A Study to Assess the Safety and Tolerability, PK and Efficacy of KPG-818 in Mild to Moderate SLE Patients

Study Purpose

SYNOPSIS. 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. Brief Title: Phase 1b/2a study to evaluate safety and efficacy of KPG-818 in SLE. Objectives. Phase 1b. The primary objectives of the study are:

  • - to assess the safety and tolerability of multiple oral doses of KPG-818 in patients with mild to moderate systemic lupus erythematosus (SLE).
  • - to characterize the multiple oral dose pharmacokinetics (PK) of KPG-818 and its metabolite, KPG-818H, at Week 2.
The exploratory objectives of the study are: • to evaluate the change from baseline in potential biomarkers (Aiolos, Ikaros, CRBN proteins) of KPG-818 in peripheral blood mononuclear cells and CD19+ B Cell at Week 2. Phase 2a. The primary objective of the study is: • to evaluate the preliminary efficacy of KPG-818 on disease activity by the change from baseline in Safety of Estrogens in Lupus National Assessment (SELENA)- Systemic Lupus Erythematosus Disease Activity Index (SLEDAI, SELENA- SLEDAI) at Week 12. The secondary objectives of the study are:
  • - to evaluate the efficacy of KPG-818 by the change from baseline in Physician Global Assessment (PGA) at Week 12.
  • - to evaluate the effects of KPG-818 by the change from baseline in cutaneous manifestations by the change in Cutaneous Lupus erythematosus disease Area and Severity Index (CLASI) activity score of SLE Week 12.
  • - to assess the safety and tolerability of multiple oral doses of KPG-818 at Week 12.
  • - to assess the safety and tolerability of multiple oral doses of KPG-818 at Week 16.
  • - to characterize the multiple oral dose pharmacokinetics (PK) of KPG-818 and its metabolite, KPG-818H, at Week 12.
The exploratory objectives of the study are:
  • - to evaluate the change from baseline in potential biomarkers (Aiolos, Ikaros, CRBN proteins) of KPG-818 in peripheral blood mononuclear cells and CD19+ B Cell at Week 12.
  • - to evaluate pharmacodynamics of KPG-818 at Week 12.
  • - to select dosing regimens for a Phase 2b/phase 3 study.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion Criteria

Inclusion criteria are listed as follows: 1. Male or female of 18 years of age or older at the time of signing the informed consent form (ICF). 2. Body mass index (BMI) between 18 and 40 kg/m2. 3. Able and willing to adhere to the visit schedule and other protocol requirements. 4. Fulfils the 2019 EULAR/ACR classification criteria for SLE (See Appendix 1). 5. Fulfils below requirements:

