Effect of Ocrelizumab on Brain Innate Immune Microglial Cells Activation in MS Using PET-MRI With 18F-DPA714

Inclusion criteria for all MS subgroups:

1. Signed informed consent form
2. Able to comply with the study protocol, in the investigator's judgment
3. Social security registration
4. Age 18 - 60 years, inclusive
5. For women of childbearing potential: agreement to use an acceptable birth controlmethod during the treatment period and for at least 12 months after the last dose ofstudy drug. RMS
6. Have a definite diagnosis of RMS, confirmed as per the revised McDonald 2010 criteria (Polman et al. 2011);
7. Absence of history of Secondary Progressive Multiple Sclerosis (SPMS) or history ofPrimary Progressive Multiple Sclerosis (PPMS)
8. Have an active disease: Activity determined by clinical relapses and/or MRI activity (contrast-enhancing lesions; new or unequivocally enlarging T2 lesions assessed atleast annually (Lublin et al. 2014))
9. Neurological stability for ≥30 days prior to both screening and baseline
10. EDSS of 0.0 to 5.5, inclusive, at screening
11. Have a length of disease duration, from first symptom, of < 15 years
12. Have received no more than first line injectable treatments (i.e. IFNs and GA,possible switchs within this class) + 1 other treatment (e.g. teriflunomide, DMF,fingolimod, natalizumab, no switch allowed within this group). More details in section 6.1.1.2.1
13. Have a suboptimal response to the last received DMT: a suboptimal response is definedby having at least one of the following events while being on a stable dose of thesame DMT for at least 6 months:
14. One or more clinically reported relapse(s)
15. OR one or more T1 Gd-enhanced lesion(s)
16. OR one or more new and/or enlarging T2 lesions on MRI
17. In addition, in patients receiving stable doses of the same approved DMT for more thana year, at least one of the above events must have occurred within the last 12 monthsof treatment with this DMT. RMS
18. Diagnosis of SPMS according to Lublin et al. 2014 criteria
19. Prior history of RRMS (Have a definite diagnosis of RRMS, confirmed as per the revisedMcDonald 2010 criteria
20. Have an active disease during the two years preceding the study entry: Activitydetermined by clinical relapses and/or MRI activity (contrast-enhancing lesions; newor unequivocally enlarging T2 lesions assessed at least annually (Lublin et al. 2014))
21. Evidence of any disability progression unrelated to relapse within the 2 year periodprior to study baseline. Progression in the last year will be reported by the treatingphysician and documented using a disease progression rating system checklist (seeAppendix 1)
22. Progression is defined as steadily increasing objectively documented neurologicdysfunction/disability without unequivocal recovery (fluctuations and phases ofstability may occur) (Lublin, 2014)
23. Absence of history of Primary Progressive Multiple Sclerosis or Progressive RelapsingMultiple Sclerosis at screening
24. EDSS at screening ≤ 6.5points
25. Score of ≥ 2.0 on the Functional Systems (FS) scale for the pyramidal system that isdue to lower extremity findings
26. Disease duration from the onset of Secondary Progressive MS symptoms of less than 10years if baseline EDSS ≤5
27. Disease duration from the onset of Secondary Progressive MS symptoms of less than 15years if baseline EDSS >5
28. Have received no more than first line treatments (either injectable, i.e. IFNs and GA,or oral, either teriflunomide and dimethyl fumarate, possible switchs within thisgroup) + 1 second line treatment (e.g., fingolimod, natalizumab, no switch allowedwithin this group). PPMS
29. Diagnosis of PPMS in accordance with the 2010 revised McDonald criteria :
30. One year of disease progression (retrospectively or prospectively determined)
31. Plus 2 of the 3 following criteria :
32. Evidence for DIS in the brain based on ≥ 1 T2 lesions in at least 1 areacharacteristic for MS (periventricular, juxtacortical, or infratentorial)
33. Evidence for DIS in the spinal cord based on ≥ 2 T2 lesions in the cord
34. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevatedIgG index)
35. Absence of history of Relapsing Remitting Multiple Sclerosis, Secondary Progressive,or Progressive Relapsing Multiple Sclerosis at screening
36. Evidence of any disability progression unrelated to relapse within the 2 year periodprior to study baseline. Progression in the last 2 year will be reported by thetreating physician and documented using a disease progression rating system checklist (see Appendix 1)
37. EDSS at screening between 2.0 and 6.5 points
38. Score of ≥ 2.0 on the Functional Systems (FS) scale for the pyramidal system that isdue to lower extremity findings
39. Disease duration from the onset of MS symptoms of less than 10 years if baseline EDSS ≤5
40. Disease duration from the onset of MS symptoms of less than 15 years if baseline EDSS >5 Healthy volunteers (20 subjects):
41. Signed informed consent form
42. Able to comply with the study protocol, in the investigator's judgment
43. Social security registration
44. Age 18 - 60 years, inclusive
45. For women of childbearing potential: agreement to use an acceptable birth controlmethod during the research period and for at least 1 cycle after the PET-MRI.
46. A woman is considered to be of childbearing potential if she is postmenarcheal,has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea withno identified cause other than menopause), and has not undergone surgicalsterilization (removal of ovaries and/or uterus).
47. The following are acceptable contraceptive methods: progestogen-only oralhormonal contraception, where inhibition of ovulation is not the primary mode ofaction, male or female condom with or without spermicide, and cap, diaphragm, orsponge with spermicide. A combination of male condom with cap, diaphragm, orsponge with spermicide (double barrier methods) is considered acceptable
48. Pregnancy tests will be performed at each study visit for women of childbearingpotential.

