Practical Recommendations from the Gulf Region on the Therapeutic Use of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis: Impact of the Latest Real-World Evidence on Clinical Practice.

Cladribine tablets (CladT), like alemtuzumab, acts as an immune reconstitution therapy. However, CladT is administered orally (alemtuzumab is given by infusion) and without the potential for serious side effects that limit the therapeutic use of alemtuzumab in multiple sclerosis (MS). Treatment with CladT, given initially as short courses of treatment 1 year apart, provides years of freedom from MS disease activity in responders to treatment. The appearance of mild or moderate MS disease activity after the initial 2 years of treatment may prompt careful follow-up or a further course of CladT, depending on the nature of the activity and individual circumstances. The appearance of severe MS disease activity requires a switch to an alternative high-efficacy disease-modifying treatment (DMT). The accumulating data from CladT-treated people with MS in real-world studies, including those with follow-up durations extending for years beyond the initial treatment, have demonstrated long-term freedom from MS disease activity in a good proportion of patients. This clinical experience has also confirmed that treatment with CladT is generally safe and well tolerated. The best time to prescribe a high-efficacy DMT is the subject of debate, with evidence that earlier versus later use of such agents may provide more effective long-term protection from disability progression. High-efficacy DMTs have traditionally been reserved for use in people with MS and high disease activity on presentation or breakthrough disease on one or more DMTs, as per the current product labels. The latest evidence from real-world studies suggests that CladT is effective and safe in DMT-naïve patients, including those with shorter disease duration.

Cladribine effects on patient-reported outcomes and their clinical and biometric correlates in highly active relapsing multiple sclerosis at first switch: the observational, multicenter, prospective, phase IV CLADFIT-MS study.

Patient-reported outcomes (PROs) are essential for understanding the effects of MS and its treatments on patients' lives; they play an important role in multiple sclerosis (MS) research and practice. We present the protocol for an observational study to prospectively assess the effect of cladribine tablets on PROs and their correlation to disability and physical activity in adults with highly active relapsing MS switching from a first disease modifying drug (DMD) to cladribine tablets in routine clinical practice at study sites in Italy. The primary objective will be to evaluate changes from baseline in the impact of highly active MS on self-assessed physical functioning 52 weeks after the switch to cladribine tablets using the Multiple Sclerosis Impact Scale-29 (MSIS-29). Secondary objectives will include self-assessed psychological impact of highly active MS in daily life and general health after the switch to cladribine tablets as well as changes in cognitive function, anxiety, and depression symptoms. Additional PRO measures will include the Hospital Anxiety and Depression Scale (HADS), the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), the Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis (WPAI:MS), and the Patient-Reported Outcomes Measurement Information System (PROMIS). Wearable devices will acquire activity data (step counts, walking speed, time asleep, and energy expenditure). Additional clinical, radiological, and laboratory data will be collected when available during routine management. The findings will complement data from controlled trials by providing insight from daily clinical practice into the effect of cladribine tablets on the patient's experience and self-assessed impact of treatment on daily life.

Clinical and biological predictors of Cladribine effectiveness in Multiple Sclerosis: A real-world, single Centre study considering a two-year interval from year-2 dosing.

OBJECTIVES: Cladribine tablets (CLAD) for adult patients with highly active relapsing multiple sclerosis (RMS) have been available in Italy since 2018. We aimed to assess predictors of no-evidence-of-disease-activity-3 (NEDA-3) status after 24 months of the last dose of CLAD. RESULTS: We included 88 patients (70.5% female, mean age at CLAD start 35.4 ± 11.4). Eighteen patients were treatment naïve, 48 switched to CLAD from a First line Disease Modifying Drug (DMD), and 22 from Second line DMDs. All patients were observed for a median follow-up time of 2.4 (1-4) years after the last dose of CLAD. Forty-nine patients (55.7%) showed NEDA at the last available follow-up. Naïve patients (p = 0.001), those with a lower number of previous DMDs (p < 0.001) and, even though not significantly, those switching from first line DMDs (p = 0.069) were more likely NEDA3 at the last available follow-up. In a subgroup of 30 patients (34%), Serum Light Neurofilaments (sNFL) levels showed a decrease from baseline to the 24 months of follow-up, statistically significant from baseline to the sixth month, and from the first to the second year detection. sNFL levels at 12th month showed a strong inverse correlation with the time to NEDA3 loss. CONCLUSIONS: Our experience provides information for the 2-years after the last dose of CLAD, confirming a higher effectiveness of CLAD when placed early in the treatment algorithm. Given the ongoing expansion of the therapeutic landscape in MS, sNfL could support individualized decision-making, used as blood-based biomarker for CLAD responses in clinical practice.

