Cholinesterase inhibitors (CI) remain the only drugs with a recognized efficacy in mild to moderate Alzheimer's disease (AD) in spite of enormous research efforts. However, these drugs presented as "symptomatic treatment" of AD are considered as having only a weak effect on the course of AD. The reimbursement of these drugs is regularly challenged due to the lack of evidence for the impact of these drugs on milestones stages of AD evolution (survival without severe dementia, restriction in Basic Activities of Daily Living - BADL) and on major consequences in public health (hospitalization and institutionalization). The great majority of previous randomized controlled trials conducted with CI have had a too short duration and the end points were limited to cognition (ADAS Cog scale), IADL (Instrumental Activities of Daily Living) function and Global Impression of Change. New evidences from the DOMINO trial (1) conducted in UK, independently of the pharmaceutical industry, showed that the true effect of CI might be more to avoid or to delay the cognitive or functional decline in AD than to improve patients; the institutionalisation (2) was also delayed. However, this trial was conducted in patients with moderate to severe AD, and the interest of the drugs at the mild to moderate stage remains questionable.
The investigators have shown that a good surrogate marker of survival without severe dementia would be an increase of ADAS Cog scale of more than six points (3). A post hoc reanalysis of the pivotal RCT with two CI showed that in mild to moderate patients, CI was associated with a 15% decrease of patients with a deterioration of ADAS-Cog of more than six points in six months. Thus at the beginning of dementia the real effect of CI might be more of delaying the cognitive and functional decline, than to improve the patients. The main objective of the SOS trial is to demonstrate that the benefit of CI at the early phase of dementia is the same as at the later phase.

开始日期2024-06-01

申办/合作机构-

ChiCTR2400081930 / Recruiting临床4期IIT

A real-world study of the safety and efficacy of galanthamine hydrobromide in the treatment of cognitive impairment

开始日期2024-03-15

申办/合作机构-

NCT04769206 / Recruiting临床1/2期IIT

Enhancing Parasympathetic Activity to Improve Endothelial Dysfunction, Vascular Oxidative Stress in African Americans

Specific Aim 1: To test the hypothesis that prolonged (3-month) treatment with galantamine inhibits NADPH IsoLG-protein adducts formation and improves markers of endothelial cell (EC) dysfunction in AAs.
Aim 1a: The investigators will determine if galantamine inhibits NADPH IsoLG-protein adducts formation, superoxide production, and immune cell activation compared to placebo.
For this purpose, the investigators will study peripheral blood mononuclear cell (PBMC), a critical source of systemic oxidative stress, collected from study participants.
Aim 1b: The investigators will determine if galantamine reduces intracellular Iso-LGs, ICAM-1, and 3-nitrotyrosine, a marker of vascular oxidative stress, in ECs harvested from study participants.
Specific Aim 2: To determine if prolonged (3-month) treatment with galantamine improves endothelial dysfunction as measured by vascular reactivity in AAs. The investigators will measure vascular reactivity in response to ischemia in two vascular beds: (a) in conduit arteries (brachial artery) using brachial artery diameter flow-mediated dilation (FMD), and (b) in the microvasculature (MBV) using contrast-enhanced ultrasonography in skeletal muscle.
This proposal will study a novel mechanism that could alter the oxidative and immunogenic responses that contributes to endothelial dysfunction in AAs and will offer a potential pathway for the development of more effective therapies aimed at decreasing the progression of endothelial dysfunction to cardiovascular disease in this population.

开始日期2021-12-20

申办/合作机构

Vanderbilt University Medical Center

100 项与氢溴酸加兰他敏相关的临床结果

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100 项与氢溴酸加兰他敏相关的转化医学

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100 项与氢溴酸加兰他敏相关的专利（医药）

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项与氢溴酸加兰他敏相关的文献（医药）

2024-04-02·Journal of dual diagnosis

Integrative Pharmacology in the Treatment of Substance Use Disorders

Review

作者: Shad, Mujeeb U ; Donlon, Jack ; Kumari, Pooja ; Koola, Maju Mathew ; Varghese, Sajoy P ; Stone, Trevor W ; Vadlapatla, Niyathi ; Frost, Emma D ; Rahman, Shafiqur ; Banks, John ; Florentin, Ori David ; Bai, Michael ; Kam, Olivia ; Abulseoud, Osama A

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

2024-03-01·Bioorganic chemistry

A comprehensive review of multi-target directed ligands in the treatment of Alzheimer’s disease

Review

作者: Kabra, Uma D ; Pathak, Chandni

Alzheimer's disease (AD) is the most common form of dementia affecting specifically older population. AD is an irreversible neurodegenerative CNS disorder associated with complex pathophysiology. Presently, the USFDA has approved only four drugs viz. Donepezil, Rivastigmine, Memantine, and Galantamine for the treatment of AD. These drugs exhibit their neuroprotective effects either by inhibiting cholinesterase enzyme (ChE) or N-methyl-d-aspartate (NMDA) receptor. However, the conventional therapy "one target, one molecule" has failed to provide promising therapeutic effects due to the multifactorial nature of AD. This triggered the development of a novel strategy called Multi-Target Directed Ligand (MTDL) which involved designing one molecule that acts on multiple targets simultaneously. The present review discusses the detailed pathology involved in AD and the various MTDL design strategies bearing different heterocycles, in vitro and in vivo activities of the compounds, and their corresponding structure-activity relationships. This knowledge will allow us to identify and design more effective MTDLs for the treatment of AD.

