Transthyretin stabilizers

Definition and Classification

Transthyretin stabilizers are a specialized class of orphan drugs developed to treat transthyretin amyloidosis (ATTR amyloidosis)—a progressive and potentially fatal condition caused by the misfolding and aggregation of transthyretin (TTR) protein into insoluble amyloid fibrils. These fibrils accumulate in various organs, leading to polyneuropathy, cardiomyopathy, and multi-organ dysfunction.

TTR stabilizers act by binding to the TTR tetramer and preventing its dissociation into monomers, which is the critical first step in amyloid formation. They do not remove existing amyloid deposits but slow or halt disease progression.

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Generic Names of Transthyretin Stabilizers

1. Tafamidis

2. Tafamidis meglumine (salt form of tafamidis)

3. Diflunisal (off-label use)

4. Acoramidis (formerly AG10 – investigational/emerging)

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Brand Names

• Tafamidis → Vyndaqel®

• Tafamidis meglumine → Vyndamax®

• Diflunisal → Dolobid® (NSAID repurposed for off-label TTR stabilization)

• Acoramidis → Investigational – not yet globally approved as of 2025

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Indications and Disease Context

TTR stabilizers are indicated for the treatment of:

1. Hereditary transthyretin-mediated amyloidosis (hATTR) with:

   • Polyneuropathy

   • Cardiomyopathy

2. Wild-type ATTR (wtATTR) also known as senile systemic amyloidosis, particularly for cardiomyopathy

These disorders stem from mutations in the TTR gene (hereditary) or age-related protein instability (wild-type).

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Pathophysiology of ATTR Amyloidosis

• Transthyretin is a tetrameric transport protein, primarily synthesized in the liver, that transports thyroxine (T4) and retinol-binding protein–bound vitamin A.

• In amyloidosis, the tetramer dissociates into monomers, which misfold and aggregate into amyloid fibrils.

• These deposit in peripheral nerves, heart muscle, gastrointestinal tract, and other tissues.

• Disease progression leads to neuropathy, restrictive cardiomyopathy, orthostatic hypotension, GI dysmotility, and renal/hepatic dysfunction.

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Mechanism of Action

Transthyretin stabilizers bind selectively to one or more thyroxine (T4) binding sites on the TTR tetramer and increase its kinetic stability. This stabilizing effect:

• Prevents dissociation into monomers, the initial step in amyloid formation

• Reduces amyloidogenicity

• Does not reverse existing amyloid deposits, but slows functional decline

Drug	Mechanism
Tafamidis	Binds selectively to thyroxine-binding site, stabilizes tetramer
Diflunisal	NSAID that binds T4-binding site and stabilizes TTR tetramer (off-label)
Acoramidis	TTR-selective stabilizer, designed to mimic T119M protective variant

Pharmacokinetics and Administration

Parameter	Tafamidis (Vyndaqel)	Tafamidis meglumine (Vyndamax)	Diflunisal
Route	Oral	Oral	Oral
Dosing	20 mg once daily	61 mg once daily (bioequivalent)	250 mg twice daily
Metabolism	Phase II (glucuronidation)	Phase II	Hepatic (CYP-mediated)
Half-life	~50 hours	~50 hours	8–12 hours
Protein binding	>99%	>99%	High
Excretion	Feces, urine	Feces, urine	Urine

Note: Vyndaqel and Vyndamax are not interchangeable on a mg-to-mg basis.

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Approved Indications

Drug	Indication
Tafamidis	FDA-approved for TTR amyloid cardiomyopathy (wtATTR and hATTR)
Tafamidis meglumine	Also approved for cardiomyopathy due to ATTR
Diflunisal	Off-label use for hATTR with polyneuropathy or cardiomyopathy

Tafamidis was the first and only FDA-approved treatment for ATTR cardiomyopathy as of its 2019 approval.

