CD20单抗治疗侵袭性B细胞非霍奇金淋巴瘤的疗效分析

目的　探讨CD20 单抗治疗侵袭性B 细胞非霍奇金淋巴瘤（B-NHL）的临床疗效以及对患者肝、肾功能的影响。方法　对83 例B-NHL 患者的临床资料进行回顾性分析,按照治疗方案不同分为单抗治疗组（40 例）和对照组（43 例）,比较两组的疗效及不良反应。结果　单抗治疗组的总有效率为82.50%,对照组的总治疗有效率为62.79%,两组比较,差异有统计学意义（P<0.05）。单抗治疗组的肝功能代表性指标ALT 水平低于对照组,两组AST 水平无显著差异（P>0.05）。两组肾功能代表性指标BUN 和Cr 水平比较,差异无统计学意义（P>0.05）。两组患者不良反应均为Ⅰ～Ⅱ级,其中单抗治疗组肝、肾功能异常的发生率为5.00%,显著低于对照组的32.56%（P<0.05）;单抗治疗组恶心呕吐的发生率为35.00%,对照组为37.21%,差异有统计学意义（P<0.05）。结论　CD20 单抗联合化疗治疗侵袭性B-NHL 近期疗效较好,不良反应较轻,肝、肾功能损害也相对较轻,值得临床推广应用。     

曲妥珠单抗致不良反应分析

目的：探讨曲妥珠单抗（trastuzumab）致不良反应的特点,为临床合理用药提供参考。方法：选择本院乳腺内科应用曲妥珠单抗所致不良反应38例,又检索到中国期刊全文数据库、万方数据库、维普资讯网和PubMed筛选出的曲妥珠单抗相关不良反应的文献10篇（39例）,合并作为研究对象,针对患者的一般情况、合并化疗方案、不良反应出现时间及临床表现、治疗及转归进行分析。结果：我院38例患者中不良反应发生在给药后0～90 min者21例（55%）,1~2 d者9例（24%）,3~7 d者8例（21%）;最常见不良反应为输液反应,严重不良反应为2例,表现为严重输液反应（过敏反应）,永久终止曲妥珠单抗的治疗。在数据库检索到的39例中,不良反应发生在给药后0～90 min者30例（77%）,大于7 d者4例（10%）,未报道发生时间5例（13%）;最常见不良反应为输液反应,严重不良反应为9例,包括非感染性肺炎和心脏毒性,未影响治疗。结论：曲妥珠单抗最常见的不良反应为输液反应,多在第一次输注时发生;用药前先给予苯海拉明、地塞米松预防,可降低其发生率;加强监测,预防心脏毒性,保证治疗的顺利进行。     

纳武利尤单抗相关孤立性促肾上腺皮质激素缺乏症29例文献分析

目的 分析纳武利尤单抗相关孤立性促肾上腺皮质激素缺乏症（IAD）的临床特点。方法 以“纳武利尤单抗或纳武单抗、孤立性促肾上腺皮质激素缺乏症或促肾上腺皮质激素缺乏”和“nivolumab、isolated adrenocorticotropic hormone deficiency or adrenocorticotropic hormone deficiency”为检索词，检索1998年9月至2021年10月中国知网、万方、维普和PubMed、Web of Science数据库的纳武利尤单抗相关IAD的个案报道，提取相关信息进行描述性分析。结果 共筛选出个案报道25篇，涉及纳武利尤抗相关IAD 29例，男性20例，女性9例，其中日本籍患者19例（66%）；纳武利尤单抗单药治疗27例（93%）。26例（90%）患者在纳武利尤单抗治疗后300 d内发生IAD。临床症状以乏力、纳差多见，且易合并甲状腺疾病（14例，48%），早期实验室检查异常为血钠降低22例（76%）及嗜酸性粒细胞比率升高12例（41%）。28例（97%）患者长期服用氢化可的松替代治疗，除1例因原发病进展死亡外，其余均预后良...     