  • - For the Phase 1b part of the study, patients with or without active SLE may be enrolled if, in the opinion of the Investigator, the disease activity is stable and there will be no need for change or increase in SLE therapy anticipated for the study duration.
If patients are on stable standard care of SLE treatment, this should comply with inclusion criteria No. 11.
  • - For the Phase 2a part of the study, patients must have a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) score of ≥ 6 points at Screening visit with a SLEDAI-2K clinical score ≥ 4 points at Baseline visit.
The "clinical" score is the SLEDAI-2K assessment score without the inclusion of points attributable to any urine or blood laboratory results including immunologic measures. Neurologic descriptors of the SLEDAI-2K are not counted towards the SLEDAI study entry criteria. In addition, the patient must be on stable standard care of SLE treatment with at least one of the followings: oral corticosteroids (OCS), anti-malarial, or immunosuppressant (see inclusion criteria No. 11 for allowed medications and doses). 6. Documented history or presence at Screening of positive autoantibodies associated with SLE, which must include at least 1 of the following:
  • - Positive antinuclear antibody (ANA) test with a titer of 1:80 or greater.
  • - Anti-dsDNA antibodies elevated to above normal.
  • - Anti-Smith antibody elevated to above normal.
7. Women of childbearing potential (WOCBP) must:
  • - Have 2 negative serum pregnancy tests as verified by the Investigator prior to starting study therapy, 1 at Screening and again within 3 days before taking the first dose of KPG-818, then have a negative urine pregnancy test at Baseline before dosing.
WOCBP must agree to ongoing pregnancy testing during the course of the study and after end of study treatment. This applies even if the patient practices true abstinence from heterosexual contact.
  • - Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use 2 forms of reliable contraception simultaneously.
One must be a highly effective method and 1 additional effective (barrier) method (see Appendix 5 for more details), and both must be practiced without interruption, at least 28 days before starting investigational medicinal product (IMP), during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy. 8. Male patients must: Practice true abstinence or agree to use a barrier contraception (male latex condom or non-latex condom NOT made out of natural [animal] membrane [for example, polyurethane]) during sexual contact with WOCBP while participating in the study, and for at least 90 days following IMP discontinuation, even if he has undergone a successful vasectomy. Male patients must agree not to donate semen or sperm during the treatment period and for at least 90 days following the discontinuation of KPG-818. 9. Female patients who are postmenopausal must demonstrate a follicle stimulating hormone (FSH) blood levels of equal or greater than 40 mIU/mL at the Screening visit. Women aged > 60 years old whose FSH values are not equal or greater than 40 mIU/mL may be included at the discretion of the Investigator and in consultation with the Sponsor (see Appendix 5 for more details). 10. 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.
11. In Phase 2a part of the study, the patient must be on stable standard care of SLE treatment with at least one of the followings: oral corticosteroid, anti-malarial, or immunosuppressant: 1. If taking OCS, must be on-treatment for ≥ 4 weeks before the Screening visit, and maintained on a stable dose of ≤ 20 mg/day of prednisone or equivalent for at least 4 weeks before the Baseline visit. 2. If taking an anti-malarial agent (hydroxychloroquine, chloroquine, or quinacrine), must be on-treatment for ≥ 8 weeks before the Screening visit and be on a stable dose for ≥ 4 weeks before the Screening visit. Anti-malarials at the following doses are allowed:
  • - Hydroxychloroquine (≤ 400 mg/day) - Chloroquine (≤ 500 mg/day) - Quinacrine (≤ 200 mg/day) 3.
If taking allowed immunosuppressants, must be on-treatment for ≥ 8 weeks prior to the Screening visit and be on a stable dose for ≥ 4 weeks before the Screening visit. Only 1 of the immunosuppressants below is allowed at the indicated doses:
  • - Micophenolate mofetil (≤ 2 g/day) or mycophenolic acid (≤ 1.44 g/day) - Azathioprine (≤ 200 mg/day) - Methotrexate (≤ 20 mg/week) - Leflunomide (≤ 20 mg/day) 4.
If taking NSAIDs or other regularly administered analgesics, these will be allowed if treatment started ≥ 4 weeks before the Baseline visit and dosing has not been changed within the last 2 weeks before the Baseline visit. 5. If immunosuppressants, anti-malarial, or OCS is discontinued, the last dose must be more than 4 weeks prior to Screening visit. 12. 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. 13. Patients must be willing to comply with precautions to reduce the risk of COVID-19 infection in accordance with recommendations from the applicable medical associations and the Investigator for the duration of the study, and to undergo COVID-19 polymerase chain reaction (PCR) test as required based on the Investigator judgment and/or local requirements. Exclusion criteria are listed as follows: 1. Must be off prohibited medications for a pre-specified period of time (see Appendix 6 for more details). 2. Any of the following noted at Screening (within 6 weeks before Week 1 [Day 1] in Phase 1b, within 4 weeks before Week 1 [Day 1] in Phase 2a):
  • - Aspartate aminotransferase (AST) > 2.0 × ULN.
  • - Alanine aminotransferase (ALT) > 2.0 × ULN.
  • - Total bilirubin > 1.5 × ULN (unless due to Gilbert's syndrome) - Serum creatinine > 2.5 mg/dL (or > 221 μmol/L) - Neutrophil count < 1500/µL (or < 1.5 × 109/L) (< 1000/µL [or < 1.0 × 109/L] if the neutropenia is related to SLE) - Platelet count < 50 000/µL (or < 50 × 109/L) (< 25 000/µL [or < 25 × 109/L] if the thrombocytopenia is related to SLE) - Hemoglobin < 8 g/dL (or < 80 g/L) (< 7 g/dL [or <70 g/L] if related to SLE) 3.
Have an estimated glomerular filtration rate (eGFR) of < 45 mL/min/1.73 m2 (CKD-EPI formula) at Screening. 4. Have a spot urine protein to creatinine ratio (sUPCR) > 2000 mg/g (226 mg/mmol, as an estimate of approximate proteinuria > 2 g/day) at Screening. 5. Active and/or unstable neuropsychiatric SLE (e.g., neuropsychiatric SLE including seizures, psychosis, acute confusional state, cerebrovascular accident, aseptic meningitis, or polyneuropathy). 6. Positive serology test for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV-1 and HIV-2) at Screening. In cases of a positive screening test, patient may be enrolled if a confirmatory test is negative (see Appendix 3 for details). Exception: patient who test positive for HCV antibodies may be enrolled if confirmed with cured HCV infection and documented completion of treatment more than 3 months before screening and HCV must not be detectable at screening. 7. Active or history of severe systemic bacterial, viral, fungal, mycobacterial, or parasitic infections (requires hospitalizations or IV antibiotics) within 6 months prior to Screening. 8. Any current or recent (within 4 weeks of Screening) signs or symptoms of infection, except for fungal infections of the nail beds, oral or vaginal candidiasis that has resolved, or minor infections (e.g., common cold, viral gastroenteritis, urinary tract infection) that have in the Investigator's judgment, completely resolved prior to the Baseline visit. 9. Any severe, recurrent, disseminated viral infections, particularly herpes viruses such as HSV-1, HSV-2, VZV, CMV (e.g., herpes encephalitis, ophthalmic herpes, disseminated zoster, CMV colitis) per Investigator's judgment. Recurrent is defined as 2 or more episodes in the past 2 years and/or with an episode within 3 months of Screening. 10. Known history of congenital or acquired immunodeficiency, splenectomy, or any underlying condition that predisposes the patient to infection. 11. Active tuberculosis (TB) or a history of incompletely treated TB, or a positive, QuantiFERON®-TB Gold test. If a patient's initial TB test result is indeterminate, the test can be repeated once. If the test result is again indeterminate (or positive), the patient will be excluded from the study. An exception for positive or indeterminate results may be made for patients who have documentation of having completed appropriate standard treatment for latent TB before screening and do not have other risk factors, radiologic findings, or physical evidence supporting latent or active TB. 12. Malignancy or history of malignancy, except for:
  • - Treated (e.g., cured) basal cell or squamous cell in situ skin carcinomas.
  • - Cervical cancer in situ that has been successfully treated.
13. History of antiphospholipid syndrome with thromboembolic event within 12 months of screening or not on an adequate anticoagulation regimen. However, presence of antiphospholipid antibodies alone (without a history of thromboembolic event) is not exclusionary. 14. Other non-SLE driven inflammatory joint or skin disease, mixed connective tissue disease, scleroderma, and/or overlap syndromes. An exception may be allowed for rheumatoid arthritis overlapping with SLE (i.e., RUPUS) with no erosive joint disease after a discussion with the medical monitor. Patients with SLE and secondary Sjogren syndrome are not exclusionary. 15. Clinically significant or unstable or uncontrolled acute or chronic disease not related to SLE that in the Investigator's opinion would preclude patient participation. 16. Concomitant condition (such as asthma) that required systemic corticosteroid use within 1 year before Screening. Use of inhaled corticosteroid is not exclusionary. 17. History of alcohol or drug abuse within 1 year before screening based on the Investigator's judgement. 18. Have a positive urine drug test at screening (see Appendix 3) except if the patient has a valid prescription for an allowed concomitant medication or substance abuse/dependence has been ruled out in the Investigator's judgment. 19. History of major surgery within 12 weeks prior to Screening or any planned major surgery during the study. 20. Clinically significant ECG abnormalities or have a corrected QT (QTc) interval value > 480 ms at Screening, in the Investigator's opinion would preclude patient participation. 21. Pregnant or breastfeeding female. 22. Signs or symptoms that in the opinion of the Investigator, may be suggestive of COVID-19 infection. The patient may be allowed to enter the study if a COVID-19 PCR test performed during the Screening results in a negative outcome. 23. Known allergic reaction to any of the ingredients for study drug or placebo.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT04643067
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Kangpu Biopharmaceuticals, Ltd.
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

