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.

Evaluation of therapy satisfaction with cladribine tablets in patients with RMS: Final results of the non-interventional study CLEVER.

BACKGROUND: Cladribine tablets for the treatment of relapsing multiple sclerosis (RMS) are administered in two pulsed treatment courses in two consecutive years, totalling a maximum of 20 treatment days. Here we present data collected shortly after the launch of cladribine tablets, focusing on the patient's perspective. The objective was to investigate patients' perceived effectiveness, tolerability, and convenience, as well as global satisfaction of and with cladribine tablets. METHODS: CLEVER was a non-interventional multicentre study conducted in Germany from 12/2017 to 7/2020. Adult patients with RMS initiating therapy with cladribine tablets were included. Observation time per patient was 24 weeks, comprising 3 visits (baseline, week 4 and 24). The primary endpoint was overall treatment satisfaction at week 24, assessed by the Treatment Satisfaction Questionnaire for Medication 14 items (TSQM 1.4). Subgroup analyses included stratification by prior treatment. RESULTS: In total, 491 patients (69.2 % female; mean (±SD) age 40.3 (±11.5) years, 85.1 % pre-treated, median EDSS 2.5) initiated therapy with cladribine tablets and were included in the analysis. At week 24, the mean (±SD) global TSQM satisfaction score was 75.6 (±19.0). For patients switching from either injectables or oral medication, the change in therapy satisfaction from baseline to week 24 was positive in all TSQM domains with clinically meaningful effect sizes in the global satisfaction and side effects domains. Most patients (85.5 %) remained relapse-free over 24 weeks. Out of 491 patients, 187 (38.1 %) experienced at least one adverse event and 8 patients (1.6 %) one serious adverse event. CONCLUSION: Treatment satisfaction with cladribine tablets was high. The switch from prior injectables or oral medication translated into increased treatment satisfaction at week 24 with clinically meaningful effects in the global satisfaction and side effects domains. Effectiveness and safety were consistent with results from clinical studies.

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.

Efficacy and safety of ocrelizumab in patients with relapsing multiple sclerosis: Real-world experience of two Swiss multiple sclerosis centers.

BACKGROUND: Ocrelizumab (OCR) is a humanized monoclonal antibody directed against CD-20 positive lymphocytes, mainly B-lymphocytes. OCR is approved for treatment of primary progressive (PPMS) and relapsing multiple sclerosis (RMS). This study aims to provide real-world safety and efficacy data of people with RMS treated with OCR in two Swiss Multiple Sclerosis (MS) centers. METHODS: We have conducted a retrospective data analysis using the patient cohorts from the Cantonal Hospital Aarau and Bern University Hospital (RMS: n = 235). Statistical analyses were performed with Mann-Whitney U-Test, Chi-squared test and Spearman-Rho-Correlation. Adjustment for multiple testing was performed by Bonferroni procedure. RESULTS: After initiation of OCR, there was a decrease in disease activity in RMS patients. In our study, 152/190 (80.0 %) RMS patients fulfilled the criteria for NEDA-3 12 months and 88/104 (84.6 %) showed NEDA-3 24 months after OCR initiation. The most frequent adverse events (AEs) in our study were infections, taking place in 78/235 (33.2 %) RMS patients. COVID-19 was the most common infection, followed by urinary infections and other respiratory infections and infectious adverse events occurred significantly more frequent in patients with reduced IgG serum concentration. CONCLUSIONS: Our real-world study showed OCR being associated with low rates of any type of MS disease activity as indicated by NEDA-3. The adverse event profile is comparable to the known events especially infections and an association between infections and reduced IgG serum concentration was found.

Teriflunomide in pediatric patients with relapsing multiple sclerosis: Open-label extension of TERIKIDS.

BACKGROUND: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension. METHODS: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension. RESULTS: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39-0.98; p = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33-0.98; p = 0.043) and 49% (RR 0.511; 95% CI 0.34-0.76; p = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23-0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group. CONCLUSION: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings.ClinicalTrials.gov: NCT02201108.

Treatment algorithms of relapsing multiple sclerosis: an exploration based on the available disease-modifying therapies in China.

Multiple sclerosis (MS) was defined as a rare disease in China due to its low prevalence. For a long time, interferon ß was the only approved disease-modifying therapy (DMT). Since the first oral DMT was approved in 2018, DMT approval accelerated, and seven DMTs were approved within 5 years. With an increasing number of DMTs being prescribed in clinical practice, it is necessary to discuss the standardized MS treatment algorithms depending on the disease activity and DMT availability. In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country.

