ATLANTA, GA—The third-generation PCSK9 inhibitor lerodarcivep (LIB Therapeutics) lowers LDL cholesterol levels by 56% over 1 year over placebo in patients with CVD or at very high risk of CVD, according to new randomized data. It is said that it can be lowered.

Additionally, researchers reported no safety, tolerability, or immunogenicity issues compared to placebo.

“Lerodarcivep provides a novel and effective alternative to existing PCSK9 inhibitors,” said MBBCh, who presented the LIBerate-HR study results at the American College of Cardiology (ACC) 2024 Scientific Sessions. said Eric Krug, University of Watersland, Johannesburg, South Africa. .

“In addition to existing oral medications, we are seeing significant LDL cholesterol reductions,” he told conference attendees. More than 90% of patients have the ability to achieve new goals. [European Society of Cardiology] The guidelines target a reliable reduction of all atherogenic lipids and lipoproteins. ”

Previous findings Administration of this investigational drug was shown to reduce LDL cholesterol levels by 9.26% over 24 weeks in patients with homozygous familial hypercholesterolemia; the results showed that evolocumab (Repatha; Amgen) The results were consistent with those already observed.

Lerodarcivep, which is composed of the anti-PCSK9 target binding protein Adnectin and human serum albumin, blocks PCSK9 from binding to LDL cholesterol, thereby preventing LDL receptor degradation and increasing cholesterol clearance. Unlike currently available monoclonal antibodies, it is small and highly soluble, allowing for significantly lower injection volumes (1.2 mL subcutaneously). In a Phase II trial, a monthly dose of 300 mg reduced LDL cholesterol by as much as 70%.

The study shows that lerodarcivep may be “an option for people who need a PCSK9 inhibitor,” Christie Baranton, MD, Baylor College of Medicine in Houston, Texas, told TCTMD. Told. The fact that it only requires a small injection once a month is a “slight advantage” over monoclonal drugs, which typically require injections every two weeks, he said.

Ballantine continued that the question is whether there is enough safety data for commercial approval.

“Right now they don’t seem to see the safety signals.” [and] “There is potential for approval for a phase III program for lipid lowering,” he said. “They don’t have outcomes studies, we don’t have outcomes for inclisiran, and the monoclonal drugs were approved before we had outcomes.”

But for all of these drugs, the major problem has been access and drug passage. Rigorous pre-approval process. “It would be great… if we could easily prescribe these drugs to patients who need them and allow patients to get them without too many steps or hassles,” Ballantine said. said during the session. “I hope that in the future we will be able to use these drugs more easily. There has been improvement, but the pain is still there.”

Halving LDL

In the phase III LIBerate-HR study, Klug et al. enrolled 922 patients with CVD or at very high risk of CVD (mean age 64.5 years, 46% women) from 11 countries. They randomly assigned him in a 2:1 fashion to receive monthly subcutaneous injections of Lerodarcivep 300 mg or a placebo for 52 weeks. At baseline, more than 80% of patients’ girlfriends were taking statins, of which more than two-thirds of his girlfriends were taking high-intensity statins, and 16.6% were taking ezetimibe. Her LDL cholesterol at baseline was 116 mg/dL.

At week 52, LDL cholesterol was significantly reduced by 56.19% in the lerodarcivep group compared to the placebo group (-56.33 vs. -0.14%; P < 0.001). Overall, 94% of patients who took lerodarcivep achieved at least a 50% reduction in LDL cholesterol after one year, compared to only 19% of patients who received placebo treatment.

In addition, lerodarcivep was associated with a decrease in non-HDL cholesterol (-47.3%), apolipoprotein B (-43%), Lp(a) (-33.4%), and triglycerides (-16.5%), and a 6.5% increase in was doing. Contains HDL cholesterol. The mean and median changes in free PCSK9 in the study group at week 52 were -75% and -96%, respectively.

Safety was good, with similar numbers of patients in the lerodarcivep and placebo groups experiencing events leading to drug withdrawal (4.2% vs. 4.6%), serious adverse events (12.4% vs. 13.4%), and cardiovascular death (5.7% vs. 7.8%). %), MI (0.8% vs. 2.6%), and stroke (0.2% vs. 1.0%). Injection site reactions were more common with lerodarcivep (6.9% vs. 0.3%), but they were considered “mild to moderate,” Klug said.

Klug said there were no issues with immunogenicity.

Speaking during the session, Ballantine addressed failed PCSK9 inhibitors. bococizumab, manufacturer Pfizer halted research after immunogenicity issues arose. “We remember the story of bococizumab, which is a humanized monoclonal antibody, but it turns out that humanized monoclonal antibodies are not the same as fully human monoclonal antibodies,” he said.

Ballantine told TCTMD that more data from the entire Lerodarcivep program is needed before these types of issues can be ruled out. “This one study of his is encouraging in itself, but the whole program needs to be looked at,” he said. “With repeated injections, he might see something in a year or two. [treat] The number of patients will increase. ”