Approved TTR Stabilizer Therapies Beyond Tafamidis
Diflunisal is the only other TTR stabilizer therapy that has demonstrated efficacy for transthyretin amyloidosis, though it is not FDA-approved specifically for this indication.
FDA-Approved Therapies for Transthyretin Amyloidosis
TTR Stabilizers:
- Tafamidis (Vyndaqel/Vyndamax)
- FDA-approved for ATTR-CM (cardiac manifestations)
- Available in two formulations:
- Tafamidis meglumine: 20-mg capsules (80 mg daily dose - 4 capsules)
- Tafamidis: 61-mg capsules (61 mg daily dose - 1 capsule)
- Not FDA-approved for polyneuropathy in the US (though approved in Europe)
TTR Silencers (for ATTRv with polyneuropathy):
- Patisiran - small interfering RNA
- Inotersen - antisense oligonucleotide
- Vutrisiran - small interfering RNA
Non-FDA Approved TTR Stabilizers:
- Diflunisal
- An NSAID that has shown effectiveness in slowing progression of ATTRv polyneuropathy
- Not FDA-approved specifically for ATTR but used off-label
- Demonstrated efficacy in clinical studies for polyneuropathy 1
Mechanism of Action Comparison
| Medication Class | Mechanism | Examples | Indication |
|---|---|---|---|
| TTR Stabilizers | Prevent TTR tetramer dissociation | Tafamidis, Diflunisal | Tafamidis: ATTR-CM; Diflunisal: off-label |
| TTR Silencers | Block TTR protein synthesis via RNA inhibition | Patisiran, Inotersen, Vutrisiran | ATTRv with polyneuropathy |
| TTR Disruptors | Target tissue clearance | Doxycycline, TUDCA, EGCG (green tea) | Investigational only [1] |
Clinical Considerations
Efficacy:
- Tafamidis is the only therapy proven to reduce mortality and cardiovascular hospitalizations in ATTR-CM patients with NYHA class I-III symptoms 1
- TTR silencers (patisiran, inotersen, vutrisiran) have demonstrated efficacy in slowing or reversing polyneuropathy progression in ATTRv 1
- Diflunisal has shown effectiveness in slowing ATTRv polyneuropathy progression but lacks FDA approval 1
Patient Selection:
- For cardiac manifestations (ATTR-CM): Tafamidis is first-line therapy
- For polyneuropathy in ATTRv: TTR silencers are FDA-approved options
- Patients with both cardiac and neurologic manifestations may require careful consideration of therapy options
Monitoring Requirements:
- Patisiran: Monitor for infusion reactions; premedication recommended
- Inotersen: Weekly platelet counts and biweekly serum creatinine/urine protein monitoring due to risks of thrombocytopenia and glomerulonephritis
- TTR silencers require vitamin A supplementation (3,000 IU daily) due to reduced transthyretin-mediated retinol transport 1
Pitfalls and Caveats
- Tafamidis, while effective, provides low economic value at current pricing (>$180,000 per QALY gained) 1
- Early diagnosis and treatment initiation are critical for better outcomes with all therapies
- Patients with NYHA class IV symptoms, severe aortic stenosis, or impaired renal function (eGFR <25 mL/min/1.73 m²) have not shown benefit with tafamidis 1
- Diflunisal, as an NSAID, may have limitations in patients with renal dysfunction or heart failure
In summary, while tafamidis is the only FDA-approved TTR stabilizer for ATTR-CM, diflunisal represents another TTR stabilizer option with demonstrated efficacy for polyneuropathy, though without specific FDA approval for this indication. For ATTRv with polyneuropathy, the TTR silencers (patisiran, inotersen, and vutrisiran) are the FDA-approved disease-modifying therapies.