Are there any other approved Transthyretin (TTR) stabilizer therapies besides tafamidis (Vyndamax/Vyndaqel)?

Approved TTR Stabilizer Therapies Beyond Tafamidis

Besides tafamidis (Vyndamax/Vyndaqel), acoramidis is the only other FDA-approved TTR stabilizer therapy for transthyretin amyloid cardiomyopathy (ATTR-CM). 1

Current Landscape of TTR Stabilizer Therapies

Approved TTR Stabilizers

1. Tafamidis (Vyndamax/Vyndaqel)

   • First-in-class TTR stabilizer approved for ATTR-CM 2
   • Available in two formulations:
     • Tafamidis meglumine: 80 mg (4 × 20 mg capsules) daily
     • Tafamidis: 61 mg capsule daily
   • Indicated for NYHA class I-III heart failure symptoms 2
   • Reduces cardiovascular mortality and hospitalization 3

2. Acoramidis

   • Recently approved TTR stabilizer for ATTR-CM 1
   • Newer alternative to tafamidis

Other TTR-Targeting Therapies (Not TTR Stabilizers)

TTR Silencers (RNA-Targeting Therapies)

These medications are not technically TTR stabilizers but work through a different mechanism:

• Patisiran

  • FDA-approved for ATTRv with polyneuropathy only 2
  • Not approved for cardiac amyloidosis
  • siRNA that degrades TTR mRNA

• Inotersen

  • FDA-approved for ATTRv with polyneuropathy only 2
  • Not approved for cardiac amyloidosis
  • Antisense oligonucleotide that inhibits TTR production
  • Caution: Associated with thrombocytopenia and glomerulonephritis 2

• Vutrisiran

  • Approved for ATTRv with polyneuropathy 2
  • May receive approval for ATTR-CM in the future 1
  • Newer generation TTR silencer

Non-Approved TTR Stabilizers

• Diflunisal
  • NSAID with TTR stabilizing properties
  • Not FDA-approved for ATTR-CM or polyneuropathy
  • Limited evidence for benefit on surrogate endpoints 2
  • Not recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) 2

Treatment Algorithm for ATTR Amyloidosis

1. Diagnosis confirmation

   • Bone scintigraphy (99mTc-PYP scan) with grade 2/3 cardiac uptake or H/CL ratio >1.5
   • Rule out AL amyloidosis with serum/urine immunofixation and free light chain assay
   • TTR gene sequencing to differentiate ATTRwt from ATTRv 2

2. Treatment selection based on phenotype

   • For ATTR-CM (cardiac manifestations):

     • Tafamidis or acoramidis for NYHA class I-III symptoms 2, 1

   • For ATTRv with polyneuropathy:

     • Patisiran, inotersen, or vutrisiran 2
     • Note: Tafamidis is not FDA-approved for neuropathy 2

Important Clinical Considerations

• Cost concerns: Tafamidis has an incremental cost-effectiveness ratio >$180,000 per QALY gained, considered "low value" by ACC/AHA guidelines 2

• Cardiac management specifics:

  • Anticoagulation is reasonable in ATTR-CM patients with AF regardless of CHA₂DS₂-VASc score 2
  • Standard heart failure medications may be poorly tolerated:
    • ARNi, ACEi, and ARBs may worsen hypotension
    • Beta blockers may worsen symptoms as patients rely on heart rate response 2

• Early treatment: TTR stabilizers prevent but do not reverse amyloid deposition, so early treatment is crucial 2

Future Directions

Several additional therapies are in development, including gene editing therapies and monoclonal antibodies targeting TTR amyloid 1. These may provide additional options in the future, but currently, tafamidis and acoramidis remain the only approved TTR stabilizer therapies for ATTR-CM.