Затраты на кладрибинные таблетки для лечения высокоактивных реплаксирующих множественных склерозов в Италии.

Key Summary Points

Why carry out this study?
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system [ 1 ]. With a median age of onset between the 2nd and 3rd decade of life, it represents the most common non-traumatic disabling disease in young adults. In fact, its natural history inevitably leads to accumulation of physical disability and impaired cognitive function, with significant consequences for patients’ quality of life and a deep socioeconomic impact. The aim of this study is to evaluate, in the Italian setting, the cost-effectiveness of cladribine administrated to patients with relapsing–remitting MS, compared with oral and infused high-efficacy disease-modifying therapies (DMTs).
What was learned from the study?
Cladribine tablets are associated with a benefit in terms of prolonging the non-relapsing phase in patients with highly active relapsing–remitting MS (HA-RRMS), as well as substantial direct cost savings in comparison with all other DMTs. Our analysis suggests that adopting cladribine tablets for HA-RRMS enables clinical benefits over a 4-year time horizon and savings for Italian society.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system [ 1 ]. With a median age of onset between the 2nd and 3rd decade of life, it represents the most common non-traumatic disabling disease in young adults. In fact, its natural history inevitably leads to accumulation of physical disability and impaired cognitive function, with significant consequences for patients’ quality of life and a deep socioeconomic impact [ 2 ].

Although the current model of MS classification is under scientific debate because of emerging evidence of a smoldering disease, which leads to progression of disability independent from the clinical-radiological focal inflammatory activity from the biological onset of the disease [ 3 , 4 ], MS is clinically classified into different phenotypes: (a) relapsing–remitting MS (RRMS) characterized by subacute focal neurological deficits that last for more than 24 h followed by a remission period; (b) secondary progressive MS (SPMS) characterized by a history of gradual worsening after an initial relapsing disease course, with or without acute exacerbations during the progressive course; and (c) primary progressive MS (PPMS) characterized by accumulation of disability from the onset of disease without evidence of clinical relapses [ 5 ].

Different pharmacological agents, known as disease-modifying therapies (DMTs), are proven to be effective in controlling disease activity by modifying favorably the evolution of MS. In recent decades, the number of DMTs approved for MS treatment, with improved efficacy profiles, has expanded, resulting in 15 agents now being available [ 6 ]. Mainly targeting acute inflammation, the majority of DMTs are now approved for people with RRMS. These drugs are classically divided into two groups: first-line therapies and high-efficacy therapies (HET) [ 7 ]. The superiority of HETs (natalizumab, alemtuzumab, ocrelizumab, ofatumumab, cladribine, and sphingosine-1-phosphate modulators) in reducing clinical relapses and MRI disease activity in comparison with the traditional first-line DMTs (interferon beta, glatiramer acetate, teriflunomide, and dimethyl fumarate) has been consistently proven by randomized clinical trials (RCTs) [ 8 – 12 ] and/or real-world observational studies [ 13 , 14 ].

Multiple registry studies demonstrated that patients selected to receive early HET on the basis of poor prognostic factors were those with better long-term disability outcomes. These results highlight the necessity of gaining a deeper understanding of the benefits associated with an early high-efficacy approach in the treatment of MS, independently from prognostic factors [ 15 , 16 ]. However, given all the available evidence of efficacy, HETs are associated with more complex safety profiles, monitoring requirements, and the need for hospital or day unit admission. As a consequence, treatment guidelines tend to recommend to reserve HETs for use in individuals with the most aggressive or resistant forms of MS [ 17 ]. Of note, the economic burdens of HETs vary significantly depending on efficacy, safety, treatment schedules and settings, and routes of administration. In particular, cladribine, compared to other HETs, would seem to entail lower costs while ensuring notable benefits.

Cladribine is a deoxyadenosine synthetic analogue prodrug that induces lymphocyte apoptosis resulting in transient lymphocyte depletion, with only a minimal effect on the innate immune system, followed by an immune reconstitution with improved immune tolerance [ 18 ].

Treatment with cladribine tablets was associated with significant improvement in clinical and imaging parameters in patients with highly active RMS in clinical trials (CLARITY) [ 19 ] and has been approved by the Italian regulatory agency for the treatment of highly active RRMS (HA-RRMS) since 2019 and very recently for the treatment of RMS (relapsing multiple sclerosis) [ 20 , 21 ].

