Cost-Effectiveness of Inotersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy (hATTR-NP) in Peru: An Illustrative Case of the Limits of the Cost-Per-QALY Framework in Rare Diseases IMPAC-FE Study

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Abstract
Background and objectives. Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-NP) is a rare, progressive, life-threatening disease for which inotersen, an antisense oligonucleotide, is the only disease-modifying therapy with marketing authorization in Peru. Using inotersen as an illustrative case, we examined whether the conventional cost-per-QALY (quality-adjusted life-year) framework is an adequate sole basis for coverage decisions in rare diseases, and we estimated the cost-effectiveness of inotersen versus best supportive care (BSC) under the two Peruvian public-payer perspectives — the Ministry of Health/Integral Health Insurance (MINSA/SIS) and the Social Health Insurance (EsSalud).Methods. We built a four-state Markov model (mild, moderate, severe polyneuropathy, and death) with annual cycles over a 40-year horizon and a 5% discount rate, reported per CHEERS 2022. Because longitudinal data are scarce, two alternative transition-probability matrices were used — one derived from the NEURO-TTR trial (Benson 2018) and one from the Institute for Clinical and Economic Review (ICER) 2020 evidence report — yielding nine analytical scenarios (eight deterministic plus an integrated probabilistic model, 10,000 iterations). Stage-specific utilities and direct medical costs (Peruvian soles, 2024) were obtained through top-down macro-costing. A budget impact analysis and a price-threshold analysis were performed; results were interpreted against the official Peruvian threshold (RM N° 267-2025/MINSA) and international benchmarks.Results. Annual direct medical costs rose from S/13,297 (mild) to S/68,306 (severe) under MINSA/SIS and from S/29,202 to S/139,576 under EsSalud. With Benson-2018 transitions, inotersen produced an incremental 4.44 QALYs (EsSalud) / 4.21 (MINSA) at an incremental cost of ≈ S/11.4 million, giving an incremental cost-effectiveness ratio (ICER) of S/2,563,550 (EsSalud) and S/2,735,944 (MINSA) per QALY; with ICER-2020 transitions the gain fell to 1.29 QALYs and the ICER rose to ≈ S/6.1 million per QALY. The integrated probabilistic model gave a mean ICER of S/2,512,302 per QALY. Across all scenarios the ICER was roughly 100–250 times the official Peruvian AVAC threshold (S/25,007) and ≈80–195 times GDP per capita, exceeding even the Highly Specialised Technologies (HST) ceiling of the UK National Institute for Health and Care Excellence (NICE). The eligible national population is small (≈10–30 patients), yet the 5-year budget impact reached ≈ S/51 million (range S/17–170 million).Conclusions. Under a decision rule based on the cost-utility ratio alone, inotersen would fall far outside every existing threshold — Peruvian and international ultra-orphan. Precisely for that reason, the cost-per-QALY framework, taken in isolation, cannot capture severity, rarity, unmet need and equity and — compounded by structural local-data scarcity and by the sensitivity of the point estimate to defensible structural choices — is an insufficient sole basis for coverage decisions in rare diseases. A complementary multi-criteria decision framework, aligned with Peru’s HTA network (RENETSA), is warranted.

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