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 ATTR cardiomyopathy, while acoramidis has recently been approved as a second TTR stabilizer option.

Current FDA-Approved TTR-Targeted Therapies

TTR Stabilizers

• Tafamidis: FDA-approved for ATTR-CM (wild-type or variant) in patients with NYHA class I-III symptoms 1
  • Available in two formulations:
    • Tafamidis meglumine (Vyndaqel): 20mg capsules, dosed at 80mg (4 capsules) once daily
    • Tafamidis free acid (Vyndamax): 61mg capsules, dosed at 61mg once daily
• Acoramidis: Recently approved TTR stabilizer for ATTR-CM

TTR Silencers (RNA-targeted therapies)

These are approved for ATTRv with polyneuropathy, not specifically for cardiomyopathy:

• Patisiran: FDA-approved for ATTRv polyneuropathy 1
• Inotersen: FDA-approved for ATTRv polyneuropathy 1
• Vutrisiran: FDA-approved for ATTRv polyneuropathy 2

Treatment Algorithm Based on Disease Presentation

For ATTR Cardiomyopathy (ATTR-CM):

1. First-line therapy: Tafamidis for patients with NYHA class I-III symptoms 1

   • Reduces cardiovascular mortality and hospitalizations
   • Efficacy demonstrated in both wild-type and variant ATTR
   • Note: Cost-effectiveness is poor at current pricing (>$180,000 per QALY) 1

2. Alternative options:

   • Acoramidis (newly approved TTR stabilizer)
   • Clinical trials of TTR silencers for cardiac indications

For ATTRv with Polyneuropathy:

1. TTR silencers (first-line): 1

   • Patisiran
   • Inotersen
   • Vutrisiran

2. TTR stabilizers (not FDA-approved for neuropathy):

   • Tafamidis is not FDA-approved for polyneuropathy despite some efficacy 1
   • Diflunisal (off-label): shown effective for ATTRv polyneuropathy but not FDA-approved for this indication 1

Important Clinical Considerations

• Genetic testing: If ATTR-CM is identified, genetic sequencing of the TTR gene is essential to determine if the patient has variant (ATTRv) or wild-type (ATTRwt) disease 1

• Cardiac management challenges:

  • Standard heart failure medications may be poorly tolerated in ATTR-CM
  • Beta blockers may worsen symptoms as patients rely on heart rate response 1
  • ACEi/ARBs/ARNi may exacerbate hypotension due to autonomic dysfunction 1

• Anticoagulation: Reasonable for all cardiac amyloidosis patients with atrial fibrillation regardless of CHA₂DS₂-VASc score (Class 2a recommendation) 1

• Monitoring considerations:

  • Regular assessment of neurological function, especially in the first 6 months of treatment 3
  • Monitoring for cardiomyopathy progression or new onset (occurs in ~30% of patients) 3
  • Higher baseline modified body mass index associated with better preservation of neurological function 3

Emerging Therapies

Several disease-modifying therapies are in development for ATTR-CM, including: 2

• Expanded indications for existing TTR silencers (patisiran, vutrisiran)
• Gene editing therapies
• Monoclonal antibodies targeting amyloid deposits

The field is rapidly evolving, with vutrisiran potentially receiving approval for ATTR-CM in the near future 2.