Cladribine tablets are administered orally, at a cumulative dose of 3.5 mg/kg over 2 years, with a short treatment course of 8 to 10 days annually, with a durable clinical effect of at least 4 years [ 18 ], thus offering multiple advantages in terms of treatment schedule and, possibly, costs.

Considering the high economic and societal burden of MS on the one hand and the availability of HET with different cost–benefit balances on the other hand, it is very important to apply approaches that provide valuable information to help healthcare decision makers in making their choices. The cost consequence analysis (CCA) was deemed by NICE [ 22 ] to be the most suitable type of economic analysis for this topic, comparing costs of a treatment with its consequences, such as health outcomes, cost savings, etc.

The aim of this study is to evaluate, in the Italian setting, the cost-effectiveness of cladribine tablets administrated to patients with RRMS, compared with oral and infused high-efficacy DMTs.

The data used in this study were from the literature or expert opinion. This study uses a pharmacoeconomic model and therefore the approval of an ethics committee is not necessary.

Methods

Model Structure

An economic model developed by PRECISIONheor, described in Fig.  1 , was adapted to the Italian setting. This multistate Markov model considers a cohort of patients entering a treatment pathway.

Model structure

For each DMT three consequent treatment lines are considered. Every year patients can undergo a treatment switch: in each cycle patients can be in the responsive (relapse free) or relapsing stages. In this model patients are assumed to remain alive and on treatment throughout the entire time horizon.

Population

The population eligible for treatment are patients with HA-RRMS according to current Italian Health authorities’ prescription criteria. As reported in the Italian MS Barometer (AISM) [ 23 ], considering a 0.2% MS prevalence and a 71.2% share of RRMS, applied to the Italian adult population (over 18 years old) of 49.8 million (Italian Institute of statistics, 2023), patients with RRMS comprises 76,213 individuals. Among these patients, 55,635 patients (73.0%) were considered eligible for treatment, of whom 16,691 (30.0%) had a highly active disease, e.g., the patients that constituted the study cohort.

Comparators

Three oral DMTs, namely fingolimod, ponesimod, and ozanimod, and three infused DMTs, namely ocrelizumab, natalizumab, and ofatumumab, have been assumed as relevant comparators for the present analysis. Alemtuzumab was not considered as relevant for this analysis because of its current limited use in Italy.

Perspective

The analysis adopts the societal perspective.

Horizon

Patients are followed over a 4-year period.

Clinical Inputs

Transition Rates

The transition rates assumed are based on literature evidence.

Treatment-naïve rates were applied to patients receiving an index treatment (first treatment), while treatment-experienced rates were used to model patients’ transitions to subsequent treatments (i.e., 2nd and 3rd line).

In each stage, transitions from the responsive stage to the relapsing stage were estimated using time to first relapse rates, retrieved from the relevant clinical trial (Table  1 ).

Table 1 Clinical inputs adopted to estimate the cost consequence of cladribine tablets in the treatment of patients with highly active relapsing–remitting MS (HA-RRMS) Treatment TRR (Tx-naïve) TRR (Tx-experienced) ARR (Tx-naïve) ARR (Tx-experienced) Source Cladribine tablets* 0.064 0.107 0.064 0.107 GLIMPSE study Fingolimod 0.075 0.148 0.074 0.137 GLIMPSE study Ponesimod 0.075 0.148 0.074 0.137 Fingolimod proxy Ozanimod 0.075 0.148 0.074 0.137 Fingolimod proxy Ocrelizumab 0.025 0.082 0.026 0.063 GLIMPSE study Natalizumab 0.029 0.072 0.034 0.076 GLIMPSE study Ofatumumab 0.025 0.082 0.026 0.063 Ocrelizumab proxy TRR time to first relapse rate, ARR annualized relapse rate, Tx treatment *Cladribine tablets time to first relapse is assumed to be equivalent to the annualized relapse rate

Clinical inputs adopted to estimate the cost consequence of cladribine tablets in the treatment of patients with highly active relapsing–remitting MS (HA-RRMS)

TRR time to first relapse rate, ARR annualized relapse rate, Tx treatment

*Cladribine tablets time to first relapse is assumed to be equivalent to the annualized relapse rate

For patients in a relapsing stage, the average annual number of relapse events was modeled using annualized relapse rates (Table  1 ).

