A Multicenter Phase 2, 12-week Double-blind, Placebo-controlled, Randomized, Parallel-group Study of JZP150 for the Treatment of Posttraumatic Stress Disorder

This is a 12-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter study of the safety and efficacy of JZP150 in the treatment of adult participants with post-traumatic stress disorder (PTSD).

开始日期2021-12-29

申办/合作机构

Jazz Pharmaceuticals, Inc.

NCT03386487 / Completed临床2期IIT

A Phase 2B, 8-week, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Evaluate Efficacy, Safety and Tolerability of the Fatty Acid Amide Hydrolase (FAAH) Inhibitor PF-04457845 in Adults With DSM5 Current Cannabis Use Disorder (CUD)

A Phase 2B, 8-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy, Safety and Tolerability of the Fatty Acid Amide Hydrolase (FAAH) Inhibitor PF-04457845 in Adults with DSM-5 Current Cannabis Use Disorder (CUD)

开始日期2019-01-14

申办/合作机构

Yale University

[+4]

NCT02216097 / Terminated临床2期

A Randomized, Double Blind, Placebo Controlled, Parallel Group Phase 2 Study To Assess Effects Of Pf 04457845 On Bold Functional Mri In Subjects With Ptsd

The purpose of the study is to evaluate proof of mechanism of PF-04457845, using a well-established neuroimaging paradigm including behavioral tasks selected to activate neuro-circuitry relevant to Post Traumatic Stress Disorder. It is hypothesized that PF-04457845 will modulate the Blood-oxygen-level dependent Functional Magnetic Resonance Imaging signal from the relevant neuro-circuits in patients with Post Traumatic Stress Disorder.

开始日期2014-10-01

申办/合作机构

Pfizer Inc.

100 项与 JZP150 相关的临床结果

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100 项与 JZP150 相关的转化医学

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100 项与 JZP150 相关的专利（医药）

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项与 JZP150 相关的文献（医药）

2024-02-01·Drugs

A Neuroanatomic and Pathophysiologic Framework for Novel Pharmacological Approaches to the Treatment of Post-traumatic Stress Disorder

Review

作者: Zuschlag, Zachary D ; Norred, Michael A ; Hamner, Mark B

Post-traumatic stress disorder (PTSD) is a debilitating disorder inflicting high degrees of symptomatic and socioeconomic burdens. The development of PTSD results from a cascade of events with contributions from multiple processes and the underlying pathophysiology is complex, involving neurotransmitters, neurocircuitry, and neuroanatomical pathways. Presently, only two medications are US FDA-approved for the treatment of PTSD, both selective serotonin reuptake inhibitors (SSRIs). However, the complex underlying pathophysiology suggests a number of alternative pathways and mechanisms that may be targets for potential drug development. Indeed, investigations and drug development are proceeding in a number of these alternative, non-serotonergic pathways in an effort to improve the management of PTSD. In this manuscript, the authors introduce novel and emerging treatments for PTSD, including drugs in various stages of development and clinical testing (BI 1358894, BNC-210, PRAX-114, JZP-150, LU AG06466, NYV-783, PH-94B, SRX246, TNX-102), established agents and known compounds being investigated for their utility in PTSD (brexpiprazole, cannabidiol, doxasoin, ganaxolone, intranasal neuropeptide Y, intranasal oxytocin, tianeptine oxalate, verucerfont), and emerging psychedelic interventions (ketamine, MDMA-assisted psychotherapy, psilocybin-assisted psychotherapy), with an aim to examine and integrate these agents into the underlying pathophysiological frameworks of trauma-related disorders.

2023-04-01·Molecular Pharmacology

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Article

作者: Lichtman, Aron H ; Gewirtz, David A ; Wang, Weili ; Em, Brandon ; Raymond, Marissa ; Poklis, Justin L ; Li, Ningjun ; Chen, Chaoling ; Ahmadinejad, Fereshteh

