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What Is This Summary About?: This article summarizes the findings from a previously published article in Current Medical Research and Opinion . Cladribine tablets are an oral treatment for relapsing multiple sclerosis (shortened to MS), that are given for 4 periods of 4 to 5 days over 2 years (for a total of 20 days). In this analysis, researchers looked at the effects of taking either cladribine tablets or placebo (dummy pills) in a group of people with MS who had more active MS inflammation and had participated in a clinical study (called the CLARITY study). Some of these participants had taken prior medicines for MS., What Were the Results?: Researchers found that in people with more active MS, treatment with cladribine tablets led to a lower risk of relapse and there were more people who had no relapses. People also had a lower chance of their MS worsening and had fewer new lesions in the brain. These benefits were seen regardless of whether the participants had prior treatment., What Do the Results Mean?: Researchers concluded that in these people with more active MS, treatment with cladribine tablets led to better outcomes over 2 years compared with treatment with placebo tablets, regardless of whether the participants had taken any prior MS treatments. Clinical Trial Registration : NCT00213135 (ClinicalTrials.gov).

What Is This Summary About?: This is a summary of an article originally published in the Multiple Sclerosis Journal . The article presents the results from the CLARITY and CLARITY Extension studies, which looked at how well cladribine tablets work in treating people with multiple sclerosis (shortened to MS). Cladribine tablets are a medication approved for treating relapsing forms of MS. This study looked at how treatment with cladribine tablets affects the frequency and severity of relapses in people with MS. A relapse is when new symptoms develop or old symptoms return or get worse after a period of stability or improvement., What Happened in the Studies?: In the CLARITY study, 870 people received either cladribine tablets (3.5 mg/kg, the approved dose) or placebo (a dummy pill). After the CLARITY study ended, some participants who received cladribine tablets chose to take part in a second study called the CLARITY Extension study. Of these participants, 98 were given placebo for 2 more years following an interval period of up to 10 months between participating in each study., What Were the Results?: People with MS who were treated with cladribine tablets for 2 years in the CLARITY study had lower risks of any relapse compared with those given placebo. Participants taking placebo (after cladribine tablets) in the CLARITY Extension study experienced these same benefits, which continued for up to 3 more years after having received cladribine tablets in the CLARITY study., What Do the Results Mean?: Researchers concluded the recommended 2-year dosing of cladribine tablets may reduce the number and severity of relapses in people with MS for up to 5 years. Clinical Trial Registration : NCT00213135 (ClinicalTrials.gov) Clinical Trial Registration : NCT00641537 (ClinicalTrials.gov).

What Is This Summary About?: This is a summary of an article originally published in the journal Advances in Therapy . Cladribine tablets are approved for treating people with relapsing multiple sclerosis (shortened to MS). People with MS take cladribine tablets for 2 periods of 4 to 5 days per year. This analysis looks at the results from 2 studies called the CLARITY and CLARITY Extension studies. These studies looked at what effect a 2-year course of treatment with cladribine tablets had on disability over 5 years in people with MS., How Was the Analysis Carried Out?: In this analysis, researchers measured disability worsening at regular intervals during the 2-year treatment period in the CLARITY study and thereafter in the 2-year CLARITY Extension study. As many patients had a bridging interval between CLARITY and CLARITY extension, the researchers were able to assess disability over a 5-year timeframe., What Were the Results?: When measurements were taken at Year 5 of the study, disability remained stable in more than half of participants. Over the 5-year period, 70% of participants did not experience persistent disease worsening that lasted more than 6 months., What Do the Results Mean?: Researchers concluded that a 2-year course of cladribine tablets may provide long-term benefits on disability for up to 5 years. Clinical Trial Registration : NCT00213135 (ClinicalTrials.gov) Clinical Trial Registration : NCT00641537 (ClinicalTrials.gov).

The pharmacometric analysis of the double-blind, randomized, phase II study (NCT02975349) investigating the safety and efficacy of evobrutinib, explored exposure-response relationships and suitable dosing regimens of evobrutinib for relapsing multiple sclerosis. Population pharmacokinetic (PK)/pharmacodynamic modeling was applied to data collected in fasted patients treated with placebo or evobrutinib (25 mg once-daily [q.d.], 75 mg q.d., or 75 mg twice-daily [b.i.d.]) for 24 weeks, followed by a 24-week blinded extension (placebo patients switched to 25 mg q.d.). Model-based exposures for PK and Bruton's tyrosine kinase occupancy (BTKO) were used for exposure-response analyses (maximum 207 patients). PK, BTKO profiles, and annualized relapse rate (ARR) after 48 weeks of treatment under alternative dosing regimens were simulated. Exposure-response modeling identified a relationship between evobrutinib exposure and clinical response for total number of T1 Gd+ and new/enlarging T2 lesions at weeks 12-24, and ARR at week 48. Area under the concentration-time curve over 24 h at steady-state (AUC 0-24,SS ) of 468 and ≥400 ng/ml h was associated with T1 Gd+/T2 lesion reduction and ARR improvement, respectively. These exposures were associated with steady-state (SS) predose BTKO ≥95%. Based on PK and BTKO profile simulations, evobrutinib 75 mg b.i.d. while fasted is predicted to maintain SS predose BTKO >95% in 92% of patients. Evobrutinib 45 mg b.i.d. with food is predicted to achieve similar exposure as 75 mg b.i.d. while fasted (predose BTKO >95% in 93% of patients). Evobrutinib 45 mg b.i.d. with food is predicted to have comparable exposure and BTKO to 75 mg b.i.d. without food (phase II) and will be pharmacologically effective and appropriate for clinical use in phase III multiple sclerosis studies., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

People with multiple sclerosis (also shortened to MS) may have difficulties staying on treatment due to side effects. Cladribine tablets, approved for treating relapsing forms of MS, are given by mouth for four short periods over two years. The benefit of convenient dosing may be lost if side effects prevent people with MS from finishing their treatment. This is the summary of a study that examined side effects from cladribine tablets treatment in the first 12 weeks of two clinical studies called CLARITY and ORACLE-MS. Overall, 34.7% of participants who took cladribine tablets experienced drug-related side effects compared to 23.2% of participants who took placebo. Most side effects were mild and were seen in 54.8% of participants taking cladribine tablets and 59.1% taking the placebo. A low number of participants discontinued treatment due to side effects (1.6% of participants who took cladribine tablets; 1.4% of participants who took placebo). The researchers concluded that cladribine tablets are well-tolerated and people with MS are likely to complete the full treatment course. ClinicalTrials.gov NCT numbers: CLARITY study - NCT00213135 and ORACLE-MS study - NCT00725985.

Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment., Objective: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension., Methods: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT ( n  = 433) and placebo ( n  = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension ( n  = 98)., Results: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p  < 0.0001), and qualifying or all severe relapses (all p  < 0.005), compared with placebo. This effect was sustained in CLARITY Extension without further treatment., Conclusion: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis.CLARITY: NCT00213135; CLARITY Extension: NCT00641537.

