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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. [ABSTRACT FROM AUTHOR]

A major question for gene therapy in brain concerns methods to administer therapeutic genes in a uniform manner over major portions of the brain. A second question in neuroimmunology concerns the extent to which monocytes migrate to the CNS in degenerative disorders. Here we show that CD11b+ cells (largely monocytes) isolated from the bone marrow of GFP (green fluorescent protein)-expressing donors spontaneously home to compacted amyloid plaques in the brain. Injections of these cells as a single pulse show a rapid clearance from circulation (90 min half-life) and tissue residence half-lives of ~3 d. The uptake into brain was minimal in nontransgenic mice. In transgenic mice containing amyloid deposits, uptake was dramatically increased and associated with a corresponding decrease in monocyte uptake into peripheral organs compared to nontransgenic litter mates. Twice weekly infusions of the CD11b+ bone marrow cells transfected with a genetically engineered form of the protease neprilysin completely arrest amyloid deposition in an aggressively depositing transgenic model. Exploiting the natural homing properties of peripherally derived blood cells to deliver therapeutic genes has the advantages of access to the entire CNS, expression largely restricted to sites of injury, low risk of immune reactivity, and fading of expression if adverse reactions are encountered. These observations support the feasibility of testing autologous monocytes for application of therapeutic genes in human CNS disease. Moreover, these data support the results from bone marrow grafts that circulating CD11b+ cells can enter the CNS without requiring the use of lethal irradiation. [ABSTRACT FROM AUTHOR]

Background: A better understanding of the implications of suboptimal treatment outcomes in employees with multiple sclerosis (MS) may elucidate opportunities for improving care management. Objectives: To evaluate suboptimal treatment outcomes with disease-modifying drugs (DMDs) in patients with MS from an employer perspective. Methods: US Human Capital Management Services database employees were eligible if they had: ≥2 claims with MS diagnoses (ICD-9 CM 340.xx/ICD-10 CM G35) from January 1, 2010--March 31, 2019, ≥1 once-/twicedaily oral or any self-injectable DMD claim (first claim=index), continuous eligibility 6-months pre- (baseline) and 1-year post-index (follow-up), no baseline DMD, age 18-64. Suboptimal treatment outcomes were DMD nonadherence (proportion of days covered <80%), DMD discontinuation (treatment gap >60 days), DMD switch, or relapse (MS-related hospitalization, emergency room visit, or outpatient visit with corticosteroid ±7 days). A 2-part logistic-GLM model evaluated costs controlling for age, tenure, marital status, race, exempt status, full-/part-time, salary, location, Charlson Comorbidity Index, smoking, and relapse. Results: Of 2173 employees with ≥2 MS diagnoses, 488 (22.5%) met eligibility. Half (n = 247 [50.6%]) had suboptimal treatment outcomes (39.5% nonadherence, 9.8% discontinuation, 10.9% switching, 20.7% relapse; indicators not mutually exclusive). Baseline characteristics were similar for employees with vs without suboptimal treatment outcomes: mean age: 42.60 vs 43.87; female: 73.7% vs 71.4%; white/black/Hispanic: 32.0%/5.3%/3.6% vs 29.5%/5.8%/6.6%; married: 23.1% vs 27.4%; mean salary: $61,898 vs $68,737; hypertension: 14.6% vs 16.6%; hyperlipidemia: 11.7% vs 12.9%; gastrointestinal disease: 16.6% vs 12.9%; tobacco use: 3.2% vs 2.5%; baseline magnetic resonance imaging: 57.9% vs 58.9%; baseline relapse: 22.7% vs 19.9%. Employees with vs without suboptimal treatment outcomes had higher all-cause medical ($12,730 vs $6428; P < .0001), MS-related medical ($5444 vs $2652; P < .0001), non-DMD pharmacy ($2920 vs $2169; P = .0199), sick leave ($1247 vs $908; P = .0274), and short-term disability ($934 vs $146; P = .0001) costs. Long-term disability ($751 vs $0; P = .1250) and Workers' Compensation ($56 vs $24; P = .1276) costs did not differ significantly. Conclusions: Half of employees with MS had suboptimal 1-year treatment outcomes (nonadherence, discontinuation, switching, relapse). Suboptimal response to DMD treatment was associated with higher medical, sick leave, and short-term disability costs. [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]