A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of KarXT for the Treatment of Psychosis Associated With Alzheimer's Disease

This is a Phase 3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of KarXT in male and female subjects who are aged 55 to 90 years and have mild to severe Alzheimer's Disease (AD) with moderate to severe psychosis related to AD.
The primary objective of the study is to evaluate the efficacy of KarXT compared with placebo in the treatment of subjects with psychosis associated with AD as measured by the Neuropsychiatric Inventory-Clinician (NPI-C): Hallucinations and Delusions (H+D) score.

开始日期2023-12-26

申办/合作机构

Karuna Therapeutics, Inc.

CTRI/2023/08/056449 / Not yet recruitingN/A

Explorative and Correlative Study of Karuna (à¤?à¤° ?à¤£à¤¾): As a Correlates of Human Personality, Life Satisfaction, And Mental Health - Karuna

开始日期2023-08-16

申办/合作机构-

NCT05980949 / Enrolling by invitation临床3期

A Phase 3 Global, Multicenter, Open-Label Extension Study to Assess the Long-Term Safety and Tolerability of KarXT in Subjects With Psychosis Associated With Alzheimer's Disease

This is a Phase 3 global, multicenter, 52-week, open-label extension (OLE) rollover study for subjects completing study CN012-0026 or CN012-0027. Subjects (randomized or non-randomized) who complete the 38-week CN012-0026 or CN012-0027 study will be eligible to enroll in CN012-0028.
The primary objective of the study is to assess the long-term safety and tolerability of KarXT in subjects with psychosis associated with Alzheimer's Disease.

开始日期2023-07-11

申办/合作机构

Karuna Therapeutics, Inc.

100 项与曲司氯铵/呫诺美林相关的临床结果

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100 项与曲司氯铵/呫诺美林相关的转化医学

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100 项与曲司氯铵/呫诺美林相关的专利（医药）

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项与曲司氯铵/呫诺美林相关的文献（医药）

2024-02-01·Clinical autonomic research : official journal of the Clinical Autonomic Research Society

Muscarinic control of cardiovascular function in humans: a review of current clinical evidence

Review

作者: Palma, Jose-Alberto

PURPOSE:

To review the available evidence on the impact of muscarinic receptor modulation on cardiovascular control in humans.

METHODS:

In this narrative Review we summarize data on cardiovascular endpoints from clinical trials of novel subtype-selective or quasi-selective muscarinic modulators, mostly PAMs, performed in the last decade. We also review the cardiovascular phenotype in recently described human genetic and autoimmune disorders affecting muscarinic receptors.

RESULTS:

Recent advancements in the development of compounds that selectively target muscarinic acetylcholine receptors are expanding our knowledge about the physiological function of each muscarinic receptor subtype (M1, M2, M3, M4, M5). Among these novel compounds, positive allosteric modulators (PAMs) have emerged as the preferred therapeutic to regulate muscarinic receptor subtype function. Many muscarinic allosteric and orthosteric modulators (including but not limited to xanomeline-trospium and emraclidine) are now in clinical development and approaching regulatory approval for multiple indications, including the treatment of cognitive and psychiatric symptoms in patients with schizophrenia as well as Alzheimer's disease and other dementias. The results of these clinical trials provide an opportunity to understand the influence of muscarinic modulation on cardiovascular autonomic control in humans. While the results and the impact of each of these therapies on heart rate and blood pressure control have been variable, in part because the clinical trials were not specifically designed to measure cardiovascular endpoints, the emerging data is valuable to elucidate the relative cardiovascular contributions of each muscarinic receptor subtype.

CONCLUSION:

Understanding the muscarinic control of cardiovascular function is of paramount importance and may contribute to the development of novel therapeutic strategies for treating cardiovascular disease.

2024-01-01·Lancet (London, England)1区 · 医学

Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial

1区 · 医学

Article

作者: Correll, Christoph U ; Paul, Steven M ; Zhu, Haiyuan ; Sawchak, Sharon ; Kaul, Inder ; Miller, Andrew C ; Brannan, Stephen K ; Kakar, Rishi ; Breier, Alan

BACKGROUND:

New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M₁ and M₄-preferring muscarinic receptor agonist that does not block D₂ dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis.

METHODS:

EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161).

FINDINGS:

From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]).

INTERPRETATION:

In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D₂ dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia.

FUNDING:

Karuna Therapeutics.

2023-12-02·Expert opinion on investigational drugs

Muscarinic M1 and M4 receptor agonists for schizophrenia: promising candidates for the therapeutic arsenal

Review

作者: Dean, Brian

INTRODUCTION:

Successful phase 3 trials of KarXT in people with schizophrenia herald a new era of treating the disorder with drugs that do not target the dopamine D2 receptor. The active component of KarXT is xanomeline, a muscarinic (CHRM) M1 and M4 agonist, making muscarinic receptors a viable target for treating schizophrenia.

AREAS COVERED:

This review covers the process of taking drugs that activate the muscarinic M1 and M4 receptors from conceptualization to the clinic and details the mechanisms by which activating the CHRM1 and 4 can affect the broad spectrum of symptoms experienced by people with schizophrenia.

