Phase IIa Study for IPG11406 in Patients With Lupus Nephritis

This is a multi-center, multi-dose phase Ib/IIa study to evaluate the safety, tolerability, preliminary efficacy, pharmacokinetics, and impact on biomarkers of IPG11406 in patients with Lupus Nephritis.

This study has two parts.In Part A1, there will be 3 dose groups, 20 mg bid (Cohort 1), 40 mg bid (Cohort 2), 80 mg bid (Cohort 3).In Cohorts 1 to 3, there will be 3-6 participants in each cohort.In Part A2, dose expansion will be conducted at the proposed recommended Phase 2 dose (RP2D). All subjects will be screened within 28 days before administration, and eligible subjects will be administered and observed for 28 days after screening. In this part, it is planned to recruit about 36 patients with nephritis.

After each cohort has completed the 28-day dosing and evaluation, the safety monitoring committee (SMC) will evaluate the safety and tolerability of IPG11406 based on all accumulated safety data (including follow-up data) and available PK data. Based on the evaluation results of safety and tolerability, the SMC will decide whether to administer the next dose group.Part A1 will determine the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of IPG11406.

The design of Part B will be finalized based on the results of Part A.

Criteria for Inclusion and Exclusion <Inclusion Criteria>

• Aged 18-70 years (inclusive), male or female.
• In line with the revised classification criteria of the American College of Rheumatology (ACR) 1997, adult subjects diagnosed with systemic lupus erythematosus prior to screening.
• Confirmed disease activity during screening: SLEDAI-2K score ≥6.
• The patient's 24-h urine protein-to-creatinine ratio (UPCR) is >0.5 g/g or 24-h urine protein is ≥0.5 g during the screening period, and the estimated glomerular filtration rate (eGFR) calculated using the MDRD formula is ≥60 mL/min/1.73 m^2.
• The patient's baseline blood IFN-γ level exceeded the upper limit of normal (Part B only).
• Patients with baseline peripheral blood Th1/Th2 ratio ≥14 (Part B only).
• (1) Subjects who have not received induction therapy or have not received treatment in the past 2 months are allowed to be enrolled, but other treatments for systemic lupus erythematosus and lupus nephritis (including hormones, immunosuppressants, hydroxychloroquine sulfate, and biologics) are not allowed to be added during the study and follow-up period except for the study treatment.

(2) Subjects are allowed to be receiving any of the following standard treatment regimens at the time of enrollment: 1) Oral prednisone (or equivalent) monotherapy: a. Treatment duration: ≥ 2 weeks prior to screening and have a stable dose for ≥ 2 weeks prior to enrollment; b. Dose requirements: maximum daily dose: 1 mg/kg/day; 2) Immunosuppressants: a. Permitted medications include: antimalarials, azathioprine, cyclophosphamide, mycophenolate mofetil/mycophenolic acid, methotrexate, cyclosporine A, and tacrolimus; b. Treatment duration: ≥ 12 weeks prior to screening and have a stable dose for ≥ 8 weeks prior to enrollment; c. Dose requirements: hydroxychloroquine ≤ 400 mg/day, azathioprine ≤ 100 mg/day, cyclophosphamide ≤ 800 mg/4 weeks, mycophenolate mofetil/mycophenolic acid ≤ 2 g/day, oral, subcutaneous (SC), or intramuscular methotrexate ≤ 15 mg/week, cyclosporine A ≤ 3 mg/kg/day, tacrolimus ≤ 3 mg/day; 3) Oral prednisone (or equivalent) monotherapy ± hydroxychloroquine sulfate ± ≥ one immunosuppressant a. The above requirements for treatment duration and dose stability of oral corticosteroids (OCS) and immunosuppressants should be met; b. The maximum daily/weekly dose of each drug in 1) and 2) should not be exceeded.

8.Female subjects are required to be non-pregnant and non-lactating during the trial.

9.Subjects who do not have a pregnancy plan, voluntarily take effective contraceptive measures (see the Appendix for details), and have no sperm or egg donation plan from screening to 6 months after the end of the study.

The subject voluntarily participates in the study, is able to sign the informed consent form, and complies with the requirements on the informed consent form.