Finally, patients’ transitions (switching rates) from the index treatment to subsequent treatments were estimated using GLIMPSE study evidence (Supplementary Table  1 ). Notably, for some molecules, in the absence of GLIMPSE study data, data for another specific comparator was used as a proxy.

Economics Inputs

Pharmacological Treatment Costs

Drug treatment costs were estimated using the ex-factory prices published in the Italian Official Journal and the posology reported in each Summary of Product Characteristics (SmPC) (Table  2 ). Administration costs were assumed to be equal to the tariff of drug infusion, similarly, retrieved from the Italian National Tariff List for outpatient services, considering the number of infusions indicated in the posology.

Table 2 Total treatment cost for patients with HA-RRMS Treatment Acquisition cost Administration costs Monitoring costs Year 1 Year 2 Year 3 Year 4 Year 1 Year 2 Year 3 Year 4 Year 1 Year 2 Year 3 Year 4 Cladribine tablets 24.367.0 24.367.0 0.0 0.0 0.0 0.0 0.0 0.0 673.1 422.4 422.4 422.4 Fingolimod 21.176.5 21.176.5 21.177.5 21.177.5 0.0 0.0 0.0 0.0 947.8 470.0 470.0 470.0 Ponesimod 13.562.3 13.562.3 13.562.3 13.562.3 0.0 0.0 0.0 0.0 793.8 425.5 425.5 425.5 Ozanimod 14.850.8 14.850.8 14.851.8 14.851.8 0.0 0.0 0.0 0.0 763.6 429.5 429.5 429.5 Ocrelizumab 22.562.4 22.562.4 22.562.4 22.562.4 40.0 40.0 40.0 40.0 535.2 247.5 247.5 247.5 Natalizumab 21.118.5 21.118.5 21.119.5 21.119.5 130.0 130.0 130.0 130.0 824.7 745.5 745.5 745.5 Ofatumumab 17.265.0 14.798.0 14.798.0 14.798.0 120.0 120.0 120.0 120.0 527.5 247.5 247.5 247.5 Cladribine tablets are administered to patients in years 1 and 2, but no treatment is provided in years 3 and 4

Total treatment cost for patients with HA-RRMS

Cladribine tablets are administered to patients in years 1 and 2, but no treatment is provided in years 3 and 4

Monitoring Costs

The costs associated with follow-up, including day admissions, consultations, and diagnostics, were estimated on the basis of the monitoring frequencies retrieved from the SmPCs, expert opinion, and the Italian National Tariff List (Table  2 ). The complete list of services included in the follow-up, the relative frequencies, and tariffs are reported in Supplementary Table  2 .

Relapse Costs

Relapse management costs were obtained from Battaglia et al. [ 24 ] and include costs for inpatient care, day admissions, consultations, and tests (Supplementary Table  3 ).

Adverse Events

A comparative analysis of the safety profiles of available drugs for the treatment of HA-RRMS was conducted. The analysis focused on adverse events associated with two classes of drugs: oral disease-modifying therapies (O-DMTs) which include cladribine tablets, fingolimod, ponesimod, and ozanimod; and infused/subcutaneous monoclonal antibody DMTs (IS-DMTs) which include ocrelizumab, ofatumumab, and natalizumab.

The analysis is grounded in data derived from pivotal clinical trials for each product evaluated. Presented below is a list of studies incorporated into the analysis for the respective treatments:

The CLARITY study for cladribine tablets (ClinicalTrials.gov identifier NCT00213135 ), a phase III clinical trial titled “Cladribine Tablets Treating Multiple Sclerosis Orally,” involved a total of 1326 patients and is one of the largest studies conducted for this type of treatment. The primary objective of the study was to determine the safety profile and efficacy of cladribine tablets compared to placebo, with particular focus on the reduction in the annual relapse rate and disability progression.

Two pivotal studies on fingolimod, FREEDOMS and FREEDOMS II. The FREEDOMS study ( NCT00289978 ), “Efficacy and Safety of Fingolimod in Patients with Relapsing-remitting Multiple Sclerosis,” is a phase III clinical trial involving 1272 patients. The primary objective was to assess the safety and efficacy profile of fingolimod compared to placebo. The second study, FREEDOMS II “Efficacy and Safety of Fingolimod (FTY720) in Patients with Relapsing-Remitting Multiple Sclerosis” ( NCT00355134 ), further explored the efficacy and safety of fingolimod through another phase III trial. This study involved a total of 1083 patients, confirming the results obtained in the first FREEDOMS study.

