A First-in-Human Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of RO7507062 in Participants With Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RO7507062 in participants with systemic lupus erythematosus (SLE). The study will have 2 parts: Part 1 is a single ascending dose-finding (SAD) part and Part 2 is a dose escalation with fractionated dosing part.

Detailed Description
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Tocilizumab is an additional investigational medicinal product (IMP), which will be used when required in case of clinical presentation of cytokine release syndrome (CRS). Data on the efficacy of tocilizumab in ameliorating the symptoms of CRS related to RO7507062 will be collected in this study.

Official Title
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An Open-label, Multicenter, Dose Escalation, First-in-Human Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Subcutaneously Administered RO7507062 in Participants With Systemic Lupus Erythematosus

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: RO7507062
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a diagnosis of SLE according to the 2019 European League Against Rheumatism (EULAR) or American College of Rheumatology (ACR) Classification Criteria at least 24 weeks prior to Screening and must have been treated for SLE according to standard clinical practice. Presence of anti-double stranded DNA (dsDNA), anti-Smith (Sm), anti-ribonucleoprotein (RNP) or anti-Sjögren's syndrome antigen A (SS-A) above the upper limit of normal (ULN); or, positive anti-nuclear antibody (ANA; ≥ 1:160). Active SLE disease, as demonstrated by a The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score of ≥4 with at least 1 positive clinical. For participants receiving oral corticosteroids (OCS), treatment with ≤ 20 milligram per day (mg/day) prednisone or equivalent, during Screening, at a dose that has been stable for at least 7 days prior to Day 1. For participants receiving conventional immunosuppressants (e.g., azathioprine, sulfasalazine, mycophenolate mofetil [≤ 3.0 grams per day], mycophenolic acid [≤ 3 grams per day], methotrexate [oral, SC, or intramuscular routes]), and calcineurin inhibitors [oral]), treatment should be at a stable dose for at least 6 weeks prior to Screening and during Screening and expected to remain stable during the study. Exclusion Criteria: Active or unstable lupus-associated neuropsychiatric disease. Catastrophic or severe antiphospholipid syndrome within 12 months prior to Screening or during Screening. Presence of severe lupus-associated renal disease that is likely to require treatment with protocol-prohibited therapies. Organ-threatening SLE manifestations (e.g., active myocarditis) considered to be severe by the Investigator. Severe active systemic autoimmune disease other than SLE. Active infection of any kind, excluding fungal infection of the nail beds. History of serious recurrent or chronic infection, especially; recurring, chronic infections specifically related to respiratory issues. Moderate or severe chronic obstructive pulmonary disease (COPD). History of progressive multifocal leukoencephalopathy (PML). History of macrophage-activation syndrome and/or hemophagocytic lymphohistiocytosis. History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ, within the past 5 years (with the exception of basal cell carcinoma, non melanoma skin cancer, and cervical cancer in situ, if these have been adequately treated and are considered cured). Intolerance or contraindication to study therapies including history of severe allergic or anaphylactic reactions to monoclonal antibodies (mAbs) or known hypersensitivity to any component of the RO7507062 injection. History of infection with hepatitis B virus (HBV), or positive serology indicative of current or past HBV infection. Human immunodeficiency virus (HIV; positive HIV antibody test) and active hepatitis C virus (HCV) infection (detectable HCV ribonucleic acid [RNA]). Active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection. Receipt of any anti- cluster of differentiation (CD)19 or anti-CD20 therapy such as blinatumomab, obinutuzumab, rituximab, ocrelizumab, or ofatumumab less than 6 months prior to screening or during screening. Receipt of Inhibitors of Janus kinase (JAK), Bruton tyrosine kinase, or tyrosine kinase 2 including baricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, and fenebrutinib,or any investigational agent within 30 days prior to screening or during screening. Receipt of Cyclophosphamide or a biologic therapy such as, but not limited to, adalimumab, etanercept, golimumab, infliximab, belimumab,ustekinumab, anifrolumab, secukinumab, or atacicept, within 4 weeks prior to enrollment. History of active or latent tuberculosis or a positive Interferon Gamma Release Assay (IGRA). Receipt of an investigational therapy (except severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] vaccines) within 30 days or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment and during the study. Immunoglobulin (IgG) level of <6 gram per liter (g/L). Estimated glomerular filtration rate (eGFR) <45 milliliter per minute (mL/min)/1.73-meter square (m^2).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: SAD: RO7507062<br>Participants will receive RO7507062 at an assigned dose as subcutaneous (SC) injection on Day 1. | Drug: RO7507062<br>* RO7507062 solution for injection will be administered SC as specified in each treatment arm.<br>Drug: Tocilizumab<br>* Tocilizumab solution for infusion will be administered intravenously at 8 milligram per kilogram (mg/kg) for participants >/= 30 kg or at 12 mg/kg for participants < 30 kg.<br>* Other names: Actemra, RoActemra;|
| Experimental: Part 2: Dose Escalation with Fractionated Dosing: RO7507062<br>Participants will receive RO7507062 as SC injection at the dose determined in Part 1, on Day 1 and at an escalated dose, based on emergent safety data, on Day 8. | Drug: RO7507062<br>* RO7507062 solution for injection will be administered SC as specified in each treatment arm.<br>Drug: Tocilizumab<br>* Tocilizumab solution for infusion will be administered intravenously at 8 milligram per kilogram (mg/kg) for participants >/= 30 kg or at 12 mg/kg for participants < 30 kg.<br>* Other names: Actemra, RoActemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants with Dose Limiting Adverse Events (DLAEs) |  | Day 1 through Day 28 | 
| Part 2: Number of Participants with DLAEs |  | Day 8 through Day 36 | 
| Number of Participants with Adverse Events (AEs) and CRS | Adverse events will be reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0), and CRS, will be graded based on the American Society for Transplantation and Cell Therapy (ASTCT) criteria. | Up to approximately 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentration of RO7507062 |  | Up to approximately 12 months | 
| Time to Maximum Serum Concentration (Tmax) of RO7507062 |  | Up to approximately 12 months | 
| Maximum Serum Concentration (Cmax) of RO7507062 |  | Up to approximately 12 months | 
| Area Under the Serum Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of RO7507062 |  | Up to approximately 12 months | 
| Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUClast) of RO7507062 |  | Up to approximately 12 months | 
| Apparent Terminal Half-Life (T1/2) of RO7507062 |  | Up to approximately 12 months | 
| Terminal Rate Constant (λz) of RO7507062 |  | Up to approximately 12 months | 
| Apparent Volume of Distribution (Vz/F) of RO7507062 |  | Up to approximately 12 months | 
| Apparent Total Body Clearance (CL/F) of RO7507062 |  | Up to approximately 12 months | 
| Number of Participants with Anti-Drug Antibodies (ADAs) to RO7507062 |  | Up to approximately 12 months |