Pioneering SMA therapies for all types: survival gains, cost dynamics, and performance-based agreements

Abstract

Background

The purpose of this study was to assess the impact of survival improvements and performance-based managed entry agreements (PBMEAs) on the cost implications of introducing innovative spinal muscular atrophy (SMA) treatments, nusinersen, onasemnogene abeparvovec, and risdiplam, for managing SMA Types 1, 2, and 3 from the perspective of the Saudi Ministry of Health (MoH).

Methods

A budget impact model was created using inputs such as total population, market share, median survival, and resource utilization obtained through literature review and validated by expert committees. The model projected the overall cost (drug acquisition, administration, and disease management) for best supportive care (BSC) with and without these interventions over a 5-year period using Microsoft Excel as the analytical tool.

Results

For SMA Type 1, the overall net budget impact of introducing onasemnogene abeparvovec, nusinersen, or risdiplam was significant, ranging from 112 to 225%. The impact was even greater for SMA Type 2 and 3, ranging from 171 to 283% due to high survival rates. However, the budget impact could be mitigated by improved clinical management and PBMEAs, reducing it to 77–84% for Type 1 and 36–117% for Types 2 and 3.

Conclusion

the introduction of these pioneering interventions for SMA management would raise the overall budget for the payer, primarily due to drug acquisition costs. Nevertheless, this increase could be offset by improvements in clinical management and PBMEAs.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12962-025-00647-3.

Background

Spinal muscular atrophy (SMA) is a hereditary autosomal recessive disorder that affects nerves and muscles, causing muscles to become increasingly weak. It stems from the mutation in the survival-motor neuron-1 (SMN1) gene located on chromosome 5q of the human genome [1–4]. The SMN1 gene encodes the SMN protein that is crucial for maintaining specialized nerve cells known as motor neurons responsible for regulating voluntary muscle movements [5, 6]. The absence of the SMN protein triggers the deterioration of alpha motor neurons from the ventral grey horn of the spinal cord resulting in a spectrum of symptoms, such as muscle weakness, atrophy, and, in severe instances, paralysis, causing difficulty in sitting, standing, and walking [7, 8].

SMA is divided into five distinct types, Type 0, Type 1, Type 2, Type 3, and Type 4, based on disease severity and the age of onset. Type 0 is the most severe form with an onset in the uterus, leading to death before 6 months of age. The age of onset for Type 1, 2, and 3, respectively is less than 6 months, 6–18 months, and greater than 18 months. Type 4 occurs during adulthood [2, 6]. Type 1, being the most prevalent, constitutes around 45% of all SMA cases [6, 9]. Infants diagnosed with SMA Type 1 lack the ability to sit, stand, or walk independently and require assistance even for essential functions such as breathing, mucus clearance, nutrition, and mobility [10]. Additionally, SMA-related respiratory illness makes them vulnerable to pneumonia and may necessitate hospitalization [11]. Babies with SMA Type 2 can sit unaided but can’t stand or walk independently as muscle weakness affects the lower limbs more than the upper limbs. It accounts for 20% of SMA cases. They usually have respiratory complications but can live to young adulthood or beyond. Children with SMA Type 3 often develop foot deformities, respiratory muscle weakness, or lose the ability to stand or walk in their adolescence or adulthood while SMA Type 4 patients can maintain their ambulation throughout their life [12, 13].

Globally, the prevalence of SMA (all types) is about 1–2 in 100,000 and incidence is around 10 in 100,000 live births with high mortality and morbidity rates [6]. However, in Middle Eastern countries, the prevalence rate of SMA has been reported to be higher compared to other countries of the world. This could be attributed to the practice of consanguineous marriages in these countries. For instance, the carrier frequency of the mutated SMN1 gene among Saudi individuals is 2.6% with an incidence rate of 32 per 100,000 births which is significantly higher in comparison to the globally reported incidence rate of SMA [14].

Though SMA is a rare disease, its impact on the patient’s quality of life and economic and emotional impact on the family is huge. SMA majorly hampers the physical functioning of the patients which substantially impairs their overall quality of life [15]. Moreover, as SMA patients need constant care and support throughout their lives, the economic burden of the disease on caregivers and/or payers is immense. For SMA Type 1, the annual average cost of illness has been estimated to range from $75,047 to $196,429 per year, and for SMA Type 2, 3, and 4 combined, the value ranged from $27,157 to $82,474 per year. These costs are exclusive of the drug costs for SMA treatment and only include the supportive care (healthcare and non-healthcare costs) [16].