2024-03-01·Bioorganic chemistry

Synthesis, biochemical and computational evaluations of novel bis-acylhydrazones of 2,2′-(1,1′-biphenyl)-4,4′-diylbis(oxy))di(acetohydrazide) as dual cholinesterase inhibitors

Article

作者: Ullah, Samee ; Abdalla, Ashraf N ; Ali, Sajid ; Ibrahim, Muhammad ; Al-Harrasi, Ahmed ; Halim, Sobia Ahsan ; Khan, Ajmal ; Ahmad, Manzoor ; Latif, Abdul ; Khalid, Asaad ; Ali, Mumtaz

A series of twenty-seven bis(acylhydrazones) were successfully synthesized with high yields through a multistep process, which entailed the esterification of hydroxyl groups, hydrazination with an excess of hydrazine hydrate, and subsequent reactions with various carbonyl moieties (aldehydes). In the final stage of synthesis, different chemical species including aromatic, heterocyclic, and aliphatic compounds were integrated into the framework. The resulting compounds were characterized using several spectroscopic techniques (¹H NMR, ¹³C NMR, and mass spectrometry). Their anticholinesterase activities were assessed in vitro by examining their interactions with two cholinesterase enzymes: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the synthesized hits, compounds 3, 5, 6, 9-12, and 14 exhibited good to moderate inhibition of AChE. Specifically, 10 (IC₅₀ = 26.3 ± 0.4 μM) and 11 (IC₅₀ = 28.4 ± 0.5 μM) showed good inhibitory activity against AChE, while 9, 12, 3, and 6 exhibited significant inhibition potential against AChE with IC₅₀ values ranging from 35.2 ± 1.1 μM to 64.4 ± 0.3 μM. On the other hand, 5 (IC₅₀ = 22.0 ± 1.1 μM) and 27 (IC₅₀ = 31.3 ± 1.3 μM) displayed significant, and 19 (IC₅₀ = 92.6 ± 0.4 μM) showed moderate inhibitory potential for BChE. Notably, 5 and 27 exhibited dual inhibition of AChE and BChE, with greater potency than the standard drug galantamine. The binding patterns of these molecules within the binding cavities of AChE and BChE were anticipated by molecular docking which showed good correlation with our in vitro findings. Further structural optimization of these molecules may yield more potent AChE and BChE inhibitors.

