Do TTR (transthyretin) stabilizers, such as tafamidis (generic name), benefit patients with polyneuropathy?

TTR Stabilizers for Polyneuropathy in Transthyretin Amyloidosis

TTR stabilizers benefit patients with ATTRv polyneuropathy by slowing disease progression, but are not proven beneficial for polyneuropathy associated with ATTRwt amyloidosis.

Disease-Modifying Therapies for ATTR Polyneuropathy

TTR Stabilizers

• Tafamidis:

  • Demonstrated efficacy in slowing neurological deterioration in early-stage ATTRv polyneuropathy, particularly in patients with Val30Met mutation 1
  • Long-term studies (up to 5.5 years) show sustained delay in neurologic progression and preservation of nutritional status when started early 2
  • While FDA-approved for ATTR cardiomyopathy, tafamidis does not have FDA approval specifically for ATTRv polyneuropathy 3
  • Generally well-tolerated with favorable long-term safety profile 4

• Diflunisal:

  • Demonstrated effectiveness in slowing disease progression in ATTRv polyneuropathy 3
  • Not FDA-approved for this indication 3

TTR Silencers (RNA-targeted therapies)

• Currently FDA-approved only for ATTRv with polyneuropathy 3:
  • Patisiran: 0.3 mg/kg IV every 3 weeks (maximum 30 mg)
  • Inotersen: 284 mg SC once weekly
  • Vutrisiran: 25 mg SC every 3 months

Clinical Considerations

Patient Selection

• Early intervention is crucial for optimal outcomes:
  • Patients treated earlier with tafamidis showed 55.9% greater preservation of neurologic function compared to delayed treatment 5
  • Benefits are most pronounced in patients with early-stage disease (mild neuropathy) 2

Monitoring

• For patients on tafamidis:

  • Regular assessment of neurologic function using validated tools (e.g., NIS-LL)
  • Monitor quality of life measures
  • Assess nutritional status

• For patients on TTR silencers:

  • Patisiran: Requires premedication with dexamethasone, acetaminophen, diphenhydramine, and famotidine 3
  • Inotersen: Weekly platelet count monitoring and biweekly monitoring of serum creatinine, eGFR, and urine protein-creatinine ratio due to risk of thrombocytopenia and glomerulonephritis 3
  • All silencers require vitamin A supplementation (3,000 IU daily) 3

Symptomatic Management

• Neuropathic pain management:

  • First-line: Pregabalin (75 mg twice daily, titrate to max 600 mg/day) or Gabapentin (300 mg at bedtime, titrate to max 3,600 mg/day) 3
  • Second-line: Duloxetine (20-30 mg daily, titrate to max 60-120 mg/day) 3
  • Use with caution: Tricyclic antidepressants may worsen orthostatic hypotension and autonomic symptoms 3

• Orthostatic hypotension:

  • Increased fluid intake, salt tablets, compression stockings
  • Medications: fludrocortisone, midodrine, droxidopa, or pyridostigmine
  • Caution with these medications in patients with concurrent heart failure 3

Important Caveats

1. No proven benefit in ATTRwt polyneuropathy: Currently, there is no evidence that TTR stabilizers or silencers benefit polyneuropathy associated with wild-type ATTR amyloidosis 3, 6

2. Genetic testing is essential: Genetic sequencing of the TTR gene is necessary to determine if the patient has variant (ATTRv) or wild-type (ATTRwt) disease, as this impacts treatment options 3

3. Early diagnosis and treatment: Initiating treatment early in the disease course is critical for optimal outcomes, as these medications primarily prevent progression rather than reverse existing damage 5, 2

4. Multidisciplinary approach: Management often requires collaboration between neurologists, cardiologists, and other specialists, especially when cardiac involvement is present 6