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

• Signed informed consent form
• Age ≥ 18 and ≤ 85 at the time of signing informed consent form 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 LA test
• Persistently positive aCL IgG isotype
• Persistently positive aβ2GPI IgG isotype
• Clinical criteria

• Livedoid vasculopathy and presence of skin ulcer
• Acute/chronic aPL nephropathy
• BP cohort:

• Predominant cutaneous lesions 2) Diagnosis with BP with following assessments positive:

• Positive direct immunofluorescence, and either
• Positive indirect immunofluorescence, or
• Positive serology on ELISA for BP180 autoantibody 3) BPDAI score >= 20 4) Weekly average of daily Peak Pruritus NRS >=4 5) Accept to take photograph of bullous lesions

• BS cohort:
• Diagnosed with BS
• Oral ulcers that occurred at least 3 times in the previous 12 month period
• Have at least 2 oral ulcers over the 4 weeks prior to screening
• Have at least 2 oral ulcers at Week 0
• Have prior treatment with at least 1 non-biologic BS therapy
• Patients who need systemic therapy as whose oral or mucocutaneous ulcers cannot be adequately controlled by topical therapy

• DM cohort:
• Diagnosed with definite or probable inflammatory myopathies and categorized as DM
• Patients with inadequate response to corticosteroids and/or immune-suppressants or intolerance to DM therapies
• MMT-8 score < 142, with at least one abnormality in the following Core Set Measures:

• PtGA-VAS >= 2 cm
• PhGA-VAS >= 2 cm
• Global extra-muscular activity >= 2 cm
• At least one muscle enzyme > 1.5 times ULN
• HAQ >= 0.25
• Moderate to severe DM defined as CDASI activity score > 14

• IMNM cohort:
• Clinically Diagnosed with IMNM as anti-HMGCR myopathy or anti-SRP myopathy
• CK > 1,000 U/L
• Patients who have an inadequate response to corticosteroids and/or immunesuppressants or intolerance to IMNM therapies
• MMT-8 score < 142

• ITP cohort:
• 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
• Lack of an sustained adequate platelet count response to a thrombopoietin receptor agonist and at least one other ITP treatment or a second TPO-RA
• 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
• 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
• 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
• 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
• 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