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Clinical Trials and Efficacy Data

1. ATTR-ACT Trial (Tafamidis)

   • Double-blind, placebo-controlled, phase 3

   • Patients with ATTR cardiomyopathy (wtATTR and hATTR)

   • Tafamidis reduced all-cause mortality and CV-related hospitalizations

   • Improved 6-minute walk distance and quality of life scores

2. NEURO-TTR Trial (Tafamidis in polyneuropathy)

   • Evaluated in familial ATTR with neuropathic phenotype

   • Slowed progression of neurologic decline and preserved daily function

3. Acoramidis (AG10)

   • ATTRibute-CM Trial showed mixed results in phase 3

   • Aimed to outperform tafamidis in stabilizing TTR in patients with cardiomyopathy

   • Regulatory reviews ongoing as of 2025

4. Diflunisal

   • Cleveland Clinic studies showed slowed neuropathic progression in hATTR patients

   • However, NSAID toxicity limits its long-term use (GI bleeding, renal dysfunction)

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Adverse Effects and Safety Profile

Tafamidis / Vyndamax	Diflunisal (NSAID)
Well-tolerated overall	GI bleeding, peptic ulcers
Mild side effects:	Renal impairment
– Diarrhea	Cardiovascular risk (e.g., MI)
– Urinary tract infections	Sodium/fluid retention
– Arthralgia	Hepatotoxicity (rare)

Black Box Warning (Diflunisal):

• NSAID-related: GI bleeding, ulceration, and cardiovascular events

Tafamidis does not carry boxed warnings and is safe for long-term use in elderly populations.

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Contraindications

Tafamidis	Diflunisal
Hypersensitivity	Hypersensitivity to NSAIDs
Severe hepatic impairment	Active GI ulcer/bleeding
Use in pregnancy (risk unknown)	Cardiovascular disease
Pediatric use not established	Renal impairment

Pregnancy and Lactation

• Tafamidis: Not enough data; use only if benefits outweigh risks

• Diflunisal: Contraindicated in late pregnancy (risk of premature closure of ductus arteriosus)

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Drug Interactions

Drug	Interaction Type
Tafamidis	Minimal CYP interaction; low potential for interactions
Diflunisal	High risk: interacts with warfarin (↑ bleeding risk)
	Inhibits CYP2C9 → affects phenytoin, sulfonylureas, etc.
	Renal effects potentiated with ACE inhibitors

Monitoring Parameters

Parameter	Tafamidis	Diflunisal
Liver enzymes (baseline)	Optional	Mandatory
Renal function (baseline)	Not essential	Baseline + periodic
Cardiovascular parameters	Functional class, ECG, Echo	NYHA class, symptoms
Neuropathy scales	mNIS+7, R-ODS	mNIS+7
Drug levels	Not required	Not routinely monitored

Clinical Advantages

• Tafamidis and Vyndamax offer:

  • Disease-modifying treatment

  • Oral once-daily dosing

  • Excellent tolerability

  • Improved quality of life and survival

  • Effective for both wild-type and hereditary ATTR

• Diflunisal provides:

  • Cost-effective alternative

  • Slows neurologic progression

  • Useful where tafamidis is inaccessible

  • However, limited by NSAID toxicity risks

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Limitations

• Cost: Tafamidis has been criticized for extremely high price (~$225,000/year in the U.S.)

• Does not reverse amyloid deposition

• Diflunisal is off-label and requires careful monitoring

• Limited pediatric data

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Emerging Alternatives and Pipeline Drugs

1. Acoramidis (AG10):

   • Mimics T119M protective TTR variant

   • Binds with greater stability than tafamidis (higher occupancy)

   • Trials ongoing

2. TTR gene silencers (not stabilizers but relevant alternatives):

   • Patisiran (Onpattro) – siRNA

   • Inotersen (Tegsedi) – antisense oligonucleotide

   • Vutrisiran – second-gen siRNA

3. CRISPR/Cas9 editing (NTLA-2001, in development)

   • Single-dose, in vivo genome editing of TTR gene

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Clinical Guidance and Use Considerations

• Tafamidis is first-line for ATTR-CM (both hereditary and wild-type)

• Neurological involvement may benefit from combined use of stabilizers and silencers

• Patient selection depends on:

• Genetic profile (TTR variant)

• Organ involvement (cardiac vs. neurologic)

• Tolerability and access