Phase 1b Trial of RAY121 in Immunological Diseases (RAINBOW Trial)

Eligibility Criteria

• 1. Signed informed consent form
• 2. Age \>= 18 and \<=75 at the time of signing informed consent form (except for BP; Age \>=18 and \<= 85 with Karnofsky score \>= 60% at screening)
• 3. Ability to comply with the study protocol
• 4. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods
• 5. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
• 6. APS cohort: Established primary APS defined by the following criteria (at least one of the laboratory criteria and one of the clinical criteria must be met):
• * Laboratory criteria (aPL profile)
• * Persistently positive lupus anticoagulant (LA) test
• * Persistently positive anticardiolipin (aCL) immunoglobulin G (IgG) isotype
• * Persistently positive anti-beta-2 glycoprotein-1 (aβ2GPI) IgG isotype
• * Clinical criteria
• * Livedoid vasculopathy and presence of skin ulcer
• * Acute/chronic aPL nephropathy
• 7. BP cohort:
• * 1) Age \>= 18 and \<= 85 with Karnofsky score \>= 60 %
• * 2) Predominant cutaneous lesions
• * 3) Diagnosis with BP with following assessments positive:
• * a Positive direct immunofluorescence, and either
• * b Positive indirect immunofluorescence, or
• * c Positive serology on ELISA for BP180 autoantibody
• * 4) Bullous Pemphigoid Disease Area Index (BPDAI) score \>= 20
• * 5) Weekly average of daily Peak Pruritus Numerical Rating Score (PP-NRS) \>=4
• * 6) Accept to take photograph of bullous lesions
• 8. BS cohort:
• * 1) Diagnosed with BS
• * 2) Oral ulcers that occurred at least 3 times in the previous 12 month period
• * 3) Have at least 2 oral ulcers over the 4 weeks prior to screening
• * 4) Have at least 2 oral ulcers at Week 0
• * 5) Have prior treatment with at least 1 non-biologic BS therapy
• * 6) Patients who need systemic therapy as whose oral or mucocutaneous ulcers cannot be adequately controlled by topical therapy
• 9. DM cohort:
• * 1) Diagnosed with definite or probable inflammatory myopathies and categorized as DM
• * 2) Patients with inadequate response to corticosteroids and/or immune-suppressants or intolerance to DM therapies
• * 3) Manual Muscle Test-8 (MMT-8) score \< 142, with at least one abnormality in the following Core Set Measures:
• * Patient Global Activity Visual Analogue Scale (PtGA-VAS) \>= 2 cm
• * Physician Global Activity Visual Analogue Scale (PhGA-VAS) \>= 2 cm
• * Global extra-muscular activity \>= 2 cm
• * At least one muscle enzyme \> 1.5 times upper limit of normal (ULN)
• * Health Assessment Questionnaire (HAQ) \>= 0.25
• * 4) Moderate to severe DM defined as CDASI activity score \> 14
• 10. IMNM cohort:
• * 1) Clinically Diagnosed with IMNM as anti-HMGCR myopathy or anti-SRP myopathy
• * 2) Creatine kinase (CK) \> 1,000 U/L
• * 3) Patients who have an inadequate response to corticosteroids and/or immunosuppressants or intolerance to IMNM therapies
• * 4) MMT-8 score \< 142
• 11. ITP cohort:
• * 1) Confirmed diagnosis of persistent/chronic ITP based on the following criteria:
• * ITP defined per the current guidelines
• * Platelet count \<= 30 × 10\^9/L on 2 consecutive occasions
• * 2) Lack of an sustained adequate platelet count response to a thrombopoietin receptor agonist and at least one other ITP treatment or a second thrombopoietin receptor agonist (TPO-RA)
• * 3) A history of response with an platelet counts increase more than 20 × 10\^9/L from baseline by at least one prior line of therapy
• 1. History of anaphylaxis or hypersensitivity to a biologic agent
• 2. Active infection requiring systemic antiviral, antibiotics or antifungal
• 3. Planned surgery during the study
• 4. Pregnant or breastfeeding, or intending to become pregnant
• 5. Any serious medical condition or abnormality in clinical laboratory tests that precludes the patient's safe participation in and completion of the study
