Clinical Study of EVM18001 in the Treatment of Refractory Autoimmune Diseases

The main questions it aims to answer are:

• If EVM18001 is safe and tolerate in patients with active refractory autoimmune diseases (SLE, MG, and SSc)?
• What the recommended dose for subsequent treatment?
• What the PK/PD profiles of EVM18001 in patients with active refractory autoimmune diseases (SLE, MG, and SSc)?
• What the efficacy of EVM18001 in patients with active refractory autoimmune diseases (SLE, MG, and SSc)#
• What the biomarkers and immunogenicity of EVM18001 in treating of patients with active refractory autoimmune diseases (SLE, MG, and SSc)?

Participants will:

• Inform the investigator in a timely manner when unable to attend a visit.
• Report any changes in their health condition to the study doctor, including discomfort or other health issues during the screening period.
• Inform the study doctor of any other medications taken before and during the study; inform the study doctor before starting any new medications.
• Be informed of any medications which may be affected by the study drug that should not be used during the study.
• Agree to use effective contraception during the study and for 12 months after the last infusion of EVM18001EVM injection.

Inclusion criteria

• Voluntarily sign the Informed Consent Form (ICF), which must be signed by the participant or their legal guardian.
• At the time of signing the ICF, the age must be between 18 and 70 years (inclusive), regardless of gender.
• At screening, peripheral blood B cells must be CD19 positive, and T cells must express CD7.
• Confirmed autoimmune diseases based on recognized diagnostic criteria, including:

• SLE: Diagnosed with SLE according to the 2012 Systemic Lupus International Collaborating Clinics (SLICC) or 2019 European League Against Rheumatism (EULAR)/ACR criteria;
• MG: Diagnosed with MG according to the Myasthenia Gravis Foundation of America (MGFA) clinical classification;
• SSc: Diagnosed with SSc according to the 2013 ACR/EULAR classification criteria.
• History of autoimmune disease for at least 6 months before screening and meets any of the following criteria. Definitions of active refractory SLE, active refractory SSc, and active refractory MG are as follows:

• Definition of active refractory SLE: SLEDAI-2000 score ≥6; and disease activity or relapse persists after at least 3 months of standard therapy (glucocorticoids combined with at least 2 immunosuppressants, or at least 1 imunosuppressant and 1 targeted therapy).
• Definition of active refractory SSc: Patients meeting the 2013 ACR/EULAR classification criteria for SSc who still show disease activity or progression after at least 6 months of standard therapy (including steroids, immunosuppressants, vasodilators, or antifibrotic agents). Specific criteria include but are not limited to: mRSS increase ≥5 points or ≥25% from baseline; absolute value of predicted FVC% decrease ≥5%; DLCO% corrected for hemoglobin absolute value decrease ≥10%; new or worsening digital ulcers after ≥3 months of vasodilator therapy; persistent or recurrent organ involvement requiring intensified treatment.
• Definition of active refractory MG: Refers to generalized MG patients meeting MGFA diagnostic criteria with ongoing disease activity (MGFA II-IV, QMG ≥12, or MG-ADL ≥6), and includes at least one of the following: poor control after at least 12 months of standard therapy (including at least 2 immunosuppressants); need for ≥2 intravenous immunoglobulin (IVIG) or plasma exchange treatments in the past 12 months to control symptoms; relapse with prednisone ≥20 mg/day or reduction to <10 mg/day; persistent or recurrent disease activity.
• Patients must meet the following conditions for concomitant medication:

• Corticosteroids must have been used for more than 6 weeks prior to screening and at a stable dose of ≤ 10 mg/day prednisone or equivalent for at least 14 days prior to administration of EVM18001. Concurrent treatment with topical or inhaled corticosteroids (or other immunomodulators) is allowed;
• Continued use during treatment is allowed if antimalarial drugs (eg, hydroxychloroquine, chloroquine, etc.) are started ≥ 12 weeks prior to screening and maintained at a stable dose for ≥ 8 weeks (maximum dose limit: hydroxychloroquine, 400 mg/day; chloroquine, 500 mg/day).
• Examination at screening meet any of the following criteria:

• SLE: positive for blood ANA, and/or positive for anti-dsDNA, anti-Smith antibodies;
• MG: Positive serology for anti-AChR antibodies or anti-musclespecific tyrosine kinase receptor (MuSK) antibodies.
• Life expectancy greater than 6 months.
• Bone marrow reserve and organ function are normal:

