A Single Arm Study Evaluating the Efficacy, Safety and Tolerability of Ofatumumab in Patients With Relapsing Multiple Sclerosis
A Single Arm Study Evaluating the Efficacy, Safety and Tolerability of Ofatumumab in Patients With Relapsing Multiple Sclerosis
A single arm study evaluating the continued efficacy, safety and tolerability of ofatumumab
 in patients with relapsing multiple sclerosis who are transitioning from aCD20 mAb therapy
This is a single-arm multi-center, study in approximately 100 participants with relapsing
 multiple sclerosis who were previously treated with aCD20 mAb therapy. Eligible participants
 will receive open label ofatumumab 20 mg subcutaneous every 4 weeks for 12 months following
 initial loading regimen of 20 milligrams subcutaneous doses on Days 1, 7 and 14. Assessments
 will include but are not limited to Magnetic Resonance Imaging (MRI) assessed for quality by
 central reading center, multiple Patient Reported Outcome measurements and safety
 assessments..Participants that do not continue onto commercial ofatumumab or another therapy
 within one month of the End of Study Visit must continue into the safety Follow Up phase,
 consisting of every 3 month visits including B cell monitoring until they are able to start
 on commercial ofatumumab or switch to another therapy or until their B cells are repleted
 defined as a B cell concentration greater than the individual participant's baseline value or
 greater than the lower limit of normal. All participants will have a safety follow-up phone
 call at 30 days post study.
Inclusion Criteria:

 Participants eligible for inclusion in this study must meet all of the following criteria:

 1. Written informed consent must be obtained before any assessment is performed.

 2. Male or female participants aged 18 to 55 years (inclusive) at screening.

 3. Diagnosis of relapsing MS (RMS) according to the 2017 Revised McDonald criteria
 (Thompson et al.

 2018), including CIS, RRMS or SPMS with disease activity as defined by (Lublin et al.
 2014).

 4. Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive). 5. Received
 at least 2 but no more than 5 courses of intravenous aCD20 mAb (loading doses are
 considered 1 course):

 • Participants currently treated with ocrelizumab must have received (meet all three
 criteria below):

 1. 2 fully infused initial 300 mg ocrelizumab iv infusions

 2. From 1 to 4 fully infused 600 mg ocrelizumab iv infusions 6 months (+/- one month)

 3. Last fully infused ocrelizumab dose must have occurred within 4-9 months prior to
 baseline

 Participants currently treated with rituximab must have received (meet both criteria
 below):

 1. At least 2, but no more than 5, fully infused courses of rituximab 500 mg - 1000 mg iv
 every 6 months (+/- one month).

 a. Initial loading regimens of rituximab i.e. 500 mg - 1000 mg on day 1 and on day 15,
 are allowed but this is consider a single course and must be followed by additional
 infusion(s) every 6 months (+/- one month)

 2. Last fully infused rituximab dose must have occurred within 4-9 months prior to
 baseline.

 6. Participants discontinuing aCD20 therapy for reasons including, but not limited to:
 physician/participant preference, access to commercial drug (e.g. insurance coverage
 issues) or for other logistical reasons (such as geographical relocation, travel, etc.) are
 eligible for this study. 7. Participants with CD19 B cells that are depleted to < 1% of the
 participant's baseline CD19 B cell concentration. 8. Neurologically stable within 1 month
 prior to first study drug administration. 9. Must be able to use a smart device or have a
 caregiver that can assist.

 Exclusion Criteria:

 Participants meeting any of the following criteria are not eligible for inclusion in this
 study:

 1. Participants that have demonstrated suboptimal response to aCD20 therapy to include:
 documented relapse while on previous aCD20 treatment, or signs of MRI activity,
 defined as ≥ 2 active Gd+ T1 lesions, or any new or newly enlarging T2 lesions, or any
 signs of clinical worsening as measured by EDSS or any clinical measure, documented
 within the last 6 months.