Treatment algorithms of relapsing multiple sclerosis in China In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country: 1) CIS and RRMS account for more than 90% of the MS patients and most of them are mild to moderate; 2) MS patients should initiate DMT treatments as soon as the disease has been diagnosed in order to reduce the risk of disease progression; 3) Patients who have been diagnosed with MS should start treatment with fundamental DMTs unless the disease course has been highly active; 4) MAGNIMS score may be a suitable and simplified assessment tool for measuring treatment response to DMTs; 5) Patients treated with corticosteroids and NSIS should be switched to the standardized DMT treatment during remission in accordance with disease activity.

Comparative efficacy of ofatumumab versus oral therapies for relapsing multiple sclerosis patients using propensity score analyses and simulated treatment comparisons.

Background: Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers. Objectives: A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies. Design: Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab versus the oral therapies cladribine, fingolimod, and ozanimod. Data sources and methods: As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP). Results: The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS. Conclusion: Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies.

Meaningful Change Thresholds and Fatigue Severity Points on Patient-Reported Outcomes by the Fatigue Symptoms and Impacts Questionnaire in Patients With Relapsing Multiple Sclerosis.

OBJECTIVES: The Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a new content-valid, concise, and reliable 20-item patient-reported outcome measure to evaluate the symptoms and impacts of fatigue in patients with relapsing forms of multiple sclerosis. Analyses were performed to derive meaningful change thresholds (MCTs) on patient-reported outcomes as measured by FSIQ-RMS and generate receiver operating characteristic (ROC) curves to determine fatigue severity cut points at baseline and change in severity at post-baseline and supplement the anchor-based MCT results. METHODS: Analyses were based on data from the OPTIMUM trial (NCT02425644). An anchor-based approach using uncollapsed changes on the Patient Global Impression of Severity at week 108 were used to determine the MCT for only the FSIQ-RMS Symptoms domain; distribution-based MCT estimations were conducted using baseline FSIQ-RMS Impacts scores. ROC curves with calculation of area under the curve were used to identify the best cut point. RESULTS: Based on the evidence provided by the anchor-based analyses using the Patient Global Impression of Severity as an anchor for the FSIQ-RMS Symptoms domain, meaningful score changes for improvement and deterioration were -6.3 and 6.3, respectively. Meaningful score changes for the FSIQ-RMS Physical, Cognitive/Emotional, and Coping Impacts domains using distribution-based methods were 10.8, 8.4, and 9.8, respectively. These results are supported by the ROC analyses. CONCLUSIONS: Thresholds to support interpretation of the FSIQ-RMS, such as MCTs, can be used to determine and categorize patients who have experienced a meaningful change in their MS-related fatigue (eg, responder analyses) in future clinical research studies.

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Background: Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. Aim: To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Methods: Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Results: Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). Conclusions: CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Neutralizing antibody titers over 12 months after SARS-CoV-2 mRNA vaccine booster in patients with relapsing multiple sclerosis continuously treated with ofatumumab.

Booster vaccinations against SARS-CoV-2 are recommended 6-12 months after the last dose or infection in elderly and high-risk groups. The present analysis aims to evaluate whether an interval shorter than 12 months is required in multiple sclerosis patients receiving ofatumumab. Neutralizing antibody status over 1 year in patients receiving booster vaccination in the non-interventional, multicenter KYRIOS study under continued ofatumumab treatment was analyzed. Fifteen patients were included. At the time of the first booster vaccination, ten patients were seropositive for neutralizing antibodies, four patients were seronegative, and for one patient, no baseline levels were available. All patients who were seropositive at baseline showed >2-fold increase in neutralizing antibody titers after the first booster and two patients (20%) showed a >10-fold increase. Among seronegative patients, three (75%) had a >10-fold increase in neutralizing antibody titers. Seropositivity was maintained in almost all patients until month 12. One initially seronegative patient had less than 2-fold increase in neutralizing antibody titers after the booster vaccination and can be considered a non-responder. Most patients with continued ofatumumab treatment are able to maintain permanent seropositivity and therefore presumably constant protection against severe courses of COVID-19 if repeated booster vaccinations are applied.

Personalized Use of Disease-Modifying Therapies in Multiple Sclerosis.

