This is a Phase II clinical study to evaluate the effectiveness and safety of different doses of DNV001 injection in patients with primary hypercholesterolemia or mixed dyslipidemia who have not achieved adequate control of low-density lipoprotein cholesterol (LDL-C) despite statin therapy.

The study will enroll approximately 120 participants and will be conducted at 10-15 centers in China. Participants will be randomly assigned to one of four dose groups (50 mg, 150 mg, 300 mg-1, or 300 mg-2) or placebo, administered as subcutaneous injections. The study includes a 2-week screening period, a 4-week run-in period, a 36-week double-blind treatment period, and a 12-week follow-up period, for a total of up to 54 weeks.

The main goal is to see how much DNV001 lowers LDL-C levels after 24 weeks of treatment. The study will also look at long-term effectiveness, safety, how the body processes the drug, and whether it causes an immune response.

All participants will continue taking their stable dose of statin medication throughout the study.

Study Title:

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Study to Evaluate the Efficacy and Safety of Different Doses of DNV001 Injection in Patients with Primary Hypercholesterolemia or Mixed Dyslipidemia with Elevated LDL-C Despite Statin Therapy.

Sponsor:

Hangzhou Dinovate Biotech Co., Ltd.

Protocol Number:

DNV001-201

Phase:

Phase II

Study Design:

This is a randomized, double-blind, multicenter, placebo-controlled study. Eligible participants will be assigned in a 1:1:1:1 ratio to one of four dose groups: 50 mg, 150 mg, 300 mg-1, or 300 mg-2. Within each dose group, participants will be further randomized 4:1 to receive either DNV001 or placebo. Each dose group will include 24 participants receiving active drug and 6 receiving placebo, for a total of approximately 96 active and 24 placebo participants.

Study Duration:

Each participant will be involved for up to 54 weeks, including:

• Screening: 2 weeks
• Run-in: 4 weeks
• Double-blind treatment: 36 weeks
• Follow-up: 12 weeks

Key Eligibility Criteria:

Inclusion:

• Adults ≥18 years with primary hypercholesterolemia or mixed dyslipidemia
• Inadequate LDL-C control despite stable statin therapy
• Fasting LDL-C ≥70 mg/dL (with ASCVD history) or ≥100 mg/dL (without ASCVD history)
• Fasting triglycerides ≤400 mg/dL
• Willing to comply with study visits and lifestyle/dietary guidelines

Exclusion:

• Homozygous familial hypercholesterolemia
• Recent major cardiovascular event or procedure
• Uncontrolled hypertension, diabetes, or thyroid disease
• Significant liver, kidney, or heart disease
• Use of other lipid-lowering therapies (except stable statins)
• Recent participation in another clinical trial

Endpoints:

Primary:

· Percent change in LDL-C from baseline at Week 24.

Secondary:

• Percent change in LDL-C at other timepoints up to Week 48
• Proportion of participants achieving LDL-C reduction ≥50%, LDL-C <70 mg/dL, etc.
• Safety (adverse events, lab abnormalities, ECG, vital signs)
• Pharmacodynamics (PCSK9, lipids, lipoproteins)
• Pharmacokinetics (Cmax, Tmax, AUC)
• Immunogenicity (anti-drug antibodies)

Intervention:

DNV001 or matching placebo will be administered subcutaneously in the abdomen, upper arm, or thigh. Dosing schedules vary by group (e.g., 50 mg group: doses at Day 1, Week 12, Week 36; 300 mg-2 group: Day 1 and Week 24).

Statistical Methods:

Analyses will be performed on the Full Analysis Set, Per Protocol Set, and Safety Set. The primary endpoint will be analyzed using a mixed model for repeated measures. Safety and other endpoints will be summarized descriptively.