This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN β-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were analyzed. All investigated biomarkers were significantly upregulated 1.5-4-fold in response to sc IFN β-1a treatment versus baseline (p ≤ 0.008). The validity of MX1, 2'5'OAS, and IL-1RA as biomarkers of response to sc IFN β-1a was confirmed in this large patient cohort, with biomarkers consistently upregulated in a dose-dependent manner. Neopterin, TRAIL, and IP-10 were confirmed as biomarkers associated with long-term sc IFN β-1a treatment efficacy over 5 years., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: In the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study, cladribine tablets significantly reduced relapse rates and improved findings on magnetic resonance imaging versus placebo in patients with relapsing multiple sclerosis. In the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by placebo for 2 years produced similar clinical benefits to 4 years of cladribine tablets. The objective of this exploratory post hoc analysis was to evaluate long-term disease stability (assessed by the Expanded Disability Status Scale [EDSS] score) after treatment with cladribine tablets., Methods: Patients enrolled into CLARITY Extension who were previously randomized to cladribine tablets 3.5 mg/kg in the CLARITY study were included in this post hoc analysis. Two treatment groups were investigated-patients randomized to cladribine tablets 3.5 mg/kg in CLARITY and thereafter randomized to placebo in CLARITY Extension (the CP3.5 group) or to cladribine tablets 3.5 mg/kg in CLARITY Extension (the CC7 group). In each treatment group, EDSS scores at 6-month intervals, EDSS score improvement/worsening each year, and time to 3- and 6-month confirmed EDSS progression were assessed from CLARITY baseline over 5 years of follow-up (including a variable bridging interval between studies). All analyses are descriptive, and no statistical comparisons were performed for between-treatment group differences., Results: The median (95% confidence interval [CI]) EDSS score for patients in the CP3.5 group at 5 years was 2.5 (2.0-3.5) compared with 3.0 (2.5-3.5) at baseline. In the CC7 group, median EDSS score (95% CI) at 5 years was 2.0 (2.0-3.0) compared with 2.5 (2.5-3.0) at baseline. During year 5 for the CP3.5 group, and based on changes in minimum score each year, EDSS score stability was observed in 53.9% of patients, improvement in 21.3%, and worsening in 24.7%. In the CC7 group, EDSS score remained stable in 66.1%, improved in 18.1%, and worsened in 15.8% of patients. Over 70% of patients in both treatment groups did not show 3- or 6-month confirmed EDSS progression at 5 years from CLARITY baseline., Conclusions: These findings confirm long-term beneficial effects on disability afforded by either the recommended dose of cladribine tablets over 4 years (cumulative dose, 3.5 mg/kg) or a higher cumulative dose., Trial Registration: ClinicalTrials.gov NCT00213135 (CLARITY); NCT00641537 (CLARITY Extension)., (© 2021. The Author(s).)

Background: In the Phase 3, 96-week ORACLE-MS study, cladribine 10 mg tablets (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly reduced the rate of conversion to clinically definite multiple sclerosis (CDMS) per the Poser criteria (henceforth referred to as CDMS), multiple sclerosis (MS) per the 2005 McDonald criteria, and the number of new or persisting T1 gadolinium-enhancing (Gd+), new or enlarging T2, and combined unique active (CUA) lesions versus placebo in participants with a first clinical demyelinating event (FCDE). Patient demographic and disease characteristics may be predictors of disease progression. The current study analyzed the effect of cladribine tablets in subgroups of participants in the ORACLE-MS study by baseline demographics and disease characteristics., Methods: This analysis retrospectively examined data collected from 616 participants enrolled in the ORACLE-MS study (placebo, n=206; cladribine tablets 3.5 mg/kg, n=206; cladribine tablets 5.25 mg/kg, n=204). Five subgroups were predetermined by baseline demographics, including sex, age (<30 or ≥30 years), classification of FCDE, and lesion characteristics, including absence or presence of T1 Gd+ lesions and number of T2 lesions (<9 or ≥9). Selected endpoints of the ORACLE-MS study were re-analyzed for these subgroups. The primary and main secondary endpoints were time to conversion to CDMS and MS (2005 McDonald criteria), respectively. Secondary magnetic resonance imaging (MRI) endpoints included cumulative T1 Gd+ and new or enlarging T2 lesions. Cox proportional hazards models were used to evaluate time to conversion to CDMS and MS (2005 McDonald criteria). This analysis focused primarily on the results for the cladribine tablets 3.5 mg/kg group because this dosage is approved for relapsing forms of MS., Results: In the overall intent-to-treat (ITT) population, cladribine tablets 3.5 mg/kg significantly reduced the risk of conversion to CDMS (hazard ratio [HR]=0.326; P<0.0001) and MS (2005 McDonald criteria; HR=0.485; P<0.0001) versus placebo. Similar effects of cladribine tablets on risk of conversion were observed in post hoc analyses of subgroups defined by various baseline characteristics. In both the ITT population and across subgroups, cladribine tablets 3.5 mg/kg reduced the numbers of cumulative T1 Gd+ (range of rate ratios: 0.106-0.399), new or enlarging T2 (range of rate ratios: 0.178-0.485), and CUA (range of rate ratios: 0.154-0.384) lesions versus placebo (all nominal P<0.03). Multivariate Cox proportional hazards models revealed that age (HR=0.577, nominal P<0.0001), FCDE classification (HR=0.738, nominal P=0.0043), presence of T1 Gd+ lesions (HR=0.554, nominal P<0.0001), and number of T2 lesions (HR=0.417, nominal P<0.0001) at baseline were factors associated with risk of conversion to MS (2005 McDonald criteria), whereas no baseline factors examined were associated with risk of conversion to CDMS., Conclusion: In this post hoc analysis of the ORACLE-MS study, cladribine tablets reduced the risk of conversion to multiple sclerosis and lesion burden in participants with an FCDE in the overall ITT population and multiple subgroups defined by baseline demographics and lesion characteristics., (Copyright © 2020. Published by Elsevier B.V.)

