SG301-SC Injection Safety Study in Subjects With Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled phase I clinical study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single dose in healthy volunteers and multiple doses of SG301 SC injection in participants with systemic lupus erythematosus (SLE).

Detailed Description
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This a phase I single ascending dose (SAD) study in healthy volunteers and multiple ascending dose (MAD) study in participants with mild or moderate SLE, which consists of Parts A and B. Part A adopts a single-center, open-label, dose escalation trial design, and Part B adopts a multi-center, randomized, double-blind, placebo-controlled trial design to evaluate the safety, tolerability, PK, and immunogenicity of single dose of SG301 SC Injection in healthy volunteers, as well as the safety, tolerability, PK, PD, immunogenicity, and preliminary efficacy of multiple doses of SG301 SC Injection in patients with mild to moderate SLE. Part A adopts a single-center, open-label, and dose escalation design, where SAD will be performed in healthy volunteers at two tentative dose groups, namely 1 mg/kg dose group and 2 mg/kg dose group; all 4 participants in each group will receive a single dose of SG301 SC Injection by abdominal subcutaneous injection. Part A consists of a screening period (28 days), a single dose and safety observation period (15 days), and a follow-up period (14 days). After all participants in each dose group in Part A have completed the single dose and D1-D15 safety observation period, the available data will be reviewed by the Safety Monitoring Committee (SMC) to determine whether or not to escalate to the next dose group of SAD study. If no Grade 2 or higher drug-related AEs have occurred, it can be considered to exempt the SMC meeting. The 4 participants in each group need to be enrolled one by one at least 48 hours apart from each other. SMC will review the SAD after the last participant in the 2 mg/kg dose group has completed the 15-day safety observation period to decide whether or not to proceed with the MAD study. Part B adopts a multi-center, randomized, double-blind, placebo-controlled dose escalation trial design, where MAD will be performed for SLE participants in 4 dose groups (n=10/group), namely 2 mg/kg, 4 mg/kg, 8 mg/kg, and 12 mg/kg dose groups. Participants enrolled in 2 mg/kg dose group will be randomized in an 8:2 ratio to receive multiple doses of SG301 SC Injection (n=8) or SG301 SC placebo (n=2); among participants enrolled in 4 mg/kg, 8 mg/kg and 12 mg/kg dose groups, the first 2 participants in each group will receive the investigational drug SG301 SC Injection as open-label sentinels, and the remaining 8 participants will be randomized in a 6:2 ratio to receive multiple doses of SG301 SC Injection (n=6) or SG301 SC placebo (n=2). The SG301 SC Injection or SG301 SC placebo will be subcutaneously injected every 2 weeks [Q2W] in a 2-week cycle for a total of 6 doses in the MAD study. Part B consists of a screening period (28 days), a multiple dose period (12 weeks, including D1-D28 safety observation period), and a follow-up period (6 weeks). After all participants in each dose group in Part B have completed the D1-D28 safety observation period, the available data will be reviewed by the SMC to determine whether or not to escalate to the next dose group of MAD study. If no Grade 2 or higher drug-related AEs have occurred, it could be considered to exempt the SMC meeting. In Part B, when enrolling participants in 2 mg/kg dose group, the previous participant should have been observed for at least 24 hours before enrolling the next participant. The 2 sentinel participants in each of the 4 mg/kg, 8 mg/kg and 12 mg/kg dose groups should be enrolled one by one at least 48 hours apart from each other; the second sentinel participant should have been observed for at least 48 hours before starting to enroll the next participant; for the remaining participants in each group, the previously enrolled participant should have been observed for at least 24 hours before enrolling the next participant.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Characteristics of SG301 SC Injection in Single-dose Healthy Subjects and Multiple-dose Systemic Lupus Erythematosus (SLE) Subjects

Conditions
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Systemic Lupus Erythematosus (SLE)

Intervention / Treatment
