We designed, conducted, and validated our cost-effectiveness analysis in alignment with good modeling practice guidelines and recommendations [30,31,32]. The scope and design of the model were informed by a structured review of the clinical and economic literature in SCD and refined through a collaborative process with patient and expert clinical perspectives, including an individual with SCD and hematologists with experience treating and managing SCD in pediatric and adult populations. We also convened a panel of independent clinical and economic advisors to solicit feedback on the validity of our approach.

2.1 Modeling Approach

We developed a patient-level simulation modeling approach to predict the lifetime health and economic outcomes of patients with SCD treated with lovo-cel in comparison with common care (Fig. 1). Among economic modeling methodologies [30], this approach is best suited to reflect the heterogeneity of the SCD population, the comprehensive set of SCD-related events and complications potentially impacted by a gene therapy, and the time-dependent relationships between events, complications, and mortality in SCD [30, 33]. This rationale is similarly reflected in other recent cost-effectiveness modeling frameworks for gene therapies in SCD [22, 23, 29].

Fig. 1

Model structure. Hb hemoglobin, HU hydroxyurea, SCD sickle cell disease, VOC vaso-occlusive crisis, VOE vaso-occlusive event, VOE-CR complete resolution of vaso-occlusive events. a Number of each event per year sampled from annual incidence rates that vary over time. b Timing of incidence for each complication sampled from cumulative complication-free survival curves that are updated each year based on annual development probabilities. c Timing of death sampled from cumulative survival curves that are updated each year based on annual mortality risks

The model specification details are presented in Table 1. The target population was aligned with the transplant population for VOE (TPVOE) baseline criteria in the HGB-206 clinical trial (see Table S1 in the Supplementary Information for subject disposition details) [15, 34, 35]. We modeled a population reflecting the HGB-206 TPVOE criteria (age of ≥ 12 years with ≥ 4 VOEs in the prior 24 months), which is a narrower and potentially more severe subset of the approved lovo-cel indication (age of ≥ 12 years with any history of VOEs) [15]. The target intervention was one-time treatment with lovo-cel gene therapy administered according to the HGB-206 Group C treatment protocol as authorized by the FDA [15, 35]. The comparator was common care for SCD, which includes proportions of patients treated with HU or chronic exchange RBC transfusions. Emerging disease-modifying therapies for SCD (l-glutamine, crizanlizumab, and voxelotor) were not considered as comparators, as their use remains limited in the US [36]. Similarly, allogeneic HSCT was not considered as a comparator due to lovo-cel protocol specifications (exclusion of subjects with a willing matched sibling donor) [35] as well as the low proportion of patients with SCD for whom this treatment is an option [13].

Table 1 Model characteristics and key parameters

Other model settings were defined in accordance with US cost-effectiveness modeling guidelines and recommendations [30, 37, 38]. We used a lifetime time horizon to reflect the progressive, lifelong nature of SCD [37, 38]. The analysis perspective determines the scope of outcomes included; we considered co-base-case analyses from both a US third-party payer perspective (including patient health outcomes and direct medical costs only) and a US societal perspective (including caregiver quality-of-life impacts and indirect costs related to productivity loss and unpaid caregiving) [37,38,39]. Discount rates were used to calculate the present value of future costs and health outcomes [37]. The model was programmed in Microsoft Excel (RRID:SCR_016137) for Windows with Visual Basic for Applications (Microsoft Corporation).

2.2 Model Structure

According to the model framework (Fig. 1), a simulated cohort of individual patients meeting the target population criteria was created. Each individual patient was simulated twice, once assuming treatment with common care and once with lovo-cel. Accounting for baseline demographics and SCD status, the model used an annual cycle length to predict patient-level trajectories of acute events, chronic complications, and mortality over time.

Selection of the seven acute events and nine chronic complications included in the model (Table 1 and Fig. S1 in the Supplementary Information) was informed by the HGB-206 protocol-defined VOE endpoint, the SCD clinical and economic literature, and recommendations from clinician and patient advisors. Events in the HGB-206 VOE endpoint (vaso-occlusive crisis [VOC], acute chest syndrome [ACS], priapism, and splenic sequestration) were included in the model as separate events. The primary factors for selecting other events and complications for inclusion in the model were established precedent from prior SCD economic models and the strength of supporting evidence from the literature (see the Supplementary Information for additional details on our literature review). Additional patient-relevant outcomes, such as pain, fatigue, depression, and anxiety, were assumed to be reflected in the health-related quality-of-life (HRQOL) estimates used in the model. The fertility impacts of SCD and of the myeloablative conditioning required for autologous HSCT were not modeled, although fertility preservation costs were included for patients receiving lovo-cel.

