Ofatumumab in the treatment of multiple sclerosis –⁠ from clinical outcomes to the economic sustainability of treatment

Overview

The importance of early initiation of therapy for the long-term prognosis of patients with relapsing-remitting MS is supported by evidence from open-label extension studies as well as real-world clinical data, both consistently demonstrating an association between early intervention and a slower disability progression. Given the growing number of available disease-modifying drugs and the substantial socioeconomic burden associated with MS, it is essential to identify not only cost-effective pharmaceutical agents, but also optimal therapeutic strategies that take into account both clinical efficacy and long-term sustainability within the healthcare system. Ofatumumab fulfills the criteria of a modern 21^st-century drug and represents a therapy with dual benefits –⁠ for both the patient and the healthcare system.

Keywords:

costs – Multiple sclerosis – Pharmacoeconomics – ofatumumab – high-efficacy therapy

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version

 

Introduction

Multiple sclerosis is a chronic autoimmune demyelinating and neurodegenerative disease of the central nervous system (CNS) that is associated with a significant clinical and socioeconomic burden for both patients and healthcare systems. The disease is most commonly diagnosed in young, economically active adults between the ages of 20 and 40, which has significant impacts on their ability to work, social and family functioning, and quality of life [1].

The chronic course of the disease, the need for long-term therapy, and the gradual progression of disability make MS one of the most common potentially disabling neurological diseases among people of working age and, at the same time, one of the most costly diagnoses in neurology—both in terms of direct healthcare expenditures (diagnostics, pharmacotherapy, hospitalization, rehabilitation, other specialized care) as well as indirect costs associated with loss of work productivity, early disability, the need for assisted care, or the need for social support (Table 1) [2–5]. Consequently, in recent years, increasing attention has been focused not only on evaluating the efficacy and safety of new drugs but also on their pharmacoeconomic aspects.

Ofatumumab, a fully human anti-CD20 monoclonal antibody intended for subcutaneous self-administration at home, represents a modern, sophisticated treatment option that, in addition to proven long-term efficacy and a favorable safety profile, also offers significant health-economic and patient benefits —⁠ its attractive dosing regimen provides greater flexibility in tailoring treatment to individual patient needs, enhances patient comfort and adherence to treatment, and may simultaneously lead to more efficient use of healthcare resources.

 

Pharmacoeconomics (for Beginners)

Pharmacoeconomics emerged as a response to the growing mismatch between the expanding capabilities of modern medicine and limited healthcare funding. Healthcare costs are rising faster each year than revenues from the health insurance system. Given this situation, it is essential to allocate available resources as effectively and economically as possible [6]. The main objective of pharmacoeconomic analyses is therefore to provide a basis for the effective allocation of limited healthcare resources; more precisely, to identify the optimal solution that is most beneficial to the patient while also being economically acceptable [6,7].

Pharmacoeconomic evaluation is particularly important in the case of chronic, progressive, and costly diseases such as MS, where treatment is long-term or lifelong, is associated with high economic costs, and has a significant impact on patients’ quality of life and employment prospects [3,5]. The increasing consumption of medicines and rising drug prices are not only a problem for the Czech Republic but a common issue across all developed countries. Due to the high cost of modern disease-modifying drugs (DMDs) and the growing number of approved medications, pharmacoeconomic evaluation is essential for deciding whether to include them in reimbursement schemes. Even medicinal products with a higher purchase price (monoclonal antibodies, immunoreconstructive therapies) can, in the long term, result in lower cumulative healthcare costs—in the sense of reduced costs for hospitalizations or sick leave—due to their greater efficacy (more sustained reduction in disease activity) [8–11]. In other words, although drugs with a higher upfront investment represent higher direct costs in the short term, their ability to effectively reduce relapse frequency can have a positive impact on the overall economic burden on the system over a longer period (Fig. 1) [12].

