A PHASE 2, MULTICENTER, MULTINATIONAL,RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLEDSTUDY TO ASSESS THE SAFETY, EFFICACY, ANDPHARMACOKINETICS OF MULTIPLE DOSE LEVELS OFESK-001 IN ADULT PATIENTS WITH SYSTEMIC LUPUSERYTHEMATOSUS
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Alumis Inc
- 入组人数
- 388
- 试验地点
- 16
- 主要终点
- Group (BILAG)-based Composite Lupus
研究概览
简要总结
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects multiple organ systems and presents in a variety of clinical features. The cause of SLE development is unknown, and both genetic and environmental factors appear to contribute to disease susceptibility. The systemic effects of SLE lead to many different symptoms, including arthritis and neurological, renal, cutaneous, and gastrointestinal disorders. These effects have a substantial impact on patient quality of life (QoL). Patients with SLE report decreased vitality and general health. SLE can also lead to loss of employment, lower health-related QoL, and a 10-year decrease in lifespan (American College of Rheumatology). Current treatment options such as chronic oral corticosteroids (OCs) and immunosuppressive agents also cause side effects that further contribute to SLE disease burden. There remains a large, unmet medical need to improve treatment options for patients with SLE. Development of targeted therapies for the treatment of SLE will improve long-term patient prognosis and decrease toxic effects associated with current therapies.The pathogenesis of SLE is complex, involving the interplay of genetic and environmental factors, resulting in an autoimmune reaction where the innate and adaptive immune systems direct an inappropriate immune response to nucleic acid-containing cellular particles. The immune system activation, along with a dysregulated repair response orchestrates the tissue damage associated with SLE. Certain cytokines produced by both innate and adaptive immune system cells promote inflammation and contribute to tissue damage. Type I interferons (IFNs), IFNγ, interleukin (IL)-6, IL-12, IL-21, and IL-23 mediate inflammation by altering the function of local tissue cells and activating T cells, B cells, macrophages, and dendritic cells in target organs.
The search for effective small molecules led to the discovery of tyrosine kinase 2 (TYK2) inhibitors. TYK2 is required for signaling through IFN-α, IL-12, and IL-23. Importantly, TYK2 has also been validated as a therapeutic target by studies examining the use of oral TYK2 inhibitors in Phase 3 studies in psoriasis, as well as a Phase 2 study in SLE with deucravacitinib. Based on available clinical data it appears these inhibitors’ specificity for TYK2 avoids the safety liabilities associated with Janus kinase (JAK) inhibitors.
Based on its ability to inhibit key signaling pathways driving immune activation and tissue damage, ESK-001 has the potential to downregulate inflammation and reduce tissue damage in SLE.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Participant and Investigator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 70.00 Year(s)（—）
- 性别
- All
入选标准
- •Able and willing to provide written informed consent (signed and dated) to participate in this study and comply with all requirements in the study protocol
- •Males or females, age 18 to 70 years, inclusive, at the time of informed consent
- •Body mass index 18 to 40 kg/m2 and total body weight >40 kg (88 lbs).
- •Adequate peripheral venous access
- •Diagnosed with SLE ≥6 months prior to screening, fulfills the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria at the time of screening, AND has at least one of the following: i) Positive antinuclear antibody test at screening by immunofluorescent assay at the central laboratory with titer ≥1:80; ii) Elevated anti-dsDNA antibodies as determined by the central laboratory; iii) Elevated anti-Smith antibody at screening as determined by the central laboratory; or IV) C3 or C4 below the lower limit of normal as determined by the central laborator
- •During screening and prior to first administration of study drug, Central Review Team’s confirmation of the following: 6.a SLEDAI-2K Criteria: At screening the SLEDAI-2K score of ≥
- •â€œClinical†SLEDAI-2K score of ≥4 points.