成人急性淋巴细胞白血病单克隆抗体治疗的研究进展

ALL是一组异质性造血系统恶性肿瘤,不同亚型有着不同的生物学特性和预后,对治疗反应差别甚远。虽然近几年成人ALL的疗效有了长足的进步,然而,目前成人ALL长期无病生存率及治疗效果仍大大逊色于儿童ALL,复发、难治仍然是临床面临的难题,寻找新的治疗手段非常必要。急性淋巴细胞白血病原始细胞表面表达一系列作为单克隆抗体目标的特殊抗原,CDl9、CD20、CD22和CD52。至今为止,CD20单抗已经与化疗联合治疗成熟B细胞急性淋巴细胞白血病（ALL）及Burkitt’s淋巴瘤。另外一个抗原是CDl9,在急性淋巴细胞白血病中呈高表达,Blinatumomab是双特异性单克隆抗体,可以直接对抗CDl9和CD3。CD52单抗（阿仑单抗）、CD22单抗（依帕珠单抗）的有效性在一些小研究和个案报道中亦有显示。然而,有关单克隆抗体治疗使用方面,如：抗原表达所需达到的水平,何时开始以及何时结束治疗,单克隆抗体的最佳剂量,单药治疗抑或联合治疗,是否需要维持治疗等,仍有待进一步明确。     

17例卡瑞利珠单抗致不良反应的文献分析

目的 分析卡瑞利珠单抗致药物不良反应（ADR）发生的临床特点及规律,为临床合理用药提供参考。方法 检索国内外数据库（截至2022年3月1日）关于卡瑞利珠单抗致ADR的文献报道,提取数据并进行分析。结果 卡瑞利珠单抗致ADR个案报道15篇,涉及患者17例,其中男性12例,女性5例,ADR发生年龄多分布在50～79岁（13例,76.47%）,且多发生在用药后30 d内（9例,52.94%）。卡瑞利珠单抗致ADR主要以皮肤及其附件损害较多（9例,52.94%）,14例经停药和（或）对症治疗后好转或痊愈。结论 卡瑞利珠单抗致ADR涉及多个年龄段患者,累及多个系统/器官,尤其是皮肤及其附件损害较多,需引起高度重视,临床使用时需加强用药监测,综合评估患者利益风险,及早识别药品ADR,及时进行临床处理。     

尼妥珠单抗在晚期胰腺癌综合治疗中的疗效分析

目的：观察尼妥珠单抗在晚期胰腺癌综合治疗中的临床疗效。方法回顾性分析19例经泰欣生初治（10例）或者复治（9例）的晚期胰腺癌患者的临床资料,所有患者在治疗过程中应用尼妥珠单抗（200mg/周）靶向治疗至少3周,且疗效可以评价。结果近期疗效：患者中无CR,PR1例,疾病控制率（DCR）为52.6%（10/19）。疾病相关症状有较好改善,包括疼痛程度减轻、KPS评分提高等。19例患者均可获得PFS结果,中位PFS为3.57个月。2例患者仍存活,17例患者可获得总生存（OS）结果,最短3.0个月,最长31.7个月（患者系复治,应用尼妥珠单抗综合治疗后生存时间为24个月）,中位OS 11.75个月。结论尼妥珠单抗在晚期胰腺癌的综合治疗中疗效及安全性值得肯定,并能较好地改善此类疾病的相关症状,可能是会成为晚期胰腺癌患者的有效选择之一,其疗效有待进一步的大样本量的临床研究确认。     

单克隆抗体用于治疗溃疡性结肠炎的研究进展

溃疡性结肠炎（UC）发病机制复杂,与免疫因素及炎性介质等因素相关。单克隆抗体因为能特异性结合并选择性杀伤靶细胞、体内呈靶向性分布、不良反应少,所以成为治疗中重度UC的研究热点,其中包括抗肿瘤坏死因子类单抗（如英夫利昔单抗、阿达木单抗、戈利木单抗）,α₄β₇整合素抗体（如维多珠单抗、etrolizumab、SHP647）,白细胞介素（IL）-12和IL-23拮抗剂等。对治疗UC单克隆抗体的作用机制和临床疗效研究进展进行综述,以期为该类新药的研发及临床应用提供依据。     

