Cost/effectiveness of elivaldogene autotemcel vs. hematopoietic stem cells transplantation in patients with cerebral adrenoleukodystrophy (CALD)

Abstract

Cerebral adrenoleukodystrophy (CALD) is a severe, rare neurological disease with a progressive course and poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is still considered the standard of care for CALD. Elivaldogene autotemcel is a novel gene therapy for the treatment of childhood-onset CALD. Since many novel gene therapies are associated with high costs, our aim was to compare costs and effectiveness of elivaldogene autotemcel with the costs and effectiveness of allogeneic HSCT treatment of childhood-onset CALD. The analysis used an 80-year horizon and the perspective of the Serbian Republic Health Insurance Fund. Quality-adjusted life years (QALYs) gained with elivaldogene autotemcel and HSCT, as well as direct treatment costs, were our major outcomes. For the purposes of the economic analysis, we constructed and simulated a discrete-event simulation model to calculate the outcomes. We obtained the results of the model using a Monte Carlo simulation, which we conducted on 1000 virtual CALD patients. The analysis indicated that elivaldogene autotemcel was not cost-effective when compared to HSCT, and the net monetary benefit was negative. The base case incremental cost/effectiveness ratio was 259,848,512 RSD/QALY. Elivaldogene autotemcel is not more cost-effective than HSCT for the treatment of CALD from the perspective of the Serbian Republic Health Insurance Fund, according to classic pharmacoeconomic analysis and criteria. To ensure that the treatment is affordable for all patients for whom it is prescribed, a differentiated pricing strategy with lower drug prices in developing nations seems to be required.

Keywords:

• Cerebral adrenoleukodystrophy
• elivaldogene autotemcel
• cost-effectiveness analysis
• insurance
• health

Introduction

Adrenoleukodystrophy is a disorder of peroxysomes, which is manifested by dysfunction of peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 [1]. Since very long chain saturated and branched fatty acids cannot enter the peroxysomes in sufficient quantity, they avoid peroxysomal beta-oxydation and are being accumulated in the cytoplasm. Lipid droplets could be found in almost all cells of the human body, but tissues that suffer the worst consequences are the adrenal glands and glial cells in the nervous system, resulting with adrenal insufficiency and demyelination [2]. The cause of this inherited disease are mutations of the ABCD1 coding gene on the X-chromosome: men are affected with more severe disease forms than women, who have to be homozygous for the mutated gene to develop the most debilitating clinical picture. There are several clinical forms of adrenoleukodystrophy: Addison-only (AOLD), Cerebral adrenoleukodystrophy (CALD), Adrenomyeloneuropathy (AMN) and Asymptomatic form (AS) [3]. CALD that affects children is the most difficult form, usually becoming visible in boys around their six to eight years of age; it is characterized by rapid and progressive clinical course, with neurological deterioration and transition to almost vegetative state in just four to five years [1–3].

The first inaugurated disease-modifying therapy of CALD, which is currently considered to be the treatment standard, was allogeneic hematopoietic stem cell transplantation (HSCT) [4]. Although the mechanism of HSCT action is not yet clear, significant prolongation of survival and delay of neurological deterioration were demonstrated in clinical trials if HSCT was administered early enough [5]. However, the HSCT cannot cure the disease or lead to survival comparable to that of unaffected children [6]. Recently, further improvement in therapy of CALD was achieved with infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector encoding ABCD1 cDNA [7], which further prolonged survival for more than two years. A new variant of elivaldogene autotemcel (Skysona®) gave even better results, and in 2021 it received marketing authorization by the United States Food and Drug Administration (FDA) for treatment of childhood-onset CALD. Problems in the treatment of patients with CALD are created by extremely high cost of causal therapy with elivaldogene autotemcel (about 3 million US dollars per patient for complete one-time treatment), and its low availability, especially in developing countries [8].

In order to evaluate the costs, effects and justification of the application of a new drug or other health technology to a wide population, it is necessary to conduct an analysis of the relationship between the costs and the effects of the new drug compared to the standard method(s) of treatment (the cost-effectiveness analysis). The analysis of the ratio of costs and effects implies a detailed determination of all treatment costs and the total effect corrected for the achieved quality of life. By comparing the ratio of costs and effects of a new drug or health technology with the old (standard) treatment, incremental costs and incremental effects are obtained, which gives an estimate of how much it is necessary to pay additionally for the gain in terms of life adjusted for quality per person. This assessment enables rational decision-making on the financing of new drugs or other health technologies at the level of society as a whole.

