ATTR-CM). There are no other FDA-approved TTR stabilizer therapies besides tafamidis for ATTR-CM, though several other agents are approved or in development for specific ATTR indications.

Current Approved Therapies for ATTR

TTR Stabilizers:

• Tafamidis: Available in two formulations:
  • Tafamidis meglumine (Vyndaqel): 20mg capsules, dosed at 80mg (4 capsules) once daily
  • Tafamidis (Vyndamax): 61mg capsules, dosed at 61mg once daily
  • Indication: FDA-approved for wild-type or variant ATTR-CM with NYHA class I-III symptoms 1
  • Efficacy: Reduces cardiovascular mortality and hospitalization in ATTR-CM 2

TTR Silencers (for ATTRv with polyneuropathy only):

• Patisiran: FDA-approved for ATTRv with polyneuropathy
• Inotersen: FDA-approved for ATTRv with polyneuropathy
• Vutrisiran: FDA-approved for ATTRv with polyneuropathy 1

Non-FDA Approved TTR Stabilizers

• Diflunisal: An NSAID with TTR stabilizing properties
  • Not FDA-approved for ATTR but has shown effectiveness in slowing ATTRv polyneuropathy progression 1
  • Caution: Not generally recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload due to potential adverse effects on kidney function 1

Investigational Agents

• Benzbromarone: A uricosuric drug showing potential as a TTR stabilizer in preclinical studies 3
• AG10: Granted orphan drug designation by the FDA, currently in clinical trials 4
• TTR disruptors: Agents targeting tissue clearance (doxycycline, tauroursodeoxycholic acid, epigallocatechin-3-gallate) have shown limited benefit on surrogate endpoints but lack data on cardiovascular outcomes 1

Treatment Algorithm for ATTR

1. For ATTR-CM with NYHA class I-III symptoms:

   • Tafamidis is the first-line therapy (Class I recommendation) 1

2. For ATTRv with polyneuropathy:

   • TTR silencers (patisiran, inotersen, or vutrisiran) are first-line therapies
   • Tafamidis is not FDA-approved for polyneuropathy despite evidence of efficacy 1

3. For patients with cardiac amyloidosis and atrial fibrillation:

   • Anticoagulation is recommended regardless of CHA₂DS₂-VASc score (Class 2a recommendation) 1

Important Clinical Considerations

• Tafamidis provides greater benefit when administered early in the disease course, with survival curves separating after 18 months of treatment 1
• 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
• Standard heart failure medications may be poorly tolerated in ATTR-CM:
  • ACEi, ARBs, and ARNi may exacerbate hypotension
  • Beta blockers may worsen symptoms as patients with ATTR-CM rely on heart rate response 1
• Cost remains a significant barrier to tafamidis use, with an annual cost of approximately $225,000, providing low economic value (>$180,000 per QALY gained) 1

Conclusion

While tafamidis remains the only FDA-approved TTR stabilizer for ATTR-CM, TTR silencers are approved for ATTRv with polyneuropathy. Research continues on additional TTR stabilizers, but none have yet received FDA approval for ATTR-CM.