Ublituximab in Autoantibody Positive Immune Mediated Necrotizing Myopathy

Inclusion Criteria:

1. Participant must be able to understand and provide informed consent.

2. Age 18 years or older at disease onset.

3. Definite or probable IIM per the 2017 EULAR/ACR classification criteria.

4. Diagnosis of IMNM, meeting the 2016 ENMC classification criteria and having eitherof the following antibodies:

5. Anti-SRP

6. Anti-HMGCR

7. Early disease as defined as onset of objective muscle weakness assessed by aphysician and/or CK elevation attributed to IMNM within 1 year of the time ofinformed consent.

8. Muscle weakness as assessed by an MMT-8 score < 142 of 150 and CK > 1.5x ULN alongwith abnormality in at least 1 of the following 4 CSMs at screening:

9. PhGA ≥ 2 cm

10. PtGA ≥ 2 cm

11. Extramuscular global assessment ≥ 2 cm

12. HAQ-DI ≥ 0.25

13. Treatment with only one of the following background immunosuppressant medicationsfor IMNM for at least 12 weeks prior to randomization and the same dose for at least 4 weeks prior to randomization:

14. Methotrexate up to 25 mg weekly

15. Mycophenolate mofetil up to 3000 mg daily

16. Mycophenolic acid up to 2160 mg daily

17. Azathioprine up to 2.5 mg/kg daily

18. Tacrolimus up to 0.2 mg/kg daily

19. Cyclosporine up to 5 mg/kg daily

20. Current therapy consisting of glucocorticoid ≤ 20 mg/day of prednisone. The dosemust be stable for at least 4 weeks prior to randomization. Participants who stoppedtreatment with glucocorticoids are eligible if the last dose of the glucocorticoidswas at least 4 weeks before the time of informed consent.

21. Female participants of childbearing potential and male participants with a partnerof childbearing potential must agree to consistently and correctly use FDA approvedhighly effective methods of birth control, as shown in Appendix 1: AcceptableContraception Methods for Females of Reproductive Potential, for the entire durationof the study and 6 months after last study drug infusion. Female participants ofreproductive potential must have a negative pregnancy test at screening and atbaseline.

Exclusion Criteria:

1. End-stage myositis with end-organ involvement that poses additional risk to theparticipant or confounds the assessment of the participant in the study. Conditionsinclude but are not limited to advanced symptomatic interstitial lung disease (e.g.,Forced Vital Capacity (FVC) <60% and/or requiring oxygen therapy) or severedysphagia.

2. Irreversible muscle involvement and/or severe atrophy that will pose additional riskto the participant or confound the assessment of the participant in the study. Thisincludes Muscle Damage VAS ≥ 3 cm at screening, documented history of severe atrophyof multiple muscle groups (based on MRI), and/or wheelchair bound.

3. Uncontrolled interstitial lung disease or any other uncontrolled IIM manifestationthat in the opinion of the investigator would be likely to require treatment withprohibited medication during the study.

4. Diagnosis of other inflammatory or noninflammatory myopathies, includingantibody-negative IMNM, inclusion body myositis, overlap myositis, metabolicmyopathies, muscular dystrophies or family history of muscular dystrophy, druginduced, cancer-associated myositis, or endocrine-based myositis (except statininduced anti-HMGCR associated IMNM).

5. Severe liver disease, such as signs of ascites or hepatic encephalopathy.

6. History of malignancy (excluding non-melanoma skin cancer) unless cured by adequatetreatment, with no evidence of recurrence for ≥ 5 years from the time of informedconsent.

7. Recent or ongoing bacterial, viral, or fungal infection requiring systemic treatmentwithin 14 days of the time of informed consent.

8. Current suppressive therapy for any chronic infections including herpes simplexvirus (HSV).

9. Infection with Mycobacterium tuberculosis (TB) as defined by any of the following:

10. Positive interferon gamma release assay (IGRA) performed at screening or within 12 weeks prior to the time of informed consent.

11. Indeterminate IGRAs must be repeated (with same or other IGRA per local policy)and shown to be negative. Alternatively, if the assay remains indeterminant, aparticipant must have a negative purified protein derivative (PPD) skin test.Finally, if the participant has had the Bacille Calmette-Guerin (BCG) vaccineor has some other condition complicating the interpretation of TB testing,consultation with infectious disease specialist must be obtained beforerandomization.

12. Medical history or serologic evidence at screening of chronic infections, including: a. Human immunodeficiency virus (HIV) infection b. Hepatitis B virus (HBV) asindicated by surface antigen or hepatitis B core antibody positivity c. Hepatitis Cvirus (HCV) as indicated by anti-hepatitis C antibody positivity. If a participantis Hepatitis C antibody positive, they will be eligible to participate in the studyif they have a negative viral load at Screening.

13. Known hypersensitivity reaction to ublituximab.

14. Received a live or live-attenuated vaccine < 4 weeks before the time of informedconsent. Received any other type of vaccine < 2 weeks before the time of informedconsent.

15. Any of the following laboratory tests at screening: a. Hemoglobin < 10 g/dL b. Absolute white blood cell count < 3,000 cells/mm3 c.Platelet count < 100,000 cells/mm3 d. Absolute neutrophils < 1,500 cell/mm3 e.Peripheral B-cell < 40 cells/µL f. IgG < 690 mg/dL g. Estimated GFR < 50 mL/min/1.73m2

16. Treatment with any immunosuppressive or immunomodulatory agent, such ascyclophosphamide, biologics, and Janus kinase (JAK) inhibitors, except those listedin the inclusion criteria 7 within 12 weeks prior to randomization.

17. Prior receipt of B-cell depleting agents such as rituximab, ocrelizumab, ofatumumab,or belimumab at any time.

18. Treatment of IMNM with IVIG or subcutaneous immunoglobulin (SCIG) within 12 weeks ofrandomization, or prior receipt of more than one cycle of IVIG at any time.

19. Participant has current or history (within 12 months of screening) of alcohol, drug,or medication abuse.

20. Participant is pregnant or lactating or intends to become pregnant during the study.

21. Use of any investigational drug within 24 weeks of the time of informed consent.

22. Past or current medical problems or findings from physical examination or laboratorytesting that are not listed above, which, in the opinion of the investigator, maypose additional risks from participation in the study, may interfere with theparticipant's ability to comply with study requirements, or that may impact thequality or interpretation of the data obtained from the study.