In addition to the need for satisfactory efficacy and safety, during the registration of each new drug, it is also necessary to raise the question of its cost-effectiveness. The cost-effectiveness of drugs for the treatment of rare diseases must also be examined. The issue of the cost-effectiveness of elivaldogen autotemcel in the treatment of CALD is controversial [9]. Shortly after receipt of marketing authorization for elivaldogene autotemcel in the European Union, the producer decided to leave this market and requested from the European Medicine Agency (EMA) to withdraw the marketing authorization, which was subsequently carried out by EMA [10]; the reason for withdrawal was failure to make an agreement with European payers on reimbursement. Medicines for the causal treatment of rare diseases are very expensive and represent a significant burden on patients, their caregivers and families, health insurance funds, and health systems [11,12]. Therefore, it is important to test whether and how health systems around the world can cope with such a burden. This especially applies to developing countries, which have limited budgets for the health system. Therefore, our aim was to compare the cost-effectiveness of elivaldogene autotemcel with HSCT treatment of childhood-onset CALD in the economic conditions prevailing in an upper-middle-income European country such as the Republic of Serbia.

Methods

The authors’ pre-established plan for the cost/effectiveness analysis was followed for conducting this study. The summary of the study plan is the following. The aim of the study was to evaluate the cost-effectiveness of elivaldogene autotemcel in comparison to HSCT in patients with childhood-onset CALD. The study was be conducted using the Discrete-Event Simulation (DES) model, which represents the pathway of the CALD and whose states may change only at discrete moments in time [13,14]. The model, which was considered from the perspective of the Republic Health Insurance Fund (RHIF) of Serbia with one-month increments and an 80-year time horizon [14], only took direct costs into account. Costs and quality-adjusted life years (QALYs) were discounted starting in year 2 at a rate of 5.25% annually. The study population was be composed of patients suffering from childhood-onset CALD. The model was be simulated for 1000 virtual patients in each subgroup using the Monte Carlo method. We performed one-way and probabilistic sensitivity analyses with to test the robustness of the model. The predicted power of the study was greater than 0.99. The study plan is available in detail at the following link: https://osf.io/27h5s/?view_only=38c3b0987417445b80f2cb3f57970f43.

The study cohort consisted of both male and female patients with progressing form of CALD with disease onset at an age between 2 and 10 years. The study’s context was the state-owned healthcare system in Republic of Serbia, based on obligatory health insurance managed by the Republic Health Insurance Fund (RHIF) [15,16].

The intervention tested in CALD patients for cost-effectiveness was elivaldogene autotemcel; its comparison in this study was HSCT, which was the only other available causal treatment option [17]. Great diversity of natural course of childhood-onset CALD led to the establishment of a temporal horizon of 80 years [18]. Table 1 displays the model inputs, variability and evidence used to support the inputs. Table 1 lists the model inputs, variability and references supporting the inputs.

Table 1. The model inputs.

