What are alternative treatments to tafamidis (Tafamidis) for TTR-related amyloidosis?

Alternative Treatments to Tafamidis for TTR-Related Amyloidosis

For TTR-related amyloidosis, TTR silencers (patisiran, inotersen, and vutrisiran) are the recommended alternatives to tafamidis, particularly for patients with polyneuropathy, as they have demonstrated ability to slow or reverse disease progression and improve quality of life. 1

First-Line Alternatives to Tafamidis

TTR Silencers

1. Patisiran

   • Mechanism: Small interfering RNA that blocks TTR protein synthesis
   • Dosing: 0.3 mg/kg IV every 3 weeks
   • Requires premedication with corticosteroids, acetaminophen, and antihistamines
   • FDA-approved for ATTRv polyneuropathy
   • Requires vitamin A supplementation (3,000 IU daily) 1

2. Inotersen

   • Mechanism: Antisense oligonucleotide that inhibits TTR production
   • FDA-approved for ATTRv polyneuropathy
   • Requires monitoring for thrombocytopenia and glomerulonephritis
   • Weekly platelet counts and biweekly serum creatinine/urine protein monitoring needed 1

3. Vutrisiran

   • Mechanism: Small interfering RNA (similar to patisiran)
   • Newer agent in the TTR silencer class
   • FDA-approved for ATTRv polyneuropathy 1

TTR Stabilizers (Besides Tafamidis)

1. Diflunisal

   • Non-FDA approved but demonstrated effectiveness in ATTRv polyneuropathy
   • Slows disease progression in polyneuropathy
   • Consider for patients who cannot access or tolerate tafamidis
   • Requires careful monitoring of renal function and GI symptoms 1, 2

2. EGCG (Green Tea Extract)

   • Reduces amyloid fibril formation
   • Has shown some benefit in small, non-randomized studies
   • Associated with decreased wall thickness and improved LV function 2

Treatment Selection Algorithm

1. For ATTRv with Predominant Polyneuropathy:

   • First choice: TTR silencers (patisiran, inotersen, or vutrisiran)
   • These agents have demonstrated ability to slow or reverse disease progression 1
   • Early treatment is crucial - patients treated earlier show better neuropathy outcomes and quality of life than those with delayed treatment 1

2. For ATTRv with Mixed Presentation (Cardiac + Neuropathy):

   • Consider TTR silencers if neuropathy is significant
   • For patients with NYHA class I-III cardiac symptoms, consider acoramidis (recently FDA-approved) 2

3. For ATTRwt (Wild-type) with Cardiac Predominance:

   • Acoramidis (Attruby) - reduced all-cause mortality by up to 42% and cardiovascular hospitalizations by ~50% 2
   • Currently no evidence that TTR silencers benefit polyneuropathy associated with ATTRwt 1

Special Considerations

Monitoring Requirements

• Patisiran: Monitor for infusion reactions
• Inotersen: Weekly platelet counts, biweekly serum creatinine and urine protein-creatinine ratio 1
• All TTR silencers: Vitamin A supplementation (3,000 IU daily) required 1

Advanced Disease Options

• Liver Transplantation:

  • Consider for early-stage disease, especially in younger patients
  • Most effective for certain mutations (particularly Val30Met)
  • Replaces the source of mutant TTR with wild-type TTR 3

• Combined Heart and Liver Transplantation:

  • May be considered for selected patients with hereditary ATTR 2

Symptomatic Management

For neuropathic symptoms while on disease-modifying therapy:

• Pregabalin, gabapentin, or duloxetine for sensory neuropathy
• For autonomic dysfunction: increased salt/fluid intake, fludrocortisone, midodrine, droxidopa, or pyridostigmine 1

Pitfalls and Caveats

1. Cardiac Involvement: Medications for orthostatic hypotension (except pyridostigmine) may be poorly tolerated in patients with cardiac involvement 1

2. Timing of Treatment: Early diagnosis and treatment is critical - delayed treatment by 1 year or more results in worse outcomes 1

3. Medication Access: TTR silencers may have limited availability or high cost in some regions

4. Monitoring Burden: The monitoring requirements for inotersen (weekly platelet counts, biweekly renal function) may be burdensome for some patients 1

5. Vitamin A Supplementation: Required with TTR silencers due to TTR's role in transporting retinol 1

The treatment landscape for TTR amyloidosis continues to evolve, with newer agents like acoramidis showing promising results in recent trials 2, 4. For optimal outcomes, treatment should be initiated as early as possible after diagnosis.