Alternative TTR Stabilizers to Tafamidis for Transthyretin Amyloidosis
For patients with transthyretin amyloidosis who cannot use tafamidis, diflunisal is the most effective alternative TTR stabilizer, followed by patisiran, inotersen, or vutrisiran for those with ATTRv polyneuropathy.
TTR Stabilizers
Diflunisal
- Non-steroidal anti-inflammatory drug repurposed as a TTR stabilizer
- Binds to the thyroxine-binding site of TTR, preventing tetramer dissociation
- Demonstrated effectiveness in slowing disease progression in ATTRv polyneuropathy 1, 2
- Not FDA-approved specifically for ATTR but used off-label
- Typical dosing: 250 mg twice daily
- Mean plasma concentration of 282.2 μM ± 143.7 μM has been shown to reduce wild-type TTR dissociation rate by 95% 2
- Requires careful monitoring of renal function and GI symptoms
Acoramidis (Attruby)
- Recently FDA-approved novel TTR stabilizer 3
- Reduced all-cause mortality by up to 42% and cardiovascular hospitalizations by ~50% in ATTR-CM patients over 30-42 months
- May be considered when tafamidis is not an option
TTR Silencers (for ATTRv with polyneuropathy)
These medications are particularly useful for patients with hereditary variant ATTR (ATTRv) with polyneuropathy:
Patisiran
- Small interfering RNA that reduces TTR production
- Administered as IV infusion every 3 weeks
- FDA-approved for ATTRv with polyneuropathy
- Slows progression of polyneuropathy compared to placebo 1
- Requires vitamin A supplementation (3,000 IU daily)
- Pre-medication with corticosteroids, acetaminophen, and antihistamines recommended
Inotersen
- Antisense oligonucleotide that reduces TTR production
- FDA-approved for ATTRv with polyneuropathy
- Requires monitoring for thrombocytopenia and glomerulonephritis
- Weekly platelet counts and biweekly serum creatinine/urine protein monitoring required 1
Vutrisiran
- Newer TTR silencer for ATTRv polyneuropathy
- Less frequent dosing schedule than other silencers 1
TTR Disruptors (Limited Evidence)
These options have limited evidence but may be considered when other options are unavailable:
Doxycycline plus TUDCA (tauroursodeoxycholic acid)
- Targets tissue clearance of amyloid deposits
- Limited benefit on surrogate endpoints such as LV mass 1
- Impact on cardiovascular morbidity and mortality not well established
EGCG (epigallocatechin-3-gallate from green tea)
- Natural compound that may disrupt amyloid fibrils
- Some evidence of reduced wall thickness and improved LV function in small studies 3
- Limited clinical trial data on cardiovascular outcomes
Clinical Decision Algorithm
First choice: Tafamidis (if available and tolerated) - only FDA-approved therapy shown to improve cardiovascular outcomes in ATTR-CM 1
If tafamidis unavailable/contraindicated:
- For ATTR-CM: Diflunisal (with careful renal monitoring) or Acoramidis
- For ATTRv with polyneuropathy: Patisiran, inotersen, or vutrisiran
If TTR stabilizers and silencers contraindicated:
- Consider doxycycline plus TUDCA or EGCG as experimental options
Important Considerations
- Early treatment is critical - all therapies are more effective when started earlier in disease course 1, 4
- Higher BMI at baseline is associated with better preservation of neurological function and slower disease progression 5, 4
- Approximately one-third of patients may show disease stabilization even after 3 years of therapy 4
- Older age at disease onset or treatment initiation correlates with poorer response to therapy 4
- Poor clinical status at baseline predicts more rapid disease progression despite treatment 4
Monitoring During Treatment
- Regular assessment of neurological function and cardiac status every 6-12 months
- Neurophysiological testing including small nerve fiber assessment
- Cardiac biomarkers (BNP/NT-proBNP, troponins)
- Body weight/BMI monitoring (higher BMI associated with better outcomes)
- Medication-specific monitoring (e.g., platelet counts for inotersen)