A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS

Freedman, Mark S.; Bar‐Or, Amit; Oger, Joél; Traboulsee, Anthony; Patry, David G.; Young, Carolyn A; Olsson, Tomas; Li, D.; Hartung, Hans Peter; Krantz, Mark J.; Ferenczi, L. Z.; Verco, T.

doi:10.1212/wnl.0b013e318233b240

Cited by 120 publications

(102 citation statements)

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“…This is in agreement with the lack of efficacy of this compound in a phase III randomised, placebo-controlled trial. 20 We used a cross-sectional approach to study the levels of the CSF biomarkers in SPMS and PPMS, and used RRMS relapse patients and a group of NINDs as control groups. This approach is usual given the limited availability of CSF samples, and suitable for establishing an involvement of the CSF biomarkers.…”

Section: Discussionmentioning

confidence: 99%

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CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

et al. 2012

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Background:The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. Objectives: To study cerebrospinal fluid (CSF) biomarkers and clarify whether inflammation and axonal damage are associated in progressive MS. Methods: Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing-remitting (RRMS) and 20 non-inflammatory neurological disease (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF followup after one year. Results: Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13 was increased in RRMS and SPMS patients. Biomarkers of axonal damage (NFL) and demyelination (MBP) were increased in all MS patients. In progressive MS patients CSF levels of osteopontin and CXCL13 correlated with NFL while osteopontin and MMP9 correlated with MBP. MBP8298 treatment did not affect the levels of the biomarkers after one year of treatment. All biomarkers were continuously increased after one year of follow-up except MBP, which decreased. Conclusion: CSF biomarkers of inflammation, axonal damage and demyelination are continuously increased in progressive MS patients and correlate. These findings parallel pathology studies, emphasise a relationship between inflammation, axonal damage and demyelination and support the use of CSF biomarkers in progressive MS clinical trials.

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Section: Discussionmentioning

confidence: 99%

“…In addition, we studied the effect of treatment with the peptide MBP8298 in repeated lumbar puncture samples from patients participating in a pivotal treatment trial of this compound in SPMS. 20 …”

Section: Introductionmentioning

confidence: 99%

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

et al. 2012

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“…The role of peptides derived from various myelin proteins, including proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in both MS onset and induction of antigen-specific T-cell tolerance is still intensively discussed [22,23] and myelin-peptides or proteins or their respective specific immune responses have traditionally been a target of therapeutic approaches. However, it still remains unclear whether modification of myelin-(peptide)-specific immune responses are capable of impacting MS [24,25]. The One idea of an immune therapy to treat MS is to re-establish antigen-specific peripheral tolerance in patients by administering ex vivo generated autologous tolDCs.…”

Section: Chances and Pitfalls Of The Therapeutic Use Of Toldcsmentioning

confidence: 99%

Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis

2012

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Autoimmune diseases including multiple sclerosis (MS) are the result of an imbalanced immune tolerance network. Dendritic cells (DCs) are key players in both initiating immunity (immunogenic DCs) and regulating immune responses (tolerogenic DCs= IntroductionMultiple sclerosis (MS) is the prototype of a central nervous system (CNS) directed, antigen-driven, predominantly T-cell medi- Immunological tolerance induction, its maintenance by DCs and what goes wrong in MSThe major subtypes of human DCs are conventional myeloid (CD11c + ) DCs (mDCs) and type I interferon-secreting plasmacytoid (CD11c dim CD123 + ) DCs (pDCs). Depending on the antigen presented and the activation status of the DCs, both subsets can either exhibit immunogenic or tolerogenic features [9,10]. Immature DCs are located in the peripheral tissues where they constantly encounter/sample antigens. While TLR ligands and pro-inflammatory cytokines induce maturation into immunogenic DCs that migrate to secondary lymphoid organs where they prime naïve T cells, anti-inflammatory cytokines including IL-10 and TGF-β induce DCs with a more tolerogenic phenotype (tolDCs) [10]. The term tolDCs summarizes a heterogeneous group of different DC subsets (mDCs and pDCs) located in various tissues where they use different mechanisms to induce and maintain both central and peripheral tolerance. In the thymus, DCs eliminate autoreactive T cells by clonal deletion of high-affinity thymocytes or diversion into Treg cells [11]. Despite these central tolerance mechanisms, some low avidity autoreactive T cells escape into the periphery, where peripheral tolerance mechanisms are required to prevent spontaneous autoimmunity. Multiple peripheral tolerance mechanisms have been identified for myelin-specific T cells, most importantly Treg cells and tolerogenic DCs [5,12]. TolDCs keep autoreactive T cells under control by inducing anergy, apoptosis, phenotypic skewing, and/or Treg cells [13][14][15].In MS, both immunogenic and tolerogenic features of different DC subsets are disrupted [7,12]. Elevated numbers of mature mDCs have been found in the peripheral blood of MS patients, and the occurrence of both mDCs and pDCs in the CSF of MS patients suggests their active participation in disease pathogenesis [12]. Furthermore, alterations in phenotype and/or function of different DC subsets have been observed in MS [7,12]. pDCs for example show an imbalance in the ratio between tolerogenic and immunogenic subtypes generating a propensity to generate proinflammatory Th17 cell responses in MS [16]. The "dysfunctional state" of certain DC subsets in MS could be linked to the observation of dysfunctional Treg-cell responses in MS [5]. Therefore, therapies targeting DCs for MS aim to either diminish their immunogenic potential or enhance their tolerogenic features [7]. Chances and pitfalls of the therapeutic use of tolDCsSo far, most of our knowledge in using tolDCs to treat autoimmunity is derived from extensive work in animal models including experimental autoimmune encephalitis (EA...

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“…Another attempt was made using intravenous administrations of soluble MBP peptide (MBP82-96). While this treatment was well tolerated and showed promising effects in phase I/II clinical trials [116,117], a subsequent doubleblind, placebo-controlled phase III trial in > 600 human leukocyte antigen (HLA)-DR2/4-positive patients with secondary progressive MS (SPMS) failed [118]. Negative results were also reported for intravenous injections of another approach using a soluble major histocompatibility complex (MHC)-peptide complex in patients with SPMS (MHC-MBP84-102 [119]).…”

Section: Myelin Peptide-based Approachesmentioning

confidence: 99%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific Tcell pathways. While the concept of BT-cell-specific therapyî mplies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cellselective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

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A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS

Abstract: This study provides Class 1 evidence that MBP8298 is not effective in patients with SPMS who are HLA DR2(+) or DR4(+).

Cited by 120 publications

References 29 publications

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

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