Long-Term Efficacy and Safety Evaluation of Lerodalcibep in Familial Hypercholesterolemia and Cardiovascular Disease Patients on Stable Lipid-Lowering Therapy

Trial ID: 2023-510057-41-00
Protocol: LIB003-007
Sponsor: LIB Therapeutics Inc.

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Diseases & Conditions

Cardiovascular disorder Type IIa hyperlipidaemia

Objectives

The primary objective of this study is to evaluate the long-term **safety**, tolerability, and efficacy of the investigational drug LIB003, also known as **lerodalcibep**, in patients with **homozygous and heterozygous familial hypercholesterolemia** (HoFH and HeFH), cardiovascular disease (CVD), or those at high risk for CVD. The study focuses on patients who are on a stable diet and maximally tolerated oral low-density lipoprotein cholesterol (LDL-C) lowering therapy and have completed a LIB003 Phase 3 base study. The assessment will be conducted over 48 and 72 weeks with monthly subcutaneous administration of 300 mg of LIB003. This evaluation is clinically relevant as it aims to determine the potential of LIB003 to provide additional LDL-C reduction in patients who are at very high risk for cardiovascular events, thereby addressing an unmet need in lipid management.

Participants

The clinical trial involves a total of **2210 participants** who are patients with **Homozygous and Heterozygous Familial Hypercholesterolemia**, cardiovascular disease, or at high risk for cardiovascular disease. The study population includes both male and female subjects, with age categories spanning from young adults to older adults. Participants were selected based on their completion of a LIB003 Phase 3 base study, ensuring they are at very-high or high risk for cardiovascular disease and are on a stable diet with maximally tolerated oral LDL-C lowering drug therapy. The trial population is considered otherwise healthy, as determined by medical history, physical examination, vital signs, ECGs, and laboratory tests. Participants are required to maintain their current lifestyle, including diet and medication regimen, throughout the study. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.

Plans and Procedures

The clinical trial is designed to evaluate the long-term efficacy and safety of **Lerodalcibep** in patients with **homozygous and heterozygous familial hypercholesterolemia**, cardiovascular disease, or those at high risk for cardiovascular disease. This is a Phase 3, open-label extension study, involving monthly subcutaneous administration of 300 mg of Lerodalcibep. The trial employs a randomized, controlled design and is expected to last until August 2025, with participant involvement spanning up to 72 weeks. The primary objectives are to assess the long-term safety, tolerability, and efficacy of the investigational drug, with endpoints focusing on changes in low-density lipoprotein cholesterol (LDL-C) levels and other lipid parameters.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as completion of a previous Phase 3 base study and the absence of serious adverse events related to Lerodalcibep. Follow-up visits are scheduled at regular intervals, including Weeks 12, 24, 36, 48, 60, and 72, to monitor efficacy, safety, and pharmacokinetic parameters. The end-of-study visit will occur at Week 72 or upon early termination. Conditions that may lead to early termination include the occurrence of significant adverse events or withdrawal of consent by the participant.

Throughout the trial, participants are required to maintain a stable diet and continue their current lipid-lowering therapy. Female participants of childbearing potential must adhere to strict contraception guidelines, and male participants must agree to specific contraceptive measures. The study will measure various endpoints, including changes in LDL-C, total cholesterol, high-density lipoprotein cholesterol, and triglycerides, as well as the presence of anti-drug antibodies and pharmacokinetic concentrations of Lerodalcibep. Safety assessments will include monitoring adverse events, cardiovascular events, and laboratory parameters, with particular attention to hepatic and skeletal muscle toxicities.

Treatment

The clinical trial involves the administration of **Lerodalcibep**, an experimental medication, to evaluate its long-term efficacy and safety in patients with familial hypercholesterolemia, cardiovascular disease, or those at high risk for cardiovascular disease. **Lerodalcibep** is a **solution for injection** and is administered subcutaneously. The dosage is 300 mg, delivered once every four weeks (Q4W, ≤31 days). The maximum daily dose is 300 mg, with a total maximum dose of 5.4 grams over the treatment period. The treatment duration is up to 72 weeks. The medication is provided in a single-use 2.25 mL Type 1 glass pre-fillable syringe, equipped with a 27G 1/2” staked needle, a rigid needle shield, and a bromobutyl plunger stopper. The syringe is assembled with a plunger rod, ensuring precise administration.

**Lerodalcibep** is a recombinant fusion protein consisting of a proprotein convertase subtilisin/kexin type 9-binding domain and human serum albumin. It is of biological/biotechnological origin, specifically a protein of other origin, and is not classified as an advanced therapy investigational medicinal product. The study includes patients who have completed a previous Phase 3 base study and are on stable lipid-lowering therapy. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

In addition to the experimental treatment, participants continue their standard-of-care therapy, which includes maximally tolerated oral low-density lipoprotein cholesterol (LDL-C) lowering drug therapy. This non-experimental treatment is maintained to provide a consistent therapeutic background against which the effects of **Lerodalcibep** can be assessed. The trial does not utilize a placebo or comparator treatment, focusing solely on the evaluation of **Lerodalcibep** in conjunction with existing therapies.

