Ocrelizumab Effects on Physiological and Cognitive Changes in Multiple Sclerosis

Grey matter (GM) atrophy develops early in the multiple sclerosis (MS) disease process. Over
2 years, clinically isolated syndrome (CIS) patients developed significant thalamic and
cortical volume loss. In our preliminary study, including 50 MS patients, the investigators
found that the presence of leptomeningeal (LM) contrast enhancement (CE) was associated with
progression of cortical atrophy over 5 years, as measured by the loss of cortical volume, in
patients with MS. About 40% of relapsing-remitting MS (RRMS) patients presented with LM CE.
MS patients with LM CE showed significantly greater percentage decreases cortical (-3.4% vs.
-1.8%, p=0.007) volumes, compared to those without. RRMS patients with LM CE showed
significantly greater percentage decrease in cortical (-3.8% vs. -1.9%, p=0.006) volume over
the follow-up, compared to those without. No differences in deep GM volume changes were found
in relapsing-remitting (RR) and secondary progressive (SP) MS patients with and without LM
CE. Three LM CE positive and one LM CE negative RRMS patients developed secondary progressive
MS (SPMS) course over the follow-up. More MS subjects with LM CE had disability progression
(7, 28%) compared to those without (4, 16%), but this was not significantly different
(p=0.306). The median EDSS in MS patient with LM CE increased to 4.0, while decreased to 2.5
in those without. No differences in total number of relapses, annual relapse rate, nor being
relapse free were detected in MS patients with and without LM CE over the follow-up. However,
in RRMS patients with LM CE, the investigators found that there was a trend for greater
increase in absolute change of EDSS (0.9 vs. -0.03, p=0.05).

The proposed study will extend these preliminary findings in a cohort of MS patients, who
will be treated with Ocrelizumab and who will be assessed at 12 and 24 months using same MRI
hardware and software. The longitudinal serial MRI assessment study design will allow us to
examine temporal relationship of LM CE, development of GM pathology, cognitive dysfunction
and Ocrelizumab. Based on our preliminary results, the investigators expect that
approximately 12 (40%) of MS patients will present with LM CE at baseline in the proposed
study.

Substantial evidence shows that Epstein-Barr virus (EBV) infection plays a major role in the
risk of developing MS. Mononucleosis and seropositivity of anti-Epstein-Barr nuclear antigen
(EBNA) Immunoglobulin G (IgG) along with Vit D deficiency and smoking are risk factors for
MS. Serial studies reveal that the risk of developing MS is extremely low among individuals
not infected with EBV but increases sharply in the same individuals following EBV infection.
EBV-infected B cells were identified in MS brain lesions. Therefore the elimination of the
virus from the persistently infected B-cells could potentially inhibit/delay disease
progression. Our data show correlation of anti-EBV levels with atrophy (more degeneration)
hence an effect on disease chronicity/progression. Besides high Vit D administration studies
that showed an effect on decreasing the EBV antibody levels, no other DMT's were able to show
a beneficial effect on EBV antibody level, and some treatments increased EBV levels.

EBV viremia occurs in the hematopoietic stem transplantation setting and has been treated
successfully with rituximab, an antibody that targets B-lymphocyte antigen (CD20) on B cells
in a manner analogous to Ocrelizumab. It has been reported that 92% of patients with EBV
viremia responded upon dosing with rituximab and the EBV copies per 100,000 peripheral blood
mononuclear cell (PBMC) decreased from 2578 to 71 at Day 15 and 0 by Day 21.

Therefore, our hypothesis is that Ocrelizumab treatment will reduce both B cells and EBV
exposure in treated patients leading to benefit on LM inflammation and to less GM atrophy
development.

Inclusion Criteria:

- Patient diagnosed with MS according to McDonald criteria

- Age 18-60

- Relapsing disease course

- Expanded Disability Status Scale (EDSS) ≤5.5

- Disease duration <20 years

- Treatment naive to Ocrelizumab

- Willing and able to comply with the study procedures for the duration of the trial

- Given written informed consent and signed HIPAA Authorization prior to the study

- Normal kidney functioning (creatinine clearance >59)

- None of the exclusion criteria

Exclusion Criteria:

- PI guidelines for contraindications of Ocrelizumab (available after FDA approval)

- Significant cognitive impairment (in the opinion of the investigator) or other
significant neurological or medical condition that would compromise adherence and
completion of the trial, including major depression and developmental disorders
affecting cognition

- Have received treatment within 30 days prior to enrollment with steroids or any other
concomitant immunomodulatory therapies

- Have received treatment with Natalizumab within 8 weeks prior to enrollment; this is
needed to increase confidence that there are no signs of progressive multifocal
leukoencephalopathy (PML) on baseline MRI

- Less than 6 months from the use of immunosuppressant agents (e.g., including but not
limited to mitoxantrone, cyclophosphamide, azathioprine, methotrexate, mycophenolate
mofetil)

- Have received an investigational drug or experimental procedure within the past 30
days

- Women who are pregnant, lactating, or of childbearing age who do not consent to
approved contraceptive use during the study

- Any other factor that, in the opinion of the investigator, would make the subject
unsuitable for participation in this study

- Hypersensitivity to trial medications