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

Approved TTR Stabilizer Therapies Beyond Tafamidis

Tafamidis (Vyndamax/Vyndaqel) is currently the only FDA-approved TTR stabilizer therapy for transthyretin amyloid cardiomyopathy (ATTR-CM). There are no other approved TTR stabilizer therapies besides tafamidis for the treatment of ATTR-CM. 1

Available Disease-Modifying Therapies for ATTR

Approved Therapies:

1. TTR Stabilizers:

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

2. TTR Silencers (RNA-targeted therapies):

   • Inotersen: FDA-approved only for ATTRv with polyneuropathy, not for ATTR-CM 1
   • Patisiran: FDA-approved only for ATTRv with polyneuropathy, not for ATTR-CM 1
   • Vutrisiran: FDA-approved only for ATTRv with polyneuropathy, not for ATTR-CM 1

Non-FDA Approved TTR Stabilizers:

• Diflunisal: An NSAID with TTR stabilizing properties, used off-label in some cases, but not FDA-approved for ATTR-CM
  • Not generally recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload due to potential adverse effects on kidney function 1

Clinical Considerations

Efficacy of Tafamidis

• Tafamidis significantly reduces all-cause mortality (29.5% vs 42.9%) and cardiovascular-related hospitalizations (0.48 vs 0.70 per year) in patients with ATTR-CM compared to placebo 1, 2
• Benefits are most pronounced in patients with NYHA class I-III symptoms 1
• Treatment benefits are consistent between wild-type TTR and variant TTR genotypes 2

Important Caveats

1. Disease Stage Matters:

   • Tafamidis is indicated for patients with NYHA class I-III symptoms
   • No demonstrated benefit in NYHA class IV heart failure 1
   • Earlier treatment initiation may provide greater benefit as tafamidis prevents but does not reverse amyloid deposition 1

2. Cost Considerations:

   • Tafamidis provides low economic value at 2020 list prices (>$180,000 per QALY gained) 1
   • Cost would need to decrease by approximately 80% to reach intermediate value 1

3. Emerging Therapies:

   • Several TTR silencers are being evaluated in clinical trials for ATTR-CM 3
   • Acoramidis is a newer TTR stabilizer that has recently gained approval for ATTR-CM 3

Treatment Algorithm for ATTR-CM

1. Diagnosis confirmation:

   • Genetic sequencing to determine if ATTRv or ATTRwt 1

2. For confirmed ATTR-CM with NYHA class I-III symptoms:

   • Tafamidis is the first-line therapy (Class 1 recommendation) 1

3. For ATTRv with polyneuropathy:

   • Consider TTR silencers (inotersen, patisiran, or vutrisiran) 1

4. For patients with atrial fibrillation and cardiac amyloidosis:

   • Anticoagulation is reasonable regardless of CHA₂DS₂-VASc score (Class 2a recommendation) 1

5. For patients with advanced disease or contraindications:

   • Individualized heart failure management
   • Consider clinical trials of emerging therapies

In summary, while tafamidis remains the only FDA-approved TTR stabilizer for ATTR-CM, several other disease-modifying therapies are available for specific ATTR subtypes or are in development. The choice of therapy should be guided by disease subtype, presence of polyneuropathy, and disease stage.