Multiple sclerosis is an important neurological disease affecting millions of young patients globally. It is encouraging that more than ten disease-modifying drugs became available for use in the past two decades. These disease-modifying therapies (DMTs) have different levels of efficacy, routes of administration, adverse effect profiles and concerns for pregnancy. Much knowledge and caution are needed for their appropriate use in MS patients who are heterogeneous in clinical features and severity, lesion load on magnetic resonance imaging and response to DMT. We aim for an updated review of the concept of personalization in the use of DMT for relapsing MS patients. Shared decision making with consideration for the preference and expectation of patients who understand the potential efficacy/benefits and risks of DMT is advocated.

Quantifying the administration and monitoring time burden of several disease-modifying therapies for relapsing multiple sclerosis in the United Kingdom: A time and motion study.

BACKGROUND: The treatment landscape for relapsing multiple sclerosis (MS) has changed dramatically in recent decades, including an increasing number of high-efficacy disease-modifying therapies (DMTs) with varied administration and monitoring requirements. Coupled with greater focus on earlier treatment, these factors have resulted in stretching of the capacity of MS specialist services and allied healthcare professionals (HCPs). To assist with the effective planning of MS services in the UK NHS, this study quantified the administration and monitoring time burden associated with high-efficacy DMTs (alemtuzumab, cladribine tablets, fingolimod, natalizumab, and ocrelizumab) for relapsing MS. METHODS: A Time and Motion (T&M) study was conducted across four MS centres in the UK, over 3-4 months per centre (Aug 2019-Feb 2021). Time dedicated by HCPs (including but not limited to neurologists, MS specialist nurses, infusion nurses, and healthcare assistants) to pre-specified drug administration and monitoring activities, elicited during pre-study interviews at each centre, was assessed for each of the selected DMTs. Administration activities included: installing peripheral access; pre-medication administration (if needed); preparing drug for infusion; infusion initiation, monitoring, and disconnection; and patient monitoring post-infusion. Monitoring activities included: booking appointments for blood draws; blood draw; retrieval and review of blood results; maintaining blood records and follow-up with the patient; checking availability of MRI results and follow-up with the patient; booking appointments for neurologist or nurse consultations; and checking patient files prior to clinic visits. A T&M model was built using observational T&M study results, data obtained through pre-study interviews, as well as stipulated monitoring intervals from relevant Summaries of Product Characteristics for the selected DMTs, to estimate active HCP time with each DMT, extrapolated over a period of 4 years per-patient. RESULTS: For oral DMTs, projected total active HCP time (monitoring only) per-patient over 4 years was 14.7 h for cladribine tablets and 19.2 h for fingolimod. For infused DMTs, total time (administration and monitoring) for alemtuzumab was 37.7 h (6.0 and 31.6 h, respectively), 48.1 h for natalizumab (17.4 and 30.8 h, respectively), and 23.5 h for ocrelizumab (6.1 and 17.4 h, respectively). CONCLUSIONS: While active HCP time varied across centres, infused DMTs were projected to require the greatest amount of HCP time associated with administration and monitoring over 4 years versus oral DMTs. These findings may assist MS-specific HCPs in planning and delivering the equitable provision of DMT services for patients with relapsing MS.

Adherence to subcutaneous interferon beta-1a treatment among patients with relapsing multiple sclerosis: the MAIN-MS study.

