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 transthyretin amyloid cardiomyopathy (ATTR-CM) 1. While other disease-modifying therapies exist, they work through different mechanisms or are approved for different indications.

Current Approved TTR-Targeting Therapies

TTR Stabilizers:

• Tafamidis: FDA-approved for ATTR-CM (both wild-type and variant forms) in patients with NYHA class I-III symptoms 1
  • Available in two formulations:
    • Tafamidis meglumine (Vyndaqel): 80 mg (four 20-mg capsules) once daily
    • Tafamidis (Vyndamax): 61 mg once daily

Other Approved Therapies (Non-Stabilizers):

• TTR Silencers (approved only for ATTRv polyneuropathy, not cardiomyopathy):
  • Patisiran: RNA interference therapy 1
  • Inotersen: Antisense oligonucleotide 1
  • Vutrisiran: RNA interference therapy 2

Off-Label TTR Stabilizer:

• Diflunisal: An NSAID with TTR-stabilizing properties, used off-label 1
  • Not recommended for patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload due to potential adverse renal effects 1

Clinical Considerations

Efficacy of Tafamidis

• Tafamidis significantly reduces all-cause mortality and cardiovascular-related hospitalizations compared to placebo 3, 4
• Slows deterioration in functional capacity (6-minute walk test) and quality of life 3
• Benefits observed in both wild-type and variant TTR genotypes 3

Treatment Selection Algorithm

1. Confirm ATTR-CM diagnosis through:

   • Bone scintigraphy (99mTc-PYP scan) with grade 2/3 cardiac uptake or H/CL ratio >1.5
   • Absence of monoclonal protein in serum/urine
   • Genetic sequencing to determine wild-type vs. variant TTR 1

2. Assess disease stage and comorbidities:

   • NYHA functional class (I-III eligible for tafamidis)
   • Renal function (caution with diflunisal if eGFR <45)
   • Presence of polyneuropathy (may consider TTR silencers if ATTRv with polyneuropathy)

3. Initiate appropriate therapy:

   • ATTR-CM: Tafamidis is first-line therapy
   • ATTRv with polyneuropathy: Consider patisiran, inotersen, or vutrisiran

Important Caveats

• Tafamidis is extremely expensive with an annual cost of approximately $225,000, providing low economic value (>$180,000 per QALY gained) 1
• Benefit has not been demonstrated in NYHA class IV heart failure 1
• Treatment should be initiated early as tafamidis prevents but does not reverse amyloid deposition 4
• One-third of patients may still show disease progression despite treatment 5
• Higher baseline modified body mass index is associated with better preservation of neurological function 5

Emerging Therapies

Several disease-modifying therapies are in development for ATTR-CM, including:

• Acoramidis: A TTR stabilizer recently approved for ATTR-CM 2
• Additional gene editing therapies and monoclonal antibodies in clinical trials 2

In conclusion, while tafamidis remains the only FDA-approved TTR stabilizer for ATTR-CM, several other disease-modifying therapies targeting different mechanisms are approved for ATTRv polyneuropathy, and new treatments are emerging in clinical development 1, 2.