Efficacy

The efficacy of the clinical trial will be assessed through several primary endpoints focusing on changes in low-density lipoprotein cholesterol (**LDL-C**) levels. These changes will be evaluated both in absolute terms and as a percentage compared to the original baseline LDL-C at Day 1 in the base study. The calculations will utilize the Friedewald and Hopkins formulas, as well as preparative ultracentrifugation, at Weeks 48 and 72 for patients entering the open-label extension (OLE) directly from studies LIB003-004, -005, -006, -008, -011, and -012. Additionally, the trial will assess the effects of LIB003 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) at the same time points.

Further efficacy assessments will include the evaluation of apo B and Lp(a) serum concentrations at Weeks 48 and 72, with additional assessments at Week 12 for patients entering from the LIB003-011 and -012 studies. The trial will also measure the effects of LIB003 on serum unbound (free) PCSK9 concentration at Weeks 48 and 72. The percentage of patients achieving current European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines will be determined as part of the efficacy evaluation. Immunogenicity will be assessed by measuring anti-LIB003 antibodies initially at Week 72 or early termination, with additional measurements at Weeks 12, 24, 36, 48, and 60 as indicated by the Data Safety Monitoring Board (DSMB). Pharmacokinetic assessments will include measuring the PK concentration for LIB003 at Week 72 or early termination, with further measurements at specified intervals in response to anti-drug antibodies (ADAs) as indicated by the DSMB.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient has received study drug through the end of study (EOS) with a complete EOS Visit in 1 of the Phase 3 base studies, LIB003-003, -004, - 005, -006, -008, -011 and -012, without SAEs related to LIB003;
Patient has the provision of written and signed informed consent prior to any study-specific procedure;
Female patients of childbearing potential 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; o Note: 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, 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 folliclestimulating 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 bilateral oophorectomy. Birth control should be maintained for 60 days after the last dose of study drug (ie, 30 days after the last study visit). Postmenopausal women and those who are sterilised will be deemed of non-childbearing potential. All other women will be considered of childbearing potential and will be required to follow the contraception requirements as well as the pregnancy testing in the protocol. o Note: WOCBP will also have a pregnancy test prior to randomization, every 4 weeks for the duration of the study and at the final visit. Any participant who considers they or their partner is pregnant should undergo a pregnancy test until 60 days after last dose of study drug and if there is a positive test should follow the standard guidance for pregnancy in the clinical trial.
Male patients will either be surgically sterile or agree to continue to use the following forms of contraception if their partner is of childbearing potential and not using a highly effective form of birth control as defined in Inclusion Criterion #3: male or female condom with spermicide and a female partner who is sterile or who agrees to use the following contraceptives; diaphragm or cervical cap with spermicide; or intrauterine device, oral, implantable, or injectable contraceptives;
Male patients must refrain from sperm donation until 90 days following the last dose of study drug;
Patient is willing to maintain appropriate diet and stable dose of current LLT, including statins, ezetimibe, bile acid sequestrants, niacin, lomitapide, bempedoic acid, bezafibrate or fenofibrate, and/or OM-3 compounds; and o Note: Use of lomitapide will be allowed in patients from LIB003-003. o Note: Use of bempedoic acid will be allowed in patients from LIB003- 004, -005, and -006. o Note: Patients still requiring apheresis may add the procedure after Week 12.
Patient is considered by the Investigator to be otherwise healthy, based on medical history review, a defined complete physical examination, as well as vital sign measurements, ECGs, and laboratory test results in the base trial.

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Exclusion Criteria

Failure to receive study drug through the EOS or to complete the EOS Visit in the Phase 3 base study (LIB003-003, -004, -005, -006, -008, - 011 or -012) and/or had an SAE that was related to study drug during the Phase 3 base study;
Development since the final visit in the Phase 3 base study (LIB003- 003, -004, -005, -006, -008, -011 or -012) of any concomitant clinical condition or acute and/or unstable systemic disease compromising patient inclusion, at the discretion of the Investigator, including but not limited to, the following: a history or presence of clinically significant pulmonary, hepatic, gallbladder or biliary tract, 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;
Use of prohibited oral lipid-lowering agents, including PCSK9 mAbs, mipomersen, lomitapide, gemfibrozil, or bempedoic acid, started since completion of the base study; o Note: Use of lomitapide is not approved for, and will be prohibited in, patients from LIB003-004, -005, -006, -008, -011 and -012. o Note: Use of bempedoic acid is not approved for, and will be prohibited in, patients from LIB003-003, -008, -011 and -012.
Not available for protocol-required study visits or procedures, to the best of the patient's and Investigator's knowledge;
Has any other findings since the completion of the base study which, in the opinion of the Investigator, would compromise the patient's safety or participation in the study; or
Is an employee or family member of the Investigator or study site personnel.