EXPERT OPINION:

Schizophrenia is a syndrome which means drugs that activate muscarinic M1 and M4 receptors, as was the case for antipsychotic drugs acting on the dopamine D2 receptor, will not give optimal outcomes in everyone within the syndrome. Thus, it would be ideal to identify people who are responsive to drugs activating the CHRM1 and 4. Given knowledge of the actions of these receptors, it is possible treatment non-response could be restricted to sub-groups within the syndrome who have deficits in cortical CHRM1 or those with one of the cognitive endophenotypes that may be identifiable by changes in the blood transcriptome.

305

项与曲司氯铵/呫诺美林相关的新闻（医药）

2024-06-25

·同写意

“没花冤枉钱”的重磅交易TOP10

同写意20周年大会：中国医药创新未来之路！“意”同创新，穿越周期，赢取未来。7月中旬，苏州金鸡湖畔，让我们与“新药写意人”一起为中国医药创新“同写意”！在过去的几年中，大型制药公司纷纷投入巨资，在ADC、核药和减肥药物等热门领域进行巨额押注。 Fierce Pharma此前已整理罗列了2023年全球金额最大的并购交易TOP 10，近日，Fierce Biotech又一次回顾了近年最吸引眼球的、最明智的交易。顾名思义，该篇汇总从“回报”情况评估这些大额交易——哪些重磅交易钱花的不亏？当然，这里的“回报”，包括陆续发布的临床数据、可能的历史性批准，以及组合疗法的规模化应用等等，并综合考虑了交易方在全球市场的长期布局。 1 BMS 140亿美元收购Karuna 2023年的最后一个月，向来“低调”的CNS领域接连发生了两起重磅交易，其中之一就是BMS斥资140亿美元收购Karuna Therapeutics。 Karuna最终被以每股330美元现金收购，较2023年12月21日收盘时的股价溢价53%。收购总价为140亿美元，或扣除预计获得的现金后的127亿美元。这场交易标志着BMS重返神经精神病学领域。可以看到，BMS对于该交易的热情，在目前的会议巡回之旅中有所表现。今年4月展示数据显示，KarXT在精神分裂症中可以持续改善症状，且患者体重不会增加。 BMS有理由说这是一笔明智的交易——早在2023年1月，业内就预测Karuna是制药公司必收购的股票之一。据悉，交易后公布的监管文件中显示，另一家公司曾在最后一刻对Karuna公司发起竞购，难怪BMS会急于完成这笔交易。 KarXT是今年最受期待的药物之一，分析师估计，它可以在2028年带来28亿美元的销售额。FDA预计将在今年第三季度做出审批决定。值得关注的是，该药物的中国市场权益由再鼎医药持有。虽然BMS趁热打铁是明智之举，但真正值得称赞的是开发KarXT的Karuna团队，目前该药物也正在阿尔茨海默病精神病领域进行测试。 2 罗氏巧妙截胡 31亿美元收购Carmot 诺和诺德和礼来都从各自的GLP-1资产中赚取了数十亿美元，其他大药厂也正跃跃欲试。但罗氏的入局方式比较巧妙，在Carmot准备IPO时，罗氏与Carmot进行了秘密收购谈判。最后，Carmot甚至还没来得及登陆纳斯达克，罗氏就抢先一步，以31亿美元（27亿美元预付款）收购了这家Biotech，获得了其皮下和口服肠促胰岛素的临床产品线，包括目前正在进行临床III期试验的每周一次和每天一次注射用GLP-1/GIP双受体激动剂。临床试验正在如期推进。5月份进行的一项为期24周的Ib期研究显示，每周一次的CT-388试验组，经安慰剂调整后的平均体重减轻了18.8%。对比15mg的替尔泊肽的数据——52周体重较基线时减轻了17.5%，该药物未来数据十分可期。同时，Carmot的CT-388如果与罗氏的抗肌肉生长抑制素抗体联合，31亿美元的高昂交易价格就十分合理了。罗氏正在研究RO7204239增强脊髓性肌肉萎缩症患者肌肉的潜力，他们提前布局了减肥药的下半场——减重不减肌。罗氏似乎非常偏爱这笔交易，希望以此为跳板进一步扩大研发规模。在今年2月份与分析师召开的全年收益电话会议上，罗氏制药首席执行官Teresa Graham暗示，“收购Carmot还将带来更多收益”，并称罗氏将把该笔收购所得资产，视为未来在心脏代谢领域以及其他潜在疾病领域开展业务的支柱。 