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

Approved TTR Stabilizer Therapies for Transthyretin Amyloidosis

Tafamidis is currently the only FDA-approved transthyretin (TTR) stabilizer therapy for transthyretin amyloid cardiomyopathy (ATTR-CM). 1

Current Approved TTR Stabilizer Landscape

Tafamidis is available in two formulations:

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

Mechanism of Action

Tafamidis works by binding to the thyroxine-binding sites of the TTR tetramer, preventing its dissociation into monomers, which is the rate-limiting step in amyloid formation 2. This stabilization of the TTR tetramer inhibits the formation of amyloid fibrils that would otherwise deposit in cardiac tissue.

Clinical Evidence

The ATTR-ACT clinical trial demonstrated that tafamidis significantly reduced:

• All-cause mortality (29.5% vs 42.9% with placebo)
• Cardiovascular-related hospitalizations (0.48 vs 0.70 per year with placebo)
• Rate of functional decline in patients with ATTR-CM 1

Other TTR-Targeting Therapies (Not TTR Stabilizers)

While tafamidis is the only approved TTR stabilizer for ATTR-CM, there are other approaches to treating transthyretin amyloidosis:

1. TTR Silencers (not stabilizers):

   • Inotersen and patisiran are approved only for ATTRv (variant) with polyneuropathy, not for cardiomyopathy 1
   • These medications work by disrupting hepatic synthesis via mRNA inhibition/degradation
   • Clinical trials are ongoing to assess their impact on cardiovascular morbidity and mortality

2. Other TTR Stabilizers (not FDA-approved for ATTR-CM):

   • Diflunisal (an NSAID) has shown limited benefit on surrogate endpoints such as LV mass, but its impact on cardiovascular morbidity and mortality has not been fully assessed 1

3. TTR Disruptors (investigational):

   • Doxycycline plus tauroursodeoxycholic acid (TUDCA)
   • Epigallocatechin-3-gallate (EGCG, found in green tea)
   • These agents target tissue clearance but have limited evidence for cardiovascular outcomes 1

Important Clinical Considerations

• Tafamidis is indicated for patients with wild-type or variant ATTR-CM with NYHA class I-III heart failure symptoms 1
• Treatment benefits are greater when tafamidis is initiated earlier in the disease course 3
• Tafamidis has not shown benefit in patients with NYHA class IV symptoms, severe aortic stenosis, or impaired renal function (eGFR <25 mL/min/1.73 m²) 1
• Cost is a significant barrier - at 2020 list prices ($225,000 annually), tafamidis provides low economic value (>$180,000 per QALY gained) 1

Genetic Testing Considerations

If ATTR-CM is identified, genetic sequencing of the TTR gene is recommended to determine if the patient has:

• ATTRv (variant) - which would trigger genetic counseling and potential screening of family members
• ATTRwt (wild-type) disease 1

This distinction is important because TTR silencers (inotersen and patisiran) are currently approved only for ATTRv with polyneuropathy, not for cardiomyopathy.