Cisplatin is a potent first-line therapy for many solid malignancies, such as breast, ovarian, lung, testicular, and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits anti-inflammatory effects; however, little is known about its role in cisplatin nephrotoxicity. The current study tested the hypothesis that genetic deletion of Faah mitigates cisplatin-induced AKI. Male wild-type C57BL6 (WT) and Faah^-/- mice were administered a single dose of intraperitoneal injection of cisplatin (30 mg/kg) and euthanatized 72 hours later. Faah^-/- mice showed a reduction of cisplatin-induced blood urea nitrogen, plasma creatinine levels, kidney injury markers, and tubular damage in comparison with WT mice. The renal protection from Faah deletion was associated with enhanced tone of AEA-related N-acylethanolamines (palmitoylethanolamide and oleoylethanolamide), attenuated nuclear factor-κB/p65 activity, DNA damage markers p53 and p21, and decreased expression of the inflammatory cytokine interleukin-1β, as well as infiltration of macrophages and leukocytes in the kidneys. Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Our work highlights that FAAH inactivation prevents cisplatin-induced nephrotoxicity in mice and that targeting FAAH could provide a novel strategy to mitigate cisplatin-induced nephrotoxicity. SIGNIFICANCE STATEMENT: Mice lacking the Faah gene are protected from cisplatin-induced inflammation, DNA damage response, tubular damage, and kidney dysfunction. Inactivation of FAAH could be a potential strategy to mitigate cisplatin-induced nephrotoxicity.

2023-01-01·Cell Death & Differentiation

FAAH served a key membrane-anchoring and stabilizing role for NLRP3 protein independently of the endocannabinoid system

Article

作者: Zhang, Wenbin ; Yang, Zhenyu ; Zhang, Hao ; Xu, Youcui ; Chen, Sirong ; Mao, Huawei ; Wang, Meimei ; Zhang, Yue ; Song, Yang ; Meng, Guangxun ; Zhang, Yunjiao ; Qin, Xiaohua ; Hao, Xiaohan ; Shen, Jiani ; Zhao, Zhibin ; Huang, Xiaowan ; Wen, Longping ; Li, Juan ; Yan, Kai ; Wang, Liansheng ; Zhu, Yangyang ; Zhong, Suqin ; Yao, Han ; Ye, Zhiming ; Huang, Yubing

NLRP3, the sensor protein of the NLRP3 inflammasome, plays central roles in innate immunity. Over-activation of NLRP3 inflammasome contributes to the pathogenesis of a variety of inflammatory diseases, while gain-of-function mutations of NLRP3 cause cryopyrin-associated periodic syndromes (CAPS). NLRP3 inhibitors, particularly those that inhibit inflammasome assembly and activation, are being intensively pursued, but alternative approaches for targeting NLRP3 would be highly desirable. During priming NLRP3 protein is synthesized on demand and becomes attached to the membranes of ER and mitochondria. Here, we show that fatty acid amide hydrolase (FAAH), the key integral membrane enzyme in the endocannabinoid system, unexpectedly served the critical membrane-anchoring and stabilizing role for NLRP3. The specific interaction between NLRP3 and FAAH, mediated by the NACHT and LRR domains of NLRP3 and the amidase signature sequence of FAAH, was essential for preventing CHIP- and NBR1-mediated selective autophagy of NLRP3. Heterozygous knockout of FAAH, resulting in ~50% reduction in both FAAH and NLRP3 expression, was sufficient to substantially inhibit the auto-inflammatory phenotypes of the NLRP3-R258W knock-in mice, while homozygous FAAH loss almost completely abrogates these phenotypes. Interestingly, select FAAH inhibitors, in particular URB597 and PF-04457845, disrupted NLRP3-FAAH interaction and induced autophagic NLRP3 degradation, leading to diminished inflammasome activation in mouse macrophage cells as well as in peripheral blood mononuclear cells isolated from CAPS patients. Our results unraveled a novel NLRP3-stabilizing mechanism and pinpointed NLRP3-FAAH interaction as a potential drug target for CAPS and other NLRP3-driven diseases.