Until recently, SMA patients have been managed only through best supportive care (BSC) as there were no specific treatments available. However, in the last 7–8 years, three first-in-class interventions have been introduced for the treatment of SMA. In 2016, the first disease-modifying therapy, nusinersen, was approved for SMA. Nusinersen contains an antisense oligonucleotide that targets mutations occurring on chromosome 5q. It binds with the RNA and regulates gene expression, thereby augmenting the levels of functional SMN protein in SMA patients [17–19]. Subsequently, in 2019, the first gene replacement therapy, onasemnogene abeparvovec, was approved for SMA patients under 2 years of age [20]. Onasemnogene abeparvovec is a vector-based gene therapy that delivers a functional copy of the SMN1 gene [21]. In 2020, the first orally administered medication, risdiplam obtained approval for treating SMA patients aged 2 months and above [22]. It is known to elevate systemic SMN protein concentrations by enhancing the efficiency of transcription of the SMN2 gene [22]. SMN2 gene also expresses SMN protein but in very low quantities to that of SMN1 gene. SMA severity is highly dependent on the number of SMN2 gene copies in an individual [12].

In the Kingdom of Saudi Arabia (KSA), the availability of these three first-in-class interventions is a significant advancement in the ongoing efforts to address and manage SMA. However, these treatments also increase the overall cost of SMA management. All three drugs are registered in the KSA and per unit costs around SAR 394,762.5 for nusinersen, SAR 7,984,675.90 for onasemnogene abeparvovec, and SAR 46,543.40 for risdiplam as per the Saudi Food and Drug Authority (SFDA) database.

As the KSA healthcare system is undergoing a transformation towards value-based care as part of its National Transformational Program 2020, economic evaluations of new health technologies are also increasing to improve overall healthcare quality and effectiveness. Therefore, a budget impact analysis is necessary to provide decision-makers with evidence-based research to inform them about the impact of new healthcare interventions on population outcomes and the overall budget from the payer’s perspective.

The objective of this study was to assess the budgetary implications of the three interventions for the management of SMA from the Saudi Ministry of Health’s (MoH) standpoint. The specific goals included comprehending the overall treatment costs associated with different SMA interventions, determining the net-budgetary impact of SMA interventions when compared to best supportive care for SMA Type 1, 2, and 3, and examining the effects on both direct medical costs and other related expenses.

Model structure

A budget impact model (BIM) was developed specifically from the perspective of Saudi MoH to estimate budgetary implications associated with the introduction of onasemnogene abeparvovec, nusinersen, and risdiplam with BSC in a healthcare setting catering to SMA Types 1, 2, and 3 patients. The model estimated the total costs for a world with and without these interventions and presented the net budget impact. The analysis spanned a period of 5 years (from 2021 to 2025) with Microsoft Excel as the primary tool for comprehensive evaluation.

Scenario analysis

The following distinct scenarios were evaluated using the BIM. In addition to assessing each intervention against the BSC, this study also compares the newly introduced treatments—onasemnogene abeparvovec and risdiplam—with nusinersen plus BSC, which serves as the standard of care (SOC). This comparison is necessary because nusinersen is already included in the KSA formulary, and some patients were receiving this treatment at the time of the study.

For SMA Type 1,

• Scenario I: The introduction of either nusinersen, risdiplam, or onasemnogene abeparvovec with BSC versus BSC alone.

• Scenario II: The introduction of onasemnogene abeparvovec with nusinersen and BSC as the SOC versus nusinersen and BSC.

• Scenario III: The introduction of onasemnogene abeparvovec or risdiplam with nusinersen and BSC as the SOC versus nusinersen and BSC.

For SMA Type 2 (under 2 years of age),

• Scenario IV: The introduction of onasemnogene abeparvovec with BSC versus BSC alone.

• Scenario V: The introduction of onasemnogene abeparvovec or risdiplam with nusinersen and BSC as the SOC versus nusinersen and BSC.

For SMA Type 2 (all ages) and Type 3 combined,

• Scenario VI: The introduction of either nusinersen or risdiplam with BSC versus BSC alone.

• Scenario VII: The introduction of both nusinersen and risdiplam with BSC versus BSC alone.