• 6. Clinically significant ECG abnormalities
• 7. Illicit drug or alcohol abuse
• 8. Clinical diagnosis of autoimmune diseases other than the target disease (except for Sjögren's syndrome in DM and IMNM)
• 9. Positive for hepatitis B surface antigen
• 10. Positive for hepatitis C virus antibody
• 11. Positive for human immunodeficiency virus antibody
• 12. Evidence of current infection with tuberculosis
• 13. History of cancer within 5 years
• 14. Treatment with investigational therapy within 28 days or 5 half-lives
• 15. Previous and current treatment with anti-C1s antibody at any time
• 16. Other complement inhibitors within 3 months
• 17. Patients who receive any treatments which fall into the Prohibited Therapy Criteria
• 18. Patients with an elevated alanine aminotransferase or aspartate aminotransferase \> 1.5 × ULN in combination with an elevated total bilirubin \> 1.5 × ULN
• 19. APS cohort:
• * 1) APS associated with other systemic autoimmune disease
• * 2) Acute thrombosis (arterial or venous acute thrombosis diagnosis) within 30 days before screening
• * 3) Patients with thrombotic APS without any anticoagulation treatment
• * 4) Treatment with prohibited medications
• 20. BP cohort:
• * 1) Initiation of treatment with or increase in the dose of systemic or topical corticosteroid within 2 weeks
• * 2) Current treatment with a drug that may cause or exacerbate BP unless the dose has been stable
• * 3) Initiation of treatment with topical calcineurin inhibitor, or topical phosphodiesterase (PDE) 4 inhibitor within 7 days
• * 4) Treatment with prohibited medications
• 21. BS cohort:
• * 1) BS-related active major organ involvement-ocular lesions requiring immunosuppressive therapy, pulmonary (e.g., pulmonary artery aneurysm), vascular (e.g., thrombophlebitis), gastrointestinal (e.g., ulcers along the gastrointestinal tract), and central nervous systems (e.g., meningoencephalitis) manifestations
• * 2) History of venous or arterial thrombosis within 1 year
• * 3) Treatment with prohibited medications
• 22. DM cohort:
• * 1) PhGA-VAS improvement \>= 3, or clinically relevant improvement between screening and baseline
• * 2) Overlap myositis (except for overlap with Sjögren's syndrome), connective tissue disease associated DM, inclusion body myositis, polymyositis, IMNM, juvenile DM or drug-induced myopathy
• * 3) Cancer-associated myositis
• * 4) Significant muscle damage
• * 5) Past history of severe Interstitial lung disease flare, severe non-infectious lung inflammation which required active intervention, or multiple episodes of lung disease
• * 6) Severe respiratory muscle weakness
• * 7) Severe bulbar palsy
• * 8) Treatment with prohibited medications
• 23. IMNM cohort:
• * 1) PhGA-VAS improvement \>= 3, or clinically relevant improvement between screening and baseline
• * 2) Overlap myositis (except for overlap with Sjögren's syndrome), connective tissue disease associated DM, inclusion body myositis, polymyositis, juvenile DM or druginduced myopathy
• * 3) Cancer-associated myositis
• * 4) Significant muscle damage
• * 5) Past history of severe Interstitial lung disease (ILD) flare, severe non-infectious lung inflammation which required active intervention, or multiple episodes of lung disease
• * 6) Severe respiratory muscle weakness
• * 7) Severe bulbar palsy
• * 8) Treatment with prohibited medications
• 24. ITP cohort:
• * 1) Secondary ITP
• * 2) Clinical diagnosis or history of Myelodysplastic Syndrome or autoimmune hemolytic anemia
• * 3) History of venous or arterial thrombosis within 12 months
• * 4) Patients who experienced major bleeding within 4 weeks
• * 5) Treatment with prohibited medications
• * 6) Any laboratory test results meet either of the following criteria at screening:
• * Hemoglobin \<10 g/dL
• * Thyroid-stimulating hormone \>= 10 μIU/mL