Healthy Subjects, Hyperlipidemia, Hypertriglyceridemia
Conditions
Brief summary
ISH0688 is a human IgG1 Fc-FGF21 fusion protein. The objectives of the planned clinical investigation will be to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single- and multiple-ascending doses of ISH0688 via subcutaneous injection.
Interventions
DRUGISH0688 for injection
75、150、300、600 mg; s.c. Q4W; Sterile powder for injection
DRUGPlacebo
75、150、300、600 mg; s.c. Q4W; Sterile powder for injection
Sponsors
SUNHO（China）BioPharmaceutical CO., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Female subjects: * Not of childbearing potential: Including surgical sterilization performed at least 6 weeks prior to screening (with documented records of bilateral tubal ligation, bilateral salpingectomy, hysterectomy, or bilateral oophorectomy), or postmenopausal with continuous amenorrhea for ≥12 months; or * Of childbearing potential: Must not be pregnant or breastfeeding, and must agree to use adequate contraception from 30 days prior to first dosing throughout the study period and for 6 months after the last dose; * Serum β-human chorionic gonadotropin (β-hCG) pregnancy test results must be negative at both screening and baseline visits; 2. Male subjects with female partners of childbearing potential must agree to use adequate contraception from 30 days prior to first dosing throughout the study period and for 6 months after the last dose; 3. Male subjects must have no plan to donate sperm from the time of informed consent signing until 6 months after study completion; female subjects must have no plan to donate eggs from the time of informed consent signing until 6 months after study completion; 4. All subjects must be able to understand the procedures and methods of this study, be willing to strictly comply with the clinical study protocol to complete this study, and voluntarily sign the informed consent form. Additional inclusion criteria for Part 1: 1. Male or female subjects aged 18 to 65 years (inclusive); 2. Male body weight ≥50.0 kg, female body weight ≥45.0 kg, with body mass index (BMI) ≥19.0 and \<28.0 kg/m²; 3. Fasting triglycerides (TG) \<2.3 mmol/L (200 mg/dL); 4. Comprehensive vital signs, physical examination, 12-lead electrocardiogram (ECG), chest X-ray, abdominal ultrasound, and laboratory tests (complete blood count, blood biochemistry, urinalysis, stool routine, coagulation function, thyroid function) showing no abnormalities or only minor abnormalities that are judged by the investigator to be of no clinical significance. For clinically significant abnormal laboratory findings, retesting may be performed within one week if there is a clear and reasonable justification, and the retest results will be used to determine subject eligibility. Additional screening period inclusion criteria for Part 2: 1. Male or female subjects aged 18 to 75 years (inclusive); 2. Male body weight ≥50.0 kg, female body weight ≥45.0 kg, with body mass index (BMI) in the range of 19.0 to 45.0 kg/m² (inclusive); 3. Lipid levels at screening or within 1 week prior to screening (at this site) meeting: fasting TG ≥2.3 mmol/L (200 mg/dL); 4. Lipid-lowering medication use within 28 days prior to screening must meet the following criteria: For TG \<5.7 mmol/L (500 mg/dL): no lipid-lowering medication use or receiving stable-dose lipid-lowering therapy for ≥28 days; For TG ≥5.7 mmol/L (500 mg/dL): must first receive stable-dose lipid-lowering therapy for ≥28 days; (Lipid-lowering therapy: niacin, prescription-grade fish oil, fibrates, statins, cholesterol absorption inhibitors, etc.; PCSK9 inhibitors require 6 months of stability prior to screening); 5. At screening, liver fat content (LFC) assessed by MRI-PDFF ≥8% in some participants; 6. Able to accept therapeutic lifestyle interventions consistent with local standards and maintain stable lifestyle throughout the study period, avoiding alcohol consumption and strenuous exercise within 48 hours prior to each visit. Additional double-blind treatment period inclusion criteria for Part 2: 1. Meet all inclusion criteria and do not meet any
Exclusion criteria
during the screening period; 2. Undergo therapeutic lifestyle intervention during the lead-in period, maintain a stable lifestyle, and be judged by the investigator as capable of complying with the protocol to receive study treatment and complete other clinical trial procedures; 3. Two TG tests during the lead-in period with an interval of ≥7 days, with the mean of the 2 TG values meeting 2.3 mmol/L (200 mg/dL) ≤ fasting TG \< 11.3 mmol/L (1000 mg/dL); 4. The last TG test is within 7 days prior to the first dosing (D1).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with treatment-emergent adverse events [Safety and Tolerability] | baseline through day 99 (part 1) or day 84 (part 2) | Number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0 |
