A Phase 1, Open-Label Study Comparing the Safety, Tolerability, and Pharmacokinetics of Single-Dose Intravenous Sabirnetug (ACU193) and Multiple-Dose Subcutaneous Sabirnetug (ACU193) + rHuPH20 in Healthy Participants

A Study Comparing the Safety, Tolerability, and Pharmacokinetics of Sabirnetug IV and Sabirnetug + rHuPH20 SC in Healthy Participants

开始日期2024-06-25

申办/合作机构

Acumen Pharmaceuticals, Inc.

NCT06335173

/ Active, not recruiting临床2期

A Phase 2 Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Intravenous Sabirnetug in Early Alzheimer's Disease

The primary purpose of this study is to evaluate the efficacy of sabirnetug infusions administered once every four weeks (Q4W) in slowing cognitive and functional decline as compared to placebo in participants with early Alzheimer's disease.

开始日期2024-02-29

申办/合作机构

Acumen Pharmaceuticals, Inc.

NCT04931459

/ Completed临床1期

A Phase 1 Placebo-Controlled, Single- and Multiple-Dose Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous ACU193 in Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease

This Phase 1 study is a single ascending dose (SAD) and multiple ascending dose (MAD), placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous ACU193 when administered to participants diagnosed with Mild Cognitive Impairment (MCI) or Mild Dementia due to Alzheimer's disease (AD).

开始日期2021-06-21

申办/合作机构

Acumen Pharmaceuticals, Inc.

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100 项与 Sabirnetug 相关的临床结果

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100 项与 Sabirnetug 相关的转化医学

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100 项与 Sabirnetug 相关的专利（医药）

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项与 Sabirnetug 相关的文献（医药）

2025-01-01·JPAD-Journal of Prevention of Alzheimers Disease

INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease

Article

作者: Salloway, Stephen ; Feaster, Todd ; Johnson, Kimball ; Zhang, Hao ; Siemers, Eric ; Cline, Erika N ; Skljarevski, Vladimir ; Dodds, Michael G ; Sethuraman, Gopalan ; Trame, Mirjam N ; Sundell, Karen ; Honig, Lawrence S ; Sperling, Reisa ; Jerecic, Jasna

BACKGROUND:

Soluble species of multimeric amyloid-beta including globular amyloid-beta oligomers (AβOs) and linear amyloid-beta protofibrils are toxic to neurons. Sabirnetug (ACU193) is a humanized monoclonal antibody, raised against globular species of soluble AβO, that has over 650-fold greater binding affinity for AβOs over monomers and appears to have relatively little binding to amyloid plaque.

OBJECTIVES:

To assess safety, pharmacokinetics, and exploratory measures including target engagement, biomarker effects, and clinical efficacy of sabirnetug in participants with early symptomatic Alzheimer's disease (AD; defined as mild cognitive impairment and mild dementia due to AD).

DESIGN:

Randomized, double-blind, placebo-controlled, ascending dose first-in-human phase 1 study.

SETTING:

Fifteen study centers in the United States.

PARTICIPANTS:

Sixty-five participants with early symptomatic AD.

INTERVENTION:

Participants received one infusion of sabirnetug 2 mg/kg, 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part A) or three infusions of sabirnetug 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part B).

MEASUREMENTS:

Safety, tolerability, serum pharmacokinetics, and central target engagement of single and multiple doses of sabirnetug, cerebrospinal fluid (CSF) concentrations of sabirnetug, and amyloid plaque load, as determined by positron emission tomography.

RESULTS:

Sabirnetug was generally well tolerated. A larger percentage of participants receiving sabirnetug (56.3%) versus placebo (42.9%) had at least one treatment emergent adverse event, with approximately 29% in each group considered related to study drug. Most events were mild-to-moderate in severity. Of 48 participants given sabirnetug, five developed amyloid related imaging abnormalities - edema/effusion, including one instance that was mildly symptomatic in a participant who had received one dose sabirnetug 60 mg/kg. Notably, none of the six apolipoprotein E Ɛ4 homozygotes who received sabirnetug developed amyloid related imaging abnormalities - edema/effusion or - hemorrhage/hemosiderin deposition. Infusion reactions, such as rash, pain, or erythema, were not frequent (6.3% for sabirnetug versus 0.0% for placebo). Sabirnetug exposure was dose proportional in both serum and CSF. Target engagement, defined as drug bound to AβOs in CSF, was shown to be dose and exposure dependent. Over three months, approximately 25% and 20% reduction in amyloid plaques, respectively, were observed in participants receiving three infusions of sabirnetug 60 mg/kg every four weeks and 25 mg/kg every two weeks.

CONCLUSIONS:

The Phase 1 INTERCEPT-AD study provided safety, tolerability, dosing, and target engagement data that supported the design of the ongoing ALTITUDE-AD study (NCT06335173).

2025-01-01·BIODRUGS

Relevance of Neutralizing Antibodies for the Pharmacokinetics of Pegunigalsidase Alfa in Patients with Fabry Disease

Article

作者: Brand, Eva ; Rudnicki, Michael ; Cybulla, Markus ; Menke, Elise Raphaela ; Lenders, Malte

BACKGROUND:

Pegunigalsidase alfa is a newly approved drug for the treatment of Fabry disease, designed to increase the plasma half-life and reduce immunogenicity of infused α-galactosidase A (AGAL). We provide the first comprehensive pharmacokinetic and immunogenic data apart from industry-initiated studies.

METHODS:

Pharmacokinetics of pegunigalsidase alfa, amino acid, and polyethylene glycol (PEG)-specific antibodies and immune complexes were measured in treated patients (11 switched, two naïve). Measurements were performed in serum samples drawn directly before and after infusions over three to ten consecutive infusions. Only three patients started directly with 1.0 mg/kg body weight.