Introduction and background: Adherence is a critical factor for optimal clinical outcomes in multiple sclerosis (MS) treatment. This study investigated the adherence and clinical outcomes of MS patients treated with subcutaneous (sc) interferon (IFN) (ß)-1a, an established immunomodulatory treatment for relapsing MS. The benefits of a patient support programme (PSP) were also studied. Methods: This phase-IV prospective, observational multicentre study enrolled patients with relapsing MS who were treated with sc IFN ß-1a for 24 months was conducted at 53 centres across 17 countries. The primary endpoint was adherence to sc IFN ß-1a treatment, as assessed using Morisky Green Levine Medication Adherence Scale (MGLS) scores at 24 months. The MGLS is a self-reported diagnostic tool to address medication non-adherence, with a score ranging from 0 to 4, with 0 representing high adherence, 1-2 representing medium adherence, and 3-4 representing low adherence. Other endpoints included time to study and treatment discontinuation over 24 months, the proportion of relapse-free patients, and Expanded Disability Status Scale (EDSS) progression (defined as ≥1.0 point increase sustained for 3 months) at 24 months. A subgroup analysis was performed for endpoints based on patients assigned to PSP (yes/no-PSP versus non-PSP subgroup). Results: Of the 577 patients enrolled, 408 had evaluable MGLS scores at 24 months. A total of 336 (58.2%; 95% confidence interval [CI]: 54.1-62.3%) patients reported high adherence, 57 (9.9%; 95% CIs: 7.6-12.7%) reported medium adherence, and 15 (2.6%; 95% CI: 1.5-4.3%) reported low adherence at 24 months. The PSP subgroup reported higher adherence (n = 206; 65.8%) than the non-PSP subgroup (n = 130; 56.5%). By 24 months, 52.2% of the patients were relapse-free and 17.2% patients experienced ≥1 relapse. Expanded Disability Status Scale progression was observed in 12.3% of patients. Over the 24-month period, 30.8% of the patients discontinued treatment, and the most common reasons for treatment discontinuation were adverse events (AEs, 10.4%), being lost to followup (7.1%), and a lack of efficacy (5.5%). Overall, 39.6% patients experienced ≥1 AE, which ranged from mild to moderate. Conclusion: The study demonstrated high adherence to sc IFN ß-1a treatment with an added benefit of PSP participation. More than half of the patients remained relapse-free over a 24-month period. No new safety concerns to sc IFN ß-1a treatment were observed. Clinical trial registration: https://clinicaltrials.gov/study/NCT02921035, NCT02921035.

Tolerability of subcutaneous ofatumumab with long-term exposure in relapsing multiple sclerosis.

Background: Ofatumumab is approved for treating relapsing multiple sclerosis (RMS). Examining tolerability will enable understanding of its risk-benefit profile. Objective: Report the tolerability profile of ofatumumab in RMS during treatment of up to 4 years and the effect of pre-medication. Methods: Cumulative data from the overall safety population included patients taking continuous ofatumumab or being newly switched from teriflunomide. Injection-related reactions (IRRs) by incidence and severity, and post-marketing surveillance data, with an exposure of 18,530 patient-years, were analyzed. Results: Systemic IRRs affected 24.7% of patients (487/1969) in the overall safety population; most (99.2% [483/487]) were mild (333/487) to moderate (150/487) in Common Terminology Criteria for Adverse Events severity; most systemic IRRs occurred after first injection. Local-site IRRs affected 11.8% (233/1969) and most (99.6% [232/233]) were mild/moderate. Incidence and severity of systemic and localized IRRs were similar between continuous and newly switched patients across repeated injections. Systemic IRR incidence and severity were not substantially affected by steroidal or non-steroidal pre-medication. Post-marketing surveillance identified no new tolerability issues. Conclusion: Ofatumumab is well tolerated, displays a consistent safety profile during continuous use or after switching from teriflunomide and does not require pre-medication. This enables home management of RMS with a high-efficacy treatment.

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.

Humoral immune response to COVID-19 mRNA vaccines in patients with relapsing multiple sclerosis treated with ofatumumab.

BACKGROUND: There are limited data available regarding the impact of ofatumumab, an anti-CD20 B-cell-depleting monoclonal antibody for relapsing multiple sclerosis (RMS), on vaccination response. The study objective was to assess humoral immune response (HIR) to non-live coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination in patients with RMS treated with ofatumumab. METHODS: This was an open-label, single-arm, multicenter, prospective pilot study of patients with RMS aged 18-55 years who received 2 or 3 doses of a COVID-19 mRNA vaccine after ≥1 month of subcutaneous ofatumumab (20 mg/month) treatment. The primary endpoint was the proportion of patients achieving HIR, as defined by local laboratory severe acute respiratory syndrome coronavirus-2 qualitative immunoglobulin G assays. Assay No. 1 was ≥14 days after the second or third vaccine dose. Assay No. 2 was 90 days thereafter. RESULTS: Of the 26 patients enrolled (median [range] age: 42 [27-54] years; median [range] ofatumumab treatment duration: 237 [50-364] days), HIR was achieved by 53.9% (14/26; 95% CI: 33.4 - 73.4%) at Assay No. 1 and 50.0% (13/26; 95% CI: 29.9 - 70.1%) at Assay No. 2. Patients who received 3 vaccine doses had higher HIR rates (Assay No. 1: 70.0% [7/10]; Assay No. 2: 77.8% [7/9]) than those who received 2 doses (Assay No. 1: 46.7% [7/15]; Assay No. 2: 42.9% [6/14]). Of patients aged <40 years without previous anti-CD20 therapy, HIR was achieved by 90.0% (9/10) at Assay No. 1 and 75.0% (6/8) at Assay No. 2. No serious adverse events were reported. CONCLUSION: Patients with RMS treated with ofatumumab can mount HIRs following COVID-19 vaccination. A plain language summary, infographic and a short video summarizing the key results are provided in supplementary material. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04847596 (https://clinicaltrials.gov/ct2/show/NCT04847596).

Do the current MS clinical course descriptors need to change and if so how? A survey of the MS community.

BACKGROUND AND OBJECTIVES: The current clinical course descriptors of multiple sclerosis (MS) include a combination of clinical and magnetic resonance imaging (MRI) features. Recently there has been a growing call to base these descriptors more firmly on biological mechanisms. We investigated the implications of proposing a new mechanism-driven framework for describing MS. METHODS: In a web-based survey, multiple stakeholders rated the need to change current MS clinical course descriptors, the definitions of disease course and their value in clinical practice and related topics. RESULTS: We received 502 responses across 49 countries. In all, 77% of the survey respondents supported changing the current MS clinical course descriptors. They preferred a framework that informs treatment decisions, aids the design and conduct of clinical trials, allows patients to understand their disease, and links disease mechanisms and clinical expression of disease. Clinical validation before dissemination and ease of communication to patients were rated as the most important aspects to consider when developing any new framework for describing MS. CONCLUSION: A majority of MS stakeholders agreed that the current MS clinical course descriptors need to change. Any change process will need to engage a wide range of affected stakeholders and be guided by foundational principles.

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.

Real-world use of ofatumumab to treat multiple sclerosis 9 months post-FDA approval during COVID-19 pandemic.

BACKGROUND: Relapsing multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disease of the central nervous system that causes episodes of neurological dysfunction (relapse) alternating with variable intervals of stability. Disease-modifying therapies (DMTs) aim to reduce the rate of relapse and slow disease progression in people with MS, particularly in those with relapsing MS. Ofatumumab is a fully human anti-CD20 monoclonal antibody approved to treat patients with relapsing forms of MS. This study describes the demographics, clinical characteristics, and prior DMT use of patients with at least one ofatumumab prescription claim following approval by the United States (US) Food and Drug Administration (FDA). Understanding ofatumumab utilization patterns and patient characteristics can help define the journey of patients with MS and aid future clinical decision-making. METHODS: This retrospective study is based on data from IQVIA's Longitudinal Prescription Data (LRx) and Medical Claims (Dx) databases in the US, collected between August 01, 2019 and May 31, 2021. The index date was defined as the date of the first ofatumumab prescription. The pre-index period was defined as the 12 months prior to the index date. Adult patients (aged ≥18 years) with a diagnosis of MS and at least one prescription for ofatumumab between August 2020 and May 2021 in the LRx database were included. Only patients with at least one medical claim in the Dx database and a diagnosis of MS 24 months prior to the index date were included. Descriptive analyses were conducted 3, 6, and 9 months after FDA approval. RESULTS: Overall, 3,600 patients with a prescription for ofatumumab were identified in the LRx claims database, and 2,101 patients remained in the study after inclusion and exclusion criteria had been applied. At the 9-month post-approval time point, patients with ofatumumab claims were characterized as primarily female (74%) and middle-aged (median age: 48 years); two-thirds (64.7%) had a mild MS disability level. Patients were otherwise generally healthy with limited comorbid conditions. Most patients (81.7%) in the study did not experience relapse during the pre-index period. DMT-naïve patients who were prescribed ofatumumab at 3, 6, and 9 months post-approval accounted for 46.9%, 54.8%, and 58.4% of the study population, respectively. Over time, this increase in DMT-naïve ofatumumab initiators was statistically significant (p = 0.0003). Among patients who had been treated with DMTs during the previous year, most had taken them orally (50.6%), some had received them via intravenous infusion (32.2%), and some via subcutaneous/intramuscular injection (21.1%). Intravenous ocrelizumab was the most common DMT switch observed (n = 205, 23.4%) among these patients. CONCLUSION: This real-world study is the first to describe patients treated with ofatumumab since FDA approval during the COVID-19 pandemic. The majority of patients in this study were middle-aged women with mild MS symptoms. Ofatumumab was increasingly used as a first-line DMT. Additionally, a number of patients aged ≥55 years (beyond the trial population) used ofatumumab, which may suggest expanding clinician confidence in the safety and clinical utility of ofatumumab therapy. However, future long-term observational studies are needed to confirm these results.

The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice.