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Article ; Online: Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial.

Arnold, Douglas L / Elliott, Colm / Martin, Emily C / Hyvert, Yann / Tomic, Davorka / Montalban, Xavier

2024 Volume 102, Issue 5, Page(s) e208058

Abstract: Background and objectives: Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and axonal loss. Evobrutinib is a highly selective, covalent, ...

Abstract	Background and objectives: Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and axonal loss. Evobrutinib is a highly selective, covalent, CNS-penetrant, Bruton tyrosine kinase inhibitor. This post hoc analysis evaluated the effect of evobrutinib on slowly expanding lesion (SEL) volume, an MRI marker of CALs, assessed baseline-week 48 in a phase 2, double-blind, randomized trial (NCT02975349) in relapsing MS (RMS). Methods: In the 48-week, double-blind trial, adult patients received evobrutinib (25 mg once daily [QD], 75 mg QD, or 75 mg twice daily [BID]), placebo (switched to evobrutinib 25 mg QD after week 24), or open-label dimethyl fumarate (DMF) 240 mg BID. SELs were defined as slowly and consistently radially expanding areas of preexisting T2 lesions of ≥10 contiguous voxels (∼30 mm Results: The SEL analysis set included 223 patients (mean [SD] age: 42.4 [10.7] years; 69.3% female; 87.4% relapsing/remitting MS). Mean (SD) SEL volume was 2,099 (2,981.0) mm Discussion: Evobrutinib reduced SEL volume in a dose-dependent manner in RMS, with a significant reduction with evobrutinib 75 mg BID. This is evident that evobrutinib affects brain lesions associated with chronic inflammation and tissue loss. Trial registration information: ClinicalTrials.gov number: NCT02975349. Submitted to ClinicalTrials.gov on November 29, 2016. First patient enrolled: March 7, 2017. Classification of evidence: This study provides Class II evidence that evobrutinib reduces the volume of SELs assessed on MRI comparing baseline with week 48, in patients with RMS.
MeSH term(s)	Adult ; Humans ; Female ; Male ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Multiple Sclerosis, Relapsing-Remitting/pathology ; Dimethyl Fumarate/therapeutic use ; Piperidines/therapeutic use ; Double-Blind Method ; Recurrence ; Pyrimidines
Chemical Substances	evobrutinib (ZA45457L1K) ; Dimethyl Fumarate (FO2303MNI2) ; Piperidines ; Pyrimidines
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Clinical Trial, Phase II ; Randomized Controlled Trial ; Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000208058
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Article ; Online: Efficacy and safety results after >3.5 years of treatment with the Bruton's tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis: Long-term follow-up of a Phase II randomised clinical trial with a cerebrospinal fluid sub-study.

Montalban, Xavier / Piasecka-Stryczynska, Karolina / Kuhle, Jens / Benkert, Pascal / Arnold, Douglas L / Weber, Martin S / Seitzinger, Andrea / Guehring, Hans / Shaw, Jamie / Tomic, Davorka / Hyvert, Yann / Harlow, Danielle E / Dyroff, Martin / Wolinsky, Jerry S

Multiple sclerosis (Houndmills, Basingstoke, England)

2024 Volume 30, Issue 4-5, Page(s) 558–570

Abstract: Background: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS.: Objective: Report ... ...

Abstract	Background: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS. Objective: Report results of the Phase II open-label extension (OLE; up to week 192 from randomisation) and a cerebrospinal fluid (CSF) sub-study. Methods: In the 48-week double-blind period (DBP), patients received evobrutinib 25 mg once-daily, 75 mg once-daily, 75 mg twice-daily or placebo (switched to evobrutinib 25 mg once-daily after week 24). Patients could then enter the OLE, receiving evobrutinib 75 mg once-daily (mean (± standard deviation (SD)) duration = 50.6 weeks (±6.0)) before switching to 75 mg twice-daily. Results: Of 164 evobrutinib-treated patients who entered the OLE, 128 (78.0%) completed ⩾192 weeks of treatment. Patients receiving DBP evobrutinib 75 mg twice-daily: annualised relapse rate at week 48 (0.11 (95% confidence interval (CI) = 0.04-0.25)) was maintained with the OLE twice-daily dose up to week 192 (0.11 (0.05-0.22)); Expanded Disability Status Scale score remained stable; serum neurofilament light chain fell to levels like a non-MS population ( Conclusion: Long-term evobrutinib treatment was well tolerated and associated with a sustained low level of disease activity. Evobrutinib was present in CSF at concentrations similar to plasma.
MeSH term(s)	Humans ; Multiple Sclerosis/drug therapy ; Tyrosine Kinase Inhibitors ; Follow-Up Studies ; Recurrence ; Double-Blind Method ; Treatment Outcome ; Piperidines ; Pyrimidines
Chemical Substances	evobrutinib (ZA45457L1K) ; Tyrosine Kinase Inhibitors ; Piperidines ; Pyrimidines
Language	English
Publishing date	2024-03-04
Publishing country	England
Document type	Randomized Controlled Trial ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	1290669-4
ISSN	1477-0970 ; 1352-4585
ISSN (online)	1477-0970
ISSN	1352-4585
DOI	10.1177/13524585241234783
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Article ; Online: Antibody response to SARS-CoV-2 vaccines in patients with relapsing multiple sclerosis treated with evobrutinib: A Bruton's tyrosine kinase inhibitor.

