What are the alternative TTR stabilizers to tafamidis?

Alternative TTR Stabilizers to Tafamidis for Cardiac Amyloidosis

Diflunisal is the primary alternative TTR stabilizer to tafamidis for patients with cardiac amyloidosis, though several TTR silencers (patisiran, inotersen, and vutrisiran) are FDA-approved options for patients with ATTRv polyneuropathy and may be considered in appropriate cases. 1

TTR Stabilizers

Diflunisal

• Non-steroidal anti-inflammatory drug (NSAID) that acts as a TTR stabilizer
• Has demonstrated effectiveness in slowing progression of ATTRv polyneuropathy 1, 2
• Not FDA-approved specifically for ATTR amyloidosis but used off-label
• Important caution: Not generally recommended for patients with:
  • Significant kidney impairment (typically eGFR <45 mL/min/1.73 m²)
  • Volume overload
  • Heart failure symptoms 1

Acoramidis (Attruby)

• Novel TTR stabilizer recently FDA-approved
• Reduced all-cause mortality by up to 42% and cardiovascular hospitalizations by ~50% in ATTR-CM patients 3

TTR Silencers

These medications act by blocking the translation of RNA to synthesize the transthyretin protein:

Patisiran

• Small interfering RNA (siRNA)
• Dosing: 0.3 mg/kg every 3 weeks IV (maximum 30 mg)
• Currently only FDA-approved for ATTRv polyneuropathy 1
• Requires premedication with:
  • Dexamethasone 10 mg IV
  • Acetaminophen 500 mg
  • Diphenhydramine 50 mg
  • Famotidine 20 mg

Inotersen

• Antisense oligonucleotide
• Dosing: 284 mg once weekly, subcutaneous injection
• Currently only FDA-approved for ATTRv polyneuropathy 1
• Safety monitoring required:
  • Weekly platelet counts
  • Biweekly serum creatinine, eGFR, and urine protein-creatinine ratio
  • Risk of thrombocytopenia and glomerulonephritis

Vutrisiran

• Small interfering RNA
• Dosing: 25 mg every 3 months, subcutaneous injection
• Currently only FDA-approved for ATTRv polyneuropathy 1

Important Considerations

1. Vitamin A supplementation:

   • All TTR silencers require vitamin A supplementation (3,000 IU daily) as transthyretin normally transports retinol 1

2. Efficacy in cardiac disease:

   • While TTR silencers are primarily approved for polyneuropathy, clinical trials are ongoing to assess their impact on cardiovascular morbidity and mortality 1

3. Other investigational agents:

   • Epigallocatechin-3-gallate (EGCG) from green tea extract
   • Doxycycline plus tauroursodeoxycholic acid (TUDCA)
   • These have shown limited benefit on surrogate endpoints such as LV mass 1, 3

4. Disease progression monitoring:

   • Regular assessment of cardiac function is essential when using alternative TTR stabilizers
   • Monitoring cardiac biomarkers (BNP/NT-proBNP and troponins) for disease progression 3

Treatment Algorithm

1. First-line therapy: Tafamidis for ATTR-CM with NYHA class I-III symptoms 1
2. If tafamidis is unavailable or not tolerated:
   • Consider diflunisal if renal function is adequate (eGFR >45 mL/min/1.73 m²) and no significant heart failure symptoms
   • Consider EGCG (green tea extract) as an alternative stabilizer 3
3. For patients with ATTRv with polyneuropathy:
   • Consider TTR silencers (patisiran, inotersen, or vutrisiran) 1
4. For advanced disease or failure of other therapies:
   • Consider evaluation for heart transplantation in appropriate cases 3

Remember that early diagnosis and treatment initiation are critical for better outcomes, as patients treated earlier have better measures of neuropathy impairment and quality of life than those whose treatment is delayed 1.