The lovo-cel treatment effect was modeled over patients’ remaining lifetimes according to the achievement and maintenance of VOE-CR, reduction in VOEs relative to baseline for those without VOE-CR, and change from baseline in total Hb levels for all patients [15, 17]. The VOE treatment effect also included reduced frequency of severe VOEs as defined in the HGB-206 protocol [15, 35]. We assumed no reduction in VOEs during the first 6 months to account for the lovo-cel engraftment period. All VOE efficacy outcomes reflect HGB-206 TPVOE Group C data after central adjudication of clinician-identified VOEs.

Based on the assumption that VOE-CR represents a curative level of impact for patients receiving lovo-cel, our clinician advisors developed a categorization for the impact of lovo-cel on SCD events, complications, and mortality in which the age of treatment serves as proxy for preexisting disease-related morbidity (Fig. 2). Specifically, this framework categorizes events and complications into those covered by the VOE endpoint (VOC, ACS, priapism, splenic sequestration), those with evidence-based links to total Hb levels (stroke, pulmonary hypertension, and chronic kidney disease), those driven primarily by sickling blood cells and hemolysis (avascular necrosis, gallstones, and neurocognitive impairment [excluding due to overt stroke]), and those driven partly by sickling blood cells and hemolysis and partly by vascular damage (venous thromboembolism, retinopathy, heart failure, chronic lung disease, and leg ulcers). In the context of the framework presented in Fig. 2, direct risk reductions refer to treatment effects applied directly to event and complication risks (e.g., reduction in the rate of VOCs by virtue of the VOE-CR endpoint), and indirect risk reductions refer to those stemming from evidence-based relationships with other events or complications (e.g., reduction in the risk of avascular necrosis by virtue of not having a recent VOC hospitalization).

Fig. 2

Framework for lovo-cel’s impact on events, complications, and mortality. ACS acute chest syndrome, AVN avascular necrosis, CKD chronic kidney disease, Hb hemoglobin, HF heart failure, PH pulmonary hypertension, SCD sickle cell disease, VOE vaso-occlusive event, VOE-CR complete resolution of vaso-occlusive events, VTE venous thromboembolism. aThe VOE definition in HGB-206 clinical trial protocol also included acute hepatic sequestration. This event was not included in the analysis due to a lack of supporting evidence in the SCD clinical literature (see Supplementary Information for additional details)

The resulting framework for reductions in the risk of events, complications, and mortality for patients with VOE-CR reflects our clinically informed understanding of the relationship between the lovo-cel mechanism of action (erythroid precursor production of anti-sickling HbAT87Q) and disease pathogenesis through hemolysis, vaso-occlusion, and vasculopathy. For patients not achieving VOE-CR, partial reductions in VOE risk and increases in total Hb levels were linked to indirect reductions in the risk of other events, complications, and mortality based on evidence-based relationships identified in the SCD clinical literature. Regardless of VOE-CR status, the model does not assume that lovo-cel reverses any chronic complications present at the time of treatment. This clinician-informed framework is novel to our analysis and is intended to provide a balanced view of the potential long-term clinical benefits following lovo-cel therapy.

2.3 Model Parameters2.3.1 Clinical Parameters

The individual patients included in the modeled cohort were simulated from aggregated demographic and SCD status data from the HGB-206 TPVOE population (Table 1 and Table S2 in the Supplementary Information). Common care treatment use (HU, chronic RBC transfusions, or neither) at baseline was derived from published literature [40] and clinical opinion. For the common care arm, treatment use and associated clinical benefits were assumed to remain constant for the duration of the model.

Data on patients’ acute event histories and existing chronic complications at model entry were obtained from a combination of aggregated HGB-206 TPVOE baseline data (Table S2 in the Supplementary Information) and studies identified in the SCD clinical literature [41,42,43,44,45]. We relied on the SCD clinical literature to identify acute event incidence rates and chronic complication development probabilities, including differences by age and SCD genotype where available. We also identified studies presenting evidence on risk factors for and relationships among SCD events and complications (Table S7 in the Supplementary Information) [46]. We prioritized data from recently published studies to reflect the impact of contemporary HU and chronic transfusion use on SCD events and complications. However, for some events and complications, robust evidence on incidence rates and risk factors were available only from older, landmark SCD cohort studies (e.g., the Cooperative Study of Sickle Cell Disease [47]). A comprehensive presentation of all parameters for events and complications used in the model is provided in Tables S8 and S9 in the Supplementary Information.

