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

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

Side effects that occurred early in people with multiple sclerosis during the first year of treatment with cladribine tablets: a plain language summary.

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.

Treatment-emergent adverse events occurring early in the treatment course of cladribine tablets in two phase 3 trials in multiple sclerosis.

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.

Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

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 96 weeks. 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).

CLICK-MS and MASTER-2 Phase IV trial design: cladribine tablets in suboptimally controlled relapsing multiple sclerosis.

Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) are approved for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS and active secondary progressive MS. However, real-world data on cladribine tablets are limited. CLICK-MS and MASTER-2 are single arm, observational, 30-month, Phase IV studies in the US evaluating the effectiveness and safety of cladribine tablets 3.5 mg/kg in patients with relapsing-remitting MS or active secondary progressive MS who had suboptimal response to prior injectable (CLICK-MS), or infusion/oral (MASTER-2) disease-modifying therapy. The primary end point is 24-month annualized relapse rate. Key secondary end points include patient-reported outcomes on quality of life measures, treatment adherence and adverse events. Studies began in 2019 and are expected to be completed in 2023. Trial registration number • CLICK-MS: NCT03933215 (ClinicalTrials.gov) Full title; CLadribine tablets: observational evaluation of effectIveness and patient-reported outcomes in suboptimally Controlled patients previously taKing injectable disease-modifying drugs for relapsing forms of Multiple Sclerosis • MASTER-2: NCT03933202 (ClinicalTrials.gov) Full title; Cladribine tablets: observational evaluation of effectiveness and patient-reported outcomes in suboptiMAlly controlled patientS previously Taking oral or infusion disEase-modifying dRugs for relapsing forms of multiple sclerosis.

Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis.

Increasing evidence suggests ion channels have critical functions in the differentiation and plasticity of T cells. Kv1.3, a voltage-gated K(+) channel, is a functional marker and a pharmacological target for activated effector memory T cells. Selective Kv1.3 blockers have been shown to inhibit proliferation and cytokine production by human and rat effector memory T cells. We used Kv1.3 knockout (KO) mice to investigate the mechanism by which Kv1.3 blockade affects CD4(+) T cell differentiation during an inflammatory immune-mediated disease. Kv1.3 KO animals displayed significantly lower incidence and severity of myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis. Kv1.3 was the only K(V) channel expressed in MOG 35-55-specific CD4(+) T cell blasts, and no K(V) current was present in MOG-specific CD4(+) T cell-blasts from Kv1.3 KO mice. Fewer CD4(+) T cells migrated to the CNS in Kv1.3 KO mice following disease induction, and Ag-specific proliferation of CD4(+) T cells from these mice was impaired with a corresponding cell-cycle delay. Kv1.3 was required for optimal expression of IFN-γ and IL-17, whereas its absence led to increased IL-10 production. Dendritic cells from Kv1.3 KO mice fully activated wild-type CD4(+) T cells, indicating a T cell-intrinsic defect in Kv1.3 KO mice. The loss of Kv1.3 led to a suppressive phenotype, which may contribute to the mechanism by which deletion of Kv1.3 produces an immunotherapeutic effect. Skewing of CD4(+) T cell differentiation toward Ag-specific regulatory T cells by pharmacological blockade or genetic suppression of Kv1.3 might be beneficial for therapy of immune-mediated diseases such as multiple sclerosis.