Phase 1b/2a Study to Evaluate Safety and Efficacy of KPG-818 in SLE

Study Overview
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Brief Summary
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Study Title A phase 1b/2a multicenter, randomized, double-blind, placebo-controlled study to assess the safety and tolerability, pharmacokinetics and preliminary efficacy of KPG-818 in patients with mild to moderate systemic lupus erythematosus

Detailed Description
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This is a Phase 1b/2a multicenter study to evaluate the safety, PK, PD, and clinical efficacy of KPG-818 in patients with SLE. The trial will consist of 2 parts: Phase 1b, a multiple-ascending dose (MAD) study; and Phase 2a, a proof of concept (POC) study.

Official Title
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A Phase 1b/2a Multicenter Study to Assess the Safety and Tolerability, Pharmacokinetics, and Preliminary Efficacy of KPG-818 in Patients With Systemic Lupus Erythematosus

Conditions
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SLE; Drug

Intervention / Treatment
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* Drug: KPG-818 low dose
* Drug: KPG-818 mid dose
* Drug: KPG-818 high dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria are listed as follows: Age≥18 BMI between 18-40kg/m² Diagnosed with SLE according to the 2019 EULAR/ACR criteria for SLE Meeting SLE activity requirements Males and females childbearing potential must agree to use contraception methods All patients must: Understand that KPG-818 could have potential teratogenic risk. Agree not to share KPG-818 with another person. Be counseled about pregnancy precautions and risks of fetal exposure as described in the Pregnancy Prevention Plan. Patients must agree not to donate blood (or any component of blood) from 3 months before Screening until 3 months after the last dose of KPG-818. Patients must be willing to comply with precautions to reduce the risk of COVID-19 infection and to undergo COVID-19 PCR test. Exclusion criteria are listed as follows: Use of any prohibited medications within the pre-specified time Patients must meet exclusionary lab criteria Active and/or unstable neuropsychiatric SLE Active or history of severe systemic bacterial, viral, fungal, mycobacterial, or parasitic infections within 6 months prior to Screening Current or recent sign or symptoms of infections, or severe viral infections Conditions predisposes patient to infection Active TB or positive QuantiFERON®-TB Gold test Patients with malignancy and antiphospholipid syndrome history Inflammatory joint or skin disease, mixed connective tissue disease, scleroderma, and/or overlap syndromes, or acute or chronic disease Concomitant condition that required systemic corticosteroid use within 1 year before Screening Alcohol or drug abuse history Positive urine drug test at screening History or planned major surgery Pregnant or breastfeeding female Signs or symptoms of COVID-19 infection Known allergic reaction to any of the ingredients for study drug or placebo

