Efficacy and Safety Evaluation of Subcutaneous Sibeprenlimab in Sjögren’s Disease: A Phase 2 Randomized, Double-blind, Placebo-controlled Trial

Trial ID: 2024-516295-14-00
Protocol: 417-201-00042
Sponsor: Otsuka Pharmaceutical Development & Commercialization Inc.

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Diseases & Conditions

Sjogren's syndrome

Objectives

The primary objective of this study is to compare the effect of **sibeprenlimab** versus placebo, when added to background treatment, on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) at 28 weeks. This is clinically relevant as it aims to assess the efficacy of sibeprenlimab in reducing disease activity in patients with Sjögren’s disease, potentially offering a new therapeutic option for managing this condition.

Secondary objectives include:

Evaluating the safety and tolerability of sibeprenlimab versus placebo added to background treatment.
Assessing the proportion of participants with minimal clinical improvement for ESSDAI and ESSPRI achieved with sibeprenlimab versus placebo at 28 weeks.
Evaluating the individual domains of the ESSDAI composite score after treatment.
Assessing the salivary flow rate and tear flow rate after treatment.
Evaluating the effect of sibeprenlimab versus placebo on disease activity as measured by clinical outcome assessments at 28 weeks.
Assessing the effect of sibeprenlimab on pharmacodynamic (PD) biomarkers.
Evaluating the pharmacokinetics (PK) and immunogenicity of sibeprenlimab.
Comparing the effect of sibeprenlimab versus placebo on the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at 28 weeks.

Participants

The clinical trial involves a total of **40 participants** diagnosed with **Sjögren’s disease**, aiming to evaluate the effect of sibeprenlimab versus placebo on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) at 28 weeks. The study population includes both male and female subjects, aged between **18 to 75 years**, who meet the 2016 American College of Rheumatology (ACR)/EULAR criteria for Sjögren’s disease. Participants are required to be seropositive for anti-Ro52 and/or anti-Ro60 antibodies and have a screening ESSDAI score of 5 or higher, excluding activity in specific domains. The trial includes individuals who are on stable doses of systemic corticosteroids, hydroxychloroquine, methotrexate, leflunomide, or azathioprine, provided these medications have been well-tolerated for at least 30 days prior to randomization. The selection process ensures that participants can communicate effectively with the investigator and comply with trial requirements. The trial population is not limited by gender, and it includes vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **sibeprenlimab** administered subcutaneously in participants with **Sjögren's disease**. The trial will span an estimated duration from April 2025 to September 2027, with a primary objective to compare the effect of sibeprenlimab versus placebo on the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) at 28 weeks. Participants will be randomly assigned to receive either sibeprenlimab or a placebo, with the investigational product being a solution for injection in a pre-filled syringe.

The study will commence with an inclusion (screening) visit, where participants will be assessed for eligibility based on criteria such as age, seropositivity for specific antibodies, and a minimum ESSDAI score. Following successful screening, participants will be enrolled and randomized. The trial will include multiple follow-up visits to monitor safety and efficacy, with assessments including changes in ESSDAI and ESSPRI scores, incidence of treatment-emergent adverse events (TEAEs), and other clinical parameters. The end-of-study visit will occur at the conclusion of the 28-week treatment period, where final evaluations will be conducted.

Participant involvement is expected to last approximately 28 weeks, with conditions for early termination including non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial will ensure that all procedures are conducted in accordance with ethical standards and regulatory requirements, with informed consent obtained from all participants prior to any trial-specific procedures. The study aims to provide valuable insights into the therapeutic potential of sibeprenlimab for the treatment of Sjögren's disease.

