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

Approved TTR Stabilizer Therapies Beyond Tafamidis

Currently, tafamidis (Vyndaqel/Vyndamax) is the only FDA-approved TTR stabilizer therapy for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) 1. However, there are other disease-modifying therapies that target different aspects of the TTR amyloidosis pathway.

Current FDA-Approved TTR Stabilizers

• Tafamidis: Available as Vyndaqel (80 mg daily, four 20-mg capsules) or Vyndamax (61 mg daily, one capsule) 2, 1
  • Indicated for treatment of wild-type or hereditary ATTR-CM
  • Mechanism: Binds to thyroxine-binding sites of TTR tetramer to prevent dissociation
  • Proven to reduce cardiovascular mortality and hospitalizations in NYHA class I-III patients

Other Disease-Modifying Therapies (Not TTR Stabilizers)

TTR Silencers (RNA-targeting therapies)

• Inotersen: FDA-approved for ATTRv with polyneuropathy only 2

  • Not approved for ATTR-CM
  • Caution: Associated with glomerulonephritis in 3% of patients 2

• Patisiran: FDA-approved for ATTRv with polyneuropathy only 2

  • Not approved for ATTR-CM

• Vutrisiran: Approved for ATTRv with polyneuropathy 3

  • Not yet approved for ATTR-CM

Other TTR Stabilizers (Not FDA-Approved for ATTR-CM)

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

Investigational TTR-Targeting Therapies

• Acoramidis: Recently approved TTR stabilizer 3
• TTR Disruptors: Target tissue clearance (e.g., doxycycline, tauroursodeoxycholic acid, epigallocatechin-3-gallate) 2
  • Limited evidence on surrogate endpoints
  • Not FDA-approved for ATTR-CM

Clinical Decision Algorithm for ATTR-CM Treatment

1. Confirm diagnosis of ATTR-CM

   • Bone scintigraphy (99mTc-PYP scan) with grade 2/3 cardiac uptake or H/CL ratio >1.5
   • Rule out AL amyloidosis with serum/urine immunofixation and free light chain assay
   • Genetic testing to differentiate ATTRwt from ATTRv

2. Assess NYHA functional class

   • For NYHA class I-III: Consider tafamidis (only FDA-approved TTR stabilizer)
   • For NYHA class IV: Limited evidence for benefit with tafamidis

3. For patients with ATTRv with polyneuropathy

   • Consider TTR silencers (inotersen, patisiran, vutrisiran) in addition to tafamidis
   • Genetic counseling and family screening

Important Considerations

• Cost issues: Tafamidis provides low economic value at current pricing (>$180,000 per QALY gained) 2
• Early treatment: Tafamidis is more effective when started early in disease course 4
• Nutritional status: Higher modified body mass index at baseline is associated with better preservation of neurological function during treatment 5

Despite the availability of other disease-modifying approaches, tafamidis remains the only FDA-approved TTR stabilizer for ATTR-CM, with demonstrated mortality and hospitalization benefits 2, 6.