ECTRIMS-ACTRIMS: OBOE study explores biomarkers of neurodegeneration and inflammation in multiple sclerosis

ECTRIMS-ACTRIMS: OBOE study explores biomarkers of neurodegeneration and inflammation in multiple sclerosis

1920 1080 Peter Stevenson, PhD

The development and characterisation of biomarkers in multiple sclerosis (MS) could be a crucial step in understanding disease pathways, as well as the therapeutic mechanisms of disease-modifying treatments. So was the message of a poster1 presented at MSParis2017, the 7th Joint European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Meeting, held 25–28 October 2017 in Paris, France.

Biomarkers in the cerebrospinal fluid (CSF) could be used as surrogates for central nervous system (CNS) integrity. With the role of B cells in MS pathology being of particular interest, as well as the effects of B-cell depletion on patient outcomes, several studies have investigated anti-CD20 B-cell depleting agents. For example, a Phase II study examining B-cell depletion via rituximab, a monoclonal antibody to CD20, showed a 90% reduction of CD19+ B cells in the CSF in a relapsing-remitting MS (RMS) cohort.2

Furthermore, two Phase III studies using ocrelizumab, another anti-CD20 antibody, demonstrated a reduction in MS disease activity in both RMS and primary progressive MS (PPMS) patients.3,4

The poster served to introduce the OBOE study, a hypothesis-generating, open-label, multicentre biomarker study that aims to assess multiple biomarkers of neurodegeneration and inflammation, and better understand the mechanism of action of ocrelizumab and B-cell biology in RMS or PPMS.1,5

The primary endpoints include: Presence of biomarkers in the CSF, i.e. surrogate markers of CNS integrity; presence of neurofilament light chain (NfL), an axonal cytoskeletal protein that is released into the CSF in response to injury (and thus may be a sensitive marker for neuronal damage); the number of CNS inflammation biomarkers present in the CSF, including CD19+ B cells and CD3+ T cells.1

Exploratory endpoints include other markers indicative of B-cell activity, and markers of neurodegeneration and inflammation in the periphery that will be compared to whole blood.

Study participants will receive ocrelizumab administered either as two 300-mg IV infusions or as single 600-mg IV infusions, every 24 weeks.6 The majority of study participants will be RMS patients, but PPMS patients will also be featured. In the RMS cohort, key inclusion criteria include: An Expanded Disability Status Scale (EDSS) score of 0-5.5 points at screening; treatment naivety or receipt of treatment with interferon β-1a, β-1b or glatiramer acetate; at least one clinical relapse in the past year, and/or at least one T1-weighted Gd-enhancing lesion and/or new T2 lesion in the past year.6

In the PPMS cohort, inclusion criteria are: An EDSS score of 3.0-6.5 inclusive; disease duration <10 years in patients with EDSS ≤5.0; and a documented history of elevated immunoglobulin G (IgG) index and/or a presence of IgG oligoclonal bands (OCBs) in the CSF.6

Exclusion criteria for all cohorts includes any previous treatment with B-cell targeted therapies or anti-CD4 agents, and fingolimod, dimethyl fumarate or similar treatment within six months prior to enrolment.

A flow cytometry immunophenotyping assay will be used to assess cell signatures in CSF and whole blood. A panel of antibodies are to be used for staining, including D19-BV421, IgD-FITC, CD38-PE, CD3PerCP/Cy5.5, CD138-PE/Cy7, CD27-APC and CD4-APC/H7, as well as a Zombie Aqua™ viability dye (BioLegend, Inc., San Diego, CA, USA).1

Assay quality at each of the clinical trial sites will also be monitored using an assay control that cross-references assay results within permitted published ranges. As an additional quality-control measure, all flow cytometry standard (FCS) analyses of patient samples will be completed centrally by a single analyst, and then checked/confirmed by a second.

Baseline results from the first patient enrolled in the study were included in the poster, but at this early stage, it is OBOE’s promise that stands out. Indeed, it is hoped to provide important information on putative disease biomarkers in the blood and CSF of patients with RMS and PPMS, and the effects of selectively depleting CD20+ B cells on those markers.1 Therefore, as the authors note, OBOE has the potential to inform future research efforts across the spectrum of MS.



1. Cross AH, et al. ‘CSF Cell Signature and Biomarkers of Neuroinflammation and Neurodegeneration in MS: Immunophenotyping Standardisation in the OBOE Study’, poster presentation at MSParis2017: The 7th Joint ECTRIMS-ACTRIMS Meeting, 25-28 October 2017, Paris, France.

2. Cross AH, et al. ‘Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients’, J Neuroimmunol, vol. 180, 2006, p. 63.

3. Hauser SL, et al. ‘Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis’. N Engl J Med, vol. 376, 2017, p.221.

4. Montalban X, et al. ‘Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis’, N Engl J Med, vol. 376, 2017, p. 376.

5. ‘Study to Explore the Mechanism of Action of Ocrelizumab and B-Cell Biology in Participants With Relapsing Multiple Sclerosis (RMS) or Primary Progressive Multiple Sclerosis (PPMS)’,, (accessed October 27, 2017).

6. Cross, AH, et al. ‘Effects of Ocrelizumab on Neurofilament Light Chain and Other Biomarkers of Neuroinflammation and Neurodegeneration in MS: OBOE Study Design’, poster presentation at the 69th American Academy of Neurology (AAN) Annual Meeting; April 22–28, 2017, Boston, MA, USA.

Brainwork is supported by unrestricted grants from: