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 has shown effectiveness for ATTR polyneuropathy but lacks FDA approval for this indication.

FDA-Approved TTR-Targeted Therapies

TTR Stabilizers

• Tafamidis (Vyndaqel/Vyndamax): FDA-approved for ATTR cardiomyopathy (ATTR-CM)
  • Available in two formulations:
    • Tafamidis meglumine: 20-mg capsules (FDA-approved dose: 80 mg/day)
    • Tafamidis: 61-mg capsules (FDA-approved dose: 61 mg/day) 1
  • Not FDA-approved for ATTR polyneuropathy in the US (though approved in Europe) 1

TTR Silencers (for ATTRv with polyneuropathy)

1. Patisiran: FDA-approved for ATTRv polyneuropathy 1

   • Small interfering RNA (siRNA)
   • Administered via infusion
   • Requires premedication with corticosteroids, acetaminophen, and antihistamines

2. Inotersen: FDA-approved for ATTRv polyneuropathy 1

   • Antisense oligonucleotide
   • Requires monitoring for thrombocytopenia and glomerulonephritis
   • Weekly platelet counts and biweekly renal function monitoring needed

3. Vutrisiran: FDA-approved for ATTRv polyneuropathy 1

   • Newer generation siRNA

Non-FDA Approved Options with Evidence

TTR Stabilizers

• Diflunisal: Not FDA-approved for ATTR but has demonstrated effectiveness in slowing progression of ATTRv polyneuropathy in clinical studies 1, 2
  • Off-label use only

Other Investigational Approaches

• TTR Fibril Disrupters:

  • Doxycycline with tauroursodeoxycholic acid (TUDCA) 1, 2
  • Limited benefit on surrogate endpoints like LV mass

• Alternative Agents:

  • Epigallocatechin-3-gallate (EGCG) in green tea extract 1, 2
  • Curcumin 2

Clinical Considerations

Disease-Specific Treatment Selection

1. For ATTR Cardiomyopathy (ATTR-CM):

   • Tafamidis is the only FDA-approved therapy shown to reduce cardiovascular morbidity and mortality in patients with NYHA class I-III symptoms 1
   • Most beneficial when started early in disease course 1
   • Not beneficial in NYHA class IV, severe aortic stenosis, or impaired renal function (eGFR <25 mL/min/1.73 m²) 1

2. For ATTRv Polyneuropathy:

   • First-line options: Patisiran, inotersen, or vutrisiran 1
   • These agents can slow progression and potentially reverse disease 1

Important Caveats

• TTR silencers require vitamin A supplementation (3,000 IU daily) due to reduced retinol transport 1
• Early diagnosis and treatment of polyneuropathy leads to better outcomes 1
• Cost considerations: Tafamidis provides clinical benefit but at high cost (>$180,000 per QALY gained) 1
• Genetic testing is crucial to differentiate ATTRwt from ATTRv, as this impacts treatment selection and family screening 1

In summary, while tafamidis remains the only FDA-approved TTR stabilizer, the TTR silencers (patisiran, inotersen, and vutrisiran) are approved specifically for ATTRv polyneuropathy. Treatment selection should be guided by the specific disease manifestation (cardiomyopathy vs. polyneuropathy) and genetic status (variant vs. wild-type).