Best Available Therapy Versus Autologous Hematopoetic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS)

Inclusion Criteria:

1. Age 18 to 55 years, inclusive, at the time of the screening Visit -2.

2. Diagnosis of MS according to the 2017 McDonald Criteria139.

3. EDSS ≤ 6.0 at the time of randomization (Day 0).

4. T2 abnormalities on brain MRI that fulfill the 2017 McDonald MRI criteria fordissemination in space139. A detailed MRI report or MRI images must be available forreview by the site neurology investigator.

5. Highly active treatment-resistant relapsing MS, defined as ≥ 2 episodes of diseaseactivity in the 36 months prior to the screening visit (Visit -2). The two diseaseactivity episodes will be a clinical MS relapse or MRI evidence of MS diseaseactivity and must meet all the criteria described below:

6. At least one episode of disease activity must occur following ≥ 1 month oftreatment with one of the following: (i) an oral DMT approved by the FDA forthe treatment of relapsing MS, or (ii) a monoclonal antibody approved by theFDA for the treatment of relapsing MS, or (iii) rituximab. Qualifying DMTsinclude: dimethyl fumarate, diroximel fumarate, monomethyl fumarate,teriflunomide, cladribine, daclizumab, ponesimod, siponimod, ozanimod,fingolimod, rituximab, ocrelizumab, natalizumab, alemtuzumab, ublituximab, andofatumumab, and

7. At least one episode of disease activity must have occurred within the 12months prior to the screening visit (Visit -2), and

8. At least one episode of disease activity must be a clinical MS relapse (seeitem c.i. below). The other episode(s) must occur at least one month before orafter the onset of the clinical MS relapse, and must be either another clinicalMS relapse or MRI evidence of disease activity (see item c.ii. below): i. Clinical MS relapse must be confirmed by a neurologist's assessment anddocumented contemporaneously in the medical record. If the clinical MS relapse isnot documented in the medical record, it must be approved by the study adjudicationcommittee (see Section 3.5), and ii. MRI evidence of disease activity must include ≥ 1 unique active lesion on one or more brain or spinal cord MRIs. Detailed MRIreports or MRI images must be available for review by the site neurologyinvestigator. A unique active lesion is defined as either of the following:

9. A gadolinium-enhancing lesion, or 2. A new non-enhancing T2 lesion compared to areference scan obtained not more than 36 months prior to the screening visit (Visit -2).

10. Candidacy for treatment with at least one of the following high efficacy BAT DMTs:cladribine, natalizumab, alemtuzumab, ocrelizumab, ofatumumab, ublituximab andrituximab. Candidacy for treatment for each BAT DMT is defined as meeting all of thefollowing:

11. No prior disease activity episode, as defined in Inclusion Criterion #5, with thecandidate BAT DMT, and

12. No contraindication to the candidate BAT DMT, and

13. No treatment with the candidate BAT DMT in the 12 months prior to screening.

14. Completion of COVID-19 vaccination series, according to the current Centers forDisease Control and Prevention (CDC) Advisory Committee on ImmunizationPractices (ACIP) recommendations, ≥ 14 days prior to randomization (Day 0).

15. Positive for VZV antibodies, or completion of at least one dose of thevaricella zoster glycoprotein E (gE) Shingrix vaccine at least 4 weeks prior torandomization (Day 0).

16. Insurance approval for MS treatment with at least one candidate BAT DMT (seeInclusion Criterion #6).

17. Ability to comply with study procedures and provide informed consent, in theopinion of the investigator.

18. Females of childbearing potential (defined in Section 5.4.3.1) and males withfemale partners of childbearing potential are required to adhere to thecontraception provisions of Section 5.4.3.1.

19. For participants who use medicinal or recreational marijuana, willingness tosubstitute MARINOL® if randomized to AHSCT (Section 5.4.2.6).

Exclusion Criteria:

1. Diagnosis of primary progressive MS according to the 2017 McDonald criteria.

2. History of neuromyelitis optica spectrum disorder or MOG antibody disease.

3. Prior treatment with an investigational agent within 3 months or 5 half-lives,whichever is longer. Agents authorized by the FDA for prevention or treatment ofCOVID-19 are not considered investigational.

4. Either of the following within one month prior to randomization (Day 0):

5. Onset of acute MS relapse, or

6. Treatment with intravenous methylprednisolone 1000 mg/day for 3 days orequivalent.

7. Initiation of any BAT DMT (see Section 5.2.1) between Visit -2 and randomization (Day 0).

8. Brain MRI or cerebrospinal fluid (CSF) examination indicating a diagnosis ofprogressive multifocal leukoencephalopathy (PML).

9. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS).

10. Presence of unexplained cytopenia, polycythemia, thrombocythemia or leukocytosis.

11. History of sickle cell anemia or other hemoglobinopathy.

12. Evidence of past or current hepatitis B or hepatitis C infection, including treatedhepatitis B or hepatitis C. Hepatitis B surface antibody following hepatitis Bimmunization is not considered to be evidence of past infection.

13. Presence or history of mild to severe cirrhosis.

14. Hepatic disease with the presence of either of the following:

15. Total bilirubin ≥ 1.5 times the upper limit of normal (ULN) or total bilirubin ≥ 3.0 times the ULN in the presence of Gilbert's syndrome, or

16. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 2.0 timesthe ULN.

17. Positive COVID-19 PCR test, or alternative nucleic acid amplification test (NAAT)per institutional standards, within 14 days prior to randomization (Day 0).

18. Evidence of HIV infection.

19. Positive QuantiFERON - TB Gold,TB Gold Plus, or T-SPOT®.TB test results. PPDtuberculin test may be substituted for QuantiFERON - TB Gold, TB Gold Plus, orT-SPOT®.TB test.

20. Active viral, bacterial, endoparasitic, or opportunistic infections.

21. Active invasive fungal infection.

22. Hospitalization for treatment of infections or parenteral (IV or IM) antibacterials,antivirals, antifungals, or antiparasitic agents within the 30 days prior torandomization (Day 0) unless clearance is obtained from an Infectious Diseasespecialist.

23. Receipt of live or live-attenuated vaccines within 6 weeks of randomization (Day 0).

24. Presence or history of clinically significant cardiac disease including: a.Arrhythmia requiring treatment with any antiarrhythmia therapy, with the exceptionof low dose beta blocker for intermittent premature ventricular contractions. b. Coronary artery disease with a documented diagnosis of either: i. Chronicexertional angina, or ii. Signs or symptoms of congestive heart failure. c. Evidenceof heart valve disease, including any of the following: i. Moderate to severe valvestenosis or insufficiency, or ii. Symptomatic mitral valve prolapse, or iii.Presence of prosthetic mitral or aortic valve.

25. Left ventricular ejection fraction (LVEF) < 50%.

26. Impaired renal function defined as eGFR < 60 mL/min/1.73 m2, according to theCKD-EPI formula144.

27. Forced expiratory volume in one second (FEV1) < 70% predicted (no bronchodilator).

28. Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70%predicted.

29. Poorly controlled diabetes mellitus, defined as HbA1c > 8%.

30. History of malignancy, except adequately treated localized basal cell or squamousskin cancer, or carcinoma in situ of the cervix. Malignancies for which theparticipant is judged to be cured will be considered on an individual basis by thestudy adjudication committee (see Section 3.5).

31. Presence or history of any moderate to severe rheumatologic autoimmune diseaserequiring treatment, including but not limited to the following: systemic lupuserythematous, systemic sclerosis, rheumatoid arthritis, Sjogren's syndrome,polymyositis, dermatomyositis, mixed connective tissue disease, polymyalgiarheumatica, polychondritis, sarcoidosis, vasculitis syndromes, or unspecifiedcollagen vascular disease.

32. Presence of active peptic ulcer disease, defined as endoscopic or radiologicdiagnosis of gastric or duodenal ulcer.

33. Prior history of AHSCT.

34. Prior history of solid organ transplantation.

35. Positive pregnancy test or breastfeeding.

36. Failure to willingly accept or comprehend irreversible sterility as a side effect oftherapy.

37. Psychiatric illness, mental deficiency, or cognitive dysfunction severe enough tointerfere with compliance or informed consent.

38. History of hypersensitivity to rabbit or Escherichia coli-derived proteins.

39. Any metallic material or electronic device in the body, or other condition thatprecludes the participant from undergoing MRI with gadolinium administration, asdetermined by the site radiologist.

40. Presence or history of ischemic cerebrovascular disorders, including but not limitedto transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis, cerebralembolism, or cerebral hemorrhage.

41. Presence or history of other neurological disorders, including but not limited toCNS or spinal cord tumor; metabolic or infectious cause of myelopathy;genetically-inherited progressive CNS disorder; CNS sarcoidosis; or systemicautoimmune disorders potentially causing progressive neurologic disease or affectingability to perform the study assessments.

42. Presence of any medical comorbidity that the investigator determines willsignificantly increase the risk of treatment mortality.

43. Presence of any other concomitant medical condition that the investigator deemsincompatible with trial participation.