Making Information About Cladribine Tablets Accessible to People with Multiple Sclerosis: A Patient-Survey-Led Narrative Review for Healthcare Professionals.

Cladribine tablets have been granted marketing authorization in Europe and approved by the Food and Drug Administration (FDA) in the USA to treat relapsing forms of multiple sclerosis (MS). However, people with MS (PwMS) may be more familiar, and therefore more confident, with treatments requiring long-term and frequent dosing. Differences in such treatment strategies can lead to questions relating to how short-course non-continuous treatments, such as cladribine tablets, can work and how well they are tolerated. In response to this, we aimed to create an evidence-based report on patient-focused aspects of treatment with cladribine. To inform development, MS experts, including healthcare professionals (HCPs) and PwMS, proposed topics that PwMS and their families and caregivers would most like to discuss with HCPs during consultations to help them better understand cladribine treatment. The statements regarding each topic were then ranked by PwMS and used to inform the topics covered in this report. We explain here the use of cladribine tablets, which includes explanations of how cladribine tablets work, how to take cladribine tablets, and considerations required prior to and while taking cladribine tablets. We also describe how cladribine tablets affect relapse rate and quality of life and detail side effects, when they are likely to happen, and for how long. We also discuss how cladribine tablets affect family planning, fertility, and the use of vaccines. Alongside each section is a brief, plain language description of what is covered and an accompanying visual to aid conversations between HCPs and PwMS. Improved understanding by PwMS of treatments, such as cladribine, can empower them to play a bigger role in shared decision-making regarding their treatment. Additionally, the open dialogue we aim to promote with this type of report could lead to treatment choices being better tailored for individuals with chronic diseases on the basis of personal experiences, preferences, and circumstances.

Narrative Review on the Use of Cladribine Tablets as Exit Therapy for Stable Elderly Patients with Multiple Sclerosis.

The number of ageing people with relapsing multiple sclerosis (RMS) is increasing. The efficacy of disease-modifying therapies (DMTs) for RMS declines with age. Also, older persons with MS may be more susceptible to infections, hospitalisations and malignancy. Aging people with MS have higher rates of comorbidities versus aged-matched controls, increasing the individual risk of disability. We review the therapeutic properties of cladribine tablets (CladT) in ageing people with RMS, with regard to their utility for allowing these individuals to cease continuous administration of a DMT (i.e. to act as an "exit therapy"). CladT is thought to be an immune reconstitution therapy, in that two short courses of oral treatment 1 year apart provide suppression of MS disease activity in responders that far outlasts the duration of treatment and post-treatment reductions in lymphocyte counts. Post hoc analyses, long-term follow-up of populations with RMS in randomised trials, and real-world evidence suggest that the efficacy of CladT is probably independent of age, although more data in the elderly are still needed. No clear adverse signals for lymphopenia or other adverse safety signals have emerged with increasing age, although immunosenescence in the setting of age-related "inflammaging" may predispose elderly patients to a higher risk of infections. Updating vaccination status is recommended, especially against pneumococci and herpes zoster for older patients, to minimise the risk of these infections. CladT may be a useful alternative treatment for ageing people with MS who often bear a burden of multiple comorbidities and polypharmacy and who are more exposed to the adverse effects of continuous immunosuppressive therapy.

Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need. Objectives: To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets. Design: Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS. Methods and analysis: Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes. Discussion: The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.