- •The “Clinical†SLEDAI-2K is the SLEDAI-2K assessment score without the inclusion of points attributable to any urine or laboratory results including immunologic measures:
- •Includes points from the following clinical components: arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy, pericarditis, and vasculitis
- •Excludes points attributable to fever, an SLE headache, and organic brain syndrome 6b BILAG-2004 Index Level Criteria: At least 1 of the following:
- •BILAG-2004 Index level A disease in at least 1 body/organ system 1.a Excludes scores from Lupus Headache 1.b BILAG-2004 Index level B disease in more than 1 body/organ system 2.a Excludes scores from Lupus Headache 2.b PGA score of >1.0 on a 0 to 3 VAS at screening
- •Clinical SLEDAI-2K score ≥4 points with skin involvement prior to first administration of study drug
- •Currently receives at least 1 of the following: 8.a A stable dose of oral corticosteroid (≤40 mg/day prednisone or equivalent) for a minimum of 2 weeks prior to signing of the informed consent form (ICF) at the Screening Visit.
- •The dose of oral corticosteroid the patient is taking should not increase between screening and Week 0 (Day 1).
- •i) If corticosteroid is the only medication used for SLE activity, the daily dose must have been ≥10 mg and ≤40 mg prednisone equivalent for a minimum of 8 weeks prior to screening, and stable ≥10 mg and ≤40 mg for at least 2 weeks prior to screening.
- •8.b And/or antimalarial treatment (e.g., hydroxychloroquine, chloroquine, quinacrine), 8.c And/or no more than 1 of the following conventional DMARDS: i) Azathioprine ≤200 mg/day ii) Mycophenolate mofetil ≤2 g/day or mycophenolic acid ≤1.44 g/day iii) Oral, subcutaneous, or intramuscular (IM) methotrexate ≤20 mg/week.
- •Negative serum ß-human chorionic gonadotropin (ß-hCG) test at screening (women of childbearing potential [WOCBP] only) 9.a WOCBP must agree to adhere to highly effective methods of contraception for the entirety of the study and for 30 days after the last dose of study drug 9.b Nonsterilized male patients who are sexually active with WOCBP must agree to use highly effective methods of contraception for the entirety of the study and for 90 days after the last dose of study drug
- •At Day 1, prior to randomization i) “Clinical†SLEDAI-2K score of ≥4 points ii) OC dose stable for at least 2 weeks iii) WOCBP must have a negative urine pregnancy test prior to administration of IP.
排除标准
- •Any acute or chronic illness/condition or evidence of an unstable clinical condition that, in the Investigator’s judgment, will substantially increase the risk to the patient if he or she participates in the study.
- •Current or history within 1 year of screening of alcohol or drug abuse (excluding cannabis) based on Investigator’s clinical judgment.
- •Pregnant, lactating, or planning to get pregnant during the study period and for 1 month after study completion or discontinuation
- •Patients with QTcF >450 msec on ECG at screening
- •Unstable cardiovascular disease, defined as a recent clinical deterioration (eg, unstable angina,rapid atrial fibrillation) or a cardiac hospitalization within the last 3 months.
结局指标
主要结局
Group (BILAG)-based Composite Lupus
时间窗: up to 48 weeks
Assessment (BICLA) response at Week 48
时间窗: up to 48 weeks
between doses of ESK-001 & placebo
时间窗: up to 48 weeks
To compare the effect on disease activity
时间窗: up to 48 weeks
measured by the proportion of patients
时间窗: up to 48 weeks
achieving British Isles Lupus Assessment
时间窗: up to 48 weeks
次要结局
- To assess the safety & tolerability of(multiple dose levels of ESK-001)
- To compare the effect on disease activity(measured by the proportion of patients)
- To compare the annualized flare rate through(Week 48)
- To compare the effect on health-related(quality of life (HRQOL) between doses of)
- To compare disease-specific QoL between(doses of ESK-001 & placebo)
- To compare Fatigue measured by FACIT-F(between doses of ESK-001 & placebo)
- To compare patient global assessment of(disease activity (PtGA) between doses of)
- To compare corticosteroid use in patients at(Week 48)
- To compare the effect on cutaneous disease(activity measured by the proportion of)
- To compare the Lupus Low Disease Activity(State (LLDAS) response between doses of)