项与氢溴酸加兰他敏相关的新闻（医药）

2024-06-21

·CPHI制药在线

AD新药Donanemab获批在即，盘点全球在研AD新药

关注并星标CPHI制药在线阿尔茨海默病（AD）是一种普遍存在的、不断恶化的神经退行性疾病，它导致患者智力受损、精神异常，并丧失社会与生活功能[1]。这种疾病严重影响了患者的认知能力和日常生活，已经成为我国第五大致命疾病，且发病率随着年龄增长而急剧上升。据世界卫生组织估计，至2023年全球范围内已有5500万AD患者。随着全球人口老龄化的趋势，预计到2050年，这一数字可能会激增到惊人的1.39亿。在我国，流行病学调查显示，60岁以上人口中有约1507万痴呆患者，其中AD患者约983万人，另有MCI（轻度认知障碍）患者约3877万人[2]。这无疑为患者、家庭和整个社会带来了巨大的压力和沉重的负担。我国患有AD的人数虽然巨大，然而却长时间地面对着药物治疗资源不足的困境。这主要归咎于AD的复杂发病机制和极为严苛的临床试验审核过程。因此，AD新药研发领域一直存在着业界公认的99.6%的最高失败率[4]，被誉为药物研发的"死亡谷"。目前市场上用于治疗AD的药物，主要作用在于缓解疾病的症状，而无法有效地延缓疾病的进展。这种神经退行性疾病涉及到一系列复杂的生理病理过程，如Aβ沉积、Tau蛋白过度磷酸化、胆碱能系统紊乱、氧化应激和神经免疫以及神经元和突触的丢失等。传统的AD药物主要聚焦于神经递质传递的调节，代表性的药物包括卡巴拉汀、加兰他敏、美金刚和多奈哌齐等尽管这些药物能够在一定程度上减缓疾病的进展，但它们仍无法有效阻止或逆转疾病进程。值得欣慰的是，近年来，美国食品药品监督管理局（FDA）根据"加速审评"政策，先后于2021年和2023年批准了阿杜那单抗（aducanumab）和仑卡奈单抗（lecanemab）。初步临床结果表明，这些药物具备显著的疾病进展延缓效应。它们的问市为AD药物研发领域带来了新的希望，但是其临床效益仍存在一定的局限性。近年来，多种新机制与新靶点药物正陆续进入临床试验阶段，有望为AD的治疗带来更多的选择和可能性。一、PCNS全票通过，礼来Donanemab获批在望由于致病机理尚未明确、动物实验难以准确模拟以及临床开发的复杂性等诸多难题，AD药物的研发一直被视为一项极具挑战性的任务。长期以来，如礼来、辉瑞、罗氏等全球制药巨头在投入大量资金和资源对AD新药进行探索时，大多数项目最终都未能达到预期效果，这也使得AD新药研发被形容为一个"资金黑洞"。直至2023年7月，局面终于迎来了突破。经过与卫材的共同努力，渤健公司成功开发出一款针对β-淀粉样蛋白（Aβ）的AD抗体，即仑卡奈单抗，并顺利获得美国FDA的完全批准上市，这成为近20年来首款在AD治疗领域取得重大突破的疗法。此次获批的主要依据来源于大型全球Clarity AD临床试验的Ⅲ期数据，实验结果显示，在为期18个月的治疗周期内，相较于安慰剂对照组，所有早期AD患者（包括轻度认知障碍MCI和轻度阿尔茨海默病患者）的临床痴呆症评分总表（CDR-SB）的下降幅度显著减少了27%。根据渤健发布的2023年财报数据，仑卡奈单抗自获批后，在全球市场的销售额已接近1000万美元，展现出良好的市场前景。然而，卫材和渤健联合开发的阿尔茨海默病（AD）新药Leqembi(Lecanemab，仑卡奈单抗），或将很快面临对手礼来Donanemab的"贴身肉搏"。在2023年7月，礼来公司向美国食品和药物管理局（FDA）递交了关于其研发的Aβ单抗药物Donanemab的新药上市申请。这款针对阿尔茨海默病（AD）治疗的药物，在之前因种种原因未能及时获准上市，然而最近的形势却发生了戏剧性的转变。FDA的外周和中枢神经系统药物咨询委员会以压倒性的11:0投票结果，一致认可了礼来的新药Donanemab在治疗早期AD患者中的疗效显著，其带来的益处远超过可能存在的风险。这次会议的成果标志着Donanemab距离最终的市场准入仅一步之遥，有望成为又一款能够有效减缓AD患者认知衰退的创新药物。这一进展是继去年7月Donanemab在Ⅲ期临床研究中取得显著效果、达到主要研究终点之后的又一重大突破。全体一致的投票结果为Donanemab的上市前景注入了强大的信心，业内普遍预期，这款药物有可能在不久的未来，紧随卫材/渤健的仑卡奈单抗之后，成为第二个获美国FDA批准上市的同类药物。业界普遍预计，在接下来的一到两个月内，美国FDA很可能会对Donanemab做出更为积极的监管审批决定，让患者早日受益于这一创新的治疗方案。二、Donanemab临床结果分析，获益>风险 Donanemab，这款由礼来精心研发的药物，其核心特性在于能够精准识别并针对Aβ的N3pG亚型抗体，从而高效清除脑部积聚的淀粉样斑块。最近，在备受瞩目的2023年阿尔茨海默病协会国际会议上，礼来公司发布了关于Donanemab的临床3期试验的详细结果。据报告显示，Donanemab在针对阿尔茨海默病（AD）的治疗上展现出了令人瞩目的疗效。然而，与此同时，药物可能带来的不良反应也成为了一个值得深入研究和关注的潜在风险。具体来看，这次临床3期试验的结果如下：（1）对于那些处于轻度认知障碍阶段的受试者，经过长达76周的Donanemab治疗后，他们在阿尔茨海默病综合评分量表（iADRS）上的评分下降速率得到了显著的减缓，达到了惊人的60%。此外，在临床痴呆症评分总表（CDR-SB）上，这些受试者的评分下降速率同样也减缓了约46%。值得一提的是，对于因AD而患上轻度痴呆的受试者，Donanemab在iADRS和CDR-SB上的评分下降减缓效果分别为30%和38%。（2）试验数据显示，Donanemab具有年龄获益，该药物在75岁以下的受试者中受益更大。