Bar-Or, Amit / Cross, Anne H / Cunningham, Anthony L / Hyvert, Yann / Seitzinger, Andrea / Gühring, Hans / Drouin, Elise E / Alexandri, Nektaria / Tomic, Davorka / Montalban, Xavier

Multiple sclerosis (Houndmills, Basingstoke, England)

2023 Volume 29, Issue 11-12, Page(s) 1471–1481

Abstract: Background: Evobrutinib is an oral, central nervous system (CNS)-penetrant and highly selective covalent Bruton's tyrosine kinase inhibitor under clinical development for patients with relapsing multiple sclerosis (RMS).: Objective: To investigate ... ...

Abstract	Background: Evobrutinib is an oral, central nervous system (CNS)-penetrant and highly selective covalent Bruton's tyrosine kinase inhibitor under clinical development for patients with relapsing multiple sclerosis (RMS). Objective: To investigate the effect of evobrutinib on immune responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinated patients with RMS from a Phase II trial (NCT02975349). Methods: A Results: In the vaccinated subgroup, mean/minimum evobrutinib exposure pre-vaccination was 105.2/88.7 weeks. In total, 43 of 45 patients developed/increased S1/S2 IgG antibody levels post-vaccination; one patient's antibody response remained negative post-vaccination and the other had antibody levels above the upper limit of detection, both pre- and post-vaccination. Most patients ( Conclusion: These results suggest evobrutinib, an investigational drug with therapeutic potential for patients with RMS, acts as an immunomodulator, that is, it inhibits aberrant immune cell responses in patients with RMS, while responsiveness to foreign
MeSH term(s)	Humans ; Antibodies, Viral ; Antibody Formation ; COVID-19/prevention & control ; COVID-19 Vaccines ; Immunoglobulin G ; Multiple Sclerosis/drug therapy ; SARS-CoV-2 ; Tyrosine Kinase Inhibitors/pharmacology ; Tyrosine Kinase Inhibitors/therapeutic use ; Vaccination
Chemical Substances	Antibodies, Viral ; COVID-19 Vaccines ; evobrutinib (ZA45457L1K) ; Immunoglobulin G ; Tyrosine Kinase Inhibitors
Language	English
Publishing date	2023-08-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1290669-4
ISSN	1477-0970 ; 1352-4585
ISSN (online)	1477-0970
ISSN	1352-4585
DOI	10.1177/13524585231192460
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Article: Effects of cladribine tablets on lymphocyte subsets in patients with multiple sclerosis: an extended analysis of surface markers.

Stuve, Olaf / Soelberg Soerensen, Per / Leist, Thomas / Giovannoni, Gavin / Hyvert, Yann / Damian, Doris / Dangond, Fernando / Boschert, Ursula

Therapeutic advances in neurological disorders

2019 Volume 12, Page(s) 1756286419854986

Abstract: Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). This ... ...

Abstract	Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5. Methods: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48. Results: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16 Conclusions: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19
Language	English
Publishing date	2019-06-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2442245-9
ISSN	1756-2864 ; 1756-2856
ISSN (online)	1756-2864
ISSN	1756-2856
DOI	10.1177/1756286419854986
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Article: Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

Freedman, Mark S / Coyle, Patricia K / Comi, Giancarlo / L Scarberry, Susan / Damian, Doris / Hyvert, Yann / Dangond, Fernando / Galazka, Andrew / Jack, Dominic / Lebson, Lori A / Leist, Thomas P

Multiple sclerosis journal - experimental, translational and clinical

2021 Volume 7, Issue 1, Page(s) 2055217321990852

Abstract: 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 ...