Background: Relapsing-remitting multiple sclerosis (RRMS) patients with high disease activity (HDA) experience more severe disease than those without HDA. This analysis describes the efficacy of cladribine tablets 3.5 mg/kg in HDA patient subgroups that were either treated with disease-modifying drugs (DMDs) prior to study entry or were treatment naïve., Methods: Post hoc analysis of the 96 week Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study compared cladribine tablets 3.5 mg/kg to placebo in subgroups of patients meeting the high relapse activity plus disease activity on treatment definition of HDA. Patients were categorized into either prior DMD treatment or DMD treatment-naïve subgroups. Endpoints included annualized relapse rate (ARR), time to first relapse, time to disability progression and magnetic resonance imaging (MRI) outcomes. No inferential statistical analyses were conducted between subgroups., Results: The DMD-naïve cohort ( n  = 187) was larger than the prior-DMD cohort ( n  = 102). In both the DMD-naïve and prior-DMD cohorts, cladribine tablets were associated with a reduction in ARR (rate ratio [RR]: 0.26; 95% confidence interval [CI]: 0.16-0.42; p  < .0001 and RR: 0.55; 95% CI: 0.32-0.95; p  = .0324, respectively). In both subgroups, cladribine tablets increased the time to relapse versus placebo (hazard ratio [HR]: 0.36; 95% CI: 0.21-0.62; p  = .0002 for DMD-naïve cohort and HR: 0.50; 95% CI: 0.24-1.02; p  = .0557 for prior-DMD cohort). Significant differences were observed for all assessed disability and MRI outcomes independently of previous treatment., Conclusion: Post hoc evidence suggests consistent treatment benefits of cladribine tablets 3.5 mg/kg during the 96 week CLARITY study among HDA-RRMS patients who were either previously treated with DMDs or were treatment naïve.

Introduction: Although use of contraception was pre-specified during cladribine clinical trials for multiple sclerosis, some pregnancies did occur., Objective: This analysis reports on pregnancy outcomes in the cladribine clinical development program., Methods: Pregnancy outcomes in female patients (direct pregnancies) and those arising from partner pregnancies (i.e., female partners of male study participants with multiple sclerosis) were evaluated from an integrated safety analysis of ten studies of cladribine in multiple sclerosis (nine clinical trials and a long-term safety registry), with patients treated with cladribine tablets, parenteral cladribine, or placebo (all-exposed cohort; 1976 patients received cladribine and 802 received placebo). Pregnancies that occurred during the 'at-risk' period for cladribine (during treatment or within 6 months thereafter) are reported as a separate group., Results: In the all-exposed cohort, 70 direct pregnancies occurred among 62 female patients (cladribine, n = 49; placebo, n = 21). Pregnancy outcomes were: live births (cladribine, n = 19 [38.8%]; placebo, n = 9 [42.9%]), elective terminations (cladribine, n = 14 [28.6%]; placebo, n = 4 [19.0%]), spontaneous abortions (cladribine, n = 11 [22.4%]; placebo, n = 5 [23.8%]), and therapeutic terminations (cladribine, n = 5 [10.2%]; placebo, n = 2 [9.5%]); in the remaining placebo recipient, the pregnancy outcome was unknown. There were two reports of congenital malformations (cladribine, n = 1; placebo, n = 1), both of which occurred with pregnancies arising > 2 years after exposure to the last dose of study medication. Sixteen direct pregnancies occurred during the 'at-risk' period for cladribine; outcomes for these were: live births, n = 3 (18.8%); elective terminations, n = 10 (62.5%); spontaneous abortions, n = 2 (12.5%); and therapeutic terminations, n = 1 (6.2%). Corresponding findings for direct pregnancies among placebo recipients were (n = 11): live births, n = 5 (45.5%); elective terminations, n = 2 (18.2%); spontaneous abortions, n = 3 (27.3%); and unknown, n = 1 (9.1%). No cases of congenital malformation were reported for pregnancies during the 'at-risk' period. There were an additional nine partner pregnancies in female partners of cladribine-treated male patients, all of which resulted in live births; of these, two pregnancies occurred within the 'at-risk' period for cladribine., Conclusions: While limited by the small number of pregnancies and related data from the cladribine clinical development program, highlighting the need for further study, the observations made in the present analysis were generally consistent with epidemiological data on pregnancy outcomes for the general population or women with multiple sclerosis. There were no congenital malformations in pregnancies that occurred during cladribine treatment or within 6 months after the last dose. As the data available for cladribine-exposed pregnancies in patients with multiple sclerosis are limited, a non-interventional post-authorization safety study has been initiated to obtain more information on this subject., Clinical Trial Registration: CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE MS: NCT00725985; ONWARD: NCT00436826; PREMIERE: NCT01013350.

Purpose: We applied Multi-Criteria Decision Analysis (MCDA) methods in a structured benefit-risk assessment of cladribine and newer approved disease-modifying drugs (DMDs) for patients with relapsing-remitting multiple sclerosis (RRMS)., Methods: Decision conferencing with clinical neurologists as decision makers was used to create an MCDA model that incorporated available evidence on DMDs for RRMS and clinical judgments about the relevance of the evidence. Benefit-risk assessments were conducted for DMDs in both patients with RRMS and patients with RRMS with high disease activity (HDA; defined as ≥2 relapses in the previous year). Treatment options included cladribine and recently approved DMDs available in European Union countries at the time of assessment (December 2015): alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide. To account for the relative importance of DMD effects, scores for the MCDA model were weighted to ensure that the most clinically important attributes carried more weight in the final benefit-risk calculation. The neurologists weighted different efficacy and safety profile attributes without any reference to individual DMDs to disassociate the assessment of weights with any specific DMD. The neurologists did not do direct comparisons between DMDs., Findings: The highest overall weighted preference value for the RRMS model was for dimethyl fumarate (63) followed closely by cladribine (62). For patients with RRMS and HDA, cladribine had the highest overall weighted preference value (76), followed by alemtuzumab (62) and natalizumab (61). The benefit-risk balance of cladribine in patients with RRMS and specifically patients with RRMS who exhibited HDA characterized by high relapse activity (≥2 relapses in the previous year) was more favorable than the other DMDs included in the model., Implications: The balance of high efficacy and the safety profile makes cladribine an important treatment option to consider, both in patients with RRMS and patients with HDA. Regular, single-country meetings could be organized to explore how differences in cultural values (scores and weights) and updated input data might affect the usefulness of MCDA in different, real-world, dynamic clinical settings., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: On-treatment magnetic resonance imaging lesions may predict long-term clinical outcomes in patients receiving interferon β-1a. This study aimed to assess the effect of active T2 and T1 gadolinium-enhancing (Gd+) lesions on relapses and 3-month confirmed Expanded Disability Status Scale (EDSS) progression in the PRISMS clinical trial., Methods: Exploratory analyses assessed whether active T2 and T1 Gd + lesions at Month 6, or active T2 lesions at Month 12, predicted clinical outcomes over 4 years in PRISMS., Results: Mean active T2 lesion number at Month 6 was significantly lower with interferon beta-1a given subcutaneously (IFN β-1a SC) 44 μg and 22 μg 3×/week (tiw) than with placebo (p < 0.0001). The presence of ≥4 versus 0 active T2 lesions predicted disability progression at Years 3-4 in the IFN β-1a SC 22 μg group only (p < 0.05), whereas the presence of ≥2 versus 0-1 active T2 lesions predicted disability progression in the placebo/delayed treatment (DTx) (Years 2-4; p < 0.05) and IFN β-1a SC 22 μg groups (Years 3-4; p < 0.05). Greater active T2 lesion number at 6 months predicted relapses in the placebo/DTx group only (≥4 vs. 0, Years 1-4; ≥2 vs. 0-1, Years 2-4; p < 0.05), and the presence of T1 Gd + lesions at 6 months predicted disability progression in the IFN β-1a SC 44 μg group only (Year 1; p < 0.05). The presence of ≥2 versus 0-1 active T2 lesions at 12 months predicted disability progression over 3 and 4 years in the IFN β-1a SC 44 μg group., Conclusion: Active T2 lesions at 6 months predicted clinical outcomes in patients receiving placebo or IFN β-1a SC 22 μg, but not in those receiving IFN β-1a SC 44 μg. Active T2 lesions at 12 months may predict outcomes in those receiving IFN β-1a SC 44 μg and are possibly more suggestive of poor response to therapy than T2 results at 6 months.