<Exclusion Criteria>

• Pregnant and lactating women.
• Have participated in other clinical trials within 3 months before screening and/or are currently participating in other clinical trials (except for those who have not used the investigational product).
• Active severe lupus nephritis with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2 calculated using the MDRD formula.
• Severe neuropsychiatric SLE includes, but is not limited to, the following: seizures, new or worsening impaired level of consciousness, psychosis, delirium or confusional state, aseptic meningitis, ascending or transverse myelitis, chorea, cerebellar ataxia, mononeuritis multiplex, demyelinating syndromes, or any condition that prevents the subject from fully understanding the ICF.
• History or current diagnosis of clinically significant non-SLE-associated vasculitis syndrome or overlap with other connective tissue diseases.
• Any active dermatologic disease other than SLE that may interfere with study assessments of SLE, including but not limited to psoriasis, dermatomyositis, systemic sclerosis, non-SLE cutaneous lupus manifestations (eg, cutaneous vascular disease, periungual telangiectasias, sclerodactyly, rheumatoid nodules, erythema multiforme, leg ulcers), or drug-induced lupus.
• Those who have had or are currently suffering from malignant tumors in the past 5 years (except for skin squamous cell carcinoma in situ, basal cell carcinoma, papillary thyroid carcinoma, and cervical carcinoma in situ that have undergone radical treatment and do not have any evidence of recurrence).
• Patients with uncontrolled anticardiolipin antibody syndrome (APS).
• With a history of major organ transplantation (e.g., heart, lung, kidney, and liver) or hematopoietic stem cell/bone marrow transplantation.
• Major surgical procedure (craniotomy, thoracotomy, or laparotomy), or unhealed wounds, ulcers, or fractures within 4 weeks prior to screening.
• Have received a live/attenuated vaccine within 8 weeks before screening or plan to receive a live/attenuated vaccine during the trial.
• Those who are allergic to the study drugs (including excipients), suffer from severe allergic diseases, or are allergic constitution (such as allergic to two or more drugs, food, or pollen), which may cause damage to the safety of the subjects as judged by the investigator.
• Has any of the following cardiac impairment at screening: a. New York Heart Association (NYHA) Class III-IV; b. Uncontrolled angina, congestive heart failure, or myocardial infarction within 6 months prior to the first dose; c. QTcF prolongation calculated by Fridericia's formula (> 450 msec for males; > 470 msec for females); d. type II second degree atrioventricular (AV) block, third degree atrioventricular (AV) block or PR interval > 250 ms, etc.; e. various factors that may increase the risk of QTcF prolongation or arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, and unexplained sudden death before 40 years of age in first-degree relatives in family history; f. Left ventricular ejection fraction (LVEF) < 50%.
• Has active or latent tuberculosis infection at screening.
• Presence of serious herpes virus infections at screening, such as herpes encephalitis, disseminated herpes, and ophthalmic herpes.
• Use of intravenous anti-infectives (including antivirals and antibiotics) for infections within 4 weeks prior to screening.
• Has been hospitalized for an opportunistic infection within 3 months prior to screening.
• Have been treated with Chinese patent medicines such as Tripterygium wilfordii within 4 weeks before screening.
• HBsAg-positive in hepatitis B panel (HBsAg-negative but HBcAb-positive, additional HBV-DNA quantitative test is required; patients with HBV-DNA test results ≥ the upper limit of reference value at each site or requiring antiviral therapy are ineligible for study participation), hepatitis C antibody-positive (additional HCV-RNA test may be performed; if negative, the patient may be enrolled), Treponema pallidum antibody-positive (if Treponema pallidum antibody is positive, a further Treponema pallidum serological test should be performed; patients who have been infected with syphilis but have been cured as judged by the investigator are eligible), and HIV antibody-positive.
• Subjects with significant abnormalities in liver and kidney functions and hematology at screening, including: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN), serum total bilirubin > 1.5 × ULN, hemoglobin < 90 g/L, white blood cell count < 3.0 × 10^9/L, platelet count (PLT) < 75 × 10^9/L, and neutrophil count < 1.0 × 10^9/L; other abnormal laboratory test results that, in the judgment of the investigator, may affect the subject's completion of the trial or interfere with the trial results.
• Dysphagia.
• have a history of drug abuse or substance abuse.
• Subjects with acute diseases prior to the use of the investigational product. Other conditions judged by the investigator to be unsuitable for enrollment.