Phase 2 Placebo-Controlled Study to Assess the Safety and Efficacy of ESK-001 in Active Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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The purpose of this study is to assess the clinical efficacy, safety, PK, and PD of multiple dose levels of ESK-001 compared with placebo in adult patients with SLE.

Detailed Description
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This study will consist of a 5 week screening period, 48 week treatment period, and a 4 week follow up period for a total of 57 weeks. Each participant will be randomized to receive ESK-001 or placebo for 48 weeks. An open label extension study will be available for those patients who complete the study.

Official Title
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A Phase 2, Multicenter, Multinational, Randomized, Double-blind, Placebo-Controlled Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Dose Levels of ESK-001 in Adult Patients With Systemic Lupus Erythematosus

Conditions
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SLE

Intervention / Treatment
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* Drug: ESK-001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with 6 or more months of SLE according to the 2019 EULAR/ACR criteria, have positive autoantibodies or low complement at screening, and have active SLE as measured by SLEDAI-2K of 6 or more, or 4 or more if joint involvement is present. Patients need to be on treatment which can be: 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). And/or antimalarial treatment (e.g., hydroxychloroquine, chloroquine, quinacrine), And/or no more than 1 of the following conventional DMARDS: Azathioprine ≤200 mg/day Mycophenolate mofetil ≤2 g/day or mycophenolic acid ≤1.44 g/day Oral, subcutaneous, or intramuscular (IM) methotrexate ≤20 mg/week. Exclusion Criteria: Drug-induced SLE or other autoimmune diseases that, in the opinion of the Investigator, are likely to confound efficacy assessments Active, proliferative lupus nephritis that in the Investigator's opinion may require treatment not allowed by the protocol Current disease other than SLE that, in the opinion of the Investigator, is likely to interfere with SLE disease activity assessments. Examples include severe fibromyalgia, severe osteoarthritis and severe cardiorespiratory diseases. Active severe or unstable neuropsychiatric SLE including, but not limited to the following: aseptic meningitis; cerebral vasculitis; myelopathy; demyelination syndromes (ascending or transverse myelitis, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy; new seizures; cerebellar ataxia; and mononeuritis multiplex. That would make the patient unable to fully understand the ICF, or Where, in the opinion of the Principal Investigator, protocol-specified SOC is insufficient and utilization of a more aggressive therapeutic approach not permitted in the protocol, is indicated Known history of a primary immunodeficiency or an underlying condition such as HIV infection or splenectomy that predisposes the patient to infection Currently active, clinically significant infection of any kind Clinically significant chronic infection (eg, osteomyelitis, bronchiectasis) within 8 weeks prior to signing the ICF (chronic fungal nail infections are allowed) Any infection requiring hospitalization or treatment with IV anti-infectives not completed at least 4 weeks prior to signing the ICF Any infection requiring oral anti-infectives (including antivirals) within 2 weeks prior to Day 1 Any severe herpes infection at any time prior to Week 0 (Day 1), including, but not limited to, disseminated herpes (ever), herpes encephalitis (ever), recurrent herpes zoster (defined as 2 episodes within 2 years), or ophthalmic herpes (ever) Active herpes zoster infection within 12 weeks of prior to signing the ICF Active herpes simplex virus within 4 weeks of Day 1 Other protocol-defined inclusion/exclusion criteria apply