Input parameter	Basecase value with variability (± SD*)	Probability sensitivity analysis value	References
Time delay of unfavourable events in patients with childhood-onset CALD if treated with elivaldogene autotemcel (months)	30.0 ± 8.0	Inverse normal distribution (mean 30.0, SD 8.0)	Eichler et al. [17]
Mean age in months of a child with CALD when hemisyndrome is acquired	130.0 ± 20.0	Inverse normal distribution (mean 130.0, SD 20.0)	Raymond et al. [5]
Mean age in months of a child with CALD when it experiences cognitive deterioration	118.0 ± 24.0	Inverse normal distribution (mean 118.0, SD 24.0)	Kühl et al. [19]
Mean age in months of a child with CALD when it starts falling due to cerebellar dysfunction	122.0 ± 24.0	Inverse normal distribution (mean 122.0, SD 24.0)	Pierpont et al. [20]
Mean age in months of a child with CALD when it starts having pyramidal signs	180.0 ± 20.0	Inverse normal distribution (mean 180.0, SD 20.0)	Pereira et al. [21]
Mean age in months of a child with CALD when it starts having bilateral sensitive loss	170.0 ± 20.0	Inverse normal distribution (mean 170.0, SD 20.0)	Matos et al. [22]
Mean age in months of a child with CALD when it loses vision	175.0 ± 25.0	Inverse normal distribution (mean 175.0, SD 25.0)	Kanakis and Kaltsas [23]
Mean age in months of a child with CALS it starts having hearing impairment	140.0 ± 20.0	Inverse normal distribution (mean 140.0, SD 20.0)	Eichler et al. [17]
Mean age in months of a child with CALS it starts having adrenal insufficiency	96.0 ± 18.0	Inverse normal distribution (mean 96.0, SD 18.0)	Eichler et al. [17]
Mean age in months of a child with CALD when death occurs	253.0 ± 45.0	Inverse normal distribution (mean 253.0, SD 45.0)	Eichler et al. [17]
Initial quality of life of CALD	1	Inverse beta distribution (α = 99, β = 1)	Assumption
Quality of life decrement due to hearing impairment	0.027 ± 0.002	Inverse beta distribution (α = 2.7, β = 97.3)	Tordrup et al. [24]
Quality of life decrement due to loss of vision	0.244 ± 0.034	Inverse beta distribution (α = 24.4, β = 75.6)	Lloyd et al. [25]
Quality of life decrement due to mental impairment	0.048 ± 0.012	Inverse beta distribution (α = 4.8, β = 95.2)	Fattori et al. [26]
Quality of life decrement due to motor incoordination and falls	0.042 ± 0.008	Inverse beta distribution (α = 4.2, β = 95.8)	Chittrakul et al. [27]
Quality of life decrement due to pyramidal syndrome and spasticity	0.276 ± 0.024	Inverse beta distribution (α = 27.6, β = 72.4)	Ozkan [28]
Quality of life decrement due to hemiplegia	0.120 ± 0.025	Inverse beta distribution (α = 12.0, β = 88.0)	Zhang et al. [29]
Quality of life decrement due to sensory loss	0.080 ± 0.015	Inverse beta distribution (α = 8.0, β = 92.0)	Zhang et al. [29]
Quality of life decrement due to cerebellar dysfunction	0.220 ± 0.020	Inverse beta distribution (α = 22.0, β = 78.0)	Lopez/Bastida et al. [30]
Direct costs per month per patient for treating hearing impairment in Serbia	4,422 ± 682 RSD	Inverse gamma distribution (α = 16, β = 276)	McDaid et al. [31]
Direct costs per patient for treating blind person in Serbia	15,498 ± 2,714 RSD	Inverse gamma distribution (α = 16, β = 969)	Marques et al. [32]
Direct costs per month of mental disability in Serbia	6,881 ± 1,200 RSD	Inverse gamma distribution (α = 16, β = 430)	Shahat and Greco [33]
Direct costs per month per patient for treating child with spasticity in Serbia	13,838 ± 2,439 RSD	Inverse gamma distribution (α = 16, β = 865)	de Lissovoy et al. [34]
Direct costs per month of treating hemiplegia in children	945 ± 114 RSD	Inverse gamma distribution (α = 16, β = 59)	Beecham et al. [35]
Direct costs per month of treating sensory loss	5,995 ± 1,400 RSD	Inverse gamma distribution (α = 16, β = 375)	Happich et al. [36]
Direct costs per month of treating cerebellar dysfunction	64,398 ± 7,800 RSD	Inverse gamma distribution (α = 16, β = 4,025)	Lopez/Bastida et al. [30]
Unit cost of elivaldogene autotemcel (Skysona):	324,570,900 RSD	Inverse gamma distribution (α = 16, β = 20,285,000)	Liu [37]
Gross Domestic Product per capita in Serbia 2021	RSD 917,441.90	n.a.	Statistical Office of the Republic of Serbia [38]
Referent interest rate – National Bank of Serbia in 2022	5.25%	n.a.	National Bank of Serbia [39]

*SD- standard deviation.

QALYs and direct costs of treatment were the main study outcomes. We calculated the number of QALYs gained by multiplying the time a patient spent in a certain disease state by the health utility value of that state, after which we summed the values thus obtained for each health state the patient experienced during their lifetime. In the direct costs of treatment, we included the price of drugs, diagnostic and therapeutic health services, medical materials, and the costs of diagnosing and treating adverse reactions to drugs. In order to determine resources, either cost-effectiveness studies that had already been published or clinical practice recommendations for the treatment of CALD were used. The RHIF’s Tariff Book [40] served as the source for unit pricing for medical services, and the RHIF’s List of Reimbursable Drugs [15] or the Republic of Serbia’s government’s Decision on Maximum Prices of Medicines [16] served as the source for unit pricing for medications. Dinars of the Republic of Serbia (RSD) were used to calculate all costs. The expected resource amounts and unit costs for 2023 were used. Costs were converted from foreign currency to RSD using the midpoint exchange rate of the National Bank of Serbia, which was in force on the date that the primary data were published or collected. For the conversion, we used the official average exchange rates of the National Bank of Serbia for the month of March 2023, according to which 1 euro equalled 117.3144 RSD, while 1 US dollar had a value of 109.5281 RSD [41]. Starting in the second year after entering the model, a fixed annual discount rate of 5.25% was applied to both the costs and the QALYs gained [39]. This discount rate corresponds to the reference interest rate established by the National Bank of Serbia in 2023. The costs and gains of health care interventions are discounted at the same rate, since the resources used for healthcare could have been invested elsewhere and yielded a return. The net monetary benefit (NMB), which is determined as the difference in QALYs gained * willingness to pay - difference in costs, and the incremental cost-effectiveness ratio (ICER) were the outcomes of the study [14].

For the purpose of the study, we created a pharmacoeconomic model based on the principles of Discrete-Event Simulation (DES) model [13,14,42]. Virtual patients with childhood-onset CALD were the entities of our model, while their basic characteristics were the disease onset age, signs and symptoms of neurological decline, and the projected positive and negative consequences of the treatment. The main events in the model were changes in the patients’ health status. Time was separated into equal segments in the model; hence, a fixed increment was utilized to simulate patient progression across time. The simulation clock employed fixed one-month increments. Spreadsheets were used to develop the model, while its simulation was done using a macros created by the last author (SJ) in Virtual Basic. A graphic representation of the model is shown in Figure 1.

Figure 1. Graphic representation of the model. Rectangles in the graph represent events that may happen during the model horizon, which bear costs and influence quality of life. At each subsequent monthly cycle, it is checked within the model simulation whether each event would happen or not (depending on the time set in advance for onset of each event). The model ends when all of 480 cycles are completed.

A deterministic, one-way, one-factor sensitivity analysis was carried out for the input variables in the model that the authors believed to be the most important, and a Tornado diagram was generated. The results of a probabilistic sensitivity analysis (PSA) that was also conducted are tabulated. In order to conduct the PSA, input variables were entered as inverse distributions of probability density instead of single numbers; for costs, the gamma distribution was used, and for effects, the beta distribution; while continuous variables were entered as an inverse normal distribution. After entering distributions, the results of the PSA were obtained by Monte Carlo simulation. The price of elivaldogene autotemcel when it becomes cost effective was determined using the tipping points approach.

Results

Base case

The base case Monte Carlo microsimulation for 1000 virtual patients gave an average cost per patient treated with elivaldogene autotemcel of 331,717,102 ± 181,731 RSD (99% CI) and an average number of QALYs gained 9.68 ± 0.06.According to the same simulation, the average cost per patient receiving HSCT was 17,125,113 ± 209,267 RSD (99% CI), and the average number of QALYs gained was 8.43 ± 0.04.

The incremental cost-effectiveness ratio (ICER) of elivaldogene autotemcel per additional QALY versus HSCT (Figure 2) was 259,848,512 ± 23,680,857 RSD (99% CI), whereas the net financial benefit was negative at −313,439,304 ± 314,951 RSD (99% CI). The tipping point analysis revealed that for elivaldogene autotemcel to be cost-effective, its price would need to be cut to 3.3% of its current price under the willingness to spend one GDP per capita per QALY (see Supplemental Figure S1).

Figure 2. Base case ICERs for all virtual patients. The x-axis: difference in QALYs gained (elivaldogene autotemcel vs HSCT); the y-axis: difference in costs (elivaldogene autotemcel vs HSCT). The line lambda 1 – the RHIF’s willingness to pay one Gross Domestic Product (GDP) per capita for one more QALY gained with elivaldogene autotemcel in comparison to the HSCT. The line lambda 2 – the RHIF’s willingness to pay three GDPs per capita for one more QALY gained with elivaldogene autotemcel in comparison to the HSCT. The line lambda 3 – the RHIF’s willingness to pay nine GDPs per capita for one more QALY gained with elivaldogene autotemcel in comparison to the HSCT.

