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

Approved TTR Stabilizer Therapies for Transthyretin Amyloidosis

Currently, tafamidis is the only FDA-approved TTR stabilizer therapy for transthyretin amyloid cardiomyopathy (ATTR-CM), while acoramidis was recently approved as a second TTR stabilizer option. 1

Current FDA-Approved TTR Stabilizers

Tafamidis

• Formulations: Available as tafamidis meglumine 20 mg capsules (80 mg daily dose) or tafamidis 61 mg capsules (61 mg daily dose) 2
• Indication: Approved for both wild-type (ATTRwt) and variant (ATTRv) transthyretin amyloid cardiomyopathy with NYHA class I-III heart failure symptoms 2
• Efficacy: In the ATTR-ACT trial, tafamidis demonstrated:
  • Reduced all-cause mortality (29.5% vs 42.9% with placebo)
  • Reduced cardiovascular-related hospitalizations (0.48 vs 0.70 per year)
  • Slower decline in functional capacity (6-minute walk test)
  • Improved quality of life 3
• Limitations:
  • Not FDA-approved for TTR-related polyneuropathy 2
  • High cost with low economic value (>$180,000 per QALY gained) 2

Acoramidis (AG10)

• Recently approved TTR stabilizer for ATTR-CM 1
• Newer option with potential benefits in stabilizing TTR

Other TTR-Targeting Therapies (Not TTR Stabilizers)

TTR Silencers

These are approved for ATTRv polyneuropathy but not for ATTR-CM:

1. Patisiran

   • RNA interference therapy
   • FDA-approved only for ATTRv with polyneuropathy 2
   • Currently in trials for ATTR-CM 4

2. Inotersen

   • Antisense oligonucleotide
   • FDA-approved only for ATTRv with polyneuropathy 2
   • Requires monitoring for thrombocytopenia and glomerulonephritis 2
   • Not recommended for patients with significant kidney impairment 2

3. Vutrisiran

   • Newer TTR silencer
   • Approved for ATTRv polyneuropathy 2
   • May receive approval for ATTR-CM in the future 1

Off-Label TTR Stabilizers

1. Diflunisal
   • NSAID with TTR stabilizing properties
   • Not FDA-approved for ATTR-CM
   • Limited evidence of benefit on surrogate endpoints like LV mass 2
   • Not recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload 2

Investigational Therapies

1. TTR Disruptors

   • Doxycycline plus tauroursodeoxycholic acid (TUDCA)
   • Limited evidence of benefit on surrogate endpoints 2
   • No proven impact on cardiovascular morbidity or mortality 2

2. Other Agents

   • Epigallocatechin-3-gallate (EGCG) from green tea
   • Limited evidence of benefit 2, 5
   • Tolcapone (off-label use) 5

Clinical Considerations for Treatment Selection

1. Disease Subtype

   • Determine if patient has ATTRwt or ATTRv through genetic sequencing 2
   • TTR silencers (patisiran, inotersen, vutrisiran) are currently only approved for ATTRv with polyneuropathy 2

2. Organ Involvement

   • Cardiac involvement: Tafamidis is the primary approved therapy 2
   • Polyneuropathy: Consider TTR silencers if ATTRv 2
   • Mixed phenotype: Treatment selection should be based on predominant manifestation

3. Contraindications

   • Kidney impairment: Avoid diflunisal and use caution with inotersen 2
   • NYHA class IV heart failure: Limited evidence for tafamidis in this population 2

Important Pitfalls to Avoid

1. Delayed Treatment

   • TTR stabilizers like tafamidis prevent but do not reverse amyloid deposition, making early treatment crucial 2
   • Survival benefit with tafamidis becomes apparent after 18 months of treatment 2

2. Inappropriate Medication Use

   • Avoid digoxin (binds to amyloid fibrils causing toxicity) 2
   • Avoid calcium channel antagonists (bind to amyloid fibrils causing hypotension) 2
   • Use caution with vasodilators (ARNi, ACEi, ARB) which may exacerbate hypotension 2
   • Use caution with beta-blockers as patients with ATTR-CM rely on heart rate response 2

3. Overlooking Anticoagulation

   • Anticoagulation is reasonable in patients with cardiac amyloidosis and atrial fibrillation regardless of CHA₂DS₂-VASc score 2

In summary, while tafamidis and acoramidis are the only FDA-approved TTR stabilizers for ATTR-CM, several other disease-modifying therapies targeting different aspects of the amyloidosis pathway are available for specific indications or are in development. Treatment selection should be guided by disease subtype, organ involvement, and patient-specific factors.