Background: Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis (RENEW) was a 5-year, phase IV study in which the safety of Mitoxantrone was monitored in a patient cohort from the United States (US). The objective of the study was to evaluate the long-term safety profile of Mitoxantrone in patients with secondary progressive multiple sclerosis (SPMS), progressive relapsing multiple sclerosis (PRMS), and worsening relapsing-remitting multiple sclerosis (RRMS)., Methods: Overall, 509 patients (395 SPMS, 81 worsening RRMS, 33 PRMS) were enrolled and treated at 46 multiple sclerosis (MS) treatment centers located in the US. Patients received Mitoxantrone in accordance with the package insert every 3 months. During the treatment phase, patients received laboratory workups and cardiac monitoring every 3 months and then annually for a total of 5 years., Results: Five hundred and nine subjects were enrolled in this trial and received at least one infusion of Mitoxantrone. Overall, 172 (33.8%) completed the 5-year trial (i.e., participated for 5 years ± 3 months [treatment + follow-up]); 337 (66.2%) did not complete the 5-year trial. Annual follow-up data were available for 250 of 509 enrolled patients. Left ventricular ejection fraction reduction under 50% was reported in 27 (5.3%) patients during the treatment phase (n = 509) and 14 (5.6%) patients during the annual follow-up phase (n = 250). Signs and symptoms of congestive heart failure were observed in 10 (2.0%) patients (six during treatment phase and four during the annual follow-up phase). Post-hoc analyses of the risk for cardiotoxicity outcomes revealed that cumulative dose exposure is the primary risk factor associated with the risk of cardiac toxicity with Mitoxantrone. Therapy-related leukemia was reported in three (0.6%) patients who received total cumulative Mitoxantrone doses of 73.5 mg/m², 107.3 mg/m², and 97.1 mg/m² respectively. During the treatment phase, persistent amenorrhea developed in 22% (28/128) of women with regular menses and 51% (25/49) of women with irregular menses at baseline. During the annual follow-up phase, persistent amenorrhea developed in 5% (4/73) of women with regular menses at baseline., Conclusion: RENEW results are consistent with the known safety profile of Mitoxantrone, and provide additional long-term safety data for Mitoxantrone in MS patients.

Major recent advances in the field of chromatin remodeling have dramatically changed our understanding of the ways in which genes are regulated. Epigenetic regulators such as histone deacetylases (HDACs) and histone acetyltransferases (HATs) are increasingly being implicated as direct or indirect components in the regulation of expression of neuronal, immune and other tissue specific genes. HDACs and HATs have been shown to play important roles in cell growth, cell cycle control, development, differentiation and survival. Mutations in genes that encode HDAC-binding proteins cause neurological disorders, such as MeCP2 mutations in Rett's syndrome. Mutations of CBP, a gene with HAT function, cause the mental retardation-associated Rubinstein-Taybi syndrome. Recently, HDAC inhibitors have been found to ameliorate progression of the spinal muscular atrophy (SMA) motor neuron disease and the Huntington disease mouse models. The neuroprotective role of HDAC inhibitors seems to extend to other diseases that share mechanisms of oxidative stress, inflammation and neuronal cell apoptosis. HDAC inhibitors also have widespread modulatory effects on gene expression within the immune system and have been used successfully in the lupus and rheumatoid arthritis autoimmune disease models. Recently, we demonstrated the efficacy of the HDAC inhibitor Trichostatin A in ameliorating disease in the multiple sclerosis (MS) animal model, experimental autoimmune encephalomyelitis (EAE). In this review we describe the current literature surrounding these inhibitors and propose a rationale for harnessing both their neuroprotective and anti-inflammatory effects to treat MS, an autoimmune, demyelinating and degenerative disease of the human central nervous system (CNS).

BackgroundMultiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria.ObjectiveThe objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS.MethodsA post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted.ResultsCladribine tablets 3.5 mg/kg (n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo (n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg (n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached (p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg (n = 121) reduced the risk of conversion by 75% vs placebo (n = 134); p

The pharmacometric analysis of the double‐blind, randomized, phase II study (NCT02975349) investigating the safety and efficacy of evobrutinib, explored exposure–response relationships and suitable dosing regimens of evobrutinib for relapsing multiple sclerosis. Population pharmacokinetic (PK)/pharmacodynamic modeling was applied to data collected in fasted patients treated with placebo or evobrutinib (25 mg once‐daily [q.d.], 75 mg q.d., or 75 mg twice‐daily [b.i.d.]) for 24 weeks, followed by a 24‐week blinded extension (placebo patients switched to 25 mg q.d.). Model‐based exposures for PK and Bruton's tyrosine kinase occupancy (BTKO) were used for exposure–response analyses (maximum 207 patients). PK, BTKO profiles, and annualized relapse rate (ARR) after 48 weeks of treatment under alternative dosing regimens were simulated. Exposure–response modeling identified a relationship between evobrutinib exposure and clinical response for total number of T1 Gd+ and new/enlarging T2 lesions at weeks 12–24, and ARR at week 48. Area under the concentration–time curve over 24 h at steady‐state (AUC0–24,SS) of 468 and ≥400 ng/ml h was associated with T1 Gd+/T2 lesion reduction and ARR improvement, respectively. These exposures were associated with steady‐state (SS) predose BTKO ≥95%. Based on PK and BTKO profile simulations, evobrutinib 75 mg b.i.d. while fasted is predicted to maintain SS predose BTKO >95% in 92% of patients. Evobrutinib 45 mg b.i.d. with food is predicted to achieve similar exposure as 75 mg b.i.d. while fasted (predose BTKO >95% in 93% of patients). Evobrutinib 45 mg b.i.d. with food is predicted to have comparable exposure and BTKO to 75 mg b.i.d. without food (phase II) and will be pharmacologically effective and appropriate for clinical use in phase III multiple sclerosis studies. [ABSTRACT FROM AUTHOR]

Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment. Objective: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension. Methods: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT (n = 433) and placebo (n = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension (n = 98). Results: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p < 0.0001), and qualifying or all severe relapses (all p < 0.005), compared with placebo. This effect was sustained in CLARITY Extension without further treatment. Conclusion: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis. CLARITY: NCT00213135; CLARITY Extension: NCT00641537 [ABSTRACT FROM AUTHOR]

