03 Jul Lerodalcibep in Patients With or at High Risk of Cardiovascular Disease

MedicalResearch.com Interview with:

Dr. Stein

Evan A Stein MD PhD FACC
COO/CSO
LIB Therapeutics
Cincinnati. OH USA 45227

MedicalResearch.com: What is the background for this study?

Response: Cardiovascular disease (CVD) remains the main cause of morbidity and mortality worldwide and is increasing in rapidly industrializing countries and is projected to cause more than >20 million deaths annually over the next 15 years. Low-density lipoprotein cholesterol (LDL-C) is well established as a major, easily modifiable, risk factor for CVD. Reductions with statins and, more recently, PCSK9 inhibitors, all agents which directly or indirectly upregulate the LDL receptor and enhance LDL-C clearance, have demonstrated CVD event reductions in cardiovascular outcome trials. Extensive data from these trials, provide a rough estimate that every 40 mg/dL reduction in LDL-C will reduce the risk of major CV cardiovascular events by 22% to 24%. Furthermore, trials with PCSK9 inhibitors added to statins which achieve substantial additional LDL-C reduction show and CVD event reduction remains linear to very low LDL-C levels without signals of adverse events.

Based on this body of evidence, recent revisions to national and international guidelines, now advocate for greater LDL-C reductions and lower LDL-C treatment goals, for patients not achieving these goals on statins alone. The current consensus target goal for LDL-C in patients with CVD, or who are at very-high risk for of CVD, is now less than <55 mg/dL, and <70 mg/dL for those at high risk.

This global trial of over 900 patients with CVD, or at very or high risk for CVD, on maximally tolerated statins assessed the 52-week efficacy and safety of monthly lerodalcibep.

MedicalResearch.com: How does Lerodalcibep differ from other LDL-C lowering medications?

Response:   Lerodalcibep is a completely novel alternative to monoclonal antibodies with a smaller molecular scaffold, which offers reduced dose burdens. The anti-PCSK9 binding domain is an 11 kDa polypeptide, called an adnectin, derived from human fibronectin-10th type III– domain and engineered for high-affinity binding to human PCSK9.

Due to the small size, the adnectin would be rapidly filtered and excreted by the kidney, thus to enhance plasma half-life, the adnectin is fused to human serum albumin (HSA) to enhance its plasma half-life to 12- to 15 days and provides with long ambient stability. Due to the small size and high- solubility lerodalcibep provides more drug in a small volume and achieves robust LDL-C reductions with 300 mg in only 1.2 mL with monthly dosing compared to monoclonal antibodies dosed every 2 weeks.

MedicalResearch.com: What are the main findings?

Response:  In this large, diverse, trial with monthly lerodalcibep, the mean placebo adjusted reduction in LDL-C was 56% at the week 52 trough visit, 69.5% at week 50 (peak) for a time-averaged mean of weeks 50/ and 52 of 62%. Absolute mean reductions in LDL-C at trough and peak of 60.6 mg/dL and 74.5 mg/dL, respectively resulting in on treatment levels in these CVD and high-risk patients of 54 mg/dL and 41 mg/dL respectively.

This resulted in ≥90% of patients, with baseline LDL-C of 116 mg/dL despite maximally tolerated statins, and other oral agents, to both achieve both ≥50% or greater further reductions and the new lower targets set in recent guidelines.

Lerodalcibep robustly reduced all other atherogenic lipoproteins, including non–HDL-C, by 47%, apolipoprotein B by 43%, lipoprotein(a) Lp(a) by 30%.

Lerodalcibep was also well tolerated, with adverse events similar to that of placebo.

While associated with a higher incidence of injection site reactions, these were mild to moderate, and did not result in more frequent discontinuation than placebo.

Importantly, lerodalcibep, while a novel platform derived from human proteins, had minimal clinically significant immunogenicity, as long-term administration was not associated with in- vivo active antidrug antibodies ADAs or neutralizing antibodies NAbs or any attenuation in LDL-C lowering efficacy.

MedicalResearch.com: What should readers take away from your report?

Response: Lerodalcibep, provides a novel 3rd generation PCSK9 inhibitor which is dosed 12 times a year compared to current monoclonal antibodies 26 times a year. It is also stable at ambient temperatures for over 6 months and will not require refrigeration at home or during travel.

This and other trials demonstrate excellent LDL-C reducing efficacy and ability for nearly all patients with CVD, or at high risk for CVD already on maximal statin therapy to achieve the new globally harmonized lower LDL-C targets with a safety profile similar to placebo.

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Response: While we have completed the initial requirements for approval by regulatory bodies we are planning to start additional trials later this year which include;

A trial in children and adolescents with heterozygous familial hypercholesterolemia and a cardiovascular outcome trial (CVOT) which we anticipate will include a population which expands on the prior and ongoing CVOTs to extend PCSK9 inhibitors, such as lerodalcibep, to a wider patients who require further LDL-C reduction.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: With this trial and another similar very large 52 week trial in just CVD patients recently presented as a Late-Breaker at the European Atherosclerosis Society meeting we have completed the regulatory requirements for submitting lerodalcibep to FDA and EMA for approval, which will be done in the next few months.

Disclosures: Dr Stein is a founder, Chief Operating and Scientific Officer or LIB Therapeutics

Citation: Klug EQ, Llerena S, Burgess LJ, et al. Efficacy and Safety of Lerodalcibep in Patients With or at High Risk of Cardiovascular Disease: A Randomized Clinical Trial. JAMA Cardiol. Published online July 03, 2024. doi:10.1001/jamacardio.2024.1659

https://jamanetwork.com/journals/jamacardiology/article-abstract/2820248

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Last Updated on July 3, 2024 by Marie Benz MD FAAD