Should a patient with hereditary transthyretin amyloidosis (hATTR) without definitive symptoms start treatment with Amvuttra (vutrisiran)?

Treatment Initiation for Asymptomatic hATTR Patients

Yes, patients with hereditary transthyretin amyloidosis (hATTR) should start Amvuttra (vutrisiran) even without definitive symptoms, as early treatment is critical for better neuropathy outcomes and quality of life. 1

Rationale for Early Treatment

Early diagnosis and treatment initiation is paramount in hATTR amyloidosis. The evidence strongly supports that patients treated earlier demonstrate significantly better measures of neuropathy impairment and quality of life compared to those whose treatment is delayed by 1 year or more 2. This benefit is most pronounced in patients with earlier-stage disease, specifically those with baseline polyneuropathy disability (PND) scores I-II 3.

Disease Progression Without Treatment

• hATTR amyloidosis is a rapidly progressive and fatal disease that leads to rapid deterioration of physical function and quality of life 3
• The disease causes progressive polyneuropathy and cardiomyopathy through deposition of misfolded transthyretin protein in amyloid fibrils 4
• Without disease-modifying therapy, patients experience worsening neuropathy impairment, declining quality of life measures, reduced gait speed, and deteriorating nutritional status 5

FDA-Approved Indication

Amvuttra is FDA-approved for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults 6. Importantly, the indication does not require patients to have "definitive" or severe symptoms—the presence of polyneuropathy in hATTR qualifies patients for treatment 6.

Clinical Trial Evidence

The pivotal HELIOS-A study enrolled patients across disease stages:

• 70% of patients were in Stage 1 of disease at baseline 6
• 30% were in Stage 2 at baseline 6
• Vutrisiran demonstrated significant improvements across all disease stages, but benefits were most pronounced in earlier-stage patients 3

Treatment Benefits in Early Disease

Vutrisiran provides stabilization or reversal of disease progression in terms of neuropathy and quality of life relative to patients' pretreatment baseline 2. At 18 months, treatment demonstrated:

• Significant improvement in modified Neuropathy Impairment Score +7 (mNIS+7) compared to placebo (p = 3.54 × 10-12) 5
• Significant improvement in Norfolk Quality of Life-Diabetic Neuropathy total score (LSMD: -21.0; p = 1.84 × 10-10) 3
• Improvement in 10-meter walk test (LSMD: 0.239 m/s; p = 1.21 × 10-7) 3
• Improvement in Rasch-built Overall Disability Score (LSMD: 8.4; p = 3.54 × 10-15) 3
• Improvement in modified body mass index (LSMD: 140.7; p = 4.16 × 10-15) 3

Practical Administration Considerations

Vutrisiran offers significant practical advantages that support early initiation:

• Administered as 25 mg subcutaneous injection once every 3 months 2, 6
• No premedication required 2
• Must be administered by a healthcare professional 6
• Requires daily vitamin A supplementation of 3,000 IU due to reduction in serum vitamin A levels 2, 6

Safety Profile

The medication is generally well tolerated 7:

• Most common adverse reactions (≥5%): pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%) 6
• Injection site reactions occurred in only 4% of patients and were mild and transient 6
• Two cases (1.6%) of atrioventricular heart block occurred, including one complete AV block 6
• No drug-related discontinuations or deaths in clinical trials 5

Critical Caveats

Vutrisiran is only FDA-approved for ATTRv polyneuropathy (hereditary variant), not for wild-type ATTRwt amyloidosis, isolated carpal tunnel syndrome, or lumbar stenosis associated with amyloidosis 2. This distinction is crucial when determining treatment eligibility.

Monitoring Requirements

• Patients must be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness) 6
• Higher doses than the recommended daily allowance of vitamin A should not be given to achieve normal serum vitamin A levels during treatment, as serum levels do not reflect total body vitamin A 6
• In clinical trials, 98% of patients with normal baseline vitamin A levels developed low vitamin A levels during treatment 6

Window of Opportunity

The evidence demonstrates that delaying treatment by even 1 year results in worse outcomes 2. Given that hATTR is rapidly progressive and fatal without treatment 3, and that vutrisiran has an acceptable safety profile with no contraindications 6, the risk-benefit analysis strongly favors early treatment initiation rather than waiting for symptoms to become "definitive."

Real-world data shows that disease progression is a common reason for treatment switches (83.3% of switches from other therapies) 8, further supporting the importance of initiating effective therapy early in the disease course.