Background: Treatment-emergent adverse events (TEAEs) that occur close to treatment initiation may negatively affect overall tolerability and adherence. It is important to develop a clear understanding of potential early TEAEs after initiating treatment with cladribine tablets. Objective: To identify TEAEs that begin early in the course of treatment in patients enrolled in CLARITY and ORACLE-MS studies. Methods: This post hoc analysis of CLARITY and ORACLE-MS safety populations assessed the incidence of TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation in patients receiving cladribine tablets or placebo within 2, 6, and 12 weeks after treatment initiation. Results: By Week 12, 61.3% of patients treated with cladribine tablets 3.5 mg/kg and 55.2% treated with placebo experienced a TEAE. More patients receiving cladribine tablets versus placebo experienced a drug-related TEAE by Week 12 (34.7% vs. 23.2%). The most common TEAEs reported with cladribine tablets were: headache (7.2%), lymphopenia (6.8%), and nausea (6.0%). Patients receiving cladribine tablets and placebo reported similar proportions of serious TEAEs (2.2% vs. 1.7%) and TEAEs leading to treatment discontinuation (1.6% vs. 1.4%). Conclusion: Cladribine tablets were well tolerated during the first 12 weeks as evidenced by a low incidence of TEAEs leading to treatment discontinuation. [ABSTRACT FROM AUTHOR]

Therapies for infiltrative inflammation in multiple sclerosis (MS) have advanced greatly, but neurodegeneration and compartmentalized inflammation remain virtually untargeted as in other diseases of the nervous system. Consequently, many therapies are available for the relapsing-remitting form of MS, but the progressive forms remain essentially untreated. The objective of the International Progressive MS Alliance is to expedite the development of effective therapies for progressive MS through new initiatives that foster innovative thinking and concrete advancements. Based on these principles, the Alliance is developing a new funding programme that will focus on experimental medicine trials. Here, we discuss the reasons behind the focus on experimental medicine trials, the strengths and weaknesses of these approaches and of the programme, and why we hope to advance therapies while improving the understanding of progression in MS. We are soliciting public and academic feedback, which will help shape the programme and future strategies of the Alliance. [ABSTRACT FROM AUTHOR]

Background: In the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE). Objective: To determine the timing of effects of cladribine tablets on lesion activity assessed by magnetic resonance imaging (MRI). Methods: This post hoc analysis assessed the effect of cladribine tablets versus placebo in ORACLE-MS on secondary MRI endpoints including T1 gadolinium-enhancing (Gd+), new or enlarging T2 lesions, and combined unique active lesions assessed on MRI scans performed at screening and every 3 months thereafter. Results: Compared to placebo, cladribine tablets 3.5 mg/kg treatment appeared to lead to a trend of reductions in the mean number of T1 Gd+ lesions by Week 13 (first post-baseline scan: 0.37 vs. 1.00), new or enlarging T2 (0.20 vs. 1.01) and combined unique active (0.29 vs. 1.91) lesions by Week 24. Low lesion counts were maintained with cladribine tablets throughout 96weeks. Similar results were observed with the 5.25 mg/kg dosage. Conclusion: In participants with an FCDE, cladribine tablets appeared to reduce lesion numbers within 13 weeks (time of first evaluation). [ABSTRACT FROM AUTHOR]

Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to the molecule's ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the treatment of multiple sclerosis (MS). The unique proposed mechanism of action of cladribine allows for the therapy to be delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3 and 4. This review summarizes the clinical development program for cladribine tablets in patients with MS, including the efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing–remitting MS (RRMS), the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinating event at risk for developing MS. Efficacy results from the phase II ONWARD study, in which cladribine tablets were administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized. A review of all safety data, including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, including the initial parenteral formulation studies. Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years have been approved across the globe for various forms of relapsing MS. -Rur3AYxnG_ZDzfPLTCkab The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review (MP4 279143 kb) [ABSTRACT FROM AUTHOR]

Aims: Cladribine tablets have shown significant efficacy for the treatment of relapsing multiple sclerosis, a chronic and debilitating immune‐mediated disorder. This study was conducted to examine acute and/or cumulative effects of cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dose over 2 years) on heart rate, AV conduction and cardiac repolarization in patients with relapsing–remitting multiple sclerosis (RRMS). Methods: CLARITY was a 96‐week, double‐blind, placebo‐controlled, multicentre trial which evaluated the safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg body weight in patients with RRMS. A total of 135 patients were included in the ECG substudy, providing a total of 1534 post‐dose ECGs. ECG data were collected 15 minutes pre‐dose and between 0.5 and 3 hours post‐dose at pre‐study evaluation, study Day 1 and Weeks 5, 9, 13, 48 and 52. Results: For cladribine tablets 3.5 mg/kg, the maximum change in placebo‐adjusted post‐dose QTcF vs. visit‐baseline (BL) was −0.42 ms (90% CI: −3.61–4.44) at Week 1 (acute effects), and 3.20 ms (90% CI: −0.08–6.33) for cladribine tablets 5.25 mg/kg. The greatest observed differences in post‐dose QTcF vs. study BL occurred at Week 48 for both the 3.5 and 5.25 mg/kg doses of cladribine tablets with 5.99 ms (90% CI: 0.53–11.44) and 8.74 ms (90% CI: 3.18–14.31), respectively. No significant changes were observed in T‐wave morphology in either treatment group. Conclusions: Cladribine tablets 3.5 mg/kg (approved dose in Europe/other regions) did not confer clinically meaningful effects on heart rate, AV conduction and ventricular repolarization. [ABSTRACT FROM AUTHOR]

Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis. Objective: Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population. Methods: Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to study entry while on therapy with other DMDs and ⩾1 T1 Gd+ or ⩾9 T2 lesions). Results: In the overall population, Cladribine Tablets 3.5 mg/kg reduced the risk of 6-month-confirmed Expanded Disability Status Scale (EDSS) worsening by 47% vs placebo. A risk reduction of 82% vs placebo was seen in both the HRA and HRA + DAT subgroups (vs 19% for non-HRA and 18% for non-HRA + DAT), indicating greater responsiveness to Cladribine Tablets 3.5 mg/kg in patients with HDA. There were consistent results for other efficacy endpoints. The safety profile in HDA patients was consistent with the overall CLARITY population. Conclusion: Patients with HDA showed clinical and MRI responses to Cladribine Tablets 3.5 mg/kg that were generally better than, or at least comparable with, the outcomes seen in the overall CLARITY population. [ABSTRACT FROM AUTHOR]

