Preventing Long-Term Neurologic Disability in Hemophilia (A): Cost-Effectiveness of Emicizumab Prophylaxis for the Prevention of Intracranial Hemorrhage in Infants with Severe Hemophilia (A)

Introduction: Intracranial hemorrhage (ICH) and its sequela (i.e., neurologic disability) are a dreaded complication for infants with severe hemophilia A (HA). Prophylactic intravenous factor VIII replacement decreases bleeding incidence and is typically started after the age of 2. The benefits of intravenous factor prophylaxis in children less than two years of age are offset by the risks of central venous access placement in this age group. The phase III, open-label HAVEN 7 study showed the safety and efficacy of early subcutaneous emicizumab prophylaxis in protecting infants under 12 months from ICH. Given the expense of emicizumab, affordability concerns have been raised about such an approach. We hypothesized that the established reduction in ICH risk in infants with emicizumab use would sufficiently offset the expense of this approach over the course of a lifetime of benefit (i.e., reducing neurologic disability). We sought to test this hypothesis by determining the cost-effectiveness of emicizumab prophylaxis during the first two years of life for patients with severe HA.

Methods: In this independent analysis free of industry influence, we built a Markov cohort model to evaluate the cost-effectiveness of emicizumab prophylaxis versus no prophylaxis for infants aged 0-2 with severe HA without FVIII inhibitor. Our analysis was conducted from the US societal perspective over a lifetime time-horizon. Patients at age 1 month were assumed to start subcutaneous emicizumab prophylaxis at a dose of 3 mg/kg every two weeks. ICH incidence was informed by the phase III study (HAVEN 7). ICH incidence in patients in the 0-2 age group with severe hemophilia A in the standard-of-care (SOC) arm was informed from disease- and age-specific natural history data, with neurologic sequelae in this population informed by published disease-specific literature. In the SOC arm of the model, standard half-life (SHL) intravenous FVIII prophylaxis was initiated after patients experienced an ICH event. All patients in both arms were on SHL prophylaxis beyond 2 years of age. Age-, sex- and disease-specific background mortality were employed. Costs for emicizumab, SHL FVIII, and ICH treatment based on age-dependent body weight, were sourced from the Centers for Medicare & Medicaid Services. Healthcare expenditures for disabled and non-disabled individuals were obtained from the Medical Expenditure Panel Survey. For societal costs, we considered productivity losses due to the sequelae of ICH, assuming that pediatric patients with persistent neurologic disabilities had one of their parents as a caregiver and that they lost wages during their adult life. Disease-specific and complication-specific utilities were employed. The primary outcome was the incremental cost-effectiveness ratio (ICER) in USD per quality-adjusted life-year (QALY) across all accepted willingness-to-pay (WTP) thresholds in the US. In an exploratory analysis, we examined a scenario analysis that assumed non-inferiority of low-dose emicizumab in preventing ICH. We concluded with probabilistic sensitivity analyses that captured uncertainty in all parameters simultaneously over 10,000 Monte Carlo iterations.

Results: In the base-case, emicizumab prophylaxis versus SOC accrued 25.6 and 24.5 QALYs across the lifespan at costs of $9.8 million and $9.7 million, respectively. The ICER for emicizumab was $114,000/QALY (95% credible interval $92,000-165,000/QALY). In deterministic sensitivity analyses, the model result was most sensitive to the cost of emicizumab. In scenario analysis, the projected lifetime cost of low-dose emicizumab prophylaxis decreased by $9.72 million, with the ICER for emicizumab of $53,000/QALY (95% CI $41,00-78,000/QALY). In probabilistic sensitivity analyses across WTPs of $150,000, $100,000, and $50,000/QALY of each of the i) base-case and ii) scenario analysis, emicizumab was favored over SOC in i) 92%, 11%, and 0%; and ii) 100%, 100%, and 29%, of 10,000 Monte Carlo iterations, respectively.

Conclusions: Despite its high price, emicizumab prophylaxis for infants with severe HA can be a cost-effective strategy. These findings are achieved by the reduction of ICH incidence with emicizumab prophylaxis as compared to the natural history of severe HA in the age 0-2 life period.

No relevant conflicts of interest to declare.