"新时代降脂治疗：全方位了解PCSK9抑制剂与Inclisiran"

("Lipid-Lowering Therapies in the New Era: A Comprehensive Understanding of PCSK9 Inhibitors and Inclisiran")

1. 心血管疾病与 LDL-C

Cardiovascular disease and LDL-C

以动脉粥样硬化性心血管疾病（atherosclerotic cardiovascular disease, ASCVD）为主的心血管疾病（cardiovascular disease, CVD）是我国城乡居民第一位死因，低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL-C）是 ASCVD 的致病性危险因素。

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death among urban and rural residents in China, and elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for ASCVD[1, 2].

2. PCSK9 抑制剂崭露头角

PCSK9 Inhibitors Emerging

在降脂药开发领域，PCSK9 是近年来一个新兴的热门靶点。在跨国制药巨头研发出靶向 PCSK9 的单抗药物并在国内获批后，国内相关药物的研发也开始提速。已上市的 PCSK9 抑制剂主要有PCSK9单抗，而PCSK9小干扰RNA，即Inclisiran，在欧美及中国均已批准上市。

In the field of lipid-lowering drug development, PCSK9 has emerged as a popular target in recent years. After multinational pharmaceutical giants developed monoclonal antibody drugs targeting PCSK9 and obtained approval in China, the development of related domestic drugs has also begun to accelerate. The main PCSK9 inhibitors that have been marketed are PCSK9 monoclonal antibodies. Inclisiran, a synthetic, double stranded, small interfering RNA (siRNA) has been approved for market inin Europe, US and China.

国内已经批准了两款进口的 PCSK9 单抗，分别是依洛尤单抗（Evolocumab）以及阿利西尤单抗（Alirocumab）。目前这两款药物都已进入医保。

Two imported PCSK9 monoclonal antibodies have been approved in China, Evolocumab and Alirocumab. Both drugs are now covered by medical insurance.

商业保险患者可以提前向保险经纪人询问是否有降血脂针英克司兰（Inclisiran）治疗福利。如有福利，可在预约医生门诊评估是否适用针剂治疗后，由工作人员帮助申请针剂治疗福利担保。

Patients with commercial insurance can inquire with their insurance broker in advance to see if there is coverage for lipid-lowering injection treatment with Inclisiran. If such benefits are available, after scheduling a consultation with a doctor to assess suitability for injection therapy, staff can assist with the application for injection treatment benefits guarantee.

图1 Inclisiran （siRNA Blocker）是一种特异性抑制肝脏中 PCSK9 合成的新型药物, siRNA进行干预，可减少PCSK9的合成; 用PCSK9单克隆抗体干预，是阻断PCSK9的作用[3]。

Figure 1 Inclisiran (siRNA Blocker) is a novel drug that specifically inhibits the synthesis of PCSK9 in the liver. siRNA intervention can reduce the synthesis of PCSK9; intervention with PCSK9 monoclonal antibodies is to block the action of PCSK9.

3. PCSK9抑制剂与心血管风险降低

PCSK9 inhibitors and cardiovascular risk reduction

降脂新药如前蛋白转化酶枯草溶菌素 9（preprotein converting enzyme subtilisin kexin 9，PCSK9）抑制剂的应用，可使 LDL-C 水平降低 50%~70%，在他汀类药物治疗的基础上进一步减少主要不良心血管事件（major adverse cardiovascular event， MACE），再度证实了更大幅度降低 LDL-C 可带来更多的心血管保护作用[4, 5]。

Research also demonstrated that the combination of lipid-lowering drugs and use of new drug classes such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can reduce LDL-C levels by 50% to 70%, resulting in further reduction in major adverse cardiovascular events (MACE) based on statin therapy. This observation reaffirmed that additional substantial LDL-C reductions can lead to greater cardiovascular protection.