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* Drug: SG301 SC Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A (healthy volunteers) Male healthy adults aged 18-50 years (inclusive); Male participants weighing 50-100 kg (inclusive) with the body mass index [BMI=weight/height2 (kg/m2)] of 19.0-27.0 kg/m2 (inclusive); Participants whose partners are of childbearing potential must agree to use effective contraceptive methods throughout the study period and for 6 months following the last dose (see Appendix 5 Contraceptive Requirements and Methods and Definition of Childbearing Potential); Participants who fully understand the purpose, nature, and methodology of the trial, as well as the possible adverse reactions in the trial, are volunteer to be a participant, and have signed the ICF; Part B (SLE participants) Males or females aged 18-65 years (inclusive); BMI 18.5-30.0 kg/m2 (inclusive); Voluntarily participating the clinical study and having signed the written ICF, and being able to comply with the clinical visits and study-related procedures; Participants diagnosed as SLE based the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria, with inadequate response or intolerance to or having relapsed despite the standard treatment; SELENA-SLEDAI score >4 and ≤12; Autoantibody serologically tested positive, defined as follows: ANA positivity defined as per the established reference range of the central laboratory of the study and/or a positive test for anti-ds-DNA antibody; Laboratory values at screening meeting the following criteria: Liver function: e.g. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2×upper limit of normal (ULN), total bilirubin <1.5×ULN Renal function: creatinine (Cr) and blood urea nitrogen (BUN) ≤1.5×ULN; eGFR >60 ml/min (calculated by the MDRD formula: eGFR (ml/[min×1.73 m2])=175×serum creatinine ([Scr (mg/dL)]-1.154×age -0.203×sex (male=1, female=0.742); urine total protein-creatinine ratio ≤3.0 g/g or 24h urine protein ≤3.5 g; Exclusion Criteria: Part A (healthy volunteers) Those who have a history of drug or other allergies and are considered by the investigator as being associated with a high risk in participating in this study, or judged by the investigator to be allergic to the investigational drug SG301 SC Injection or SG301 SC placebo or any of their ingredients; Those who have previously received drugs of the same target (CD38); Participants who have participated in a clinical trial of any drug or medical device within 3 months prior to dosing or 5 half-lives, whichever is longer; Use of any prescription drugs or Chinese herbal medicines (including proprietary Chinese medicines) within 4 weeks prior to dosing, or any non-prescription or dietary supplements (including vitamins and calcium supplements, etc.) within 2 weeks prior to screening; Infections within 2 weeks prior to dosing (including but not limited to viral, bacterial, or fungal infections); Participants experiencing symptomatic herpes zoster within 3 months prior to dosing; Presence of any of the following diseases assessed by the investigator as abnormal with clinical significance within 6 months prior to enrollment, including but not limited to circulatory system disorders, endocrine system disorders, nervous system disorders, blood system disorders, immune system disorders, and psychiatric disorders, etc.; A history or symptoms of any of the following cardiovascular diseases within 6 months prior to dosing: chronic congestive heart failure (New York Heart Association [NYHA] Class III or IV), history of myocardial infarction, severe heart diseases (e.g., unstable angina, cardiogenic shock, arrhythmias requiring treatment, heart valve diseases, hypertrophic cardiomyopathy, and rheumatic heart disease, etc.), and familial long QT interval syndrome, etc.; Presence of gastric diseases such as gastric ulcer, chronic gastritis, or gastroesophageal reflux, or having undergone gastrointestinal surgery (excluding surgery for appendicitis) prior to screening or during the screening period; Presence of chronic nervous system symptoms such as dizziness and headache prior to screening or during the screening period; Within 1 week prior to dosing: red blood cell count, hemoglobin, white blood cell count, neutrophil count, or platelet count among the hematology tests below the lower limit of normal (LLN), or clinically significant abnormalities in any other hematology tests; Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.2×ULN, total bilirubin >1.2×ULN; ECG abnormalities with clinical significance, e.g. QTcF >450 ms, during the screening period; Resting vital signs abnormal with clinical significance (ear temperature >37.5℃, systolic blood pressure <90 or ≥140 mmHg, diastolic blood pressure <50 or ≥90 mmHg; pulse rate <50 or >100 bpm); Fasting blood glucose above ULN during the screening period; Findings from physical examination, laboratory tests, or chest CT abnormal with