Daratumumab in Primary Antiphospholipid Syndrome

Inclusion Criteria:

1. Adults 18 to 70 years of age, inclusive.

2. The completion of the following vaccinations at least 14 days prior to Visit 0:

3. At least one dose of the most recently updated COVID-19 vaccine, and

4. At least one dose of the herpes zoster vaccination series, and

5. Current seasonal influenza vaccine, if available.

6. History of APS according to the updated 2006 Sapporo classification criteria,including at least one of the following: a. Arterial thrombosis, except transient ischemic attack, confirmed by objectivevalidated criteria such as imaging, or b. Venous thrombosis, except superficialthrombophlebitis, confirmed by objective validated criteria such as imaging, or c.Pregnancy morbidity, based on the updated 2006 Sapporo APS classification criteria,or d. Microvascular APS, with at least one of the following: i. Renal biopsydocumentation of aPL-associated nephropathy, or ii. Lung biopsy or bronchoalveolarlavage documentation of diffuse alveolar hemorrhage (DAH), or iii. Skin biopsydocumentation of livedoid vasculopathy.

7. History of triple positive aPL within the prior 5 years and at least 12 weeks priorto enrollment, including all of the following:

8. aCL IgG level > Upper Limit of Normal (ULN), and

9. aβ2GPI IgG level > ULN, and

10. Positive LA test.

11. Confirmation of triple positive aPL at screening, including all of the following:

12. aCL IgG level ≥ 40 GPL, and

13. aβ2GPI IgG level ≥ 40 SGU, and

14. Positive LA test.

15. Undergoing anticoagulation with warfarin or low molecular weight heparin (LMWH), ifthere is a history of arterial or venous thrombosis.

Exclusion Criteria:

1. Inability or unwillingness to give written informed consent.

2. Inability or unwillingness to comply with study protocol.

3. Systemic autoimmune diseases other than APS, including but not limited to:

4. Systemic lupus erythematosus (SLE) meeting the EULAR/ACR classificationcriteria.

5. Rheumatoid arthritis meeting the ACR/EULAR classification criteria.

6. Small, medium, and large vessel vasculitis meeting ACR classification criteria.

7. Catastrophic APS classification within the prior 90 days.

8. Acute arterial or venous thrombosis within the prior 30 days.

9. Use of the following medications:

10. Any prior treatment with CD38 targeting monoclonal antibodies, includingdaratumumab or isatuximab-irfc.

11. Administration of the Janssen COVID-19 vaccine within the prior 14 days.

12. The following within the prior 30 days: i. Corticosteroids > 10 mg/day prednisone or equivalent. ii. Direct oralanticoagulants (DOACs). iii. Live attenuated vaccines. iv. IVIG or othersupplemental immunoglobulin. d. Azathioprine, methotrexate, mycophenolate mofetil,mycophenolate sodium, lefluonomide, or calcineurin inhibitors within the prior 90days. e. Cyclophosphamide within the prior 90 days. f. Immunomodulatory orimmunosuppressive biologic agents, including belimumab, within the prior 90 days or 5 half-lives, whichever is greater. g. Investigational agents within the prior 90 days or 5 half-lives, whichever isgreater, except for COVID-19 vaccines and medications for prevention or treatment ofCOVID-19 per FDA Emergency Use Authorization (EUA). h. Biologic B cell depleting agents including rituximab with any of the following:i. Treatment within the prior 180 days, or ii. CD19+ absolute count < 40/ μl, oriii. Serum IgG <500 mg/dL.

13. Plasma exchange within the prior 90 days.

14. Hemodialysis within the prior 90 days.

15. Major surgical procedure within the prior 60 days.

16. Known allergy, hypersensitivity, or intolerance to boron, malitol, sorbitol,corticosteroids, monoclonal antibodies including daratumumab, human proteins, ortheir excipients.

17. Allergy, intolerance, or contraindication to acyclovir, valacyclovir, andfamciclovir.

18. Active or chronic infection, including the following:

19. Active bacterial, viral, fungal, or opportunistic infection.

20. Chronic infection requiring suppressive antibiotic treatment.

21. Intravenous antibiotics or hospitalization for infection within the prior 30days.

22. Evidence of current or prior Mycobacterium tuberculosis infection.

23. Human immunodeficiency virus (HIV).

24. Current or prior infection with hepatitis B virus (HBV).

25. Current or prior infection with hepatitis C virus (HCV), except adequatelytreated HCV with sustained virologic response ≥ 12 weeks.

26. History of recurrent herpes zoster, or history of herpes zoster ophthalmicus,disseminated herpes zoster, or disseminated herpes simplex.

27. The following laboratory abnormalities: ITN093AI: DARE-APS Version 3.0 September 12, 2023 Daratumumab in PrimaryAntiphospholipid Syndrome

28. Absolute neutrophil count < 1500/mm3.

29. Platelets < 100,000/mm3.

30. Hemoglobin (Hgb) < 10 g/dL.

31. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkalinephosphatase > 2x the Upper Limit of Normal (ULN).

32. Total bilirubin > 2x ULN, except in the case of congenital bilirubinemia thendirect bilirubin > 2x ULN.

33. eGFR < 45 ml/min/1.73 m2.

34. History of primary immunodeficiency.

35. History of solid organ or hematopoietic stem cell transplantation.

36. Comorbidities requiring systemic corticosteroid therapy, including those which haverequired three or more courses of systemic corticosteroids within the 12 monthsprior to Visit 0.

37. Any of the following conditions with FEV1 < 70% predicted within the prior 90 days:

38. Asthma.

39. Chronic obstructive pulmonary disease (COPD).

40. DAH.

41. Pulmonary hypertension.

42. Adrenal insufficiency.

43. Poorly controlled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 8.0%.

44. Concomitant malignancy or history of malignancy, except adequately treated orexcised nonmetastatic squamous cell carcinoma, basal cell skin carcinoma, orcervical carcinoma in situ.

45. Clinically significant cardiac disease, including but not limited to:

46. Myocardial infarction within the prior 6 months, or

47. Unstable or uncontrolled disease or condition related to or affecting cardiacfunction, including but not limited to: i. Unstable angina, or ii. Congestive heart failure, New York Heart AssociationClass II-IV, or iii. Uncontrolled cardiac arrhythmia.

48. Current diagnosed mental illness or current diagnosed or self-reported drug oralcohol abuse which, in the opinion of the investigator, would interfere with theparticipant's ability to comply with study requirements.

49. Severe, progressive, or uncontrolled renal, hepatic, hematological,gastrointestinal, pulmonary, cardiac, or neurological disease.

50. 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 may impact the qualityor interpretation of the data obtained from the study.

51. Lack of peripheral venous access.

52. Pregnancy, or planning a pregnancy during the 48 week study duration.

53. Breast-feeding.

54. Unwillingness to use medically acceptable non-prothrombotic contraception if ofreproductive potential and engaging in sexual activity that could lead to pregnancy.