What are alternative Transthyretin (TTR) stabilizers to tafamidis?

Alternative TTR Stabilizers to Tafamidis for ATTR Amyloidosis

Diflunisal is the primary alternative TTR stabilizer to tafamidis, demonstrating effectiveness in slowing progression of ATTRv polyneuropathy, though it is not FDA-approved for this indication. 1

TTR Stabilizers and Their Mechanisms

TTR stabilizers work by preventing the dissociation of the transthyretin tetramer, which is the rate-limiting step in amyloid formation. The available options include:

1. Diflunisal

• Mechanism: Non-steroidal anti-inflammatory drug (NSAID) repurposed as a TTR stabilizer
• Efficacy: Reduces wild-type TTR dissociation rate in plasma by 95% at 250 μM concentration 2
• Dosing: Typically 250 mg twice daily
• Status: Not FDA-approved for ATTR, but has demonstrated effectiveness in clinical use
• Monitoring: Requires careful monitoring of renal function and GI symptoms 3

2. TTR Silencers (RNA-based therapies)

These represent a different therapeutic approach but are important alternatives:

• Patisiran

  • Small interfering RNA (siRNA)
  • Administered IV every 3 weeks (0.3 mg/kg)
  • FDA-approved for ATTRv polyneuropathy
  • Requires vitamin A supplementation (3,000 IU daily)
  • Requires premedication with corticosteroids, acetaminophen, and antihistamines 1

• Inotersen

  • Antisense oligonucleotide
  • FDA-approved for ATTRv polyneuropathy
  • Requires monitoring for thrombocytopenia and glomerulonephritis
  • Weekly platelet counts and biweekly renal function monitoring required 1

• Vutrisiran

  • Newer small interfering RNA
  • FDA-approved for ATTRv polyneuropathy 1

3. Other Investigational Options

• EGCG (Epigallocatechin-3-gallate): Found in green tea, has shown limited benefit on surrogate endpoints like LV mass 1, 3
• Doxycycline plus TUDCA (tauroursodeoxycholic acid): Has shown limited benefit on surrogate endpoints 1
• Acoramidis (Attruby): Recently FDA-approved novel TTR stabilizer that has shown reduction in all-cause mortality and cardiovascular hospitalizations 3

Selection Algorithm for TTR Stabilizers

1. First-line therapy (if available and covered by insurance):

   • Tafamidis for ATTR cardiomyopathy (NYHA class I-III)
   • Acoramidis (if recently approved and available)

2. If tafamidis is unavailable, contraindicated, or unaffordable:

   • Diflunisal (if no contraindications to NSAIDs)

3. For ATTRv with predominant polyneuropathy:

   • TTR silencers (patisiran, inotersen, or vutrisiran)
   • Diflunisal as an alternative

4. For patients with contraindications to both tafamidis and diflunisal:

   • Consider EGCG (green tea extract) as a less potent option

Important Considerations and Monitoring

• Vitamin A supplementation: Required with TTR silencers (3,000 IU daily) 1
• Renal function: Monitor closely with diflunisal due to NSAID properties
• Thrombocytopenia and glomerulonephritis: Monitor with inotersen (weekly platelet counts, biweekly renal function) 1
• Infusion reactions: Pre-medicate before patisiran administration 1

Pitfalls and Caveats

• Diflunisal, while effective, is not FDA-approved for ATTR and carries risks associated with chronic NSAID use
• Early treatment is critical - patients treated earlier have better outcomes than those with delayed treatment 1
• TTR silencers are currently only FDA-approved for ATTRv polyneuropathy, not for cardiomyopathy
• Standard heart failure medications may be poorly tolerated in ATTR cardiomyopathy patients 1
• Anticoagulation should be considered for all patients with ATTR and atrial fibrillation regardless of CHA₂DS₂-VASc score 1

By understanding the available alternatives to tafamidis, clinicians can make informed decisions about treatment options for patients with ATTR amyloidosis, particularly when tafamidis is unavailable, contraindicated, or unaffordable.