Underlying SCD mortality was estimated by applying sex-specific SCD standardized mortality ratios (SMRs) for genotypes HbSS/Sβ0 derived from a landmark SCD cohort [3, 47,48,49] to age-, sex-, and race-specific general population mortality risks in the US [50]. Similar sex- and genotype-specific SMRs relative to the general US population were not identified for more contemporary SCD cohorts. To facilitate a more contemporary interpretation of this landmark SCD mortality data, we adjusted the SMRs to reflect mortality risks in the absence of VOCs [47, 49]. Acknowledging the likely presence of other SCD events and complications in the selected landmark SCD cohort, and to avoid potential double-counting across the range of risk factors for SCD mortality [44, 49, 51,52,53,54,55], we modeled additional increases in mortality risks associated only with a hospitalized VOC [52] and with multiple end-organ involvement [55]. Additional details and the specific SMRs used in the model are presented in Table S10 in the Supplementary Information.

2.3.2 Lovo-Cel Attributes

Table 1 presents the lovo-cel treatment effect parameters from the HGB-206 trial used in the model. Additional details on the HGB-206 trial data and statistical methodologies are presented in the Supplementary Information. Consistent with the lovo-cel mechanism of action and the available follow-up data through February 2023, our base-case analysis assumed that the lovo-cel treatment effect on VOEs (Table S3 in the Supplementary Information) and changes from baseline in total Hb levels (Table S4 in the Supplementary Information) persist for the remainder of patients’ lifetimes. The magnitude and durability of the VOE and total Hb treatment effects were varied in scenario analyses.

Patients achieving VOE-CR (i.e., 100% reduction) experienced reductions in the risks of other events, complications, and mortality according to the framework in Fig. 2. For primarily hemolytic events and complications, risks were assumed to be reduced by 95% (to a level approximating general population risks) for patients with VOE-CR regardless of the age of treatment with lovo-cel on the basis of the sustained hemolysis improvements observed in the HGB-206 clinical trial [17]. For partly hemolytic and partly vascular events and complications, the magnitude of risk reductions associated with VOE-CR was assumed to decline with increasing age of treatment (95% for patients aged 12–17 years, 85% for patients aged 18–30 years, and 70% for patients aged > 30 years), acknowledging that lovo-cel will not reverse existing vascular damage. Similar treatment age-dependent reductions in the underlying SCD SMRs were assumed for the base case. For patients achieving a partial resolution of VOEs (i.e., < 100% reduction), a more limited indirect treatment effect was modeled, informed by literature-based relationships (Tables S7–S10 in the Supplementary Information). Scenario analyses were conducted on the magnitude of the risk reductions reflected in this framework for the lovo-cel treatment effect on other events, complications, and mortality.

The HGB-206 trial also studied the impact of lovo-cel on patient-reported HRQOL outcomes [17, 56]. The improvement in patient-reported HRQOL observed in the trial was incorporated into the model as a lovo-cel-specific utility gain estimated from the change from baseline in EQ-5D-3L utility values observed in the HGB-206 trial (Table 1 and Table S5 in the Supplementary Information). Utility values are estimates valuing specific health states on a scale where 0 represents death and 1 represents perfect health. The utility gain for lovo-cel was assumed to apply for the remainder of patients’ lives. In scenarios with partial loss of the lovo-cel treatment effect, the lovo-cel utility gain decreased proportionally with the VOE effect.

Parameters describing the safety, costs, and other HRQOL impacts of lovo-cel are presented in Table 1. Safety was considered through the increased risk of mortality (e.g., from the risk of myelodysplastic syndrome or other hematologic malignancies [15, 17]) and the long-term HRQOL impact associated with myeloablative conditioning [57], which were assumed to last for the remainder of patients’ lives. The potential fertility impacts of myeloablative conditioning were captured via a proportion of patients opting for fertility preservation [57]. Other serious adverse events observed in the HGB-206 trial were largely concentrated during the transplantation hospitalization and thus assumed to be captured in the one-time costs and HRQOL impact [58] of transplantation. As an autologous HSCT, lovo-cel does not carry the risk of graft rejection or graft versus host disease. The one-time lovo-cel drug product acquisition price was set to the publicly available list price ($3.1 million) for the base-case analysis [59]. To illustrate the impact of potential rebates on the lovo-cel list price, we included a scenario analysis using the known federal Medicaid Prescription Drug Rebate Program’s statutory minimum rebate [60]. Lovo-cel administration costs (reflecting mobilization, apheresis, conditioning, and transplantation) were estimated from resource utilization observed in the HGB-206 trial (Table S6 in the Supplementary Information) and publicly available sources using a microcosting approach (Table S12 in the Supplementary Information). Annual monitoring costs also were estimated using a microcosting approach [57] (Table S13 in the Supplementary Information) and were assumed for a total of 15 years following lovo-cel treatment [15].