Introduction: Cladribine Tablets (MAVENCLAD®) selectively reduce absolute lymphocyte counts (ALCs) in patients with multiple sclerosis. The recommended cumulative dose of Cladribine Tablets is 3.5 mg/kg over 4-5 days in months 1 and 2 of treatment years 1 and 2, followed by prolonged efficacy with no additional treatment. After the cladribine-induced reduction, ALCs recover to normal within each treatment year in most patients. Those patients with slow ALC recovery can develop Grade 3-4 lymphopenia, especially those patients with Grade ≥  2 lymphopenia at the start of year 2. Guidelines allowing treatment postponements during year 2 have been proposed for patients with a low ALC, subsequent to CLARITY, the pivotal clinical trial.Methods: A virtual population was generated using characteristics from CLARITY patients. A clinical trial simulation was performed to determine the impact of alternative treatment scenarios on ALC and relapse rate, by postponing treatment in year 2 to allow for longer ALC recovery time in patients who required it. Should a patient not recover to normal ALC (Grade 0) or Grade 1 lymphopenia within the period defined in the treatment algorithm, treatment in year 2 was suspended.Results: Results were similar across considered scenarios, which implemented different postponement durations. Specifically, ~  92% of virtual subjects did not require treatment postponement and <  1% discontinued due to Grade 2-4 lymphopenia at the end of the maximally permitted postponement. Less severe lymphopenia was observed during year 2 when a treatment algorithm was applied. The effect on relapse rate over 2 years was negligible.Conclusions: Results support treatment guidelines to decrease the risk of severe lymphopenia following treatment with Cladribine Tablets, while preserving efficacy.Trial Registration: CLARITY; ClinicalTrials.gov: NCT00213135. [ABSTRACT FROM AUTHOR]

Background: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing–remitting multiple sclerosis (MS). Objective: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. Methods: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. Results: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0–1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. Conclusion: Cladribine tablets treatment for 2 years followed by 2 years’ placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting. [ABSTRACT FROM AUTHOR]

Background: Brain volume atrophy is observed in relapsing-remitting multiple sclerosis (RRMS).Methods: Brain volume changes were evaluated in 23 patients with RRMS treated with interferon β-1a 44 μg given subcutaneously (SC) three times a week (tiw) and 15 healthy controls. Percentages of whole brain and tissue-specific volume change were measured from baseline (0 months) to 3 months, from 3 to 6 months, and from baseline to 6 months using SIENAX Multi Time Point (SX-MTP) algorithms. Immunological status of patients was also determined and correlations between subsets of T cells and changes in brain volume were assessed.Results: Interferon β-1a 44 μg SC tiw in 23 patients with RRMS resulted in significant reductions in whole brain and gray matter tissue volume early in the treatment course (baseline to 3 months; mean change; -0.95%; P = 0.030, -1.52%; P = 0.004, respectively), suggesting a short-term treatment-induced pseudoatrophy effect. From baseline to 6 months, there were significant correlations observed between decreased T- cell expression of IL-17 F and decreased whole brain and brain tissue-specific volume.Conclusions: These findings are consistent with the interpretation of the pseudoatrophy effect as resolution of inflammation following treatment initiation with interferon β-1a 44 μg SC tiw, rather than disease-related tissue loss.Trial Registration: ClinicalTrials.gov; NCT01085318. [ABSTRACT FROM AUTHOR]

Background: This pilot study investigated changes in remyelinating and demyelinating activity in normal appearing brain tissue (NABT) and lesions, by using voxel-wise magnetization transfer ratio (VW-MTR), in patients with relapsing–remitting multiple sclerosis (RRMS) receiving interferon beta-1a 44 mcg subcutaneously (IFN β-1a SC) three times weekly versus healthy controls (HCs) (NCT01085318). Methods: Increasing (suggestive of remyelination) and decreasing (suggestive of demyelination) VW-MTR changes in NABT and in T2, T1 and gadolinium (Gd)-enhancing lesion volume were measured over 24 weeks in 23 patients treated with IFN β-1a SC and in 15 HCs (where applicable). VW-MTR changes were tested using the Wilcoxon signed–rank or Wilcoxon rank–sum test. Results: A trend for greater volume of NABT with increasing VW-MTR at 24 weeks was observed for patients versus HCs (median [range] 1206 [0–15278]; 342 [0–951] mm3; p = 0.061). NABT volume with increasing VW-MTR at 12 weeks was significantly greater in patients than in HCs (852 [6–11577]; 360 [0–1755] mm3; p = 0.028). Similar findings were detected for lesion volumes. Two patients with notably high numbers of Gd-enhancing lesions at baseline had a markedly greater volume of tissue with increasing VW-MTR compared with other patients. Volume of NABT tissue with decreasing VW-MTR was significantly greater in patients versus HCs at 24 weeks (942 [0–6141]; 297 [0–852] mm3; p<0.001). Conclusions: The significant change in NABT volume with increasing VW-MTR at 12 weeks suggests that active remyelination in patients with RRMS may occur during treatment with IFN β-1a SC. Findings from two patients with the highest number of Gd-enhancing lesions at baseline suggest that extensive remyelination in NABT may occur in patients with high disease activity. Tissue volume with decreasing VW-MTR was greater in patients than in HCs, despite treatment, validating the sensitivity of this technique for detecting MS disease activity. Trial Registration: ClinicalTrials.gov NCT01085318. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Individuals with multiple sclerosis (MS) experience diminished health outcomes. However, little is known about how these outcomes differ according to disease severity. The aim of this study is to compare health-related quality of life (HRQoL), work productivity, activity impairment, and resource use between MS patients and controls, as well as across MS patients with varying self-reported disease severity. Methods: Data were analyzed from respondents reporting an MS diagnosis (n=536) and controls (n=74,451) in the U.S. 2009 National Health and Wellness Survey (administered online to a nationally representative adult population). Differences were assessed between those with and without MS, and across three MS severity groups: mild (38.4%), moderate (50%), and severe (11.6%). Results: MS patients vs. controls experienced significantly more activity impairment, decreased work productivity, increased healthcare utilization, and lower HRQoL (all p<0.001). Increasing MS severity was associated with greater activity impairment, lower work productivity, increased healthcare utilization, and lower HRQoL. More significant impairments emerged between individuals who perceived their disease severity as mild vs. moderate than moderate vs. severe. Conclusion: MS patients reported greater impairment than controls, and impairment increased with disease severity (especially from mild to moderate). These findings show that increasing MS disease severity is associated with worse health outcomes. [Copyright &y& Elsevier]

