Achiron, A

Barkhof, F

Boschert, U

Chan, A

Chudecka, A

De Stefano, N

Derfuss, T

Hodgkinson, S

Leocani, L

Montalban, X

Prat, A

Roy, S

Schmierer, K

Sellebjerg, F

Vermersch, P

Wiendl, H

Neurology

English

Queen Mary Research Online

Characterization of Peripheral Immune Cell Dynamics and Repopulation Patterns in the First 12 Months of CladribineTablets Treatment: MAGNIFY-MS StudyH. Wiendl1, K. Schmierer2,3, S. Hodgkinson4, T. Derfuss5, A. Chan6, F. Sellebjerg7, A. Achiron8,X. Montalban9, A. Prat10, N. De Stefano11, F. Barkhof12,13, L. Leocani14, P. Vermersch15, A. Chudecka16, S. Roy17, U. Boschert171Department of Neurology, Institute of Translational Neurology, University of Münster, Münster, Germany; 2Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK; 3Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK; 4Ingham Institute for Applied Medical Research, University of New South Wales Medicine, Sydney, Australia; 5Department of Neurology, University Hospital Basel, Basel, Switzerland; 6University Hospital of Berne, University of Berne, Berne, Switzerland; 7Danish MS Center, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark; 8Multiple Sclerosis Center, Sheba Academic Medical Center, Ramat Gan, Israel; 9Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Barcelona, Spain; 10Department of Neurosciences, Université de Montréal, Montréal, QC, Canada; 11Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy; 12Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands; 13UCL Institute of Neurology, London, UK; 14Experimental Neurophysiology Unit, Vita-Salute San Raffaele University, Milan, Italy; 15University of Lille, Inserm U1172 LilNCog, CHU Lille, FHU Imminent, Lille, France; 16Cytel Inc., Geneva, Switzerland; 17Ares Trading S.A., Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.AAN 2021 Virtual Congress | 17–22 AprilDisclosuresThis study was sponsored by Merck KGaA, Darmstadt, Germany.• HW is member of Scientific advisory boards/Steering Committees for Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme, and Teva. He received speaker honoraria and travel support from Bayer, Biogen, CSL Behring, EMD Serono, Fresenius Medical Care, Genzyme, Merck KGaA (Darmstadt, Germany), Omniamed, Novartis, Sanofi-Aventis, and Teva. He received compensation as a consultant from Biogen, Merck KGaA (Darmstadt, Germany), Novartis, Omniamed, Roche, and Sanofi-Genzyme. He has received research support from Bayer, Biogen, Merck KGaA(Darmstadt, Germany), Novartis, Sanofi-Genzyme, Sanofi US, and Teva Pharma, as well as German Ministry for Education and Research (BMBF), German Research Foundation (DFG), Else KrönerFresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, and RE Children’s Foundation.• KS has been principal investigator of trials sponsored by MedDay, Novartis, Roche, and Teva, and involved in trials sponsored by BIAL, Biogen, Canbex, Cytokinetics, and Genzyme. He has received speaking honoraria from, and/or served in an advisory role for, Biogen, Cinnagen, Merck Inc., Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Teva; and has received research grant support from Biogen and Novartis.• SH serves on advisory boards for Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Sanofi-Genzyme; she has received money for travel and speaker honoraria from Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Sanofi-Genzyme.• TD serves on scientific advisory boards for Bayer, Biogen, GeNeuro, MedDay, Merck KGaA (Darmstadt, Germany), Mitsubishi Pharma, Novartis Pharmaceuticals, Roche, and Sanofi-Genzyme; has received funding for travel and/or speaker honoraria from Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Novartis Pharmaceuticals, Roche, and Sanofi-Genzyme; and receives research support from Biogen, the European Union, Novartis Pharma, the Swiss MS Society, and the Swiss National Foundation.• ACha has received speakers’/board honoraria from Actelion, Almirall, Bayer, Biogen, Bristol Myers Squibb (formerly Celgene), Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Teva, all for hospital research funds; and research support from Biogen, Genzyme, and UCB.