Abstract	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 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).
Language	English
Publishing date	2021-02-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2841884-0
ISSN	2055-2173 ; 2055-2173
ISSN (online)	2055-2173
ISSN	2055-2173
DOI	10.1177/2055217321990852
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Article ; Online: Pharmacodynamic biomarkers of long-term interferon beta-1a therapy in REFLEX and REFLEXION.

Freedman, Mark S / Wojcik, Jérôme / Holmberg, Kristina H / Fluck, Markus / D'Antonio, Mauro / Hyvert, Yann / Stinchi, Sofia / D'Urso, Vittorio / Dangond, Fernando

Journal of neuroimmunology

2021 Volume 360, Page(s) 577715

Abstract: This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN β-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were ... ...

Abstract	This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN β-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were analyzed. All investigated biomarkers were significantly upregulated 1.5-4-fold in response to sc IFN β-1a treatment versus baseline (p ≤ 0.008). The validity of MX1, 2'5'OAS, and IL-1RA as biomarkers of response to sc IFN β-1a was confirmed in this large patient cohort, with biomarkers consistently upregulated in a dose-dependent manner. Neopterin, TRAIL, and IP-10 were confirmed as biomarkers associated with long-term sc IFN β-1a treatment efficacy over 5 years.
MeSH term(s)	2',5'-Oligoadenylate Synthetase/biosynthesis ; 2',5'-Oligoadenylate Synthetase/blood ; 2',5'-Oligoadenylate Synthetase/genetics ; Biomarkers ; Chemokine CXCL10/biosynthesis ; Chemokine CXCL10/blood ; Chemokine CXCL10/genetics ; Dose-Response Relationship, Drug ; Double-Blind Method ; Follow-Up Studies ; Humans ; Injections, Subcutaneous ; Interferon beta-1a/administration & dosage ; Interferon beta-1a/pharmacokinetics ; Interferon beta-1a/therapeutic use ; Interleukin 1 Receptor Antagonist Protein/biosynthesis ; Interleukin 1 Receptor Antagonist Protein/blood ; Interleukin 1 Receptor Antagonist Protein/genetics ; Multicenter Studies as Topic ; Multiple Sclerosis/blood ; Multiple Sclerosis/drug therapy ; Myxovirus Resistance Proteins/biosynthesis ; Myxovirus Resistance Proteins/blood ; Myxovirus Resistance Proteins/genetics ; Neopterin/biosynthesis ; Neopterin/blood ; Neopterin/genetics ; Randomized Controlled Trials as Topic/statistics & numerical data ; TNF-Related Apoptosis-Inducing Ligand/biosynthesis ; TNF-Related Apoptosis-Inducing Ligand/blood ; TNF-Related Apoptosis-Inducing Ligand/genetics ; Up-Regulation
Chemical Substances	Biomarkers ; CXCL10 protein, human ; Chemokine CXCL10 ; Interleukin 1 Receptor Antagonist Protein ; MX1 protein, human ; Myxovirus Resistance Proteins ; TNF-Related Apoptosis-Inducing Ligand ; TNFSF10 protein, human ; Neopterin (670-65-5) ; 2',5'-Oligoadenylate Synthetase (EC 2.7.7.84) ; Interferon beta-1a (XRO4566Q4R)
Language	English
Publishing date	2021-09-09
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	8335-5
ISSN	1872-8421 ; 0165-5728
ISSN (online)	1872-8421
ISSN	0165-5728
DOI	10.1016/j.jneuroim.2021.577715
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Article ; Online: Subgroup analysis of clinical and MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

Cree, Bruce A C / Bowen, James D / Hartung, Hans-Peter / Vermersch, Patrick / Hughes, Bruce / Damian, Doris / Hyvert, Yann / Dangond, Fernando / Galazka, Andrew / Grosso, Megan / Jones, Daniel L / Leist, Thomas P

Multiple sclerosis and related disorders

2020 Volume 49, Page(s) 102695

Abstract: Background: In the Phase 3, 96-week ORACLE-MS study, cladribine 10 mg tablets (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly reduced the rate of conversion to clinically definite multiple sclerosis (CDMS) per the Poser criteria ( ... ...

