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

Approved TTR Stabilizer Therapies for ATTR Cardiomyopathy

Tafamidis is currently the only FDA-approved TTR stabilizer therapy specifically for transthyretin amyloid cardiomyopathy (ATTR-CM), with no other approved TTR stabilizers for cardiac amyloidosis at this time. 1

Current FDA-Approved TTR Stabilizers for ATTR-CM

Tafamidis is available in two formulations:

• Tafamidis meglumine (20 mg capsules): FDA-approved dose is 80 mg (4 capsules) once daily
• Tafamidis (61 mg capsules): FDA-approved dose is 61 mg once daily 1

Other Disease-Modifying Therapies for TTR Amyloidosis

TTR Silencers (RNA Interference Therapies)

These agents are currently only FDA-approved for ATTRv with polyneuropathy, not for ATTR-CM:

• Patisiran
• Inotersen
• Vutrisiran 1

Off-Label TTR Stabilizers

• Diflunisal: An NSAID that has TTR stabilizing properties
  • Important limitation: Not 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 Efficacy of Tafamidis

The ATTR-ACT trial demonstrated that tafamidis:

• Reduced all-cause mortality (29.5% vs 42.9% with placebo)
• Reduced cardiovascular-related hospitalizations (0.48 vs 0.70 per year)
• Slowed decline in functional capacity (6-minute walk test)
• Improved quality of life in patients with ATTR-CM 1

Treatment Selection Algorithm

1. First-line therapy: Tafamidis for patients with wild-type or variant ATTR-CM with NYHA class I-III symptoms 1

2. For patients with ATTRv with polyneuropathy:

   • Consider TTR silencers (patisiran, inotersen, or vutrisiran) for the neurological manifestations
   • Note that these agents are not currently approved for cardiac manifestations 1

3. For patients who cannot access tafamidis (due to cost or availability):

   • Consider diflunisal as an alternative TTR stabilizer if:
     • eGFR ≥45 mL/min/1.73 m²
     • No significant volume overload
     • No contraindications to NSAID use 1

Important Considerations and Monitoring

• Economic impact: Tafamidis provides low economic value at current pricing (>$180,000 per QALY gained) 1
• Early treatment: Tafamidis is expected to have greater benefit when administered early in the disease course, as it prevents but does not reverse amyloid deposition 1
• Anticoagulation: Patients with cardiac amyloidosis and atrial fibrillation should receive anticoagulation regardless of CHA₂DS₂-VASc score 1

Medications to Avoid in ATTR-CM

• Digoxin: Binds to amyloid fibrils and can cause toxicity even with normal serum levels 1
• Calcium channel blockers (nifedipine, verapamil): Bind to amyloid fibrils causing exaggerated hypotension 1
• Caution with standard heart failure medications: ARNi, ACEi, ARB may exacerbate hypotension; beta-blockers may worsen symptoms as patients rely on heart rate response 1

Emerging Therapies

Several investigational therapies are in development, including:

• TTR stabilizers (AG10)
• Antifibril agents (PRX004, doxycycline/TUDCA)
• Monoclonal antibodies targeting amyloid deposits 2, 3

However, none of these are currently FDA-approved for ATTR-CM.