Acceptability curve

The changes in the percentage of virtual patients from the Monte Carlo simulation who fall below the current willingness to pay line in the ICER diagram (i.e. the likelihood that elivaldogene autotemcel is cost-effective compared to HSCT) could be inferred from the acceptability curve if RHIF is willing to pay between 200,000 and 300,000,000 RSD for each additional QALY gained. However, even with values of willingness to pay up to the 300 million RSD (approximately 2,700,000 €), all virtual patients from the simulations were significantly over the highest willingness-to-pay line (at 9 GDPs per capita/QALY). These findings imply that, independent of the willingness-to-pay value, the probability of elivaldogene autotemcel cost-effectiveness is below 50% (Figure 3).

Figure 3. Acceptability curve showing probability that elivaldogene autotemcel is considered cost/effective for treatment of CALD in comparison with HSC transplantation, which depends on willingness to pay for one additional QALY by the health insurance fund.

One-way sensitivity analysis

The input variable values were varied by 25% for each one using a one-way sensitivity analysis, and the NMB for each of the different values was determined. For clarity, the Tornado diagram shows only six of the most influential variables (Figure 4). A one-way sensitivity analysis reveals that the cost of elivaldogene autotemcel and the effectiveness of its life-extension have the greatest impacts on the drug’s NMB, i.e. its cost-utility. Even when these variables have extremely favourable values, elivaldogene autotemcel does not become cost-effective since the NMB is still negative.

Figure 4. Tornado diagram showing results of one-way deterministic sensitivity analysis The bars in the graph represent variations of net monetary benefit caused by increase and subsequent decrease of model inputs listed in the right part of the graph.

Probabilistic sensitivity analysis (PSA)

The cost variables were described by the gamma distribution (because its values were only positive), and the rate and utility variables by the beta distribution (this form of distribution is suitable for binomial data, which are estimating proportions). The time to events in the model was described using the normal distribution. After adding the distributions as input variables to the model, it was simulated to produce PSA results. After the Monte Carlo microsimulation, the values of the output variables were similarly dispersed as in the base case (Figure 5), and the mean values of the output variables also did not significantly deviate from the base case (Table 2). The PSA confirmed that elivaldogene autotemcel is not more cost-effective than HSCT for treating CALD with childhood onset from the perspective of the Serbian RHIF, due to consistently supra-threshold ICER values and negative net monetary benefit values.

Figure 5. Probability sensitivity analysis ICERs for virtual patients. The x-axis: difference in QALYs gained (elivaldogene autotemcel vs HSCT); the y-axis: difference in costs (elivaldogene autotemcel vs HSCT). The line lambda 1 – the RHIF’s willingness to pay one Gross Domestic Product (GDP) per capita for one more QALY gained with elivaldogene autotemcel in comparison to the HSCT. The line lambda 2 – the RHIF’s willingness to pay three GDPs per capita for one more QALY gained with elivaldogene autotemcel in comparison to the HSCT. The line lambda 3 – the RHIF’s willingness to pay nine GDPs per capita for one more QALY gained with elivaldogene autotemcel in comparison to the HSCT.

Table 2. Values of main output variables before and after the PSA (mean ± 99% confidence interval).

Output variables	Base case	PSA
ICER	259,848,512 ± 23,680,857 RSD	212,620,811.86 ± 250,155,384.37 RSD
Net monetary benefit	−313,439,304 ± 314,951 RSD	−315,821,281.03 ± 6,774,638.52 RSD

Discussion

Our study showed that elivaldogene autotemcel was not cost-effective when compared to HSCT for the treatment of childhood-onset CALD in the socioeconomic circumstances of the Republic of Serbia, an upper-middle-income Southeast European economy. One-way and probabilistic sensitivity analysis revealed that elivaldogene autotemcel was more effective than HSCT for CALD, but it was also much more expensive and linked to negative net monetary benefit values.

The clinical superiority of elivaldogene autotemcel in the treatment of patients with CALD compared to HSCT has been proven in clinical studies [43]. The use of elivaldogene autotemcel provides 24-month survival without major functional disabilities in 90% of CALD patients, while this level of efficiency was recorded in 67% of CALD patients receiving HSCT [43]. In addition, identifying a suitable donor is the most crucial step in HSCT [43]. Given how rapidly disease progresses, the period of time that it takes to identify a donor is often unacceptable [43]. Furthermore, HSCT is not possible in some CALD patients for whom there is no suitable donor [43]. Elivaldogene autotemcel, as an ex vivo gene therapy based on the patient’s own cell harvesting, has no such restrictions in its use [43]. Elivaldogene autotemcel also has a significantly more favourable safety profile compared to HSCT [43]. It is known that HSCT carries with it an increased risk of adverse life-threatening conditions such as opportunistic infections, acute or chronic graft-versus-host disease, graft failure and treatment-related mortality overall [5]. On the other hand, in about 10% of patients who receive elivaldogene autotemcel, adverse effects such as pancytopenia, vomiting and viral cystitis can be expected, while there is no reported graft failure or rejection, graft-versus-host disease or treatment-related mortality [43].