Background: In the phase 3 CLARITY study, patients with relapsingremitting multiple sclerosis (MS) treated with cladribine tablets (CTs) 10 mg (3.5 mg/kg [CT3.5] or 5.25 mg/kg cumulative dose over 2 years), showed significant reductions in annualized relapse rate (P < .001), time to 3-month (mo) sustained change in Expanded Disability Status Scale (EDSS) score (P ≤ .03), and lesion activity on brain magnetic resonance imaging (MRI, all P < .001) vs placebo. However, the efficacy of CTs has not been fully characterized in patients transitioning to active secondary progressive MS or not, for which EDSS scores of ≥3.5 and ≤3.0, respectively, can be used as a proxy definition. Objectives: To examine differences between placebo and CT3.5 on clinical and MRI end points and in attainment of no evidence of disease activity (NEDA) in patients with baseline EDSS scores of ≥3.5 or ≤3.0 in CLARITY. Methods: In this post hoc analysis, week 96 data from CLARITY were retrospectively examined across patients with baseline EDSS score ≥3.5 or ≤3.0 for relapses, 3- or 6-mo confirmed disability progression (CDP, per EDSS score changes), new T1 gadolinium-enhancing (Gd+) lesions, active T2 lesions, and NEDA. Results: Baseline characteristics were evenly distributed across treatment groups. Relapse, T1 Gd+ lesion, and T2 lesion numbers were greater in placebo-treated vs CT3.5-treated patients for both baseline EDSS groups (all P < .0001, nominal significance) at week 96. For patients with baseline EDSS score ≥3.5, CT3.5 treatment resulted in improvements in qualifying relapses (Kaplan-Meier estimates at last event: 78.3% vs 60.3%), 3-month CDP (83.5% vs 69.4%), and 6-month CDP (88.1% vs 78.2%) vs placebo. Differences between CT3.5 and placebo treatment in the baseline EDSS ≤3.0 group were: 81.1% vs 61.6% in qualifying relapse, 86.3% vs 80.6% in 3-month CDP, and 92.0% vs 87.2% in 6-month CDP. Odds ratios (ORs) favored CT3.5 vs placebo for NEDA based on either 3-month (OR: 4.40) and 6-month CDP (OR: 4.11) in the baseline EDSS ≥3.5 group and in the baseline EDSS ≤3.0 group (OR for 3-month CDP: 4.23; OR for 6-month CDP: 4.62; all P < .0001, nominal significance). Conclusions: CT treatment resulted in similar improvements in relapse and MRI outcomes regardless of patient baseline EDSS score. The effect of CTs on NEDA composites was also favorable across patients with baseline EDSS score ≥3.5 or ≤3.0. [ABSTRACT FROM AUTHOR]

Background: Tolerability and adherence to disease-modifying drugs (DMDs) can be influenced by treatment-emergent adverse events (TEAEs) that start soon after therapy initiation. One potential advantage of cladribine tablets is that patients only receive doses for two 4- to 5-day periods/ treatment year. Objectives: To identify TEAEs early in the course of treatment in patients enrolled in the phase 3 CLARITY and ORACLE-MS clinical trials. Methods: This was a post hoc analysis of safety populations in CLARITY and ORACLE-MS studies. Patients received cladribine tablets 3.5 mg/kg (cumulative dose over 2 years; N = 636) or placebo (N = 641). The incidence of early adverse events, TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation were summarized based on incidence within 2, 6, and 12 weeks (W) after commencement of therapy. Results: The incidence of TEAEs occurring within the first 2-12W of treatment across both trials in both treatment groups was generally low, and most events were mild (placebo: 68.4%-53.8%; cladribine tablets: 68.0%-54.4%). The most common TEAEs by time epoch after initiating placebo and cladribine tablets 3.5 mg/kg treatment, respectively, were nausea: 3.3% vs 4.9% (2W), 3.7% vs 6.4% (6W), and 4.5% vs 8.0% (12W); fatigue: 2.0% vs 1.4% (2W), 3.1% vs 2.5% (6W), and 4.4% vs 3.1% (12W); headache: 8.3% vs 9.0% (2W), 11.9% vs 14.8% (6W), and 15.1% vs 18.4% (12W); lymphopenia: 0.0% vs 2.5% (6W) and 0.5% vs 6.8% (12W); leukopenia: 0.0% vs 1.3% (12W). Other end points to be shown in the final presentation. Conclusions: Incidence of TEAEs experienced during the first 12 weeks of treatment with cladribine tablets in phase 3 clinical trials was low and mostly mild. Nausea, headache, and lymphopenia were seen more frequently in patients treated with cladribine tablets. These findings suggest that cladribine tablets are generally well tolerated, which may facilitate treatment adherence. [ABSTRACT FROM AUTHOR]

Background: In a phase 2 randomized controlled trial (RCT; trial registration: NCT02975349) in patients with relapsing multiple sclerosis (MS), evobrutinib 75 mg twice daily reduced total T1 gadolinium-enhancing lesions (primary end point) and annualized relapse rate (ARR) over 24 weeks vs placebo, with efficacy maintained through week 48. Objectives: To assess long-term efficacy and safety in the open-label extension (OLE) of the study. Methods: In the 48-week double-blind period, patients received evobrutinib 25 mg or 75 mg once daily, evobrutinib 75 mg twice daily, open-label dimethyl fumarate (240 mg twice daily), or placebo for the first 24 weeks; all arms continued with the original treatment assignment until 48 weeks, except placebo patients who were switched to evobrutinib 25 mg once daily. At week 48, all patients could enter the OLE, where treatment was initially evobrutinib 75 mg once daily (for approximately 48 weeks, median) before switching to 75 mg twice daily. The OLE assessed long-term efficacy (0-108 weeks) and safety (60-week OLE) of evobrutinib. Results: Of 267 randomized patients, 213 (79.8%) completed 108 weeks of treatment (48-week main study, 60-week OLE). For patients who received evobrutinib 75 mg twice daily in the double-blind period, the ARR (95% CI) was 0.11 (0.04-0.25) at week 48 and 0.12 (0.06-0.22) for the 108-week period. Evobrutinib was generally well tolerated, with the safety profile maintained during the 60-week OLE. Transient elevated liver aminotransferases, reported in the 48-week double-blind period, were not observed in the OLE. Conclusions: Efficacy and safety were maintained long-term. Two phase 3 RCTs evaluating the efficacy and safety of evobrutinib in patients with relapsing MS commence in 2020. [ABSTRACT FROM AUTHOR]