The OPTIMUM study (ClinicalTrials.gov identifier NCT02425644 ) is a phase III clinical trial titled “Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis” that evaluated the efficacy and safety of ponesimod in the treatment of RMS. The primary objective of this study was to compare ponesimod with teriflunomide, another treatment for MS, to determine which was more effective at reducing the annual relapse rate in patients. The trial involved a total of 1133 participants, providing a robust dataset to evaluate the safety profile and efficacy of ponesimod.

The RADIANCE ( NCT01628393 , “Efficacy and Safety Study of Ozanimod (RPC1063) in Relapsing Multiple Sclerosis Patients”) and SUNBEAM ( NCT02294058 , “Study of Ozanimod (RPC1063) in Relapsing Multiple Sclerosis”) clinical trials were instrumental in establishing the safety and efficacy of ozanimod in the treatment of RMS. The phase III RADIANCE study enrolled a total of 1320 patients and compared ozanimod with interferon beta-1a, a standard treatment for MS. The primary objective was to evaluate the reduction in the annual relapse rate in patients treated with ozanimod. The phase III SUNBEAM study evaluated the efficacy and safety of ozanimod versus interferon beta-1a, involved 1346 participants, and focused not only on annual relapse rates but also on the progression of disability associated with MS.

The OPERA I and OPERA II clinical trials were used to establish the efficacy and safety of ocrelizumab in the treatment of RRMS: these are two phase III studies that compared ocrelizumab with interferon beta-1a, a standard treatment for this condition. The OPERA I study ( NCT01247324 , “A Study of Ocrelizumab in Comparison with Interferon Beta-1a (Rebif) in Participants with Relapsing Multiple Sclerosis”) involved 821 patients and aimed to evaluate the ability of ocrelizumab to reduce the annual relapse rate and slow the progression of disability in patients with MS. The OPERA II study ( NCT01412333 , “A Study of Ocrelizumab in Comparison with Interferon Beta-1a (Rebif) in Participants with Relapsing Multiple Sclerosis”) further confirmed the results obtained in OPERA I, involved 835 participants and provided further evidence of the efficacy of ocrelizumab in reducing relapses and managing the symptoms of MS.

The ASCLEPIOS I and ASCLEPIOS II clinical trials evaluated the efficacy and safety of ofatumumab in the treatment of RMS. These phase III studies compared ofatumumab to teriflunomide, a standard treatment for this condition. The ASCLEPIOS I study ( NCT02792218 , “Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients with Relapsing Multiple Sclerosis”) involved 927 patients and aimed to determine the efficacy of ofatumumab in reducing the annual relapse rate in patients with MS. The ASCLEPIOS II study ( NCT02792231 , “Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients with Relapsing Multiple Sclerosis”) further confirmed the positive results obtained in ASCLEPIOS I and involved 955 participants.

The AFFIRM study ( NCT00027300 , “Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis”) is a phase III clinical trial that aimed to evaluate the efficacy and safety of natalizumab in patients with RRMS. The study involved a total of 942 patients and focused on the ability of natalizumab to reduce the rate of relapses and slow the progression of disability associated with the disease.

The following table summarizes the key features of the clinical trials mentioned:

Clinical trial Study design Treatments and sample size ( N ) Follow-up CLARITY RCT, double blind, phase III, multicenter, parallel groups Cladribine PO 3.5 mg/kg ( N  = 433) Nearly 2 years (96 weeks) FREEDOMS RCT, double blind, phase III, multicenter, parallel groups Versus placebo ( N  = 437) 2 years (24 months) FREEDOMS II RCT, double blind, phase III, multicenter, parallel groups Fingolimod PO 0.5 mg QD ( N  = 425) vs placebo ( N  = 418) 2 years (24 months) OPTIMUM RCT, double blind, phase III, multicenter, parallel groups Fingolimod PO 1.25 mg QD ( N  = 370) vs placebo ( N  = 358) 1 year (12 month) AFFIRM RCT, double blind, phase III, multicenter, parallel groups Ponesimod PO 20 mg ( N  = 566) > 2 year (116 weeks) RADIANCE RCT, double blind, phase III, multicenter, parallel groups Versus teriflunomide PO 14 mg QD ( N  = 567) 1 year (12 months) SUNBEAM RCT, double blind, phase III, multicenter, parallel groups Natalizumab IV 300 mg Q4 W ( N  = 627) vs placebo ( N  = 500) 1 year (12 months) OPERA I RCT, double blind, phase III, multicenter, parallel groups Ozanimod PO 1 mg ( N  = 660) 2 years (24 months) OPERA II RCT, double blind, phase III, multicenter, parallel groups Versus interferon beta-1a ( N  = 660) 2 years (24 months) ASCLEPIOS I RCT, double blind, phase III, multicenter, parallel groups Ozanimod PO 1 mg ( N  = 668) 2 years (30 months + 100 days) ASCLEPIOS II RCT, double blind, phase III, multicenter, parallel groups Versus interferon beta-1a ( N  = 668) 2 years (30 months + 100 days)

