Should a patient with hereditary transthyretin-mediated amyloidosis (hATTR) continue treatment with Amvuttra (vutrisiran) 25mg every 3 months despite lack of significant improvement in neuropathy symptoms and an increased Norfolk Qualitative Scale?

Recommendation on Vutrisiran Continuation

Do not approve continuation of vutrisiran at this time, as the patient demonstrates disease progression rather than beneficial response, evidenced by a worsening Norfolk Quality of Life scale from 47 to 56 over 9 months of treatment. 1

Rationale Based on Continuation Criteria

The insurance policy (CPB 0939) explicitly requires demonstration of "a beneficial response to treatment with the requested medication compared to baseline" for continuation therapy. 1 The patient fails to meet this criterion:

• Norfolk QOL scale increased from 47 to 56 (higher scores = greater impairment), indicating worsening rather than improvement 1
• Patient reports persistent severe neuropathic pain in legs, feet, hands, and right hip occurring 5 out of 7 nights 1
• Patient explicitly states uncertainty about vutrisiran efficacy as "it has not alleviated her neuropathy" 1
• New symptom onset: Right hip pain requiring nightly diclofenac began approximately 3 months ago (during vutrisiran treatment) 1

Evidence Supporting Need for Beneficial Response

The 2023 American College of Cardiology guidelines emphasize that TTR silencers like vutrisiran result in "stabilization or reversal of disease progression relative to patients' pretreatment baseline" at the cohort level. 1 In the pivotal HELIOS-A trial:

• Vutrisiran demonstrated significant improvements in Norfolk QOL-DN scores versus placebo (LSMD: -21.0 points at 18 months) 2
• The external placebo group showed progressive worsening in all measures 3
• Most patients showed improvement or stabilization, not progression 2

This patient's worsening trajectory contradicts expected treatment response patterns. 3, 2

Clinical Context and Timing Considerations

Early treatment initiation is critical for optimal outcomes—patients treated earlier demonstrate better neuropathy impairment measures and quality of life than those with delayed treatment. 1, 3 However, this principle applies to treatment-responsive patients, not those demonstrating progression despite therapy.

The patient has completed only 4 treatments (approximately 9 months) since starting in June 2024. 1 While the December 2024 office visit noted "it was too soon to determine efficacy," the February 2025 visit now provides sufficient follow-up data showing clear progression. 1

Alternative Explanations to Consider

Before definitively discontinuing vutrisiran, the treating neurologist should evaluate:

• Adherence to vitamin A supplementation (3,000 IU daily required with vutrisiran to prevent deficiency-related neuropathy worsening) 1
• Concurrent conditions: The patient has confirmed carpal tunnel syndrome and possible bursitis, which can mimic or exacerbate polyneuropathy symptoms 1
• Baseline disease severity: Patients with more advanced disease at baseline show less dramatic improvement, though stabilization still represents benefit 3

Recommended Next Steps

Request updated clinical documentation including:

• Confirmation of vitamin A supplementation compliance 1
• Repeat Norfolk QOL-DN assessment at current visit 1
• Modified NIS+7 scoring if available (the validated primary endpoint from trials) 4, 5
• 10-meter walk test results 4, 5
• Modified BMI trends 4, 5
• Treating neurologist's assessment of whether observed changes represent true treatment failure versus confounding factors 1

If documentation confirms treatment failure, consider:

• Alternative TTR silencer (patisiran or inotersen) if treatment failure attributed to vutrisiran-specific factors 1
• TTR stabilizer (tafamidis) though not FDA-approved for polyneuropathy 1
• Focus on aggressive symptomatic management with gabapentin (already initiated), pregabalin, or duloxetine for neuropathic pain 1

Critical Pitfall to Avoid

Do not confuse "continuity of care" with evidence-based continuation criteria. The prior authorization noted treatment was certified "for continuity of care," but this does not override the requirement for demonstrated beneficial response per CPB 0939 criteria. 1 Continuing ineffective disease-modifying therapy exposes the patient to unnecessary costs, injection burden, and potential adverse effects while delaying consideration of alternative approaches. 1, 6