Population

The study encompassed individuals with SMA Type 1, Type 2 (under 2 years of age) as well as SMA Types 2 (all ages) and 3, eligible for treatment as specified by the Saudi MoH (Table 1 and Table S1). The total SMA patients (all SMA types collectively) population per year, eligible for treatment in the 5-year period, included 173, 177, 181, 186, and 190 patients, respectively.

Table 1.

Model inputs

Parameters	Value	Source
Patient population (N)		MoH database
SMA Type 1	388
SMA Types 2 (all ages) and 3	519
Market Share		Assumed based on experts’ opinion
SMA Type 1
World with Onasemnogene abeparvovec + BSC	3%-7%
World with Nusinersen + BSC	15%-25%
World with Risdiplam + BSC	48%-62%
World with Onasemnogene abeparvovec and Nusinersen + BSC	3%-17%
World with Onasemnogene abeparvovec, Risdiplam, and Nusinersen + BSC	3%-37%
SMA Type 2 (under 2 years of age)
World with Onasemnogene abeparvovec + BSC	0%-20%
World with Onasemnogene abeparvovec, Risdiplam, and Nusinersen + BSC	0%-40%
SMA Types 2 (all ages) and 3
World with Nusinersen + BSC	40%-55%
World with Risdiplam + BSC	33%-55%
Drug acquisition cost	Cost per unit (in SAR)	NUPCO database
Onasemnogene abeparvovec
Managed entry agreement– Yes	1,350,000 (per year over 5 years)
Managed entry agreement - No	6,750,000 (1 time payment)
Risdiplam	38,465.63
Nusinersen	326,000 (without PBMEA)
Antibiotics	3.45
Acid suppressants	0.43
Supplements for bone health e.g., Vitamin D (Type 1)	46.44
Supplements for bone health e.g. Vitamin D [Types 2 (all ages) and 3]	50.67
Annual influenza vaccination	135.50
Annual pneumococcal vaccination	67.35
Services under BSC for Type 1	Cost per event (in SAR)	NUPCO and experts’ inputs
Respiratory interventions
Pulse oximetry	80
Spirometry	160
Airway clearance - manual chest physiotherapy	40
Ventilation - Invasive positive pressure ventilation	2,800
Feed tube use
Diet rich in amino acids, probiotics and adequate hydration is needed	3,600
Services under BSC for Type 2 (all ages)	Cost per event (in SAR)	NUPCO and experts’ inputs
Respiratory interventions
Spirometry	160
Sleep study	3,600
Airway clearance - manual chest physiotherapy	40
Ventilation - Non-invasive positive pressure ventilation	2,800
Wheelchair use
Rigid seat and back	11,343
Feeding evaluations
Diet rich in amino acids, probiotics and adequate hydration is needed	3,600
Services under BSC for Type 3	Cost per event (in SAR)
Physiotherapy
Aerobics	150
Stretching	150
Administration, monitoring, and diagnostic costs		NUPCO and experts’ inputs
Services and drugs needed during administration	Cost per service (in SAR)
Liver function test	160
Platelet count	64
Troponin I	300
Anti-AAV9 antibodies testing	96
Radiologist	80
Ultrasounds	600
Remove 5 mL of cerebrospinal fluid	120
Sedation	1.51 (per administration)
Corticosteroids (Prednisolone)	372.09 (per administration)
Responsible persons for administration	Cost per minute (in SAR)
Junior Doctor	83
Anesthesiologist	80
Nurse	28
Pharmacist	23
Radiologist	80
Monitoring costs	Cost per test/visit (in SAR)
Liver function test	164
Platelet count	60
Troponin I	300
Prothrombin time activated partial thromboplastin time	64
Quantitative spot urine protein testing	588
Diagnostic tests	Cost of test (in SAR)
Multiplex Ligation dependent Probe Amplification (MLPA)	2,000
Electromyogram (EMG)	500
Creatine Kinase levels	30
Adverse events costs	Cost of resource use (per test/visit) (in SAR)	NUPCO and experts’ inputs
Thrombocytopenia	60.00
Renal toxicity	588.00
Upper respiratory tract infection	7.83
Lower respiratory tract infection	7.83
Constipation	4.22
Teething	51.54
Upper respiratory tract congestion	11.23
Aspiration	3,600.00
Ear infection	0.39
Scoliosis	150.00
Vomiting	1,503.33
Fever	0.002
Diarrhea	1,503.33
Rash	23.03
Mouth and aphthous ulcers	374.00
Urinary tract infection	144.00
Pneumonia	0.19