RESULTS:

No infusion-associated reactions were reported under pegunigalsidase alfa during the observation. Patients without pre-existing neutralizing anti-AGAL antibodies showed high enzymatic AGAL peak activities and sustained AGAL serum concentrations until the next infusion, which was not observed in those with neutralizing anti-AGAL antibodies. Nine (69.2%) patients presented with pre-existing anti-PEG antibodies (IgG or IgM), which seemed to have no impact on pharmacokinetics during the observation. No new anti-PEG or anti-AGAL antibody formation was observed after treatment initiation. Three (75.0%) patients with pre-existing neutralizing anti-AGAL antibodies showed a titer increase and one (25.0%) patient a decrease. In patients with anti-AGAL antibodies (n = 4) immune-complex formation was detected.

CONCLUSION:

The pharmacokinetics of pegunigalsidase alfa show different profiles depending on the presence of pre-existing neutralizing antibodies, with reduced plasma half-life and peak enzyme activity after infusion in patients with antibodies. The clinical significance of a reduced pegunigalsidase alfa half-life and the formation of immune complexes in antibody-positive patients needs to be analyzed in future studies.

2023-01-01·The journal of prevention of Alzheimer's disease

ACU193, a Monoclonal Antibody that Selectively Binds Soluble Aβ Oligomers: Development Rationale, Phase 1 Trial Design, and Clinical Development Plan

Article

作者: Siemers, E ; Iverson, K ; Poppe, T ; Dean, R ; Edgar, C ; Jerecic, J ; Barton, R ; Sundell, K ; Hitchcock, J ; Cline, E ; Moore, J ; Fuin, N ; Manber, R

BACKGROUND:

Alzheimer's disease is a large and growing unmet medical need. Clinical trial designs need to assess disease-related outcomes earlier to accelerate the development of better treatments for Alzheimer's disease. ACU193 is a monoclonal antibody that selectively targets amyloid β oligomers, thought to be the most toxic species of Aβ that accumulates early in AD and contributes to downstream pathological effects. Nonclinical data indicate that ACU193 can reduce the toxic effects of amyloid β oligomers. ACU193 is currently being investigated in a phase 1 clinical trial designed with the properties described in this report. This phase 1 trial is designed to provide data to enable a go/no-go decision regarding the initiation of a subsequent phase 2/3 study.

OBJECTIVES:

To design a phase 1 study that assesses target engagement and incorporates novel measures to support more rapid development of a potential disease-modifying treatment for Alzheimer's disease.

DESIGN:

The INTERCEPT-AD trial for ACU193 is an ongoing randomized, placebo-controlled phase 1a/b study that assesses safety, tolerability, pharmacokinetics, target engagement, clinical measures, and several Alzheimer's disease biomarkers, including novel digital and imaging biomarkers.

SETTING:

For INTERCEPT-AD, brief inpatient stays for patients in the single ascending dose portion of the study, with the remainder of the evaluations being performed as outpatients at multiple clinical trial sites in the U.S.

PARTICIPANTS:

Patients with early Alzheimer's disease (mild cognitive impairment or mild dementia with a positive florbetapir positron emission tomography scan).

INTERVENTION:

ACU193 administered intravenously at doses of 2- 60 mg/kg.

MEASUREMENTS:

Safety assessments including magnetic resonance imaging for the presence of amyloid-related imaging abnormalities, clinical assessments for Alzheimer's disease including the Alzheimer's Disease Rating Scale-cognition and Clinical Dementia Rating scale, pharmacokinetics, a measure of target engagement, and digital and imaging biomarkers, including a computerized cognitive test battery and a measure of cerebral blood flow using arterial spin labelling magnetic resonance imaging.

RESULTS:

A phase 1 study design was developed for ACU193 that allows collection of data that will enable a go/no-go decision for initiation of a subsequent adaptive phase 2/3 study.

CONCLUSIONS:

A phase 1a/b trial and an overall clinical development plan for an Alzheimer's disease treatment can be designed that maintains patient safety, allows informed decision-making, and achieves an accelerated timeline by using novel biomarkers and adaptive study designs.

102

项与 Sabirnetug 相关的新闻（医药）

2025-02-20

·抗体圈

单克隆抗体：治疗阿尔茨海默病的关键？

科学家在治疗阿尔茨海默病方面取得了重大进展，单克隆抗体作为一种重要手段，有望阻止病情发展并缓解症状。阿尔茨海默病是由淀粉样蛋白和 tau 蛋白异常大量积累形成斑块所致。随着时间推移，这些纠结的结构会损害神经细胞，尤其是大脑中控制记忆的细胞。据阿尔茨海默病协会统计，美国近 700 万人患有阿尔茨海默病。虽然 73% 的患者年龄在 75 岁及以上，但年轻的高风险成年人群体也在不断扩大，这主要是由罕见的基因突变引起的，有时这些突变会代代相传。美国华盛顿大学医学院（WashU Medicine）牵头的一项新试验正在研究一种单克隆抗体，有望在阿尔茨海默病发病前几十年就阻止其发展。 1.单克隆抗体 remternetug 能否预防阿尔茨海默病？单克隆抗体是一种能与体内特定靶点结合的蛋白质。在治疗阿尔茨海默病时，其靶点是大脑中的淀粉样 β 蛋白聚集体。通常，单克隆抗体与这些聚集体结合后，会触发大脑中的免疫细胞（小胶质细胞）清除这些有害蛋白质，从而减缓认知能力下降。华盛顿大学医学院与制药巨头礼来公司密切合作，正在评估单克隆抗体 remternetug 预防阿尔茨海默病的效果。它旨在清除大脑中的淀粉样 β 蛋白，甚至阻止其积累。研究人员希望，在疾病早期，人们还未出现症状时，通过清除低水平的淀粉样 β 蛋白斑块或阻止其积累，能在最早阶段阻断疾病发展，让人们免于出现症状。 “在过去几年里，我们在阿尔茨海默病治疗方面取得了巨大进展。” 该试验的首席研究员、神经病学教授埃里克・麦克戴德在上周的新闻发布会上表示，“两种针对淀粉样蛋白的药物已被证明可以减缓疾病症状，目前已获得美国食品药品监督管理局（FDA）批准，用于治疗因阿尔茨海默病导致的轻度认知障碍或轻度痴呆患者。这有力地支持了我们的假设，即在淀粉样 β 蛋白斑块出现的最早阶段，症状出现之前进行干预，有可能从一开始就预防症状的出现。” 这项研究正在招募年龄在 18 至 25 岁之间、大脑中蛋白质水平几乎没有阿尔茨海默病相关变化的人，也就是在预计痴呆症状出现之前。目前，该试验仅限于有基因突变、有患阿尔茨海默病风险的人，但研究人员希望该研究结果能为未来治疗各种形式的阿尔茨海默病提供参考。该试验已投入超过 1.3 亿美元，资金来自美国国立卫生研究院（NIH）下属的国家老龄化研究所（NIA）、阿尔茨海默病协会和 GHR 基金会的资助。 “这是一种开创性的方法。”GHR 基金会的首席运营官弗雷德・米勒表示，“我们首次致力于在阿尔茨海默病病理形成之前就预防其积累。这项研究将为我们如何为这些家庭，以及预计到 2050 年美国近 1300 万阿尔茨海默病患者和全球无数患者预防该病提供思路。”2.单克隆抗体：获批用于治疗阿尔茨海默病，但仍存在问题虽然 remternetug 的研究进展是一项重大突破，但单克隆抗体在治疗阿尔茨海默病的道路上并非一帆风顺。第一种在人体中测试治疗阿尔茨海默病的单克隆抗体是 bapineuzumab，它是从小鼠体内发现的抗淀粉样 β 抗体的人源化变体。为解决无法穿过血脑屏障（BBB）的问题，研究人员采用高剂量静脉注射，但这反而导致血脑屏障破裂和液体积聚（称为血管源性水肿），最终该药物于 2012 年宣告失败。不过，这并未阻止其他单克隆抗体进入临床试验。然而，尽管这些药物能有效减少淀粉样斑块，但仍无法减缓患者认知能力的下降，挫折不断。第一种获批用于治疗阿尔茨海默病的单克隆抗体也饱受争议。2021 年，FDA 批准了渤健（Biogen）的 aducanumab（商品名 Aduhelm），但去年该药物就停产了。有报道称，该药物的审批 “存在诸多违规之处”，尤其是它仅基于一项研究就获得批准。此外，脑肿胀和出血等安全风险令人担忧，而且其最初每年 5.6 万美元的价格让保险公司和患者都难以接受。因此，渤健及其合作伙伴日本制药公司卫材（Eisai）决定将资源重新集中在另一种单克隆抗体 Leqembi 上。2023 年，Leqembi 获得 FDA 批准。Leqembi 是一种人源化免疫球蛋白 γ1（IgG1）单克隆抗体，通过清除大脑中的淀粉样 β 蛋白发挥作用。它的获批基于 3 期试验数据，Leqembi 达到了主要终点和所有关键次要终点。与安慰剂相比，使用该药物治疗 18 个月后，患者认知能力下降幅度降低了 27%。