Nancy Elena Loayza-Urcia

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.

Background and objectives. Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive disease caused by deposition of transthyretin-derived amyloid fibrils. Inotersen, an antisense oligonucleotide that inhibits hepatic transthyretin production, is approved by the FDA and EMA but is not fully implemented in low- and middle-income countries (LMICs). We systematically reviewed the evidence on the efficacy, safety and economic impact of inotersen in adults with ATTRv, jointly synthesizing clinical and economic evidence with particular attention to its transferability to LMICs, where treatment access remains limited.Methods. We searched MEDLINE (PubMed), Embase, CENTRAL and SciELO for efficacy and safety evidence, and EconLit, NHS-EED and the CEA Registry (in addition to the clinical databases) for economic evidence (July–August 2025), without language or date restrictions. We followed PRISMA guidelines for reporting our findings. We included randomized controlled trials and economic evaluations with or without economic modelling. Two reviewers screened and extracted data independently, with a senior reviewer for solving discrepancies. Risk of bias was assessed with RoB 2.0 (randomized evidence), ROBINS-I for open-label studies and the Philips and Drummond checklists for economic studies. We synthesised the information retrieved without a meta-analysis.Results. One pivotal trial (NEURO-TTR), reported across five publications including a 170-week open-label extension, and six economic evaluations were included. Inotersen improved neuropathy and quality-of-life outcomes (e.g., mNIS+7 difference −19.7; 95% CI −26.4 to −13.0; Norfolk QoL-DN −11.7; 95% CI −18.3 to −5.1), but serious adverse events — including grade 3–4 thrombocytopenia — were more frequent with inotersen. All economic evaluations adopted a payer perspective; cost-effectiveness ratios were well above conventional thresholds (e.g., ICUR CA$1,322,377/QALY [CADTH reanalysis]; £150,636/QALY [NICE]; €382,984/QALY [NCPE]). Only one study came from a middle-income country (a Mexican budget-impact analysis; US$2.3 million/year, 0.036% of the national health budget) and reported no cost-effectiveness estimate. Risk of bias was moderate for the NEURO-TTR trial and critical for the open-label extension.Conclusions. The evidence favoured inotersen for efficacy and safety in the short term, although long-term evidence is uncertain. Economic studies indicate that inotersen is not cost-effective at current market prices. Evaluation frameworks for rare and orphan diseases are needed to inform the introduction of these therapies where no treatment is currently available, particularly in LMICs.