Prospective observational study to evaluate treatment satisfaction and effectiveness in patients with relapsing multiple sclerosis starting cladribine tablets (CLADREAL) in Italy.

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing-remitting and active secondary progressive MS) who are either treatment naïve or have received at least one first-line disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient's experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022.

Holistic, Long-Term Management of People with Relapsing Multiple Sclerosis with Cladribine Tablets: Expert Opinion from France.

Cladribine tablets (CladT) has been available for therapeutic use in France since March 2021 for the management of highly active relapsing multiple sclerosis (RMS). This high-efficacy disease-modifying therapy (DMT) acts as an immune reconstitution therapy. In contrast to most high-efficacy DMTs, which act via continuous immunosuppression, two short courses of oral treatment with CladT at the beginning of years 1 and 2 of treatment provide long-term control of MS disease activity in responders to treatment, without the need for any further pharmacological treatment for several years. Although the labelling for CladT does not provide guidance beyond the initial treatment courses, real-world data on the therapeutic use of CladT from registries of previous clinical trial participants and patients treated in routine practice indicate that MS disease activity is controlled for a period of years beyond this time for a substantial proportion of patients. Moreover, this clinical experience has provided useful information on how to initiate and manage treatment with CladT. In this article we, a group of expert neurologists from France, provide recommendations on the initiation of CladT in DMT-naïve patients, how to switch from existing DMTs to CladT for patients with continuing MS disease activity, how to manage patients during the first 2 years of treatment and finally, how to manage patients with or without MS disease activity in years 3, 4 and beyond after initiating treatment with CladT. We believe that optimisation of the use of CladT beyond its initial courses of treatment will maximise the benefits of this treatment, especially early in the course of MS when suppression of focal inflammation in the CNS is a clinical priority to limit MS disease progression.

Substantial and comparable suppression of disease activity following early initiation of cladribine tablets, ocrelizumab or alemtuzumab as first pharmacologic treatment for relapsing multiple sclerosis: A real world study.

BACKGROUND: We describe the efficacy and safety of recent high efficacy disease DMTs in DMT-naive patients with highly active RMS. METHODS: This was a retrospective, cross sectional study from the Kuwait national MS registry. Patients with RMS who received alemtuzumab, cladribine tablets or ocrelizumab as their first DMT for RMS, with ≥2 year of follow up were included. The primary endpoint was the change in relapse rate from treatment initiation to 1 year; changes in disability (Expanded Disability Status Scale [EDSS]), radiologic activity, the proportion with no evidence of disease activity-3 (NEDA-3), and the frequency of adverse events were secondary endpoints. RESULTS: Among 123 RRMS patients, 59 received ocrelizumab, 32 received cladribine tablets and 32 received alemtuzumab. About two-thirds (65%) were women. Substantial and similar (p>0.05) reductions occurred at the end of follow-up in annual relapse rate (by 93.2% for ocrelizumab, 87.5% for cladribine tablets, and 90.6% for alemtuzumab). The proportion with new T2 of gadolinium-enhancing MRI lesions across the three groups was reduced from 85-100% to 7-13%. Rates of confirmed disability progression were low (ocrelizumab 6.9%, cladribine tablets 3.1%, alemtuzumab 0%; p=0.280); disability was reduced in 15%, 22% and 38%, respectively. NEDA-3 was observed in 89.8%, 87.5%, and 84.4, respectively (p=0.784). No new or unexpected safety issues occurred. CONCLUSION: Ocrelizumab, cladribine tablets and alemtuzumab reduced relapse rates and MRI activity, and prevented disease progression, when are initiated early in DMT-naive RMS patients. These data support the early use of high-efficacy DMTs for people with highly active RMS.

Sustained effects on immune cell subsets and autoreactivity in multiple sclerosis patients treated with oral cladribine.