在75岁以下的受试者中，iADRS减缓下降可达48%，CDR-SB减缓下降可达45%；但是在75岁以上的受试者中，iADRS减缓下降为25%，CDR-SB减缓下降为29%，整体不如75岁以下受试者组。（3）接受Donanemab治疗18个月后，Donanemab组所有受试者淀粉样斑块平均减少84%，而安慰剂组受试者中仅减少1%。Donanemab以上的临床3期试验结果也是FDA外周和中枢神经系统药物咨询委员会支持Donanemab的主要依据。但是FDA曾推迟了对该药物的批准，原因是担心该药物的安全性，下表1为常见的不良反应。显而易见，与安慰剂组相比，Donanemab组的受试者在接受治疗期间表现出更高的死亡率，这表明使用此药物存在潜在致命风险。此外，值得注意的是，Donanemab组受试者发生ARIA水肿或积液的几率也显著超出安慰剂组的水平。正是这些不容忽视的安全隐患，导致FDA起初并未匆忙批准Donanemab的上市。然而，如今经过审慎评估，FDA以11:0的压倒性投票结果确认了礼来公司研发的Donanemab对早期阿尔茨海默患者的治疗效果显著，且利益明显大于潜在风险。这对于礼来公司和其研发的Donanemab而言，无疑是一个峰回路转、柳暗花明的胜利时刻。三、全球在研AD新药盘点根据药渡数据提供的信息，目前在全球范围内，超过700项阿尔茨海默病（AD）新药正在研发中。在下表2中，我们列出了一些已进入临床3期或更高级别阶段的在研药物。那么，这些药物中哪些值得我们给予特别的关注呢？ Remternetug：Donanemab的"升级版" 需要格外关注的一种新兴药物即为Remternetug，它是由知名药企礼来公司所研发的一款针对阿尔茨海默病（AD）的治疗药物。这款药物被归类为新一代N3pG淀粉样抗体类药物，实质上可以被视为Donanemab的进阶版。在近期举办的2023年阿尔茨海默病与帕金森疾病国际学术研讨会上，礼来公司对外披露了关于Remternetug的部分临床研究成果。根据公布的数据，Remternetug表现出了强大的清除斑块能力，其效果显著且令人瞩目，预示着它在未来的治疗领域中将拥有广阔的应用前景 Blarcamesine：认知衰退率降低了45% Blarcamesine是一款针对Sigma-1的口服小分子药物，其在缓解神经炎症方面展现出了显著的效果。据临床数据表明，在参与Blarcamesine治疗的受试者群体中，各项指标均有显著改善： 1. 超过84%的受试者ADAS-Cog评分实现0.5分以上的降低，这证实了药物对于减缓认知衰退的积极作用。 2. 经Blarcamesine治疗后，受试者ADAS-Cog认知评分的平均降幅达到4.03分，这进一步强化了该药物在提升受试者认知能力方面的有效性。 3. 经过Blarcamesine的治疗，功能改善的可能性显著提升了167%，同时ADCS-ADL评分也实现了3.5分以上的增长，显示出药物在改善患者日常生活能力方面的良好作用。 4. 与对照组相比，使用Blarcamesine的受试者认知衰退率降低了45%，这一结果进一步验证了该药物的疗效。目前，Blarcamesine已经完成了NDA申请提交，预示着其距离正式获批上市已为期不远，未来有望为更多患者带来希望和治疗选择。四、未来展望世界卫生组织（WHO）预测表明，中枢神经系统（CNS）疾病在未来二十年的时间里，有望成为仅次于其他主要致死源的第二大杀手。目前，诸如阿尔茨海默病（AD）和肌萎缩性脊髓侧索硬化症（ALS）等神经性疾病，在医学界普遍被认为是对药物治疗的贡献度最低，且临床实践中最难以满足需求的疾病领域之一。据公开资料，2019年全球中枢神经系统（CNS）药物市场规模已达到惊人的1245亿美元，使其位列全球第四大药物市场业界普遍预计，这一市场未来将保持稳健的增长态势，至2034年，预计市场规模将攀升至1721亿美元。而在这其中，阿尔茨海默病（AD）的治疗领域被看作是尚未被充分挖掘的巨大"金矿" 与此同时，我国社会正在迈向深度老龄化。根据国家《人口发展规划（2016-2030年）》的预测，至2030年，我国总人口将达到约14.5亿人，其中60岁及以上的老年人口占比将达到25%。伴随而来的不仅是社会人口结构的深刻变革，更值得关注的是疾病图谱的改变。特别是以阿尔茨海默病（AD）为代表的老年人患者群体的迅速增长，更凸显了这一治疗领域的紧迫性和重要性根据长江证券的研究报告分析，国内针对阿尔茨海默病（AD）的用药市场规模有望在不久的将来实现显著增长，预计将于2025年和2030年分别达到131亿元和684亿元。尽管AD药物的研发一直被视为一个挑战重重的"黑洞"，但面对如此巨大的市场潜力和患者需求，各大制药企业并未止步，而是继续在该领域投入大量资源和精力，努力寻找突破。总体而言，尽管阿尔茨海默病（AD）的治疗领域充满挑战，但它仍然被视为一个充满希望的蓝海市场，具有巨大的挖掘潜力。目前，针对Aβ机制的研究领域已积累了较为丰富的管线，而Tau机制领域也正在逐步取得进展。随着科学家们对AD病理机制的深入理解，相信未来会有更多创新和有效的治疗方法问世，为患者带来新的希望，同时也将进一步扩展AD药物市场的商业潜力和发展空间。相关阅读：《礼来AD新药全票通过背后，Aβ假说遭质疑》参考文献 [1]10.1001/jama.2023.13239 [2] https://investor.lilly.com/news-releases/news-release-details/results-lillys-landmark-phase-3-trial-donanemab-presented [3] 药渡数据【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