NUPCO: National Unified Procurement Company; SAR: Saudi Riyal; BSC: Best supportive care

Model inputs

Data included as model inputs were all sourced from various clinical trials, the MOH database, and the feedback from key opinion leaders or experts in the field. These experts are experienced clinicians and healthcare professionals actively involved in the care and management of SMA patients in the KSA. The data were gathered through an extensive consensus-building process, which included a survey questionnaire (Supplementary information: MOH SMA Class Review Questionnaire) and more than 20 roundtable discussions to ensure accuracy and consistency of assumptions used in the model. MOH and NUPCO data is confidential; however all the data included in the manuscript were reverified and confirmed by the Saudi MOH.

Market share

The market shares of all three interventions across various scenarios spanning a duration of 5-years were assumed based on market research data and input from key opinion leaders in the field. These scenarios encompassed evaluation of the individual interventions, the combination of two interventions, and all three interventions with BSC. The investigation sought to provide insights into the dynamic landscape of market share, considering the diverse strategic approaches and combinations of interventions (Table 1 and Table S2).

Clinical outcomes

Clinical outcomes for SMA Type 1, SMA Type 2 (under 2 years of age), and SMA Types 2 (all ages) and 3 were derived from the clinical trials of the interventions and literature survey [23–25]. Clinical outcomes for SMA Type 1 were assessed based on factors such as motor milestones, percent ventilation support, and mortality. The evaluation for SMA Types 2 (all ages) and 3 focused specifically on motor milestones [26] (Table S3). Survival data was also considered during the analysis.

Median survival

Data on median survival with respect to nusinersen and risdiplam was also introduced in the model and used in all scenario analyses for all sub-populations of SMA, i.e. Type 1, and Type 2 and Type 3. However, since onasemnogene abeparvovec is gene therapy and given only once in the lifetime, median survival was not needed to capture as this did not impact the drug acquisition cost.

For SMA Type 1, the event free (no death or no use of permanent ventilation) survival data for nusinersen and risdiplam were calculated by extrapolating the Kaplan-Meier (KM) curve for death or permanent ventilation from the ENDEAR [27] and FIREFISH [28] trial data, respectively. In these studies, the KM curve was available for 56 weeks for nusinersen and 12 months for risdiplam, however, the median time to event was not achieved for any of the interventions by that time [24]. Thus, KM data was extrapolated by assuming the same event rate as per the last observation of trial data to estimate the median survival. The event free survival data from the published KM curve was extracted using WebPlotDigitizer tool and extrapolated by parametric fitting. This approach aligns with common practices in survival analysis where the hazard is assumed to remain constant beyond the last observed event, a method often used in piecewise or hybrid extrapolation models [29, 30]. The estimated median time to event for SMA Type 1, based on the extrapolation, was 1.29 years and 3.66 years for nusinersen and risdiplam, respectively. The calculation of median survival helped in capturing the median dosing for SMA Type 1 patients.

For SMA Types 2 and 3, the median survival data for nusinersen and risdiplam was not available. Therefore, we used the survival data reported by Zerres et al. [13], for both SMA Types 2 and 3 and applied it to nusinersen, risdiplam and BSC for our BIM analysis. While the present study focuses on the Saudi Arabian population, we reference survival data from a large European cohort study by Zerres et al. [13], owing to the shared West Eurasian genetic ancestry and the conserved monogenic nature of SMA. Although regional differences in healthcare infrastructure and potential genetic modifiers may influence survival outcomes, the European data serve as a valuable historical benchmark—particularly in the context of limited local longitudinal data available at the time of this analysis, which was conducted in 2021. For SMA Type 2, the survival rate was reported to be 98.5% at 5 years, while for SMA Type 3, the survival rate was not significantly different from that of a normal population.

Cost

The drug acquisition costs were calculated in Saudi Riyal (SAR) through median survival data and considered the cost of treatment with risdiplam, nusinersen, onasemnogene abeparvovec, and adjunct medications such as antibiotics, acid suppressants, vitamin D, annual influenza, and pneumococcal vaccination. Services under BSC such as the cost of respiratory interventions, feed tube use, physiotherapy, wheelchair use, etc. were also included in the cost input (Table 1). Administration, diagnostic, and adverse events costs were also mapped and included in the model (Table 1). The impact on direct medical costs was estimated based on the performance data of the interventions, as captured in terms of survival rates, invasive and non-invasive intensive care unit (ICU) requirements, and improvement in head control as the main clinical outcome.

Performance-based managed-entry agreement (PBMEA)

Performance-based managed-entry agreement (PBMEA) was introduced for all three interventions to assess its impact on the overall budget and treatment cost per patient. PBMEA for onasemnogene abeparvovec, risdiplam, and nusinersen was introduced in the model and used in all scenario analyses in all sub-populations of SMA, i.e. Type 1, and Type 2 and Type 3. For each intervention, various financial components of PBMEA covering the aspects of eligibility criteria, response criteria, and the time of assessment were considered during the analysis.

Model outputs

The model evaluated two scenarios in the presence and absence of survival data. The first scenario included a world without intervention (Fig. 1), wherein SMA was managed solely by BSC. In contrast, the world with intervention involved the management of SMA by introducing individual interventions, two interventions, and all three interventions with BSC. Additionally, the model estimated the net budget impact over a 5-year timeframe, considering the presence or absence of PBMEAs for all scenarios. All the estimated values were presented in Saudi SAR.

Fig. 1.

Budget Impact Model structure

Results

Overall net budget impact

SMA type 1

Among all the scenarios analyzed for SMA Type 1 without PBMEA, the greatest budget impact over a time horizon of 5 years was observed for Scenario I, where the introduction of nusinersen with BSC showed an increase in the overall net budget impact of SAR 56,918,293 (225%) over BSC alone. The budget impact was even higher (SAR 98,026,436) when the analysis was done without survival data (Table 2). A similar trend was observed for onasemnogene abeparvovec and risdiplam when introduced with BSC versus BSC alone in Scenario I (Table 2). In Scenario II and III, the overall net budget impact was significantly lower than that observed in Scenario I because, in these scenarios, nusinersen and BSC were considered as the SOC.

Table 2.

Comprehensive analysis of net budget impact with and without survival data as well as with and without PBMEA

		Overall budget impact		Net budget impact per patient	Overall budget impact		Net budget impact per patient
SMA Type	Scenario	Without survival data Without PBMEA (SAR)	With survival data Without PBMEA [SAR (%)]	Without PBMEA (SAR)	Without survival data With PBMEA (SAR)	With survival data With PBMEA [SAR (%)]	With PBMEA (SAR)
Type 1	Onasemnogene abeparvovec with BSC	65,761,658	39,590,134 (156%)	515,917	28,000,263	19,575,411 (77%)	250,117
	Nusinersen with BSC	98,026,436	56,918,293 (225%)	739,287	9,343,140	5,946,301 (84%)	278,212
	Risdiplam with BSC	59,189,273	28,373,040 (112%)	364,264	59,189,273	20,392,379 (81%)	260,105
	Onasemnogene abeparvovec vs. Nusinersen and BSC	68,064,961	41,934,068 (66%)	546,902	28,306,627	20,588,816 (54%)	263,575
	Onasemnogene abeparvovec or Risdiplam vs. Nusinersen and BSC	105,193,051	59,739,123 (94%)	775,546	65,434,717	33,573,883 (88%)	429,108
Type 2 (under 2 years of age)	Onasemnogene abeparvovec with BSC	NA	12,379,281 (254%)	2,488,960	NA	5,693,128 (117%)	1,145,031
	Onasemnogene abeparvovec or Risdiplam with Nusinersen and BSC		9,494,545 (136%)	1,692,951		2,442,373 (44%)	478,113
Types 2 (all ages) and 3	Nusinersen with BSC	311,543,058	265,013,008 (283%)	2,559,497	38,581,237	23,273,924 (76%)	692,870
	Risdiplam with BSC	178,163,516	160,408,800 (171%)	1,535,265	178,163,516	5,618,215 (36%)	317,732
	Nusinersen and Risdiplam with BSC	2,208,274	229,511,603 (80%)	2,208,274	72,917,486	13,729,637 (29%)	405,586

BSC: Best supportive care; PBMEA: performance-based managed entry agreement; SAR: Saudi Riyal; NA: not applicable

Across all scenarios, net budget impact per patient over a 5-year time horizon was primarily influenced by the drug acquisition cost. The yearly breakdown revealed the first year to be most impacted with drug acquisition cost being the highest of all 5 years for nusinersen and onasemnogene abeparvovec. While, for risdiplam, the drug acquisition cost was expected to increase with time with an increase in the number of patients treated with risdiplam (Fig. 2).The application of PBMEA had a profound effect on the overall net budget impact for all three interventions in Scenario I, but a minimal effect was observed for Scenarios II and III, which is again attributed to the consideration of nusinersen and BSC as the SOC (Table 2). However, the overall net budget impact was high when PBMEA was not considered compared to when it was considered.

Fig. 2.

Budget impact per year

SMA type 2 (under 2 years of age)

For SMA Type 2 patients who are under 2 years of age, BIM was conducted without considering the survival data for both scenarios IV and V. Since onasemnogene abeparvovec is a one-time gene therapy, the survival data will not have any impact on the analysis and SMA Type 2 patients have a reported survival rate of 98.5% at 5 years.

The overall net budget impact for onasemnogene abeparvovec with BSC was SAR 12,379,281, which was 254% more than the BSC alone. However, with the application of PBMEA, the overall net budget impact was offset from 254 to 117% (Table 2).

In the other scenario, where onasemnogene abeparvovec or risdiplam with nusinersen and BSC versus nusinersen and BSC were compared, the overall net budget impact without and with PBMEA showed a significant reduction, which was not observed for the similar scenario for SMA Type 1 patients (Table 2). This could be attributed to the number of patients and survival considerations.

SMA types 2 (all ages) and 3

The overall net budget impact for SMA Types 2 (all ages) and 3 combined was not much affected by considering the median survival data for both nusinersen and risdiplam (Table 2). SMA Type 2 patients have a reported survival rate of 98.5% at 5 years, while for those with SMA Type 3, life expectancy is not significantly different from that of a normal population [31]. However, the application of PBMEA profoundly offset the overall net budget from 283 to 76% in the scenario where nusinersen was introduced with BSC and from 171 to 36% when risdiplam was introduced with BSC. The budget impact was moderate for the scenario where risdiplam was introduced with nusinersen and BSC as the SOC (Table 2).

Table 2 provides a comprehensive summary of all scenarios, encompassing both overall net budget impact and net budget impact per patient, with or without survival data, and with and without PBMEA.

Cost per patient per intervention

PBMEA was observed to have varied effects on the cost per patient per intervention for all three interventions (Table 3). For SMA Type 1 patients, the per intervention cost can be significantly reduced for nusinersen but not for onasemnogene abeparvovec and risdiplam by introducing PBMEA. However, for SMA Types 2 (all ages) and 3, the application of PBMEA profoundly offsets the cost per patient per intervention for both nusinersen and risdiplam. For SMA Type 2 (under 2 years of age), the cost per patient per intervention is comparable for onasemnogene abeparvovec with and without PBMEA (Table 3).

Table 3.

Cost per patient per intervention

SMA Type	Nusinersen		Onasemnogene abeparvovec		Risdiplam
	Without PBMEA (in SAR)	With PBMEA (in SAR)	Without PBMEA (in SAR)	With PBMEA (in SAR)	Without PBMEA (in SAR)	With PBMEA (in SAR)
Type 1	2,314,975	1,049,603	6,774,926	6,639,570	698,905	629,909
Type 2 (under 2 years of age)	NA	NA	6,774,926	6,639,570	NA	NA
SMA Types 2 (all ages) and 3	6,011,758	4,311,734	NA	NA	4,270,214	1,600,715

NA = not applicable

Discussion

In this study, various scenarios with one, two, or all three first-in-class interventions mixed with BSC for SMA Types 1, 2, and 3 were analyzed and compared for their overall budget impact from the perspective of the Saudi MoH as the payer.

Owing to the relatively higher prevalence of SMA in the KSA, the introduction of nusinersen, onasemnogene abeparvovec, and risdiplam for the management of SMA in the country will increase the overall budget of the payer. However, the increase in budget can be offset to a greater extent by an improvement in clinical outcomes. In this study, survival data, patient eligibility, and efficacy endpoint data from clinical trials were used to estimate the budget impact. Clinical trials and post-marketing mid- and long-term studies for all three interventions reported favorable clinical outcomes and disease stabilization in SMA patients [32–34]. The increase in budget is associated with improved survival rates, contributing to the rise in management costs as a necessary aspect of treatment prioritization taking into consideration SMA’s poor prognosis and overall burden of the disease.

Various cost-effective studies were conducted on these first-in-class interventions, taking into account either a single intervention over BSC or comparing two of them for the majority of the studies. Most of these studies considered lifetime as the study time horizon and studied the cost-effectiveness in terms of incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALY) [16]. However, in this study, we analyzed the overall net budget impact on the payer in the KSA over a time horizon of 5 years. Though data from the literature could not be compared directly, an increase in cost for the management of SMA and improved clinical outcomes are implied in all the studies.

This study also considered PBMEA for all three interventions. Managed Entry Agreements (MEAs) are innovative agreements that bridge the gap between payers and manufacturers in healthcare. They enable access to medical technologies under stipulated conditions. MEAs are of two types: PBMEAs and outcome-based MEAs (OBMEAs). OBMEAs are a subset of PBMEAs, and the reimbursement or pricing of a drug is directly linked to the observed clinical outcomes or real-world evidence generated during the use of the intervention. PBMEAs consider evidence of an intervention’s benefits in terms of final results or measurable performance. MEAs applied in reimbursement programs reduce the consequences of making a poor coverage decision and help create a more adaptive and patient-centric healthcare system [35]. PBMEAs have been implemented for various interventions in European countries [36, 37]. However, to date, none of the health economic studies on nusinersen, onasemnogene abeparvovec, and risdiplam considered PBMEA in their analyses.

In this study, the introduction of PBMEA decreased the overall budget impact in all the scenarios analyzed, maintaining the eligibility characteristics, and linking the resource allocation to health outcomes. The three key factors that led to a reduction in overall budget impact after considering PBMEA were eligibility criteria, non-responsiveness of the patients, and reduction in per-patient drug acquisition cost. Differences in annual drug cost and reduction in treated patients led to a decrease in net budget impact with PBMEA for all three interventions.

This study is the first health economics evaluation to assess all three first-in-class interventions with survival data and PBMEAs. The Saudi MoH has also become the first health authority to cover the cost of all three interventions for the treatment and management of SMA.

A key limitation of this study is the reliance on clinical trial data and several underlying assumptions, which may not fully reflect the diverse and dynamic nature of real-world settings. Real-world variability, such as differences in healthcare access, treatment adherence, and cultural or systemic factors, may significantly influence the effectiveness and feasibility of these interventions in the KSA. These factors highlight the need for additional real-world evidence to complement clinical trial findings and provide a more comprehensive understanding of SMA management in this context.

Moreover, due to limited data on pre-symptomatic SMA patients in the KSA, the study was unable to account for this population completely in the model. However, as a future prospect, the inclusion of pre-symptomatic patients in BIA analysis of SMA could also significantly reduce the disease burden, treatment efficacy, and associated costs. It has been demonstrated that early intervention, particularly in the pre-symptomatic stage, yields markedly improved clinical outcomes [38]. For example, infants treated with nusinersen before the onset of symptoms often achieve developmental motor milestones similar to their healthy counterparts [39]. Timely diagnosis and treatment during the pre-symptomatic stage can significantly improve clinical outcomes by reducing morbidity, enhancing quality of life, and minimizing disease severity. In addition, early intervention has proven to be cost-effective for certain conditions [40]. Including pre-symptomatic patients in BIA models will provide policymakers with stronger evidence to guide decisions on resource allocation, program planning, and treatment reimbursement strategies.

Conclusion

This is the first analysis of first-in-class SMA treatments to estimate the budgetary impact with or without PBMEAs. The introduction of these first-in-class interventions will have an impact on the Saudi MoH budget with drug acquisition cost being the primary contributor. However, this can be offset by an improvement in clinical management and PBMEAs.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

SMA

Spinal muscular atrophy

MoH

Saudi Ministry of Health

PBMEA

Performance-based managed entry agreements

BSC

Best supportive care

SAR

Saudi Riyal

BIM

Budget impact model

HTA

Health technology assessment

SMN

Survival -motor neuron

KSA

Kingdom of Saudi Arabia

ICU

Intensive care unit

SOC

Standard of care

ICER

Incremental cost-effectiveness ratio

QALY

Quality-adjusted life years

MEAs

Managed Entry Agreements

OBMEA

Outcome-based MEAs

Author contributions

A.J., H.M., and N.A. wrote the main manuscript text. M.M. validated the data and contributed to the original draft. A.A., F.B., F.G., A.S., and R.O. conducted the investigation and data curation. R.O. and F.G. provided resources and project administration. All authors reviewed the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Not applicable.

Competing interests

No potential competing interest was reported by the authors.