What are alternative Transthyretin (TTR) stabilizers to tafamidis?

Alternative TTR Stabilizers to Tafamidis

Diflunisal is the most effective alternative TTR stabilizer for patients with transthyretin amyloidosis who cannot use tafamidis, demonstrating effectiveness in slowing disease progression in ATTRv polyneuropathy. 1

Available TTR Stabilizers

• Tafamidis: First-line FDA-approved therapy for ATTR-CM that reduces all-cause mortality and cardiovascular-related hospitalizations 1
• Diflunisal: Most effective alternative TTR stabilizer that slows disease progression in ATTRv polyneuropathy 2, 1
  • Binds to TTR tetramer, preventing dissociation (rate-limiting step in amyloidogenesis)
  • At 250 mg BID dosing, achieves plasma concentrations of ~282 μM, reducing wild-type TTR dissociation rate by 95% 3
  • Not FDA-approved specifically for ATTR but has demonstrated clinical efficacy
• Acoramidis (Attruby): Novel TTR stabilizer recently approved by FDA 1
  • Reduces all-cause mortality by up to 42%
  • Decreases cardiovascular hospitalizations by ~50% in ATTR-CM patients

TTR Silencers (Alternative Mechanism)

For patients with ATTRv polyneuropathy, TTR silencers represent another therapeutic approach:

1. Patisiran: Small interfering RNA administered IV every 3 weeks 2

   • Dosing: 0.3 mg/kg (maximum 30 mg)
   • Requires premedication with corticosteroids, acetaminophen, and antihistamines

2. Inotersen: Antisense oligonucleotide administered SC weekly 2

   • Fixed dose of 284 mg
   • Requires monitoring for thrombocytopenia and glomerulonephritis
   • Weekly platelet counts and biweekly renal function tests needed

3. Vutrisiran: Small interfering RNA administered SC every 3 months 2

   • Fixed dose of 25 mg
   • Less frequent dosing schedule than other silencers

Important Considerations

• All TTR stabilizers and silencers require vitamin A supplementation (3,000 IU daily) 2
• Diflunisal is not generally recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload due to its NSAID properties 2
• Early treatment initiation is critical as all therapies are more effective when started earlier in the disease course 1
• Regular monitoring of neurological function and cardiac status every 6-12 months is recommended 1

Experimental Options

For patients who cannot use tafamidis or diflunisal, experimental options include:

• Doxycycline plus TUDCA: May be considered, though impact on cardiovascular outcomes is not well established 1
• EGCG (green tea extract): Reduces amyloid fibril formation and has shown some benefit in small studies 1

Treatment Algorithm

1. First choice: Tafamidis (if available and affordable)
2. If tafamidis contraindicated or unavailable: Diflunisal (with careful monitoring of renal function)
3. For ATTRv polyneuropathy: Consider TTR silencers (patisiran, inotersen, or vutrisiran)
4. If conventional options contraindicated: Consider acoramidis or experimental options

Regular monitoring of disease progression and treatment response is essential regardless of the chosen therapy.