Pharmacoeconomic analyses related to MS include both direct and indirect costs, which are often higher [4,5] (Fig. 2). Particularly significant are so-called intangible costs, i.e., costs that are difficult to quantify, such as pain, discomfort, loss of autonomy, stigmatization and discrimination, psychological difficulties, and an overall reduction in quality of life. Direct costs account for the majority of expenses in the early stages of the disease, while indirect costs predominate in the advanced stages. Thus, in patients with a higher level of disability, direct costs decrease, while indirect costs rise dramatically [3,5]. The average annual costs per MS patient in the Czech Republic vary depending on disease severity and type of treatment. According to an analysis conducted in the Czech Republic, when comparing patients stratified by MS severity, annual costs increased by 42% for those with moderate disability and by 131% for those with severe disability compared to patients with mild disability [4]. Between 2011 and 2015, the average total direct costs per patient per year were approximately 118,790 CZK [13]. According to available data from 2023, the total costs of MS therapy amounted to approximately 2.54 billion CZK [14].

 

Early, highly effective therapy—a tool for mitigating the socioeconomic impacts of MS

The introduction of ofatumumab, or high-efficacy therapy (HET), as a first-line treatment for a selected group of patients with relapsing-remitting MS (RRMS) in 2022 represented a major shift in the existing treatment algorithm in the Czech Republic, reflecting current scientific knowledge. Given the presence of unfavorable prognostic signs in this patient group, we should not waste any time. Time cannot be turned back, and this is doubly true in the case of MS. With each relapse and each new lesion on brain and/or spinal cord MRI, CNS reserve is depleted, leading to a decline in the ability to compensate for neuronal damage and loss of brain tissue [15]. Evidence from clinical trials clearly favors a strategy involving initial aggressive suppression of the disease’s inflammatory activity and the induction of long-term remission via HET) [16–20]. From an economic perspective, it is far more advantageous to treat the patient as effectively as possible immediately rather than waiting for an increase in disability, which is associated with reduced self-sufficiency and a decline in the patient’s ability to work (Fig. 3). Total treatment costs rise in proportion to the progression of disability (Table 2).

Positive changes in clinical parameters have a direct impact on the economic aspects of treatment. A reduced frequency of relapses, longer maintenance of functional abilities, and a lower probability of conversion to secondary progressive MS (SP-MS) undoubtedly translate into a reduction in direct healthcare costs, particularly in relation to hospitalizations, the need for symptomatic pharmacotherapy, rehabilitation interventions, or the provision of assisted care. However, savings in indirect costs—namely, lost work productivity, sick leave benefits, disability pensions, and the burden on caregivers—are particularly significant [5,21,22]. The difference in cumulative costs between the strategy of early (“early-HET”) and delayed initiation of HET (“delayed-HET”) can amount to an estimated hundreds of thousands of CZK over a 10-year period in favor of early HET initiation—even after accounting for the higher costs of the DMDs themselves.

Maintaining the ability to work is undoubtedly a crucial factor. Many patients with RR-RS develop the disease during their productive years. Progressive disability leads to a significant decline in labor market participation. Early initiation of HET can significantly delay the point at which a patient is forced to leave the labor market, thereby reducing the socioeconomic burden on the social security system and also extending the period of active contribution to the state budget.

The psychological and behavioral aspects are also important. Patients treated with HET from the outset often demonstrate higher adherence and trust in the healthcare system, which contributes to overall better compliance and treatment efficacy. Conversely, repeated relapses and their cumulative impact can significantly increase the total costs of therapy and related patient care. A severe relapse in a patient with RR-RS is estimated to be associated with financial expenditures that are approximately 240% higher than the costs of a mild or moderate relapse [23]. The gradual loss of independence can then lead to patient resignation, depressive symptoms, and a decline in regular contact with healthcare providers, which in turn increases long-term costs and reduces quality of life.

The data available to us demonstrate that, from the perspective of the long-term sustainability of the healthcare and social systems, a strategy of early HET initiation represents not only a clinically justified but also an economically advantageous approach. Instead of short-term savings on DMD costs, there is an optimization of total costs and a maximization of the return on investment in treatment—both in terms of preserved health and in terms of saved public funds [20].

