Introduction: Patients with sickle cell disease (SCD) face substantial mortality risks and decreased quality-of-life for every year lived with disease. Once approved in the United States (US), gene therapy treatment for patients with SCD would allow the possibility of lifelong disease remission and, unlike allotransplantation, do so without the concomitant risks of allotransplantation. While gene therapy has previously been projected to be cost-ineffective using traditional cost-effectiveness criteria in the US, this does not include a quantification of the health disparities present in the clinical care of patients with SCD. We sought to address this knowledge gap by conducting the first distributional cost-effectiveness analysis, a method that quantifies the tradeoffs between traditional cost-effectiveness outcomes and health equity, for gene therapy use in SCD.

Methods: We built and validated a Markov simulation model of patients with a diagnosis of mild, moderate, or severe SCD to examine the cost-effectiveness of gene therapy versus patients treated with standard-of-care (SOC). Gender-, age-, and disease-severity-specific annual costs and transition probabilities between disease severities were informed by ten years of real-world data from commercially insured patients in the United States with SCD (2007-2017; Optum claims data). Disease severity was defined based on annual number of hospitalizations and SOC was inclusive of hydroxyurea, opioid therapy, antibiotics, vaccinations, blood transfusions, and stem cell transplantation. Quality-adjusted life-years (QALYs) were informed by published lifetime simulation of patients living with SCD and matched controls. These were originally derived from a polynomial fit linking Euroqual-5 Dimensions to the visual analog scale for pain in patients with SCD in several studies. Age-, gender- and disease-specific background mortality probabilities were employed. Traditional cost-effectiveness was quantified using an incremental cost-effectiveness ratio (ICER) and a cost-effectiveness threshold of $100,000/QALY. Base-case gene therapy was assumed to cost $2.1 million based on other recently approved indications, be 100% effective in achieving disease remission, and applied to a minimum eligibility age of 12, as studied in randomized, controlled trials. To account for health inequities in SCD we then conducted a distributional cost-effectiveness analysis (DCEA), which applies an inequality aversion parameter (i.e., equity weight) to the distribution of outcomes across relevant sub-groups. Specifically, we derived the threshold inequality aversion parameters needed for gene therapy to be favored over SOC and justify funding per DCEA standards. These were compared to prior estimates for commonly used equity weights in the US (range 0.5-3.0) and the United Kingdom (UK) (11.0-28.9).

Results: Base-case gene therapy versus SOC treatment starting at age 12 yields 25.5 versus 16.0 discounted lifetime QALYs at costs of $2.4 and $1.1 million, respectively. The ICER of $144,000/QALY is not good value for money using traditional cost-effectiveness methods and a cost-effectiveness threshold of $100,000/QALY. When using DCEA that account for health disparities in SCD, the inequality aversion parameter threshold is 1.7. This implies a preference for reducing disparities in SCD care that is in line with prior estimates in the US and well below those of the UK, per DCEA standards to favor gene therapy over SOC. A corresponding price range for gene therapy for SCD across the range of commonly used equity weights in the US is $1.4-$3.0 million (Figure 1).

Conclusion: Gene therapy can be an equitable therapeutic strategy for patients with SCD in the United States despite a projected minimum cost of $2.1 million once approved, based on commonly-used equity weight values used in DCEA. Equitable gene therapy use would include expanding eligibility to include patients with mild and moderate disease severity, in addition to those with severe SCD, assuming similar therapeutic efficacy of gene therapy across disease severity. Rather than relying on ranges of commonly-used equity weights, nationally representative surveys should be fielded to empirically deriving an inequality aversion parameter value for addressing this SCD-specific health disparity to further help inform an equitable price benchmark for gene therapy in the US.

No relevant conflicts of interest to declare.

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