N/A
Principal Investigator Affiliation N/A
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Industry
Overall Status Recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

SLE; Drug
Arms & Interventions

Arms

Active Comparator: 0.15mg KPG-818 dose

After providing informed consent, patients will be assessed for study eligibility at the Screening visit. A total of 8 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.

Active Comparator: 0.6mg KPG-818 dose

After providing informed consent, patients will be assessed for study eligibility at the Screening visit. A total of 8 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.

Active Comparator: 2mg KPG-818 dose

After providing informed consent, patients will be assessed for study eligibility at the Screening visit. A total of 8 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.

Placebo Comparator: Placebo arm

After providing informed consent, patients will be assessed for study eligibility at the Screening visit. A total of 8 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.

Interventions

Drug: - 0.15mg KPG-818 dose

The dose levels may be modified according to the results from phase 1b of the study. Dose adjustment is allowed during the study.

Drug: - 0.6mg KPG-818 dose

The dose levels may be modified according to the results from phase 1b of the study. Dose adjustment is allowed during the study.

Drug: - 2mg KPG-818 dose

The dose levels may be modified according to the results from phase 1b of the study. Dose adjustment is allowed during the study.

Drug: - Placebo

This is the comparative arm.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

SouthCoast Research Center Inc, Miami, Florida

Status

Recruiting

Address

SouthCoast Research Center Inc

Miami, Florida, 97213

Site Contact

Adonis M Maiquez

[email protected]

+8618201496205

Altoona Center for Clinical Research, Duncansville, Pennsylvania

Status

Recruiting

Address

Altoona Center for Clinical Research

Duncansville, Pennsylvania, 16635

Site Contact

Alan J Kivitz

[email protected]

+8618201496205