Efficacy and Safety Evaluation of KPL-404 in a Phase 2 Randomized, Double-blind, Placebo-controlled Study for Sjögren’s Disease

Trial ID: 2024-512986-15-00
Protocol: KPL-404-C221
Sponsor: Kiniksa Pharmaceuticals GmbH

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Diseases & Conditions

Sjogren's syndrome

Objectives

The primary objective of this study is to evaluate the effect of **abiprubart** on an established systemic disease activity measure for Sjögren’s Disease. This is clinically relevant as it aims to determine the efficacy of abiprubart in modulating disease activity, which could potentially lead to improved management strategies for patients suffering from this chronic autoimmune condition.

Secondary objectives include:

Evaluating the effect of abiprubart on established disease symptom and outcome measures for Sjögren’s Disease.
Assessing the impact of abiprubart on glandular function symptoms and systemic disease activity measures.
Investigating the effect of abiprubart on the functional status and health-related quality of life of patients.
Evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of abiprubart in the context of Sjögren’s Disease.

Participants

The clinical trial for evaluating the effect of abiprubart on an established systemic disease activity measure for **Sjögren’s Disease** involves a total of 64 participants. The study population includes both male and female subjects, aged between 18 and 80 years. Participants were selected based on their ability to understand and consent to the study requirements, and they must have a confirmed diagnosis of Sjögren’s Disease according to the 2016 ACR-EULAR Classification Criteria. The trial includes individuals with a body mass index (BMI) ranging from 18 to 40 kg/m² and a weight between 40 kg and 150 kg. Participants are required to have a stimulated whole salivary flow rate of at least 0.05 mL/min at screening. Routine adult vaccinations, including those for COVID-19, influenza, pneumonia, and zoster, should be up to date or administered at least two weeks prior to randomization. The study population is not limited by gender, and both male and female participants are included, with specific considerations for reproductive health and contraception. The trial also involves a vulnerable population, ensuring comprehensive ethical oversight and participant safety.

Plans and Procedures

The clinical trial is a **Phase 2**, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study designed to evaluate the efficacy and safety of Abiprubart in participants with **Sjogren's Disease**. The primary objective is to assess the effect of Abiprubart on an established systemic disease activity measure for Sjogren's Disease. The trial is expected to commence recruitment on November 1, 2024, and conclude by April 14, 2027. Participants will be randomly assigned to receive either the investigational product, KPL-404, administered via subcutaneous injection, or a placebo. The maximum treatment period is 48 weeks, with a maximum daily dose of 800 mg and a total dose not exceeding 10,000 mg.

The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, weight, and specific medical conditions, followed by regular follow-up visits to monitor the participants' response to the treatment and any adverse events. The primary endpoint is the change from baseline in the European League Against Rheumatism (EULAR) Sjogren's Disease Activity Index (ESSDAI) at Week 24. Secondary endpoints include the proportion of Sjogren's Tool for Assessing Response (STAR) responders, changes in stimulated and unstimulated salivary flow, and other clinical assessments over time.

Participants are expected to be involved in the study for the entire duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, non-compliance with the study protocol, or withdrawal of consent. The study is designed to ensure rigorous monitoring and data collection to evaluate the safety and efficacy of the investigational product in a controlled environment.

Treatment

The clinical trial involves the administration of **KPL-404**, an investigational medication formulated as an **injection**. The active substance, KPL-404, is a protein of other origin, developed by Kiniksa Pharmaceuticals, Ltd. The medication is administered via the **subcutaneous route**. The dosing regimen includes a maximum daily dose of 800 mg, with a total maximum dose of 10,000 mg over a treatment period of up to 48 weeks. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is utilized in this study. The placebo is a sterile, preservative-free solution that mirrors the composition of the investigational drug product, excluding the active protein component. The placebo is also administered subcutaneously, maintaining the same pharmaceutical form as the investigational product. This ensures blinding and allows for a controlled comparison of efficacy and safety between the active treatment and the placebo group.

Efficacy

The efficacy of the investigational product, Abiprubart, in the treatment of **Sjögren’s Disease** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the European League Against Rheumatism (EULAR) Sjögren’s Disease Activity Index (ESSDAI) at Week 24. This will provide a measure of the systemic disease activity and its response to the treatment over the specified period.