• Bone marrow function: defined as absolute neutrophil count (ANC) ≥ 1.0×109/L, absolute lymphocyte count (ALC) ≥0.5×109/L, hemoglobin (Hb) ≥80g/L, platelet count (PLT) ≥50×109/L. Blood transfusions and growth factors must not be used to meet these requirements within 7 days prior to screening for eligibility.
• Coagulation function: defined as international normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤ 1.5× upper limit of normal (ULN).
• Cardiac function: defined as left ventricular ejection fraction (LVEF) ≥ 45% as assessed by echocardiography (ECHO).
• Pulmonary function: defined as Common Terminology Criteria ≤for Adverse Events (CTCAE) Grade 1 dyspnea and oxygen saturation (SpO2) ≥ 92% (pulse oximetry) on room air.
• Hepatic function: defined as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5× ULN, total bilirubin < 2.0mg/dL (total bilirubin of Gilbert syndrome trial participants <3.0mg/dL).
• Renal function: defined as calculated creatinine clearance (Cockcroft-Gault) ≥ 50 mL/min without hydration assistance.
• Female trial participants of childbearing potential:

• Negative serum β human chorionic gonadotropin (β-hCG) test at screening;
• Agree to use a highly effective method of contraception for the duration of study participation and for 12 months after EVM18001 last infusion.
• Male trial participant whose partner is of childbearing potential who agrees to use a highly effective method of contraception during the study and 12 months after the last infusion of the EVM18001.

Exclusion criteria

• Concurrent autoimmune diseases requiring systemic treatment.
• The autoimmune disease meets the following criteria:

• SLE: patients with renal crisis;
• MG: MGFA clinical classification type V or experiencing myasthenic crisis;
• SSc: involving lungs and exist severe ILD and severe PAH, or patients with scleroderma renal crisis.
• Any of the following conditions exist:

• Positive for Hepatitis B surface antigen (HBsAg)/core antibody (HBcAb)/e-antibody (HBeAb)/e antigen (HBeAg);
• Positive for Hepatitis C virus (HCV) antibody;
• Positive for human immunodeficiency virus (HIV) antibody;
• Positive CMV DNA or above the upper limit of detection;
• Positive for syphilis antigen or antibody.
• Other uncontrolled active infections exist at screening.
• Creatinine clearance <50 mL/min.
• Estimated glomerular filtration rate <45 mL/min/1.73m² (calculated using the MDRD creatinine equation from the Chronic Kidney Disease Epidemiology Collaboration; or serum creatinine >2.0 mg/dL.
• History of major organ transplantation (such as heart, lung, liver, kidney) or bone marrow/hematopoietic stem cell transplantation.
• History within 6 months before screening of any of the following cardiovascular diseases: NYHA class III or IV heart failure, myocardial infarction, unstable angina, uncontrolled or symptomatic atrial arrhythmia, any ventricular arrhythmia, or other clinically significant heart disease.
• History of ≥grade 2 bleeding within 4 weeks before screening, or requiring long-term continuous anticoagulant therapy (such as warfarin, low molecular weight heparin, or factor Xa inhibitors, etc.).
• History within the past 24 weeks/6 months of severe active central nervous system disease or pathology, including but not limited to: cerebrovascular accident, aneurysm, epilepsy, convulsions/seizures, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychiatric disorders. Stable patients will be assessed by the investigator for eligibility.
• Diagnosed with malignant tumors within the past 5 years. The following are excluded: non-melanoma skin cancer treated with radical therapy, localized prostate cancer, biopsy-confirmed cervical carcinoma in situ or squamous intraepithelial lesions detected by cervical smear, and completely resected breast carcinoma in situ.
• History of live vaccine administration within the past 4 weeks.
• Have received any of the following treatments:

• Preventive therapy with short-acting oral antiretroviral drugs within 7 days before first administration, or preventive therapy with longacting antiretroviral drugs within 2 years before first administration;
• Plasma exchange, plasmapheresis, or hemodialysis within 14 days before screening;
• Any other clinical study drug within 4 weeks before screening. However, if the study treatment was ineffective or the disease progressed, and at least 3 half-lives had passed before screening, enrollment is allowed;
• History of bone marrow transplantation, gene therapy, adoptive cell therapy, or any type of CAR-T cell therapy;
• Previously received any mRNA-LNP product or other LNP-based drugs.
• Unable to complete washout of previous treatment drugs as required within 4 weeks before first administration, or unable to maintain stable doses of concomitant medications for autoimmune diseases.
• Pregnant or breastfeeding women.
• Allergic to supportive medications required for managing CAR-T cell therapy toxicities (e.g., tocilizumab).
• Other situations where the investigator judges that the trial participant has poor compliance or is unwilling or unable to adhere to the study protocol.