Treatment

The clinical trial involves the administration of **Sibeprenlimab**, an experimental medication, which is a **solution for injection in pre-filled syringe**. The active substance, **Sibeprenlimab**, is a humanised IgG2 monoclonal antibody targeting TNFSF13, also known as APRIL or Proliferation Inducing Ligand. This protein-based therapeutic agent is administered via the **subcutaneous** route. The dosing regimen allows for a maximum daily dose of 400 mg, with a total maximum dose of 5600 mg over a treatment period of up to 52 weeks. The medication is provided by Otsuka Pharmaceutical Development & Commercialization, Inc., and is identified by the sponsor product code VIS649. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** group, which receives a treatment designed to mimic the experimental medication in appearance and administration method but contains no active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This control group is essential for evaluating the efficacy and safety of Sibeprenlimab by providing a baseline for comparison. The placebo is administered in the same manner as the experimental drug, ensuring consistency in the trial's methodology.

Efficacy

The efficacy of the investigational product, **Sibeprenlimab**, in the treatment of Sjögren’s Disease will be assessed through a series of predefined endpoints. The primary endpoint is the change from baseline in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at 28 weeks. Secondary endpoints include changes from baseline in the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score, incidence of treatment-emergent adverse events (TEAEs), and the proportion of participants achieving minimal clinical improvement, defined as a reduction in ESSDAI score by at least 3 points and ESSPRI score by at least 1 point from baseline at 28 weeks.

Additional secondary endpoints involve changes in individual ESSDAI domains, salivary and tear flow rates, and various patient-reported outcomes such as the ClinESSDAI score, Physician Global Assessment (PhGA) score, Patient Global Assessment (PaGA) score, and FACIT-Fatigue score. The trial will also evaluate the pharmacokinetic (PK) profile and serum anti-drug antibodies (ADA). Efficacy assessments will be conducted at baseline and at the 28-week mark, utilizing validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent must be obtained prior to participation in the trial
Participants between 18 to 75 years of age
Classification of Sjögren’s disease according to the 2016 American College of Rheumatology (ACR)/EULAR criteria
Seropositive for anti-Ro52 and/or anti-Ro60 antibodies at screening
Screening ESSDAI score ≥ 5; activity in the pulmonary, central nervous system, or peripheral nervous system domains will not be counted towards the qualifying screening ESSDAI score
Stimulated whole salivary flow rate of ≥ 0.05 mL/min at screening
Serum IgG > 900 mg/dL as assessed prospectively by a central laboratory test
Ability to communicate well with the investigator, understand and agree to comply with the requirements of the trial
Participants may be on hydroxychloroquine (≤ 400 mg/day), methotrexate (≤ 25 mg/week), leflunomide (≤ 20 mg daily), or azathioprine (≤ 150 mg/day) if the participant has been on a stable and well-tolerated dose for at least 30 days before randomization
Participants taking systemic corticosteroids have to be on a stable dose of ≤ 10 mg/day prednisone/prednisolone or equivalent for at least 30 days before randomization
Ability to provide written informed consent prior to initiation of any trial-specific procedures, and ability, in the opinion of the principal investigator, to comply with all the requirements of the trial