 

Ofatumumab as first-line therapy in the context of clinical and pharmacoeconomic data

Ofatumumab can be considered a representative of a new generation of treatments for RR-RS, as it combines high clinical and radiological efficacy with long-term stable safety profiles while respecting patients’ needs and lifestyles. The monthly dosing regimen significantly reduces the treatment burden on patients, does not require premedication, and, thanks to the low drug dose in a small injection volume, the product is generally very well tolerated. Furthermore, subcutaneous administration aligns with the currently preferred trend across medical fields for administering biologics, which offers patients greater comfort and saves capacity and resources for the healthcare system. Since its market launch, ofatumumab has relatively quickly established itself as a significant component of the available therapeutic portfolio for treating RR-RS and has seen a dynamic increase in the number of treated patients within a short period. While approximately 40,000 patients in more than 80 countries were being treated with ofatumumab as recently as 2023, by mid-2024 that number had exceeded 100,000, and approval had been extended to more than 90 countries [24]. This increase, more than doubling in a single year, reflects the rapid implementation of the drug into routine clinical practice and confirms its role as one of the most widely used anti-CD20 drugs in the treatment of RR-RS.

Long-term data from the ASCLEPIOS I/II registration clinical trials and the subsequent ALITHIOS open-label follow-up demonstrate a favorable benefit-risk profile of continuous ofatumumab treatment in patients with RR-RS. After 7 years of follow-up, 77.3% of patients treated with ofatumumab from the start remained free of 6-month confirmed disability progression (6mCDP), and nearly 84% remained free of progression independent of relapse (6mPIRA). In the group of patients with a recent diagnosis (≤ 3 years) and treatment-naive patients, the results were even more pronounced—more than 81% remained free of 6mCDP over the 7-year period, and approximately 87.6% remained free of 6mPIRA. Compared with patients who were initially randomized to teriflunomide and later escalated to ofatumumab, in the subgroup of recently diagnosed/treatment-naive patients, continuous exposure from the start was associated with a significantly higher proportion of patients free of 3-month (79.3% vs. 71.3%; p = 0.021) and 6-month confirmed disability progression (81.5% vs. 74.3%; p = 0.031), highlighting the importance of early initiation of HET [25].

The safety profile of ofatumumab remained consistent with previously published results during the 7-year follow-up, and no new safety signals were identified. The most common adverse events were infections and injection-related reactions. The incidence of serious adverse events was low, and laboratory changes in immunoglobulin (Ig) levels were clinically insignificant in most cases—mean IgG levels remained above the lower limit of normal in 96.8% of patients and IgM levels in 64.5% of patients. Discontinuation of treatment due to hypogammaglobulinemia was rare (0.2% for IgG and 3.6% for IgM). Overall, these results indicate that ofatumumab is an effective and long-term safe alternative to first-line therapy in patients with early-stage RR-RS [25].

In an international context, several pharmacoeconomic studies have already been published, particularly cost-effectiveness analyses (CEA) and cost-consequence analyses (CCA), CCA), which compared ofatumumab with other DMDs within modeled scenarios of early and delayed initiation and analyzed their implications for clinical practice and individual healthcare systems. To illustrate the results and provide a general interpretation of these models, we cite as an example a study by Spanish authors [26], which evaluated the impact of early (first-line) versus delayed (3-year delay) initiation of ofatumumab and simultaneously assessed the long-term clinical, societal, and economic consequences of ofatumumab treatment compared with teriflunomide in patients with RR-RS. A cost-effectiveness analysis (CCA) was performed using a Markov cohort model, accounting for various degrees of neurological disability according to the Expanded Disability Status Scale (EDSS). As with other comparable model analyses, the input data were drawn from drug registration clinical trials and published scientific literature. The analysis simulated three scenarios with a 10-year time horizon. Two baseline scenarios compared treatment with ofatumumab (i.e., 10 years of first-line ofatumumab therapy) with treatment with teriflunomide (i.e., 10 years of first-line teriflunomide therapy). The third scenario modeled a 3-year delay in the initiation of ofatumumab treatment, specifically 3 years of teriflunomide treatment followed by 7 years of ofatumumab treatment.

 

Clinical outcome

After 10 years, patients treated with ofatumumab had a higher proportion of individuals with mild disability (EDSS 0–3) than those treated with teriflunomide (57.0% vs. 44.0%). Delaying the start of ofatumumab therapy by 3 years compared to its early initiation led to an 11.4% reduction in this proportion. Over a 10-year period, a lower prevalence of patients confined to a wheelchair or permanently immobile was predicted with ofatumumab than with teriflunomide (11.3% vs. 17.6%). When the initiation of ofatumumab was delayed by 3 years, a 32.2% relative increase in the risk of progression to severe disability (EDSS ≥ 7) and a 20.2% increase in relapse frequency were estimated compared to early treatment.

