DNV001 Injection in Patients With Hypercholesterolemia

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:

• Male or female, aged ≥18 years at the time of signing the informed consent form;
• 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;
• 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);
• Fasting TG ≤ 4.52 mmol/L (400 mg/dL), as tested by a local laboratory, at both the screening and run-in periods;
• 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;
• Be willing to adhere to the lifestyle requirements specified in the study protocol (including diet and physical activity level) during the study;
• 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:

• Diagnosed with homozygous familial hypercholesterolaemia prior to screening;
• Assessed as having an ultra-high risk for overall ASCVD at screening and have undergone percutaneous coronary intervention within 1 year prior to screening;
• 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);
• 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;
• 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;
• 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);
• 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;
• 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;
• 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;
• 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;
• 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);
• 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.
• QT/QTcF interval prolongation (≥ 450 ms for male subjects or ≥ 470 ms for female subjects) at screening or run-in period;
• 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;
• 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;
• 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;
• 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);
• 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);
• Weight change (gain or loss) of ≥ 10% within 3 months prior to screening;
• 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;
• 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;
• 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;
• 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;
• 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;
• 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;
• Any other conditions that, at the discretion of the investigator, would make the subject unsuitable for participation in this study.