| Injection site reactions assessments | baseline through day 99 (part 1) or day 84 (part 2) | The injection site reaction assessment will be done by the PI/investigational staff and study subject using the criteria, which consist of rating the severity of redness, swelling, skin temperature, sensitivity and pain at the injection site |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum observed serum concentration (Cmax) | baseline through day 99 (part 1) or day 84 (part 2) | Maximum observed serum concentration (Cmax) |
| Time to reach maximum observed serum concentration (Tmax) | baseline through day 99 (part 1) or day 84 (part 2) | Time to reach maximum observed serum concentration (Tmax) |
| AUC from time 0 to the time of the dosing interval (AUC0-t) | baseline through day 99 (part 1) or day 84 (part 2) | AUC from time 0 to the time of the dosing interval (AUC0-t) |
| AUC from time 0 to infinity (AUC₀-∞) | baseline through day 99 (part 1) or day 84 (part 2) | AUC from time 0 to infinity (AUC₀-∞) |
| Terminal elimination half-life (t1/2) | baseline through day 99 (part 1) or day 84 (part 2) | Terminal elimination half-life (t1/2) |
| Apparent clearance after extravascular administration (CL/F) | baseline through day 99 (part 1) or day 84 (part 2) | Apparent clearance after extravascular administration (CL/F) |
| Apparent volume of distribution during the terminal elimination phase after extravascular administration (Vd/F) | baseline through day 99 (part 1) or day 84 (part 2) | Apparent volume of distribution during the terminal elimination phase after extravascular administration (Vd/F) |
| Absolute Change From Baseline to Week 12 in Serum Triglyceride (TG) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in TG | baseline through day 84 (part 2) | — |
| Proportion of Participants Who Achieved TG <2.3 mmol/L (200 mg/dL) at Week 12 | baseline through day 84 (part 2) | — |
| Proportion of Participants Who Achieved TG <1.7 mmol/L (150 mg/dL) at Week 12 | baseline through day 84 (part 2) | — |
| Proportion of Participants With Baseline TG ≥5.7 mmol/L (500 mg/dL) Who Achieved TG <5.7 mmol/L (500 mg/dL) at Week 12 | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Total Cholesterol (TC) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in TC | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Low-density Lipoprotein Cholesterol (LDL-C) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in LDL-C | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in High-density Lipoprotein Cholesterol (HDL-C) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in HDL-C | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in Non-HDL-C | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Very Low-density Lipoprotein Cholesterol (VLDL-C) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in VLDL-C | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Apolipoprotein B (ApoB) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in ApoB | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Apolipoprotein A1 (ApoA1) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in ApoA1 | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Lipoprotein(a) (Lp(a)) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in Lp(a) | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Body Weight | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in Body Weight | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Body Mass Index (BMI) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in BMI | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Waist Circumference | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in Waist Circumference | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Fasting Plasma Glucose | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in Fasting Plasma Glucose | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Glycated Hemoglobin (HbA1c) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in HbA1c | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Fasting Insulin | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in Fasting Insulin | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Fasting C-Peptide | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in Fasting C-Peptide | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Glucagon | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in Glucagon | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Adiponectin | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in Adiponectin | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in HOMA-IR | baseline through day 84 (part 2) | — |
| Absolute Change From Baseline to Week 12 in Liver Fat Content (LFC) Measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in LFC Measured by MRI-PDFF | baseline through day 84 (part 2) | — |
| Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP) | baseline through day 84 (part 2) | — |
| Incidence of Anti-Drug Antibodies (ADA) | baseline through day 99 (part 1) or day 84 (part 2) | — |
Countries
China
Contacts
CONTACTYa Ze Jiao
Outcome results
None listed