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Exclusion Criteria

Presence of another autoimmune rheumatic disease that is active and constitutes the principal illness
Prior use of a B-cell depleting therapy within 12 months prior to randomization; if the CD19 count has returned to the baseline value prior to receipt of the B-cell depleting therapy, or at a normal reference value, as early as 9 months since the therapy, the patient may be eligible if the B-cell count is greater than: the lower limit of normal or baseline value prior to receipt of previous B cell-depleting therapy (whichever is greater) at screening
Prior treatment with any of the following within 6 months prior to randomization: belimumab, abatacept, anti-tumor necrosis factor alpha biologic agents, immunoglobulins, plasmapheresis; intravenous (IV) or oral cyclophosphamide, mycophenolate mofetil, IV or oral cyclosporine A or any other immunosuppressants not specified in the protocol
Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days or until the expected pharmacodynamic effect has returned to baseline, whichever is longer
Any one of the following laboratory values at screening. Hematologic abnormalities below these reference values will be reviewed by the Medical Monitor and investigator to determine whether the values are attributable to Sjögren’s disease. If the abnormalities are attributable to Sjögren’s disease, the participant may be enrolled. a) Hemoglobin levels < 8.0 g/dL b) White blood cells (WBC) count < 4.0 × 103/μL c) Platelet count < 100 × 103/μL d) Absolute neutrophil count (ANC) < 1.0 × 103/μL e) eGFR calculated using the 2021 Chronic Kidney Disease-Epidemiology Collaboration serum creatinine eGFR formula < 45 mL/min/1.73 m2
Active viral, bacterial, or other infections requiring systemic treatment at the time of screening or randomization, or history of recurrent clinically significant infection
History of a previous hypersensitivity or severe allergic reaction with generalized urticaria, angioedema, or anaphylaxis to any of the ingredients of the sibeprenlimab SC injection formulation
History of major organ, hematopoietic stem cell, or bone marrow transplant
Regular use of medications known to cause dry mouth/eyes as a regular and major side effect, and which have not been on a stable dose for at least 30 days prior to screening, or any anticipated change in the treatment regimen during the course of the trial
Use of topical ocular prescription medications (excluding artificial tears, gels, lubricants) that have not been on a stable dose for at least 90 days prior to randomization, or any anticipated change in the treatment regimen during the course of the trial
History of primary or secondary immunodeficiency, including a positive human immunodeficiency virus (HIV) test result
History of malignancy of any organ system (other than basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
Any history of head and neck radiation treatment
History of sarcoidosis
Presence of active fibromyalgia
Participant has uncontrolled type 2 diabetes, as evidenced by a screening hemoglobin A1c (HbA1c) value > 8%. Participant will be excluded if their antidiabetic regimen is not stable. A stable antidiabetic regimen is defined as either diet and exercise therapy alone or in combination with any approved antidiabetic medication in which the doses of oral or noninsulin injectable medications have not changed during the 8 weeks prior to enrollment; or the doses of long-acting insulin or intermediate-acting insulin have not varied by more than 20% during the 8 weeks prior to enrollment
Any surgical, medical (eg, uncontrolled hypertension, heart failure, cerebrovascular accident), psychiatric or additional physical condition that the sponsor, medical monitor, and/or investigator feels may jeopardize the participant in case of participation in this trial
Positive serology for hepatitis B surface antigen
Hepatitis C: participants with positive hepatitis C antibody and hepatitis C virus (HCV)-ribonucleic acid (RNA) at screening are excluded. Chronic hepatitis C participants who have completed HCV antiviral treatment must be HCV-RNA negative at least 12 weeks after treatment before randomization to be eligible. Cases of spontaneous HCV clearance should be discussed with the sponsor before enrollment
Evidence of active tuberculosis infection is exclusionary. Participant with previously treated tuberculosis and previously treated or newly diagnosed latent tuberculosis may be eligible
Pregnant or nursing (lactating) women
Participants with a known history of noncompliance to medication, or who were unable or unwilling to complete patient-reported outcome questionnaires, or who are unable or unwilling to use the device for collection of patient-reported outcomes
Heterosexually active biological males or participants of childbearing potential, or their partners, who do not agree to adhere to use 2 forms of highly effective contraceptives from the time of consent through the end of the participant’s participation in the trial and for an additional 90 days (biological male participants) or 30 days (biological female participants) thereafter
Biological male participants who do not agree to avoid donation of sperm from the time of consent through the end of the participant’s participation in the trial and an additional 90 days thereafter
Participant who has a recent history (ie, within the past year) of alcohol or drug/chemical abuse that would, based on the investigator’s clinical judgment, interfere with the participant’s ability to participate in the trial
Participant is judged by the investigator or the medical monitor to be inappropriate for the trial
Participants who would be likely to require prohibited concomitant therapy during the trial

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	15 Apr 2025	6
Germany	Not Recruiting	15 Apr 2025	4
Greece	Not Recruiting	15 Apr 2025	3
Poland	Not Recruiting	15 Apr 2025	18
Romania	Not Recruiting	15 Apr 2025	5
Spain	Not Recruiting	15 Apr 2025	4