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

Approved TTR Stabilizer Therapies

There are currently two FDA-approved TTR stabilizer therapies: tafamidis (available as Vyndaqel/Vyndamax) and acoramidis (Attruby), which was recently approved in November 2024 for transthyretin amyloid cardiomyopathy (ATTR-CM). 1

Available TTR Stabilizers

Acoramidis (Attruby)

• FDA-approved in November 2024
• Near-complete TTR stabilizer (~96%)
• Demonstrated significant clinical benefits in ATTR-CM patients:
  • Reduced all-cause mortality by up to 42%
  • Reduced cardiovascular hospitalizations by ~50%
  • Benefits observed over 30-42 months of treatment 1

Tafamidis (Vyndaqel/Vyndamax)

• Available in two formulations:
  • Tafamidis meglumine (20-mg capsules, dosed at 80 mg once daily)
  • Tafamidis (61-mg capsules, dosed at 61 mg once daily) 1
• Mechanism: Binds to thyroxine-binding sites of TTR tetramer, preventing dissociation into amyloidogenic monomers 2
• Clinical benefits demonstrated in the ATTR-ACT trial:
  • Reduced all-cause mortality (29.5% vs 42.9% with placebo)
  • Decreased cardiovascular-related hospitalizations (0.48 vs 0.70 per year)
  • Slowed functional decline in ATTR-CM patients 1, 3

Non-FDA Approved Options for TTR Stabilization

While not FDA-approved specifically as TTR stabilizers, the following have been studied:

Diflunisal

• An NSAID with TTR stabilizing properties
• Has shown limited benefit on surrogate endpoints
• Impact on cardiovascular morbidity and mortality not fully assessed 1
• Not FDA-approved specifically for ATTR

Investigational Approaches

• TTR disruptors (not stabilizers):
  • Doxycycline plus tauroursodeoxycholic acid (TUDCA)
  • Epigallocatechin-3-gallate (EGCG)
  • Limited evidence for cardiovascular outcomes 1

Other Treatment Approaches for Transthyretin Amyloidosis

It's important to note that TTR stabilizers are only one approach to treating transthyretin amyloidosis. Other approaches include:

TTR Silencers

• Inotersen and patisiran
• FDA-approved only for ATTRv (variant) with polyneuropathy
• Not approved for cardiomyopathy
• Work by disrupting hepatic synthesis via mRNA inhibition/degradation
• Clinical trials ongoing to assess impact on cardiovascular outcomes 1

Clinical Considerations

Patient Selection

• TTR stabilizers are indicated for patients with:
  • Wild-type or variant ATTR-CM
  • NYHA class I-III heart failure symptoms 1
• Treatment benefits are greater when initiated earlier in disease course 4
• Not shown to benefit patients with:
  • NYHA class IV symptoms
  • Severe aortic stenosis
  • Impaired renal function (eGFR <25 mL/min/1.73 m²) 1

Monitoring Considerations

• Regular assessment of neurological function is important, as progression may occur despite treatment 5
• Higher baseline modified body mass index (mBMI) is associated with better preservation of neurological function 5
• Genetic sequencing of TTR gene is recommended to determine if patient has ATTRv or ATTRwt, which impacts genetic counseling and family screening 1

Treatment Limitations

• Cost is a significant barrier:
  • Tafamidis 2020 list price: $225,000 annually
  • Provides low economic value (>$180,000 per QALY gained) 1
• Disease progression may still occur in some patients despite treatment 5

In summary, while tafamidis and acoramidis are the only FDA-approved TTR stabilizers, research continues on other approaches to manage transthyretin amyloidosis, including TTR silencers and disruptors, which target different aspects of the disease process.