Exclusion Criteria:

1. Inability to complete an MRI (contraindications for MRI include but are not restrictedto weight ≥ 140 kg, pacemaker, cochlear implants, presence of foreign substances inthe eye, intracranial vascular clips, surgery within 6 weeks of entry into the study,coronary stent implanted within 8 weeks prior to the time of the intended MRI,contraindication to gadoteric acid etc.).
2. Impossibility to complete a PET scan: pregnancy, nuclear medicine irradiation in theyear preceding baseline visit for clinical research and one year after the end oftheir participation in the study, lactation.
3. Known presence of other neurological disorders, including but not limited to, thefollowing:
4. History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemicattack) or ischemia of the spinal cord
5. History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma)
6. History or known presence of potential metabolic causes of myelopathy (e.g.,untreated vitamin B12 deficiency)
7. History or known presence of infectious causes of myelopathy (e.g., syphilis,Lyme disease, human T-lymphotropic virus 1 (HTLV-1), herpes zoster myelopathy)
8. History of genetically inherited progressive CNS degenerative disorder (e.g.,hereditary paraparesis; MELAS [mitochondrial myopathy, encephalopathy, lacticacidosis, stroke] syndrome)
9. Neuromyelitis optica
10. History or known presence of systemic autoimmune disorders potentially causingprogressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome,Sjogren's syndrome, Behçet's disease)
11. History or known presence of sarcoidosis
12. History of severe, clinically significant brain or spinal cord trauma (e.g.,cerebral contusion, spinal cord compression) - General Health:
13. Pregnancy or lactation 2. Any concomitant disease that may require chronic treatmentwith systemic corticosteroids or immunosuppressant drugs during the course of the study 3.History or currently active primary or secondary immunodeficiency 4. Lack of peripheralvenous access 5. Significant, uncontrolled disease, such as cardiovascular (includingcardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic,endocrine or gastrointestinal or any other significant disease that may preclude patientfrom participating in the study 6. History of severe allergic or anaphylactic reactions tohumanized or murine monoclonal antibodies 7. Congestive heart failure (New York HeartAssociation [NYHA] III or IV functional severity) 8. Known active bacterial, viral, fungal,mycobacterial infection or other infection [including tuberculosis [TB] or atypicalmycobacterial disease (but excluding fungal infection of nail beds)] or any major episodeof infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeksprior to baseline visit or oral antibiotics within 2 weeks prior to baseline visit; Note:Active infections should be treated and effectively controlled before possible inclusion inthe study 9. History or known presence of recurrent or chronic infection 10. History ofmalignancy, including solid tumors and hematological malignancies, except basal cellcarcinoma, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervixof the uterus that have been previously completely excised with documented, clear margins
14. History of alcohol or drug abuse within 24 weeks prior to baseline 12. History orlaboratory evidence of coagulation disorders 13. History of major opportunistic infections (i.e. cryptococcosis, Pneumocystis pneumonia, progressive multifocal leukoencephalopathy [PML]) 14. History of recurrent aspiration pneumonia requiring antibiotic therapy 15.Hypersensitivity to the active substance or to any of the excipients (Sodium AcetateTrihydrate, Glacial Acetic Acid, Trehalose Dihydrate, Polysorbate 20, Water for Injection)

