Cladribine for people with multiple sclerosis
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ABSTRACT:
SUBMITTER: Celani M
PROVIDER: S-EPMC6984410 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundA number of elements of the pivotal 'cladribine tablets treating multiple sclerosis orally' (CLARITY) trial have remained unpublished.ObjectiveTo report the impact of cladribine on health-related quality of life (QoL) in people with relapsing multiple sclerosis (pwRMS).MethodsQoL data from the phase III trial of two different doses (3.5 and 5.25 mg/kg) of oral cladribine in pwRMS were acquired from the European Medicines Agency through Freedom of Information. Spearman's rank correlation was used to analyse the relationship between baseline QoL scores and baseline Expanded Disability Status Scale (EDSS) scores. Responses of the Euro Quality of Life 5 Dimensions (EQ-5D) and Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaires were compared between treatment and control groups using univariate analyses of covariance.ResultsIn total, n = 5148 EQ-5D responses and n = 894 MSQOL-54 physical, mental health and dimension scores were extracted. Baseline EQ-5D indices correlated with EDSS scores. After 2 years, pwRMS taking 3.5 ( p = .001) and 5.25 mg/kg ( p = .022) reported significantly improved EQ-5D index scores compared with placebo. Positive, yet non-significant, differences were detected in MSQOL-54 scores between cladribine and placebo.ConclusionAnalysis of the CLARITY dataset suggests that, over and above its established clinical efficacy, cladribine leads to improved QoL over 96 weeks. ClinicalTrials.gov identifier: NCT00213135.
| S-EPMC6174629 | biostudies-literature
Project description:Cladribine is a purine nucleoside analogue that selectively depletes peripheral lymphocytes without a major impact on cells of the innate immune system. An oral formulation of cladribine has been developed to be given as short courses over two annual cycles. Oral cladribine results in the peripheral depletion of lymphocytes that is gradual, occurring over several weeks, and is not associated with a cell lysis syndrome, has a greater impact on B cells than T cells, and is followed by gradual reconstitution of the peripheral lymphocyte counts over several months. Oral cladribine is effective in relapsing forms of multiple sclerosis. As a selective immune reconstitution therapy (SIRT), cladribine acts as a short-term immunosuppressant, relative to other maintenance immunosuppressive therapies that result in long-term immunosuppression. The main safety signal that has emerge relates primarily to herpes zoster infection, which was more common in patients with higher grades of lymphopenia, in particular grade 3 and 4 lymphopenia. Data from the oral cladribine extension trial and safety register, and reanalysis of the pivotal phase III trial has indicated that oral cladribine is unlikely to be associated with an increased short- to intermediate-term risk of malignancy.
| S-EPMC5722776 | biostudies-literature
Project description:PurposeThe aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA.MethodsThis population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously.ResultsThe analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance.ConclusionsBoth CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR. Trial registration number for study 25643: NCT00213135.
| S-EPMC5591805 | biostudies-literature
Project description:ObjectiveTo report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple sclerosis (MS) patients.MethodsLitak® was offered to MS-patients irrespective of disease course. Litak® 10 mg was administered for 3-4 days during week 1. Based on lymphocyte count at week 4, patients received another 0-3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts.ResultsIn all, 208 patients received at least one course of treatment. Age at baseline was 44 (17-72) years and EDSS 0-8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data (n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data (n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months.ConclusionsLitak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.
| S-EPMC8842147 | biostudies-literature
Project description:BackgroundCladribine tablets (marketed as Mavenclad) are a new oral therapy, which has recently been listed on the pharmaceutical benefits scheme in Australia for the treatment of relapsing multiple sclerosis (MS). The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS for up to 4 years in 75% of patients (based on annualized relapse rate). However, the reinitiation of therapy after year 4 has not been studied.ObjectiveThis study aims to evaluate the safety and efficacy of cladribine tablets over a 6-year period, according to no evidence of disease activity 3.MethodsThis will be a multicenter, 6-year, phase IV, low interventional, observational study that incorporates clinical, hematological, biochemical, epigenetic, radiological and cognitive biomarkers of disease. Participants considered for treatment with cladribine as part of their routine clinical care will be consented to take part in the study. They will be monitored at regular intervals during the initial course of medication administration in years 1 and 2. After year 3, patients will have the option of redosing, if clinically indicated, or to switch to another disease-modifying therapy. Throughout the duration of the study, we will assess blood-based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation, and RNA analysis as well as magnetic resonance imaging findings (brain volume and/or lesion load) and cognitive performance.ResultsThis study has been approved by the Hunter New England Local Health District Human Research Ethics Committee. Recruitment began in March of 2019 and was completed by June 2021.ConclusionsThis will be the first long-term efficacy trial of cladribine, which offers reinitiation of therapy in the 3rd year, based on disease activity, after the initial 2 courses. We expect that this study will indicate whether any of the assessed biomarkers can be used to predict treatment efficacy or the need for future reinitiation of cladribine in people with MS.Trial registrationThis study is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619000257167) with Universal Trial Number (U1111-1228-2165).International registered report identifier (irrid)DERR1-10.2196/24969.
| S-EPMC8564661 | biostudies-literature
Project description:IntroductionLittle is known about the molecular profiling associated with the effect of cladribine in patients with multiple sclerosis (MS). Here, we aimed first to characterize the transcriptomic and proteomic profiles induced by cladribine in blood cells, and second to identify potential treatment response biomarkers to cladribine in patients with MS.MethodsGene, protein and microRNA (miRNA) expression profiles were determined by microarrays (genes, miRNAs) and mass spectrometry (proteins) in peripheral blood mononuclear cells (PBMCs) from MS patients after in vitro treatment with cladribine in its active and inactive forms. Two bioinformatics approaches to integrate the three obtained datasets were applied: (i) a multiomics discriminant analysis (DIABLO - Data Integration Analysis for Biomarker discovery using Latent variable approaches for Omics studies); and (ii) a multi-stage integration of features selected in differential expression analysis on each dataset and then merged. Selected molecules from the in vitro study were quantified by qPCR ex vivo in PBMCs from MS patients receiving cladribine.ResultsPBMCs treated in vitro with cladribine were characterized by a major downregulation of gene, protein, and miRNA expression compared with the untreated cells. An intermediate pattern between the cladribine-treated and untreated conditions was observed in PBMCs treated with cladribine in its inactive form. The differential expression analysis of each dataset led to the identification of four genes and their encoded proteins, and twenty-two miRNAs regulating their expression, that were associated with cladribine treatment. Two of these genes (PPIF and NHLRC2), and three miRNAs (miR-21-5p, miR-30b-5p, and miR-30e-5p) were validated ex vivo in MS patients treated with cladribine.DiscussionBy using a combination of omics data and bioinformatics approaches we were able to identify a multiomics molecular profile induced by cladribine in vitro in PBMCs. We also identified a number of biomarkers that were validated ex vivo in PBMCs from patients with MS treated with cladribine that have the potential to become treatment response biomarkers to this drug.
| S-EPMC10408299 | biostudies-literature
Project description:Little is known about the molecular profiling associated with the effect of cladribine in patients with multiple sclerosis (MS). Here, we aimed first to characterize the transcriptomic and proteomic profiles induced by cladribine in blood cells, and second to identify potential treatment response biomarkers to cladribine in patients with MS. PBMCs treated in vitro with cladribine were characterized by a major downregulation of gene, protein, and miRNA expression compared with the untreated cells. An intermediate pattern between the cladribine-treated and untreated conditions was observed in PBMCs treated with cladribine in its inactive form. The differential expression analysis of each dataset led to the identification of four genes and their encoded proteins, and twenty-two miRNAs regulating their expression, that were associated with cladribine treatment. Two of these genes (PPIF and NHLRC2), and three miRNAs (miR-21-5p, miR-30b-5p, and miR-30e-5p) were validated ex vivo in MS patients treated with cladribine. Conclusions: By using a combination of omics data and bioinformatics approaches we were able to identify a multiomics molecular profile induced by cladribine in vitro in PBMCs. We also identified a number of biomarkers that were validated ex vivo in PBMCs from MS patients treated with cladribine that have the potential to become treatment response biomarkers to this drug.
2024-08-14 | PXD040572 | Pride
Project description:Rebound disease following cessation of disease modifying treatment (DMT) has been reported in people with both relapsing and progressive multiple sclerosis (pwRMS, pwPMS) questioning strict separation between these two phenotypes. While licensed DMT is available for pwRMS to counter rebound disease, no such option exists for pwPMS. We report on a pwPMS who developed rebound disease, with 45 Gadolinium-enhancing lesions on T1 weighted MRI brain, within 6 months after fingolimod 0.5 mg/day was stopped. Treatment with a short course of subcutaneous cladribine 60 mg led to effective suppression of inflammatory activity and partial recovery with no short-term safety issues or adverse events.
| S-EPMC5497536 | biostudies-literature
Project description:Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the influenza vaccine in patients undergoing cladribine treatment at different stages vs. controls. The antibody response in 90 cladribine-treated MS patients was prospectively compared with 10 control subjects receiving platform immunotherapy (NCT05019248). Serum samples were collected before and six months after vaccination. Response to vaccination was determined by the hemagglutination-inhibition test. Postvaccination seroprotection rates against influenza A were comparable in cladribine-treated patients and controls (H1N1: 94.4% vs. 100%; H3N2: 92.2% vs. 90.0%). Influenza B response was lower in the cladribine cohort (61.1% vs. 80%). The increase in geometric mean titers was lower in the cladribine group vs. controls (H1N1: +98.5 vs. +188.1; H3N2: +225.3 vs. +300.0; influenza B: +40.0 vs. +78.4); however, titers increased in both groups for all strains. Seroprotection was achieved irrespective of vaccination timing and lymphocyte subset counts at the time of vaccination in the cladribine cohort. To conclude, cladribine-treated MS patients can mount an adequate immune response to influenza independently of treatment duration and time interval to the last cladribine administration.
| S-EPMC10177067 | biostudies-literature
Project description:Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system. The clinical course of MS varies among patients. Currently, interferon (IFN) products, including IFN ?-1a administered intramuscularly or subcutaneously and IFN ?-1b subcutaneously, glatiramer acetate, natalizumab, and mitoxantrone are approved disease-modifying therapies for the treatment of relapsing-remitting MS. Cladribine, also known as 2-chlorodeoxyadenosine, is a synthetic adenosine deaminase-resistant purine nucleoside analog that preferentially depletes lymphocyte subpopulations. This sustained effect on lymphocytes is advantageous for patients with MS. CLARITY (CLAdRIbine Tablets Treating MS OrallY), a Phase III trial, has demonstrated that short-term oral cladribine decreases relapse rates and risk of disability progression in comparison with placebo. Cladribine was well tolerated in the study, with the most common adverse effects being headache, nausea, upper respiratory tract infections, and lymphocytopenia. An ongoing study is evaluating the efficacy and safety of the combination of oral cladribine and IFN-? products. A further ongoing study is examining the use of oral cladribine in clinically isolated syndrome and time to conversion to MS. Although the results of CLARITY are promising, the exact role of oral cladribine may be better defined with the completion of ongoing studies.
| S-EPMC2951744 | biostudies-other