此外，用于衡量患者独立生活能力的次要终点 —— 轻度认知障碍日常生活活动合作研究量表（ADCS MCI-ADL），经阿尔茨海默病患者护理人员评估，显示出 37% 的显著益处。除了渤健的药物，制药巨头礼来公司的 Kisunla（donanemab）去年 7 月也获得了 FDA 批准。在 18 个月的试验中，与安慰剂相比，它使患者认知能力下降幅度最多减缓 35%，比 Leqembi 略高，同时将患者疾病进展风险降低了 39%。和 Leqembi 一样，它也是一种 IgG1 单克隆抗体，通过清除大脑中的淀粉样 β 蛋白斑块发挥作用。3.临床中用于治疗阿尔茨海默病的单克隆抗体生物技术公司认为他们能取得更好的成果。罗氏（Roche）的临床候选药物 trontinemab 虽然也是单克隆抗体，但作用机制与 Leqembi 和 Kisunla 略有不同。它在通过血脑屏障方面更具优势，意味着较低剂量即可达到效果，这一点优于已获批的阿尔茨海默病单克隆抗体。它是借助罗氏的 Brain Shuttle 技术开发的，该技术通过连接一个 Fab 片段（抗体中含有抗原结合位点的部分），与附着在 IgG1 抗体效应域上的人转铁蛋白受体结合。在患者中检测到的脑肿胀和出血病例较少，这表明它在减轻副作用和治疗阿尔茨海默病方面可能更具潜力。最新试验显示，在 12 至 28 周后，两个较高剂量组（1.8mg/kg 和 3.6mg/kg）使用该候选药物后，淀粉样蛋白斑块迅速且大量地被清除。然而，一名患者的死亡引发了试验方案的改变。一名 78 岁的患者因脑出血去世，现在，患有浅表性铁沉积症（一种会导致脑出血的罕见疾病）的参与者已被排除在试验之外。 “利用主动转运机制使这些药物穿过血脑屏障，将极大地加快淀粉样蛋白的清除速度，同样重要的是，能真正降低淀粉样蛋白相关影像学异常（ARIA）的发生率。” 神经科顾问凯瑟琳・穆默里在去年 11 月于西班牙举行的阿尔茨海默病临床试验会议上表示，她还补充说 trontinemab 的进展 “非常令人兴奋”。与此同时，美国 Acumen Pharmaceuticals 公司的 sabirnetug 正在进行 2 期试验，目前正在招募患者。它是第一种在临床上证明能靶向淀粉样 β 寡聚体（具有毒性的淀粉样 β 蛋白簇）的人源化单克隆抗体。该候选药物成功降低了大脑中脑脊液（CSF）生物标志物的水平，脑脊液生物标志物可通过检测其中蛋白质水平的变化来帮助诊断阿尔茨海默病。4.克服安全问题当前的试验不仅致力于提高单克隆抗体的疗效，改善其安全性也至关重要。如前所述，这类药物因其带来的健康风险而备受批评。美国家庭医生学会的一项分析表明，单克隆抗体治疗阿尔茨海默病的风险可能大于益处，其中最严重的风险是淀粉样蛋白相关影像学异常（ARIA）。在试验中还观察到了一些出血情况，如脑微出血和含铁血黄素沉着症。优化剂量是提高这些药物安全性的一种方法。目前，Leqembi 的推荐剂量是 10mg/kg，但像 trontinemab 这样更容易穿过血脑屏障的新型单克隆抗体，或许能改变给药剂量，将副作用降至最低。另一个需要注意的因素是患者的其他基础疾病。因此，根据风险因素仔细筛选患者十分重要。例如，trontinemab 试验排除了患有浅表性铁沉积症的参与者，有助于避免易出血患者出现并发症。但《神经病学》杂志发表的一项研究显示，这使得只有一小部分早期疾病患者有资格接受单克隆抗体药物治疗。 “虽然这些新的阿尔茨海默病疗法有望减缓许多患者的病情发展，但事实是这些药物仅在患有最早期疾病的人群中进行过研究。” 该研究的作者、美国神经病学学会成员玛丽亚・瓦西拉基在 2023 年的新闻发布会上表示，“导致 FDA 加速批准这些疗法的临床试验的纳入和排除标准，是决定患者是否适合接受这些药物治疗的依据。我们的研究估计，只有一小部分因阿尔茨海默病导致早期认知障碍的老年人可能有资格接受针对大脑淀粉样 β 蛋白的单克隆抗体治疗。” 也许像 trontinemab 这样的候选药物能改变现状，因为它已被证明更容易穿过血脑屏障，较低的剂量可能会让更多患者参与药物试验。此外，如果能借助 remternetug 等药物将疾病扼杀在萌芽状态，未来受阿尔茨海默病影响的人数可能会减少，治疗也可以更多地集中在晚期阿尔茨海默病上，而这一领域目前在治疗方面进展甚微。原文参考：Monoclonal antibodies: A potential game-changer for Alzheimer’s 识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

临床结果临床研究

2025-01-13

·药明康德

使100%前列腺癌患者关键指标下降的TCE疗法；受体占有率可达100%的动脉粥样硬化疗法… | 一周盘点

▎药明康德内容团队编辑本期看点 1. Vir Biotechnology旗下两款T细胞接合器（TCE）VIR-5818与VIR-5500的初步1期临床数据积极，在曾接受过多线治疗的癌症患者中观察到早期临床缓解的信号。其中，VIR-5500在治疗前列腺癌患者的临床试验中让100%患者的前列腺特异性抗原（PSA）指标产生下降。 2. 用于治疗动脉粥样硬化的CD47靶向疗法BRB-002在1期临床试验测试的最高剂量下，受体占有率（RO）可达100%。 3. AMPA受体负变构调节剂RAP-219在一项1期临床试验中，给药后的5天内就达到了临床前模型中与最大疗效相关的靶点RO（50%-70%），同时保持了与先前1期临床试验一致的差异化的耐受性特征。药明康德内容团队整理 VIR-5818、VIR-5500：公布1期临床试验数据 Vir Biotechnology公司公布了旗下两款T细胞接合器VIR-5818与VIR-5500的初步1期临床数据。VIR-5818、VIR-5500是分别靶向HER2、前列腺特异性膜抗原（PSMA）的TCE，均采用PRO-XTEN平台所开发。TCE是一类强效抗肿瘤药物，能够引导免疫系统（特别是T细胞）杀死癌细胞。PRO-XTEN平台的掩蔽技术旨在使TCE保持不活跃（掩蔽）状态，直到其到达肿瘤微环境，在特定的肿瘤蛋白酶作用下去除掩蔽并激活，从而杀伤癌细胞。 VIR-5818在一项1期临床试验中接受评估，旨在检视其作为单药的安全性和药代动力学，以及与帕博利珠单抗联合使用的效果。受试者包含多种HER2表达癌症的患者，包括乳腺癌和结直肠癌（CRC）。初步疗效数据显示，接受≥400 µg/kg VIR-5818的患者中，50%（10/20）出现剂量依赖性肿瘤缩小。其中一些患者此前已接受多达9种治疗方案。在HER2阳性CRC患者亚组中，观察到强效抗肿瘤活性，这些患者已用尽标准治疗手段。在该亚组中，33%（2/6）的患者在早期剂量下达到确认的部分缓解（cPR），其中一名患者在数据截止时持续cPR超过18个月。初步安全性数据显示，VIR-5818整体耐受性良好，79名患者中仅出现轻度1级或2级细胞因子释放综合征（CRS），占比分别为20%和10%，未观察到3级或更高等级的CRS。 ▲VIR-5818展现初步抗肿瘤效果（图片来源：参考资料[2]） VIR-5500正在一项1期临床试验中接受评估，该研究旨在检视其在转移性去势抵抗性前列腺癌（mCRPC）患者中的安全性、药代动力学和初步疗效。该研究已招募了18名具有显著疾病负担并接受过3至6线治疗的患者。初步疗效数据显示，接受≥120 µg/kg初步剂量的患者中，100%（12/12）观察到前列腺特异性抗原水平降低，58%（7/12）患者达到PSA50应答（即PSA水平降低50%）。安全性数据显示，在剂量高达1000 µg/kg且未使用预防性皮质类固醇的情况下，未观察到剂量限制性毒性。此外，仅观察到轻度1级或2级CRS（分别为17%和11%），未出现3级或更高等级的CRS。 ▲VIR-5500使患者产生强劲的PSA50应答（图片来源：参考资料[2]） BRB-002：公布1期临床试验的初步数据 Bitterroot Bio公司公布了BRB-002在健康受试者中开展的1期研究的积极结果。BRB-002是一种潜在“first-in-class”的免疫调节蛋白疗法，用于治疗动脉粥样硬化性心血管疾病。该疗法通过抑制细胞表面受体CD47（"别吃我"信号），从而改善动脉粥样硬化的根本原因，减轻炎症斑块的负担。此次公布的结果显示，BRB-002在所有测试剂量下都是安全的，没有报告严重的不良事件。此外，观察到CD47受体占有率的增加与剂量有关，在测试的最高剂量下，RO可达100%。在动脉粥样硬化的临床前模型中，CD47的RO为6-26%时，主动脉斑块的负担相对于对照组明显减少。 RAP-219：公布1期临床试验数据 Rapport Therapeutics公司公布了RAP-219的正电子发射断层扫描（PET）试验和第二次多剂量递增试验（MAD-2）的结果。RAP-219是一种临床阶段的AMPA受体负变构调节剂，旨在通过选择性靶向AMPA相关蛋白TARPγ8实现神经解剖学特异性。AMPA受体存在于整个大脑，包括小脑和脑干，它们的非选择性靶向导致耐受性差。相比之下，TARPγ8在海马和大脑皮层中表达丰富，在小脑和脑干中表达最少。RAP-219被设计为对TARPγ8具有高效力和选择性。据观察，它具有较长的半衰期（8-14天）和很小的药物相互作用，使其非常适合多药治疗。与传统的神经科学药物相比，RAP-219有可能提供更好的活性、耐受性和更高的治疗指数，从而为更多的患者提供持续的治疗益处，而不会产生无法忍受的副作用。该公司目前正在寻求RAP-219作为局灶性癫痫、糖尿病周围神经性疼痛和双相躁狂患者的潜在差异化治疗。此次公布的PET试验数据表明，RAP-219在给药后5天内就达到了先前临床前模型中与最大疗效相关的靶点RO（50%-70%），同时保持了与先前1期临床试验一致的差异化的耐受性特征。在MAD-2试验中，观察到RAP-219通常耐受性良好，与最初的MAD试验相比，剂量滴定速度更快，暴露量更高。 Sabirnetug（ACU193）：公布1期临床试验数据 Acumen Pharmaceuticals公司在Journal of Prevention of Alzheimer's Disease杂志上发表了1期临床试验INTERCEPT-AD的结果，该研究旨在评估sabirnetug（ACU193）在早期阿尔茨海默病（AD）患者中的安全性和耐受性。Sabirnetug是一种选择性靶向毒性可溶性β淀粉样蛋白寡聚体（AβOs）的人源化单克隆抗体。Sabirnetug能够结合AβOs，由于其独特的结合特性，sabirnetug有可能在产生淀粉样蛋白相关成像异常（ARIA，一种抗淀粉样蛋白抗体疗法产生的常见主要副作用）风险较低的情况下提供治疗益处，因为sabirnetug可以在不直接靶向淀粉样斑块的情况下阻断AβOs的毒性作用。此次公布的结果显示，sabirnetug的耐受性总体良好，其靶点作用和淀粉样斑块的减少具有剂量和暴露依赖性，支持sabirnetug在早期AD治疗方面的持续开发。此前公布的结果表明，sabirnetug对AβOs具有选择性、剂量依赖性的靶点作用，在较高剂量组中，淀粉样斑块的减少具有统计学意义，且ARIA-E（水肿）的总体水平较低。 QTX3544：IND申请获得FDA许可 Quanta Therapeutics公司宣布，美国FDA批准了其多KRAS抑制剂QTX3544的IND申请，可以针对携带KRAS G12V突变的实体瘤患者启动1期临床试验。QTX3544是一种口服的、偏好G12V突变、同时作用于KRAS活性（ON）和非活性（OFF）状态的KRAS抑制剂。该公司同时宣布，其用于评估另一种KRAS抑制剂QTX3046与西妥昔单抗的联用效果的1期临床试验已启动组合治疗部分。QTX3046是一种口服的选择性KRAS G12D别构抑制剂，它可以同时作用于KRAS的ON和OFF状态。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看） [1] Vir Biotechnology Announces Encouraging Safety and Efficacy Data in Ongoing Dose Escalation Trials for Dual Masked T-Cell Engagers VIR-5818 in Solid Tumors and VIR-5500 in mCRPC. Retrieved from https://www.businesswire.com/news/home/20250108263221/en/Vir-Biotechnology-Announces-Encouraging-Safety-and-Efficacy-Data-in-Ongoing-Dose-Escalation-Trials-for-Dual-Masked-T-Cell-Engagers-VIR-5818-in-Solid-Tumors-and-VIR-5500-in-mCRPC [2] Investor Event on PRO-XTEN™ Masked T Cell Engager Clinical Programs. Retrieved January 8, 2025 from https://s203.q4cdn.com/628578897/files/doc_presentations/2025/01/VIR-PRO-XTEN-TCE-Investor-Event-Jan-08-2025-V_Final-II.pdf [3] CORRECTION -- Rapport Therapeutics Announces New Phase 1 Data, Further Supporting RAP-219's Transformative Potential for CNS Disorders. Retrieved January 9, 2025 from https://www.globenewswire.com/news-release/2025/01/09/3007108/0/en/CORRECTION-Rapport-Therapeutics-Announces-New-Phase-1-Data-Further-Supporting-RAP-219-s-Transformative-Potential-for-CNS-Disorders.html [4] Acumen Pharmaceuticals Announces Journal of Prevention of Alzheimer’s Disease Publication of the Company’s Phase 1 INTERCEPT-AD Study, Including Target Engagement, Dosing Regimen and Safety Findings. Retrieved January 9, 2025 from https://investors.acumenpharm.com/news-releases/news-release-details/acumen-pharmaceuticals-announces-journal-prevention-alzheimers [5] Quanta Announces IND Clearance by U.S. FDA for QTX3544, an Oral G12V-Preferring Multi-KRAS Inhibitor, and Other Pipeline Updates. Retrieved January 9, 2025 from https://www.globenewswire.com/news-release/2025/01/08/3006334/0/en/Quanta-Announces-IND-Clearance-by-U-S-FDA-for-QTX3544-an-Oral-G12V-Preferring-Multi-KRAS-Inhibitor-and-Other-Pipeline-Updates.html [6] Emerging Clinical-Stage Neuroscience Company Nuvie Bio Announces Positive Phase 1 Data