Introduction: Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS). Recently, we showed that one year after the initiation of cladribine treatment, T and B cell crosstalk was impaired, reducing potentially pathogenic effector functions along with a specific reduction of autoreactivity to RAS guanyl releasing protein 2 (RASGRP2). In the present study we conducted a longitudinal analysis of the effect of cladribine treatment in patients with RRMS, focusing on the extent to which the effects observed on T and B cell subsets and autoreactivity after one year of treatment are maintained, modulated, or amplified during the second year of treatment. Methods: In this case-control exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing-remitting MS (RRMS) and patients treated with cladribine for 52 (W52), 60 (W60), 72 (W72) and 96 (W96) weeks, were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay. Results: We found a substantial reduction in circulating memory B cells and proinflammatory B cell responses. Furthermore, we observed reduced T cell responses to autoantigens possibly presented by B cells (RASGRP2 and a-B crystallin (CRYAB)) at W52 and W96 and a further reduction in responses to the myelin antigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) after 96 weeks. Conclusion: We conclude that the effects of cladribine observed after year one are maintained and, for some effects, even increased two years after the initiation of a full course of treatment with cladribine tablets.

Practical Guidance on the Use of Cladribine Tablets in the Management or Relapsing Multiple Sclerosis: Expert Opinion from Qatar.

The increasing availability of high-efficacy disease-modifying therapies (DMT) for the management of relapsing multiple sclerosis (RMS) has increased the potential for individualised patient management but has added complexity to the design of treatment regimens. The long-term application of immune reconstitution therapy (IRT) is supported by an increasing database of real world studies that have added important information on the long-term safety and efficacy of this approach. Cladribine tablets (CladT) is an IRT given as two annual short courses of treatment, following which a majority of patients then demonstrate no significant MS disease activity over a period of years. Whether, and how, to treat patients beyond the first two years of treatment remains a matter for debate, as clinical evidence accumulates. We, a group of neurologists who manage people with RMS in Qatar, provide our expert consensus recommendations on the application and long-term management of CladT therapy based on our experience with treatment in the last 5 years. These include pragmatic recommendations for people with MS disease activity in years 3 and 4 (ie up to four years following first dose of CladT), and for people with or without MS disease activity in subsequent years. We believe our recommendations will help to ensure the optimal application of CladT-based IRT, with the potential benefit for the patient of achieving prolonged periods free of both MS disease symptoms and the burden of regular applications of immunosuppressive DMT.

Improvements in quality of life over 2 years with cladribine tablets in people with relapsing multiple sclerosis: The CLARIFY-MS study.

BACKGROUND: Multiple sclerosis (MS) negatively affects health-related quality of life (HRQoL). OBJECTIVE: To evaluate HRQoL in people with highly active relapsing MS treated with cladribine tablets (CladT; 3.5 mg/kg cumulative dose over 2 years) in CLARIFY-MS. METHODS: Changes in the MS quality of life (MSQoL)-54 scores were analysed using a repeated mixed-effects linear model. Subgroup analyses were performed for participants who were pretreatment-naïve and those pretreated with disease-modifying therapies (DMTs) before initiating CladT. Safety and tolerability of CladT were also assessed. RESULTS: MSQoL-54 physical (mean change = 4.86; 95% confidence interval (CI) = 3.18, 6.53) and mental health (4.80; 95% CI = 3.13, 6.46) composite scores (primary endpoints) showed significant improvement at Month 24 versus Baseline (p < 0.0001). Changes in the MSQoL-54 scores were consistent across the pretreatment-naïve and DMT-pretreated subgroups. No new severe or opportunistic infections occurred. Most post-baseline lymphopenia events were Grade 1-2 in severity. Transient Grade-3 lymphopenia was observed in 19.7% (95/482) of participants. Grade-4 lymphopenia was not observed. CONCLUSIONS: CladT treatment significantly improved the mean MSQoL-54 physical and mental health composite scores over 2 years. CladT efficacy in HRQoL, relapse rates and Expanded Disability Status Scale scores demonstrates its multidimensional effects in MS treatment.

Real-world treatment patterns and effectiveness of cladribine tablets in patients with relapsing forms of multiple sclerosis in the United States.