2.3.3 Costs and Health-Related Quality of Life

The direct SCD-related costs captured in the model included costs associated with common care treatments, costs per event for all acute events, and annual costs for all chronic complications. Costs for multiple events and complications present within the same annual model cycle were applied additively. In alignment with literature showing that annual direct costs for patients with SCD are highest between ages 18 and 30 years [61, 62], we applied age-specific multipliers to the costs for all acute events and chronic complications. Although lower annual costs observed in older age groups in the literature may reflect a severity bias (i.e., survivors are those with less severe disease), we chose to use these age-specific differences to balance concerns about double-counting with our additive approach for multiple events or complications. Data sources and parameter values for direct costs used in the base-case analysis are presented in Table S11 in the Supplementary Information. We did not include non-SCD-related direct medical costs during periods of extended survival in the base-case analysis. However, we did consider these costs in a scenario analysis.

Additional indirect costs reflected in the societal perspective included the value of unpaid caregiving and patient productivity impacts. Consistent with the impact of VOE-CR on event and complication risks, the model assumed reductions in unpaid caregiving commensurate with VOE reductions and complication status (100% reduction for patients with VOE-CR and no complications; 75% reduction for patients with VOE-CR and ≥ 1 complication). The model leveraged educational pathways research [63] to project that achieving VOE-CR would support educational and work productivity gains, resulting in higher annual earnings depending on the age at treatment. Specifically, patients achieving VOE-CR with lovo-cel prior to age 15 years (i.e., early enough to affect secondary educational outcomes) would have annual earnings equal to 92% (versus 56% for SCD overall) of race-adjusted general population earnings [63]. Those achieving VOE-CR with lovo-cel after age 15 years would have annual earnings equal to 78% of race-adjusted general population earnings [63]. Data sources and parameter values for indirect costs used in the co-base-case societal perspective are presented in Table S11 in the Supplementary Information. In a scenario analysis, we also included in the societal perspective the additional consumption costs associated with consumer expenditures during periods of extended survival for patients treated with lovo-cel.

The model captured the HRQOL impacts of SCD on both patients (in both co-base-case perspectives) and their caregivers (in the co-base-case societal perspective only) in the form of utility values [64, 65]. Health-related quality-of-life impacts for multiple events and complications present within the same annual model cycle were applied additively. We conservatively assumed one caregiver per patient in our base-case analysis. The impact of lovo-cel on caregiver quality of life was modeled using the same approach as for unpaid caregiving. Data sources and parameter values for patient and caregiver utilities are presented in Table S14 in the Supplementary Information.

2.4 Model Outcomes and Analysis2.4.1 Base-Case Analysis

We used the model to predict lifetime absolute and incremental health and economic outcomes for lovo-cel in comparison with common care for a simulated cohort of 2500 patients, a sample size that was found to be sufficient for convergence in predicted model outcomes (Fig. S7 in the Supplementary Information). Results are presented as the mean per patient across the cohort, with SDs (reflecting variability among patients) and 95% confidence intervals (CIs, reflecting confidence in the mean estimates) for selected outcomes. Survival was estimated in terms of (undiscounted) life-years and age at death. Total (discounted) QALYs, a composite metric accounting for quantity and quality of life, were disaggregated into those attributable to SCD overall, gains associated with treatment, losses due to events and complications, and losses by caregivers. Total (discounted) costs were similarly disaggregated. Additional health outcomes included cumulative lifetime VOCs (the most frequent of the events in the HGB-206 VOE protocol definition) and development of chronic complications. We also estimated the equal value life-year (evLY) and health years in total (HYT) outcomes as alternatives to the QALY outcome [66, 67].

The primary outcome used to estimate the cost-effectiveness of lovo-cel compared with common care was the incremental cost per QALY gained. Incremental costs per evLY gained and per HYT gained were also reported. Due to the limitations of ratio-based outcomes, we estimated the net monetary benefit (NMB) outcome, which monetizes the benefits of a new intervention by applying a willingness-to-pay (WTP) threshold to QALY gains net of associated costs [68]. We considered WTP thresholds ranging from $50,000 to $200,000 per QALY gained [38], with the upp