加速审批

2024-06-20

·医药地理

AD治疗的巅峰对决：Donanemab VS Lecanemab，谁将主宰未来？

6月10日，美国食品药品监督管理局（FDA）外周和中枢神经系统药物咨询委员会（PCNS）举行了一次关键会议，就礼来公司（Eli Lilly）开发的Donanemab药物用于治疗早期症状性阿尔茨海默病（AD）的生物制品许可申请（BLA）进行了深入讨论和评估。在长达8小时的会议中，委员会成员对Donanemab的有效性以及其获益是否大于风险进行了投票。投票结果显示，委员会成员以11:0的全票赞成，一致认为Donanemab对参与临床试验的具有轻度认知障碍和轻度痴呆的AD患者有效，并且其获益显著超过了潜在风险。这一结果表明，Donanemab有望成为继日本卫材药业（Eisai）和美国渤健公司（Biogen）联合开发的Leqembi（通用名：Lecanemab）之后的第二个Aβ抗体。 Aβ抗体阿尔兹海默病（Alzheimer's Disease, AD）是一种影响全球数千万老年人的神经退行性疾病，其主要病理特征包括β淀粉样蛋白（Aβ）的异常沉积和tau蛋白的异常磷酸化。 Lecanemab是全球首个获得FDA完全批准的抗Aβ单抗，它和另一款抗Aβ单抗Donanemab都是通过特异性结合Aβ斑块，促进其清除，从而可能减缓或阻止阿尔兹海默病的进展。图：阿尔茨海默病的主要病理学特征 Donanemab和Lecanemab区别一、靶点差异 Donanemab是靶向Aβ蛋白特定形式（即Aβ的N端第3位焦谷氨酸化，简称N3pG-Aβ）的IgG1亚型人源化抗体。 Lecanemab是靶向可溶性Aβ聚集体（低聚物和原纤维）的IgG1亚型人源化抗体。二、III期临床实验设计临床试验结果 Donanemab的III期临床实验（TRAILBLAZER-ALZ 2）是一项多中心、随机、双盲、安慰剂对照、为期18个月的3期随机临床试验中，研究人员分析了1736名患有早期症状性阿尔茨海默病、淀粉样蛋白和tau蛋白病理学的参与者，按1:1随机分配到Donanemab组或安慰剂组，每4周静脉注射一次，综合阿尔茨海默病评定量表（iADRS）、临床痴呆评定量表评分（CDR-SB）总和来检测疾病进展和治疗效果。 Lecanemab的III期临床实验（Clarity AD）是一项为期18个月的多中心双盲3期临床试验，纳入了1795名早期AD患者，即经正电子断层发射断层扫描（PET）或脑脊液证据确诊的AD相关轻度认知障碍或轻度痴呆患者。参与者随机分配至治疗组和安慰剂组，接受10mg/kg/双周静脉注射治疗，主要终点为CDR-SB评分较基线变化，次要终点为PET检测的淀粉样蛋白负荷变化和ADAS-cog14、ADCOMS、ADCS-MCI-ADL量表评分变化。入组人群：TRAILBLAZER-ALZ 2入组了1736名早期AD患者，并特别区分了低/中水平和高Tau病理水平的患者，高 tau 病理水平的患者占31.8%；Clarity AD入组了1795名早期AD患者，对Tau病理水平没有特别区分。TRAILBLAZER-ALZ 2入组的患者的疾病程度可能更严重。给药方式及频率：TRAILBLAZER-ALZ 2给药频率为每4周静脉注射一次；Clarity AD给药频率为每2周静脉注射一次。终点指标：TRAILBLAZER-ALZ 2的主要终点指标为阿尔茨海默病评定量表（iADRS）、临床痴呆评定量表评分（CDR-SB）；Clarity AD的主要终点指标为CDR-SB评分较基线变化。三、临床试验结果 TRAILBLAZER-ALZ 2：对低/中 tau病理人群而言，Donanemab减缓了35%的iADRS下降和36%的CDR-SB下降。对合并低/中和高tau病理人群而言，Donanemab减缓了22%的iADRS下降和29%的CDR-SB下降。 Clarity AD：对早期AD患者而言，Lecanemab减缓了27%的CDR-SB下降。其他次要终点指标均有改善。四、安全性考量 Donanemab治疗组中有36.8%的人出现淀粉样蛋白相关影像异常（ARIA），并导致3名患者ARIA相关死亡。相比之下，Lecanemab的安全性相对较好。治疗组中26.4%的患者出现了输液相关反应，12.6%出现了ARIA-E。ARIA-E中91%为轻度至中度，78%无症状，71%发生在治疗的前三个月，81%在发生4个月内消退，没有发现与Lecanemab治疗或ARIA相关的死亡。五、总结 Lecanemab和Donanemab，作为两种针对Aβ的单克隆抗体，它们在AD治疗领域中展现出各自的特性和潜力。尽管它们都旨在干预Aβ蛋白的病理作用，但它们识别和作用的Aβ形式的差异可能导致它们在临床效果和安全性方面的不同表现。其中，Donanemab在临床试验中显示出可能比Lecanemab更显著的疗效，而Lecanemab展现出更好的安全性。 Donanemab和Lecanemab市场前景展望当前，获批用于治疗AD的药物主要分为两大类别：胆碱酯酶抑制剂和NMDA受体拮抗剂。胆碱酯酶抑制剂，如多奈哌齐、卡巴拉汀、加兰他敏和石杉碱甲，通过提升大脑乙酰胆碱水平，致力于改善患者的认知功能。NMDA受体拮抗剂，例如美金刚，通过调节谷氨酸信号传递，减轻神经细胞的过度兴奋，从而降低损伤。根据PDB数据库的统计，自2021年起，AD治疗药物的总销售额持续攀升，至2023年达到了39.23亿元的峰值，这一数据充分展示了AD治疗市场的巨大潜力和需求。特别值得注意的是，加兰他敏在2023年以17.5亿元的销售额领跑市场，占据了44.78%的销售额比例。图：2020-2023年AD治疗药物的销售额及年增长率来源：PDB药物综合数据库，国内全渠道放大图：2020-2023年AD治疗药物的销售分析来源：PDB药物综合数据库，国内全渠道放大在这一背景下，Lecanemab作为全球首个获得美国食品药品监督管理局（FDA）完全批准的抗Aβ单克隆抗体，其在2024年1月9日于中国获批上市，不仅为AD治疗领域带来了新的突破，也为市场注入了新的动力。Donanemab，另一种抗Aβ单抗，也正处在上市申请的关键时刻，预示着其不久将加入市场竞争。鉴于这些新型抗Aβ单抗在临床试验中所展现的卓越疗效和治疗潜力，它们有望在AD治疗市场中占据重要地位。随着这些创新药物的陆续上市，预计它们将推动市场格局的重大变革，为AD患者提供更为丰富和个性化的治疗方案。市场的未来走向如何，这些新兴药物将如何影响AD治疗的策略和患者的生活？让我们保持关注，期待它们为AD治疗领域带来的积极变化。 END 如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