利妥昔单抗联合化疗治疗非霍奇金淋巴瘤疗效的Meta分析

目的：系统评价利妥昔单抗联合化疗治疗非霍奇金淋巴瘤（non-hodgkin′s lymphoma, NHL）的临床疗效,为临床用药及药物政策提供参考。方法：计算机检索中英文数据库1998～2014年间公开发表的利妥昔单抗联合与单用化疗治疗NHL的随机或临床对照试验（RCT、CCT）文献。结果：治疗组与对照组完全缓解率CR （RR=1.35,95%CI[1.22,1.49]）、3年总生存率（RR=1.30,95%CI[1.03,1.65]）有显著性差异;但5年总生存率（RR=1.45,95%CI[0.83,2.53]）无显著差异。结论：Meta分析结果表明,利妥昔单抗联合化疗治疗NHL比单纯化疗完全缓解率、3年总生存率更高。     

某院西妥昔单抗合理使用评价标准的建立与应用

目的 建立西妥昔单抗合理应用评价标准,评价我院西妥昔单抗临床使用情况,为临床合理用药提供参考。方法 借鉴药物利用评价（DUE）标准,参考中国国家药品监督管理局（NMPA）、美国食品药品监督管理局（FDA）西妥昔单抗药品说明书,NCCN、CSCO相关指南,以及新型抗肿瘤药物临床应用指导原则等,建立西妥昔单抗DUE标准,评价我院150例患者的西妥昔单抗临床应用情况。结果 西妥昔单抗不合理用药体现在以下方面：适应证不适宜（15例,10.00%）,用法用量不适宜（8例,5.93%）,预处理不适宜（20例,13.33%）,治疗类型与治疗方案不适宜（8例,5.93%）。结论 我院建立的西妥昔单抗DUE标准有较好的实用性和科学性,可为临床合理用药提供参考。     

美罗华治疗B细胞性非霍奇金淋巴瘤临床观察

目的观察利妥昔单抗（美罗华）联合CHOP方案治疗非霍奇金淋巴瘤的疗效及毒副反应。方法9例经病理组织学证实为CD20阳性的B细胞非霍奇金淋巴瘤患者接受利妥昔单抗375mg／m^2,静脉滴注,每3周1次。共4～6次。其间联用CHOP方案治疗4—6个疗程。结果9例患者治疗后,完全缓解6例,部分缓解2例,无变化1例,总有效率88．9％。所有患者均未见严重的不良反应。结论利妥昔单抗联合CHOP方案治疗B细胞非霍奇金淋巴瘤临床疗效较好,毒副反应较小。     

Population pharmacokinetics and exposure–response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia

Evolocumab, a novel human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets low-density lipoprotein-cholesterol (LDL-C) receptors for the treatment of hyperlipidemia. The primary objective of this analysis was to characterize the population pharmacokinetics (popPK) and exposure–response relationship of evolocumab to assess if dose adjustment is needed across differing patient populations. Data were pooled for 5474 patients in 11 clinical studies who received evolocumab doses of 7–420 mg at various frequencies, either intravenously or subcutaneously. Evolocumab area under concentration–time curve from 8 to 12 weeks (AUC_wk8–12) was simulated for individuals using the popPK model and was used to predict the LDL-C response in relation to AUC_wk8–12. Evolocumab was eliminated through nonspecific (linear) and target-mediated (nonlinear) clearance. PopPK parameters and associated variabilities of evolocumab were similar to those of other monoclonal antibodies. The exposure–response model predicted a maximal 66% reduction in LDL-C from baseline to the mean of weeks 10 and 12 for doses of evolocumab 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. After inclusion of statistically significant covariates in an uncertainty-based simulation, LDL-C reduction from baseline at the mean of weeks 10 and 12 was predicted to be within 74% to 126% of the reference patient for all simulated patient groups. Evolocumab had nonlinear pharmacokinetics. The range of responses based on intrinsic and extrinsic factors was not predicted to be sufficiently different from the reference patient to warrant evolocumab dose adjustment.     