• FS has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme, and Teva.• AA has received honoraria or consulting fees from Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Roche, and Sanofi-Genzyme; and research support from Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Roche, and Sanofi-Genzyme.• XM has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Alexion, Bayer, Biogen, Bristol Myers Squibb (formerly Celgene), EMD Serono, Genzyme, Immunic, MedDay, Merck KGaA (Darmstadt, Germany), Mylan, Nervgen, Novartis, Roche, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF, and NMSS.• AP has received honoraria and operating grants from pharmaceutical companies.• NDS is a consultant for Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme, and Teva; has grants or grants pending from FISM and Novartis, is on the speakers’ bureaus of Biogen, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme, and Teva; and has received travel funds from Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme, and Teva.• FB is supported by the NIHR biomedical research centre at UCLH and is a consultant to Roche, Biogen, Merck KGaA (Darmstadt, Germany), IXICO and Combinostics.• LL has received honoraria for consulting services or speaking activities from Biogen, Novartis, Merck KGaA (Darmstadt, Germany), and Roche; and research support from Biogen, Merck KGaA (Darmstadt, Germany), and Novartis.• PV has received honoraria or consulting fees from Almirall, Biogen, Bristol Myers Squibb (formerly Celgene), MedDay, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme, and Servier; and research support from Bayer, Biogen, Merck KGaA (Darmstadt, Germany), and Sanofi-Genzyme.• AChu is an employee of Cytel Inc., Geneva Branch, Switzerland, funded by Merck KGaA (Darmstadt, Germany) to perform statistical analyses for this study.• SR and UB are employees of Ares Trading S.A., Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.Medical writing assistance was provided by Joe Ward of inScience Communications, Springer Healthcare Ltd, UK, and was funded by Merck KGaA, Darmstadt, Germany.The MAGNIFY-MS study: NCT03364036.2• In the treatment of MS, immune reconstitution therapies are used for short, intermittent periods to allow for treatment-free periods.1,2• Long-term lymphocyte dynamics have been evaluated for CLARITY, CLARITY Extension, and PREMIERE studies3, indicating immune cell repopulation after treatment with cladribine tablets.• MAGNIFY-MS aims to determine the onset of action of cladribine tablets (3.5 mg/kg cumulative dose over 2 years) in patients with highly active relapsing MS†. • The action of cladribine tablets on immune cells may be key for both onset and durability of its effect in people with MS.†Highly active relapsing MS as defined by: one relapse in the previous year and at least 1 T1 Gd+ lesion, or 9 or more T2 lesions, while on therapy with other DMTs, or two or more relapses in the previous year, whether on DMT treatment or not.1. Wiendl H. Nat Rev Neurol. 2017;13:573–574. 2. Giovannoni G. Neurotherapeutics. 2017;14:874–887. 3. Comi G, et al. Mult Scler Relat Disord. 2019;29:168–174.DMT, disease-modifying therapy; Gd+, gadolinium enhancing; MRI, magnetic resonance imaging; MS, multiple sclerosis 3Introduction• In the treatment of MS, immune reconstitution therapies are used for short, intermittent periods to allow for treatment-free periods.1,2• Long-term lymphocyte dynamics have been evaluated for CLARITY, CLARITY Extension, and PREMIERE studies3, indicating immune cell repopulation after treatment with cladribine tablets.• MAGNIFY-MS aims to determine the onset of action of cladribine tablets (3.5 mg/kg cumulative dose over 2 years) in patients with highly active relapsing MS†. • The action of cladribine tablets on immune cells may be key for both onset and durability of its effect in people with MS.†Highly active relapsing MS as defined by: one relapse in the previous year and at least 1 T1 Gd+ lesion, or 9 or more T2 lesions, while on therapy with other DMTs, or two or more relapses in the previous year, whether on DMT treatment or not.1. Wiendl H. Nat Rev Neurol. 2017;13:573–574. 2. Giovannoni G. Neurotherapeutics. 2017;14:874–887. 3. Comi G, et al. Mult Scler Relat Disord. 2019;29:168–174.DMT, disease-modifying therapy; Gd+, gadolinium enhancing; MRI, magnetic resonance imaging; MS, multiple sclerosis 4IntroductionOBJECTIVETo report on peripheral im u ell subs t dynamics and immunogl bulin levels in the first 12 months of cladribine tablets therapy.MAGNIFY-MS is an ongoing Phase IV, open-label, single-arm, multicenter, 2-year study.Patients with highly active relapsing MS† received cladribine tablets, with 2 weeks active treatment per course (Week 1 and Week 5 of each year).Time (m) 12* 1413 15 18 24Week 1 Week 52nd treatment coursePopulationHighly active relapsing MS†Primary endpointDifference in the counts of combined unique active (CUA) MRI lesions at end of 6 months compared to baseline period*Second treatment course may be delayed for some patients, according to the lymphocyte countMRIDisability (EDSS/KFS, 9HPT, T25FW)Cognition (SDMT)Relapse countImmune cell subtypeSafety (TB – active & latent; Hepatitis B & C; HIV; Pregnancy) Lymphocyte count-3 BL-1-2 1 2 3 6Week 1 Week 51st treatment course(Pre-baseline)5†Highly active relapsing MS as defined by: one relapse in the previous year and at least 1 T1 Gd+ lesion, or 9 or more T2 lesions, while on therapy with other DMTs, or two or more relapses in the previous year, whether on DMT treatment or not.9HPT, 9-hole peg test; BL, baseline; CUA, combined unique active; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; HIV, human immune deficiency virus; KFS, KurtzkeFunctional System; MRI, magnetic resonance imaging; MS, multiple sclerosis; SDMT, symbol digit modalities test; T25FW, timed 25-foot walk; TB, tuberculosisMethods• This sub-study of MAGNIFY-MS involved longitudinal evaluation of peripheral blood immune cells in patients receiving cladribine tablets.• 57 patients were treated.• Absolute cell counts and % change from baseline were assessed for adaptive immune cell subtypes and immunoglobulins.• Immunophenotyping was completed at baseline and at months 1*, 2*, 3, 6, and 12.*Months 1 and 2 are available for TBNK and B cell panelsBL, baseline; Breg, B regulatory; Ig, immunoglobulin; TEMRA, terminally differentiated effector memory RA+; Treg, T regulatory612-month interim analysisBL 321 6 12Week 1 Week 51st treatment courseWeek 12nd treatment courseCladribine tabletsTime (months)MethodsCore study immunophenotypingSub-study immunophenotypingBreg, B regulatory; NK, natural killer; TEMRA, terminally differentiated effector memory RA+; Treg, T regulatory7MethodsT cell panelCD4 naïve - (CD3+, CD8-, CD4+, CD45RA+, CCR7+)CD4 central memory - (CD3+, CD8-, CD4+, CD45RA-, CCR7+)CD4 effector memory - (CD3+, CD8-, CD4+, CD45RA-, CCR7-)CD8 naïve - (CD3+, CD4-, CD8+, CD45RA+, CCR7+)CD8 central memory - (CD3+, CD4-, CD8+, CD45RA-, CCR7+)CD8 effector memory - (CD3+, CD4-, CD8+, CD45RA-, CCR7-)CD8 TEMRA - (CD3+, CD4-, CD8+, CD45RA+, CCR7-)Th1 - (CD3+, CD8-, CD4+, CCR7-/+, CXCR3+)Treg - (CD3+, CD8-, CD4+, CD25bright, CD127dim/-)Th17 - (CD3+, CD8-, CD4+, CD45RA-, CCR7-/dim, CCR6+, CD146+)Th2 - (CD3+, CD8-, CD4+, CXCR3-, CCR6-)B cell panelCD19 B cells - (CD45bright, SSClow, CD3-, CD14-, CD56-, CD19+)CD20 B cells - (CD45bright, SSClow, CD3-, CD14-, CD56-, CD20+)Activated B cells - (CD45bright, SSClow, CD3-, CD14-, CD56-, CD19+, CD20+, CD69+)Naïve B cells - (CD45bright, SSClow, CD3-, CD14-, CD56-, CD19+, CD20+, IgD+, CD27–)Memory B cells - (CD45bright, SSClow, CD3-, CD14-, CD56-, CD19+, CD20+, CD27+)Short-lived plasma cells - (CD45bright, SSClow, CD3-, CD14-, CD56-, CD19dim, CD20-/dim, CD27bright)Breg - (CD45bright, SSClow, CD3-, CD14-, CD56-, CD19+, CD24bright, CD38bright)CD38bright plasma cells - (CD45bright, SSClow, CD3-, CD14-, CD56-, CD19dim, CD20-, CD38bright)Transitional B cells - (CD45bright, SSClow, CD3-, CD14-, CD56-, CD19+, CD20+, IgD+, CD10+, CD27–)Immune cell panels in MAGNIFY-MSImmunoglobulins IgGIgMNK cell panel NKp46 NK cells - (SSClow, CD45+, CD19-, CD3-, CD16+CD56+, CD335+)CD16 NK cells - (SSClow, CD45+, CD19-, CD3-, CD16+CD56+)CD16bright CD56dim NK cells - (SSClow, CD45+, CD19-, CD3-, CD56dim, CD16bright)CD16low CD56bright NK cells - (SSClow, CD45+, CD19-, CD3-, CD56bright, CD16-/+)CD16-CD56dim NK cells - (SSClow, CD45+, CD19-, CD3-, CD56dim, CD16-)CD16+ CD56- NK cells - (SSClow, CD45+, CD19-, CD3-, CD56-, CD16+)CD16+ CD56+ NK cells -Absolute values (106/L) of B and T cells8ResultsB cellsubtypesCD4+ T cell subtypesCD8+ T cell subtypesBL, baseline; Q1:Q3, quartile range; TEMRA, terminally differentiated effector memory RA+; Th, T helperAbsolute values (g/L) of immunoglobulins9ResultsBL, baseline; Ig, immunoglobulin; Q1:Q3, quartile rangeAbsolute values (106/L) of Natural Killer cells10BL, baseline; NK, natural killer; Q1:Q3, quartile rangeResultsSubtype Month 1 Month 2 Month 3 Month 6 Month 12CD19+ B cells -77%n=46-90%n=44-80%n=46-60%n=35-35%n=42Memory B cells -74%n=45-93%n=44-93%n=46-90%n=34-87%n=42Activated B cells (CD69+) -64%n=45-81%n=44-73%n=46-53%n=34-45%n=42CD38+ plasma cells -11%n=45-66%n=44-71%n=46-51%n=34-51%n=42Short-lived plasma cells -28%n=45-65%n=44-78%n=46-58%n=34-51%n=42Naïve B cells -80%n=45-90%n=44-75%n=46-43%n=34-5%n=42Transitional B cells -61%n=45-63%N=44+28%n=46+34%n=34+36%n=42Regulatory B cells -45%n=45-16%n=44+176%n=46+171%n=34+50%n=4211Results• There is an early onset of action, with most B cell subtypes reaching nadir levels by month 2.• Reduction in memory B cells was sustained to month 12; regulatory B cells recovered by month 3, and then increased over baseline levels.Percentage change from baseline of B cell subtypesKey: Nadir value Values above baseline levelSubtype Month 1 Month 2 Month 3 Month 6 Month 12CD4+ -22%n=46-51%n=44-54%n=46-51%n=35-40%n=42CD8+ -18%n=46-39%n=44-50%n=46-43%n=35-36%n=42CD4+ Th1 - - -51%n=46-45%n=34-35%n=42CD4+ Th17 - - -35%n=45-34%n=34-24%n=41CD4+ CM/EffM - - -56%/-35%n=46-52%/-35%n=34-40%/-15%n=42CD8+ CM/EffM - - -39%/-29%n=46-46%/-22%n=34-29%/-16%n=42CD4+ naïve/CD8+ naïve  - - -63%/-73%n=46/n=46-64%/-70%n=35/n=34-53%/-58%n=42/n=42CD4+ Treg - - -30%n=46-38%n=34-21%n=42CD8+ TEMRA - - -26%n=46-15%n=34-19%n=42Percentage change from baseline of T cell subtypesCM, central memory; EffM, effector memory; TEMRA, terminally differentiated effector memory RA+; Th, T helper; Treg, T regulatory12Results Key: Nadir value Values above baseline level• T cell subtypes show reductions at later time points.NK, natural killerPercentage change from baseline of NK cell subtypesSubtype Month 1 Month 2 Month 3 Month 6 Month 12CD16low CD56bright natural killer cells-7%n=46-2%n=34-9%n=42CD16+/CD56+ natural killer cells-34%n=46-40%n=44-34%n=46-17%n=35-14%n=42CD16bright CD56dim natural killer cells-40%n=46-19%n=34-12%n=42Results Key: Nadir value Values above baseline level13• No changes were seen for other NK cell subtypes.MRI, magnetic resonance imaging; MS, multiple sclerosis 14Conclusions• MAGNIFY-MS MRI results suggest an early onset of cladribine tablets action. This may be mediated through a specific pattern of sustained decrease and reconstitution of B and T cell subtypes.• The pronounced effect on B cells, especially memory B cells in the first 2 Months of cladribine tablet treatment suggests a contribution to early efficacy onset.• Sustained depletion of memory B cells and the moderate decrease across T cell subtypes may contribute to the long term effect of cladribine tablets.Backups

Characterization of Peripheral Immune Cell Dynamics and Repopulation Patterns in the First 12 Months of Cladribine Tablets Treatment: MAGNIFY-MS Study

https://qmro.qmul.ac.uk/xmlui/bitstream/123456789/77722/2/Schmierer%20Characterization%20of%20Peripheral%20Immune%20Cell%20Dynamics%20and%20Repopulation%20Patterns%20in%20the%20First%2012%20Months%20of%20Cladribine%20Tablets%20Treatment%3a%20MAGNIFY-MS%20Study%202022%20Accepted.pdf

Characterization of Peripheral Immune Cell Dynamics and Repopulation Patterns in the First 12 Months of Cladribine Tablets Treatment: MAGNIFY-MS Study

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