Inclusion Criteria:

• Subjects must meet all of the following criteria to be eligible for inclusion in this study:

  1. Male or female, aged ≥18 years at the time of signing the informed consent form;
  2. Diagnosed with primary hypercholesterolaemia or mixed hyperlipidaemia at screening; have been receiving statin therapy prior to screening; and agree to maintain stable statin therapy (i.e., no change in type or dosage, except for safety reasons) throughout the study;
  3. Fasting LDL-C levels at both the screening and run-in periods must meet the following criteria, as tested by a local laboratory: For subjects with a documented history of ASCVD, fasting LDL-C must be ≥ 70 mg/dL (1.8 mmol/L). For subjects without a documented history of ASCVD, fasting LDL-C must be ≥ 100 mg/dL (2.6 mmol/L);
  4. Fasting TG ≤ 4.52 mmol/L (400 mg/dL), as tested by a local laboratory, at both the screening and run-in periods;
  5. Understand the study procedures and methods, voluntarily agree to participate in this study, be willing to comply with the visit schedule and protocol requirements, and provide written informed consent;
  6. Be willing to adhere to the lifestyle requirements specified in the study protocol (including diet and physical activity level) during the study;
  7. Female subjects of childbearing potential (WOCBP) and male subjects who have not undergone vasectomy must agree to use a reliable method of contraception during the study and 6 months after study completion or discontinuation; female subjects of childbearing potential must present negative for blood human chorionic gonadotropin (hCG) pregnancy test result at the screening visit and the baseline visit prior to the first dose; male subjects must not donate sperm during the study and for 6 months after study completion or discontinuation.

Exclusion Criteria:

• Subjects who meet any of the following criteria will not be enrolled in the study:

  1. Diagnosed with homozygous familial hypercholesterolaemia prior to screening;

  2. Assessed as having an ultra-high risk for overall ASCVD at screening and have undergone percutaneous coronary intervention within 1 year prior to screening;

  3. Have other diseases that significantly affect blood lipid levels (such as nephrotic syndrome, severe liver diseases) or have dyslipidemia due to other secondary causes (such as drug-induced dyslipidemia);

  4. History of allergy to drugs or foods (two or more), or a history of specific allergic diseases (such as asthma, urticaria, eczematous dermatitis, etc.), or known allergy to any active ingredient or excipient of the investigational product;

  5. History of malignancy within the past 5 years (except for cured basal cell carcinoma of the skin, etc.), or currently being evaluated for a potential malignancy;

  6. Office blood pressure measurement during the screening and run-in periods: systolic blood pressure (SBP) ≥ 180 mmHg or diastolic blood pressure (DBP) ≥ 110 mmHg (a repeat measurement is permitted, which must be completed on the same day, and no pharmacological intervention is allowed before the repeat measurement);

  7. History of serious cardiovascular or cerebrovascular diseases (such as hypertensive encephalopathy, acute stroke, transient ischemic attack, acute myocardial infarction, severe arrhythmia), or severe aortic and/or peripheral vascular diseases (such as abdominal aortic aneurysm, lower limb arteriosclerosis obliterans), or presence of indications for surgical intervention within 6 months prior to screening or during the run-in period;

  8. Underwent major surgery within 6 months prior to screening or during the run-in period, or plan to undergo major surgery during the study period;

  9. History of New York Heart Association (NYHA) class III-IV heart failure, with a left ventricular ejection fraction (LVEF) < 40% at screening or run-in period;

  10. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) at screening or run-in period;

  11. Presence of severe thyroid disease (except for those on stable thyroxine replacement therapy or anti-thyroid drug therapy for at least 6 months prior to screening);

  12. Meet any of the following conditions in laboratory tests at screening or run-in period:

      • Thyroid stimulating hormone (TSH) > 1.5 × upper limit of normal (ULN) or < 1.0 × ULN;
      • Creatine kinase (CK) > 3×ULN;
      • Alanine aminotransferase (ALT), aspartate aminotransferase (AST) >2×ULN;
      • Total bilirubin (TBIL): 1.5×ULN.