4. 特定治疗组合

Specific treatment combinations

他汀类药物治疗后 LDL-C 未达标时应考虑联合胆固醇吸收抑制剂和（或）PCSK9抑制剂。有研究显示，提早使用 PCSK9 单抗可更早和更显著降低 ASCVD 风险，且长时间使用 （≥ 7 年 ）具有良好的安全性[6]。PCSK9 抑制剂通过减少LDLR降解、增加LDLR数量而增加血浆LDL清除，在降脂机制上与他汀类药物、胆固醇吸收抑制剂互补协同。

Combination of cholesterol absorption inhibitors and/or PCSK9 inhibitors should be considered when LDL-C targets are not met after statin therapy. Early use of PCSK9 monoclonal antibodies has been shown to reduce ASCVD risk earlier and more significantly, with good safety for prolonged use (≥7 years).PCSK9 inhibitors increase plasma LDL clearance by reducing LDLR degradation and increasing LDLR quantity, complementing and synergizing with statins and cholesterol uptake inhibitors in terms of lipid-lowering mechanisms.

5. PCSK9抑制剂作用机制

Mechanism of action of PCSK9 inhibitors

PCSK9 是肝脏合成的分泌型丝氨酸蛋白酶，可与LDLR 结合并使其降解，从而减少LDLR对血清 LDL-C的清除。通过抑制PCSK9，可阻止LDLR 降解，促进LDL-C的清除。PCSK9单抗的作用机制系靶向作用于PCSK9蛋白[7]，

PCSK9 is a secreted serine protease synthesized by the liver that binds to and degrades LDLR, thereby reducing the clearance of serum LDL-C by LDLR. By inhibiting PCSK9, LDLR degradation can be prevented, and LDL-C clearance can be promoted. The mechanism of action of PCSK9 monoclonal antibodies is based on targeting the PCSK9 protein.

PCSK9抗体结合血浆 PCSK9，减少细胞表面的LDLR分解代谢，从而降低循环LDL-C水平[8]。目前获批上市的有2种全人源单抗，分别是依洛尤单抗（evolocumab）和阿利西尤单抗（alirocumab）。研究证实依洛尤单抗和阿利西尤单抗可显著降低平均LDL-C水平达 50%~70%。

PCSK9 antibodies bind to plasma PCSK9 and reduce the catabolism of LDLR on the cell surface, thereby reducing circulating LDL-C levels.

There are currently two human monoclonal antibodies approved for marketing, evolocumab and alirocumab. Studies have confirmed that evolocumab and alirocumab significantly reduce mean LDL-C levels by 50% to 70%.

图2 PCSK9 是肝脏合成的分泌型丝氨酸蛋白酶，可与低密度脂蛋白( LDL) 受体结合并使其降解，从而减少 LDL 受体对血清 LDL-C 的清除。通过抑 制PCSK9，可阻止 LDL 受体降解，促进LDL-C 清除。PCSK9单抗的作用机制系靶向作用于PCSK9蛋白[9].

Figure 2 PCSK9 is a secreted serine protease synthesized by the liver that binds to and degrades LDLR, thereby reducing the clearance of serum LDL-C by LDLR. By inhibiting PCSK9, LDLR degradation can be prevented, and LDL-C clearance can be promoted. The mechanism of action of PCSK9 monoclonal antibodies is based on targeting the PCSK9 protein.

6. 安全性与耐受性

Safety and Tolerance

依洛尤单抗140 mg 或阿利西尤单抗75 mg， 每两周1次皮下注射，安全性和耐受性好，最常见的副作用包括注射部位发痒和流感样症状[10]。

volocumab 140 mg or alirocumab 75 mg administered subcutaneously once every two weeks was safe and well tolerated, with the most common side effects including injection site itching and flu-like symptoms.

应用 PCSK9 单抗后常常可将患者的 LDL-C 降至较低水平，有关PCSK9单抗的应用时长是临床关注的问题。最新的FOURIER开放标签扩展研究 （FOURIER-Open Label Extension，FOURIER-OLE）提 示 ASCVD 患者应用依洛尤单抗最长达 8.4 年（中位 5 年 ），中位 LDL-C 达 0.78 mmol/L 水平，其严重不良 事件、肌肉相关事件、新发糖尿病、出血性脑卒中和 神经认知事件等不良反应发生率与安慰剂组相似[6]。

The latest FOURIER-open label Extension (FOURIEROLE) study suggests that ASCVD patients on evolocumab for up to 8.4 years (median 5 years) with a median LDL-C level of 0.78 mmol/L had serious adverse events, muscle-related events, new-onset diabetes mellitus The incidence of adverse events such as hemorrhagic stroke and neurocognitive events was similar to that of the placebo group.

应用PCSK9 单抗后常常可将患者的LDL-C 降至较低水平，有关PCSK9单抗的应用时长是临床关注的问题。最新的 FOURIER 开放标签扩展研究（FOURIER-Open Label Extension，FOURIER-OLE）提示ASCVD患者应用依洛尤单抗最长达8.4年（中位 5 年 ），中位 LDL-C 达 0.78 mmol/L 水平，其严重不良事件、肌肉相关事件、新发糖尿病、出血性脑卒中和 神经认知事件等不良反应发生率与安慰剂组相似[6]。

Although the application of PCSK9 monoclonal antibodies often reduces LDL-C to lower levels in patients, the duration of application regarding PCSK9 monoclonal antibodies is a clinical concern. The latest FOURIER-open label Extension (FOURIEROLE) study suggests that ASCVD patients on evolocumab for up to 8.4 years (median 5 years) with a median LDL-C level of 0.78 mmol/L had serious adverse events, muscle-related events, new-onset diabetes mellitus The incidence of adverse events such as hemorrhagic stroke and neurocognitive events was similar to that of the placebo group.

专业知识小贴士：（开放标签扩展研究（Open Label Extension Study）通常是在一项临床试验完成后，为了进一步收集药物安全性和有效性数据而进行的跟踪研究。在这种研究中，参与者都知道他们正在接受的治疗，也就是说没有使用安慰剂（即没有“盲测”）。

在您提到的FOURIER-OLE（FOURIER开放标签扩展）研究的情况中，它意味着心血管事件的患者在最初FOURIER研究结束后，继续使用依洛尤单抗，并且为期最长可达8.4年（平均大约5年）。研究目的可能是观察这种药物在长期使用后的效果和患者的安全性。简单地说，研究者想要了解，当患者长时间使用这种药物时，它是否仍然能够安全且有效地帮助他们降低再次出现心血管问题的风险）。

Expertise Tip:（An open-label extension study is typically a follow-up study conducted after the completion of a clinical trial to collect additional information on the safety and efficacy of a drug. In such a study, participants are aware of the treatment they are receiving, meaning there is no use of placebos (i.e., no "blinding").

In the case of the FOURIER-OLE (FOURIER Open Label Extension) study mentioned, it means that patients with cardiovascular events continued to receive the drug evolocumab following the conclusion of the initial FOURIER trial, for a period of up to 8.4 years (with a median duration of about 5 years). The purpose of the study is likely to observe the effects and safety of the drug over an extended period of usage. Simply put, the researchers want to understand whether this drug can continue to safely and effectively help patients lower their risk of experiencing cardiovascular issues again when used over a long term).

7. 适应人群与临床应用

Target Population and Clinical Application

PCSK9抑制剂的应用范围正在不断拓展，涵盖不同的年龄群体和具有更高心血管风险的个体，包括老年人和有特定血脂代谢异常的患者，例如家族性高胆固醇血症 (FH) 患者。

The scope of PCSK9 inhibitors is continually broadening, covering a variety of age groups and individuals with higher cardiovascular risks, including the elderly and patients with specific lipid metabolism disorders such as familial hypercholesterolemia (FH).

7.1特定人群的血脂管理

Lipid management for specific populations

要点提示：

特定人群是指具有某些共存疾病（如高血压、 糖尿病、CKD、脑卒中）、特殊生理状态（妊娠）、 儿童、高龄老年人及特殊血脂代谢异常（家族性高 胆固醇血症）的患者。其血脂代谢状态及对药物治疗的反应具有一定的特殊性，所以需要采取更为个体化的血脂管理策略。

Key points: Specific populations are patients with certain coexisting diseases (e.g., hypertension, diabetes, CKD, stroke), special physiological states (pregnancy), children, elderly people of advanced age, and special lipid metabolism abnormalities (familial hypercholesterolemia). Their lipid metabolism status and response to drug therapy are somewhat specific, so a more individualized lipid management strategy is needed.

他汀类药物联合胆固醇吸收抑制剂或（和 ）PCSK9单抗的研究显示，合并糖尿病的 ASCVD患者可从强化降脂中获益更多。两项PCSK9抑制剂的二级预防研究中，入选患者的年龄范围分别为 40~80 岁[4] 和≥ 18 岁[11] ，均包含了≥ 75 岁的人群， 且在 FOURIER 研究中的分层分析显示，≥ 69 岁的 人群从 PCSK9 单抗降脂治疗中的获益与＜ 69 岁的 人群一致 [12]。综合以上证据提示≥ 75 岁的 ASCVD 患者可与＜75岁患者采取同样的降脂原则。

The age range of patients enrolled in the two secondary prevention studies of PCSK9 inhibitors was 40 to 80 years[10] and ≥ 18 years,[77] respectively, both of which included those ≥ 75 years, and a stratified analysis in the FOURIER study showed that those ≥ 69 years benefited from lipid-lowering therapy with PCSK9 monoclonal antibodies in consistent with those < 69 years.[206] Overall, this evidence suggests that ASCVD patients ≥ 75 years of age can be treated with the same lipid-lowering principles as patients < 75 years of age

专业知识小贴士：（二级预防研究是一类医学研究，着重于防止已经出现某种疾病的病人进一步恶化或再次发生相关健康问题。在心血管领域，二级预防通常指的是对那些已经有过心脏病发作、中风或其他心血管事件的病人实施的干预措施。

具体到PCSK9抑制剂的二级预防研究，这意味着这项研究可能集中在已经有过心血管事件的病人上，通过给予他们PCSK9抑制剂来降低他们未来出现心血管事件的风险。PCSK9抑制剂是一种降低血液中低密度脂蛋白胆固醇（LDL-C，又称为“坏”胆固醇）的药物，它有助于降低心脏病和其他心血管疾病的风险）。

Expertise Tip:（Secondary prevention studies are a category of medical research focused on preventing further deterioration or recurrence of health issues in patients who have already experienced a specific disease. In the cardiovascular field, secondary prevention typically refers to interventions for patients who have already suffered a heart attack, stroke, or other cardiovascular events.

Specifically, secondary prevention studies involving PCSK9 inhibitors would imply that the research is concentrated on patients who have experienced cardiovascular events, with the aim of reducing their risk of future cardiovascular incidents by administering PCSK9 inhibitors. PCSK9 inhibitors are a type of medication that lowers the levels of low-density lipoprotein cholesterol (LDL-C, also known as "bad" cholesterol) in the blood, which helps decrease the risk of heart disease and other cardiovascular conditions）.

8. Inclisiran：新兴的PCSK9小干扰RNA

Inclisiran: An Emerging PCSK9 Small Interfering RNA

Inclisiran是PCSK9小干扰RNA，研究表明，其LDL-C降幅与PCSK9单抗相当而作用更持久，注射一剂疗效可维持半年[13]。属超长效PCSK9抑制剂。增加患者治疗的依从性为其主要优势。

Inclisiran is a PCSK9 small interfering RNA, and studies have shown that its LDL-C reduction rate is comparable to that of PCSK9 monoclonal antibodies while its effects are longer lasting, and the efficacy of one injection can be maintained for six months. Which is an ultra-long-acting PCSK9 inhibitor. Increasing patient compliance with treatment is its main advantage.

8.1 全球首款PCSK9 siRNA药物--英克西兰（Inclisiran）

适应症： 本品可作为饮食的辅助疗法，用于成人原发性高胆固醇血症（杂合子型家族性和非家族性）或混合型血脂异常患者的治疗： 

⁃ 在接受最大耐受剂量的他汀类药物治疗仍无法达到 LDL-C 目标的患者中，与他汀类药物、或者与他汀类药物及其他降脂疗法联合用药，或者 

⁃ 在他汀类药物不耐受或禁忌使用的患者中，单独用药或与其他降脂疗法联合用药[14]。

Inclisiran, the world's first PCSK9 siRNA drug

Indications: Inclisiran is indicated as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low-density lipoprotein cholesterol (LDL-C).

In patients who are unable to achieve LDL-C goals with the maximum      tolerated dose of statin therapy, either in combination with statins, or      with statins and other lipid-lowering therapies, or

In patients who are statin-intolerant or for whom statins are      contraindicated, as monotherapy or in combination with other      lipid-lowering therapies.

推荐用法用量：推荐给药剂量为单次皮下注射 284 mg 本品：首次给药后，在 3 个月时再次给药， 然后每 6 个月给药一次。 

The recommended dosage of Inclisiran, is 284 mg administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months.

9. 高级化学修饰与GalNAc递送系统

The Application of Advanced Chemical Modifications and the GalNAc Delivery System

9.1 长程药效：得益于siRNA药物化学修饰技术的不断进步

英克西兰siRNA的“高级ESC（Enhanced Stability Chemistry）化学修饰”，能增强siRNA对核酸酶的抵抗能力，延长其在肝细胞内的存活时间[15, 16]

Prolonged Drug Efficacy: Thanks to the continuous advancement in siRNA medicinal chemical modification technology,

Inclisiran's "advanced ESC (Enhanced Stability Chemistry) chemical modification" can enhance the resistance of siRNA to nucleases, thus extending its survival time within hepatocytes.

9.2 靶向肝脏：GalNAc递送系统

N-乙酰半乳糖胺（GalNAc）与RNA药物偶联，递送至肝脏[17]

Liver Targeting: GalNAc Delivery System

N-acetylgalactosamine (GalNAc) conjugated with RNA therapeutics is delivered to the liver.

9.3 高度特异：siRNA需要整条RNA链完全匹配才能激活RISC[18]

siRNA（小干扰RNA）是一种用来干预生物体内基因表达的工具。它的工作机制是通过精确地与目标基因的RNA序列配对，进而引导一种叫RISC（RNA诱导沉默复合体）的蛋白质复合体来降解这些RNA序列，阻止其转化成蛋白质。这种配对需要非常精确，siRNA的整条RNA链需要与目标基因的RNA序列完全匹配，只有这样，RISC复合体才会被正确地激活，并且特定的基因表达才会被抑制。

简单来说，siRNA就像是一个定制的“指令码”，只有当它完全符合特定的“目标代码”时，才能发动攻击，关闭那个基因的活动。这种高度的特异性意味着siRNA可以非常精确地对特定基因进行干预，同时降低了对其他非目标基因错伤的可能性。

High Specificity: siRNA requires complete matching of the entire RNA strand to activate RISC.

siRNA (small interfering RNA) is a tool used to intervene in gene expression within an organism. Its mechanism of action involves precise pairing with the RNA sequence of the target gene, which then directs a protein complex known as RISC (RNA-induced silencing complex) to degrade these RNA sequences and prevent them from being translated into proteins. This pairing must be highly precise; the entire RNA chain of the siRNA must perfectly match the RNA sequence of the target gene. Only with such a complete match can the RISC complex be properly activated, and the expression of the specific gene can be inhibited.

In simpler terms, siRNA acts like a custom "instruction code" that can initiate an attack and shut down gene activity only when it completely corresponds to the specific "target code." This high specificity means that siRNA can intervene in a very precise manner on particular genes while reducing the likelihood of off-target effects on other genes.

9.4 高安全性：化学修饰、GalNAc递送系统降低siRNA潜在风险

High Safety: Chemical modifications and the GalNAc delivery system reduce the potential risks of siRNA.

10 药品使用：

本药品是处方药，需要医生开具处方，并根据患者情况合理使用。

ADMINISTRATION

This drug is a prescription drug that requires a doctor's prescription and is used appropriately according to the patient's condition.

参考文献

References

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2           2023 China Guidelines for Lipid Management.

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14         英克司兰钠注射液(乐可为) 药品说明书 核准日期：2023年08月22日.

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