 

Social Outcome

Modeling suggested that administration of ofatumumab would lead to a higher employment rate (40.0% vs. 35.2%) and a relatively lower proportion of patients with early retirement (13.0% vs. 15.4%) over the 10-year follow-up period compared with teriflunomide therapy. Delaying the initiation of therapy by 3 years was associated with a decline in labor productivity, specifically a 6% lower proportion of employed patients and a 9.1% increase in the proportion of individuals taking early retirement compared to timely treatment.

 

Economic Outcome

The predicted cumulative costs per patient over 10 years were 17.4% lower with ofatumumab therapy compared to the teriflunomide-treated group (€167,327 vs. €202,655). Delaying the start of treatment by 3 years resulted in incremental costs of 24,373 euros per patient (191,700 vs. 167,327 euros), representing a 14.6% increase in total expenditures compared to timely therapeutic intervention with HET (Fig. 4) [26].

Similar conclusions in favor of ofatumumab, from both clinical and economic perspectives, have also emerged from other analyses conducted in various countries, in which ofatumumab was compared not only with so-called platform DMDs but also with other HETs such as natalizumab, cladribine, and ocrelizumab [27–30]. However, it is important to emphasize that developing a realistic pharmacoeconomic model presents a significant methodological challenge. Given the complexity of clinical practice, it is not possible to fully account for all individual and systemic factors that may influence the costs and efficacy of a given therapy. Results are always influenced to some extent by the structure and assumptions of the model used, particularly the method of modeling the natural course of the disease, transitions between individual stages of disability, and response to therapy. In the case of chronic diseases such as MS, the length of the time horizon plays a significant role; it must be sufficiently long to capture the cumulative effects of treatment. At the same time, it is necessary to use a discount rate that accounts for the lower present value of future costs and benefits. Other factors can also significantly influence the results, such as the possibility of treatment discontinuation due to adverse effects or insufficient efficacy, or transitions between treatment lines, which cannot always be predicted. For these reasons, the results of pharmacoeconomic analyses should be viewed as model estimates based on certain assumptions, rather than as definitive conclusions applicable to every patient or specific healthcare setting [5,31].

 

Conclusion

Although MS cannot yet be cured, modern HET, combined with an individualized approach and the utilization of the early “window of opportunity,” significantly alters the disease prognosis. Early initiation of HET allows for the achievement of long-term clinical stability in appropriately indicated patients, minimizes the risk of irreversible neurological damage, and thereby delays the onset of severe disability. Such an approach can not only significantly improve patients’ quality of life but also reduce the systemic socioeconomic burden associated with this chronic disease. However, the challenge remains to accurately determine the extent to which early initiation of HET can actually delay the progression of disability, thereby contributing to reduced healthcare costs and mitigating broader economic impacts in the form of productivity losses and the need for long-term social support. At the same time, it must be taken into account that some HETs are relatively new, and long-term safety data are not yet fully available. Although the concept of early HET is associated with high efficacy, it may be accompanied by increased safety risks, particularly in relation to long-term effects on the immune system. Ongoing research in this area is crucial for a comprehensive assessment of the societal benefits of early HET in selected patients with RR-RS and may provide evidence to support its widespread use as a cost-effective investment in healthcare with a significant impact on society as a whole.

 

Conflict of Interest

The authors declare that they have no conflict of interest regarding the subject of this study.

 

 

Table 1. Overview of the number of disability pensions paid to patients with multiple sclerosis in 2024. Adapted from [2].

 

 

Age	0–19	20–24	25–29	30–34	35–39	40–44	45–49	50–54	55–59	60–64	65+	Total
ID I	2	20	75	204	356	495	658	672	477	265	0	3,224
ID II	0	6	23	69	140	216	367	407	328	193	0	1,749
ID III	0	4	11	40	85	198	479	650	688	670	4	2,829

	Mild disability (EDSS 0–3)	Moderate disability (EDSS 4–6.5)	High disability level (EDSS 7–9)
Total costs (CZK)	257,000 (228,000)	425,500 (291,000)	489,000 (327,500)
Total direct costs	222,605 (200,286)	240,723 (236,585)	254,441 (239,507)
Total indirect costs	34,497 (106,189)	184,765 (191,791)	234,756 (195,838)

Table 2. Average total annual costs per patient by disease severity. Adapted from [12].