Study Evaluating Safety, Tolerability, PK/PD of Surovatamig in Adult RA or SLE Participants

Официальное название

An Open-label, Phase I Study to Assess Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Surovatamig Following Single-ascending Dose and Step-up Dose Administration to Adult Participants With Rheumatoid Arthritis or Systemic Lupus Erythematosus

Обзор

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.

Подробное описание

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).

Вмешательства

• Биопрепарат Surovatamig
  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

Первичные конечные точки

• Safety evaluation of surovatamig: Number of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs) [Срок оценки: Day 1 to end of the study (up to 52 weeks)]
• Safety evaluation of surovatamig: Frequency of dose limiting toxicities (DLTs). [Срок оценки: Day 1 to end of the study (up to 52 weeks)]
• Safety of surovatamig: Incidence of AEs/SAEs leading to discontinuation of surovatamig [Срок оценки: Day 1 to end of the study (up to 52 weeks)]
• Tolerability of surovatamig: Incidence of treatment-related vital signs abnormalities [Срок оценки: Day 1 to end of the study (up to 52 weeks)]
• Tolerability of surovatamig: Incidence of treatment-related clinical laboratory abnormalities [Срок оценки: Day 1 to end of the study (up to 52 weeks)]
• Tolerability of surovatamig: Number of participants with abnormal ECG [Срок оценки: From baseline through Day 180.]

Вторичные конечные точки (4)

• Serum Pharmacokinetics (PK) parameters of surovatamig - Cmax [Срок оценки: From Day 1 through Day 180]
• Absolute counts at Day 180 in blood CD20+ B-cells [Срок оценки: Day 180]
• Serum Pharmacokinetics (PK) parameters of surovatamig - AUC0-last [Срок оценки: From Day 1 through Day 180]
• Serum Pharmacokinetics (PK) parameters of surovatamig - AUCinf [Срок оценки: From Day 1 through Day 180]

Критерии участия

Критерии включения

• 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.
• For RA participants, only:

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• Diagnosis of RA as defined by the 2010 EULAR/ACR classification criteria
• Positive for ≥ 1 disease-specific autoantibody performed by the central laboratory.

(a) RF (b) ACPA

• 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:

• Diagnosis of SLE as defined by the 2019 EULAR/ACR classification criteria
• 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.
• Moderate or severe disease activity defined as clinical SLEDAI-2K > 4

(a) US-specific criterion: clinical SLEDAI-2K ≥ 6

• 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.
• 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:

• Completed the 6-month treatment period OR
• 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)

Критерии исключения

• 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
• History of HLH/MAS.
• For RA participants, only:

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• Juvenile idiopathic arthritis or idiopathic arthritis diagnosed before the age of 16.
• 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 exclusion criteria include: (a) Vitiligo or alopecia (b) Hypothyroidism stable on hormone replacement (c) Controlled type I diabetes mellitus on insulin (d) Any chronic skin condition that does not require systemic immunosuppressant or biologic therapy (e) Celiac disease, controlled by diet alone (f) Participants with secondary Sjögren's disease are eligible provided that immunosuppression is primarily prescribed for the disease under study (ie, SLE or RA) and not for secondary Sjögren's. 6. Significant CNS co-morbidity (eg, Parkinson's, stroke, CNS vasculitis, severe brain injury, dementia, neurodegenerative diseases, cerebellar disease, epilepsy/seizure disorders, PML, severe uncontrolled mental illness, psychosis, CNS involvement of autoimmune diseases).

7\. Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection.

8\. Exclusion Criteria Related to Infection:

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 (for example osteomyelitis, bronchiectasis) with treatment completed less than 2 months prior to signing the ICF (except for chronic nail infections which are not exclusionary) 4. Any infection requiring hospitalisation or treatment with IV anti-infectives with treatment completed less than 4 weeks prior to signing the ICF.

5\. Any infection requiring oral anti-infectives within 2 weeks prior to signing the ICF.

6\. 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).

9\. Participants who, as judged by the Investigator, have evidence of active TB, or latent TB or have a household contact with known diagnosis of current active TB.

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• TB evaluation will be performed according to the local SoC as determined by local guidelines and may include history and physical examinations, chest X-ray, or TB test (eg, purified protein derivative or QuantiFERON® test).
• Participants with a prior diagnosis of active or latent TB who have documented evidence they have completed a full course of appropriate treatment are not excluded.

However, a previous history of multidrug-resistant or extensively drug-resistant TB is exclusionary regardless of treatment status. 10. Participant with human immunodeficiency virus infection (confirmed by central laboratory at screening) 11. Participant with active EBV or CMV, assessed clinically. 12. Participant with evidence of chronic or active hepatitis B defined as HBsAg positive or HBcAB positive (tested at screening visit).

13\. Participant with evidence of chronic or active Hepatitis C, meeting any of the criteria below: (a) HCV RNA positive or detectible at screening (b) HCV antibody positive at screening (apart from those with negative HCV RNA >12 weeks after completion of curative antiviral treatment for HCV or those with sustained negative HCV RNA 12 weeks apart following resolution of HCV infection if not treated).

14\. Participant positive with COVID-19 PCR at screening. If patients test positive at screening or Day 1 but meet other eligibility criteria, they may be re-tested after ≥ 2 weeks. If this falls within the screening window, then they do not require re-screening.

15\. Receipt of any of the following treatments or interventions ever: (a) TCEs, with the exception of surovatamig under the conditions specified in Inclusion Criterion 19 (b) Bone marrow transplant (c) Stem cell transplant (d) Total lymphoid irradiation (e) CAR-T cell therapy (f) Alemtuzumab 16. For females only - currently pregnant (confirmed with positive pregnancy test), planning to become pregnant within the study period, or breast feeding.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 5 центров

• Research Site — Birmingham
• Research Site — Fullerton
• Research Site — St Louis
• Research Site — Allen
• Research Site — Mesquite

Германия · 5 центров

• Research Site — Bonn
• Research Site — Jena
• Research Site — Mainz
• Research Site — München
• Research Site — Münster

Бельгия · 4 центра

• Research Site — Edegem
• Research Site — Leuven
• Research Site — Liège
• Research Site — Merksem (Antwerpen)

Тайвань · 4 центра

• Research Site — Kaohsiung City
• Research Site — Taichung
• Research Site — Taipei
• Research Site — Taoyuan

Бразилия · 3 центра

• Research Site — Porto Alegre
• Research Site — Salvador
• Research Site — São Paulo

Китай · 3 центра

• Research Site — Пекин
• Research Site — Чэнду
• Research Site — Нанкин

Испания · 3 центра

• Research Site — Barcelona
• Research Site — Córdoba
• Research Site — Madrid

Украина · 3 центра

• Research Site — Kyiv
• Research Site — Ternopil
• Research Site — Vinnytsia

Австралия · 2 центра

• Research Site — Birtinya
• Research Site — Clayton

Великобритания · 2 центра

• Research Site — London
• Research Site — London

Идентификаторы

NCT: NCT07201558 · D740AC00001 · 2025-522273-10-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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