Overview

The purpose of this study is to measure the safety, tolerability, PK, and PD of AZD5492 administered subcutaneously in adult participants with SLE or IIM.

Study details include:

• The study duration will be a minimum of 180 days in addition to the screening period.

Additional follow-up visits may be required up to 12 months from study start.

• Depending on the study part they are assigned to, participants will be administered AZD5492 once (Part 1) or twice (Part 2).
• Study visits will occur at:

Screening, Days 1-4, 8, 15, 22, 30, 60, 90, 120, 150, and 180 in Part 1, Screening, Days 1-4, 8-11, 15, 22, 29, 43, 60, 90, 120, 150, and 180 in Part 2.

Eligibility

Inclusion Criteria:

1. Participant must be 18 to 70 years of age inclusive, at the time of signing the informed consent.
2. Diagnosis of SLE:
   1. Diagnosis of SLE according to the 2019 EULAR/ACR classification criteria for SLE
   2. Positive for one or more of: anti-nuclear antibodies (titre ≥ 1:80), anti-dsDNA or anti-Sm at screening.
   3. Active, moderate-severe disease at screening, defined as clinical SLEDAI-2K ≥ 4.
   4. Intolerance or inadequate response to ≥ 3 available SOC treatments, used for at least 3 months each, for which at least one must be a biologic SoC or cyclophosphamide.
3. Diagnosis of IIM:
   1. Must have "probable" or "definite" diagnosis of PM or DM (excluding IBM and cancer associated myositis) according to the 2017 EULAR/ACR classification criteria for adult myositis.
   2. Positive for ≥ 1 disease-specific autoantibody at screening.
   3. MMT-8 score of ≤ 142/150 and/or CDASI-A > 6
   4. Fulfill at least one of the following criteria of active disease at screening:

     (i) One or more muscle enzyme elevation (CK, AST, ALT, aldolase, LDH) ≥ 1.3 × ULN
     (ii) If criterion 3(d)(i) is not met, then at least one of the following criteria
     must be met:
       1. Report from MRI performed within 3 months prior to screening with evidence of
          muscle inflammation
       2. Report from muscle biopsy performed within 3 months prior to screening that
          demonstrates active inflammation
       3. Report from electromyography performed within 3 months prior to screening that
          exhibits irritable myopathic pattern.
     (e) Intolerance or inadequate response to corticosteroids and ≥2 other SoC
     treatments, used for at least 3 months each, for which at least one must be a
     biologic SoC, immunoglobulin or cyclophosphamide.

4. For participants receiving any of the following therapies at screening:

1. Oral prednisone (or equivalent): Daily dose ≤ 20 mg/day and must be stable for ≥ 1 week prior to Day 1.
2. Immunosuppressive treatment: for ≥ 3 months prior to Day 1 and at a stable dose for ≥ 4 weeks prior to Day 1.

Exclusion Criteria:

1. Any complications of the disease under study which are judged by the investigator to be life or organ threatening or to require treatments which are not permitted in the protocol, including but not limited to:
   1. Active severe SLE-driven renal disease.
   2. History of, or current diagnosis of, catastrophic or severe APS (for example diagnosis of an arterial or central/pulmonary venous clot) within 1 year prior to signing the ICF.
   3. Rapidly progressive and/or severe ILD or ILD that requires oxygen supplementation/therapy (of any type).
   4. Inclusion Body Myositis or cancer associated myositis.
2. Active severe, unstable or history of neuropsychiatric SLE
3. IIM: Pulmonary function tests at screening (or within one month of screening, provided participant confirms no change in respiratory symptoms in the interim) which meet any of the following criteria:
   1. FVC ≤60% of predicted
   2. DLCO ≤70% of predicted
   3. Deterioration in either FVC or DLCO at screening compared to pulmonary function tests performed ≥3 months previously.
4. Significant history of or at risk of severe infections.
5. Participants with HIV infection
6. Participants with active EBV or CMV.
7. Participants with evidence of chronic or active hepatitis B defined as HBsAg positive or HBcAB positive
8. Participants with evidence of chronic or active hepatitis C
9. Participants with positive COVID-19 PCR.
10. Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection.
11. Significant CNS pathology.
12. Receipt of B-cell-depleting therapy including CD19 or CD20 directed monoclonal antibodies (including but not limited to, ocrelizumab, ofatumumab, obinutuzumab, or rituximab) <3 months prior to Day 1.