Recaticimab, a novel humanized antiproprotein convertase subtilisin/kexin type 9 (PCSK9) antibody, significantly lowered low-density lipoprotein cholesterol (LDL-C) levels compared with placebo in adults with heterozygous familial hypercholesterolemia (HeFH), according to results from the multicenter, randomized, double-blind, placebo-controlled phase 3 REMAIN-3 trial published in Cardiovascular Research.
The study demonstrated a mean percentage change in LDL-C from baseline of −54.4% (95% CI, −57.9% to −50.8%) in the recaticimab group compared to −4.5% (95% CI, −9.4% to 0.3%) in the placebo group at week 12, with a measured treatment difference of −49.8% (95% CI, −55.8% to −43.0%; P < .0001).
Addressing Critical Unmet Need in Genetic Hypercholesterolemia
Patients with HeFH, an inherited genetic disorder, face seriously heightened plasma concentrations of LDL-C from birth. The condition complicates the liver's ability to metabolize particles carrying LDL-C through the bloodstream, with individuals often presenting with LDL-C levels 2 to 3 times higher than normal according to the National Institutes of Health. Because of these dangerously high LDL-C levels, individuals with HeFH are at increased risk for cardiovascular events, and because it is a genetic condition, lifestyle changes alone cannot manage patients' LDL-C levels.
Novel PCSK9 options are sorely needed given the limited number of these medications currently approved by the FDA for use to lower LDL-C. PCSK9 inhibitors differ from typical lipid-lowering therapies like statins in that they are injected by a healthcare professional every 3 months, which could allow for more stringent adherence and more effective LDL-C lowering.
Phase 3 Trial Design and Patient Population
The REMAIN-3 trial took place across 25 sites in China, enrolling individuals with HeFH who were on stable lipid-lowering therapy for at least 28 days. Participants had fasting LDL-C of 2.6 mmol/L or more—or 1.8 mmol/L or more for those with a history of cardiovascular disease—and fasting triglyceride levels of 5.6 mmol/L or less.
In total, 143 patients were randomly assigned 2:1 to receive a 150-mg dose of subcutaneous recaticimab (n = 95) or a matching placebo (n = 48) every 4 weeks for 12 weeks. The primary endpoint evaluated the percentage change in LDL-C from baseline to week 12.
Comprehensive Lipid Profile Improvements
Beyond the primary endpoint, recaticimab was more effective than placebo at improving other lipid variables, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein A, according to the investigators.
The drug builds on previous success from the phase 3 REMAIN-2 trial, where recaticimab as an add-on to stable statin therapy—in doses of either 150 mg, 300 mg, or 450 mg—significantly decreased LDL-C levels with a dosing interval of every 12 weeks, demonstrating its potential for effective LDL-C regulation.
Safety Profile and Clinical Implications
Regarding safety, there were comparable rates of treatment-related adverse events (TRAEs) between groups (27.4% with recaticimab vs 25.0% with placebo). Common TRAEs that occurred more frequently with recaticimab than placebo were injection site reaction (8.4% vs 0%) and increased blood creatine phosphokinase (5.3% vs 2.1%).
"Recaticimab significantly lowered the LDL-C level compared with placebo, with an acceptable safety profile, providing a new effective treatment option for patients with inadequately controlled HeFH," the REMAIN-3 authors concluded.
The results suggest recaticimab could transform the treatment paradigm for HeFH by offering a safe and effective option to lower LDL-C without compromising other aspects of patient health, potentially addressing the critical need for additional therapeutic options in this challenging patient population.
