What is the treatment regimen for Vutrisiran (Vutrisiran) in patients with transthyretin-mediated amyloidosis?

Vutrisiran Treatment Regimen for Transthyretin-Mediated Amyloidosis

Vutrisiran is administered as a 25 mg subcutaneous injection once every 3 months for patients with transthyretin-mediated amyloidosis with polyneuropathy. 1, 2

Dosing Information

• Vutrisiran is administered as a fixed dose of 25 mg via subcutaneous injection once every 3 months 1, 2
• No dose adjustment is required for patients ≥65 years of age 2
• No dose adjustment is recommended for patients with mild or moderate renal impairment (eGFR ≥30 to <90 mL/min/1.73 m²) 2
• No dose adjustment is recommended for patients with mild hepatic impairment 2
• Daily vitamin A supplementation of 3,000 IU is required during treatment due to vutrisiran's effect on reducing serum vitamin A levels 1, 2

Mechanism and Efficacy

• Vutrisiran is a small interfering RNA (siRNA) that targets both mutant and wild-type transthyretin (TTR) mRNA, causing degradation through RNA interference 1, 2
• It is conjugated with N-acetylgalactosamine (GalNAc) to enable targeted delivery to hepatocytes 2, 3
• Vutrisiran reduces mean serum TTR at steady state by approximately 83% 2
• Treatment results in stabilization or reversal of disease progression in terms of neuropathy and quality of life relative to patients' pretreatment baseline 1

Clinical Considerations

• Vutrisiran is FDA-approved specifically for ATTRv polyneuropathy (variant transthyretin amyloidosis with polyneuropathy) 1
• Early diagnosis and treatment is important as patients treated earlier have better measures of neuropathy impairment and quality of life than those whose treatment is delayed by 1 year or more 1
• Vutrisiran has a short plasma half-life (median 5.2 hours) but provides sustained TTR reduction for at least 90 days post-dose 2, 4
• No premedication is required before administration (unlike patisiran, which requires premedication with corticosteroids and antihistamines) 1, 2

Monitoring and Safety

• Vutrisiran reduces serum vitamin A levels by approximately 62% over 9 months, necessitating vitamin A supplementation 2
• The most common treatment-related adverse events are pain in extremity and arthralgia 3
• Unlike inotersen (another TTR silencer), vutrisiran does not require regular monitoring of platelet counts, serum creatinine, or urine protein-creatinine ratio 1
• Vutrisiran has an acceptable safety profile with similar incidence of adverse events compared to placebo in clinical trials 5, 6

Symptomatic Management of Neuropathy

• In addition to disease-modifying therapy with vutrisiran, symptomatic management of neuropathy is important 1
• For neuropathic pain, pregabalin (75 mg twice daily, up to 600 mg/day), gabapentin (300 mg initially, up to 3,600 mg/day), or duloxetine (20-30 mg daily, up to 120 mg/day) may be beneficial 1
• For autonomic symptoms such as orthostatic hypotension, options include increased fluid intake, salt tablets, fludrocortisone, midodrine, droxidopa, or pyridostigmine 1
• Compression stockings and abdominal binders can help manage orthostatic hypotension without medication side effects 1

Emerging Evidence

• Recent data from the HELIOS-B trial suggests vutrisiran may also be beneficial in ATTR amyloidosis with cardiomyopathy, showing reduced risk of death from any cause and cardiovascular events compared to placebo 5, 6
• The greatest benefit appears to be in earlier, less severe disease stages 7

Common Pitfalls and Caveats

• Vutrisiran is only FDA-approved for ATTRv polyneuropathy, not for ATTRwt amyloidosis, carpal tunnel syndrome, or lumbar stenosis associated with amyloidosis 1
• Medications for autonomic symptoms (except pyridostigmine) may be poorly tolerated in patients with cardiac involvement due to restrictive physiology 1
• Tricyclic antidepressants, though effective for neuropathic pain, may have increased side effects in patients with amyloid neuropathy who have orthostatic hypotension or other autonomic symptoms 1
• Older patients with amyloidosis are at greater risk for medication side effects; consultation with a geriatric specialist and reference to the Beers Criteria may be helpful 1