A list of adverse events was established and data were retrieved from www.clinicaltrials.gov and from published papers. Data from the two sources were compared and merged, if needed. If more than one published paper was available, only the first one was considered to ensure consistency in follow-up periods. Only safety data regarding the authorized drug dosages were considered; when more than one pivotal study used the same dosage and schedule, the cumulative incidence of events was registered by summing the number of events and dividing by the total number of patients. When clinically relevant, severe adverse events were reported separately from other intensity grades.

The cost evaluation for each adverse event was conducted and based on the DRG tariffs, the tariff nomenclature for specialist care and the scientific literature, thus providing a solid basis for the economic analysis. To ensure the accuracy and relevance of the economic data, all costs derived from the literature were adjusted to the year 2024, using the euro (€) as the reference currency. This adjustment was made via the Cost Conversion website ( https://eppi.ioe.ac.uk/costconversion/ ), which allows the economic values to be updated considering inflation and other relevant economic factors (Supplementary Table  4 ).

The comparison of total costs associated with adverse events identifies fingolimod as the drug with the highest costs (€ 436.9) while the drug with the lowest total costs is ozanimod (€ 173.2) (Fig.  2 ).

Adverse events cost per patient per year (€)

Adverse events were also classified into three categories: oncological, infectious, and drug-related events (Fig.  3 ).

Adverse events cost per category (€)

The analysis by event type (oncological, drug-related, infectious) identifies infectious and drug-related events as the primary cost contributors for most medications.

We categorized the adverse events into these three categories to best represent the real-world setting, embracing a range of events from the most frequent but relatively low-impact ones (drug-related), up to the rarer but high-impact ones (oncological), through those that could show characteristics of both conditions depending on the specific case (infectious).

Indirect Cost

Indirect costs considered productivity loss, including informal care and short-term absence. Productivity losses (sickness absences, early retirement, invalidity) were estimated by the human-capital method using the national average age- and gender-adjusted cost of labor. Loss of leisure time for informal care was attributed to all carers, regardless of age, gender, or occupation, and calculated using the national average disposable income after contributions and taxes. Costs were derived from [ 25 ] and converted from GBP to 2024 euros.

Results

The results of the model comparing cladribine tablets versus either oral or infused DMT comparators are reported in Table  3 . The complete set of results is reported in Supplementary Table  4 .

Table 3 Cost-effectiveness of cladribine tablets, base case scenario Cladribine tablets vs oral DMTs Cladribine tablets vs infused DMTs Difference (high) Difference Difference (high) Difference Patient months in responsive stage of index treatment 1.3 1.4 2.4 5.7 Number of relapses − 0.01 − 0.01 0.02 0.02 Total costs − 36.506.3 − 5693.4 − 38.782.0 − 17.248.3 Total cost per month of index treatment − 796.0 − 139.0 − 1050.6 − 685.9 Incremental results Cost per averted relapse 6.610.975.8 6.711.097.8 No averted relapses No averted relapses Percent reduction in total costs 69.9% 10.9% 74.3% 33.0% Cost savings per additional month in responsive stage of index treatment* − 27.663.2 − 4154.3 − 16.224.5 − 3035.3 *Negative values indicate cost savings vs comparators

Cost-effectiveness of cladribine tablets, base case scenario

*Negative values indicate cost savings vs comparators

Treatment with cladribine tablets was associated with a prolongation of patients’ responsive stage, in the range of 1.4 (best scenario) and 1.3 (worst scenario) months versus oral DMTs and between 5.7 and 2.4 versus infused DMTs. Compared to others oral DMTs, cladribine tablets also showed a slight reduction in the number of relapses (− 0.01).