项与 JZP150 相关的新闻（医药）

2024-05-10

·药融圈

阴差阳错！分离自辉瑞孤儿药公司，明星小分子获批，市值超31亿美金

▲5月30-31日第八届广州生物医药创新者峰会扫码立即报名注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。罕见肿瘤新药获批，获NCCN指南1类推荐药融云数据www.pharnexcloud.com显示，2023年11月27日，美国FDA正式批准Ogsiveo（Nirogacestat）片剂用于治疗需要全身治疗的进展性硬纤维瘤成人患者。该药是FDA批准的首个也是唯一一个硬纤维瘤治疗药物，也是FDA批准的首个罕见非癌性肿瘤治疗药物。截图自FDA官网硬纤维瘤（DT）又称为侵袭性纤维瘤病，是一种罕见的软组织肉瘤亚型，是非癌性的，但可具有局部侵袭性。虽然硬纤维瘤并非癌症，但会像癌症一样生长到附近的结构和器官中，因此，硬纤维瘤患者通常由癌症医生负责治疗。该病的特征是非癌性软组织生长，通常导致严重的疼痛、影响运动能力、生活质量降低以及毁容。虽然手术切除历来是该病的首选治疗方案，但肿瘤复发风险（高达77%）或其他健康风险依然很高。Ogsiveo（Nirogacestat）的有效性已在一项国际、多中心、随机、双盲、安慰剂对照的临床试验中进行了评估，该研究包括了142例不适合手术的进行性硬纤维瘤患者。结果表明，与安慰剂相比，Ogsiveo在无进展生存期方面提供了具有临床意义和统计学意义的改善，疾病进展风险降低了71%。同时，Ogsiveo组的客观缓解率为41%，安慰剂组为8%，具有统计学差异。Ogsiveo组患者报告的疼痛评估也支持了无进展生存期的改善。药融云数据www.pharnexcloud.com显示，Ogsiveo（Nirogacestat）此前被FDA授予优先审评资格、突破性疗法认定、快速通道资格，以及孤儿药资格认定，用于治疗硬纤维瘤（侵袭性纤维瘤病）。截图自药融云数据库Ogsiveo（Nirogacestat）是一种新型口服选择性小分子γ分泌酶抑制剂，γ分泌酶是一种蛋白酶复合物，可切割多种跨膜蛋白，包括Notch蛋白，而Notch蛋白被认为能够激活导致硬纤维瘤生长的信号通路。据了解，Nirogacestat入围了Drug Hunter 2023年度十大小分子药物榜单。来源：Drug Hunter在Ogsiveo（Nirogacestat）获批两周之内，2023年12月，美国NCCN肿瘤临床实践指南更新，Nirogacestat获NCCN指南1类推荐，作为硬纤维瘤的首选治疗方案。除了在美国推出以外，2024年2月，欧洲药品管理局（EMA）验证了Nirogacestat的上市许可申请（MAA），并开始了集中审查程序。从辉瑞分离的公司，新药“身世曲折”Ogsiveo（Nirogacestat）是美国制药公司SpringWorks Therapeutics(NASDAQ:SWTX)的第一个商业化产品，最初SpringWorks是辉瑞设想的一家独立公司，该公司设立的目标是在患者迫切需要的治疗领域推进有前景的研究性治疗药物。据报道，Nirogacestat（PF-03084014）一开始是辉瑞为阿尔兹海默症开发的药物，2006年启动1期临床，但在2009年停止阿尔兹海默症临床研究。而在肿瘤领域，Nirogacestat最先也是针对乳腺癌开发，但当时在美国国家癌症研究所（National Cancer Institute）领导早期临床试验开发的Shivaani Kummar博士从1期篮式实体瘤试验中看到了该药物在硬纤维瘤患者中的阳性反应。Shivaani Kummar博士2014年，Kummar博士领导了一项在进展性硬纤维瘤成人患者中开展的开放标签2期试验，并受到了硬纤维瘤肿瘤研究基金会的帮助，在不到6个月的时间里招募了17名患者。2017年9月，SpringWorks正式推出，获得了来自贝恩资本生命科学、Bain Capital Double Impact、奥博资本、辉瑞、LifeArc（原英国MRC Technology）的1.03亿美元的A轮融资，并从辉瑞引进了包括Nirogacestat在内的共4种临床阶段项目资产。融资历程截图自药融云数据库辉瑞制药将SpringWorks Therapeutics视为一种开创性的合作新模式，旨在通过与各种利益相关者（包括科学家、生物制药合作伙伴、患者团体、资助者和慈善家）的合作，提供社会和财务回报。当时辉瑞的全球研发战略和产品组合解决方案副总裁Lara Sullivan博士是SpringWorks的创始人兼总裁，前辉瑞执行副总裁兼首席医学官Freda Lewis-Hall博士加入SpringWorks的董事会。在SpringWorks Therapeutics的首款产品Ogsiveo（Nirogacestat）获批之后，四周之内，该药卖出了540万美元。同时，SpringWorks还推出了CareConnections™患者支持计划，为符合条件的患者提供全面的个性化服务。研发进展SpringWorks Therapeutics目前拥有差异化、靶向肿瘤的小分子资产组合，研发管线主要聚焦于罕见肿瘤类型和高度流行的、基因驱动的肿瘤。除了全资项目外，SpringWorks还与工业界和学术界的创新者进行合作，以释放产品潜力。