clinical significance during the screening period; Hepatitis B surface antigen (HBsAg) or core antibody (HBcAb) positive, hepatitis C virus (HCV) antibody positive, TPPA positive, or HIV antibody positive; Mycobacterium tuberculosis infection, i.e., positivity for T cell spot test for tuberculosis infection (T-SPOT.TB) or interferon-γ-releasing (IGR) test, or for other hematological tests for tuberculosis infection; Abnormalities in the skin at administration site (abdomen), including but not limited to birthmarks, scars, black moles, tattoos, and open wounds; Part B (SLE participants) 1. Within 2 months prior to the first dose: central nervous system disorders caused or not caused by SLE or that in the investigator's opinion may require treatment with a prohibited therapy as defined in the protocol. Central nervous system disorders caused by SLE include but are not limited to meningitis, retinitis, cerebral vasculitis, myelopathy, demyelinating syndrome, acute confusional state, psychosis, acute stroke or stroke syndrome, cranial neuropathy, epileptic state or seizure, cerebellar ataxia, and multiple mononeuritis; 2. Within 12 months prior to the first dose: other concomitant rheumatic diseases, including but not limited to rheumatoid arthritis, spondyloarthritis, dermatomyositis/polymyositis, Sjogren's syndrome, systemic sclerosis, mixed connective tissue disease, and overlap syndrome, etc.; 3. Presence of severe antiphospholipid syndrome within 12 months prior to the first dose; 4. Within 12 months prior to the first dose: a history of non-SLE inflammatory skin or joint disease that in the investigator's opinion may interfere with the assessment of the skin or joint manifestations of SLE; 5. Chronic active infection or acute infection within 4 weeks prior to screening or superficial skin infection within 1 week prior to screening; 6. A known or suspected history of immunosuppression, or known or suspected recurrent or prolonged infection; 7. Having undergone a major surgery within 12 weeks prior to the first dose or having an unhealed wound, ulcer or fracture, or planning to undergo a major surgery during the study; 8. Having participated in any clinical trial within 12 weeks prior to the first dose (but those who have signed the ICF but did not receive treatment in a clinical trial are acceptable), or being within 5 half-lives (whichever is longer) of the investigational product in a clinical trial that they previously participated in before the first dose; participants who participated in screening in a clinical trial after signing the ICF within 12 weeks prior to the first dose without receiving clinical trial treatment and being enrolled are acceptable; 9. Use of any drugs targeting T or B lymphocytes (e.g., rituximab) within 6 months prior to the first dose or within 5 half-lives after drug discontinuation for therapeutic drugs of cytokines or receptors (e.g., belimumab, telitacicept, etc.); 10. Having received treatment with JAK inhibitors within 12 weeks prior to the first dose; or being within 5 half-lives after discontinuation of such a drug prior to the first dose, whichever is shorter; 11. Having received any of the following treatment within 12 weeks prior to the first dose: Intravenous immunoglobulin (IVIG) Plasma exchange Intravenous cyclophosphamide; 12. The following diseases of major clinical significance within 6 months prior to enrollment, including but not limited to circulatory system disorders, endocrine system disorders, nervous system disorders, blood system disorders, immune system disorders, and psychiatric disorders, etc.; 13. A history or symptoms of any of the following cardiovascular diseases within 6 months prior to the first dose: chronic congestive heart failure (NYHA Class III or IV), history of myocardial infarction, severe heart diseases (e.g., unstable angina, cardiogenic shock, arrhythmias requiring treatment, heart valve diseases, hypertrophic cardiomyopathy, and rheumatic heart disease, etc.), QTcF >450 ms or familial long QT interval syndrome, poorly controlled hypertension (resting blood pressure: systolic ≥140 mmHg and/or diastolic ≥90 mmHg); 14. Mycobacterium tuberculosis infection, i.e., positivity for T-SPOT.TB or IGR test; 15. In the presence of active hepatitis, the participant may not be enrolled if any of the following is met: HBsAg positive and/or HBcAb positive and HBV DNA positive (above the LLN of the central laboratory); HCV antibody positive and HCV RNA positive; 16. Known allergy to monoclonal antibody drugs or to any excipient of the investigational drug;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: This a phase I single ascending dose (SAD) study in healthy volunteers and multiple ascending dose (MAD) study in participants with mild or moderate SLE, which consists of Parts A and B. Part A adopts a single-center, open-label, dose escalation trial design, and Part B adopts a multi-center, randomized, double-blind, placebo-controlled trial design to evaluate the safety, tolerability, PK, and immunogenicity of single dose of SG301 SC Injection in SLE volunteers, as well as the safety.