In the context of the Italian healthcare system, the treatment with cladribine tablets was linked to significant cost savings when compared to others DMTs. Specifically, these savings ranged from 69.9% to 10.9% with regard to oral DMTs, and from 74.3% to 33.0% when compared to infused DMTs.

In terms of cost-effectiveness, assuming the time in the responsive stage as our endpoint, direct cost savings per additional month in that stage of treatment ranged between € 27,663.2 and € 4154.3 versus others oral DMTs, and between € 16,224.5 and € 3035.3 versus infused DMTs.

The comparative analysis of cladribine tablets against other drugs reveals that cladribine tablets generally incur lower costs for managing adverse events, except when compared to ozanimod. Specifically, cladribine tablets demonstrate a 49% cost reduction compared to fingolimod, 18% compared to ponesimod, 45% compared to natalizumab, and 38% compared to ofatumumab, while showing a 30% cost increase relative to ozanimod.

Sensitivity Analysis

A deterministic sensitivity analysis was conducted. As a result of the structure of the model, which considers different index treatments, a tornado diagram was developed for each of them, i.e., for each comparison of cladribine tablets with a different initial treatment. Tornado diagrams illustrating the effects of the eight variables that have the greatest impact on the cost of treatment are reported in Supplementary Fig.  1 ; all the variables were varied by ± 20%.

Discussion

This study reports the results of a cost-effectiveness analysis of cladribine tablets for the treatment of patients with HA-RRMS in Italy, adopting the societal perspective and a time horizon of 4 years. The analysis was performed by adapting a multistate Markov model developed by PRECISIONheor to the Italian setting, comparing cladribine tablets with other oral and infused DMTs.

As reported in Table  3 , treatment with cladribine tablets resulted in extending the duration of patients’ responsive stage from 1.3 to 1.4 months when compared to oral DMTs and from 2.4 to 5.7 months when compared to monoclonal antibody DMTs.

Direct cost savings associated with cladribine tablets ranged from 69.9% to 10.9%, when compared to oral DMTs, and from 74.3% to 33.0% when compared to infused DMTs. Orally administered cladribine resulted in direct cost savings per additional month in responsive stage of treatment—considering the best and worst scenarios—ranging from € 27,663.2 to € 4154.3 when compared to oral DMTs, and between € 16,224.5 and € 3053.3 when compared to infused DMTs.

Cladribine tablets are an effective treatment opportunity and provide significant savings over more expensive therapeutic opportunities (Supplementary Fig.  2 ).

These results are in line with findings reported in previously published research. In a study conducted in England, treatment with cladribine tablets was dominant (i.e., associated with cost savings and increased clinical effectiveness) and showed a 93.0% probability of being cost-effective at a willingness-to-pay of GBP 30,000/QALY when compared to alemtuzumab and natalizumab for the treatment of HA-RRMS [ 26 ].

Similarly, two recent studies conducted in the Middle East evaluating the cost-effectiveness of cladribine tablets resulted in costs savings and better treatment performance versus all the comparators considered [ 27 , 28 ]. The primary source of cost savings was drug acquisition costs, which accounted for over 90% of the total savings, in line with what was reported by Michels et al., who attribute the cost-effectiveness of cladribine tablets largely to its lower acquisition costs [ 29 ].

The model used has several limitations. Firstly, the model is populated with data extracted from pivotal trials enrolling populations that are not fully comparable. Secondly, data does not account for patient mortality, assuming that all patients remain alive within the model time horizon. This assumption may result in overlooking key clinical outcomes associated with the natural course of the disease. Furthermore, the model only considers three treatment lines for HA-RRMS, thus excluding further treatment lines and therapies from the analysis. Lastly, treatment discontinuation and transitions to relapsing stages are assumed to implicitly reflect ongoing disease progression, but disease progression is not explicitly modelled.

In this discussion, it is important to highlight the design differences in historical clinical trials, particularly those for the registration of cladribine tablets, fingolimod, and natalizumab. These trials utilized a placebo control arm, contrasting with more recent studies that have employed another disease-modifying drug (DMD) as the comparator. This shift in trial design has significantly influenced the reporting rates of adverse events. Specifically, the variation in adverse event rates observed in trials with a placebo control appears to be higher compared to those that use another DMD for comparison.

