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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]

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]

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. 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. 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. 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. [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]

Background: Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage. Methods: In the CLARITY study (ClinicalTrials.gov NCT00213135), the effect of 2 years' treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS). Results: Compared with placebo (-0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (-0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (-0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p < 0.001), with patients with lower PBVC/y showing the highest probability of remaining free from disability progression at 2 years and vice versa. Conclusions: Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates. [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: 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: 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]

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]