Systematic review of published Phase 3 data on anti‐PCSK9 monoclonal antibodies in patients with hypercholesterolaemia

AimsTwo anti‐proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, alirocumab and evolocumab, have been approved for the treatment of hypercholesterolaemia in certain patients. We reviewed data from Phase 3 studies to evaluate the efficacy and safety of these antibodies.MethodsWe systematically reviewed Phase 3 English‐language studies in patients with hypercholesterolaemia, published between 1 January 2005 and 20 October 2015. Congress proceedings from 16 November 2012 to 16 November 2015 were also reviewed.ResultsWe identified 12 studies of alirocumab and nine of evolocumab, including over 10 000 patients overall. Most studies enrolled patients with hypercholesterolaemia and used anti‐PCSK9 antibodies with statins. The ODYSSEY FH I, FH II and HIGH FH alirocumab studies and the RUTHERFORD‐2 evolocumab study exclusively recruited patients with heterozygous familial hypercholesterolaemia. Two evolocumab studies focused mainly on homozygous familial hypercholesterolaemia (HoFH): TESLA Part B and TAUSSIG (a TESLA sub‐study); only those data for HoFH are reported here. All comparator studies demonstrated a reduction in LDL cholesterol (LDL‐C) with the anti‐PCSK9 antibodies. No head‐to‐head studies were conducted between alirocumab and evolocumab. Up to 87% of patients receiving alirocumab and up to 98% receiving evolocumab reached LDL‐C goals. Both antibodies were effective and well tolerated across a broad population of patients and in specific subgroups, such as those with type 2 diabetes.ConclusionsUsing anti‐PCSK9 antibodies as add‐on therapy to other lipid‐lowering treatments or as monotherapy for patients unable to tolerate statins may help patients with high cardiovascular risk to achieve their LDL‐C goals.     

Efficacy and safety of different proprotein convertase subtilisin/kexin type 9 inhibitors in patients with hypercholesterolemia at high cardiovascular risk: a systematic review and meta-analysis

OBJECTIVE To evaluate the efficacy and safety of different PCSK9 inhibitor therapy in hypercholesterolemia patients at high cardiovascular risk.METHODS Pubmed, Embase, Cochrane Library and Clinical Trials.gov were searched from their inception up to January 2019. Inclusion criteria were randomized clinical trials, hypercholesterolemia patients at high cardiovascular risk and received PCSK9 inhibitor. Study-arm-level weighted mean differences(WMDs) and 95% CIs were pooled for continuous data, meanwhile relative risks(RRs) and 95%CIs were pooled for discontinuous data, both using random-effects model. Subgroup analysis based on drug types, doses, race and control types were conducted.The primary outcomes were mean or percent change in low density lipoprotein cholesterol(LDL-C) and percentages of participants who have experienced treatmentemergent adverse events(TEAEs). The secondary outcomes were percent change in other lipid profiles, incidence of major cardiovascular events and incidence of adverse events of interest. RESULTS 27 trials recruiting37,630 individuals were included in the meta-analysis. Of these, 27 062(71.9%) were men and the mean age was61.6; 4 trials included only Asians and the population of the remaining trials were mainly Caucasian(>75%).Alirocumab and evolocumab presented significant reduction of LDL-C(alirocumab: WMD: 1.48; 95% CI:-1.74～1.22; P<0.01; evolocumab: WMD:-2.14; 95%CI:-2.43～-1.85; P<0.01) and no racial difference was found. Results of indirect comparison with placebo as reference control showed that evolocumab was superior to alirocumab for the levels of absolute change of LDL-C(WMD: 0.60; 95%CI: 0.24～0.97; P=0.01) and percent change of several other lipid profiles(P<0.05). Evolocumab was also associated with lower risk of major cardiovascular events(RR: 0.86; 95% CI: 0.80 to 0.92; P<0.01). PCSK9 inhibitor presented overall good safety except the significantly increased risk of injection site reactions(RR: 1.82; 95%CI: 1.28～2.60; P=0.01). Bococizumab presented a notable increase of TEAEs(RR: 1.15; 95%CI:1.08-1.23; P<0.01)and higher risk of injection site reactions(RR: 6.57, 95%CI: 4.28-10.08; P<0.01). CONCLUSION Both alirocumab and evolocumab were effective and safe for hypercholesterolemia patients at high cardiovascular risk of all races.Evolocumab performed relatively better for the lipid-management improvement.     

依洛尤单抗治疗高胆固醇血症有效性、安全性和经济性的快速卫生技术评估

目的:快速评价依洛尤单抗治疗高胆固醇血症的有效性、安全性和经济性,旨在为临床药物选择和决策提供循证依据。方法:计算机检索PubMed、Cochrane图书馆、中国知网、万方数据和卫生技术评估(HTA)相关官方网站,收集依洛尤单抗单用或联合标准治疗方案对比标准治疗方案或安慰剂或依折麦布用于高胆固醇血症的HTA报告、系统评价/Meta分析和药物经济学研究,检索时限均为建库/建站起至2020年1月。在筛选文献、提取资料的基础上,分别采用HTA checklist、系统评价评估测量工具AMSTAR-2量表、综合卫生经济评价报告标准量表评价纳入HTA报告、系统评价/Meta分析和药物经济学研究的文献质量,并对有效性、安全性结果进行定量描述,对经济学评价结果进行定性描述。结果:共纳入13篇文献,其中6篇为Meta分析文献、7篇为经济学文献;Meta分析文献质量偏低,经济学研究质量较好。在有效性方面,与安慰剂/依折麦布比较,依洛尤单抗可显著降低患者低密度脂蛋白胆固醇、总胆固醇、三酰甘油、极低密度脂蛋白胆固醇水平以及心血管事件、心肌梗死、冠状动脉缺血、卒中发生率,增加高密度脂蛋白胆固醇水平(P<0.05);而两者不稳定性心绞痛住院风险、心脏死亡率或心血管疾病死亡率比较,差异均无统计学意义(P>0.05)。在安全性方面,依洛尤单抗任一不良事件发生率、任一治疗紧急不良事件发生率、背部疼痛发生率、肌肉骨骼和结缔组织疾病合并发病率与安慰剂比较,差异均无统计学意义(P>0.05)。在经济性方面,在标准治疗方案基础上加用依洛尤单抗,对血脂仍不达标的高危动脉粥样硬化性心血管疾病(ASCVD)患者具有一定的成本-效果优势。结论:依洛尤单抗对于高胆固醇血症患者的有效性和安全性均较好;对于经标准治疗方案治疗后血脂仍不达标的高危ASCVD患者,该药具有一定的经济性,可作为备选方案。     

Evolocumab: A Review in Hyperlipidemia

Evolocumab (Repatha^®) is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered subcutaneously at a dosage of 140 mg every 2 weeks or 420 mg once monthly. Across 12-week phase III trials in patients with primary hypercholesterolemia or mixed dyslipidemia, evolocumab was more effective than placebo (treatment difference ?54.8 to ?76.3 %) and/or ezetimibe (treatment difference ?36.9 to ?47.2 %) at reducing low-density lipoprotein cholesterol (LDL-C) levels, including when added to statin therapy, when administered to statin-intolerant patients, when administered as monotherapy, and in patients with heterozygous familial hypercholesterolemia who were receiving statins with or without other lipid-lowering drugs. Evolocumab also significantly lowered LDL-C levels (treatment difference of ≈30 % vs. placebo) in patients with homozygous familial hypercholesterolemia when added to statins with or without ezetimibe in a 12-week phase III trial. The efficacy of evolocumab was maintained in the longer term, and it was well tolerated. In conclusion, subcutaneous evolocumab is a valuable new treatment for use in primary hypercholesterolemia or mixed dyslipidemia and homozygous familial hypercholesterolemia, particularly in patients unable to reach LDL-C goals despite treatment with statins with or without other lipid-lowering therapies and in patients who do not tolerate or are not able to receive statins.     

Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data

Introduction: To answer the need of a better low-density lipoprotein (LDL) cholesterol control in statin-treated patients at high risk for cardiovascular disease, new injectable lipid-lowering drugs with innovative mechanisms of action are in advanced phase of development or have just been approved.

Areas covered: Evolocumab and alirocumab are fully human monoclonal antibodies inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) that binds to hepatic LDL receptor and prevents it from normal recycling by targeting it for degradation. Mipomersen specifically binds to a segment of the human apolipoprotein B100 messenger RNA, blocking the translation of the gene product. Phase II (for evolocumab and alirocumab) and III (for evolocumab) trials show that PCSK9 inhibitors are equally well tolerated, with adverse events mainly limited to mild-to-moderate nasopharyngitis, injection-site pain, arthralgia and back pain. Mipomersen use is mainly associated to hepatosteatosis, increased transaminases (> 3 times the upper limit of normal), mild-to-moderate injection-site reactions and flu-like symptoms.

Expert opinion: PCSK9 inhibitors have demonstrated their good safety and tolerability in a large number of subjects with different clinical conditions, including statin-intolerance, enlarging their potential use in a broader range of patients. Further data on long-term mipomersen safety are required.     

基于open FDA对PCSK9抑制剂致认知障碍的分析研究

目的 评价前蛋白转化酶枯草溶菌9(proprotein convertase subtilisin/kexin type 9,PCSK9)抑制剂(阿利西尤单抗、依洛尤单抗)致认知障碍的风险,为临床安全用药提供参考。方法 根据MedDRA标准词典,将认知障碍分为广义认知障碍和狭义认知障碍两部分,并获取相应的检索词,调用美国openFDA数据库,检索时限自2015年1月1日至2021年9月18日。采用比例报告比值法(proportional reporting ratio,PRR)和贝叶斯可信区间神经网络传递法同时进行信号检测。结果 共检索到阿利西尤单抗致认知障碍的相关不良事件1144份,整体风险的95%CI(PRR)下限值为0.81,IC-2SD值为–0.43,2种检测方法在广义认知障碍的相关不良事件共检测出健忘症、记忆障碍、感觉异常3个弱阳性信号,狭义认知障碍的相关不良事件未检测出信号;依洛尤单抗致认知障碍的相关不良事件3 632份,整体风险的95%CI(PRR)下限值为0.58,IC-2SD值为–0.86,2种检测方法在广义认知障碍的相关不良事件共检测出记忆障碍、感觉异常2个弱阳性信...     

A safety evaluation of evolocumab

Introduction: Evolocumab is an injectable, fully human monoclonal antibody and a member of the newest class of low density lipoprotein cholesterol (LDL-C) lowering agents called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The PCSK9 inhibitors are the most significant advance in lipid therapy since the introduction of the first statin 30 years ago.

Areas covered: The PCSK9 monoclonal antibodies have demonstrated a consistently high LDL-C lowering efficacy with and without statins and/or other lipid lowering therapies (LLT). LDL-C levels achieved with these agents are lower than has ever been possible before. This review will focus on the overall safety of evolocumab including cognitive impairment, very low LDL-C levels, new onset diabetes and glucose abnormalities, effect on vitamin E and steroid hormones, liver and muscle abnormalities, and immunogenicity and injection site reactions. The phase II and III clinical trials had relatively low patient-years of exposure, but the open label extension studies and the recently published outcomes trial, FOURIER, will be the focus of this paper. The safety profile of evolocumab to date is remarkable and extremely encouraging as will be demonstrated.

Expert opinion: The PCSK9 inhibitors will be responsible for a new era in lipid therapy that will expand our knowledge of lipid levels and cardiovascular disease (CVD) prevention with an efficacy and safety profile not previously available in clinical practice.     

PCSK9 inhibitors for treating hypercholesterolemia

ABSTRACT

Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.

Areas covered: The purpose of this narrative review is to summarize the current knowledge of PCSK9-i, with particular regard to pharmacodynamic, pharmacokinetic, and clinical data on evolocumab and alirocumab.

Expert opinion: PCSK9-I are effective in reducing atherosclerotic events through their significant LDL-C-lowering action similarly to statins. Furthermore, these drugs can be considered safe and well-tolerated. However, some controversies remain with regard to their efficacy in reducing mortality and the paucity of data on both pleiotropic effects and long-term safety of these drugs. However, future studies will focus on understanding the effects of very low cholesterol levels on health. At present, we know that the genetic model of PCSK9 deficiency is characterized by very low LDL-C levels without particular health problems. Yet, we do not know the effect of prolonged PCSK9 inhibition induced by antibody action during the lifetime of normal subjects.