First-in-Human Study of ISH0688: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics

Inclusion criteria

• 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;
• 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;
• 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;
• 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:

• Male or female subjects aged 18 to 65 years (inclusive);
• Male body weight ≥50.0 kg, female body weight ≥45.0 kg, with body mass index (BMI) ≥19.0 and <28.0 kg/m²;
• Fasting triglycerides (TG) <2.3 mmol/L (200 mg/dL);
• 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:

• Male or female subjects aged 18 to 75 years (inclusive);
• 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);
• Lipid levels at screening or within 1 week prior to screening (at this site) meeting: fasting TG ≥2.3 mmol/L (200 mg/dL);
• 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);
• At screening, liver fat content (LFC) assessed by MRI-PDFF ≥8% in some participants;
• 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:

• Meet all inclusion criteria and do not meet any exclusion criteria during the screening period;
• 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;
• 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);
• The last TG test is within 7 days prior to the first dosing (D1).

Exclusion criteria

• Subjects with current allergic diseases, history of allergy to therapeutic or diagnostic protein products, or allergy to two or more drugs and/or non-drug factors;
• Subjects with history of malignant tumors (regardless of cure status, except for basal cell carcinoma, squamous cell skin cancer, and cervical carcinoma in situ);
• Subjects with positive results for one or more of the following: hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV-Ab), human immunodeficiency virus antibody (HIV-Ab), or serum treponema pallidum antibody (TP-Ab) (if HBsAg positive, must also have positive HBV-DNA; if HCV-Ab positive, must also have positive HCV-RNA);
• Subjects with severe trauma or surgical history within 6 months prior to screening; or subjects planning to undergo surgery (including cosmetic surgery, dental surgery, and oral surgery, etc.) during the trial period;
• Subjects with body weight change ≥5% within 3 months prior to screening (self-reported), or use of other medications/treatments for weight reduction within 1 month prior to screening or planned during the study period;
• Subjects with history of frequent orthostatic hypotension episodes within 6 months prior to screening;
• Subjects with history of chronic pancreatitis or acute pancreatitis attack within 1 year prior to screening;
• Subjects with gallbladder history and symptoms (such as: common bile duct stones, multiple gallbladder stones, etc., unless cholecystectomy performed and ≥6 months since surgery);
• Subjects with alcohol consumption >14 units per week within 3 months prior to screening (1 unit of alcohol = 360 mL beer, 150 mL wine, or 45 mL spirits with 40% alcohol content), or positive alcohol breath test (at baseline);
• Drug abusers or subjects using soft drugs (e.g., marijuana) within 3 months prior to screening or hard drugs (e.g., cocaine, phencyclidine, etc.) within 1 year prior to screening, or positive drug abuse screening (morphine, ketamine, tetrahydrocannabinol acid, methamphetamine, methylenedioxymethamphetamine, cocaine);
• Subjects who have used products targeting FGF21 within 1 year prior to screening, such as BIO89-100, DR10624, etc.;
• Subjects with history of vaccination within 3 months prior to screening, or planning to receive vaccination during the trial period;
• Subjects who participated in any other clinical trial of drugs or medical devices within 3 months prior to screening (except those who did not use investigational drugs/medical devices); or subjects within 5 half-lives of a drug (if 5 half-lives of the investigational drug exceed 3 months);
• Subjects who donated blood or experienced massive blood loss (>400 mL, excluding female menstrual period) or received blood transfusion or blood products within 3 months prior to screening, or subjects planning to donate blood during the trial period;
• Subjects with severe infection within 3 months prior to screening, including but not limited to: severe pneumonia, lung abscess, meningitis, cellulitis, etc., judged by the investigator as unsuitable for participation in this trial;
• Subjects with strenuous exercise during the trial period, or significant changes in exercise or dietary habits;
• History of needle phobia or blood phobia, or inability to tolerate venipuncture;
• Subjects with dermatitis or abnormal skin conditions at or around the administration site;
• Subjects whom the investigator considers unsuitable for participation in this study for any other reason.

Additional exclusion criteria in Part 1:

• Abnormal vital signs at screening in one or more parameters, or abnormal 12-lead electrocardiogram, or clinically significant abnormal physical examination findings;
• Clinically significant abnormal laboratory findings meeting the following criteria: alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin (TBIL) >1.5×ULN; estimated glomerular filtration rate (eGFR) <90 mL/min/1.73m²;
• Presence of severe, progressive, or uncontrolled diseases, including but not limited to immune system, endocrine system, hematological system, urinary system, hepatobiliary system, respiratory system, nervous system, psychiatric system, cardiovascular system, or digestive system disorders, which in the judgment of the investigator would increase the risk to the subject by participating in this study;
• Use of any prescription drugs, over-the-counter drugs, proprietary Chinese medicines, or herbal medicines within 14 days or 5 half-lives prior to screening (whichever is longer) (excluding oral contraceptives, acetaminophen, and ibuprofen);
• Smoking more than 5 cigarettes per day on average within 3 months prior to screening;
• Excessive consumption of tea, coffee, or caffeine-containing beverages within 3 months prior to screening (more than 8 cups per day of corresponding beverages, 1 cup = 250 mL), or consumption of any caffeine-containing food or beverages (such as coffee, strong tea, chocolate, cola, etc.) within 48 hours prior to first dosing.

Additional exclusion criteria in Part 2:

• Known diagnosis of familial chylomicronemia syndrome (FCS) (Fredrickson Type I), apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III); or strong suspicion of any of the above 3 conditions;
• Body weight decrease ≥5% from screening period to prior to receiving double-blind treatment;
• Clinically significant 12-lead electrocardiogram (ECG) abnormalities at screening;
• Clinically significant abnormal laboratory findings meeting the following criteria: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3.0×ULN, total bilirubin (TBIL) >2.0×ULN, creatine kinase (CK) >1.5×ULN; creatinine (Cr) >176 μmol/L and/or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m²; hemoglobin <110 g/L (males) or <100 g/L (females); platelet count (PLT) <60×10⁹/L; thyroid stimulating hormone (TSH) <lower limit of normal (LLN) or >1.5×ULN; serum amylase or lipase >2.0×ULN;
• Type 1 diabetes mellitus; or newly diagnosed Type 2 diabetes mellitus within 3 months; or poorly controlled Type 2 diabetes mellitus (HbA1c ≥9.5%); or Type 2 diabetes mellitus with severe complications; or failure to maintain stable dose of hypoglycemic agents for ≥3 months prior to screening;
• Uncontrolled or poorly controlled hypertension at screening: resting seated systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg; or failure to maintain stable dose of antihypertensive agents for ≥3 months prior to screening;
• Use (≥3 days) of other drugs significantly affecting blood lipids from 28 days prior to screening through the entire trial period (excluding lipid-lowering drugs specified in Inclusion Criterion 4), including proprietary Chinese medicines containing statin components, and other drugs and health supplements with lipid-lowering effects;
• Presence of other severe, progressive, or uncontrolled diseases in addition to T2DM, hypertension, and dyslipidemia, including but not limited to immune system, endocrine system, hematological system, urinary system, hepatobiliary system, respiratory system, nervous system, psychiatric system, cardiovascular system, or digestive system disorders, which in the judgment of the investigator would increase the risk to the subject by participating in this study;
• Subjects who, in the investigator's assessment, require systemic corticosteroid therapy during the study period due to comorbidities, or who have received continuous or cumulative systemic corticosteroid therapy for more than 14 days within 6 months prior to screening (stable-dose inhaled or topical corticosteroids are permitted);
• Presence of contraindications to MRI examination or inability to cooperate with MRI examination;
• New York Heart Association (NYHA) Class III or IV congestive heart failure;
• Atherosclerotic cardiovascular disease within 6 months prior to screening;
• Major cardiovascular or cerebrovascular events within 6 months prior to screening;
• Severe arrhythmia within 3 months prior to screening;
• History of or current nephrotic syndrome, severe liver disease, Cushing's syndrome, or other diseases significantly affecting blood lipid levels;
• History of or current hyperthyroidism or hypothyroidism.