麻豆传媒

ATLANTA -- A novel PCSK9 inhibitor safely reduced LDL cholesterol levels with just a single, quick, once-monthly dose, the phase III LIBerate-HR trial showed.

Lerodalcibep reduced LDL cholesterol by 56% more than placebo from baseline to week 52 (-56.33% vs -0.14%, P<0.0001), Eric Klug, MBBCh, of the University of the Witwatersrand in Johannesburg, South Africa, reported at the American College of Cardiology (ACC) annual meeting.

With the novel agent, 90% of patients achieved at least a 50% reduction in LDL cholesterol to below 70 mg/dL compared with 16% in the placebo group.

Convenience and acceptability would likely be advantages, Klug noted.

Lerodalcibep is a third-generation PCSK9 inhibitor comprised of a small binding protein derived from human fibronectin that is fused with human serum albumin. It has a plasma half-life of 12 to 15 days. Like the monoclonal antibody drugs, it binds to PCSK9 to prevent degradation of LDL receptors; unlike those current generation drugs, though, lerodalcibep is a smaller molecule with high solubility that allows for a much lower injection volume and is shelf stable without refrigeration.

Most patients on currently available PCSK9 inhibitors have opted for more frequent dosing. "It's like a 9-minute autoinjector for evolocumab [Repatha] to give the amount of milligrams for that month, whereas lerodalcibep is 1.2 mL injection for a month," Klug told 麻豆传媒. "It's an instant shot, a few seconds to give the shot, and that's the dose given for the month."

Dave Dixon, PharmD, of Virginia Commonwealth University in Richmond, suggested that there could be room in the armamentarium for another PCSK9 inhibitor if it was an easy once-monthly shot.

"I think it's always important for patients and clinicians to have options," he said. "Both LDL lowering and safety/tolerability seem positive and would certainly support moving forward with a clinical outcomes trial."

The trial included 922 adults in 11 countries who were randomized 2:1 to once-monthly 1.2 mL subcutaneous lerodalcibep (300 mg) or placebo for 52 weeks. Participants had to have an LDL cholesterol level of 70 mg/dL or higher and cardiovascular disease or at least 100 mg/dL and high risk for cardiovascular disease, as well as be on a preexisting stable statin regimen with or without ezetimibe (Zetia). The median LDL level at baseline was 116 mg/dL.

Among additional endpoints, the trial showed a 43% placebo-adjusted reduction in apolipoprotein B (ApoB), 33% in Lp(a), and 17% in triglycerides.

Adverse events occurred in 71.6% of lerodalcibep-treated patients and 68.1% of those in the placebo group, with similar rates of serious and treatment-discontinuation events as well. Injection site reactions were more common with lerodalcibep (6.9% vs 0.3%) but didn't lead to more discontinuation.

In terms of immunogenicity, there were low levels of transient and sporadic antidrug antibodies, with in vitro neutralizing antibodies in 0.4% not associated with injection site reactions or any attenuation in PCSK9 or LDL cholesterol-lowering efficacy, Klug noted, pointing also to lack of antidrug or neutralizing antibodies in a large familial hypercholesterolemia trial with the drug.

A 1-year open-label extension of the study will monitor for those reactions as well, he added.

ACC session study discussant Christie M. Ballantyne, MD, of Baylor College of Medicine in Houston, called those facts reassuring.

"We currently have two monoclonals, we have siRNA -- they all have terrific efficacy. The problem has been access and the issue of dealing with prior authorizations," he said. "If we're able to somehow make it so that we can easily prescribe these drugs to the patients who need them and that the patients can get the medications without so many steps and so much hassle -- that's an editorial comment -- but I hope that the future will allow us to use these drugs much more easily. [There have] been improvements, but it's still a pain in the ass."

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