BACKGROUND: Real-world evidence on the use of cladribine tablets (CladT) for relapsing forms of multiple sclerosis (RMS) in the United States is emerging. The objective of this study was to assess the real-world treatment patterns and effectiveness of CladT in RMS. METHODS: Adults with RMS initiating CladT were selected from the Symphony Integrated Dataverse. Baseline and follow-up periods were the 12 months before and 24 months after CladT initiation (index date). Switching to another disease-modifying therapy (DMT) and number of CladT courses were described during follow-up. Annualized relapse rate (ARR), MS disease severity, Expanded Disability Status Scale-Derived Disability Indicators (EDSS-DDI), corticosteroid use, and healthcare resource utilization (HRU) were described during Years 1 and 2 of follow-up and compared with baseline. RESULTS: A total of 539 CladT-treated patients were included (mean age: 49.9 years; 77.6 % female). Over the 2-year follow-up, 91 % and 59 % of patients had one and two CladT courses, respectively, and 7 % of patients had evidence of switching to another DMT. ARR, MS disease severity score, and corticosteroid use decreased significantly during follow-up compared with baseline, while EDSS-DDI remained stable. All-cause and MS-related HRU decreased during follow-up. CONCLUSION: CladT-treated patients with RMS had low switch rates, reduced ARR, disease severity, corticosteroid use, and HRU.

The CLARION study: first report on safety findings in patients newly initiating treatment with cladribine tablets or fingolimod for multiple sclerosis.

OBJECTIVES: As part of the CLARION study: (1) characterize the incidence of severe infections, herpes zoster, and malignancies in patients newly initiating cladribine or fingolimod for relapsing multiple sclerosis (MS); (2) estimate the incidence of severe lymphopenia among cladribine users; and (3) describe prior/subsequent disease-modifying therapy (DMT) in both cohorts. METHODS: Patients were identified from seven participating MS registries/data sources. The incidence rate (IR) of each outcome per 1000 patient-years and its 95% confidence interval (95%CI) were estimated for cohorts using Poisson regression. RESULTS: By cut-off date (01-April-2020), 742 cladribine and 867 fingolimod users were included. Mean follow-up was ∼1 year. The IR for severe infections from all contributing sources (except Denmark) was: cladribine, 7.37 (2.76,19.6); fingolimod, 6.55 (2.46,17.4). The corresponding IR for herpes zoster was 5.51 (1.78,17.1) and 3.27 (0.82,13.1), respectively, while values for opportunistic infections were 0 (0,6.76) and 1.63 (0.23,11.6), respectively. There were no events of progressive multifocal leukoencephalopathy in either cohort. The IR of severe lymphopenia was 63.9 (40.7,100.1) in 349 cladribine users from contributing sources. The IR of malignancies (cut-off date 01-April-2022) was 3.55 (1.59,7.90) for the cladribine cohort (n = 1035) and 3.55 (1.48,8.52) for the fingolimod cohort (n = 843) from three MS registries/data sources. In the combined data sources, 36.8% of cladribine and 27.4% of fingolimod users were DMT-naïve; after initiation of study treatment, 2.5% and 20.2% switched to another DMT, respectively. CONCLUSION: No new safety signal was observed in patients treated with cladribine tablets, although results are limited by a relatively short duration of follow-up.

Evaluation of Patient-Reported Outcomes in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets in the CLAWIR Study: 12-Month Interim Analysis.

