Patients with atherosclerotic cardiovascular (CV) disease (ASCVD) or high risk of ASCVD who need additional LDL-C reduction MedDRA version: 20.1 Level: LLT Classification code 10007648 Term: Cardiovascular disease, unspecified System Organ Class: 100000004849
Conditions
Sponsors
LIB Therapeutics, LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Provision of signed informed consent prior to any study-specific procedure; 2.Male or female, =18 years of age at the first Screening Visit; 3.Weight of =40 kg (88 lb) and body mass index (BMI) =16 and =42 kg/m2; 4.At very-high risk for CVD which includes history of stable CVD, defined as previous myocardial infarction (MI) (ST-elevation MI or non-ST-elevation MI), angioplasty, documented coronary artery disease (stress echo, computed tomography [CT] coronary angiography or invasive angiography) or cerebrovascular or peripheral arterial disease without a recent event within 3 months prior to screening (ie, acute coronary syndrome, unstable angina, coronary artery bypass grafting, percutaneous coronary intervention, stroke, MI, carotid endarterectomy); OR At high risk for CVD (ASCVD risk equivalent) which includes as type 2 diabetes, FH, untreated LDL-C >190 mg/dL or a 10-year risk of a CVE of =10% as assessed by the ACC/AHA or ESC/EAS guidelines; 5.At the defined eligibility visit (screening or post washout/stabilization), a calculated LDL-C (Friedewald) =2.3 mmol/L (=85 mg/dL) and TG =4.52 mmol/L (=400 mg/dL) while on stable lipid-lowering oral drug therapy (including high-intensity statin with or without ezetimibe); 6.On a stable diet and lipid-lowering oral therapies (high intensity statin with or without any of the following: ezetimibe, bile-acid sequestrants, OM-3 compounds, bezafibrate or fenofibrate, and nicotinic acid) or combinations thereof for at least 4 weeks (excluded oral lipid lowering agents and include non-high intensity statins, mipomersen, lomitapide, gemfibrozil, and bempedoic acid); 7.Patients previously on a PCSK9 mAb at a dose of 75 mg, 140 mg or 150 mg Q2W must undergo a washout period of =4 weeks after the last dose; for those on a dose of alirocumab 300 mg or evolocumab 420 mg Q4W (=31 days) the washout period is =8 weeks following the last dose. For patients who have received an siRNA PCSK9 inhibitor the washout period is =360 days post last dose; Any decision to stop treatment with a PCSK9 inhibitor prior to study start will be at the discretion of the investigator and outside of the conduct of the clinical trial. Any patient who has recently stopped a PCSK9 inhibitor due to clinical or other reasons or due to completion of a clinical trial will require this wash out period prior to randomization and commencement of study drug. 8.Women of childbearing potential (WOCBP) must continue using a highly effective form of birth control if sexually active and have a negative urine pregnancy test on Day 1 prior to dosing; Note: A woman is considered of childbearing potential, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Highly effective methods of birth control include refraining from heterosexual sexual intercourse during the entire period of risk, birth control pills or patches, intrauterine devices (IUDs), sexual activity with a male partner who has had a vasectomy, or IUD, oral, implantable, or injectable contraceptives. Menopause is defined as 1 year of spontaneous and continuous amenorrhea in a female =55 years old or 1 year of spontaneous and continuous amenorrhea with a follicle-stimulating hormone (FSH) level >40 IU/L (or according to the definition of “postmenopausal range” for the laboratory involved) in a female <55 years old unless the patient has undergone b
Exclusion criteria
Exclusion criteria: 1.Patient not on stable high-intensity statin (daily atorvastatin 40/80 mg or rosuvastatin 20/40 mg) 2.Use of prohibited oral lipid lowering agents mipomersen or lomitapide within 6 months of screening or gemfibrozil (excluded due to potential increased risk of myotoxicity with statins) within 6 weeks of screening or bempedoic acid within 4 weeks of screening or non-high intensity statins or doses; 3.Low-density lipoprotein or plasma apheresis within 2 months prior to randomization 4.Documented history of HoFH defined as clinical and/or genetic with true HoFH (ie, identical pathogenic variants) or compound heterozygous (ie, 2 different pathogenic LDLR variants) or combined heterozygous (2 different pathogenic FH variants such as LDLR plus apo B, or LDLR plus PCSK9 GOF) 5.History of any prior or active clinical condition or acute and/or unstable systemic disease, including cancer, compromising patient inclusion or preclude completion of the study, at the discretion of the Investigator, including but not limited to clinically significant pulmonary, hematologic, gastrointestinal, endocrine (excluding diabetes), immunologic, dermatologic, neurologic, or psychiatric disease, which in the Investigator’s opinion would not be suitable for the study from a patient safety consideration or could interfere with the results of the study 6.Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate 2.5 × the ULN as determined by central laboratory analysis at screening (tests that result in ALT or AST up to 3 × ULN may have 1 repeat test to confirm eligibility during the Screening Period); 8.Uncontrolled thyroid disease: hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone (TSH) below the lower limit of normal (LLN) or >1.5 × ULN, respectively, at the Screening Visit. If TSH is above/below these cut points, patients can enter if free triiodothyronine (T3) is within the reference range. If controlled, treatment should be stable for at least 3 months prior to the Screening Visit 9.Uncontrolled Type 1 or Type 2 diabetes mellitus, defined as fasting glucose =200 mg/dL and glycated hemoglobin (HbA1c) of >9% 10.Uncontrolled serious cardiac arrhythmia (sustained ventricular tachycardia, frequent non sustained ventricular tachycardia, any ventricular fibrillation episode, wide-complex tachycardia, atrial fibrillation with rapid ventricular response, and severe second degree or third degree atrioventricular block), MI, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, placement of implantable cardioverter defibrillator or biventricular pacemaker, aortic valve surgery, or stroke within 3 months prior to the Screening Visit 11.Planned cardiac surgery or revascularization 12.New York Heart Association class III-IV heart failure; or patients with last documented left ventricular ejection fraction <30% by standard of care assessments, eg, echocardiography, cardiac magnetic resonance imaging, nuclear imaging, CT angiography, or angiography with ventriculogram, within 12 months; 13. Uncontrolled hypertension defined as a reproducible (repeated 5 minutes apart) sitting blood pressure =180 mmHg systolic or =110 mmHg dias
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to compare LDL-C reductions at Day 270 of monthly (QM [=31 days]) dosing of lerodalcibep (LIB003) 300 mg administered subcutaneously (SC) to inclisiran (Leqvio®) 284 mg administered SC at Days 1 and 90 in patients with very-high risk CVD or at high risk for CVD on a stable diet and oral LDL-C-lowering drug therapy. ;Secondary Objective: The secondary objectives of this study will be assessed similarly to the primary objective: - To compare the LDL-C-lowering effects with LDL-C calculated by Hopkins formula and preparative ultracentrifugation; -To compare safety and tolerability, including the frequency and severity of injection site reactions (ISRs); -To compare the effects on serum unbound (free) proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations; -To compare the effects on serum lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non–HDL-C, very low-density lipoprotein cholesterol (VLDL-C), and triglycerides (TG); ---To compare the effects on apolipoprotein (apo) B and lipoprotein (a) (Lp[a]) serum concentrations; -To assess percentage of patients achieving current European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines. ;Primary end point(s): The primary efficacy endpoint is to assess percent change from baseline (Day 1) in LIB003 compared to inclisiran in LDL-C level at Day 270 (calculated by Friedewald formula).;Timepoint(s) of evaluation of this end point: Day 270 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints will be summarized similarly to the primary endpoints (absolute and/or percent change from baseline compared to inclisiran): •Percent change in: o LDL-C level at Day 270 (by Hopkins formula); and o LDL-C level at Day 270 (by preparative ultracentrifugation); •Absolute and percent change (where not assessed prior) from baseline (Day 1) in LDL-C level by Friedewald and Hopkins formulas at all visits; •Serum unbound (free) PCSK9 concentrations at Days 1, 90 and 270; •Absolute and percent change from baseline (Day 1) in TC, HDL-C, non–HDL-C, VLDL-C, and TG at all visits; •Absolute and percent change from baseline (Day 1) in apo B and Lp(a) serum concentrations Day 270; and •Percentage of patients achieving current ESC/EAS guidelines at Day 270. ;Timepoint(s) of evaluation of this end point: Days 1, 90 and 270 | — |
Countries
France, Germany, Norway, Spain, United Kingdom
Contacts
Public ContactLIB clinical trials
LIB Therapeutics, LLC
Outcome results
None listed