with its Lead Migraine Program. Retrieved January 9, 2025 from https://www.businesswire.com/news/home/20250108581271/en/Emerging-Clinical-Stage-Neuroscience-Company-Nuvie-Bio-Announces-Positive-Phase-1-Data-with-its-Lead-Migraine-Program/ [7] Bitterroot Bio Reports Data on Safety and Target Engagement from Phase 1 First-in-Human Study of BRB-002 in Healthy Volunteers. Retrieved January 9, 2025 from https://www.globenewswire.com/news-release/2025/01/08/3006220/0/en/Bitterroot-Bio-Reports-Data-on-Safety-and-Target-Engagement-from-Phase-1-First-in-Human-Study-of-BRB-002-in-Healthy-Volunteers.html [8] Seres Therapeutics Announces New Translational Biomarker Results from SER-155 Phase 1b Clinical Study and Provides Corporate Updates. Retrieved January 9, 2025 from https://www.globenewswire.com/news-release/2025/01/09/3006947/0/en/Seres-Therapeutics-Announces-New-Translational-Biomarker-Results-from-SER-155-Phase-1b-Clinical-Study-and-Provides-Corporate-Updates.html [9] Karolinska Development’s portfolio company AnaCardio raises SEK 205 million and reports positive Phase 1b data of AC01. Retrieved January 9, 2025 from https://www.globenewswire.com/news-release/2025/01/09/3006892/0/en/Karolinska-Development-s-portfolio-company-AnaCardio-raises-SEK-205-million-and-reports-positive-Phase-1b-data-of-AC01.html [10] Solid Biosciences Announces FDA IND Clearance for First-In-Industry Dual Route of Administration Gene Therapy to Treat Both Neurologic and Cardiac Manifestations of Friedreich’s Ataxia. Retrieved January 7, 2025 from https://www.globenewswire.com/news-release/2025/01/07/3005854/0/en/Solid-Biosciences-Announces-FDA-IND-Clearance-for-First-In-Industry-Dual-Route-of-Administration-Gene-Therapy-to-Treat-Both-Neurologic-and-Cardiac-Manifestations-of-Friedreich-s-At.html [11] Sana Biotechnology Announces Positive Clinical Results from Type 1 Diabetes Study of Islet Cell Transplantation Without Immunosuppression. Retrieved January 8, 2025 from https://www.globenewswire.com/news-release/2025/01/07/3005841/0/en/Sana-Biotechnology-Announces-Positive-Clinical-Results-from-Type-1-Diabetes-Study-of-Islet-Cell-Transplantation-Without-Immunosuppression.html [12] BrainChild Bio, Inc. to Clinically Advance BCB-276, an Autologous B7-H3 Targeting CAR T-cell Therapy for Incurable Pediatric Brain Tumors. Retrieved January 8, 2025 from https://www.businesswire.com/news/home/20250106302628/en/BrainChild-Bio-Inc.-to-Clinically-Advance-BCB-276-an-Autologous-B7-H3-Targeting-CAR-T-cell-Therapy-for-Incurable-Pediatric-Brain-Tumors [13] Genascence Announces Six-Month Results from Phase 1b DONATELLO Trial Indicating GNSC-001 Was Safe and Well Tolerated Across Multiple Dosing Arms. Retrieved January 9, 2025, from https://www.prnewswire.com/news-releases/genascence-announces-six-month-results-from-phase-1b-donatello-trial-indicating-gnsc-001-was-safe-and-well-tolerated-across-multiple-dosing-arms-302345061.html [14] Adcentrx Therapeutics Announces First Patient Dosed in the Phase 1a/b Study of ADRX-0405, a Potential First-in-Class ADC Targeting STEAP1 for the Treatment of Advanced Solid Tumors. Retrieved January 9, 2025, from https://www.prnewswire.com/news-releases/adcentrx-therapeutics-announces-first-patient-dosed-in-the-phase-1ab-study-of-adrx-0405-a-potential-first-in-class-adc-targeting-steap1-for-the-treatment-of-advanced-solid-tumors-302342200.html [15] OPKO Health’s ModeX Therapeutics Announces Epstein-Barr Virus Vaccine Candidate Enters Phase I Clinical Study in Collaboration with Merck. Retrieved January 9, 2025, from https://www.opko.com/investors/news-events/press-releases/detail/512/opko-healths-modex-therapeutics-announces-epstein-barr-virus-vaccine-candidate-enters-phase-i-clinical-study-in-collaboration-with-merck [16] Cyclarity Therapeutics Secures Approval for First-in-Human Clinical Trial. Retrieved January 9, 2025, from https://www.globenewswire.com/news-release/2025/01/07/3005518/0/en/Cyclarity-Therapeutics-Secures-Approval-for-First-in-Human-Clinical-Trial.html#:~:text=NOVATO%2C%20Calif.%2C%20Jan.%2007%2C%202025%20%28GLOBE%20NEWSWIRE%29%20--,clinical%20research%20centers%2C%20in%20partnership%20with%20Monash%20University. [17] IMBRIUM THERAPEUTICS ANNOUNCES RESULTS OF A SUNOBINOP PHASE 1B STUDY IN PATIENTS WITH OVERACTIVE BLADDER SYNDROME. Retrieved January 9, 2025, from https://imbriumthera.com/news/imbrium-therapeutics-announces-results-of-a-sunobinop-phase-1b-study-in-patients-with-overactive-bladder-syndrome/ [18] Cocrystal Pharma Reports Phase 1 Results with Oral, Broad-Acting Antiviral Drug CDI-988 for Prophylaxis and Treatment of Norovirus, Coronaviruses and Other Viral Infections. Retrieved January 9, 2025, from https://www.globenewswire.com/news-release/2025/01/08/3006202/0/en/Cocrystal-Pharma-Reports-Phase-1-Results-with-Oral-Broad-Acting-Antiviral-Drug-CDI-988-for-Prophylaxis-and-Treatment-of-Norovirus-Coronaviruses-and-Other-Viral-Infections.html 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床1期临床结果