 2. Discontinuing aCD20 mAb therapy due to the following treatment- emergent adverse
 events:

 1. Severe infusion-related reactions (Grade 3 or above)

 2. Recurrent infections defined as ≥ 2 severe infections or ≥ 3 respiratory
 infections or the need for ≥ 2 courses of antibiotics since starting aCD20
 therapy

 3. Decreased IgG requiring treatment with Intravenous immunoglobulin

 3. Participants with primary progressive MS (Polman et al 2011) or SPMS without disease
 activity (Lublin et al 2014).

 4. Participants meeting criteria for neuromyelitis optica (Wingerchuk et al 2015).

 5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
 female after conception and until the termination of gestation, confirmed by a
 positive hCG laboratory test.

 6. Women of child-bearing potential, defined as all women physiologically capable of
 becoming pregnant, unless they are using highly effective methods of contraception
 during dosing and for at least 6 months after stopping study medication. Highly
 effective contraception methods include:

 -  Total abstinence

 -  Female sterilization

 -  For female participants on the study, the vasectomized male partner should be the
 sole partner

 -  Use of oral, (estrogen and progesterone), injected or implanted hormonal methods
 of contraception or placement of an intrauterine device (IUD) or intrauterine
 system (IUS) or other forms of hormonal contraception that have comparable
 efficacy (failure rate <1%), for example hormone vaginal ring or transdermal
 hormone contraception.

 7. Participants with active chronic disease (or stable but treated with immune therapy)
 of the immune system other than MS (e.g.

 rheumatoid arthritis, scleroderma, Sjögren's syndrome, Crohn's disease, ulcerative
 colitis, etc.) or with immunodeficiency syndrome (hereditary immune deficiency,
 drug-induced immune deficiency).

 8. Participants with active systemic bacterial, viral or fungal infections, or known to
 have acquired immunodeficiency syndrome (AIDS).

 9. Participants with neurological symptoms consistent with PML or with confirmed PML.

 10. Participants at risk of developing or having reactivation of syphilis or tuberculosis
 (eg. Participants with known exposure to, or history of syphilis, or active or latent
 tuberculosis, even if previously treated).

 Testing for syphilis and tuberculosis will be done at Screening. Testing must be done
 by the central lab (for syphilis e.g. by positive rapid plasma reagin (RPR); for
 tuberculosis testing, QuantiFERON®-TB Gold test to assess participant's eligibility at
 Screening).

 11. Participants at risk of developing or having reactivation of hepatitis:

 Positive results at Screening for serological markers for hepatitis (H)

 A, B, C, and E indicating acute orpchronic infection:

 -  anti-HA Immunoglobulin M (IgM)

 -  HBs Ag and/or anti-HBc IgM and/or HB virus deoxyribonucleic acid (DNA)

 -  anti-HBs negative and Anti-HBc positive

 -  anti-HC IgG (if positive IgG, HCV-RNA PCR will be performed and if negative,
 participant can be enrolled)

 -  anti-HE IgM (if positive IgG and/or IgM, perform HE-RNA PCR and if negative,
 participant can be enrolled) NOTE: If the Investigator suspects false positive
 hepatitis serology results, such as an antibody pattern indicating acute
 hepatitis infection but no corresponding elevated liver enzymes and no signs or
 symptoms of liver disease, an infectious disease expert may be consulted. If the
 infectious disease expert finds no evidence of acute or chronic hepatitis
 infection and considers the serology results false positive and not clinically
 relevant, the Investigator must document (in source data and as a comment in the
 eCRF) that the serology results are considered false positive and may then enroll
 the participant.

 12. Have received any live or live-attenuated vaccines (including for varicella-zoster
 virus or measles) within 2 months prior to first study drug administration.

