Clinical Study of EVM18001 in the Treatment of Refractory Autoimmune Diseases

Exploratory Clinical Study of EVM18001 Injection in the Treatment of Active Refractory Systemic Lupus Erythematosus, Myasthenia Gravis and Scleroderma

A FIH, single arm, open-label, Investigator Initiated Trial (IIT) study to evaluate the safety and tolerability of EVM18001 in the treatment of active refractory autoimmune diseases (SLE, MG, and SSc), and determine the recommended dose for subsequent treatment. At the same time, the PK/PD characteristics of EVM18001 will be evaluated, preliminary efficacy will be observed, and related biomarkers and immunogenicity will be explored.

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:

1. Voluntarily sign the Informed Consent Form (ICF), which must be signed by the participant or their legal guardian.

2. At the time of signing the ICF, the age must be between 18 and 70 years (inclusive), regardless of gender.

3. At screening, peripheral blood B cells must be CD19 positive, and T cells must express CD7.

4. 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.

5. 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.

6. Patients must meet the following conditions for concomitant medication:

   1. 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;
   2. 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).

7. 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.

8. Life expectancy greater than 6 months.

9. 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.

10. 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.

11. 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:

1. Concurrent autoimmune diseases requiring systemic treatment.

2. 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.

3. 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.

4. Other uncontrolled active infections exist at screening.

5. Creatinine clearance <50 mL/min.

6. 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.

7. History of major organ transplantation (such as heart, lung, liver, kidney) or bone marrow/hematopoietic stem cell transplantation.

8. 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.

9. 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.).

10. 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.

11. 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.

12. History of live vaccine administration within the past 4 weeks.

13. 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.

14. 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.

15. Pregnant or breastfeeding women.

16. Allergic to supportive medications required for managing CAR-T cell therapy toxicities (e.g., tocilizumab).

17. Other situations where the investigator judges that the trial participant has poor compliance or is unwilling or unable to adhere to the study protocol.