2025-01-09

·GlobeNewswire-Health Care

Acumen Pharmaceuticals Announces Journal of Prevention of Alzheimer’s Disease Publication of the Company’s Phase 1 INTERCEPT-AD Study, Including Target Engagement, Dosing Regimen and Safety Findings

Phase 1 INTERCEPT-AD data published in Journal of Prevention of Alzheimer’s Disease supports continued development of sabirnetug (ACU193) for treatment of early Alzheimer’s disease (AD) Sabirnetug demonstrated selective, dose-dependent target engagement of amyloid beta oligomers (AβOs), statistically significant amyloid plaque reduction within higher dose cohorts, and low overall levels of ARIA-E Phase 2 ALTITUDE-AD clinical trial of sabirnetug is ongoing with enrollment completion expected 1H 2025 NEWTON, Mass., Jan. 09, 2025 (GLOBE NEWSWIRE) -- Acumen Pharmaceuticals, Inc. (NASDAQ: ABOS), a clinical-stage biopharmaceutical company developing a novel therapeutic that targets toxic soluble amyloid beta oligomers (AβOs) for the treatment of Alzheimer’s disease (AD), today announced that the Journal of Prevention of Alzheimer’s Disease published the results of the Phase 1 INTERCEPT-AD clinical trial demonstrating that sabirnetug (ACU193) was generally well-tolerated with dose- and exposure-dependent target engagement and reduction in amyloid plaques. Acumen is developing sabirnetug as a potential next-generation antibody treatment for early symptomatic AD. Sabirnetug is the first humanized monoclonal antibody to clinically demonstrate selective target engagement of AβOs in patients with early symptomatic AD. Soluble AβOs are a highly toxic form of Aβ that begin to accumulate before a clinical diagnosis of symptomatic AD and are an early and persistent trigger of synaptic dysfunction and neurodegeneration. “The robust data package generated by this Phase 1 study provides important evidence of sabirnetug’s safety profile, further confirms the mechanism of action of sabirnetug and establishes the foundation for our ongoing Phase 2 ALTITUDE-AD clinical trial, including the doses used in ALTITUDE-AD,” said Eric Siemers, M.D., Chief Medical Officer of Acumen. “We are pleased to highlight the strength of our study design and the creation of advanced tools for drug development, including an assay that can detect very small amounts of sabirnetug bound to toxic soluble amyloid beta oligomers in human cerebrospinal fluid.” INTERCEPT-AD was a randomized, double-blind, placebo-controlled Phase 1 clinical trial designed to evaluate the safety and tolerability of sabirnetug in patients with early AD. A total of 65 individuals with early AD (mild cognitive impairment or mild dementia due to AD) enrolled in this first-in-humans study of sabirnetug. The results, which were previously presented at scientific congresses, demonstrated selective target engagement of AβOs in a dose-dependent and exposure-dependent manner, statistically significant amyloid plaque reduction within higher dose multiple-ascending dose cohorts, and low overall levels of amyloid-related imaging abnormalities (ARIA) with edema/effusion (ARIA-E) or hemorrhage/hemosiderin deposition (ARIA-H). One participant experienced mildly symptomatic ARIA-E, which resolved within four weeks. None of the six participants who were apolipoprotein E Ɛ4 homozygotes and received sabirnetug developed ARIA-E or ARIA-H. “The publication of this data in the Journal of Prevention of Alzheimer’s Disease is a significant milestone in our ongoing clinical development of sabirnetug, and reflects our commitment to advancing the collective understanding about the underlying pathology of Alzheimer’s disease and developing a next-generation treatment for this burdensome disease,” said Daniel O’Connell, Chief Executive Officer of Acumen. The publication titled, “INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease,” is available online here. ALTITUDE-AD is a Phase 2, multi-center, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of sabirnetug in patients with early Alzheimer’s disease. The study drug will be evaluated in approximately 540 adults ages 50 to 90 years. Thus far, the study is enrolling at 75 sites across the U.S., Canada, EU and U.K. The first patient was dosed in ALTITUDE-AD in May 2024, and Acumen expects to complete enrollment in the first half of 2025. About Sabirnetug (ACU193) Sabirnetug (ACU193) is a humanized monoclonal antibody (mAb) discovered and developed based on its selectivity for soluble amyloid beta oligomers (AβOs), which are a highly toxic and pathogenic form of Aβ, relative to Aβ monomers and amyloid plaques. Soluble AβOs have been observed to be potent neurotoxins that bind to neurons, inhibit synaptic function and induce neurodegeneration. By selectively targeting toxic soluble AβOs, sabirnetug aims to address the hypothesis that soluble AβOs are an early and persistent underlying cause of the neurodegenerative process in Alzheimer’s disease (AD). Sabirnetug has been granted Fast Track designation for the treatment of early AD by the U.S. Food and Drug Administration and is currently being evaluated in a Phase 2 study in patients with early AD. About INTERCEPT-AD (Phase 1) Completed in 2023, INTERCEPT-AD was a Phase 1, U.S.-based, multi-center, randomized, double-blind, placebo-controlled clinical trial evaluating the safety and tolerability, and establishing clinical proof of mechanism, of sabirnetug in patients with early Alzheimer’s disease (AD). Sixty-five individuals with early symptomatic AD (mild cognitive impairment or mild dementia due to AD) enrolled in this first-in-human study of sabirnetug. The INTERCEPT-AD study consisted of single-ascending-dose (SAD) and multiple-ascending-dose (MAD) cohorts and was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and target engagement of intravenous doses of sabirnetug. More information can be found on www.clinicaltrials.gov, NCT identifier NCT04931459. About ALTITUDE-AD (Phase 2) Initiated in 2024, ALTITUDE-AD is a Phase 2, multi-center, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of sabirnetug (ACU193) infusions administered once every four weeks in slowing cognitive and functional decline as compared to placebo in participants with early Alzheimer's disease. The study will enroll approximately 540 individuals with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to AD). The global study is currently ongoing at multiple investigative sites located in the United States, Canada, the United Kingdom, and the European Union. More information can be found on www.clinicaltrials.gov, NCT identifier NCT06335173. About Acumen Pharmaceuticals, Inc. Acumen Pharmaceuticals is a clinical-stage biopharmaceutical company developing a novel therapeutic that targets toxic soluble amyloid beta oligomers (AβOs) for the treatment of Alzheimer’s disease (AD). Acumen’s scientific founders pioneered research on AβOs, which a growing body of evidence indicates are early and persistent triggers of Alzheimer’s disease pathology. Acumen is currently focused on advancing its investigational product candidate, sabirnetug (ACU193), a humanized monoclonal antibody that selectively targets toxic soluble AβOs, in its ongoing Phase 2 clinical trial ALTITUDE-AD (NCT06335173) in early symptomatic Alzheimer’s disease patients, following positive results in its Phase 1 trial INTERCEPT-AD. The company is headquartered in Newton, Mass. For more information, visit www.acumenpharm.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Any statement describing Acumen’s goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Words such as “potential,” “will” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Forward-looking statements include statements concerning the therapeutic potential and potential clinical efficacy of Acumen’s product candidate, sabirnetug (ACU193) and the timing of enrollment completion of the ALTITUDE-AD trial. These statements are based upon the current beliefs and expectations of Acumen’s management, and are subject to certain factors, risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing safe and effective human therapeutics. Such risks may be amplified by the impacts of geopolitical events and macroeconomic conditions, such as rising inflation and interest rates, supply disruptions and uncertainty of credit and financial markets. These and other risks concerning Acumen’s programs are described in additional detail in Acumen’s filings with the Securities and Exchange Commission (“SEC”), including in Acumen’s most recent Annual Report on Form 10-K, and in subsequent filings with the SEC. Copies of these and other documents are available from Acumen. Additional information will be made available in other filings that Acumen makes from time to time with the SEC. These forward-looking statements speak only as of the date hereof, and Acumen expressly disclaims any obligation to update or revise any forward-looking statement, except as otherwise required by law, whether, as a result of new information, future events or otherwise. Investors: Alex Braunabraun@acumenpharm.com Media:Jon YuICR Healthcare AcumenPR@icrhealthcare.com

