What are the approved Transthyretin (TTR) stabilizer therapies besides Tafamidis (Tafamidis meglumine and Tafamidis free acid)?

Approved TTR Stabilizer Therapies Beyond Tafamidis

Currently, tafamidis (available as tafamidis meglumine and tafamidis free acid) is the only FDA-approved TTR stabilizer therapy for ATTR cardiomyopathy, with no other approved TTR stabilizers available for this indication. 1

Available Approved TTR-Targeting Therapies

TTR Stabilizers

• Tafamidis: The only FDA-approved TTR stabilizer for ATTR cardiomyopathy
  • Available in two formulations:
    • Tafamidis meglumine: 80 mg (4 × 20-mg capsules) once daily
    • Tafamidis free acid: 61 mg once daily (bioequivalent to 80 mg of tafamidis meglumine) 2

TTR Silencers (RNA-targeting therapies)

These are approved only for ATTRv with polyneuropathy, not for cardiomyopathy:

• Patisiran (FDA-approved for ATTRv polyneuropathy)
• Inotersen (FDA-approved for ATTRv polyneuropathy)
• Vutrisiran (FDA-approved for ATTRv polyneuropathy) 1

Non-Approved TTR Stabilizers

• Diflunisal: An NSAID with TTR-stabilizing properties
  • Has shown some efficacy in slowing ATTRv polyneuropathy progression
  • Not FDA-approved for ATTR
  • Not generally recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload 1

Important Clinical Considerations

Patient Selection for Tafamidis

• Indicated for patients with wild-type or variant ATTR-CM with NYHA class I-III symptoms
• Greatest benefit when administered early in disease course
• Not shown to be beneficial in:
  • NYHA class IV symptoms
  • Severe aortic stenosis
  • Impaired renal function (eGFR <25 mL/min/1.73 m²) 1

Economic Considerations

• Tafamidis provides significant clinical benefits (increased survival by 1.97 years and QALY by 1.29)
• However, at 2020 list prices ($225,000 annually), it provides low economic value (>$180,000 per QALY gained) 1

Management of ATTR with Polyneuropathy

For patients with ATTRv polyneuropathy, TTR silencers (patisiran, inotersen, vutrisiran) are the approved disease-modifying therapies. Although tafamidis has shown efficacy in slowing progression of ATTRv polyneuropathy, it is not FDA-approved for this specific indication. 1

Practical Algorithm for ATTR Management

1. Confirm ATTR type:

   • Genetic sequencing to determine ATTRv vs. ATTRwt
   • Assess for presence of polyneuropathy vs. cardiomyopathy

2. For ATTR cardiomyopathy (NYHA I-III):

   • Tafamidis is the only approved disease-modifying therapy
   • Choose appropriate formulation based on patient preference:
     • Tafamidis meglumine 80 mg (4 × 20-mg capsules) daily OR
     • Tafamidis free acid 61 mg (single capsule) daily

3. For ATTRv with polyneuropathy:

   • Consider FDA-approved TTR silencers (patisiran, inotersen, vutrisiran)
   • Monitor for treatment-specific adverse effects:
     • Inotersen: thrombocytopenia, glomerulonephritis
     • Patisiran: infusion-related reactions

4. For patients with both cardiomyopathy and polyneuropathy:

   • Clinical decision must weigh relative severity of each manifestation
   • Consider referral to specialized amyloidosis center for optimal management

Key Pitfalls to Avoid

• Do not assume tafamidis will reverse existing amyloid deposits; it prevents new formation
• Do not delay treatment, as benefits are greater when started earlier in disease course
• Do not overlook the need for genetic counseling and family screening in ATTRv cases
• Do not use diflunisal in patients with significant kidney impairment or heart failure with volume overload

In summary, while tafamidis remains the only approved TTR stabilizer for ATTR cardiomyopathy, TTR silencers represent important therapeutic options for patients with ATTRv polyneuropathy. Clinical trials of TTR silencers for cardiomyopathy are ongoing, which may expand treatment options in the future.