3 诺和诺德收购Inversago 减肥药后继有人诺和诺德在肥胖症领域一直处于领先地位，但这家公司已经在考虑下一步的战略布局。近几个月来，诺和诺德开展了一系列动作，包括2023年8月的两次连续收购。先是以1500万欧元（约合1600万美元）收购了是总部位于丹麦的Embark Therapeutics，这是诺和诺德的一家长期合作企业。另一项收购的对象是加拿大公司Inversago Pharma，总金额高达10.7亿美元，包括未披露的开发和商业里程碑金额，这一收购获得的主要资产是该公司管线CB1反向激动剂INV-202。如果接下来的试验取得成功，这场豪赌将带来丰厚的回报。 Inversago正在研发阻断大麻素CB1受体的药物（INV-202）——16年前，赛诺菲曾因该领域遭受重创，欧洲监管机构因CB1受体阻断剂减肥药Acomplia存在精神障碍风险，撤销了对该药的批准。 INV-202正在糖尿病肾病患者中进行II期试验。但诺和诺德更关注其在治疗肥胖症上的潜力，据悉，该候选药物在Ib期试验中已证明具有减肥效果。诺和诺德已将这种更名为monlunabant的药物转入肥胖症的II期临床试验。此外，原本Inversago旗下名为INV-347的下一代CB1受体阻断剂，也被推向临床。 4 GSK收购Bellus Health 开战默沙东有时，明智的交易，一个主要作用就是向竞争对手开战，GSK在2023年8月斥资20亿美元收购Bellus Health时就是这么做的。 GSK因此获得了慢性咳嗽药camlipixant，其作用机制与默沙东的gefapixant相同。这两种药物都是P2X3的拮抗剂，P2X3是一种外周神经系统受体，可引发神经元过敏，与咳嗽冲动有关。默沙东的gefapixant在监管方面遇到了麻烦，其首次上市申请于2022年被FDA拒批，但在日本和欧洲却已成功上市。2023年末，FDA第二次拒批这款药物。这使camlipixant迎来绝佳机会。 Bellus已经引起了海外分析师们的关注，他们当时称该公司“凭借更具选择性的产品和差异化的数据集，一举成为P2X3抑制剂领域的佼佼者”。到2023年6月GSK完成收购时，其首席商务官Luke Miels将这次收购描述为，“与GSK在呼吸药物领域的优势高度协同”。此后，GSK一直在推进camlipixanIII期临床试验，预期2026年获得FDA批准，在2031年及以后实现大规模销售。 5 渤健73亿美元收购Reata 孤注一掷 2023年7月，渤健宣布以73亿美元收购Reata Pharmaceuticals引发关注。这家公司过去几年一直在走下坡路，73亿美元对于渤健来说并不是一个小数目，渤健2023全年营收仅98.36亿美元，产品收入仅为72.47亿美元。收购最终以每股172.50美元的价格进行，较交易宣布前一天收盘价高出59%。用近全年产品收入押注罕见病，主要为获得Reata的主要资产Skyclarys——这是第一个批准用于治疗遗传性神经疾病弗里德里克共济失调的药物。该药物于2023年2月获得FDA批准，分析师预测，Skyclarys到2030年的销售额有望达到15亿美元。 Reata首席执行官Warren Huff在一份新闻稿中表示：“凭借对罕见病患者和现有商业基础设施的清晰了解，我们相信Biogen能够把Skyclarys确立为治疗这种毁灭性遗传病的标准疗法。” Skyclarys自带一份“优先审批券“，用于加快FDA对药品申请或销售的审查流程。Reata还拥有其他几种针对神经系统疾病的药物，但都处于早期开发阶段。此前备受争议的是，就在这次收购之前，渤健刚宣布计划在2024年底前裁员1000人，占员工总数的11%。裁员是对公司进行重组的一部分，过去三年来，该公司的收入一直在下降。 6 礼来收购Versanis Bio 减肥药物联用的回击去年7月，礼来以19.2亿美元的价格收购了Versanis Bio。Versanis Bio的管线主要是激活素受体II型拮抗剂bimagrumab。礼来如今已经凭借Zepbound占据了领先地位，19.2亿美元的收购价对其他人来说是一笔巨款，但对礼来来说甚至算不上九牛一毛。该交易带来了一种名为bimagrumab的II期单克隆抗体，目前正在对超重或肥胖的成年人进行单独测试，并与司美格鲁肽进行肥胖症的联合临床测试。换句话说，最终买下Versanis Bio如果不是礼来，那就可能是他的老对手诺和诺德。 bimagrumab曾经是诺华的临床资产，其在开发包涵体肌炎时因临床失败而被迫中止。礼来之所以看中Versanis的产品组合，是因为它能与肠促胰岛素药物结合起来，有望实现减脂不减肌。虽然Zepbound和Wegovy对肥胖或超重人群的减肥效果不错，但这些药物可能会导致肌肉损失。因此，借助Versanis，礼来或许有望稳住其减重产品组合及Zepbound在市场上占据多年的主导地位。 7 诺华收购Chinook 变废为宝去年6月，诺华花费32亿美元买下Chinook，该公司手握曾被艾伯维放弃的管线Atrasentan，交易仅四个月，这项资产就为诺华带来了回报。虽然诺华已经有自己的IgA肾病候选药物iptacopan，目前正在进行III期临床试验，但它跟Atrasentan的机制并不相同。该药物最初由艾伯维开发，2013年，该公司因该药物临床数据低于预期而停止了慢性肾病的III期试验。幸运的是，2023年10月公布的一项为期36周的中期分析显示，在该药物的III期研究中，蛋白尿的改善程度明显高于安慰剂组。受此消息鼓舞，诺华计划于2024年上半年在美国申请加速审批，随后不久将提交iptacopan的IgA肾病适应症审批。同时，诺华还从Chinook获得了另一项IgA肾病资产，名为zigakibart，目前正在进行III期试验。诺华首席执行官Vasant Narasimhan在4月份的财报电话会议上解释：“我们认为，拥有三种IgA肾病药物将使我们在患者、医生、美国供应链各个环节以及全球范围内占据有利地位。” 8 罗氏71亿美元收购Televant 前雇主卖“后悔了” 我们可以通过“前雇主”是否难以释怀来判断这笔交易是否“划算”。Televant的情况确实如此，交易达成的几个月后，其前身公司Roivant首席执行官Matt Gline坦言，他仍然对出售Televant感到“后悔不已”。 2022年12月，Roivant与辉瑞合作，成立了一家专注于炎症和纤维化疾病的新公司即Televant，用于开发TL1A定向抗体RVT-3101。一个月后，公布的IIb期数据显示，RVT-3101使32%的IBD患者得到缓解，而安慰剂组这一比例仅为12%。当时，各大制药公司对抗TL1A的兴趣十分浓厚，默沙东以108亿美元收购了Prometheus，赛诺菲也与Teva就IBD治疗药物TEV-574展开了合作。到2023年10月，罗氏以71亿美元拿下了同样热门的Televant。 Gline在1月份表示，收购完成后，他一直感到遗憾，是因为RVT-3101的“机会实在太大了”。罗氏对新收购感到十分满意，并宣布计划今年将RVT-3101投入III期试验。2月份举行的财报电话会议上，罗氏制药首席执行官Teresa Graham形容，该资产“有机会真正重新设定患有毁灭性疾病患者的护理标准”。 Graham对外宣称：“我们相信TL1A还有很多其他的适应症，我们期待着为其探索更多的试验计划。请继续关注它的发展方向，前景一片光明。” 9 BMS收购RayzeBio 冲进核药赛道 BMS一举以41亿美元收购了RayzeBio，加入了核药赛道竞逐，瞄准α射线同位素。收购交易以每股62.50美元的价格进行，这一价格是RayzeBio几个月前IPO价格的三倍多。 BMS的出价，足以击败另外两家也提出报价的未具名公司。竞争和中标价格，也能表明核药领域有多火爆，并使BMS能够与诺华同台竞争。与诺华获批的核药疗法Lutathera和Pluvicto（使用名为镥的β发射同位素）不同，RayzeBio的研究基于名为锕-225的α发射同位素。 RayzeBio的主要资产是RYZ101，该药物靶向生长抑素受体2（SSTR2），这是一种在胃肠胰神经内分泌肿瘤（GEP-NET）和广泛期小细胞肺癌（ES-SCLC）中过度表达的蛋白质。该药物的3期试验目前正在进行中，试验对象为之前接受过镥-177生长抑素疗法治疗的SSTR阳性GEP-NET患者，预计2025年将公布研究数据。 BMS还获得了RayzeBio位于印第安纳波利斯的“最先进”制造工厂。礼来也于2023年进入了核药领域，以14亿美元收购Point Biopharma Global，后者是一家专注于放射性配体疗法且拥有内部制造能力的生物技术公司。 10 阿斯利康收购Fusion 押注RDC BMS并非唯一一家刚踏入核药领域的大型制药公司。阿斯利康也大手笔投资入局，今年3月以24亿美元（预付20亿美元）将Fusion纳入其资产配置。该交易确保FPI-2265的II期临床试验如期推进，该药物可提供锕-225，其释放的能量比诺华的Pluvicto等β疗法更高。阿斯利康认为，FPI-2265有可能成为首个获批用于治疗镥后转移性去势抵抗性前列腺癌的PSMA靶向放射治疗方法。但这笔交易的意义远不止将FPI-2265送上FDA审批关口。在宣布收购消息的一个月后，第一季度财报电话会议上，阿斯利康肿瘤研发部执行副总裁Susan Galbraith热情洋溢地谈到，将“放射性结合物与我们研发线中的其他疗法相结合的巨大潜力，包括下一代免疫肿瘤双特异性抗体、细胞疗法、T细胞接合剂和我们的DNA损伤反应剂”。交易也带来了制造方面的好处，放射性同位素的半衰期较短，而且全球生产基地相对较少，这使得制药公司很难进入该领域。幸运的是，Fusion已经在自己的工厂生产临床GMP剂量，并与服务商展开了密切合作。 Galbraith解释说，这意味着此次收购将加速阿斯利康实现商业规模核药生产能力的目标，并强调这一目标将在“三年内”完成，同时还能确保锕的供应。参考资料： 1.Top 10 smartest deals in biopharma；Fierce Biotech 近期直播推荐:

并购临床3期抗体药物偶联物IPO申请上市

2024-06-25

·医药魔方Pro

生物制药领域最明智交易TOP10

过去几年，大型跨国制药公司（MNC）纷纷掏出钱包，在抗体药物偶联物（ADC）、放射性药物和肥胖药物等炙手可热的竞赛中下注。这些交易中，被收购方的产品可能在交易前就已取得了非常好的临床数据，或即将获得批准，也有的产品尚处于临床早期阶段。 6月24日，知名媒体Fierce Pharma统计并报道了，在过去一年中，医药领域最明智的、有趣的十项交易。其中，有的交易会为MNC带来巨大的收益，有的交易会助力MNC进入一个全新的领域（如核药），有的交易帮助MNC和竞争对手抗衡。 1. BMS收购Karuna Therapeutics 2023年12月，百时美施贵宝（BMS）宣布以140亿美元收购Karuna Therapeutics。 Karuna的主要资产KarXT（xanomeline-trospium）具有新颖的作用机制（MoA）以及差异化的功效和安全性。KarXT是一种口服的M1/M4首选毒蕈碱激动剂，用于治疗精神和神经系统疾病，包括精神分裂症和阿尔茨海默症中的精神症状。 KarXT可持续改善症状，而不影响患者体重。KarXT已申请上市，预计FDA在今年第三季度会给出回复。分析师估计，到2028年，KarXT可能会带来28亿美元的销售额。 2. 罗氏收购Carmot Therapeutics 2023年12月，罗氏宣布以27亿美元的现金和4亿美元的里程碑付款，收购了专注于肠促胰岛素类药物的生物技术公司Carmot Therapeutics。 Carmot Therapeutics的主要资产是CT-388，一种可注射的GLP-1/GIP双重受体激动剂，被收购时已处于Ib期试验阶段。今年5月，罗氏公布Ib期数据，所有接受治疗的受试者体重减轻了5%以上，其中85%的体重减轻了10%以上，45%的体重减轻了20%以上。罗氏似乎非常喜欢这笔交易，希望将其作为进一步研发扩张的跳板。在今年2月份的全年财报电话会议上，罗氏首席执行官Teresa Graham表示，“我们知道肠促胰岛素可能适用于其他疾病领域。我们将把从Carmot交易中获得的资产，作为未来在心脏代谢以及其他疾病领域发挥作用的支柱。” 3. 诺和诺德收购Inversago Pharma 2023年8月，诺和诺德宣布将以不超过10.8亿美元的价格收购Inversago Pharma，以扩大其减肥产品组合。对Inversago的收购包括该公司的主要开发资产INV-202，一种口服CB1反向激动剂。INV-202被设计为优先阻断脂肪组织、胃肠道、肾脏、肝脏、胰腺、肌肉和肺部等外周组织中的受体蛋白CB1，CB1在代谢和食欲调节中发挥重要作用。诺和诺德已将该药物（更名为monlunabant）应用到肥胖症的II期试验中，还将另一款CB1受体阻滞剂INV-347推进到临床。 4. GSK收购Bellus Health 2023年6月，GSK完成收购Bellus Health，获得了慢性咳嗽治疗药物camlipixant。 Camlipixant与默克公司的gefapixant作用机制相同，二者都是P2X3的拮抗剂，P2X3是一种周围神经系统受体，可触发神经元超敏反应，并与咳嗽冲动有关。gefapixant的第一份批准申请在2022年被FDA拒绝了，这就给了GSK机会。 GSK首席商务Luke Miels将这项收购描述为“与GSK在呼吸系统医学方面的专业知识高度协同”。此后，GSK一直在推进camlipixant进行III期试验，其目标是“在2026年获得FDA的批准，然后在2031年及以后进行大量销售。” 5. Biogen收购Reata Pharmaceuticals 2023年7月，Biogen宣布以73亿美元收购Reata Pharmaceuticals，并将Skyclarys收入囊中。 Skyclarys已获美国FDA批准，是美国首个、也是唯一一个批准的治疗弗里德赖希共济失调（FA）的药物，目前正在欧洲监管审查中。此外，Reata正在为一系列神经疾病开发一系列创新产品。 Biogen首席执行官Chris Viehbacher在电话会议上称Biogen为“Skyclarys的天然所有者”。分析师称，这种每日一次的口服药到2030年的销售潜力为15亿美元。 6. 礼来收购Versanis Bio 2023年7月，礼来宣布以19.25亿美元收购Versanis Bio。 Versanis的主要资产是bimagrumab，这是一种结合激活素II型A和B受体以阻断激活素和肌肉抑制素信号传导的单抗（ActRIIA/B）。bimagrumab的突出特点是减脂肪的同时保留肌肉质量，目前正在III期进行单药试验，并与司美格鲁肽联合，用于超重或肥胖的成年人。虽然已获批的替尔泊肽和司美格鲁肽在减轻肥胖或超重人群的体重方面创造了奇迹，但这些药物会导致肌肉流失，所以bimagrumab可以弥补其缺陷。 7. 诺华收购Chinook Therapeutics 2023年6月，诺华宣布达以35亿美元收购Chinook Therapeutics。 Chinook管线包括两项临床开发后期资产，用于治疗免疫球蛋白A肾病（IgAN）。其中，atrasentan是一种口服内皮素A受体拮抗剂（ERA），zigakibart（BION-1301）是一种皮下给药的抗APRIL单克隆抗体。诺华的押注得到了回报。2023年10月，一项为期36周的中期分析显示，蛋白尿（尿液中蛋白质，是肾脏疾病的征兆）在诺华III期研究的阿曲生坦组中比安慰剂队列中的改善明显更多。受此消息的鼓舞，诺华计划于2024年上半年在美国申请加速批准。 8. 罗氏收购Telavant 2023年10月，罗氏与Roivant Sciences子公司Telavant达成收购协议，以72.5亿美元获得Telavant在研核心产品TL1A抗体RVT-3101。 Telavant成立于2022年12月，由Roivant与辉瑞合作创办，专注于炎症和纤维化疾病，以TL1A定向抗体（称为RVT-3101）为中心。两家公司仅用了一个月的时间就公布了IIb期数据，显示RVT-3101在32%的炎症性肠病（IBD）患者中诱导缓解，而安慰剂组为12%。罗氏对这项收购感到满意，并公布了今年将RVT-3101投入III期试验的计划。 9. BMS收购RayzeBio 2023年12月，BMS以41亿美元收购了RayzeBio，进入放射性药物竞赛。 RayzeBio的主要候选药物RYZ101是一种锕系元素RPT，靶向体生长激素受体2（SSTR2）。RYZ101目前正在进行SSTR阳性GEP-NET患者的III期试验，以及ES-SCLC患者的Ib期试验，与标准疗法联合使用。此外，BMS还获得了RayzeBio在印第安纳波利斯的制造工厂。 10. 阿斯利康收购Fusion Pharmaceuticals BMS并不是唯一一家进军放射性药物的大型制药公司。2024年3月，阿斯利康24亿美元收购Fusion Pharmaceuticals。阿斯利康获得了Fusion开发的放射性偶联物管线，包括进展最快的项目FPI-2265，这是一种针对转移性去势耐受性癌症（mCRPC）患者的潜在新治疗方法。FPI-2265靶向前列腺特异性膜抗原（PSMA），这是一种在mCRPC中高度表达的蛋白质，目前正在进行II/III期试验。阿斯利康认为，FPI-2265有可能成为首个获批用于治疗镥转移后去势抵抗性前列腺癌的基于锕的PSMA靶向放射疗法。此外，Fusion已经在自己的工厂生产临床GMP剂量。阿斯利康肿瘤学研发执行副总裁Susan Galbraith表示，此次收购将“加速阿斯利康在三年以上内实现商业规模放射性药物生产能力的雄心，同时确保锕的供应”。参考资料 https://www.fiercebiotech.com/biotech/smartest-pharma-acquisitions Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

并购抗体药物偶联物财报放射疗法临床2期

2024-06-24

·BioSpace

5 FDA Decisions to Watch in the Second Half of 2024

Pictured: FDA headquarters with money and pill bottles/Taylor Tieden for BioSpace There has been no shortage of landmark approvals from the FDA this year. From the first tumor-infiltrating lymphocytes therapy to the first gene therapy for a rare pediatric disease to the first targeted therapy for MASH, 2024 has already seen its fair share. Along with being the first TIL therapy, Amtagvi is also the first one-time cell therapy for a solid tumor. Meanwhile, Orchard’s Lenmeldy offers a glimmer of hope to children with metachromatic leukodystrophy, a fatal genetic metabolic disease, and Rezdiffra is Madrigal’s first approved product. While the first half of the year belonged to cell and gene therapy, the second half is dominated by FDA decisions for other modalities in cancer and diseases of the brain. Here are five target action dates to watch for in the second half of 2024: Eli Lilly’s Donanemab Indication: Alzheimer’s disease PDUFA: Unknown Eli Lilly is one step closer to the long-anticipated decision on its Alzheimer’s therapy, donanemab, after an advisory committee voted unanimously in favor of the anti-amyloid antibody. In June, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee deemed donanemab to be an effective treatment for Alzheimer’s patients with mild cognitive impairment and mild dementia and said the benefits outweighed the risks. Donanemab has not had the smoothest regulatory path. The FDA refused accelerated approval for the candidate in January 2023, taking issue with a Phase II trial design that allowed patients to end treatment when amyloid plaques had been cleared past a certain pre-defined level. This meant that fewer than 100 patients were on donanemab for 12 continuous months, something the regulator requested in its Complete Response Letter. Lilly submitted for traditional approval of donanemab in the second quarter of 2023. In the Phase III TRAILBLAZER-ALZ 2 study, study participants with low-medium levels of tau saw their cognitive decline decrease by around 35% on two different clinical rating scales compared to placebo. Across all amyloid-positive early symptomatic participants, these numbers were 22% and 29%, respectively. If approved, donanemab will be a direct competitor of Biogen and Eisai’s Leqembi, which received the FDA’s full nod in July 2023. Adaptimmune’s afami-cel Indication: Advanced synovial sarcoma PDUFA: Aug. 4 Riding the momentum in the cell and gene therapy space, Adaptimmune is anticipating approval of its T cell therapy afami-cel on or before August 4. If approved, afami-cel would be the first engineered T cell therapy for solid tumors and “the first effective treatment option for synovial sarcoma in more than a decade,” according to Adaptimmune. Synovial sarcoma, which makes up 5% to 10% of soft tissue sarcomas, typically affects individuals under 30, with a five-year survival rate of 20% for metastatic cases. In the SPEARHEAD-1 trial, nearly 40% of patients experienced clinical responses, with a median response duration of around 12 months. Median overall survival was approximately 17 months, contrasting with historical data of less than 12 months for those who received two or more prior lines of therapy; 70% of responders to afami-cel were alive two years after treatment. If successful, afami-cel would be the first product in Adaptimmune’s sarcoma franchise. Lykos Therapeutics’ MDMA Indication: Post-traumatic stress disorder PDUFA: Aug. 11 One of the most-watched FDA decisions this summer, an approval for Lykos Therapeutics’ MDMA-assisted post-traumatic stress disorder (PTSD) therapy would be paradigm-changing. However, on June 4, an FDA advisory committee—the first held for a potential new PTSD treatment this century—voted overwhelmingly against such an approval. In a 10-1 tally, the FDA’s Psychopharmacologic Drugs Advisory Committee said the candidate’s potential benefits do not outweigh its risk, even with a strict risk evaluation and mitigation strategy. Seven out of nine external advisors voted that Lykos had not provided sufficient proof of MDMA’s efficacy in PTSD. A key issue highlighted in FDA briefing documents was that of “functional unblinding,” where “the vast majority” of trial participants were able to accurately guess their treatment assignment. Lykos is backing its New Drug Application with two pivotal Phase III studies, MAPP1 and MAPP2, in which the MDMA-assisted regimen “demonstrated clinically meaningful improvements in PTSD symptoms,” according to the company’s briefing documents. If ultimately approved, Lykos’s therapy would be the first psychedelic drug for a neuropsychiatric disease in the U.S. Bristol Myers Squibb’s KarXT Indication: Schizophrenia PDUFA: Sept. 26 By September 26, the FDA will render a decision on another highly anticipated neuropsychiatric treatment: Bristol Myers Squibb’s KarXT (xanomeline-trospium). BMS came into possession of KarXT following its December 2023 acquisition of Karuna Therapeutics. If approved, KarXT, an investigational muscarinic antipsychotic treatment, would represent the first new drug class for schizophrenia in “several decades,” according to a Karuna press release announcing acceptance of the NDA. Unlike existing schizophrenia treatments, KarXT does not directly block dopamine receptors. Instead, it works through the dual activation of the M1 and M4 muscarinic acetylcholine receptors in the central nervous system, a mechanism believed to improve positive, negative and cognitive symptoms in patients with schizophrenia. Combined data from three completed registrational and placebo-controlled trials show “statistically significant and clinically meaningful improvements,” Karuna reported in November. In April, BMS revealed interim data from a fourth study showing the drug can elicit significant and sustained symptom improvement in patients with schizophrenia. More than 75% of KarXT-treated patients saw at least a 30% improvement in symptoms at 52 weeks of follow-up, according to data presented at the Annual Congress of the Schizophrenia International Research Society 2024 conference. Daiichi Sankyo and AstraZeneca’s Dato-DXd Indication: Non-small cell lung cancer PDUFA: Dec. 20 Daiichi Sankyo and AstraZeneca are looking to add Dato-DXd (datopotamab deruxtecan) to a limited club—antibody drug conjugates (ADCs) approved to treat non-small cell lung cancer (NSCLC). The partners are specifically seeking approval for Dato-DXd to treat adults with locally advanced or metastatic nonsquamous NSCLC who have previously received systemic therapy. AstraZeneca and Daiichi Sankyo are backing the Biologics License Application with data from the Phase III Tropion-Lung01 study, in which Dato-DXd reduced the risk of disease progression or death by 25% compared to chemotherapy. Median progression-free survival was 4.4 months, and the overall response rate was confirmed in 26.4% of patients. In terms of overall survival, high-level results “numerically favored” DatoDXd in the overall trial population, but were not statistically significant, the companies reported in May. Clinically significant improvement was demonstrated in a prespecified subgroup of patients. “We’re very optimistic about this, and we think that [Dato-DXd] can be an important drug for non-squamous non-small cell lung cancer patients,” Mark Rutstein, SVP and head of global oncology clinical development at Daiichi Sankyo, told BioSpace in May. If approved, Dato-DXd could be the first TROP2-directed ADC for lung cancer. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

临床3期临床结果上市批准细胞疗法临床2期

100 项与曲司氯铵/呫诺美林相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
精神分裂症	申请上市	美国	Karuna Therapeutics, Inc.	2023-09-28
阿尔茨海默症	临床3期	中国	Karuna Therapeutics, Inc.	2023-06-23
阿尔茨海默症	临床3期	比利时	Karuna Therapeutics, Inc.	2023-06-23
阿尔茨海默症	临床3期	加拿大	Karuna Therapeutics, Inc.	2023-06-23
阿尔茨海默症	临床3期	智利	Karuna Therapeutics, Inc.	2023-06-23
阿尔茨海默症	临床3期	希腊	Karuna Therapeutics, Inc.	2023-06-23
阿尔茨海默症	临床3期	匈牙利	Karuna Therapeutics, Inc.	2023-06-23
阿尔茨海默症	临床3期	墨西哥	Karuna Therapeutics, Inc.	2023-06-23
阿尔茨海默症	临床3期	秘鲁	Karuna Therapeutics, Inc.	2023-06-23
阿尔茨海默症	临床3期	波兰	Karuna Therapeutics, Inc.	2023-06-23

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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


NCT05643170 (CTgov)	临床3期	精神分裂症	4	Trospium Chloride Capsules	鏇鹽鏇鑰積築壓壓廠蓋(遞鏇構鑰艱獵築顧齋糧) = 製壓蓋襯願淵醖齋壓鬱鏇廠鏇鹽餘構憲觸艱窪 (廠壓鬱鹽壓簾艱觸鏇積, 構簾鹽鑰糧鏇衊獵淵窪 ~ 繭糧顧築獵窪鹹網簾鬱) 更多	-	2024-06-12
NCT04659174 (EMERGENT-4, Corporate Publications) 人工标引	临床3期	精神分裂症	110	KarXT	顧廠餘積鹹憲繭鹽衊顧(齋鬱窪鹽衊願糧構窪構) = 蓋鹽範顧鑰廠蓋鏇鹽齋衊積壓糧選淵製窪壓淵 (憲襯鹽觸網築鬱願鏇製 ) 更多	积极	2024-04-06
NCT04659174 \| NCT04820309 (EMERGENT-5, Corporate Publications) 人工标引	临床3期	精神分裂症	718	KarXT	窪糧鹽襯鹽鹹艱糧繭鬱(夢膚艱淵鹽獵網醖壓積) = 62% of participants reported at least one. The most common treatment-related adverse events (≥5%) were nausea, vomiting, constipation, dry mouth, dyspepsia, dizziness, hypertension, and diarrhea, of which nearly all were mild or moderate in severity and transient in nature. 遞鏇壓鑰網獵遞製鑰觸 (獵獵鏇構簾襯艱鏇廠築 ) 更多	积极	2024-04-06
EMERGENT-3 (NEWS) 人工标引	临床阶段不明	精神分裂症	314	KarXT (EMERGENT-1)	廠鑰獵淵獵餘襯廠膚憲(築衊繭廠蓋淵壓遞遞蓋) = 構鬱憲餘顧膚艱構廠憲構夢餘淵簾觸襯窪範選 (鏇淵顧鹽鬱鹽製襯醖淵 ) 更多	积极	2024-01-08
				placebo (EMERGENT-1)	廠鑰獵淵獵餘襯廠膚憲(築衊繭廠蓋淵壓遞遞蓋) = 醖醖繭廠廠構獵齋鏇鏇構夢餘淵簾觸襯窪範選 (鏇淵顧鹽鬱鹽製襯醖淵 ) 更多
NCT04659161 (EMERGENT-2, Pubmed \| Lancet)	临床3期	精神分裂症	252	KarXT	繭遞糧網願選憲網構鬱(積壓獵鑰糧膚範鏇糧積) = 範顧廠膚觸鑰膚窪遞壓鹽簾鹹鹹築製鬱齋衊鹽 (簾鑰觸網淵蓋憲糧製構 ) 更多	积极	2024-01-01
				Placebo	繭遞糧網願選憲網構鬱(積壓獵鑰糧膚範鏇糧積) = 艱窪廠憲淵繭網鬱顧廠鹽簾鹹鹹築製鬱齋衊鹽 (簾鑰觸網淵蓋憲糧製構 ) 更多
NCT04659161 (EMERGENT-2, Corporate Publications) 人工标引	临床3期	精神分裂症	252	KarXT	遞簾廠鬱衊繭積憲醖獵(膚淵觸鬱願憲遞鹽觸築) = 窪鬱壓鏇膚膚選齋積簾廠壓齋鹽鏇壓遞鹹膚鬱 (衊遞範築憲繭窪願獵願 ) 更多	积极	2023-12-14
				Placebo	遞簾廠鬱衊繭積憲醖獵(膚淵觸鬱願憲遞鹽觸築) = 衊壓鑰獵鑰餘壓糧齋醖廠壓齋鹽鏇壓遞鹹膚鬱 (衊遞範築憲繭窪願獵願 ) 更多
NCT04659161 (CTgov)	临床3期	精神障碍 \| 精神分裂症	252	Trospium Chloride Capsules (KarXT)	夢選鹽鹹鹹觸膚願顧糧(醖衊齋餘獵襯積醖獵廠) = 鹹艱觸選齋顧願鹽簾鏇壓鏇獵膚壓憲蓋膚艱觸 (蓋積憲範憲鹹觸壓觸製, 鬱艱構糧獵夢製窪鑰願 ~ 構遞顧構顧願鏇窪餘網) 更多	-	2023-12-12
				Placebo (Placebo)	夢選鹽鹹鹹觸膚願顧糧(醖衊齋餘獵襯積醖獵廠) = 鹽鹹鑰蓋襯觸獵簾襯膚壓鏇獵膚壓憲蓋膚艱觸 (蓋積憲範憲鹹觸壓觸製, 廠顧膚廠廠夢繭淵膚遞 ~ 顧鬱積遞網積廠膚築衊) 更多
Corporate Publications 人工标引	临床1期	精神分裂症	133	KarXT	製願築觸齋鹹製襯鏇壓(鹽願夢獵遞醖鹹鹽鹽顧) = 壓憲醖衊鹹廠網壓鏇膚鏇顧鏇淵鏇選糧鹽鑰夢 (顧壓艱鏇範構築壓鹹製 )	积极	2023-11-16
NCT04659161 (EMERGENT-2, Corporate Publications) 人工标引	临床3期	精神分裂症	252	KarXT	醖構鹹願襯鑰願鬱構蓋(餘鏇襯範蓋構製鏇衊鏇) = 簾觸鏇廠簾壓鬱衊糧繭製製顧艱構壓願遞餘築 (觸築範蓋鹹鬱膚簾鹹製 ) 更多	积极	2022-08-08
				Placebo	醖構鹹願襯鑰願鬱構蓋(餘鏇襯範蓋構製鏇衊鏇) = 製鬱繭廠窪遞廠繭憲遞製製顧艱構壓願遞餘築 (觸築範蓋鹹鬱膚簾鹹製 ) 更多
NCT03697252 (EMERGENT-1, Pubmed \| Br Dent J) 人工标引	临床2期	精神分裂症	182	xanomeline	鹽顧繭壓製網繭觸觸衊(衊鏇壓窪遞願糧衊遞齋) = 廠膚壓願築網艱糧範廠鏇鏇網遞夢憲鹹衊醖壓 (製膚醖願鑰夢鑰築築鬱 )	积极	2021-02-25
				Placebo	鹽顧繭壓製網繭觸觸衊(衊鏇壓窪遞願糧衊遞齋) = 築糧遞蓋網獵觸願築簾鏇鏇網遞夢憲鹹衊醖壓 (製膚醖願鑰夢鑰築築鬱 )