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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ESK-001 Dose Level 1<br>ESK-001 administered as an oral tablet | Drug: ESK-001<br>* Oral tablet<br>|
| Experimental: ESK-001 Dose Level 2<br>ESK-001 administered as an oral tablet | Drug: ESK-001<br>* Oral tablet<br>|
| Experimental: ESK-001 Dose Level 3<br>ESK-001 administered as an oral tablet | Drug: ESK-001<br>* Oral tablet<br>|
| Placebo Comparator: Placebo<br>Placebo administered as an oral tablet | Drug: Placebo<br>* Oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the effect on disease activity measured by the proportion of patients achieving British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response at Week 48 between doses of ESK-001 and placebo |  | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety and tolerability of multiple dose levels of ESK-001 | Safety and Tolerability will be assessed with clinical and laboratory assessments including blood tests for liver and kidney function, ECGs, hematological measures and physical examinations throughout the time of the study and safety follow up. The number and proportion of TEAEs, SAEs, AEs of greater than grade 3 severity and AEs of Clinical Interest will be recorded. | Week 48 | 
| To compare the effect on disease activity measured by the proportion of patients achieving an SLE Responder Index of ≥4 (SRI[4]) response at Week 48 |  | Week 48 | 
| To compare corticosteroid use in patients at Week 48 | To compare the number and percentage of patients using corticosteroids and continuous summaries of dose used will be assessed as well as the frequency and percentage of patients able to taper corticosteroids and maintain low doses following taper. | Week 48 | 
| To compare the effect on cutaneous disease activity measured by the proportion of patients with a CLASI activity score of ≥8 at baseline achieving ≥ 50% reduction in the CLASI activity score at Week 48 between doses of ESK-001 and placebo |  | Week 48 | 
| To compare the effect on disease activity measured by the proportion of patients achieving BICLA responses at Week 48 between doses of ESK-001 and placebo by stratification groups |  | Week 48 | 
| To compare the Lupus Low Disease Activity State (LLDAS) response between doses of ESK-001 and placebo at Week 48 |  | Week 48 | 
| To compare the annualized flare rate through Week 48 |  | Week 48 | 
| To use the SF-36 (Short Form-36 item QoL measure) to compare the effect on health-related quality of life (HRQOL) between doses of ESK-001 and placebo | Efficacy: Comparing the effects of Esk-001 doses vs Placebo on Patient Reported Outcome (PRO) as it relates to Health-Related Quality of Life (HRQoL) as measured by self-reporting using the SF-36 (Short Form-36 item QoL measure) Questionnaire which uses a scale of 0 to 100. The higher numbers mean better health. | Week 48 | 
| To use the SLE-specific Lupus Quality of Life (LQoL) questionnaire to compare the effect on health-related quality of life (HRQOL) between doses of ESK-001 and placebo | Efficacy: Comparing the effects of Esk-001 doses vs Placebo on Patient Reported Outcome (PRO) as it relates to Health-Related Quality of Life (HRQoL) as measured by self-reporting using the SLE-specific Lupus Quality of Life (LQoL) questionnaire which uses a scale of 0 to 100. The higher numbers mean better health. | Week 48 | 
| To compare disease-specific QoL between doses of ESK-001 and placebo | Efficacy: To compare disease-specific QoL between doses of ESK-001 and placebo using the SLE Disease Activity Index 2000 (SLEDAI2K) measured on a scale of 0 to 105 where the higher numbers mean more disease activity. | Week 48 | 
| To compare disease-specific QoL between doses of ESK-001 and placebo | Efficacy: To compare disease-specific QoL between doses of ESK-001 and placebo using the British Isle Lupus Assessment Group 2004 (BILAG-2004) with a scale of A to E (A meaning very active disease and E no current or previous disease). | Week 48 | 
| To compare disease-specific QoL between doses of ESK-001 and placebo | Efficacy: To compare disease-specific QoL between doses of ESK-001 and placebo using the Physician's Global Assessment (PGA) evaluating disease response using the 4-point VAS (Visual Analog Scale) of 0 to 3 (0 means no flares and 3 means severe flare in disease). | Week 48 | 
| To compare Fatigue measured by FACIT-F between doses of ESK-001 and placebo | To compare patient-reported fatigue as measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire between doses of ESK-001 and placebo, where the score range is 0 to 52 and a lower score indicates greater fatigue/worse outcome. | Week 48 | 
| To compare patient global assessment of disease activity (PtGA) between doses of ESK-001 and placebo | Efficacy: To compare disease-specific QoL between doses of ESK-001 and placebo using the PtGA (Patient Global Assessment) instrument. Patients record on a visual analog scale (VAS) how well or badly they feel as a result of the disease in their own estimation over the course of the study. | Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autoimmune Diseases, Immune System Diseases, Connective Tissue Diseases, Immune-mediated Diseases, Active Systemic Lupus Erythematosus, SLE, Lupus, LUMUS, Lupus Erythematosus, Systemic