Abstract	Background: In the Phase 3, 96-week ORACLE-MS study, cladribine 10 mg tablets (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly reduced the rate of conversion to clinically definite multiple sclerosis (CDMS) per the Poser criteria (henceforth referred to as CDMS), multiple sclerosis (MS) per the 2005 McDonald criteria, and the number of new or persisting T1 gadolinium-enhancing (Gd+), new or enlarging T2, and combined unique active (CUA) lesions versus placebo in participants with a first clinical demyelinating event (FCDE). Patient demographic and disease characteristics may be predictors of disease progression. The current study analyzed the effect of cladribine tablets in subgroups of participants in the ORACLE-MS study by baseline demographics and disease characteristics. Methods: This analysis retrospectively examined data collected from 616 participants enrolled in the ORACLE-MS study (placebo, n=206; cladribine tablets 3.5 mg/kg, n=206; cladribine tablets 5.25 mg/kg, n=204). Five subgroups were predetermined by baseline demographics, including sex, age (<30 or ≥30 years), classification of FCDE, and lesion characteristics, including absence or presence of T1 Gd+ lesions and number of T2 lesions (<9 or ≥9). Selected endpoints of the ORACLE-MS study were re-analyzed for these subgroups. The primary and main secondary endpoints were time to conversion to CDMS and MS (2005 McDonald criteria), respectively. Secondary magnetic resonance imaging (MRI) endpoints included cumulative T1 Gd+ and new or enlarging T2 lesions. Cox proportional hazards models were used to evaluate time to conversion to CDMS and MS (2005 McDonald criteria). This analysis focused primarily on the results for the cladribine tablets 3.5 mg/kg group because this dosage is approved for relapsing forms of MS. Results: In the overall intent-to-treat (ITT) population, cladribine tablets 3.5 mg/kg significantly reduced the risk of conversion to CDMS (hazard ratio [HR]=0.326; P<0.0001) and MS (2005 McDonald criteria; HR=0.485; P<0.0001) versus placebo. Similar effects of cladribine tablets on risk of conversion were observed in post hoc analyses of subgroups defined by various baseline characteristics. In both the ITT population and across subgroups, cladribine tablets 3.5 mg/kg reduced the numbers of cumulative T1 Gd+ (range of rate ratios: 0.106-0.399), new or enlarging T2 (range of rate ratios: 0.178-0.485), and CUA (range of rate ratios: 0.154-0.384) lesions versus placebo (all nominal P<0.03). Multivariate Cox proportional hazards models revealed that age (HR=0.577, nominal P<0.0001), FCDE classification (HR=0.738, nominal P=0.0043), presence of T1 Gd+ lesions (HR=0.554, nominal P<0.0001), and number of T2 lesions (HR=0.417, nominal P<0.0001) at baseline were factors associated with risk of conversion to MS (2005 McDonald criteria), whereas no baseline factors examined were associated with risk of conversion to CDMS. Conclusion: In this post hoc analysis of the ORACLE-MS study, cladribine tablets reduced the risk of conversion to multiple sclerosis and lesion burden in participants with an FCDE in the overall ITT population and multiple subgroups defined by baseline demographics and lesion characteristics.
MeSH term(s)	Adult ; Cladribine/therapeutic use ; Disease Progression ; Humans ; Magnetic Resonance Imaging ; Multiple Sclerosis/diagnostic imaging ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis/epidemiology ; Retrospective Studies
Chemical Substances	Cladribine (47M74X9YT5)
Language	English
Publishing date	2020-12-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2645330-7
ISSN	2211-0356 ; 2211-0348
ISSN (online)	2211-0356
ISSN	2211-0348
DOI	10.1016/j.msard.2020.102695
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Article ; Online: Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial.

Kappos, Ludwig / Hartung, Hans-Peter / Freedman, Mark S / Boyko, Alexey / Radü, Ernst Wilhelm / Mikol, Daniel D / Lamarine, Marc / Hyvert, Yann / Freudensprung, Ulrich / Plitz, Thomas / van Beek, Johan

The Lancet. Neurology

2014 Volume 13, Issue 4, Page(s) 353–363

Abstract: Background: Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody ... ...

