Background

Currently available antiproprotein convertase subtilisin/kexin type 9 monoclonal antibodies can effectively decrease low-density lipoprotein cholesterol (LDL-C) levels, but require frequent dosing. Recaticimab is a novel humanized monoclonal antibody against proprotein convertase subtilisin/kexin type 9. In a phase 1b/2 trial, recaticimab as add-on to stable statins showed robust LDL-C reduction with a dosing interval up to every 12 weeks (Q12W) in patients with hypercholesterolemia.

Objectives

REMAIN-2 (REcaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia) aimed to assess the efficacy and safety of 48-week treatment with recaticimab as add-on therapy to statins in nonfamilial hypercholesterolemia.

Methods

REMAIN-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. During the run-in period, patients received stable moderate or high-intensity statin, with or without cholesterol absorption inhibitors (ezetimibe) or fenofibrate, for ≥4 weeks. Patients with an LDL-C of ≥1.8 mmol/L (if with atherosclerotic cardiovascular disease [ASCVD]) or ≥2.6 mmol/L (if without ASCVD) were then randomized (2:2:2:1:1:1) to receive recaticimab 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg Q12W, or matching placebo injections (Q4W, Q8W, or Q12W) for 48 weeks. The primary efficacy endpoint was percentage change from baseline to week 24 in LDL-C level.

Results

A total of 689 randomly assigned patients received treatment (mean age, 55.8 years; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe, 11.2%; mean baseline LDL-C, 2.8 mmol/L). Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (P < 0.0001), with least-squares mean differences of −62.2% (95% CI: −67.0% to −57.4%), −59.7% (95% CI: −65.0% to −54.4%), and −53.4% (95% CI: −58.7% to −48.2%) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The decreases in LDL-C with recaticimab were maintained through week 48. Secondary lipid variables, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) also favored the recaticimab groups. During the treatment period, the incidence of treatment-related adverse events (28.5% vs 26.6%) and serious treatment-related adverse events (0.4% vs 0.4%) was similarly low in both the recaticimab and placebo groups.

Conclusions

Recaticimab as add-on to stable statin therapy significantly decreased LDL-C levels at week 24 and sustained the decreases through week 48, providing a novel therapeutic alternative with a dosing interval of up to every 12 weeks in patients with nonfamilial hypercholesterolemia.

中文翻译：

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Recaticimab 作为他汀类药物治疗非家族性高胆固醇血症的附加疗法：随机 3 期 REMAIN-2 试验

 背景

目前可用的抗前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型单克隆抗体可有效降低低密度脂蛋白胆固醇 （LDL-C） 水平，但需要频繁给药。Recaticimab 是一种针对前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型的新型人源化单克隆抗体。在一项 1b/2 期试验中，recaticimab 作为稳定他汀类药物的附加药物在高胆固醇血症患者中显示出 LDL-C 的强烈降低，给药间隔高达每 12 周 （Q12W）。

 目标

REMAIN-2 （REcaticiMab Add-on therapy In patients with Non-familyial hypercholesterolemia） 旨在评估 recaticimab 作为他汀类药物附加疗法 48 周治疗非家族性高胆固醇血症的疗效和安全性。

 方法

REMAIN-2 是一项多中心、随机、双盲、安慰剂对照的 3 期试验。在磨合期，患者接受稳定的中度或高强度他汀类药物，联合或不联合胆固醇吸收抑制剂 （依折麦布） 或非诺贝特，持续 ≥4 周。LDL-C 为 ≥1.8 mmol/L（如果患有动脉粥样硬化性心血管疾病 [ASCVD]）或 ≥2.6 mmol/L（如果没有 ASCVD）的患者随机分配 （2：2：2：1：1：1） 接受 recaticimab 150 mg 每 4 周 （Q4W）、300 mg 每 8 周 （Q8W） 或 450 mg Q12W，或匹配的安慰剂注射（Q4W、Q8W 或 Q12W），持续 48 周。主要疗效终点是 LDL-C 水平从基线到第 24 周的百分比变化。

 结果

共有 689 名随机分配的患者接受了治疗 （平均年龄 55.8 岁;男性 64.4%;ASCVD 病史，69.5%;伴随依折麦布，11.2%;平均基线 LDL-C，2.8 mmol/L）。与安慰剂相比，recaticimab 组从基线到第 24 周的 LDL-C 百分比变化显著更明显（P < 0.0001），最小二乘均数差为 -62.2%（95% CI：-67.0% 至 -57.4%）、-59.7%（95% CI：-65.0% 至 -54.4%）和 -53.4%（95% CI：-58.7% 至 -48.2%）对于 150 mg Q4W、300 mg Q8W 和 450 mg Q12W 方案， 分别。recaticimab 组 LDL-C 的降低一直持续到第 48 周。次级脂质变量，包括非高密度脂蛋白胆固醇、载脂蛋白 B 和脂蛋白 （a） 也有利于 recaticimab 组。在治疗期间，recaticimab 和安慰剂组的治疗相关不良事件发生率（28.5% 对 26.6%）和严重治疗相关不良事件（0.4% 对 0.4%）的发生率相似。

 结论

Recaticimab 作为稳定他汀类药物治疗的附加治疗在第 24 周显著降低了 LDL-C 水平，并在第 48 周持续下降，为非家族性高胆固醇血症患者提供了一种新的治疗选择，给药间隔高达每 12 周一次。