Rheumatoid Arthritis, Systemic Lupus Erythematosus
Conditions
Keywords
adult participants, rheumatoid arthritis, systemic lupus erythematosus, surovatamig
Brief summary
This open-label, Phase I study will assess the safety and tolerability of surovatamig and characterise its PK and PD following subcutaneous administration to participants with RA or SLE.
Detailed description
This is an open-label, Phase I, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of surovatamig administered subcutaneously in adult participants aged 18 to 65 years with rheumatoid arthritis or systemic lupus erythematosus. The study includes single-ascending dose cohorts in adult participants with RA (Part 1) and step-up dosing cohorts in adult participants with RA or SLE (Parts 2 and 3).
Interventions
BIOLOGICALSurovatamig
Surovatamig is a bispecific T-cell engager administered subcutaneously. This is an open-label, dose-escalation study evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of Surovatamig in adult participants with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). The study consists of up to three parts: Part 1 (SAD): Single ascending dose - participants receive one dose of Surovatamig. Part 2 (sSUD): Single step-up dosing - participants receive two doses. Part 3 (dSUD): Double step-up dosing - participants receive three doses. Participants are assigned to a study part based on protocol-defined criteria. The study includes follow-up for a minimum of 179 days post-first dose, with extended monitoring up to 12 months for certain participants.
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open-label study consisting of up to 3 parts: SAD (Part 1), sSUD (Part 2), and optional dSUD (Part 3). Depending on the assigned study part, participants will either receive surovatamig once (Part 1), twice (Part 2), or three times (Part 3).
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Participant must be 18 (or the legal age of consent in the jurisdiction in which the study is taking place) to 65 years of age, inclusive, at the time of signing the informed consent. 2. For RA participants, only: <!-- --> 1. Diagnosis of RA as defined by the 2010 EULAR/ACR classification criteria 2. Positive for ≥ 1 disease-specific autoantibody performed by the central laboratory. (a) RF (b) ACPA 3. Moderate or severe disease activity defined as: DAS28-CRP \> 3.2 AND * 4 tender joints and ≥ 4 swollen joints (a) US-Specific Criterion: DAS28-CRP \> 3.2 AND ≥ 6 tender joints and ≥ 6 swollen joints 4. Intolerance to or inadequate response following approximately 3 month's treatment or longer to ≥2 b/tsDMARDs (with different mechanisms of action) after failing csDMARD therapy (unless csDMARD therapy is contraindicated). There is no minimum duration for taking a treatment in cases of intolerance. 5\. Background standard of care is not a requirement for participation, however, the following therapies are permitted and may be continued during the study (alone or in combination). Any other systemic immunosuppressive treatment or immune modulating biologic drug must be discontinued in line with the washout periods listed in Inclusion Criterion 12: (a) Oral prednisone (or equivalent). Dose must be stable and ≤ 10mg a day for ≥ 2 weeks prior to Day 1. (b) Oral anti-malarial (e.g. hydroxychloroquine ≤ 400 mg a day). Dose must be stable for ≥ 4 weeks prior to Day 1. (c) Treatment with one of the following csDMARDs for ≥ 3 months and at a stable dose for ≥ 4 weeks prior to Day 1. (i) Methotrexate ≤ 25 mg per week, without change of route of administration for 8 weeks prior to Day 1 (ii) Sulfasalazine ≤ 3g/day (iii) Leflunomide ≤ 20 mg/day 3. For SLE participants, only: 1. Diagnosis of SLE as defined by the 2019 EULAR/ACR classification criteria 2. Positive for ≥ 1 disease-specific autoantibody performed by the central laboratory. If autoantibodies are negative on central laboratory test, documented history of test results may be used. (a) ANA immunofluorescent assay test (titer ≥ 1:80) (a) Anti-dsDNA (b) Anti-Sm. 3. Moderate or severe disease activity defined as clinical SLEDAI-2K \> 4 (a) US-specific criterion: clinical SLEDAI-2K ≥ 6 4. Intolerance to or inadequate response following approximately 3 months treatment or longer ≥ 3 SoC (includes: corticosteroids, anti-malarial drugs, calcineurin inhibitor, methotrexate, azathioprine, leflunomide, mycophenolic acid or its derivatives, cyclophosphamide, belimumab, anifrolumab, telitacicept, or B-cell depleting monoclonal antibodies). There is no minimum duration for taking a treatment in cases of intolerance. 5. Background standard of care is not a requirement for participation, however, the following therapies are permitted and may be continued during the study (alone or in combination). Any other systemic immunosuppressive treatment or immune modulating biologic drug must be discontinued in line with the washout periods listed in Inclusion Criterion 12: (a) Oral prednisone (or equivalent. Dose must be stable and ≤ 20mg a day for ≥ 2 weeks prior to Day 1. (b) Oral anti-malarial (eg, hydroxychloroquine ≤ 400 mg a day). Dose must be stable for ≥ 4 weeks prior to Day 1. (c) Treatment with one of the following immunosuppressive treatments. for ≥ 3 months and at a stable dose for ≥ 4 weeks prior to Day 1. (i) Methotrexate ≤ 25 mg/week, without change of route of administration for 8 weeks prior to Day 1 (ii) Mycophenolate mofetil or equivalent ≤ 2 g/day (dose must be ≤ 2 g/day for 3 months prior to Day 1) (iii) Azathioprine ≤ 200 mg/day (iv) Leflunomide ≤ 20 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 4\. Blood B cells ≥ 50 cells/μL at screening. 5. IgG levels ≥ 6 g/L at screening. 6. Eligibility for re-treatment of previously treated participants only. The following criterion applies only to participants being considered for re-treatment and is not applicable to participants undergoing initial screening for study entry. 1\. Participants treated in prior study cohorts who did not experience an IMP-related DLT or discontinue treatment and/or participation due to an IMP-related AE are eligible for re-treatment in Parts 2 and 3. Participants must otherwise meet all protocol-defined eligibility criteria, with the exception of Inclusion Criterion 17 (B cell count), and meet one of the 2 criteria below: 1. Completed the 6-month treatment period OR 2. Completed a minimum of 90 days in the treatment period and have peripheral B cell counts that are ≥ 90% of baseline or above lower limit of normal (LLN)
Exclusion criteria
1. Any complications of disease under study that 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: (a) Active severe SLE-driven renal disease. (b) Severe lung or cardiac involvement. (c) History of, or current diagnosis of, catastrophic or severe APS (eg, 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. (d) Rapidly progressive and/or severe ILD or ILD that requires oxygen supplementation/therapy (of any type). (e) Felty's syndrome 2. History of HLH/MAS. 3. For RA participants, only: <!-- --> 1. Juvenile idiopathic arthritis or idiopathic arthritis diagnosed before the age of 16. 2. Axial spondylarthritis or any other disease associated with inflammatory arthritis 4\. For SLE participants, only: 1.History of active, severe or unstable neuropsychiatric SLE, except for headache and peripheral neuropathies. 5. Other active or prior documented severe, complex, autoimmune or inflammatory disorders. Exceptions to this
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety evaluation of surovatamig: Number of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs) | Day 1 to end of the study (up to 52 weeks) | Number and percentage of participants with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) |
| Safety evaluation of surovatamig: Frequency of dose limiting toxicities (DLTs). | Day 1 to end of the study (up to 52 weeks) | Number and percentage of participants with DLTs (dose-limiting toxicities) as defined in the study protocol |
| Safety of surovatamig: Incidence of AEs/SAEs leading to discontinuation of surovatamig | Day 1 to end of the study (up to 52 weeks) | Number of participants with AEs/SAEs leading to discontinuation of surovatamig |
| Tolerability of surovatamig: Incidence of treatment-related vital signs abnormalities | Day 1 to end of the study (up to 52 weeks) | Number and percentage of participants with treatment-related vital signs abnormalities |
| Tolerability of surovatamig: Incidence of treatment-related clinical laboratory abnormalities | Day 1 to end of the study (up to 52 weeks) | Number of participants with treatment-related clinical laboratory abnormalities |
| Tolerability of surovatamig: Number of participants with abnormal ECG | From baseline through Day 180. | Number and percentage of participants with abnormal ECG. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Pharmacokinetics (PK) parameters of surovatamig - Cmax | From Day 1 through Day 180 | Maximum observed serum drug concentration (Cmax) |
| Absolute counts at Day 180 in blood CD20+ B-cells | Day 180 | Absolute counts in peripheral CD20+ B cells |
| Serum Pharmacokinetics (PK) parameters of surovatamig - AUC0-last | From Day 1 through Day 180 | Area under the serum concentration time curve from time zero to the time of last quantifiable analyte concentration (AUClast) |
| Serum Pharmacokinetics (PK) parameters of surovatamig - AUCinf | From Day 1 through Day 180 | Area under the serum concentration time curve from time zero to infinity (Part 1 only) |
Countries
Australia, Belgium, Brazil, China, Germany, Spain, Taiwan, Ukraine, United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed