What are alternative transthyretin (TTR) stabilizer treatments?

Alternative TTR Stabilizer Treatments

Diflunisal is an alternative TTR stabilizer that has demonstrated effectiveness in slowing disease progression in ATTRv polyneuropathy, though it is not FDA approved for this indication. 1

TTR Stabilizers Overview

TTR stabilizers work by preventing the misfolding and inhibiting the formation of TTR amyloid fibrils. The currently available options include:

1. Tafamidis - FDA approved for:

   • ATTR cardiomyopathy (wild-type or hereditary) to reduce cardiovascular mortality and hospitalization 2
   • In Europe, it's also approved for polyneuropathy (not in the US) 1

2. Diflunisal - An NSAID that functions as a TTR stabilizer:

   • Demonstrated effectiveness in slowing ATTRv polyneuropathy progression
   • Not FDA approved for this indication
   • Lower cost alternative to tafamidis 3

TTR Silencers (Alternative Disease-Modifying Therapies)

For patients with ATTRv polyneuropathy, TTR silencers are FDA-approved options that act by blocking the translation of RNA to synthesize the TTR protein:

1. Patisiran - Small interfering RNA (siRNA):

   • Administered intravenously every three weeks
   • Requires premedication
   • FDA approved for ATTRv polyneuropathy 1, 3

2. Vutrisiran - Small interfering RNA:

   • FDA approved for ATTRv polyneuropathy 1

3. Inotersen - Antisense oligonucleotide:

   • Administered subcutaneously once weekly
   • FDA approved for ATTRv polyneuropathy
   • Requires monitoring for thrombocytopenia and glomerulonephritis 1, 3

Other Investigational Approaches

Several other approaches have been studied with varying levels of evidence:

1. Epigallocatechin-3-gallate (EGCG) - A polyphenol found in green tea:

   • Shown to reduce amyloid fibril formation
   • In a small, non-randomized study of cardiac AL amyloidosis, regular green tea consumption was associated with decreased wall thickness and improved LV function 1

2. Doxycycline plus TUDCA (tauroursodeoxycholic acid):

   • Limited benefit shown on surrogate endpoints such as LV mass
   • Impact on cardiovascular morbidity and mortality not yet assessed 1

3. Organ transplantation (for selected cases):

   • Liver transplantation for hereditary ATTR (as TTR is synthesized in the liver)
   • Combined cardiac and liver transplantation has shown 5-year survival rates of 50-80% in selected patients 1

Clinical Considerations When Choosing Therapy

• Disease type: Different treatments are approved for different manifestations (cardiomyopathy vs. polyneuropathy)
• Mutation status: Some treatments are only approved for variant TTR (ATTRv)
• Disease severity: Early treatment shows better outcomes; tafamidis efficacy correlates with disease severity at initiation 4, 5
• Patient characteristics: Age, sex, and native TTR concentration are relevant predictors of response to tafamidis 4
• Monitoring requirements: Some treatments require regular laboratory monitoring (e.g., inotersen)
• Administration route: Options include oral (tafamidis, diflunisal), subcutaneous (inotersen), or intravenous (patisiran)

Important Caveats

• All TTR silencers require vitamin A supplementation (3,000 IU daily) as transthyretin normally transports retinol 1
• Early diagnosis and treatment are crucial as patients treated earlier have better outcomes 1
• There is currently no evidence that TTR stabilizers or silencers benefit polyneuropathy associated with wild-type ATTR amyloidosis 1
• Diflunisal, being an NSAID, may have contraindications in patients with certain comorbidities
• Treatment response should be monitored as approximately 30% of patients may continue to progress despite therapy 4

For patients with cardiac involvement, careful consideration of medication interactions is essential, as some symptomatic treatments for neuropathy may be poorly tolerated in patients with cardiac amyloidosis.