  13. QT/QTcF interval prolongation (≥ 450 ms for male subjects or ≥ 470 ms for female subjects) at screening or run-in period;

  14. Positive result for either human immunodeficiency virus antibody (HIV-Ab) or treponema pallidum antibody (TP-Ab); positive for hepatitis B surface antigen (HBsAg) with hepatitis B virus load (HBV-DNA) exceeding the upper limit of the local laboratory reference range; or positive for hepatitis C virus antibody (HCV-Ab) with hepatitis C virus load (HCV-RNA) exceeding the upper limit of the local laboratory reference range;

  15. Poorly controlled type 1 or type 2 diabetes mellitus during the screening or run-in period, defined as glycosylated hemoglobin (HbA1c) > 8.5%; or newly diagnosed type 2 diabetes mellitus within 3 months prior to screening;

  16. History of drug abuse, including repeated high-dose use of dependence-inducing drugs or substances unrelated to medical purposes, including addictive or habitual drugs that cause physical or psychological dependence;

  17. History of alcohol abuse, defined as consumption of more than 14 standard units of alcohol per week within the past 6 months (one standard unit equals 14 g of pure alcohol, e.g., 360 mL beer, 45 mL spirits [≥ 40% alcohol], or 150 mL wine);

  18. History of blood donation within 3 months prior to screening or during the run-in period or blood loss ≥ 400 mL within 6 months prior to randomization (except blood loss due to menstruation);

  19. Weight change (gain or loss) of ≥ 10% within 3 months prior to screening;

  20. Received any medication or health product, other than the investigational product and stable-dose statin background therapy, that affects blood lipid levels within 4 weeks or 5 drug half-lives (whichever is longer) prior to randomization, including but not limited to: other statins (except stable statins), ezetimibe and similar agents (e.g., hybutimibe), fibrates, fish oil, niacin, bile acid sequestrants (e.g., cholestyramine), obesity treatment drugs, soluble fiber supplements, plant sterol-enriched margarines, glucagon like peptide-1 (GLP-1) receptor agonists, traditional Chinese medicines or Chinese patent medicines with lipid-lowering effect;

  21. Received monoclonal antibody PCSK9 inhibitors within 180 days prior to randomization, or small interfering RNA (siRNA)-based PCSK9 inhibitors (e.g., inclisiran) within 12 months prior to randomization;

  22. Use of drugs or foods contraindicated with statins prior to screening or randomization, without a discontinuation period of at least 5 drug half-lives, e.g., cyclosporine;

  23. Received systemic glucocorticoids (e.g., prednisone > 15 mg/d or other equivalent doses), thiazide diuretics, β-blockers, and other medications that may affect blood lipid levels within 4 weeks or 5 drug half-lives (whichever is longer) prior to screening or randomization, except for stable, low-dose use deemed by the investigator not to affect blood lipids;

  24. Participated in any clinical study and received the investigational drug/device within 3 months prior to screening or 5 half lives (whichever is longer) of the investigational drug, or before randomization, or planning to participate in any other clinical study during the study period;

  25. Pregnant or lactating women, or women of childbearing potential, male participants who plan to conceive (including sperm and egg donation) during the study period and/or who do not agree to use effective contraception;

  26. Any other conditions that, at the discretion of the investigator, would make the subject unsuitable for participation in this study.

Eligibility for participation is based on biological sex (male or female), as defined in the study protocol. All individuals who meet the medical eligibility criteria, regardless of their gender identity, are welcome to participate.

A decision regarding sharing of de-identified individual participant data (IPD) has not yet been made by the sponsor. Any future plan for data sharing will consider factors such as the completion of the study, publication of primary results, and regulatory approvals. This record will be updated if a sharing plan is established.

This is a double-blind study where both the participants and the investigators (including site personnel involved in treatment administration and clinical evaluation) are masked to treatment assignment. The placebo is matched in packaging, and administration to maintain blinding. The sponsor's clinical and monitoring staff are also masked. Unblinding may occur only in medical emergencies per the study protocol. An independent unblinded pharmacist,nurses or designated staff at each site will handle randomization and drug dispensing to maintain allocation concealment.