Ofatumumab: State of the art in 2024 –⁠ Where are we now and where are we going

Overview

Ofatumumab represents the first fully human anti-CD20 monoclonal antibody, developed for subcutaneous self-administration once a month. It is indicated for the treatment of active relapsing-remitting multiple sclerosis (RR-MS) and can be used as a first-line therapy in patients with negative prognostic factors suggestive of an unfavorable disease course. Ofatumumab demonstrated clear superiority over teriflunomide in registration clinical trials and long-term data from open-label extension studies which confirmed its sustained efficacy, favorable safety profile, and also a high level of patient compliance. From the patient‘s point of view, it is an attractive treatment option with a high-efficacy drug that is easy to administer via subcutaneous injection at home, requiring no premedication. Ofatumumab meets the requirements of modern pharmacotherapy and is one of the breakthrough drugs that can significantly improve the prognosis of patients with RR-MS.

Keywords:

compliance – Safety – Multiple sclerosis – ofatumumab – high effi cacy therapy – effi cacy

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

The importance of B-lymphocytes in the pathogenesis of MS has been demonstrated relatively recently through the effect of anti-CD20 therapy, targeted specifically at B cells. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed for subcutaneous autoapplication at monthly intervals. To date, ofatumumab has been approved in the treatment of relapsing-remitting form of MS (RR -⁠ -RS) in adult patients in 90 countries with more than 100,000 patients treated worldwide (data as of March 2024) [1]. The aim of the development process of ofatumumab as a modern molecule, meeting strict quality, efficacy, safety and tolerability criteria, was to bring to market a highly effective product with a favourable safety and tolerability profile as well as a positive benefit vs. risk ratio, allowing for widespread use within the RR-RS population, by subcutaneous home administration by the patient in a user-friendly regimen. The unique binding site of ofatumumab to unrelated sequences of the small and large extracellular loop of the CD20 surface antigen or its higher affinity for B-lymphocytes, among other factors, contributed to achieving this ambition. The initiation dosing regimen (20 mg on days 1, 7 and 14) then facilitates rapid B cell depletion (with minimal repletion between doses), which is associated with suppression of inflammatory activity followed by long-term administration of a low dose of the drug in a low injection volume (20 mg/0.4 ml) [2]. In terms of mechanism of action, ofatumumab is primarily an activator of complement dependent cytotoxicity (CDC), but to a lesser extent it also mediates antibody-dependent cellular cytotoxicity (ADCC) [3,4]. It is distributed to target organs via the lymphatic system, which provides a rapid and higher concentration at sites where B and T cells interact and which form a reservoir of autoreactive lymphocytes [5,6].

The remarkable results of ofatumumab have already been observed in the main clinical trials of the ASCLEPIOS I and II trials, where it demonstrated superiority over the active comparator, oral teriflunomide, in terms of its positive impact on radiological and clinical parameters, such as a reduction in the annualized relapse rate; ARR), as well as a reduction in the risk of achieving three -⁠ and six-month confirmed disability progression (CDP) or achieving NEDA-3 (No Evidence of Disease Activity) status in the majority of patients in the second year of treatment. The safety profile of the drug was similar to teriflunomide [7]. Patients who completed the double-blind phase in the registration trials could enter the currently ongoing open-label follow-up. Patients treated with ofatumumab in the baseline arm continued with established therapy, and patients who initially received teriflunomide were switched to ofatumumab in the extension arm.

The paper discusses the position ofatumumab in the available therapeutic portfolio of RR-RS and highlights the advantages of the drug, which fulfils the prerequisites of modern pharmacotherapy. The benefits of ofatumumab treatment are supported by the current state of knowledge.

Ofatumumab in the light of the latest findings

Compliance, adherence, persistence

The basic condition for successful therapy is optimal patient cooperation and an active approach to treatment. In general, the patient usually has a good adherence to therapy for acute diseases -⁠ he is able to regularly take painkillers or antibiotics against the infection that causes him trouble. However, adherence to lifelong treatment for chronic diseases, the course of which may be asymptomatic most of the time, is very difficult [8,9]. A patient can only become a "partner in treatment" if he or she has relevant information about his or her disease and treatment options.

Apart from the doctor-patient relationship, many other factors contribute to good adherence and persistence, especially sufficient therapeutic effect, method and frequency of administration or the occurrence of adverse effects on the part of the drug. The attractive administration of ofatumumab once a month is a welcome alternative for patients and also represents a certain psychological aspect -⁠ compared to the regular frequent administration of the drug, which constantly reminds patients of their disease, in this case the patient does not have to think about his disease on a daily basis. Therefore, given the dosing schedule, the ease of subcutaneous administration by the patient from the comfort of home with virtually no side effects and the ease of ongoing laboratory monitoring, very good compliance can be expected, as confirmed by data from clinical trials. In the ASCLEPIOS trials, patient compliance was high and fewer patients discontinued ofatumumab treatment for various reasons overall compared to the teriflunomide-treated arm (14.0 vs. 21.2% in ASCLEPIOS I and 20.0 vs. 21.5% in ASCLEPIOS II) [10]. The long-term compliance and persistence of RR-RS patients on ofatumumab therapy for 4 years was analyzed in a recent paper from 2022. Compliance ≥ 80% was found in up to 95% of patients. Persistence also remains high over the long term, with nearly 9/10 patients remaining on ofatumumab therapy in the ongoing open-label extension of registration trials, ALITHIOS [11].

Other analyses have shown higher persistence rates in patients treated with ofatumumab compared with patients treated with oral and injectable disease modifying drugs (DMDs) [12,13].

Tolerability, safety

The most commonly reported adverse events in clinical development programs with ofatumumab were infusion-related reactions (IRRs) [7,14-17]. In the ASCLEPIOS I and II trials, IRRs occurring within 24 h of injection were reported in 20.2% of patients treated with ofatumumab and 15.0% of patients in the teriflunomide (placebo injection) group [7,18], with the most frequent reactions occurring after the first dose of ofatumumab and being mostly mild, with spontaneous regression [7,16-18]. Analyses of the overall population (1,969 patients from phase 2 and 3 trials) treated with ofatumumab and postmarketing surveillance data demonstrate a consistent, favorable safety profile and good tolerability of the drug with long-term administration, without the need for premedication. Systemic IRRs affected 24.7% of patients, and local IRRs were reported by 11.8% of patients, with the vast majority (>99%) of both reactions being mild to moderate in severity. Only 0.3% of patients with systemic IRRs discontinued ofatumumab treatment [19]. A study comparing intravenous administration of ofatumumab showed a higher incidence of systemic IRRs than subcutaneous administration of the drug [20].

Long-term treatment with ofatumumab has also been shown not to reduce the body's defences and exposure to the drug for ~3.5 years has been assessed as safe in patients with RR-RS. No new safety risks were found; the most common infections were nasopharyngitis, uncomplicated upper respiratory tract infections and uroinfections, there were no cases of progressive multifocal encephalopathy (PML) or other opportunistic infections, and the risk of malignancy was low. Decreases in IgG/IgM immunoglobulin levels were not associated with the occurrence of serious infections [18,21]. The severity and frequency of adverse events are likely to be reduced by the subcutaneous form of administration, the order of magnitude lower drug dose compared to anti-CD20 biologics administered intravenously, and the fully human structure of the antibody [15,22].

The subcutaneous application of mAbs has its advantages for both the patient and the healthcare professionals and is gradually becoming the standard in many fields. The benefits include not only a less invasive and gentler method of administration, reduced incidence of adverse events, increased availability of therapy, but also improved patient adherence to treatment, time savings, lower consumable costs and freeing up capacity in overburdened healthcare facilities. Moreover, subcutaneous administration of ofatumumab using the Sensoready^® pen autoinjector (Novartis, Basel, Switzerland) is easy, fast, intuitive, low risk of injury and, according to research, has a high success rate of correct injection (>80%), even in patients with no previous experience with injection therapy or patients without prior training by a healthcare professional [23,24].

Efficiency

The long-term efficacy of ofatumumab is being continuously evaluated in the open-label extension study, ALITHIOS.

