Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis

• Status: Active, not recruiting
• Trial end date: 2024-03-01
• Target enrollment: 0
• Participant gender: All

Summary

B-cells have an important role in the pathogenesis of multiple sclerosis (MS). Ocrelizumab, a medication that targets B-cells have been found to be highly effective in stopping the disease activity in relapsing-remitting MS.

The efficacy of ocrelizumab might be related to the specific pattern of B-cell tolerance defect in patients with MS and the potential of its normalization with treatment with ocrelizumab. By analyzing the reactivity of recombinant antibodies expressed from single B-cells, the investigators' collaborators have demonstrated that the pattern of B-cell tolerance defect is different in people with MS who only display an impaired removal of developing autoreactive B-cells in the periphery while central B-cell tolerance in the bone marrow is functional in most patients. In contrast, patients with rheumatoid arthritis (RA), type-1 diabetes (T1D) or Sjögren's syndrome (SS) show defective central and peripheral B-cell tolerance checkpoints. As a consequence, while anti-B-cell therapy does not correct defective early B-cell tolerance checkpoints in T1D and only temporarily slows down autoimmune processes before newly generated autoreactive B-cells likely induce patient relapse, the investigators postulate that the efficacy of ocrelizumab in MS may be linked to normal central B-cell tolerance and the production of a normal B-cell and T-cell compartment after ocrelizumab therapy.

In an open-label study, 10 patients with relapsing MS will be treated with two courses of ocrelizumab and will be followed clinically and radiologically for at least two and a half years. Assessment of T and B-cell phenotypes and function at baseline and 18-24 months post-B-cell depletion will be the primary outcome of the study.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Johns Hopkins University
• Collaborator: Genentech, Inc.
• Treatments: Ocrelizumab

Criteria

Inclusion Criteria:

• Diagnosis of relapsing remitting multiple sclerosis (RRMS) based on revised McDonald criteria

• At least one Gd-enhancing lesions on the brain or spinal cord MRI done in the prior three months OR at least one new T2/FLAIR lesion on the brain or spinal cord MRI done in the prior three months (compared to a prior MRI performed within 18 months of the most recent MRI)

• Naïve to Disease modifying therapy (DMT) or at least off these DMTs (natalizumab, fingolimod, DMF) for three months or on an injectable DMT (interferons or glatiramer acetate)

• Expanded Disability Status Scale (EDSS) score at the time of screening =<3

• Negative urine or serum pregnancy test must be available for premenopausal women and for women <12 months after the onset of menopause unless these women have undergone surgical sterilization

• Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use one method of contraception with a failure rate of <1% per year or a barrier method supplemented with spermicide. Contraception must continue for the duration of study treatment and for at least 24 weeks after the last dose of study treatment

Exclusion Criteria:

• Contraindication to treatment with an anti- cluster of differentiation antigen 20 (CD20) antibodies, including being seropositive for HBsAg

• Active hepatitis B virus infection

• Ever received B-cell depleting antibodies (rituximab, ocrelizumab, ofatumumab), alemtuzumab, daclizumab, mitoxantrone or hematopoietic stem-cell transplant

• Pregnant or lactating women

• Hypersensitivity to ocrelizumab

• Treatment with steroids in the past 30 days