Abstract	Background: Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production. Methods: In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18-60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT). Findings: Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43-1·74; 75 mg, 0·79, 0·40-1·58; 150 mg, 0·98, 0·52-1·81; placebo, 0·38, 0·17-0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97-5·27; 75 mg, 2·30, 1·08-4·92; 150 mg, 2·49, 1·18-5·27; placebo, 3·07, 1·40-6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group Interpretation: Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted. Funding: Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA).
MeSH term(s)	Adult ; Brain/pathology ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Multiple Sclerosis, Relapsing-Remitting/pathology ; Recombinant Fusion Proteins/administration & dosage ; Treatment Outcome ; Young Adult
Chemical Substances	Recombinant Fusion Proteins ; TACI receptor-IgG Fc fragment fusion protein (K3D9A0ICQ3)
Language	English
Publishing date	2014-03-06
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2079704-7
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(14)70028-6
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Article: Role of the Spätzle Pro-domain in the Generation of an Active Toll Receptor Ligand

Weber, Alexander N.R / Gangloff, Monique / Moncrieffe, Martin C / Hyvert, Yann / Imler, Jean-Luc / Gay, Nicholas J

Journal of biological chemistry. 2007 May 4, v. 282, no. 18

2007

Abstract: The cytokine Spätzle is the ligand for Drosophila Toll, the prototype of an important family of membrane receptors that function in embryonic patterning and innate immunity. A dimeric precursor of Spätzle is processed by an endoprotease to produce a form ...

Abstract	The cytokine Spätzle is the ligand for Drosophila Toll, the prototype of an important family of membrane receptors that function in embryonic patterning and innate immunity. A dimeric precursor of Spätzle is processed by an endoprotease to produce a form (C-106) that cross-links Toll receptor ectodomains and establishes signaling. Here we show that before processing the pro-domain of Spätzle is required for correct biosynthesis and secretion. We mapped two loss-of-function mutations of Spätzle to a discrete site in the pro-domain and showed that the phenotype arises because of a defect in biosynthesis rather than signaling. We also report that the pro-domain and C-106 remain associated after cleavage and that this processed complex signals with the same characteristics as the C-terminal fragment. These results suggest that before activation the determinants on C-106 that bind specifically to Toll are sequestered by the pro-domain and that proteolytic processing causes conformational rearrangements that expose these determinants and enables binding to Toll. Furthermore, we show that the pro-domain is released when the Toll extracellular domain binds to the complex, a finding that has implications for the generation of a signaling-competent Toll dimer.
Language	English
Dates of publication	2007-0504
Size	p. 13522-13531.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: Role of the Spatzle Pro-domain in the generation of an active toll receptor ligand.

Weber, Alexander N R / Gangloff, Monique / Moncrieffe, Martin C / Hyvert, Yann / Imler, Jean-Luc / Gay, Nicholas J

The Journal of biological chemistry

2007 Volume 282, Issue 18, Page(s) 13522–13531

Abstract	The cytokine Spätzle is the ligand for Drosophila Toll, the prototype of an important family of membrane receptors that function in embryonic patterning and innate immunity. A dimeric precursor of Spätzle is processed by an endoprotease to produce a form (C-106) that cross-links Toll receptor ectodomains and establishes signaling. Here we show that before processing the pro-domain of Spätzle is required for correct biosynthesis and secretion. We mapped two loss-of-function mutations of Spätzle to a discrete site in the pro-domain and showed that the phenotype arises because of a defect in biosynthesis rather than signaling. We also report that the pro-domain and C-106 remain associated after cleavage and that this processed complex signals with the same characteristics as the C-terminal fragment. These results suggest that before activation the determinants on C-106 that bind specifically to Toll are sequestered by the pro-domain and that proteolytic processing causes conformational rearrangements that expose these determinants and enables binding to Toll. Furthermore, we show that the pro-domain is released when the Toll extracellular domain binds to the complex, a finding that has implications for the generation of a signaling-competent Toll dimer.
MeSH term(s)	Animals ; Cytokines/biosynthesis ; Cytokines/genetics ; Cytokines/metabolism ; Dimerization ; Drosophila Proteins/biosynthesis ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Ligands ; Protein Binding/physiology ; Protein Processing, Post-Translational/physiology ; Protein Structure, Tertiary/genetics ; Signal Transduction/physiology ; Toll-Like Receptors/metabolism
Chemical Substances	Cytokines ; Drosophila Proteins ; Ligands ; Toll-Like Receptors ; spz protein, Drosophila
Language	English
Publishing date	2007-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M700068200
Database	MEDical Literature Analysis and Retrieval System OnLINE

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