What are the approved Transthyretin (TTR) stabilizer therapies besides tafamidis (Vyndaqel)?

FDA-Approved TTR Stabilizer Therapies Beyond Tafamidis

Besides tafamidis (Vyndaqel/Vyndamax), there are currently no other FDA-approved TTR stabilizer therapies for transthyretin amyloid cardiomyopathy (ATTR-CM). However, there are other approved therapies that target TTR amyloidosis through different mechanisms.

FDA-Approved Therapies for TTR Amyloidosis

TTR Stabilizers

• Tafamidis (Vyndaqel/Vyndamax): The only FDA-approved TTR stabilizer for ATTR-CM 1
  • Available in two formulations:
    • Tafamidis meglumine: 20 mg capsules (80 mg daily dose - 4 capsules)
    • Tafamidis: 61 mg capsules (61 mg daily dose - 1 capsule)

TTR Silencers (RNA-targeting therapies)

These are FDA-approved specifically for ATTRv (variant transthyretin amyloidosis) with polyneuropathy:

• Patisiran: Small interfering RNA (siRNA) 1
• Inotersen: Antisense oligonucleotide 1
• Vutrisiran: Small interfering RNA (siRNA) 1

Important Clinical Considerations

Mechanism Differences

• TTR Stabilizers (tafamidis): Prevent TTR tetramer dissociation, inhibiting amyloid formation 1
• TTR Silencers: Block translation of RNA to synthesize TTR protein 1

Indication Differences

• Tafamidis: Indicated for ATTR-CM (both wild-type and variant) with NYHA class I-III symptoms 1
• TTR Silencers: Only approved for ATTRv with polyneuropathy, not for cardiac manifestations 1

Off-Label TTR Stabilizer

• Diflunisal: A non-steroidal anti-inflammatory drug shown to slow progression of ATTRv polyneuropathy but not FDA-approved for this indication 1
  • Has demonstrated effectiveness in clinical studies for ATTRv polyneuropathy

Treatment Selection Considerations

1. Disease Manifestation:

   • Cardiac predominant: Tafamidis is the only approved option 1
   • Polyneuropathy predominant: Consider TTR silencers (patisiran, inotersen, vutrisiran) 1

2. Genotype:

   • ATTRwt (wild-type): Only tafamidis is approved 1
   • ATTRv (variant):
     • With cardiomyopathy: Tafamidis 1
     • With polyneuropathy: TTR silencers 1

3. Disease Stage:

   • Early disease: Better outcomes with earlier treatment 1
   • Advanced disease (NYHA class IV): Tafamidis has not shown benefit 1

Monitoring Requirements

• Patisiran: Monitor for infusion-related reactions; premedication recommended 1
• Inotersen: Weekly platelet counts, biweekly serum creatinine and urine protein-creatinine ratio due to risks of thrombocytopenia and glomerulonephritis 1
• All TTR silencers: Vitamin A 3,000 IU daily supplementation required 1

Key Takeaway

For TTR stabilization specifically, tafamidis remains the only FDA-approved option, while TTR silencers represent an alternative disease-modifying approach for patients with ATTRv polyneuropathy.