Novel PCSK9 inhibitor recaticimab linked to durable LDL reduction
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Key takeaways:
- Less frequent anti-PCSK9 monoclonal antibody dosing is possible with recaticimab.
- When dosed every 12 weeks, the novel immunoglobulin G1 monoclonal antibody conferred significant LDL reductions at 48 weeks.
PHILADELPHIA — Recaticimab, a novel anti-PCSK9 drug, conferred significant LDL reductions at 48 weeks in a cohort of patients with mixed hyperlipidemias already on statin therapy, a speaker reported.
The results of the multicenter, randomized, double-blind, placebo-controlled phase 3 REMAIN-2 trial of recaticimab (Jiangsu Hengrui Pharmaceuticals), a monoclonal antibody designed to inhibit PCSK9 in less frequent doses than other anti-PCSK9 monoclonal antibodies, were presented at the American Heart Association Scientific Sessions.
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“In many patients, despite statin therapy, particularly in those with moderate or high risk of atherosclerotic CVD, anti-PCSK9 monoclonal antibody is efficacious as an add-on therapy, but compliance is affected due to a frequent dosing strategy in clinical practice,” Xin Du, MD, of the department of cardiology at Beijing Anzhen Hospital, Capital Medical University, China, said during a presentation. “Recaticimab is unique in that there is a mutation in the Fc region in the antibody ... therefore prolonging its half-life by around 7 to 10 days.”
There are three PCSK9 inhibitors approved for commercial use in the United States. Two are monoclonal antibodies: alirocumab (Praluent, Sanofi/Regeneron), which is given in 75 mg to 150 mg doses once every 2 weeks or in a 300 mg dose once every 4 weeks, and evolocumab (Repatha, Amgen), which is given in a 140 mg dose once every 2 weeks or a 420 mg dose once per month. The third is inclisiran (Leqvio, Novartis), a small interfering RNA molecule, which is given in a 284 mg dose administered initially and at 3 months, then once every 6 months thereafter.
Recaticimab is a long-acting anti-PCSK9 immunoglobulin G1 monoclonal antibody with a half-life of 18.6 to 27.4 days.
In a prior phase 1b/2 trial published in BMC Medicine, recaticimab, as an add-on to moderate-intensity statin therapy, reduced LDL compared with placebo on a dosing schedule with subcutaneous injections as far as 12 weeks apart.
For the present study, Du and colleagues randomly assigned 692 patients to recaticimab 150 mg/kg every 4 weeks, 300 mg/kg every 8 weeks, 450 mg/kg every 12 weeks or placebo.
Mean age was 55 to 57 years across dosage groups, which ranged from 61% to 71% men. Baseline characteristics were balanced across all groups.
All participants had non-familial hypercholesterolemia and mixed hyperlipidemia; were already taking a moderate- or high-intensity statin; had LDL level of 1.8 mmol/L or more or 2.6 mmol/L or more for patients with or without ASCVD; and had fasting triglycerides of 5.6 mmol/L or less.
The assigned recaticimab regimen was initiated after a 4-to-6-week run-in period during which patients were on a low-fat diet and healthy lifestyle on top of their background lipid-lowering therapies.
Compared with placebo, recaticimab further reduced mean LDL by 62.2% in those who received 150 mg/kg every 4 weeks; 59.7% in those who received 300 mg/kg every 8 weeks; and 53.4% in those who received 450 mg/kg every 12 weeks (P for all < .0001), Du said during the presentation.
Reductions were also observed in non-HDL, apolipoprotein B and lipoprotein(a) among those assigned to recaticimab, Du said.
The reductions in LDL level conferred by add-on recaticimab were maintained through 48 weeks, according to the presentation.
At 24 weeks, goal LDL was achieved in 85.8% to 94.5% of the overall population, in 84.4% to 94.3% of those with ASCVD and in 87.8% to 95% of those without ASCVD.
LDL lowering with recaticimab remained significant across dosing regimens and across all prespecified subgroups, including those groups by age, BMI, baseline LDL, history of ASCVD and diabetes status, Du said.
Moreover, recaticimab was reported to be well tolerated over 48 weeks, with similarly low incidence and severity of treatment-related adverse events in the treatment and placebo arms, Du said, noting the rate of serious adverse events in both groups was 0.4%.
“The REMAIN-2 study demonstrated long-term efficacy and safety of an add-on effect from recaticimab given in infrequent dosing interval,” Du said during the presentation. “After 24 weeks treatment, recaticimab reduced LDL cholesterol by 62%, 60% and 53%, respectively, when given every 4 weeks, every 8 weeks and every 12 weeks. The effect of recaticimab was maintained through week 48 and the safety profile was comparable to placebo.”
The phase 3 results of REMAIN-3, a study of the efficacy and safety of recaticimab in patients with heterozygous familial hypercholesterolemia, with be presented at a later date.
Reference:
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Du X, et al. LBS.06. Future of lipid lowering therapy – Novel mechanisms and approaches. Presented at: American Heart Association Scientific Sessions; Nov. 11-13, 2023; Philadelphia.
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