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: KPG-818 low dose<br>After providing informed consent, patients will be assessed for study eligibility at the Screening visit. A total of 8 to 12 patients will be randomized to receive this dose level of KPG-818 in a double-blind fashion. Patients will receive treatment for 12 weeks with a 4-week safety follow-up. Capsules of this level of dosage will be taken orally in the morning once a day. All patients will return for follow-up visits after their final dose. The total duration of study participation for each patient (from Screening through Follow-up visit) is anticipated to be approximately 20 weeks. | Drug: KPG-818 low dose<br>* The dose levels may be modified according to the results from phase 1b of the study. Dose adjustment is allowed during the study.<br>|
| Active Comparator: KPG-818 mid dose<br>After providing informed consent, patients will be assessed for study eligibility at the Screening visit. A total of 8 to 12 patients will be randomized to receive this dose level of KPG-818 in a double-blind fashion. Patients will receive treatment for 12 weeks with a 4-week safety follow-up. Capsules of this level of dosage will be taken orally in the morning once a day. All patients will return for follow-up visits after their final dose. The total duration of study participation for each patient (from Screening through Follow-up visit) is anticipated to be approximately 20 weeks. | Drug: KPG-818 mid dose<br>* The dose levels may be modified according to the results from phase 1b of the study. Dose adjustment is allowed during the study.<br>|
| Active Comparator: KPG-818 high dose<br>After providing informed consent, patients will be assessed for study eligibility at the Screening visit. A total of 8 to 12 patients will be randomized to receive this dose level of KPG-818 in a double-blind fashion. Patients will receive treatment for 12 weeks with a 4-week safety follow-up. Capsules of this level of dosage will be taken orally in the morning once a day. All patients will return for follow-up visits after their final dose. The total duration of study participation for each patient (from Screening through Follow-up visit) is anticipated to be approximately 20 weeks. | Drug: KPG-818 high dose<br>* The dose levels may be modified according to the results from phase 1b of the study. Dose adjustment is allowed during the study.<br>|
| Placebo Comparator: Placebo arm<br>After providing informed consent, patients will be assessed for study eligibility at the Screening visit. A total of 8 to 12 patients will be randomized to receive this dose level of KPG-818 in a double-blind fashion. Patients will receive treatment for 12 weeks with a 4-week safety follow-up. Capsules of this level of dosage will be taken orally in the morning once a day. All patients will return for follow-up visits after their final dose. The total duration of study participation for each patient (from Screening through Follow-up visit) is anticipated to be approximately 20 weeks. | Drug: Placebo<br>* This is the comparative arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessment by the occurrence of adverse events (AEs) | To calculate the occurrence rate of adverse events (AEs) | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| Safety assessment by the changes from baseline in laboratory parameters | To calculate the occurrence rate of out of normal ranges of laboratory parameter changes from baseline. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| Safety assessment by out of normal range of vital signs | To calculate the occurrence rate of out of normal range of vital signs from baseline. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| Safety assessment by out of normal range of ECG results | To calculate the occurrence rate of out of normal range of ECG results. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of time to peak (Tmax) for KPG-818 and KPG-818H (if applicable). | This will be measured on Day 1 after dose administration and after the plasma concentration reaches a steady state. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of peak plasma concentration (Cmax) for KPG-818 and KPG-818H (if applicable). | This will be measured on Day 1 after dose administration. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of elimination half-life (t1/2) for KPG-818 and KPG-818H (if applicable). | This will be measured on Day 1 after dose administration and after the plasma concentration reaches a steady state. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of the area under the concentration-time curve (AUC0-24h) for KPG-818 and KPG-818H (if applicable). | This will be measured on Day 1 after dose administration. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of the mean retention time (MRT) for KPG-818 and KPG-818H (if applicable). | This will be measured after the plasma concentration reaches a steady state. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of trough concentrations at steady state (Css_min) for KPG-818 and KPG-818H (if applicable). | This will be measured after the plasma concentration reaches a steady state. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of peak concentrations at steady state (Css_max) for KPG-818 and KPG-818H (if applicable). | This will be measured after the plasma concentration reaches a steady state. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of the area under the concentration-time curve at steady state (AUCτ, AUC0-∞) for KPG-818 and KPG-818H (if applicable). | This will be measured after the plasma concentration reaches a steady state. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of the clearance (CL/F) for KPG-818 and KPG-818H (if applicable). | This will be measured after the plasma concentration reaches a steady state. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of the apparent volume of distribution ((Vz/F) for KPG-818 and KPG-818H (if applicable). | This will be measured after the plasma concentration reaches a steady state. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| PK profile of the cumulative coefficient (R) for KPG-818 and KPG-818H (if applicable). | This will be measured after the plasma concentration reaches a steady state. | 4 weeks for phase Ib and 16 weeks for phase IIa | 
| Assess the proportion of patients with improvement of clinical scores of SELENA-SLEDAI (safety of estrogens in lupus national assessment-systemic lupus erythematosus disease activity index) improvement ≥ 4 points from baseline at Week 12. | To calculate the proportion of patients with SELENA-SLEDAI (safety of estrogens in lupus national assessment-systemic lupus erythematosus disease activity index) improvement ≥ 4 points from baseline at Week 12. Note: the SELENA-SLEDAI scale ranges from 0 105, with 105 as the highest disease activity. | 16 weeks for phase IIa | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in PGA (Physician Global Assessment) score at Week 12. | Mean change from baseline in PGA (Physician Global Assessment) score at Week 12. Note: the PGA is a visual scale for the physician to mark, from 0mm to 100mm, with 0mm being no disease activity and 100mm being the extreme disease activity. | 16 weeks for phase IIa | 
| The proportion of patients with a ≥ 50% reduction from baseline in CLASI (Cutaneous Lupus erythematosus disease Area and Severity Index) activity score at Week 12, in patients with baseline CLASI activity score ≥ 10. | The proportion of patients with a ≥ 50% reduction from baseline in CLASI (Cutaneous Lupus erythematosus disease Area and Severity Index) activity score at Week 12, in patients with baseline CLASI activity score ≥ 10. Note: the total CLASI score ranges from 0 to 114, with 0 being the least disease activity and 114 being the most. | 16 weeks for phase IIa | 
| Number of patients with adverse event at Week 12 | Number of patients with adverse event at Week 12 | 12 weeks for phase IIa | 
| Number of patients with adverse event at Week 16. | Number of patients with adverse event at Week 16. | 16 weeks for phase IIa | 
| The PK endpoint of the measurement of area under the curve (AUC) at Week 12 (AUC0-last) for assessment of KPG-818 and KPG-818H (if applicable). | The PK endpoint of the measurement of area under the curve (AUC) at Week 12 (AUC0-last) for assessment of KPG-818 and KPG-818H (if applicable). | 12 weeks for phase IIa | 
| The PK endpoint of the maximum observed concentration (Cmax) at Week 12 for assessment of KPG-818 and KPG-818H (if applicable) | The PK endpoint of the maximum observed concentration (Cmax) at Week 12 for assessment of KPG-818 and KPG-818H (if applicable) | 12 weeks for phase IIa | 
| The PK endpoint of time to Cmax (tmax) at Week 12 for assessment of KPG-818 and KPG-818H (if applicable) | The PK endpoint of time to Cmax (tmax) at Week 12 for assessment of KPG-818 and KPG-818H (if applicable). | 12 weeks for phase IIa | 
| The PK endpoint of Ctrough throughout the dosing period for assessment of KPG-818 and KPG-818H (if applicable) | The PK endpoint of Ctrough throughout the dosing period for assessment of KPG-818 and KPG-818H (if applicable) | 12 weeks for phase IIa | 
| The PK endpoint of serum concentrations by scheduled timepoints for assessment of KPG-818 and KPG-818H (if applicable) | The PK endpoint of serum concentrations by scheduled timepoints for assessment of KPG-818 and KPG-818H (if applicable) | 12 weeks for phase IIa |