Alemtuzumab in Autoimmune Inflammatory Neurodegeneration: Mechanisms of Action and Neuroprotective Potential

INTERVENTION: Trade Name: LEMTRADA 12 mg Konzentrat zur Herstellung einer Infusionslösung Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Alemtuzumab CAS Number: 216503‐57‐0 Other descriptive name: ALEMTUZUMAB Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ CONDITION: relapsing‐remitting multiple sclerosis ; MedDRA version: 20.0 Level: PT Classification code 10063399 Term: Relapsing‐remitting multiple sclerosis System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: Combining clinical data with ex vivo and in vitro data, the study aims to shed more light on the mechanisms of action and the neuroprotective potential of alemtuzumab Primary end point(s): Absolute and relative change from baseline of the following cell‐counts in the peripheral blood: ; a. T cell subsets: ; ‐ CD4 and CD8 positive T cells: naïve T cells, T effector cells, T memory cells, regulatory T cells; ; ‐ T‐helper subsets: Th1, Th2, Th17 ; b. B cell subsets:; ‐ Recent bone marrow emigrants, mature naïve, memory B cells ; ‐ Plasma cells ; c. Natural killer cells: ; ‐ CD56bright, CD56dim; ‐ Natural killer T cells; d. Antigen‐Presenting cells:; ‐ Dendritic cells: CD303+ plasmacytoid, CD11c+ and CD141+ myeloid dendritic cells ; ‐ Monocytes and macrophages ; e. Myeloid‐derived suppressor cells.; Secondary Objective: Not appicable Timepoint(s) of evaluation of this end point: 12, 24 and 36 months after initiaton of investigational treatment. In addition, on an optional basis: 6, 18 and 30 months after treatment initiation. SECONDARY OUTCOME: Secondary end point(s): 1. Absolute and relative change from baseline in cell‐counts in the CSF. The same cell‐types as indicated for the primary endpoints will be evaluated. ; ; 2. Functional characterization of T‐cells in the peripheral blood and the CSF: ; a. Activation status of cell surface receptors assessed by flow cytometry: ; Relative and absolute change from baseline of mean fluorescence intensity (MFI) and of proportion of positive cells regarding CD25, HLA‐DR, LFA‐1, CD29, CD69, CD71 expression ; b. Expression of co‐inhibitory molecules assessed by flow cytometry: ; Relative and absolute change from baseline of MFI and of proportion of positive cells regarding PD‐1 = CD279, ICOS = CD278, TIM‐3, CTLA4 expression ; c. Effector functions of CD4 and CD8 positive T cells: ; ‐ Relative and absolute change from baseline of the results of cell proliferation assays assessed as percentage of proliferated cells ; ‐ Relative and absolute change from baseline of cytokine production measurement assessed as concentration ; ‐ Relative and absolute change from baseline of cytolytic activity assessed by flow cytometry measurement of MFI and proportion of positive cells regarding Granzyme B, Perforin and CD107a expression ; ‐ Relative and absolute change from baseline of intracellular calcium response assessed as concentration ; d. Migrational capacity: ; ‐ Relative and absolute change from baseline MFI and proportion of positive cells assessed by flow cytometry expression analysis of CD11a, CD31, CD44, CD49d, CCR5, CCR6, CCR7 ; ‐ Absolute and relative change of cell numbers of migrated cells compared to baseline assessed in an in vitro model by flow cytometry analysis ; e. Spectratyping of the T cell repertoire concerning the expansion of distinct clones: ; ‐ Relative and absolute change from baseline for complexity scores ; ‐ Qualitative comparison of the distribution of CDR3 sequences ; f. Regulatory T‐cell function: ; ‐ Relative and absolute change from baseline in production of TGF‐beta and IL‐10 of CD4+CD25+FOXP3+ regulatory T cells ; ‐ Suppression of T cell proliferation: Relative and absolute change from baseline in responder T cell proliferation assessed by suppression assays. ; ; 3. Neuroprotective potential of alemtuzumab: ; a. Relative and absolute change from baseline concentration in the CSF of following markers: ; S100ß, Tau, phospho‐Tau, ß‐Amyloid, Neurofilament (low weight), Neurofilament (high weight), N‐acetylaspartate (NAA), Tubulin, Actin, neuron‐specific enolase (NSE), glial fibrillary acidic protein (GFAP) ; b. Relative and absolute change from baseline in neuronal activity, action potential generation and cellular integrity by obtained human CSF supernatant samples using multi‐electrode arrays ; c. Relative and absolute change from baseline concentration in the peripheral blood and the CSF of following neurotrophic factors: ; Nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), neurotrophin‐3 (NT‐3), and neurotrophin‐4 (NT‐4), ciliary neurotrophic factor (CNTF) ; d. Percent change from Baseline in the following MRI findings which are defined as markers for neurodegeneration: ; MRI‐T1‐measured cerebral volume, MRI‐T1‐measured number of black holes ; e. Relative and absolute change from baseline in retinal nerve fiber layer thickness (assessment by optical coherence tomography). ; ; Safety endpoints: Data on Adverse Events. Timepoint(s) of evaluation of this end point: Effficacy endpoints: ; 12, 24 and 36 months after initiation of investigational treatment. In addition, on an optional basis: 6, 18 and 30 months after treatment initiation, evaluation of certain non‐invasive investigations even every 3 months. Examinations of CSF every 12 months only using samples collected on an optional basis. ; ; Safety endpoints: ; At least monthly monitoring for autoimmune diseases, at least quarterly monitoring for autoimmune thyroid diseases, at least semiannual performance of any other safety assessments. INCLUSION CRITERIA: 1. Signed informed consent form (ICF) 2. Age 18 to 55 years old (inclusive) as of the date the ICF is signed 3. Diagnosis of MS according to the McDonald criteria 2010 and cranial MRI scan demonstrating white matter lesions attributable to MS within 10 years before screening 4. Onset of MS symptoms (as determined by a neurologist, either at present or retrospectively) within 10 years of the date the ICF is signed 5. EDSS score 0.0 to 5.0 (inclusive) at Screening 6. Patients with (highly) active RRMS disease course indicated to receive alemtuzumab according to the following conditions (at least 1 out of 3 conditions has to be fulfilled): 1. =2 MS relapses within 24 months 2. clinical (=1 relapse) or MRI (new gadolinium enhancing lesions) disease activity under therapy with other disease‐modifying therapies 3. severe relapse with high disease activity (=9 T2 hyperintense Lesions and =1 gadolinium enhancing lesion) on MRI. 7. C