• Laboratory Findings:

1. TSPO polymorphism indicating a low affinity profile.
2. Positive serum β human chorionic gonadotropin (hCG) measured at screening andbefore each PET-Scan procedure
3. Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg]positive, or positive hepatitis B core antibody [total HBcAb] confirmed by apositive viral DNA polymerase chain reaction [PCR]) or hepatitis C (HepCAb)
4. Lymphocyte count below lower limit of normal (LLN)
5. CD4 count <300/μL.
6. Absolute neutrophil count <1.0 × 103/µL

• Medications:

1. Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to thebaseline visit. In rare cases when patient requires vaccination with a livevaccine, the screening period may be extended but cannot exceed 8 weeks
2. Treatment with any investigational agent within 24 weeks of screening or fivehalf-lives of the investigational drug (whichever is longer) or treatment withany experimental procedures for MS (e.g., treatment for chronic cerebrospinalvenous insufficiency)
3. Treatment with Flumitrazepam, triazolam, diazepam

• Treatment of Multiple Sclerosis:

1. Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab,atacicept, belimumab, or ofatumumab)
2. Systemic corticosteroid therapy within 4 weeks prior to screeningii
3. Treatment with IV immunoglobulin (Ig) within 12 weeks prior to baseline
4. Any previous treatment with alemtuzumab, daclizumab, anti-CD4, total bodyirradiation or bone marrow transplantation
5. Any previous treatment with biotin in the last month prior to screening
6. Previous treatment with mitoxantrone, cyclosporine or cladribine in the last 96weeks
7. Previous treatment with azathioprine, cyclophosphamide, mycophenolatemofetil,methotrexate, or laquinimod in the last 24 weeks
8. Previous treatment with teriflunomide, unless an accelerated eliminationprocedure is implemented before screening visit. Accelerated eliminationprocedure after stopping treatment with teriflunomide:
9. cholestyramine 8g is administered 3 times daily for a period of 11 days, orcholestyramine 4g three times a day can be used, if cholestyramine 8g threetimes a day is not well tolerated,
10. alternatively, 50g of activated powdered charcoal is administered every 12hours for a period of 11 days
11. Previous treatment with natalizumab in the last 12 weeks
12. Previous treatment with fingolimod or dimethyl fumarate if at baseline thelymphocyte count is below lower limit of normality (LLN). Apart from thelymphocytes count within normal ranges, 12 weeks of a washout period offingolimod or dimethylfumarate would be required before the start of ocrelizumabadministration
13. History of recurrent aspiration pneumonia requiring antibiotic therapy
14. Treatment with fampridine/dalfamipridine (Fampyra®)/Ampyra®) unless on stabledose for ≥ 30 days prior to screening. Wherever possible, patients should remainon stable doses throughout the 96-week treatment period
15. Treatment with β interferons, glatiramer acetate, plasmapheresis, or otherimmunomodulatory therapies within 4 weeks prior to baselinei Healthy volunteers:
16. Inability to complete an MRI (contraindications for MRI include but are not restrictedto weight ≥ 140 kg, pacemaker, cochlear implants, presence of foreign substances inthe eye, intracranial vascular clips, surgery within 6 weeks of entry into the study,coronary stent implanted within 8 weeks prior to the time of the intended MRI,contraindication to acid gadoteric etc.)
17. Impossibility to complete a PET scan: pregnancy, nuclear medicine irradiation in theyear preceding baseline visit for clinical research
18. Known presence of any neurological disorders
19. Pregnancy or lactation
20. Lack of peripheral venous access
21. Significant, uncontrolled disease, such as cardiovascular (including cardiacarrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic,endocrine or gastrointestinal infectious, neoplasic or any other significant diseasethat may preclude patient from participating in the study
22. History of alcohol or drug abuse within 24 weeks prior to baseline
23. TSPO polymorphism indicating a low affinity profile.
24. Treatment with Flumitrazepam, triazolam, diazepam