 13. Have been treated with any of the medications listed below within the time specified
 Medication Exclusionary if used within the timeframe specified below Intravenous,
 oral, intra-articular or intramuscular corticosteroids, adrenocorticotropic hormone
 exclusionary within 30 days prior to Screening MRI scan

 Immunosuppressive, chemotherapeutic medications (e.g. natalizumab, mitoxantrone,
 cyclophosphamide, cladribine, S1P modulators) exclusionary within 2 years prior to
 first study drug administration

 Mitoxantrone (with evidence of cardiotoxicity following treatment or cumulative
 life-time dose > 60mg/m2) Alemtuzumab Lymphoid irradiation; bone marrow
 transplantation Other strongly immunosuppressive treatments (with effects potentially
 lasting over 6 months), Ofatumumab, aCD20+ monoclonal antibodies in development (e.g.
 ublituximab or obinutuzumab) and Daclizumab exclusionary if taken Anytime

 14. Use of other investigational drugs at the time of enrollment (Screening) or within the
 prior 30 days, or five elimination half-lives, or until the expected pharmacodynamic
 effect has returned to baseline, whichever is longer.

 15. History of malignancy of any organ system (other than basal cell carcinoma, in situ
 squamous cell carcinoma of skin, or in situ carcinoma of cervix or the uterus that
 have been radically treated e.g. completely excised with clear margins), within the
 past 5 years, regardless of whether or not there is evidence of local recurrence or
 metastases.

 16. Any of the following conditions or treatments that may impact the safety of the
 participant:

 -  History of, or current, significant cardiac disease including cardiac failure
 (NYHA functional class II-IV), myocardial infarction (within 6 months), unstable
 angina (within 6 months), transient ischemic attack (within 6 months), stroke,
 cardiac arrhythmias requiring treatment or uncontrolled arterial hypertension

 -  Concomitant clinically significant cardiac arrhythmias, e.g. sustained
 ventricular tachycardia and clinically significant second or third degree AV
 block without a pacemaker on screening electrocardiogram (ECG)

 -  History of or active severe respiratory disease, including Chronic Obstructive
 Pulmonary Disease, interstitial lung disease or pulmonary fibrosis

 -  Participants with asthma requiring regular treatment with oral steroids

 -  Severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary
 disease

 -  Participants with severe renal impairment (Glomerular Filtration Rate < 30
 ml/min/1.73 m2)

 -  Any medically unstable condition as determined by the Investigator

 17. Any of the following abnormal laboratory values as confirmed by the central laboratory
 prior to first study drug administration:

 -  Total or conjugated bilirubin (BIL) greater than 3 times upper limit of normal
 (ULN) range, unless in the context of Gilbert's syndrome

 -  Alkaline phosphatase (ALP) greater than 5 times the ULN range

 -  ALT between 1.5 and 5 times the ULN range and an active infection with
 hepatotropic viruses (Herpes simplex virus, Cytomegalovirus and Epstein-Barr
 Virus)

 -  Serum IgG < 300mg/dL (according to central laboratory range) Any other clinically
 significant laboratory assessment as determined by the Investigator (e.g.
 significant anemia, neutropenia, thrombocytopenia, signs of impaired bone marrow
 function)

 18. Participants with severe hypoproteinaemia e.g. in nephrotic syndrome.

 19. Participants with any of the following neurologic/psychiatric disorders prior to first
 study drug administration:

 • Score "yes" on item 4 or item 5 of the Suicidal Ideation section of the Columbia-
 Suicide Severity Rating Scale (C-SSRS), if this ideation occurred in the past 6
 months, or "yes" on any item of the Suicidal Behavior section, except for the
 "Non-Suicidal Self-Injurious Behavior" (item also included in the Suicidal Behavior
 section), if this behavior occurred in the past 2 years.

 20. History of hypersensitivity to any of the study drugs or excipients (including rare
 hereditary problems of galactose intolerance, Lapp lactase deficiency and
 glucose-galactose malabsorption) or to drugs of similar chemical classes.