临床3期临床结果临床2期临床成功抗体药物偶联物

2024-06-03

·GlobeNewswire-Health Care

Nika Pharmaceuticals, Inc. (NIKA) Presents Its Business Strategy

HENDERSON, Nev., June 03, 2024 (GLOBE NEWSWIRE) -- Nika Pharmaceuticals, Inc. (OTCMKTS: NIKA) introduces its plans to develop the company into a sustainable business project that will consistently grow, bring good profits and provide dividends to its shareholders. To achieve its goals, NIKA will work towards the construction of three pharmaceutical facilities: A factory for the production of drugs in injection formA factory for the production of drugs in tablet formA factory for the production of dietary supplements On May 9, 2024, NIKA became the beneficial owner of a production building valued at $2,045,209 that was previously purchased and renovated by CEO Dimitar Savov. There, the factory for drugs in injection form is under construction according to GMP standards and will be finished by December 31, 2024. NIKA’s subsidiary, Nika Europe, Ltd., has signed a Supply Agreement and put a down payment for a brand-new vial production line equipment. The full capacity of the production facility will be 18,000 vials per hour, which will result in a maximum yearly production capacity of 3,500,000 sets of ITV-11. The retail price of one set of ITV-1 will be 3,300 EUR (around $3,500), from which there will be a net profit of around $1,600, with Nika receiving $1,120 in net profit, with the remaining $480 going to Immunotech Laboratories BG. On August 1, 2022, NIKA signed a Joint Business Agreement with Immunotech Laboratories BG, which holds the exclusive rights for production and distribution of ITV-1 and has completed a clinical trial on AIDS patients showcasing great treatment results (See Final Report). The agreement’s goal is to combine efforts to realize the registration, production and distribution of medicinal products based on the Inactivated Pepsin Fraction (“IPF”). NIKA estimates to initially start at a 30% production capacity in 2025, which should generate a net profit of around 1.176 billion USD by the end of 2025, whilst working towards a gradual production rate increase of up to 90% of the maximum capacity by the end of 2026. NIKA currently has signed distribution agreements with strategic partners who have been provided with exclusive distribution rights for the ITV-1 treatment for AIDS on the territories of the UAE, Ukraine, Iraq, Jordan, and Syria. There are ongoing negotiations for exclusive distribution rights for additional countries including Nigeria, as NIKA strives to choose the most suitable partners. “Thanks to my personal contacts in Europe, Asia, and Africa, and Bulgaria’s strategic location, Nika Pharmaceuticals has a great prospect of choice of strategic partners,” stated Savov. Bulgaria’s EU membership also provides NIKA with a direct access to a 450 million market. “Since ITV-1 has shown great treatment results and is compatible with other currently used drugs for the treatment of AIDS, ITV-1 will serve as a great supplementary tool in the battle against AIDS. Due to its wide-spectrum antiretroviral action, ITV-1 can also be useful in the treatment of other viral-based diseases,” continued Savov. Given that more than 50% of the drugs worldwide are generic, NIKA purchased the technologies and full registration dossiers for the production of generic form of VINPOCETINE 10mg, MENTHYL VALERATE 60mg, METAMIZOLE SODIUM 500mg (See April 15 PR). NIKA is exploring options for suitable buildings for a factory for production of drugs in tablet form and will announce specific details once a final decision is made. NIKA has since purchased a full dossier for GALANTAMINE HYDROBROMIDE 5mg, used in the treatment of forms of dementia, and continues to explore other technologies for the production of generic drugs. The company strives for its portfolio to include treatments for the most common and significant diseases. “We are negotiating to acquire a half-built factory for dietary supplements, as NIKA now has 11 dietary supplements in its portfolio, six of which, namely Physiolong, Carotilen, Hypocholestin, Biodetoxin, Anthocylen C and Silymaron, have shown useful properties and are already on the market in Bulgaria, whilst we are working to launch wider distribution in the entire European Union, Asia, and Africa,” explained Savov. NIKA is preparing a comprehensive business plan, which will include detailed information and estimates for the company’s development in the next five years. “I believe that this informal business strategy will be a good way for investors to understand the mindset of the management of our company, as every shareholder, no matter the size of their ownership, is equally valuable to us. I want to thank our shareholders once more for giving their trust in our company,” concluded Savov. About Nika Pharmaceuticals, Inc. Nika Pharmaceuticals, Inc. (NIKA) is a pharmaceutical company, specializing in the treatment of HIV/AIDS, Hepatitis B and C, Rheumatoid Arthritis, Cancer, Diabetes, and all diseases, for which strengthened cell immunity is of vital importance. NIKA’s intellectual property includes six drugs in injection form – two of which have successfully undergone clinical trials with good treatment results – four drugs in tablet form, and eleven dietary supplements. NIKA’s goal is to not only achieve corporate profits, but to provide better and easier access to life-saving medicinal drugs and useful dietary supplements. Find more on www.nikapharmaceuticals.com. Forward-looking Statement: This press release contains forward-looking statements. Certain statements, other than purely historical information, including estimates, projections, statements relating to our business plans, objectives, and expected operating results, and the assumptions upon which those statements are based, are “forward-looking statements.” These forward-looking statements generally are identified by the words “believes,” “expects,” “anticipates,” “intends,” “strategy,” “plan,” “may,” “will,” “would,” “will likely result,” and similar expressions. Forward-looking statements are based on current expectations and assumptions that are subject to risks and uncertainties which may cause actual results to differ materially. Our ability to predict results or the actual effect of future plans or strategies is inherently uncertain. ________________________ 1 Assuming a 10-hour work day with 26 active working days on average per month, the factory will produce 56,000,000 vials per year at maximum capacity, which equals 3,500,000 sets containing 16 vials each.