更新截至2024年2月·γ分泌酶抑制剂Nirogacestat：潜在BCMA靶向药物增强剂Ogsiveo（Nirogacestat）获批治疗进展性硬纤维瘤成人患者的同时，小儿适应症的研究也在进行。目前，Nirogacestat用于治疗小儿硬纤维瘤的研究处于2期临床阶段。作为一种新型口服选择性小分子γ分泌酶抑制剂，Nirogacestat有治疗多种疾病的潜力。除了硬纤维瘤，Nirogacestat针对卵巢颗粒细胞瘤正在开展一项2期试验，2023年5月完成患者入组，预计将在2024年下半年报告该研究的初步数据。由于γ分泌酶能够直接切割细胞膜上的BCMA（B细胞成熟抗原），而BCMA是经临床验证的多发性骨髓瘤治疗靶点（包括ADC药物、CAR-T疗法、单克隆抗体、双特异性药物）。因此γ分泌酶的抑制剂已被证明能够增加多发性骨髓瘤细胞上BCMA的表达，从而有望在临床上增强BCMA靶向治疗的效果，提高应答率、延长临床获益的持续时间或通过低剂量给药减少副作用。SpringWorks正与多个合作伙伴共同研究Nirogacestat与BCMA靶向药物联用治疗多发性骨髓瘤的潜力，包括葛兰素史克（与BCMA靶向ADC药物Belamaf联用）、再生元（与靶向BCMA/CD3双抗Linvoseltamab联用）、强生（与靶向BCMA/CD3双抗Teclistamab联用）、辉瑞（与靶向BCMA/CD3双抗Elranatamab联用）、Seagen（与靶向BCMA单抗SEA-BCMA联用）、艾伯维（与靶向BCMA/CD3双抗ABBV-383联用）。·MEK抑制剂Mirdametinib：潜在best in class罕见肿瘤药物Mirdametinib（PD-0325901，也是来自辉瑞）是一种口服变构MEK1/2（丝裂原活化的细胞外信号调节激酶1和2）小分子抑制剂。MEK蛋白在MAPK（丝裂原活化蛋白激酶）通路中占据着关键位置，MAPK通路是调节细胞生长和存活的关键信号网络，在多种肿瘤和罕见疾病中起着核心作用。SpringWorks正在研究将Mirdametinib用于治疗1型神经纤维瘤相关丛状神经纤维瘤（NF1-PN）。NF1-PN是一种罕见的疾病，由NF1基因的突变引起，其特征是MAPK通路畸变，引起周围神经鞘肿瘤的生长，从而导致明显的疼痛、毁容，极少数情况下是致命的。目前尚无药物获批治疗NF1-PN。药融云数据www.pharnexcloud.com显示，Mirdametinib此前已获得孤儿药资格认定、快速通道资格，以及罕见儿科疾病用药资格认定，用于治疗NF1-PN。截图自药融云数据库2023年11月16日，SpringWorks宣布了Mirdametinib在成人和儿童NF1-PN患者中关键2b期ReNeu试验的阳性结果。结果显示，儿童患者的确认客观缓解率为52%，成人患者的确认客观缓解率为41%；在儿童与成人患者队列中，靶肿瘤体积相对于基线的最佳百分比变化中位数分别为-42%和-41%。通过多个患者报告结果（PRO）工具的评估，在ReNeu试验中，儿童和成人患者在疼痛、生活质量和身体功能方面也经历了统计学上的显著改善。基于这些结果，SpringWorks认为Mirdametinib有望成为治疗儿童和成人NF1-PN的潜在best in class治疗方案。2024年3月4日，SpringWorks宣布已向美国FDA滚动递交Mirdametinib的NDA申请，用于治疗NF1-PN儿童和成人患者。此外，SpringWorks正在评估Mirdametinib单药治疗或采用联合疗法，用于治疗MAPK信号通路基因相关实体肿瘤。例如，该公司正与百济神州合作研究Mirdametinib与RAF二聚体抑制剂Lifirafenib（BGB-283）联用治疗携带NRAS突变的晚期或难治性实体肿瘤患者（双方在2018年8月建立合作）；Mirdametinib治疗儿童和青年成人低级别胶质瘤患者的研究正在由圣犹大儿童研究医院进行1/2期临床试验。·RAF抑制剂：来自百济神州合资公司2019年，SpringWorks与百济神州成立合资企业MapKure，以开发一种由百济神州科学家发现的在研高选择性新一代口服小分子RAF激酶抑制剂Brimarafenib（BGB-3245）。MapKure正在推进Brimarafenib用于BRAF驱动突变和BRAF融合的实体瘤，这些患者在临床前研究中被观察到对该化合物敏感。MapKure、百济神州与SpringWorks正在开展一项1期临床研究，评估Brimarafenib在MAPK通路畸变的晚期或难治性实体瘤患者中的疗效，预计将在2024年下半年分享最新的数据。2023年2月，SpringWorks在一项1/2a期开放标签、剂量递增和扩展试验中完成首例患者给药，该试验旨在评估Brimarafenib（BGB-3245）联合MEK1/2抑制剂Mirdametinib治疗携带MAPK激活突变的晚期实体肿瘤患者的潜力，目前正在美国和澳大利亚招募患者。2023年8月，MapKure递交了Brimarafenib与靶向EGFR的单克隆抗体帕尼单抗联用，治疗已知MAPK通路畸变的结肠直肠和胰腺癌患者的IND申请，MapKure预计将在2024年第一季度启动1b期试验。