What are the approved Transthyretin (TTR) stabilizer therapies besides tafamidis (Vyndaqel)?

FDA-Approved TTR Stabilizer Therapies Beyond Tafamidis

Currently, tafamidis (Vyndaqel/Vyndamax) is the only FDA-approved TTR stabilizer therapy for ATTR cardiomyopathy, while diflunisal is used off-label as a TTR stabilizer despite not having FDA approval for this indication.

FDA-Approved Therapies for ATTR Amyloidosis

TTR Stabilizers

• Tafamidis (Vyndaqel/Vyndamax)
  • FDA-approved for ATTR cardiomyopathy (both wild-type and variant)
  • Available in two formulations:
    • Tafamidis meglumine 20 mg (4 capsules = 80 mg daily dose)
    • Tafamidis 61 mg (single daily capsule)
  • Not FDA-approved for neuropathy (though approved in Europe for this indication) 1

TTR Silencers (RNA-targeting therapies)

These are approved for ATTRv polyneuropathy but not for cardiomyopathy:

1. Patisiran

   • Small interfering RNA (siRNA)
   • FDA-approved for ATTRv polyneuropathy
   • Administered via intravenous infusion
   • Requires vitamin A supplementation (3,000 IU daily)
   • Pre-medication with corticosteroids, acetaminophen, and antihistamines needed 1

2. Inotersen

   • Antisense oligonucleotide
   • FDA-approved for ATTRv polyneuropathy
   • Administered via subcutaneous injection
   • Requires monitoring for thrombocytopenia and glomerulonephritis
   • Weekly platelet count and biweekly serum creatinine/urine protein monitoring required 1

3. Vutrisiran

   • Newer siRNA therapy
   • FDA-approved for ATTRv polyneuropathy
   • Less frequent dosing than patisiran 1, 2

Non-FDA Approved TTR Stabilizers

• Diflunisal
  • Non-steroidal anti-inflammatory drug (NSAID)
  • Demonstrated effectiveness in slowing ATTRv polyneuropathy progression
  • Used off-label (not FDA-approved for amyloidosis)
  • Caution in patients with cardiac involvement due to NSAID effects 1, 2

Treatment Selection Considerations

For ATTR Cardiomyopathy:

• Tafamidis is the only FDA-approved disease-modifying therapy
• Most beneficial in NYHA class I-III heart failure
• Less effective in advanced disease (NYHA class IV) 1

For ATTRv Polyneuropathy:

• TTR silencers (patisiran, inotersen, vutrisiran) are first-line therapies
• Early treatment is crucial for better outcomes 1

Important Clinical Considerations

1. Cost considerations: Tafamidis has an incremental cost-effectiveness ratio >$180,000 per QALY gained, considered "low value" by ACC/AHA guidelines 1

2. Diagnostic approach: Genetic sequencing is essential to differentiate ATTRwt from ATTRv, which guides therapy selection 1

3. Monitoring requirements:

   • Patisiran: Monitor for infusion reactions
   • Inotersen: Monitor platelet counts weekly and renal function biweekly 1

4. Common pitfalls:

   • Delayed diagnosis leading to irreversible organ damage
   • Failure to differentiate between ATTR and AL amyloidosis
   • Not providing vitamin A supplementation with TTR silencers
   • Inappropriate use of standard heart failure medications in ATTR-CM patients (beta-blockers, ACEi, ARBs may be poorly tolerated) 1

In summary, while tafamidis remains the only FDA-approved TTR stabilizer for ATTR cardiomyopathy, patisiran, inotersen, and vutrisiran are approved for ATTRv polyneuropathy. Treatment selection should be based on disease subtype, organ involvement, and patient-specific factors.