Safety and Preliminary Clinical Activity of Itolizumab in Dermatomyositis

A Phase 1 Study to Evaluate the Safety, Tolerability and Preliminary Clinical Activity of Itolizumab in Subjects With Dermatomyositis

To evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of Itolizumab in subjects with Dermatomyositis.

The study will enroll approximately 44 subjects in two parts:

Part 1 is an open label, 3+3 single dose escalation and then mutiple dose administration phase. 9~30 patients with DM are expected to be enrolled across 3 dose cohorts.

Part 2 is a randomized phase and will enroll approximately 14 additional subjects, randomized in a 1:1 ratio to one of the 2 doses based on efficacy data obtained from Part 1. All participants in this study will receive Itolizumab intravenously every two weeks for a total of 7 doses.

Inclusion Criteria:

1. Male or female subject aged 18-75 years old (inclusive).
2. Fulfill one of the following criteria for DM:1) Bohan and Peter criteria for definite or probable DM;2) ENMC 2018 Dermatomyositis Classification Criteria
3. Disease activity fulfills at least three of the following criteria:1) MMT-8 score < 142; 2) physician's global disease activity ≥2 cm; 3) patient's global activity ≥2 cm; 4) extra-muscular activity ≥2 cm; 5) Health Assessment Questionnaire [HAQ] ≥0.25; 6) at least one muscle enzyme >1.5 times ULN
4. Under treatment with corticosteroids and/or at least 1 immunesuppressant, and being on stable therapy for at least 4 and 8 weeks for corticosteroids and immunesuppressant respectively (see Section 5.7.1)
5. Fulfill all of the following criteria: 1) % predicted values of FVC≥70%; 2) % predicted values of DLCO≥60%; 3) chest HRCT indicating the extent of disease lesion of DM-ILD < 20% as determined by the investigator
6. Negative result of serum HCG within 72 hours before enrollment for female with potential fertility
7. Able to understand and comply with the planned procedure as required by the protocol, and sign a written informed consent form (ICF)

Exclusion Criteria:

1. Subject with other connective tissue diseases (e.g., systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, Sjogren's syndrome, mixed connective tissue disease, etc.) or ANCA associated vasculitis.

2. Diagnosed with polymyositis or IMNM.

3. Diagnosed with systemic, severe musculoskeletal disorder that unrelated to DM and will interfere with the investigator's assessment of the subject's muscle strength.

4. Subject who plans to start a physical therapy program during the trial.

5. Subject who has a medical history of New York Heart Association class III or IV congestive heart failure, clinically significant or uncontrolled unstable angina or myocardial infarction, cerebrovascular accident, or pulmonary embolism within 6 months prior to screening

6. Subject with impaired renal function (serum creatinine > 1.5 x ULN or creatinine clearance < 30 mL/min [Cockcroft-Gault formula]) at screening.

7. Any of following significant abnormalities in liver function at screening:

   1. Serum alanine transaminase (ALT) or glutathione transaminase (AST) ≥ 3 x ULN, except when judged by the investigator to be due to DM;
   2. Total bilirubin ≥ 1.5 x ULN;
   3. Cirrhosis classification of Child-Pugh grade C.

8. Any of the following abnormalities at screening:

   1. Hepatitis B-related tests: ① positive hepatitis B surface antigen (HBsAg); ② positive hepatitis B core antibody (HBcAb); ③ positive hepatitis B surface antibody (HBsAb) and no history of hepatitis B vaccination; ④ positive hepatitis B e antigen or hepatitis B e antibody;
   2. Positive hepatitis C virus nucleic acid test (HCV-RNA);
   3. Positive acquired immunodeficiency syndrome antibody (HIV-Ab);
   4. Positive anti-syphilis spiral antibody (TP-Ab);
   5. Other acute or chronic infections requiring treatment.

9. Absolute lymphocyte count < 0.5×109/L at screening

10. Subject who has a medical history of tuberculosis or those who deny a history of tuberculosis but has a positive gamma-interferon release test at screening.

11. Any other clinically significant clinical condition or laboratory tests abnormality that, in the judgment of the investigator, may affect the safety evaluation

12. Any malignant tumor other than the cured carcinoma in situ or basal cell carcinoma within 5 years before screening

13. Suspected allergic to the investigational drug or any of its excipients

14. Subject who had participated in other clinical studies (other than those not receiving interventions, such as observational study or questionnaires survey) within 3 months prior to screening, or who are participating in other experimental treatments.

15. Subject who requires to be administrated with higher dose of corticosteroids and/or immunesuppressant than the allowed maximum dose specified in the protocol (section 5.7.1)

16. Subject who had been treated by one or more of the following drugs during the corresponding time window prior to screening:

    1. cyclophosphamide, rituximab within 12 months prior to screening;
    2. belizumab, tetrasip within 24 weeks prior to screening;
    3. intravenous immunoglobulin injections, baliximab, infliximab, adalimumab, tolimumab, JAK inhibitors within 12 weeks prior to screening;
    4. Other monoclonal antibodies or other biological agents within 12 weeks or 5 half-lives [whichever is longer] prior to screening.

17. Currently pregnant, breastfeeding,or planning to become pregnant or not using reliable method to avoid pregnancy during study and within 3 months after the last study treatment

18. As determined by the investigator, any medical, psychiatric, or other condition or circumstance that is likely to negatively affect the reliability of the study data.