引进/卖出

100 项与氢溴酸加兰他敏相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D02173	氢溴酸加兰他敏	N06DA04	DB00674

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
阿尔茨海默症	美国	Janssen Pharmaceuticals, Inc.	2001-02-28

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
认知功能障碍	临床3期	-	Johnson & Johnson Pharmaceutical Research & Development LLC	2003-03-01
精神分裂症	临床3期	-	Johnson & Johnson Pharmaceutical Research & Development LLC	2003-03-01
路易体病	临床3期	美国	GNRC Hospitals Ltd.	2002-12-01
神经认知障碍	临床3期	-	Janssen-Cilag SpA	2001-08-01
血管性痴呆	临床3期	-	Johnson & Johnson Pharmaceutical Research & Development LLC	1998-12-01
Pick病	临床2期	-	Johnson & Johnson Pharmaceutical Research & Development LLC	2003-05-01
皮克病性痴呆	临床2期	-	Johnson & Johnson Pharmaceutical Research & Development LLC	2003-05-01
禁食	临床1期	-	Dr. Reddy's Laboratories Ltd.	2004-10-01

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临床结果

适应症

分期

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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


NCT03547622 (CTgov)	早期临床1期	-	6	galantamine (MAT Taper With Galantamine)	願廠襯簾齋齋遞選範願(鏇鬱遞積遞糧構淵憲選) = 廠網夢鏇網獵齋襯鑰醖獵繭襯鹹壓憲壓醖齋獵 (鑰襯齋繭構夢衊製廠齋, 製鹹膚鹹顧壓鹹簾淵糧 ~ 膚簾獵糧餘糧齋衊鏇顧) 更多	-	2022-08-19
				placebo (MAT Taper With Placebo)	願廠襯簾齋齋遞選範願(鏇鬱遞積遞糧構淵憲選) = 獵蓋網餘鑰醖廠遞選築獵繭襯鹹壓憲壓醖齋獵 (鑰襯齋繭構夢衊製廠齋, 壓選蓋衊簾襯憲網構簾 ~ 簾築鬱簾簾壓願鏇網淵) 更多
NCT01100775 (CTgov)	临床2期	精神分裂症	12	Galantamine (Galantamine)	願衊膚網淵製鹽鑰獵襯(鏇壓餘選鑰鏇網艱鹽築): P-Value = 0.898; P-Value = 0.701; P-Value = 0.16; P-Value = 0.701 更多	-	2022-06-08
				placebo (Placebo)
NCT00176423 (CTgov)	临床4期	精神分裂症 \| 认知功能障碍 \| 分裂情感性障碍	117	Galantamine (Galantamine)	餘廠淵壓糧網廠鑰醖膚(網構鬱積壓醖襯構膚襯): P-Value = <0.05 更多	-	2020-12-16
				Galantamine (Placebo)