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100 项与 Sabirnetug 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床2期	美国	Acumen Pharmaceuticals, Inc.	2024-02-29
阿尔茨海默症	临床2期	加拿大	Acumen Pharmaceuticals, Inc.	2024-02-29
阿尔茨海默症	临床2期	法国	Acumen Pharmaceuticals, Inc.	2024-02-29
阿尔茨海默症	临床2期	德国	Acumen Pharmaceuticals, Inc.	2024-02-29
阿尔茨海默症	临床2期	西班牙	Acumen Pharmaceuticals, Inc.	2024-02-29
阿尔茨海默症	临床2期	英国	Acumen Pharmaceuticals, Inc.	2024-02-29
轻度认知障碍	临床1期	美国	Acumen Pharmaceuticals, Inc.	2021-06-21

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04931459 (INTERCEPT-AD, Pubmed \| GlobeNewswire) 人工标引	临床1期	轻度认知障碍 \| 阿尔茨海默病引起的痴呆症	65	Sabirnetug	廠積範艱廠鬱壓艱醖積(糧獵糧獵夢憲壓衊廠築) = 壓蓋夢製鏇襯齋網壓構繭選憲蓋蓋觸積醖糧艱 (繭艱遞鏇鏇糧構糧膚鏇 )	积极	2025-01-01
				Placebo	廠積範艱廠鬱壓艱醖積(糧獵糧獵夢憲壓衊廠築) = 淵衊艱衊獵網齋鏇製遞繭選憲蓋蓋觸積醖糧艱 (繭艱遞鏇鏇糧構糧膚鏇 )
NCT06335173 (INTERCEPT-AD, Pubmed \| J Prev Alzheimers Dis)	临床1期	轻度认知障碍 \| 阿尔茨海默病引起的痴呆症 amyloid-beta oligomers	65	Sabirnetug 2 mg/kg	積鹽壓夢網繭顧憲觸選(糧願鏇鹽糧襯製顧觸觸) = five developed amyloid related imaging abnormalities - edema/effusion, including one instance that was mildly symptomatic in a participant who had received one dose sabirnetug 60 mg/kg 鹽壓餘襯鬱鹹糧鬱構鹹 (蓋觸製築簾觸艱糧鑰獵 ) 更多	积极	2025-01-01
				Sabirnetug 25 mg/kg
NCT04931459 (INTERCEPT-AD, GlobeNewswire) 人工标引	临床2期	阿尔茨海默症	540	sabirnetug	夢築壓簾膚蓋選夢遞選(餘繭鑰繭構醖襯壓鹽網) = The study revealed that three administrations of sabirnetug significantly lowered CSF levels of both pre- and post-synaptic proteins, consistent with its proposed mechanism of action to inhibit synaptic binding of AβOs. 鏇糧範鏇遞製鑰簾衊製 (簾鏇顧積觸壓網醖憲簾 )	积极	2024-07-28
NCT04931459 (INTERCEPT-AD, GlobeNewswire) 人工标引	临床1期	阿尔茨海默症 Aβ42/Aβ40 Ratio \| pTau217 Expression \| Neurogranin Expression \| ... 更多	65	ACU193	蓋築夢衊淵構選夢鬱憲(選淵艱鹽鏇齋蓋選鏇簾) = 齋觸壓淵獵簾淵襯糧憲廠鹹蓋衊簾鬱齋積齋壓 (鏇鏇願繭糧築醖繭淵鬱 ) 更多	积极	2024-03-08
				Placebo	-
NCT04931459 (INTERCEPT-AD, Corporate Publications) 人工标引	临床1期	阿尔茨海默症	48	ACU193 25 mg/kg	夢醖壓繭構積淵簾蓋淵(觸觸簾壓積鹽鬱蓋繭鬱) = 鬱鹹衊製糧艱築夢壓鏇鹽築醖顧鹽築膚選範窪 (夢壓顧製網鏇廠選網淵 ) 更多	积极	2023-07-16
				ACU193 60 mg/kg	夢醖壓繭構積淵簾蓋淵(觸觸簾壓積鹽鬱蓋繭鬱) = 製憲廠顧壓窪淵顧選醖鹽築醖顧鹽築膚選範窪 (夢壓顧製網鏇廠選網淵 ) 更多