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: SG301 SC Injection<br>Healthy volunteers at two tentative dose groups, namely 1 mg/kg dose group and 2 mg/kg dose group | Drug: SG301 SC Injection<br>* This Study consists of Parts A and B. Part A ：SG301 SC Injection In healthy volunteers at 1 mg/kg dose group (n=4) and 2 mg/kg dose group(n=4) ; all 4 participants in each group will receive a single dose of SG301 SC Injection by abdominal subcutaneous injection. Part B：SG301 SC Injection/SG301 SC placebo MAD will be performed for SLE participants in 4 dose groups (n=10/group), namely 2 mg/kg, 4 mg/kg, 8 mg/kg, and 12 mg/kg dose groups. 2 mg/kg dose groups:SG301 SC Injection (n=8) or SG301 SC placebo (n=2); 4 mg/kg, 8 mg/kg and 12 mg/kg dose groups, the first 2 participants in each group will receive the investigational drug SG301 SC Injection , and the remaining 8 participants will be randomized in a 6:2 ratio to receive multiple doses of SG301 SC Injection (n=6) or SG301 SC placebo will be subcutaneously injected every 2 weeks [Q2W] in a 2-week cycle for a total of 6 doses in the MAD study.<br>|
| Placebo Comparator: Part B: SG301 SC Injection/Placebo<br>Systemic lupus erythematosus participants in 4 dose groups (n=10/group), namely 2 mg/kg, 4 mg/kg, 8 mg/kg, and 12 mg/kg dose groups. | Drug: SG301 SC Injection<br>* This Study consists of Parts A and B. Part A ：SG301 SC Injection In healthy volunteers at 1 mg/kg dose group (n=4) and 2 mg/kg dose group(n=4) ; all 4 participants in each group will receive a single dose of SG301 SC Injection by abdominal subcutaneous injection. Part B：SG301 SC Injection/SG301 SC placebo MAD will be performed for SLE participants in 4 dose groups (n=10/group), namely 2 mg/kg, 4 mg/kg, 8 mg/kg, and 12 mg/kg dose groups. 2 mg/kg dose groups:SG301 SC Injection (n=8) or SG301 SC placebo (n=2); 4 mg/kg, 8 mg/kg and 12 mg/kg dose groups, the first 2 participants in each group will receive the investigational drug SG301 SC Injection , and the remaining 8 participants will be randomized in a 6:2 ratio to receive multiple doses of SG301 SC Injection (n=6) or SG301 SC placebo will be subcutaneously injected every 2 weeks [Q2W] in a 2-week cycle for a total of 6 doses in the MAD study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events(Part A and Part B) | Number and percentage of AEs which is calculated by worst CTCAE grade by CTCAE 5. | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RP2D (PartB) | RP2D will be determined based on the DLTs and safety data | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 
| Pharmacokinetics (PK) Cmax (Part A and Part B) | Cmax to maximum drug concentration administration | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 
| Pharmacokinetics (PK):limination half-life (T1/2) (Part A and Part B) | limination half-life (T1/2) of the drug after administration. | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 
| Immunogenicity (Part A and Part B) | Anti-SG301 antibody (ADAdrug), neutralizing antibody (Nabdrug, to be detected only in case of the presence of ADAdrug), and anti-hyaluronidase antibody (ADArHu). | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 
| PD endpoints: CD38 RO.( Part B) | Detect the CD38 RO; | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 
| Biomarkers evaluation.( Part B) | It includes anti-ds-DNA autoantibody and complement factors C3 and C4. | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 
| Efficacy evaluation.( Part B) | Activity will be evaluated by SELENA SLEDAI. | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 
| immunoglobulins (Part B ) | Changes from baseline in immunoglobulins IgG, IgM and IgA with the investigational drug SG301 SC Injection and SG301 SC placebo. | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 
| BILAG-2004 /PGA (Part B ) | Changes from baseline in BILAG-2004 and PGA with the investigational drug SG301 SC Injection and SG301 SC placebo. | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject | 
| immune cell (Part B ) | Changes from baseline in the immune cell subsets including NK cells (activated and total), B cell subsets, plasmacytes, and plasmablasts, etc. | From baseline through the end of study. Part A: Average 2 months per subject, Part B: Average 5 months per subject |