The ARR in the group of patients with earlier initiation and continued ofatumumab therapy remained in the low range (core: 0.11, extension: 0.05; relative reduction 49.4%; p < 0.001) for up to 4 years after initiation of treatment, which translates to one relapse in 20 years. In the second year of treatment, 9 out of 10 patients were free of measurable disease activity, i.e., NEDA-3 status was achieved, and the odds of maintaining this parameter were more than 3-fold higher in patients receiving ofatumumab from the start of the study compared with those initially receiving teriflunomide. In the continuous ofatumumab group, almost complete suppression of activity on MRI also persisted for 4 years. Continued exposure to ofatumumab led to a reduction in both the number of gadolinium enhancing T1 lesions (mean number per scan, core: 0.02, extension: 0.01; relative reduction 65.0%; p = 0.003) and the number of new T2 lesions (annual rate, core: 0.66, extension: 0.08; relative reduction 87.9%; p < 0.001) [21]. Also, the annual loss of brain tissue volume remained low in the 5th year of ofatumumab therapy (core: -0.34%, extension: -0.27%) [25]. Recent data indicate the persistent efficacy of ofatumumab as the first-line treatment for up to 6 years in adult patients with RR-RS [26].

Comparative analyses demonstrated that longer retention on ofatumumab therapy was associated with reduced ARR rates, reduced 3-month and 6-month CDP, and suppressed activity on MRI compared with patients who were first treated with teriflunomide and only switched to ofatumumab in the open-label phase of the study [21,26]. Patients treated with ofatumumab for 6 years experienced 44% fewer relapses, had 96.4% and 82.7% fewer lesions on MR (gadolinium enhancing T1 and new/increasing T2), and had 24.5% and 21.6% lower risk of 3-month and 6-month CDP compared to those who were escalated to ofatumumab from teriflunomide. Continuous ofatumumab also favourably influenced the three -⁠ and six-month progression independent of relapse activity (PIRA) rates, a parameter that plays an important role in disease progression and may become a major contributor to the increase in disability over time [26,27]. Although the later switch to ofatumumab led to a significant improvement in the monitored parameters, the lost time resulting in irreversible disability accumulation could no longer be made up [26]. The observed differences in efficacy, seen repeatedly in both groups, highlight the benefit of early initiation of high-efficacy therapy (HET) [28-31].

"To wait or too late?"

Until recently, the completely dominant escalation model has proven itself over the years in patients with low/moderate disease activity, but in patients with unfavourable prognostic factors and high clinical and radiological activity from the beginning of the disease, such treatment did not bring the expected results. The concept of "inverting the pyramid", which corresponds to the use of HET (in a selected group of patients) at the very beginning of the disease, i.e. after the first disease attack, is no longer a mere theory. On the contrary, it is gradually being implemented in routine clinical practice in many countries. The purpose of all currently approved drugs for the treatment of RR-RS is to effectively suppress inflammatory activity, which is most pronounced in the early stages of disease development, and therefore it is logical to focus all therapeutic efforts on the early phase of RR-RS. One of the key goals of treatment for RR-RS is to reverse the accumulation of irreversible neurological deficits and prevent conversion to secondary progressive phase (SP-RS) [28-31]. The literature reports a 29% lower risk of disability progression in patients treated with HET after diagnosis [32], and other data suggest that earlier initiation of HET results in a lower long-term risk of conversion to SP-RS in RR-RS [33].

According to cost-effectiveness analyses, it is preferable to treat the patient as effectively as possible immediately and not to wait for the increase in disability, which is associated with limited self-sufficiency and a decline in the patient's ability to work. Disability is a driver of costs, which increase substantially with increasing levels of disability [34,35].

Conclusion

As the number of DMDs increases, patient expectations and preferences play an increasingly important role in the decision-making process for selecting the appropriate product. Ongoing analyses from patient satisfaction surveys repeatedly favour convenient-to-use DMDs that suit the lifestyle of largely young, socially and economically active patients and do not interfere with their daily life with bothersome side effects. The vast majority of patients naturally prefer the option of taking their medication at home rather than visiting a hospital; moreover, self-administration of the drug gives patients a sense of satisfaction that they have taken control of their own treatment.

Ofatumumab fulfils the vision of a modern 21st century drug. It represents the first B-cell therapy designed for home subcutaneous administration once a month. As a highly effective drug, it is designed for the treatment of active RR-RS and can be used as first-line therapy in patients with signs of an unfavourable disease prognosis. Cumulative safety and efficacy data for up to 6 years suggest that long-term treatment with ofatumumab is well tolerated in patients with RR-RS, with a persistent excellent effect on both clinical and radiological parameters. Time is of the essence in this respect, and if we have the opportunity to give patients the chance to achieve the best possible long-term results, it is appropriate to use it rationally.

Conflict of interest

The authors declare that they have no conflict of interest in relation to the subject of the study.