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

Inclusion criteria

• Signed informed consent form
• 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)
• Ability to comply with the study protocol
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
• 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
• 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
• 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
• 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
• 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
• 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

Exclusion criteria

• History of anaphylaxis or hypersensitivity to a biologic agent
• Active infection requiring systemic antiviral, antibiotics or antifungal
• Planned surgery during the study
• Pregnant or breastfeeding, or intending to become pregnant
• Any serious medical condition or abnormality in clinical laboratory tests that precludes the patient's safe participation in and completion of the study
• Clinically significant ECG abnormalities
• Illicit drug or alcohol abuse
• Clinical diagnosis of autoimmune diseases other than the target disease (except for Sjögren's syndrome in DM and IMNM)
• Positive for hepatitis B surface antigen
• Positive for hepatitis C virus antibody
• Positive for human immunodeficiency virus antibody
• Evidence of current infection with tuberculosis
• History of cancer within 5 years
• Treatment with investigational therapy within 28 days or 5 half-lives
• Previous and current treatment with anti-C1s antibody at any time
• Other complement inhibitors within 3 months
• Patients who receive any treatments which fall into the Prohibited Therapy Criteria
• Patients with an elevated alanine aminotransferase or aspartate aminotransferase \> 1.5 × ULN in combination with an elevated total bilirubin \> 1.5 × ULN
• 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
• 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
• 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
• 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
• 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
• 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