Study to Assess the Effect of Ofatumumab in Treatment Naïve, Very Early RRMS Patients Benchmarked Against Healthy Controls.

AGNOS: An 18-month, Open-label, Multi-Center Phase IV Study to Assess the Effect of Ofatumumab 20mg SC Monthly in Treatment Naïve, Very Early Relapsing Remitting Multiple Sclerosis Patients Benchmarked Against Healthy Controls on Select Outcomes.

This study evaluates the impact of ofatumumab in Relapsing Remitting Multiple Sclerosis (RRMS) participants that are very early in the course of their disease using clinical and magnetic resonance imaging (MRI) outcomes. The study also assesses changes in disease using monitoring techniques including digital biometric device use, biomarker analysis and non-conventional MRI. Select outcomes in the ofatumumab treated group will be compared to a group of Healthy participants to determine if there are similarities between the groups after the patients with MS undergo treatment with ofatumumab.

The study is an open-label, multi-center, prospective 18-month study in 119 MS participants with early RRMS (defined as within 6 months of diagnosis of clinically definite RRMS) and who are treatment naïve. It is designed to determine if RRMS participants treated with 20 mg subcutaneous monthly ofatumumab during the earliest part of their disease will benefit from the use of ofatumumab as their first disease modifying therapy. Additionally, RRMS patients will be compared to age- and sex-matched healthy participants (n=61) for select outcomes to observe similarities and differences between the groups.

After giving consent, participants have a 28-day screening/qualification period. If they qualify to continue, they start study measures including assessments of clinical and magnetic resonance imaging (MRI) metrics and use of a digital monitoring watch. Additionally, samples are collected for laboratory and biomarker analysis. RRMS participants begin treatment with ofatumumab for the next 18 months. Healthy participants undergo similar assessments; however they do not receive any treatment during the course of the study. Over the 18 months, participants have regular clinical visits with assessments and sample collection. After 18 months in the trial, participants in both groups have the option to enter into a 12-month extension (up to 30 months total in study) to collect further information on long-term clinical and MRI outcomes.

Key Inclusion Criteria:

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

1. Signed informed consent must be obtained prior to participation in the study

2. Age 18-35 years

   Patients in the healthy control arm eligible for inclusion must fulfill the following criteria:

3. Able to obtain MRI (HC with abnormal MRI at Screening will be excluded) and use wearable device

4. Able to provide blood sample (no CSF will be collected in HC)

   Patients in the ofatumumab-treated arm eligible for inclusion must fulfill the following criteria:

5. Diagnosis of RRMS per McDonald Criteria (2010/2017)

6. Within 6 months of diagnosis of clinically definite MS (CDMS)

7. EDSS 0-3.0 (Inclusive)

8. Treatment-naïve to MS DMT

9. Able to obtain MRI and attend study visits at sites

10. Able to use wearable device

11. Able to provide blood sample (and CSF for sub-group n=15)

Key Exclusion Criteria:

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

1. Confounding medical condition as determined by the investigator

   RRMS patients fulfilling any of the following exclusion criteria are not eligible for inclusion in this study:

2. Diseases other than multiple sclerosis responsible for the clinical or MRI presentation

3. Patients with neuromyelitis optica, Radiologic/ Clinically Isolated Syndrome, Secondary Progressive or Primary Progressive MS diagnosis

4. Use of experimental or investigational drugs for MS

5. Previous use of Disease Modifying Therapy (DMT) or chemotherapeutic medications for MS

6. Relapse between screening and Baseline visits

7. Known sensitivity to gadolinium; patients with chronic, severe kidney disease

8. Known history of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes

9. CNS anomalies that are better accounted for by another disease process or MRI anomalies causing clinically apparent impairments

10. Known active malignancies

11. Pregnant or nursing (lactating) women

12. Females of childbearing potential (all women physiologically capable of becoming pregnant) should use effective contraception while receiving ofatumumab and for 6 months after the last treatment of ofatumumab

13. Patients with an active chronic disease (or stable but treated with immune therapy) of the immune system other than MS or with immunodeficiency syndrome

14. Patients with active infections including systemic bacterial, viral (including SARS-CoV-2/COVID-19) or fungal infections, or known to have AIDS or to test positive for HIV antibody at Screening

15. Patients with neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML), or confirmed PML

16. Patients with IgG or IgM levels below LLN at Screening

17. Patients that have received any live or live-attenuated vaccines within 4 weeks prior to first dose of study drug administration

18. Patients at risk of developing or having reactivation of hepatitis