Neurofilament and B-cell CSF levels reduced substantially in MS patients receiving ocrelizumab
Wayne Kuznar, for MDLinx | June 12, 2018
After treatment with ocrelizumab in patients with relapsing multiple sclerosis (RMS), the level of neurofilament in the spinal fluid—a measure of injury to the axons and neurons—was found to be quickly and substantially reduced, according to results from an interim analysis of the Ocrelizumab Biomarker Outcome Evaluation (OBOE). The decrease in neurofilament levels at 12 weeks was enhanced at 24 weeks, reported Amit Bar-Or, MD, at the 2018 meeting of the American Academy of Neurology (AAN), held in Los Angeles, CA, in April.
Ocrelizumab for MS
Ocrelizumab, a humanized anti-CD20 monoclonal antibody that targets CD20 marker on B lymphocytes, removes B cells from cerebrospinal fluid, thus reducing B cell-T cell interactions which may contribute to injury in CNS axons in patients with MS.
Ocrelizumab for MS
Ocrelizumab, a humanized anti-CD20 monoclonal antibody that targets CD20 marker on B lymphocytes, removes B cells from cerebrospinal fluid, thus reducing B cell-T cell interactions which may contribute to injury in CNS axons in patients with MS.
Dr. Bar-Or, professor of neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, presented 24-week data from the open-label OBOE study, in which patients with RMS or primary progressive MS received ocrelizumab (600 mg) every 24 weeks.
Patients in the RMS cohort were randomized to undergo lumbar puncture before treatment and at weeks 12, 24, or 52 following the first dose of ocrelizumab. A control arm in the RMS cohort underwent two pre-treatment lumbar punctures 12 weeks apart. Cerebrospinal fluid (CSF) for biomarker analysis was available for interim analysis in 40 RMS patients pretreatment and at 12 weeks (arm 1) and 24 weeks (arm 2) post-treatment. The primary outcome was the change in neurofilament light levels in the CSF.
At 12 weeks after treatment with ocrelizumab, the median concentration of neurofilament light chain was reduced by 24%, and decreased further to a 47% reduction at 24 weeks. The median number of B cells in the CSF decreased by 86% at 12 weeks and this persisted (-82%) at 24 weeks. The median number of CD3 T cells declined by 60% and 67% at weeks 12 and 24, respectively.
The study provides new insights into the importance of interaction between B cells and T cells and their apparent contribution to central nervous system (CNS) injury within the CNS of MS patients, indicated Dr. Bar-Or in correspondence with MDLinx.
“We found that the levels of neurofilament correlated well with the numbers of B cells and T cells in the spinal fluid, and there was also a strong correlation between the number of B cells and T cells themselves,” he said. “Together, this provides evidence supporting the view that both B cells and T cells participate in the MS disease process and interact with one another in doing so.”
The data support that ocrelizumab works by removing B cells, thereby diminishing the B cell-T cell interactions, and also indicate “that the B cell-T cell interactions within the CNS (and not just in the periphery) are likely to contribute to injury to the CNS axons,” Dr. Bar-Or added.
OBOE findings provide the framework for further understanding and developing directed treatments for the CNS processes that are likely important contributors to ongoing CNS injury in people with MS. Final results of OBOE are expected in early 2019.
In a second presentation at AAN, investigators from the open-label VELOCE study found that vaccine responses were attenuated in patients with RMS treated with ocrelizumab.
Researchers randomized 102 patients 2:1 to receive a single 600-mg dose of ocrelizumab (n=68) or a control group (n=34) to assess whether RMS patients would raise adequate humoral responses to selected vaccines.
All received a tetanus toxoid-containing vaccine, keyhole limpet hemocyanin (KLH), and a 23-valent pneumococcal polysaccharide vaccine (23-PPV). The ocrelizumab arm was further divided into two groups: one group that received a pneumococcal booster vaccine (13-PCV) 4 weeks after 23-PPV and another group that received seasonal influenza vaccine. The control arm was treated the same as the second ocrelizumab group.
A positive response to tetanus vaccine at 8 weeks occurred in 23.9% of ocrelizumab recipients compared with 54.5% of controls. At 4 weeks, a positive response to ≥ 5 serotypes in 23-PPV was 71.6% in the ocrelizumab group vs 100% in the control. A booster vaccine (13-PCV) given to ocrelizumab recipients did not enhance the response to the 12 serotypes it had in common with 23-PPV.
Also at 4 weeks, seroprotective titers against five influenza strains (season 2015/2016 and 2016/2017) ranged from 55.6% to 80.0% in ocrelizumab recipients and 75.0% to 97.0% in controls.
The OBOE study was sponsored by Genentech, Inc., and the VELOCE trial by F. Hoffmann-La Roche Ltd.