Monthly PCSK9 inhibitor shows ‘robust’ long-term LDL lowering for high-risk CVD
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Key takeaways:
- Large LDL reductions were maintained long term with lerodalcibep, a monthly PCSK9 inhibitor.
- Results were similar across subgroups and people with heterozygous familial hypercholesterolemia.
CHICAGO — For adults at high or very high CVD risk, a monthly PCSK9 inhibitor added to maximally tolerated oral lipid-lowering therapy maintained LDL reductions of more than 60% through 72 weeks, with no signals of attenuation.
New data from an open-label extension of the LIBerate studies also demonstrated that lerodalcibep (LIB003, LIB Therapeutics), an investigational biologic PCSK9 inhibitor and alternative to monoclonal antibodies, showed similar benefit for adults with heterozygous familial hypercholesterolemia (HeFH) through an additional 72 weeks, supporting the drug’s long-term use.
“We saw no evidence of attenuation in LDL lowering effect for patients treated up to 2.4 years,” Michelle L. O’Donoghue, MD, MPH, cardiovascular medicine specialist and senior investigator of the TIMI Study Group at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said during a featured science presentation at the American Heart Association Scientific Sessions. “Possible advantages [of lerodalcibep] are once-monthly low-volume dosing and stability at ambient temperatures. We can argue that more competition in the space is actually great news for our patients. The more availability that we have, that will help to drive down costs and improve access.”
Low LDL maintained
As Healio previously reported, data from LIBerate-HR showed lerodalcibep was associated with “robust” reductions in all atherogenic lipids and lipoproteins, with more than 90% of patients able to achieve new European Society of Cardiology cholesterol guideline targets at the end of the study. Data from LIBerate-HeFH, also reported by Healio, showed lerodalcibep further reduce LDL vs. placebo in well-treated patients with HeFH.
The two base trials included 1,655 adults from 76 sites across 11 countries, including 1,096 assigned lerodalcibep and 559 assigned placebo for 52 weeks. Of those, 90% continued in the ongoing open-label extension period (mean age, 63.9 years; 63% men, 79.5% white), with 94% and 60% of participants now at weeks 48 and 72, respectively. Primary endpoints were percent and absolute LDL reduction after 48 and 72 weeks of open-label treatment.
At week 48, mean LDL was 42.4 mg/dL, an absolute change from baseline of –67 mg/dL and a mean percent change of –61.4. Results were maintained at 72 weeks and were similar across all subgroups, according to Dean J. Kereiakes, MD, FACC, MSCAI, president of The Christ Heart Hospital and Vascular Institute.
“Lerodalcibep results in approximately 90% of patients achieving both a reduction in LDL of at least 50% and the recommended LDL targets ... and reduced mean apolipoprotein B by 45% and median lipoprotein(a) by 32%,” Kereiakes said.
Strong benefit in HeFH
For the 703 adults with HeFH enrolled in the open-label extension (mean age, 53.8 years; 52.9% men; 87.8% white), mean LDL fell 49.8%, from 144.9 mg/dL at baseline to 71.7 mg/dL at week 48, an absolute change of –72.3 mg/dL. At 72 weeks, mean LDL held steady at 72.8 mg/dL, according to Frederick J. Raal, MMed, PhD, distinguished professor and director of the carbohydrate and lipid metabolism research unit at the University of the Witwatersrand in South Africa. Treatment resulted in 80% of people with FH achieving at least a 50% reduction in LDL and 70% achieving recommended LDL targets for those with high atherosclerotic CVD risk during the 72 weeks, Raal said, while also reducing mean ApoB by 36% and median Lp(a) by 25%.
“These results support the long-term use of monthly lerodalcibep for the management of HeFH [patients] unable to achieve LDL target,” Raal said. “It requires only 12 doses per year with home dosing and combined with robust LDL reductions, good tolerability and safety, offers the potential for improved long-term adherence for lifelong therapy needed for people with HeFH.”
Discussing the findings, O’Donoghue said the absence of a control arm precludes the assessment of longer-term safety; however, adverse events leading to drug discontinuation were infrequent. Fewer than 1% of doses in the open label for LIBerate-HR and 2.3% of doses in LIBerate-FeFH were associated with mild or moderate injection site reactions. There were no new safety concerns.
“Ultimately, a clinical outcomes study will be important to better understand the complete efficacy and safety profile, including effects within subgroups of interest,” O’Donoghue said.
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Kereiakes DJ, et al. Featured Science: Novel approaches to managing lipid risk. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2024; Chicago.
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