Background: Bruton's tyrosine kinase (BTK) plays an important role in proinflammatory pathways potentially involved in multiple sclerosis (MS). Consequently, BTK inhibition is being investigated as a potential therapeutic approach for MS. Evobrutinib, a highly selective BTK inhibitor (BTKi), has a dual mechanism of action, affecting both B cells and macrophages through inhibition of B-cell receptor, Fc receptor, and granulocyte--macrophage colony-stimulating factor receptor signaling, and has demonstrated clinical efficacy in MS in a phase 2 study (trial registration: NCT02975349; Montalban et al, ECTRIMS 2018 [P322]). Objectives: To examine the effect of evobrutinib on immune cells and immunoglobulins (Igs) over 48 weeks. Methods: Patients aged 18-65 years with active relapsing--remitting MS or secondary progressive MS and superimposed relapses were randomized to receive either doubleblind evobrutinib (25 mg once daily [qd], 75 mg qd, or 75 mg twice daily), placebo, or open-label dimethyl fumarate 240 mg (reference arm). After 24 weeks, placebo-treated patients were switched to evobrutinib 25 mg qd; other treatment arms continued under original allocation. Safety of evobrutinib, including assessment of B-cell count and Ig level, was a key secondary end point; investigations of the effects of evobrutinib on B-cell subsets, T-cell subsets, and natural killer cells in peripheral blood over 48 weeks were exploratory. Results: Of 267 patients randomized to treatment, 227 patients completed 48 weeks of treatment. No clinically relevant changes in the number of total B cells, or of memory B, mature naive B, total T, helper T, cytotoxic T, or natural killer cells, were observed in any evobrutinib treatment group over 48 weeks. No changes in IgG or IgG subtype levels were observed over 48 weeks in any treatment group. At week 48, there were slight increases from baseline in IgA and reductions in IgM for all evobrutinib groups, which were numerically greater than those with placebo at week 24. Conclusions: Patients with MS treated with the BTKi evobrutinib showed no evidence of B-cell depletion or change in mature vs naive B-cell subsets over 48 weeks. IgG levels remained stable and slight elevations in IgA levels were observed. These findings demonstrate that, in contrast to genetic deletion of BTK, continued pharmacologic BTK inhibition does not lead to B-cell depletion or signifi- cant reductions in circulating Igs. [ABSTRACT FROM AUTHOR]

Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5. Methods: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48. Results: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16+/CD56+ cells (week 5 nadir), a more marked reduction in CD19+ B cells (week 13 nadir), and a less-pronounced effect on CD4+ (week 13 nadir) and CD8+ T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4+ T cells. Conclusions: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19+ B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5. [ABSTRACT FROM AUTHOR]

Background: In the PRISMS study, interferon beta-1a subcutaneously (IFN β-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing-remitting multiple sclerosis. The study aimed to characterize efficacy of IFN β-1a SC 44 μg and 22 μg three times weekly (tiw) at Year 1.Methods: Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was < 6.0 [0.5-point if baseline was ≥6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN β-1a SC in prespecified patient subgroups was also assessed.Results: Patients were randomized to IFN β-1a 22 μg (n = 189), 44 μg (n = 184), or placebo (n = 187). At 1 year, IFN β-1a SC tiw reduced ARR (p < 0.001), risk of disability progression (p ≤ 0.029), and mean number of active T2 lesions per patients per scan (p < 0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN β-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p ≤ 0.006).Conclusion: Clinical, radiological, and NEDA outcomes at Year 1 were consistent with Year 2 results. Treatment efficacy was consistent in pre-specified patient subgroups. [ABSTRACT FROM AUTHOR]

Abstract: The effect of pharmacologically relevant doses of interferon (IFN) β-1a on B-cell expression of B7.1 and B7.2 was investigated. Culture of peripheral blood mononuclear cells with IFN β-1a 100IU/mL decreased B-cell expression of B7.1 and increased B7.2 expression. Interleukin-10 in B cells was significantly enhanced by IFN β-1a. Anti-CD3 and anti-CD28 monoclonal antibody-mediated T-cell proliferations were partially suppressed in the presence of B cells pretreated with IFN β-1a. These data suggest that IFN β-1a and B cells can interact to play a beneficial role in the treatment of multiple sclerosis. [Copyright &y& Elsevier]

Background: Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.Methods: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS).Results: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib.Conclusions: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.). [ABSTRACT FROM AUTHOR]

Introduction ‘No evidence of disease activity’ (NEDA) is increasingly used as a treatment target with disease-modifying drugs for relapsing multiple sclerosis. Methods This post-hoc analysis of the randomised EVIDENCE trial compared interferon beta-1a injected subcutaneously three times weekly (IFN β-1a SC tiw) with interferon β-1a injected intramuscularly once weekly (IFN β-1a IM qw) on NEDA and clinical activity-free (CAF) status. The influence of the frequency of magnetic resonance imaging (MRI) scanning on NEDA and the effect of baseline T1 gadolinium-enhancing (Gd +) lesions on NEDA and CAF were also investigated. Results More patients in the IFN β-1a SC tiw group achieved NEDA compared with the IFN β-1a IM qw group, although rates were lower when monthly MRI scans through 24 weeks were included (35.0% vs. 21.6%, respectively; p < 0.001) versus the 24-week scan alone (59.5% vs. 41.2%; p < 0.001). Absence of baseline Gd + lesions predicted NEDA through Week 72 in the IFN β-1a IM qw group ( p = 0.022), and CAF through Week 48 in patients receiving IFN β-1a SC tiw ( p = 0.024). Conclusions IFN β-1a SC tiw was associated with significantly higher rate of NEDA status compared with IFN β-1a IM qw. Baseline Gd + lesions augured less frequent CAF or NEDA status. Inclusion of more MRI scans in the analysis reduced rates of NEDA status. [ABSTRACT FROM AUTHOR]

Subanalysis of a pilot study ( NCT01085318 ) assessed correlations between serum ferritin and imaging assessments in relapsing–remitting multiple sclerosis patients (n = 23) receiving 44 μg interferon beta-1a subcutaneously three times weekly. At baseline, 12, and 24 weeks, mean ferritin was 75, 127 (p < 0.001 vs baseline), and 101 (p = 0.020 vs baseline) ng/mL. No relationship between ferritin and susceptibility-weighted imaging (SWI)-filtered phase of subcortical deep gray matter was found. Increasing ferritin correlated with decreasing lesion numbers on both fluid attenuated inversion recovery and SWI phase at 12 weeks (r = − 0.62; p = 0.003; n = 21), and with decreasing gadolinium-enhancing lesion volume at 24 weeks (r = − 0.71; p = 0.050; n = 8). [ABSTRACT FROM AUTHOR]

Abstract: We demonstrate that the histone deacetylase (HDAC) inhibitor drug trichostatin A (TSA) reduces spinal cord inflammation, demyelination, neuronal and axonal loss and ameliorates disability in the relapsing phase of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). TSA up-regulates antioxidant, anti-excitotoxicity and pro-neuronal growth and differentiation mRNAs. TSA also inhibits caspase activation and down-regulates gene targets of the pro-apoptotic E2F transcription factor pathway. In splenocytes, TSA reduces chemotactic, pro-Th1 and pro-proliferative mRNAs. A transcriptional imbalance in MS may contribute to immune dysregulation and neurodegeneration, and we identify HDAC inhibition as a transcriptional intervention to ameliorate this imbalance. [Copyright &y& Elsevier]

We performed microarray analysis of peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients and detected a profile of immune cell activation, autoantigen upregulation, and enhanced E2F pathway transcription. Accordingly, E2f1-deficient mice manifested only mild disability upon induction of experimental autoimmune encephalomyelitis (EAE). Furthermore, PBMCs from Avonex-treated patients had lower expression of E2F targets. The profile was enriched in genes known to harbor MS-associated polymorphisms, or localized to MS susceptibility chromosomal regions. Our study shows that PBMC microarrays reflect MS pathobiology that can be validated in the EAE model. [Copyright &y& Elsevier]