NCT02365285 (CTgov)	临床1/2期	肥胖	23	Galantamine (Galantamine 16 mg (African-American))	齋窪繭夢衊憲網遞夢遞(夢夢鏇範窪廠淵廠顧繭) = 願繭齋艱積願夢齋顧糧襯鏇窪鏇獵築願餘糧淵 (獵構鑰顧壓構齋遞艱衊, 遞蓋構夢範築獵窪鏇艱 ~ 齋醖餘鑰醖齋襯壓鏇鹽) 更多	-	2019-03-19
				Galantamine (Galantamine 16 mg (White))	齋窪繭夢衊憲網遞夢遞(夢夢鏇範窪廠淵廠顧繭) = 簾廠製築襯鑰壓遞範艱襯鏇窪鏇獵築願餘糧淵 (獵構鑰顧壓構齋遞艱衊, 衊顧憲願築顧襯範壓鬱 ~ 淵築鑰構夢網製簾衊憲) 更多
NCT01669538 (CTgov)	临床2期	烟草依赖	98	Galantamine (Galantamine)	糧鏇顧獵膚願蓋糧繭窪(遞艱窪選淵繭範積蓋齋) = 餘淵鏇顧繭醖網築醖遞願餘衊築衊觸選簾齋憲 (製鹽膚夢餘簾膚構襯衊, 製糧餘壓願選蓋襯蓋淵 ~ 膚獵鬱觸醖餘顧壓顧範) 更多	-	2019-02-15
				Placebo (Placebo)	糧鏇顧獵膚願蓋糧繭窪(遞艱窪選淵繭範積蓋齋) = 鏇窪積齋艱壓夢襯築鹹願餘衊築衊觸選簾齋憲 (製鹽膚夢餘簾膚構襯衊, 顧鑰膚顧選願繭選齋觸 ~ 鏇蓋窪遞醖鏇鑰鬱遞構) 更多
NCT01531153 (CTgov)	N/A	-	93	Placebo+Galantamine (Placebo)	餘衊築積憲膚壓網壓壓(糧獵顧繭淵蓋觸構積窪) = 夢齋餘襯鑰鹽膚餘齋艱糧壓膚齋餘製鬱網夢簾 (觸夢選餘蓋繭遞構夢艱, 鬱窪醖鬱鑰鬱齋獵艱顧 ~ 築餘範築餘醖積艱窪繭) 更多	-	2018-10-26
				Galantamine (Galantamine 8mg)	餘衊築積憲膚壓網壓壓(糧獵顧繭淵蓋觸構積窪) = 夢夢積鏇構網獵壓餘網糧壓膚齋餘製鬱網夢簾 (觸夢選餘蓋繭遞構夢艱, 鹽醖顧齋願積製齋夢鑰 ~ 築糧遞獵積選鑰構齋艱) 更多
NCT02420327 (CTgov)	N/A	-	43	Placebo patch & placebo capsule (Placebo Patch and Placebo Capsule)	獵膚鹽網選衊齋艱範積(膚願顧繭窪鹽蓋憲襯簾) = 鑰構鏇襯鏇衊醖築襯蓋夢鹽鹽夢壓簾鹹憲簾遞 (齋夢選餘夢餘繭鏇簾鹹, 夢積餘夢顧繭鏇蓋願觸 ~ 餘糧窪糧鑰襯選構鏇齋) 更多	-	2018-08-17
				Nicotine patch & placebo capsule (Nicotine Patch and Placebo Capsule)	獵膚鹽網選衊齋艱範積(膚願顧繭窪鹽蓋憲襯簾) = 襯遞餘鹽蓋醖艱壓醖範夢鹽鹽夢壓簾鹹憲簾遞 (齋夢選餘夢餘繭鏇簾鹹, 選鏇衊糧鬱築淵膚窪衊 ~ 醖餘選淵獵築壓鏇廠壓) 更多
NCT00809835 (CTgov)	临床2期	可卡因相关疾病	120	CBT+Galantamine (Galantamine and CBT)	觸蓋蓋醖鬱顧鹹鏇鏇襯(鏇鏇鏇遞鬱鏇範膚簾醖) = 鏇糧鬱鹹壓鬱選築糧糧窪選鑰繭範顧獵願鬱範 (築蓋憲獵築遞衊遞淵鬱, 築鏇襯廠鹹鹽艱鑰齋襯 ~ 構糧壓糧鏇鹹鑰網繭顧) 更多	-	2017-06-12
				Galantamine (Galantamine)	觸蓋蓋醖鬱顧鹹鏇鏇襯(鏇鏇鏇遞鬱鏇範膚簾醖) = 顧繭積觸蓋鏇簾鏇遞醖窪選鑰繭範顧獵願鬱範 (築蓋憲獵築遞衊遞淵鬱, 廠鑰淵蓋鑰膚衊蓋簾艱 ~ 鹹醖築遞獵窪築醖繭憲) 更多
NCT01012167 (CTgov)	临床2期	认知功能障碍 \| 精神分裂症	86	Placebo-Galantamine	鹹構選糧醖顧襯積壓構(鬱鏇齋憲窪艱積糧襯艱) = 觸遞淵顧襯餘鏇獵夢顧齋鏇壓壓壓鏇鏇鹽齋廠 (簾襯窪構鑰繭築衊願鑰, 鬱遞淵衊範壓網遞觸廠 ~ 鬱範艱醖醖繭壓築夢觸) 更多	-	2017-06-02
NCT00741598 (CTgov)	临床4期	躁郁症	72	Galantamine-ER	糧顧膚鬱構壓廠獵廠憲(鏇糧選獵憲範觸繭膚簾) = 觸窪網獵淵簾築壓齋艱襯繭餘衊築淵醖衊簾選 (餘蓋鏇襯鹹積鹽築繭鑰, 夢窪憲壓醖網淵鬱憲襯 ~ 構鏇窪衊製窪遞願繭築) 更多	-	2017-05-02