INTRODUCTION: Patient-reported outcomes (PROs) provide an insightful method of assessing the subjective impact of therapies for those affected by multiple sclerosis (MS), a chronic neurologic disease notable for symptoms of fatigue and reduced physical function. The ongoing CLAWIR study aims to assess the effect of cladribine tablets (3.5 mg/kg cumulative dose over 2 years) in patients with highly active relapsing MS focusing on PROs of fatigue, physical function, treatment satisfaction, and work productivity. Here, we report on a pre-planned analysis at 12 months after treatment initiation with cladribine tablets. METHODS: CLAWIR is a 2-year, multicenter, prospective, observational study of patients with relapsing MS newly initiating cladribine tablets. The following PROs were analyzed: PRO Measurement Information System (PROMIS®) Fatigue MS (v1.0) and Physical Function MS (v2.1), Treatment Satisfaction Questionnaire for Medication (TSQM, v1.4), and Work Productivity and Activity Impairment MS Questionnaire (WPAI-MS). Data were analyzed descriptively. RESULTS: In total, 128 patients were eligible for analysis: 95 females (74.2%); median (range) age 34.5 (29, 44) years; 34 patients (26.6%) were treatment-naïve, and 89 (69.5%) were early switchers from platform therapies (the remaining 5 patients [3.9%] switched from a high-efficacy disease-modifying therapy). PROMIS® Fatigue MS mean (± standard deviation [SD]) T-scores decreased from 54.6 (± 9.59) at baseline to 51.8 (± 10.30) at 12 months, indicating an alleviation of fatigue, whereas PROMIS® Physical Function MS mean T-scores remained stable over time [baseline: 49.4 (± 10.69); 12 months: 50.3 (± 10.88)]. TSQM v1.4 mean scores indicated an improvement over time, increasing from 52.2 (± 27.79) at baseline to 81.4 (± 17.06) at 12 months for global satisfaction. WPAI-MS scores also showed an improvement across all four domains over 12 months. CONCLUSION: This real-world study demonstrates the effect of cladribine tablets over 12 months on PROs of fatigue, physical function, treatment satisfaction, and work productivity. TRIAL REGISTRATION: The CLAWIR study is registered at the German Federal Institute for Drugs and Medical Devices with the internal NIS number 7469.

[New neuroimaging methods in assessing the activity of neuroinflammation in multiple sclerosis]. / Novye metody neirovizualizatsii otsenki aktivnosti neirovospaleniya pri rasseyannom skleroze.

The review presents current data on the use of positron emission tomography and single-photon emission computed tomography in multiple sclerosis (MS) to assess the activity of the pathological process, including neuroinflammation, demyelination, activation of microglia, neurodegeneration and local blood flow disorders. These methodologies are a new approach for studying the mechanisms of action and evaluating the clinical effect of disease modifying therapy of MS, especially those capable of penetrating into brain tissue. Among them, the most attention is attracted by cladribine tablets acting on the mechanism of immune reconstitution therapy, most likely with the modulation of immune reactions directly in the brain tissue.

A plain language summary on assessing the long-term effectiveness of cladribine tablets in people living with relapsing multiple sclerosis: The CLASSIC-MS study.

WHAT IS THIS SUMMARY ABOUT?: Previous studies have shown that people living with multiple sclerosis (MS) treated with cladribine tablets have fewer relapses (where new symptoms occur or existing symptoms get worse for 24 hours or more) and delayed disability progression (slowing down of the disease getting worse). The CLASSIC-MS study looked at the long-term effectiveness of treatment with cladribine tablets in people living with MS who had taken part in the original CLARITY and CLARITY Extension clinical studies. WHAT WERE THE RESULTS?: Results showed that people treated with cladribine tablets maintained their mobility (the ability to move freely) for longer and experienced other positive effects long after their treatment ended, including being less likely to need further treatment for their MS. WHAT DO THE RESULTS MEAN?: The results obtained from CLASSIC-MS show that the benefits of taking cladribine tablets carry on even when patients stop taking the treatment.

Real-world use of cladribine tablets (completion rates and treatment persistence) in patients with multiple sclerosis in England: The CLARENCE study.

