Clinical trial NCT06916806: A Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD5492 in Adult Participants With Systemic Lupus Erythematosus or Idiopathic Inflammatory Myopathies.
Official title: An Open-label, Phase I Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD5492 Following Single-ascending Dose and Step-up Dose Administration to Adult Participants With Systemic Lupus Erythematosus or Idiopathic Inflammatory Myopathies
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Systemic Lupus Erythematosus
Idiopathic Inflammatory Myopathies
Keywords: Lupus
Inflammatory Myopathy
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Muscular Diseases
Myositis
Dermatomyositis
Polymyositis
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Fortrea
First posted: 2025-04-08
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Open-Label, single-arm treatment study. The study consists of 2 parts:

Part 1 - Single ascending dose (SAD) Part 1 will be a sequential SAD design in adult participants with SLE. Up to 5 dose levels of AZD5492 are planned to be investigated. Depending on emerging data, up to 4 additional dose levels may be added at the discretion of the Sponsor.

Part 2 - Step-up dosing (SUD) Part 2 will be a SUD design in adult participants with SLE, who previously did not participate in Part 1, and in adult participants with IIM. In Part 2, participants will receive 2 dose administrations, where the second dose will be administered 7 days after the first dose. The first (priming) dose of the step-up regimen will be agreed by safety review committee. The second (target) dose will be escalated, and a minimum of 3 target dose levels are planned to be investigated in Part 2.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: This is an open-label, multi-centre Phase I study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD5492 in adult participants with either SLE or IIM.

Participants will be enrolled in approximately 20 sites in 8 countries.

The study consists of 2 parts:

Part 1 - Single ascending dose (SAD) Part 1 will be a sequential SAD design in adult participants with SLE. Up to 5 dose levels of AZD5492 are planned to be investigated. Depending on emerging data, up to 4 additional dose levels may be added at the discretion of the Sponsor.

The decision to open Part 2 will be made by the Safety Review Committee (SRC) based on the evaluation of all available data including safety, tolerability, PK, and PD from Part 1, and the dose levels and dosing strategy for Part 2 will be confirmed.

After a screening period of up to 42 days, participants will receive 1 dose of AZD5492 and be followed up for at least 179 days post-dose.

Part 2 - Step-up dosing (SUD) Part 2 will be a SUD design in adult participants with SLE, who previously did not participate in Part 1, and in adult participants with IIM. In Part 2, participants will receive 2 dose administrations, where the second dose will be administered 7 days after the first dose. The first (priming) dose of the step-up regimen will be agreed by the SRC. The second (target) dose will be escalated, and a minimum of 3 target dose levels are planned to be investigated in Part 2.

Eligibility criteria: Inclusion Criteria:

1. Participant must be 18 to 65 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 performed by the central laboratory at screening. If anti-dsDNA or anti- Sm tests are negative, documented history of test results may be used.
   3. Active, moderate-severe disease at screening, defined as clinical SLEDAI-2K ≥ 4.
   4. Intolerance or inadequate response to ≥ 3 available treatments, used for at least 3 months each, such as the following: corticosteroids, anti-malarial drugs, calcineurin inhibitor, methotrexate, azathioprine, leflunomide, mycophenolic acid or its derivatives, cyclophosphamide, belimumab, anifrolumab, or B-cell depleting monoclonal antibodies.
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 performed by the central laboratory at screening.
   3. MMT-8 score of ≤ 142/150.
   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:

   a. Report from MRI performed within 3 months prior to screening with evidence of muscle inflammation b. Report from muscle biopsy performed within 3 months prior to screening that demonstrates active inflammation c. Report from electromyography performed within 3 months prior to screening that exhibits irritable myopathic pattern.

   (e) Intolerance or inadequate response to corticosteroids and ≥2 of the following treatments, used for at least 3 months each: calcineurin inhibitor, methotrexate, azathioprine, leflunomide, mycophenolic acid or its derivatives, cyclophosphamide, intravenous immunoglobulin (IVIG), or B-cell depleting monoclonal antibodies.
4. Must be receiving one of the following therapy regimens at screening:

   1. Oral prednisolone (or equivalent) without additional immunosuppressive medication: Daily dose between 7.5 mg and 20 mg (inclusive) a day for ≥ 2 months prior to signing the ICF. Dose must be stable for ≥ 2 weeks prior to signing the ICF.
   2. Immunosuppressive treatment with one of the following medications, at a stable dose for ≥ 3 months prior to signing the ICF:

   (i) Methotrexate ≤ 25 mg/week, without change of route of administration for 8 weeks prior to signing the ICF. (ii) Mycophenolate mofetil ≤ 2g/day (iii) Azathioprine ≤ 200 mg/day (iv) Leflunomide ≤ 15 mg/ day (v) Tacrolimus ≤ 0.1 mg/kg/day with maximum dose of 5 mg/day (vi) Cyclosporin ≤ 3 mg/kg/day with maximum dose of 200 mg/day
5. Blood B-cells above 50 cells/μL at screening.
6. IgG levels \> 6g/L at screening.

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. Participants with clinically evident APS which is adequately controlled by anticoagulants or aspirin for at least 12 weeks can be recruited into the study.
   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 including, but not limited to: aseptic meningitis; cerebral vasculitis; myelopathy; demyelination syndromes (ascending, transverse, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy; status epilepticus; cerebral ataxia' and mononeuritis multiplex.
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 Infections

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   1. Any clinical suspicion or diagnosis of active infection at screening.
   2. Opportunistic infection that meets criteria to be an SAE within 3 years.
   3. Clinically significant chronic infection (eg, osteomyelitis, bronchiectasis) with treatment completed less than 2 months prior to signing the ICF (except for chronic nail infections, which are allowed).
   4. Any history of infection requiring:

   (i) Hospitalisation within the previous two months (ii) Treatment with IV anti-infectives with treatment completed less than 4 weeks prior to signing the ICF (iii) Oral anti-infectives within 2 weeks prior to signing the ICF. (e) History of recurrent infection requiring hospitalisation or IV antibiotics eg 3 or more of the same type of infection, including systemic fungal infections, over the previous 52 weeks.

5 Participants with HIV infection (confirmed by central laboratory at screening) 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 defined as:

(a) HCV IgM Ab positive (b) Detectable HCV RNA (c) Positive result for HCV IgG Ab is acceptable in the following circumstances: (i) HCV RNA is undetectable \>12 weeks after completion of curative antiviral treatment for HCV. (ii) HCV RNA is undetectable on two occasions at least 12 weeks apart following resolution of HCV infection if not treated. 9 Participants with positive COVID-19 PCR. For participants with a positive COVID-19 reverse transcription PCR at screening, rescreening will be conducted not earlier than 6 weeks after the positive result. Only one rescreening is allowed. 10 Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection.

11 CNS pathology including but limited to the following: CNS vasculitis, severe brain injury, dementia, Parkinson's disease, neurodegenerative diseases, cerebellar disease, stroke, seizure disorder/epilepsy, PML, severe uncontrolled mental illness, psychosis, CNS involvement of autoimmune diseases.

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 signing the ICF. If therapy was administered ≥3 months ago, exclude if absolute B-cell less than the lower limit of normal.

13 Prednisolone (or equivalent) \> 20 mg within 2 months of signing the ICF.

Primary outcomes:
measure: Safety evaluation of AZD5492: Number of participants with treatment-related adverse events.
timeFrame: Day 1 to end of the study (up to 52 weeks)
measure: Safety evaluation of AZD5492: Number of participants with related treatment-related adverse events.
timeFrame: Day 1 to end of the study (up to 52 weeks)
measure: Safety evaluation of AZD5492: Frequency of dose limiting toxicities (DLTs).
timeFrame: Day 1 to end of the study (up to 52 weeks)
measure: Safety evaluation of AZD5492: Number of SAEs leading to death
timeFrame: Day 1 to end of the study (up to 52 weeks)
measure: Safety evaluation of AZD5492: Number of participants with treatment-related adverse events by grade.
timeFrame: Day 1 to end of the study (up to 52 weeks)
measure: Tolerability evaluation of AZD5492: Number of participants with treatment-related vital signs abnormalities.
timeFrame: Day 1 to end of the study (up to 52 weeks)
measure: Tolerability evaluation of AZD5492: Number of participants with treatment-related clinical laboratory abnormalities.
timeFrame: Day 1 to end of the study (up to 52 weeks)
measure: Tolerability evaluation of AZD5492: Number of participants with abnormal ECG.
timeFrame: From Day 1 up to Day 180
Secondary outcomes:
measure: Serum Pharmacokinetics (PK) parameters of AZD5492 (maximum observed serum (peak) drug concentration (Cmax))
timeFrame: Part 1: Day1 pre-dose, Day1, Day2, Day3, Day4, Day8, Day15, Day22, Day30, Day60, Unscheduled.
measure: Serum Pharmacokinetics (PK) parameters of AZD5492 (area under the serum concentration-time curve (AUC))
timeFrame: Part 1: Day1 pre-dose, Day1, Day2, Day3, Day4, Day8, Day15, Day22, Day30, Day60, Unscheduled.
measure: Serum Pharmacokinetics (PK) parameters of AZD5492 (terminal elimination half-life. (t1/2λz))
timeFrame: Part 1: Day1 pre-dose, Day1, Day2, Day3, Day4, Day8, Day15, Day22, Day30, Day60, Unscheduled.
measure: Serum Pharmacokinetics (PK) parameters of AZD5492 - area under the serum concentration time curve from time zero to the time of last quantifiable analyte concentration (AUClast)
timeFrame: Part 2: Day1, pre-dose, Day1, Day2, Day3, Day4, Day8 pre-dose, Day8, Day9, Day10, Day11, Day15, Day22, Day29, Day43, Day60, Unscheduled]
measure: Serum Pharmacokinetics (PK) parameters of AZD5492 - Cmax
timeFrame: Part 2: Day1, pre-dose, Day1, Day2, Day3, Day4, Day8, pre-dose, Day8, Day9, Day10, Day11, Day15, Day22, Day29, Day43, Day60, Unscheduled]
measure: Incidence of ADAs to AZD5492 measured in serum.
timeFrame: Part 1: Day1 pre-dose, Day15, Day30, Day60, D180 Part 2: Day1 pre-dose, Day15, Day29, Day60, Day90,Day120, Day180
measure: Absolute counts at Day 180 in blood CD19+ B-cells.
timeFrame: Day 180
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Research Site
state: Alabama
city: Hamilton
country: Canada
facility: Research Site
state: Ontario
city: Sherbrooke
country: Canada
facility: Research Site
state: Quebec
city: Beijing
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Wuhan
country: China
facility: Research Site
city: Bordeaux
country: France
facility: Research Site
city: Montpellier
country: France
facility: Research Site
city: Nancy
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Strasbourg Cedex
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Erlangen
country: Germany
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Magdeburg
country: Germany
facility: Research Site
city: Bunkyo-ku
country: Japan
facility: Research Site
city: Kita-gun
country: Japan
facility: Research Site
city: Kitakyushu-shi
country: Japan
facility: Research Site
city: Kyoto
country: Japan
facility: Research Site
city: Nagasaki-shi
country: Japan
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Leiden
country: Netherlands
facility: Research Site
city: Mérida
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Valladolid
country: Spain
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Southampton
country: United Kingdom
facility: Research Site
Study officials:
References: