Treatment of children with Spinal Muscular Atrophy with Nusinersen: An analysis of efficacy, safety and reimbursement dilemmas

Abstract

This thesis evaluates the efficacy and safety of nusinersen in children with spinal muscular atrophy (SMA) and examines the ethical and policy implications of its reimbursement within a solidarity-based healthcare system. SMA is an autosomal recessive neuromuscular disorder caused by loss of function of the SMN1 gene, resulting in progressive degeneration of motor neurons. Disease severity is partially modulated by SMN2 copy number. Nusinersen, an antisense oligonucleotide that modifies SMN2 pre-mRNA splicing to increase functional SMN protein levels, was the first disease-modifying therapy approved for SMA. Part I: Clinical efficacy and safety A nationwide, population-based cohort study was conducted in Dutch children with SMA types 1–3a treated with nusinersen. Longitudinal analyses demonstrated that treatment resulted in clinically meaningful improvement or stabilization of motor function in approximately 90% of patients, contrasting with the progressive decline observed in natural history cohorts. Motor function gains were most pronounced during the first 12–24 months of treatment and were significantly associated with shorter disease duration at treatment initiation, underscoring the importance of early intervention. Despite these improvements, bulbar and respiratory outcomes did not show significant longitudinal improvement, indicating a domain-specific treatment effect. Safety analyses revealed that nusinersen was well tolerated, with adverse events occurring in a minority of injections and not leading to treatment discontinuation. Complementary analyses of cerebrospinal fluid biomarkers were performed to investigate potential treatment-related inflammatory responses, addressing concerns raised by early post-marketing reports. No concerning elevation of inflammatory markers were found, and nusinsersen was found to be a safe treatment. Part II: Reimbursement and ethical analysis The second part of the thesis uses nusinersen as a case study to evaluate the Dutch Coverage Lock (CL) policy, a reimbursement mechanism applied to high-cost hospital drugs. Due to its substantial budget impact and uncertain cost-effectiveness, nusinersen was initially excluded from reimbursement pending further evaluation. The CL process, which incorporates assessments of efficacy, cost-effectiveness, necessity, and societal feasibility, resulted in restricted initial access based on age and disease duration criteria, thereby excluding a subset of patients. This led to intrafamilial inequities and ethical concerns regarding fairness and distributive justice. Qualitative and quantitative analyses of stakeholder perspectives and public opinion demonstrated that reimbursement decisions are not solely driven by economic and clinical evidence but are also shaped by societal values, including solidarity, equity, and perceived disease severity. Comparative analyses across European countries revealed variation in access to nusinersen, suggesting that moral considerations and procedural differences influence national reimbursement outcomes. Conclusion Nusinersen is an effective and safe disease-modifying therapy for pediatric SMA, particularly when initiated early in the disease course. However, its high cost presents substantial challenges for healthcare systems. The Dutch Coverage Lock policy provides a structured framework for managing these challenges but raises ethical concerns regarding equitable access. This thesis highlights the need for integrated decision-making frameworks that balance clinical benefit, economic sustainability, and societal values to ensure fair allocation of innovative therapies.