Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alirocumab in Healthy Chinese Subjects: A Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study

Abstract

Background The addition of alirocumab (a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 [PCSK9]) to background statin therapy provides significant incremental low-density lipoprotein cholesterol (LDL-C) lowering and cardiovascular event risk reduction. Objectives Our objectives were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of alirocumab in healthy Chinese subjects. Methods In this double-blind, placebo-controlled, phase I study, 35 Chinese subjects (aged 21-45 years) with baseline LDL-C > 100 mg/dL (2.59 mmol/L) were randomized to receive a single 1 mL subcutaneous injection of alirocumab 75, 150, or 300 mg, or placebo, and followed up for ~ 12 weeks. Results Treatment-emergent adverse events, most frequently nasal congestion and dry throat, were reported in three of seven or eight subjects in each alirocumab dose group (two of seven in the placebo group). One patient receiving alirocumab 300 mg had a mild local injection-site reaction. No alirocumab recipients demonstrated antidrug antibodies. Maximum alirocumab serum concentrations (6-34 mg/dL) occurred at a median of 3-7 days across the dose groups. Maximum mean LDL-C reductions from baseline were observed on days 8, 15, and 22 with alirocumab 75 (55.3%), 150 (63.7%), and 300 mg (73.7%), respectively. Mean free PCSK9 levels were reduced to below the lower limit of quantification within 4 h of dosing. Total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were reduced with alirocumab. Conclusions In Chinese subjects, alirocumab 75, 150, and 300 mg was safe and well-tolerated. Pharmacokinetic/pharmacodynamic parameters, including clinically meaningful reductions in LDL-C and other lipids/lipoproteins, were consistent with data from Japanese and Western populations. Clinicaltrials.gov identifier: NCT02979015.

Tafolecimab in Chinese patients with non-familial hypercholesterolemia (CREDIT-1): a 48-week randomized, double-blind, placebo-controlled phase 3 trial

“…In studies of evolocumab and alirocumab, the LDL-C and PCSK9 levels remained around the nadir through day 22 for 420 mg evolocumab and through day 29 for 300 mg alirocumab. 16 , 17 However, the reduction of LDL-C and PCSK9 levels were maintained to more than 6 weeks after a single dose of 450 mg or 600 mg tafolecimab administration, 18 supporting the exploration of a long-interval dosing regimen in further studies. Thus, to evaluate long-term efficacy and safety and explore long-interval dosing regimen, we conducted this CREDIT-1 study.…”

PCSK9 Antagonists: Clinical Efficacy and Main Trends in the Development of New Medicines

“…После однократного подкожного введения C max в плазме крови достигается в течение 3-7 сут, абсолютная биодоступность препарата составляет 85%. Основные параметры фармакокинетического профиля и эффективности сходны с таковыми у эволокумаба [23].…”

Alirocumab effect on preventing periprocedural ischaemic events in coronary heart disease patients undergoing coronary stenting (APPEASE trial): study protocol of a multicentre, open-label, randomised controlled trial

“…Therefore, mechanically, we deduce that PCSK9 is associated with periprocedural myocardial injury during PCI. As alirocumab could significantly and promptly decrease serum PCSK9 levels 26 and further inhibit the classical and non-classical atherogenic mechanisms of PCSK9, [27][28][29] we consider that the use of alirocumab before elective PCI could effectively reduce the occurrence of PCI-related MI or major myocardial injury. To test this hypothesis, we designed the Alirocumab effect on Preventing Periprocedural ischaemic Events in coronary heart diseAse patients undergoing coronary StEnting (APPEASE) trial.…”