Secondary endpoints include a variety of measures to further evaluate the efficacy of the treatment. These include the proportion of Sjögren’s Tool for Assessing Response (STAR) responders, defined as those achieving a score of ≥ 5 points at Week 24, and the evaluation of individual STAR domains. Additional secondary endpoints involve changes from baseline in ESSDAI over time, stimulated and unstimulated salivary flow rates, ESSPRI, Schirmer’s test, clinESSDAI, FACIT-Fatigue, and EQ-5D 5L at Week 24 and over time. The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), as well as clinically significant laboratory or electrocardiogram (ECG) changes, will also be monitored. Pharmacokinetic parameters, including Abiprubart serum concentrations and antidrug antibodies, will be assessed, along with receptor occupancy at U.S. clinical sites.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Is capable of understanding the written ICF, has provided signed written informed consent, and agrees to comply with protocol requirements.
If female, must be either postmenopausal (defined as no menses for 12 months without other medical cause), permanently surgically sterile (i.e., removal of ovaries, fallopian tubes, and/or uterus), or, for women of childbearing potential, must: a. Be nonpregnant, nonlactating, and agree to remain abstinent or use a method of contraception with a failure rate of < 1% per year from the screening visit until after the EOS visit. Examples of contraception methods with a failure rate of < 1% per year include: i. hormonal contraceptives associated with inhibition of ovulation (stable dose for at least 4 weeks prior to first dose of study drug); hormonal contraceptive methods must be supplemented by a barrier method ii. hormone-releasing or copper intrauterine device iii. bilateral tubal occlusion iv. vasectomized male partner v. abstinence from heterosexual intercourse; the reliability of sexual abstinence should be evaluated based on duration of the study and usual lifestyle of the participant. Intermittent abstinence (such as calendar, ovulation, symptothermal or postovulation) and withdrawal are not considered acceptable contraceptive methods b. The definition of childbearing potential may be adapted for alignment with local guidelines or regulations
Sexually active male participants must have documented vasectomy or must agree to use a condom or method of contraception with a failure rate of <1% per year, as defined above with their partners of childbearing potential from first dose of study drug until after the EOS visit.
Male participants must agree to refrain from donating sperm from first dose of study drug until 30 days after the last study drug administration. Female participants must agree to refrain from donating eggs from first dose of study drug until after the EOS visit.
Females of childbearing potential must have a negative serum β-human chorionic gonadotropin test during screening and negative urine pregnancy test on Day 1.
Is male or female at birth, and > 18 years of age and < 81 years of age at Screening.
Has a diagnosis of Sjögren’s Disease according to 2016 ACR-EULAR Classification Criteria.
Has ESSDAI value ≥ 5, counting only the biological, hematological, articular, cutaneous, glandular, lymphadenopathy, and constitutional organ domains at Screening.
Is seropositive at Screening for anti-SSA antibodies tested at a central laboratory.
Has stimulated whole salivary flow rate at Screening of ≥ 0.05 mL/min.
Weighs at least 40 kg and no more than 150 kg and has a body mass index (BMI) within the range of 18-40 kg/m2.
Routine adult vaccinations, including COVID-19, influenza, pneumonia, and zoster, should be up to date and/or vaccines offered at least 2 weeks prior to randomization according to regional and national guidelines based on medical history or presence of risk factors, in the opinion of the Investigator.
[Original Criterion deleted]
A full list of inclusion criteria can be found in the current protocol.

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Exclusion Criteria

Prior exposure to any other anti-CD40/CD154 agent.
Has received immunization with a live (attenuated) vaccine within 4 weeks prior to randomization or is expected to receive live (attenuated) vaccine during the study or within 6 weeks after the last study drug administration.
Positive or indeterminate results for hepatitis C virus infection or chronic active hepatitis B infection (at Screening) as defined below: a. Hepatitis C antibody positive b. Hepatitis B surface antigen positive c. Hepatitis B anti-core antibody positive but anti-surface antibody negative
History of thromboembolic event or a significant risk of future thromboembolic events (defined as a definitive diagnosis of thrombophilia OR an ongoing condition associated with an increased incidence of intravascular thrombosis, such as atrial fibrillation or anti-phospholipid syndrome). All history of intravascular thrombosis should be approved by the medical monitor.
Has any prior history of lymphoid malignancy associated with Sjögren’s Disease diagnosis.
Diagnosis of Sjögren’s Disease overlap syndromes where another autoimmune rheumatic disease constitutes the principal illness, including fibromyalgia with currently active, inadequately controlled symptoms.
Is currently enrolled in another clinical study (at the time of Screening), with the exception of observational studies.
Concurrent or prior disease modifying treatments prior to study treatment period defined in the table within protocol section 4.2
Has received cataract surgery, Lasik, or other ophthalmologic surgery procedure (e.g., lachrymal plug) in the 6 months prior to Screening.
Injectable corticosteroids (including intra-articular) within 8 weeks prior to randomization. (Note: Concomitant-treatment with nonsteroidal anti-inflammatory drugs, acetaminophen, oral corticosteroids [equivalent to prednisone ≤ 10 mg/day], or inhaled corticosteroids at a stable dose ≥ 4 weeks prior to baseline for stable medical conditions is allowed and should be kept at a stable dose throughout the study).
Has started, stopped or adjusted dose/regimen of medications for treatment of, or known to cause, dry mouth/eyes (such as sialagogues, artificial saliva, artificial tears, other topical ophthalmologic agents, antihistamines, antidepressants, anticholinergics, sedatives, antipsychotic drugs, or anti-Parkinson agents), within the 30 days prior to screening or is anticipating change to these treatment regimens during the study.
Has history of immunodeficiency (e.g., immune disorders or disorders that result in decreased immunity), including human immunodeficiency virus (HIV). HIV test will be performed during screening unless participant has a previously documented negative HIV result within 8 weeks prior to Screening.
Positive (or 2 indeterminate) QuantiFERON® test results unless confirmation of prior completion of appropriate treatment for latent TB and no evidence of active TB – QuantiFERON TB-Gold (QFT) testing should be performed through the central laboratory. QFT testing may be performed by a local laboratory with approval from the medical monitor. QFT test will be performed during screening unless participant has a previously documented negative QFT result within 8 weeks prior to Screening or documented prior positive QFT at any time. – An indeterminate QFT test should be repeated. – A positive QFT test or two successive indeterminate QFT results should be considered a positive diagnostic TB test. – An indeterminate QFT test followed by a negative QFT test should be considered a negative diagnostic TB test. – When possible, QFT test should be performed at least 4 weeks after receiving an mRNA COVID-19 vaccine.
A full list of exclusion criteria can be found in the current protocol.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Czechia	Not Recruiting	01 Nov 2024	6
France	Not Recruiting	01 Nov 2024	28
Germany	Not Recruiting	01 Nov 2024	16
Hungary	Not Recruiting	01 Nov 2024	12
Poland	Not Recruiting	01 Nov 2024	56
Spain	Not Recruiting	01 Nov 2024	18