This effect is particularly evident in the reporting of infectious events and oncological risks. The historical trials, by comparing treatments against a placebo, may have resulted in an inflated perception of the safety profile of the treatments when evaluated against more contemporary therapies. As such, it is crucial to consider these design differences when interpreting the safety data of newer DMDs in relation to those established in earlier clinical trials.

Moreover, another important difference between clinical trials conducted in such different time periods is the diversity of the study population. Patients enrolled in more recent trials are often those with historically milder and more manageable conditions. This is not only due to the increased availability of therapies over the past decade but also because updated diagnostic criteria have facilitated earlier diagnoses, allowing patients to manage their conditions more effectively from the beginning.

Another critical point to consider is that some adverse events are reported as risks within the individual product’s SmPC. However, as a result of their rarity, these events may not have been observed in the respective registration studies, which typically have a limited duration of up to 2 years. A prominent example is the risk of progressive multifocal leukoencephalopathy (PML) associated with certain immunosuppressive drugs. Consequently, in the cost analysis of adverse events, these specific risks were not included, as the primary reference source for the various medications remains the clinical trials.

It is well known that long-term exposure to natalizumab increases the risk of PML in patients with MS [ 30 , 31 ]. The global incidence of PML in natalizumab-treated patients is 4.08/1000 patients (95% confidence interval (CI) 3.80–4.36/1000 patients), and the survival rate is approximately 70–75% [ 32 ].

An increased risk in PML also after long-term fingolimod exposure was described in the literature. The current estimated risk of PML with fingolimod treatment is 0.069 (95% CI 0.039–0.114) per 1000 patients and the incidence rate is 3.12/100,000 patient-years [ 33 ].

Furthermore, some side effects were not quantified in this model because of the inability to identify the rate ratio in the pivotal trials, as they are rare events, such as PML, or due to incidences associated with long-term exposure to the drug. For this reason, the respective SmPCs recommend appropriate monitoring for each treatment class, such as S1P receptor modulators, and monitoring the skin to prevent malignant neoplasms. This aspect becomes particularly important when considering that some recently registered therapies, which belong to classes of already approved drugs such as S1P receptor antagonists or anti-CD20 antibodies, have reported significantly fewer adverse events within their registration trials. Meanwhile, the attention to monitoring remains similar to other treatments within their respective SmPCs, possibly as a result of a class effect where adverse events may manifest over the long term.

The findings of this analysis highlight significant cost differences in adverse event management across MS treatments. These results emphasize the importance of considering both efficacy and safety profiles, as well as associated costs, to guide personalized therapeutic approaches and sustainable treatment choices.

It is important to acknowledge that the study’s reliance on registration trial data may not fully reflect real-world clinical practice.

Conclusions

Overall, this study demonstrates that treatment with cladribine tablets for patients with HA-RRMS in the Italian setting is effective in maintaining patients in the responsive stage. Additionally, it is associated with significant cost savings, ultimately representing an efficient treatment option.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 477 KB)

Author Contribution

Barbara Polistena and Anna Maria Provenzano concept and design. Barbara Polistena: pharmacoeconomics analysis. Barbara Polistena, Anna Maria Provenzano, Caterina Rizzi, Elena Colombo, Roberto Bergamaschi wrote the manuscript.

Funding

This work, and the rapid service fee, has been funded by Merck Serono S.p.A., Rome, Italy, an affiliate of Merck KGaA (CrossRef Funder ID: 10.13039/100009945).

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflicts of interest

Anna Maria Provenzano and Caterina Rizzi are employees of Merck Serono S.p.A., Rome, Italy, an affiliate of Merck KGaA. Barbara Polistena received payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from the following commercial sources: Allergan, Amgen, Astellas, Eli Lilly, Janssen Cilag, Nestlé HS, Novartis, Novo Nordisk, Pfizer, Servier, Takeda, Teva; in addition she received consulting fees from UCB.

Ethical Approval

The data used in the study were from the literature or expert opinion. This study uses a pharmacoeconomic model and therefore the approval of an ethics committee is not necessary .

Disclosures

Roberto Bergamaschi has received funding for travel, speaker honoraria, research support from Biogen, Bristol Myers, Janssen, Merck, Novartis, Roche, Sanofi. Elena Colombo reports travel expenses, speaker honoraria, advisory board work and research support from Sanofi, Biogen, Novartis, Merck, Roche, Bristol MS, Janssen, Alexion. All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

References

Associated Data

Supplementary Materials

Supplementary file1 (PDF 477 KB)

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.