What are the alternatives to tafamidis (TTR stabilizer) for treating transthyretin-related amyloidosis?

Alternatives to Tafamidis for Treating Transthyretin-Related Amyloidosis

For patients with transthyretin-related amyloidosis, diflunisal is the most effective alternative TTR stabilizer when tafamidis cannot be used, while TTR silencers (patisiran, inotersen, and vutrisiran) are FDA-approved options specifically for ATTRv polyneuropathy. 1, 2

TTR Stabilizers

Diflunisal

• Non-FDA approved but clinically effective TTR stabilizer
• Demonstrated effectiveness in slowing disease progression in ATTRv polyneuropathy 1, 2
• Binds to TTR tetramer and prevents dissociation into amyloidogenic monomers
• Caution: As an NSAID, may have renal effects and increased bleeding risk

Acoramidis (Attruby)

• Novel TTR stabilizer recently approved by FDA
• Reduced all-cause mortality by up to 42% and cardiovascular hospitalizations by ~50% in ATTR-CM patients 2
• May be considered when tafamidis is not an option

TTR Silencers (RNA-Targeting Therapies)

These medications are FDA-approved specifically for ATTRv polyneuropathy, not for cardiac manifestations:

Patisiran

• Small interfering RNA (siRNA) therapy administered intravenously every 3 weeks (0.3 mg/kg)
• Reduces TTR production by targeting TTR mRNA
• Requires premedication with corticosteroids, acetaminophen, and antihistamines to prevent infusion reactions 1
• Vitamin A supplementation (3,000 IU daily) required due to reduced TTR-mediated vitamin A transport 1

Inotersen

• Antisense oligonucleotide administered subcutaneously
• Important monitoring requirements:
  • Weekly platelet counts
  • Biweekly serum creatinine and urine protein-creatinine ratio
  • Risk of thrombocytopenia and glomerulonephritis 1, 2
• Vitamin A supplementation (3,000 IU daily) required

Vutrisiran

• Newer siRNA with less frequent dosing schedule than other silencers
• Administered subcutaneously
• Improved convenience compared to patisiran 1, 2
• Vitamin A supplementation required

Clinical Decision Algorithm

1. Determine ATTR subtype:

   • ATTRv (variant/hereditary) vs. ATTRwt (wild-type)
   • Presence of polyneuropathy vs. cardiomyopathy

2. For ATTR-CM (cardiac manifestations):

   • First choice: Tafamidis (if available and affordable)
   • Alternative if tafamidis unavailable: Diflunisal or Acoramidis

3. For ATTRv with polyneuropathy:

   • First choice: TTR silencers (patisiran, inotersen, or vutrisiran)
   • Alternative: Diflunisal (if TTR silencers contraindicated)

4. For mixed phenotype (cardiac + neurologic):

   • Consider TTR silencers for patients with predominant polyneuropathy
   • Consider tafamidis for patients with predominant cardiomyopathy

Important Considerations

• Early treatment is critical - patients treated earlier have better outcomes in terms of neuropathy impairment and quality of life 1
• TTR silencers require vitamin A supplementation (3,000 IU daily) due to reduced TTR-mediated vitamin A transport 1
• Diflunisal, while effective, is not FDA-approved for ATTR and should be used with caution in patients with renal impairment or heart failure
• Regular monitoring of disease progression is essential, including neurological function and cardiac status every 6-12 months 2

Symptomatic Management

In addition to disease-modifying therapies, symptomatic management is important:

• For neuropathic pain: Pregabalin, gabapentin, duloxetine 1
• For orthostatic hypotension: Increased fluid intake, salt tablets, fludrocortisone, midodrine, droxidopa, or pyridostigmine 1
• For heart failure symptoms: Judicious diuresis (caution against overdiuresis to avoid hypotension) 2
• For atrial fibrillation: Anticoagulation regardless of CHA₂DS₂-VASc score 1, 2

The choice of alternative therapy should be guided by the specific disease manifestation, with TTR silencers being particularly beneficial for polyneuropathy in ATTRv, while diflunisal may be considered when tafamidis is not an option for cardiac manifestations.