Are there any other approved Transthyretin (TTR) stabilizer therapies besides Tafamidis (Tafamidis)?

Approved TTR Stabilizer Therapies Beyond Tafamidis

Currently, tafamidis is the only FDA-approved TTR stabilizer therapy for transthyretin amyloid cardiomyopathy (ATTR-CM), with no other approved TTR stabilizers available for this indication. 1

Current Approved Therapies for ATTR

TTR Stabilizers

• Tafamidis (available as tafamidis meglumine 20mg capsules or tafamidis 61mg capsules)
  • Only FDA-approved TTR stabilizer for ATTR-CM
  • Indicated for wild-type or variant ATTR-CM with NYHA class I-III HF symptoms
  • Reduces cardiovascular morbidity and mortality
  • Mechanism: Binds to thyroxine-binding sites of TTR tetramer, preventing dissociation

TTR Silencers (for ATTRv with polyneuropathy only)

These are not TTR stabilizers but represent other disease-modifying therapies:

• Patisiran (small interfering RNA)
• Inotersen (antisense oligonucleotide)
• Vutrisiran (small interfering RNA)

These TTR silencers are FDA-approved only for ATTRv with polyneuropathy, not for ATTR-CM. 1

Therapeutic Considerations

Tafamidis Efficacy

• Reduces all-cause mortality (29.5% vs 42.9% with placebo)
• Reduces cardiovascular-related hospitalizations (0.48 vs 0.70 per year)
• Slows deterioration in 6-minute walk test distance and quality of life
• Benefits seen after 18 months of treatment 1

Tafamidis Limitations

• High cost ($225,000 annually) with low economic value (>$180,000 per QALY gained)
• Would need 80% price reduction to reach intermediate value 1
• Less effective in NYHA class III HF patients
• Not indicated for NYHA class IV symptoms, severe aortic stenosis, or impaired renal function (eGFR <25 mL/min/1.73 m²) 1

Other Potential TTR Stabilizers (Not FDA-Approved for ATTR-CM)

• Diflunisal: Has shown some efficacy in ATTRv polyneuropathy but not FDA-approved for this indication 1

Management Algorithm for ATTR

1. Diagnosis and Classification

   • Confirm ATTR-CM diagnosis
   • Perform TTR gene sequencing to differentiate ATTRwt from ATTRv

2. Treatment Selection

   • For ATTR-CM (wild-type or variant) with NYHA class I-III symptoms:

     • Tafamidis (only approved TTR stabilizer)
     • Dosing: Either tafamidis meglumine 80mg (4×20mg capsules) daily OR tafamidis 61mg once daily

   • For ATTRv with polyneuropathy:

     • Consider TTR silencers (patisiran, inotersen, or vutrisiran)
     • Note: Tafamidis is not FDA-approved for neuropathy despite some evidence of efficacy

3. Special Considerations

   • For patients with atrial fibrillation: Anticoagulation regardless of CHA₂DS₂-VASc score
   • For patients with HFrEF: Standard HF therapies may be poorly tolerated
     • ARNi, ACEi, ARB may worsen hypotension
     • Beta blockers may worsen HF symptoms

Clinical Pearls and Pitfalls

• Early treatment is crucial: Tafamidis prevents but does not reverse amyloid deposition
• Monitoring: Regular assessment of neurological function, cardiac status, and nutritional status
• Avoid: Digoxin and calcium channel blockers (bind to amyloid fibrils causing toxicity)
• Consider: Higher body mass index at baseline is associated with better preservation of neurological function 2

In conclusion, while research continues on other potential TTR stabilizers, tafamidis remains the only FDA-approved option for ATTR-CM, with TTR silencers approved only for the polyneuropathy manifestation of variant ATTR.