CALD carries a significant clinical, social and economic burden [43]. The irreversible progression and devastating nature of CALD have a serious impact on both patients and their families [42]. Kuratsubo et al. [44] showed that parents of children with CALD have a high risk of developing depressive disorders and neuroses. In addition, some of the parents, after the onset of CALD in their children, also developed some somatic damage and diseases that can be associated with stress and increased effort, such as duodenal ulcer, irritable colon, lumbar strain and herniated lumbar disc [44]. The results of that study also showed that the development of CALD in children often leads to disruption of the relationship between family members, and other social problems [44]. Families with children who have CALD experience severe financial hardships because of the rising costs of patient care as well as the decline in income brought on by the parents’ limited ability to work or job loss [44]. Even in the case of the implementation of HSCT, this psychological, economic and social burden on parents and caregivers of children with CALD is not negligible, given that part of these patients can expect the need to repeat transplantation due to graft rejection [43].

It is obvious that the unfavourable pharmacoeconomic profile of elivaldogene autotemcel is mainly due to its extremely high price, which amounts to about 3 million dollars [8]. However, the influence of other factors is not negligible either, primarily those originating from large differences in the prices of health services between highly developed and developing countries. We conducted the study in the pharmacoeconomic conditions that prevail in the Republic of Serbia, where the prices of health services are significantly lower compared to the prices of the same services in more developed countries of the world [14,42]. Because elivaldogene autotemcel significantly improves patients’ quality of life and decreases the need for supportive therapy [43], high-income countries can be expected to have a much more favourable pharmacoeconomic evaluation of the clinical effectiveness of this drug in treating patients with CALD. It should be noted that the economic burden of treating CALD in high-income countries was extremely high even before the development of causal therapy. In a 2012–2018 claims database examination of 14 patients with CALD in the United States, the cost per patient for HSCT and the first year of care post-treatment ranged from $118,912 to $ 2,327,603 with a median of $588,233 [45].

Elivaldogene autotemcel is not the only orphan drug for which pharmacoeconomic analyses have shown lack of cost-effectiveness. Pharmacoeconomic evaluations based on traditional cost-effectiveness criteria have shown that new causal therapies for the treatment of Pompe disease [46], Niemann-Pick disease type C [14] and late-infantile neuronal ceroid lipofuscinosis type 2 [42] are also not cost-effective. Given the basic humanitarian and egalitarian principles as well as the principle of health care that all patients have the right to the best available therapy and care [47], it is necessary that pharmaceutical companies, health insurance funds and associations for the treatment of rare diseases find ways to make these drugs available to all patients for whom their use is indicated.

We were unable to determine the price of elivaldogene autotemcel in the Republic of Serbia because it is not registered this country. As a result, we had to use the pricing information that was available from the manufacturer, which was the study’s primary limitation. Due to the lack of published data from Western Balkan countries, another limitation is the fact that the majority of the utility inputs in our study came from developed nations. This may have overestimated gains in QALYs, as the living conditions for ill children are more resource-constrained in Serbia than in developed nations. Our inputs, however, were only based on reliable evidence from systematic reviews, clinical trials, and large observational studies in order to strengthen the model’s accuracy.

Conclusions

The results from this analysis showed that elivaldogene autotemcel is not a cost-effective option for treating childhood-onset CALD in the socioeconomic context of the Republic of Serbia at the current pricing compared to symptomatic therapy. Given the drug’s efficacy in treating people with severe forms of the disease, pharmaceutical companies, health insurance providers and national organizations for the treatment of rare diseases should seek a way to make elivaldogene autotemcel available to all CALD patients for whom it is indicated.

Author contributions

Conception, study design, analysis and data interpretation: JS, MM and VM; Software: JS; Visualization: MM; Validation: JS; Funding acquisition: JS, MM; Writing – original draft: JS, MM and VM; Writing – review and editing: JS. All authors agree for the final version of the manuscript to be published.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings reported in this study are available from the corresponding author upon reasonable request.

Additional information

Funding

The study was financially supported by Serbian Ministry of Science, Technological Development and Innovations, contract No 451-03-65/2024-03/200111.