BACKGROUND: Treatment with cladribine tablets, a high-efficacy disease-modifying therapy (DMT), has been available in England since 2017 for patients with highly active relapsing multiple sclerosis (MS). Real-world data on treatment completion, persistence and switching in patients treated with cladribine tablets are beginning to emerge, but only small single and multicentre cohorts have reported so far. This longitudinal retrospective observational study (CLARENCE) evaluated a large cohort (>1900) of patients with highly active relapsing MS, receiving cladribine tablets across England, to determine rates of treatment completion, persistence and switching in the real world. METHODS: Using data obtained from Blueteq® forms, a compulsory requirement for DMT reimbursement in England, we evaluated rates of treatment completion (defined as the proportion of patients who received the full 2-year course of cladribine tablets), treatment persistence (defined as the proportion of patients who did not switch and/or discontinue treatment before receiving the full 2-year course) and treatment switch (defined as the proportion of patients who switched treatment from cladribine tablets to another DMT at any point after their first course). The change in Expanded Disability Status Scale (EDSS) score between Years 1 and 2 of treatment was also determined. All data were analysed descriptively. RESULTS: Blueteq® forms were completed for 1934 MS patients treated with cladribine tablets; of these patients, 691 (36%) were treatment naïve. The median EDSS score (range) at treatment initiation with cladribine tablets was 2.5 (0, 8.5). At time of analysis (September 2021, last follow-up point), a total of 1020 (53%) patients had completed the full 2-year course of cladribine tablets. At the same time point, 1762 (91%) patients were considered as treatment persistent (i.e., the patient had completed either 1 course of tablets with <18 months of follow-up data or the full 2-year course of cladribine tablets). Overall, 78 (4%) patients switched to another DMT at any point after their first course, which included 33 (1.7%) patients who switched after completing the full 2-year course. In terms of their disability, 469 (84%) patients had stable EDSS scores between Years 1 and 2 of treatment. CONCLUSION: In this large real-world study of patients receiving cladribine tablets across England, high rates of treatment persistence and low rates of switching were observed, with only 1.7% of patients receiving the full 2-year course and switching treatment. The majority (84%) of evaluable patients showed stable disability between Years 1 and 2 of treatment. These findings complement earlier data from clinical trials and real-world studies, confirming the effectiveness of cladribine tablets for patients with highly active relapsing MS.

Multiple sclerosis patients treated with cladribine tablets: expert opinion on practical management after year 4.

Multiple sclerosis (MS) is a chronic, progressive neurological disease involving neuroinflammation, neurodegeneration, and demyelination. Cladribine tablets are approved for immune reconstitution therapy in patients with highly active relapsing-remitting MS based on favorable efficacy and tolerability results from the CLARITY study that have been confirmed in long-term extension studies. The approved 4-year dosing regimen foresees a cumulative dose of 3.5 mg/kg administered in two cycles administered 1 year apart, followed by 2 years of observation. Evidence on managing patients beyond year 4 is scarce; therefore, a group of 10 neurologists has assessed the available evidence and formulated an expert opinion on management of the growing population of patients now completing the approved 4-year regimen. We propose five patient categories based on response to treatment during the first 4-year regimen, and corresponding management pathways that envision close monitoring with clinical visits, magnetic resonance imaging (MRI) and/or biomarkers. At the first sign of clinical or radiological disease activity, patients should receive a highly effective disease-modifying therapy, comprising either a full cladribine regimen as described in regulatory documents (cumulative dose 7.0 mg/kg) or a comparably effective treatment. Re-treatment decisions should be based on the intensity and timing of onset of disease activity, clinical and radiological assessments, as well as patient eligibility for treatment and treatment preference.

Practical recommendations on treatment of multiple sclerosis with Cladribine: an Israeli Experts Group Viewpoint.

Cladribine tablets (Mavenclad®) were approved by the European Union in 2017 as high-efficacy therapy for highly active relapsing-remitting multiple sclerosis. In Israel, Mavenclad® was approved in 2018. Real-life experience has confirmed the efficacy of cladribine tablets over at least 4 years from the initial course. During the last years, several questions were raised concerning the management of people with MS who show disease activity during years 3 and 4 post-cladribine initiation and what treatment decisions are needed beyond year 4. A few expert boards have tried to provide insight based on research data and to suggest recommendations on the therapeutic dilemmas and treatment decisions with cladribine. However, there is currently no widely accepted consensus about these issues. The vast clinical experience gained in Israel in the past 5 years in several MS centers across the country allows for a broad perspective of the outcomes with long-term cladribine use. This article summarizes previously published recent recommendations and describes the insights of Israeli neurology key opinion leaders that convened for an advisory board meeting on January 29th, 2023, with the aim of reaching a consensus regarding cladribine long-term treatment and follow-up.