·TEAD抑制剂早期研究项目SW-682是一种口服小分子TEAD（转录增强缔合域）抑制剂，由SpringWorks于2021年从鲁汶大学和弗兰德斯生物技术研究所获得全球独家许可，目前正在评估用于治疗Hippo河马信号通路突变的实体瘤。2024年第一季度，FDA批准了SW-682的临床试验申请，公司预计在2024年上半年启动1a期临床试验。·EGFR抑制剂项目2021年10月，SpringWorks宣布与达纳-法伯癌症研究所签订全球独家许可协议，据此引进了一种新型小分子EGFR抑制剂，用于治疗EGFR突变肺癌。与此同时，SpringWorks与斯坦福医学院签订了一项为期多年的研究赞助协议，以资助斯坦福医学实验室以及达纳-法伯合作实验室的研究和开发工作。该项目中的领先资产最快已进入先导化合物优化阶段，针对C797S耐药突变。·两度转手的FAAH抑制剂，现终止研发2020年10月，爵士制药以3500万美元预付款从SpringWorks引进了一款脂肪酸酰胺水解酶（FAAH）抑制剂PF-04457845（后称JZP150），用于治疗创伤后应激障碍（PTSD）及相关症状。该产品由辉瑞于2017年许可给SpringWorks。2023年12月，爵士制药宣布了其JZP150治疗PTSD的2期临床试验的初步结果。该试验没有达到其主要或次要终点。爵士制药预计将不再推进JZP150用于PTSD的进一步研究。（相关阅读：收购医药大麻第一品牌，爵士制药肿瘤与CNS双管齐下）截图自药融云数据库财务状况自2017年成立以来，SpringWorks将资源投入于候选产品研发、执行业务发展战略、建立知识产权组合、组织和配备公司、建设商业化能力、商业规划、筹集资金和提供销售，以及一般和行政支持。截至2023年底，SpringWorks拥有现金、现金等价物和有价证券共6.626亿美元。成立至今公司累计赤字为8.95亿美元。2024年12月，SpringWorks Therapeutics的首款产品Ogsiveo（Nirogacestat）在美国正式开始销售，为2024财年贡献了544.7万美元业绩收入。2023全年，SpringWorks公司研发费用为1.505亿美元，与上年同期相比持平；全年销售、一般和行政费用为1.976亿美元，同比增长47%，主要归因于支持美国市场推出Ogsiveo（Nirogacestat）的商业准备活动；年度净亏损为3.251亿美元，或每股亏损5.15美元。具体项目研发支出：截至2024年5月8日，SpringWorks Therapeutics（NASDAQ:SWTX）总市值为31.31亿美元。此文仅用于向医疗卫生专业人士提供科学信息，不代表平台立场，不作任何用药推荐参考：NMPA/CDE；药融云数据www.pharnexcloud.com；FDA/EMA/PMDA；相关公司公开披露（正文图片均来自企业官方，除非另有说明）；https://springworkstx.com/pipeline/；https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-type-non-cancerous-tumors；https://drughunter.com/molecule/nirogacestat/；https://www.fiercepharma.com/pharma/fda-approves-pfizer-spinout-springworks-ogsiveo-first-treatment-disfiguring-rare-tumor-type；https://www.prnasia.com/story/221878-1.shtml；https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-provides-update-phase-2-trial；等等活动推荐 5月 • 第八届大湾区生物医药创新者峰会关键词：小分子，XDC，多肽及GLP-1热点话题，80+行业专家（点击下方图片查看详情）▼【关于药融圈】药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。

孤儿药优先审批突破性疗法上市批准快速通道

2024-03-12

·BioSpace

Alkermes and Jazz: Two Different Approaches to Neuroscience, Oncology Portfolios

Pictured: A fork in a dirt road/iStock, by-studio Dublin-based Alkermes is one of the industry’s most recent examples of a global biopharma spinning off a business as part of its strategy to generate profitability and cash flow. Alkermes entered 2024 as a pure-play neuroscience company focused on difficult-to-treat psychiatric and neurological disorders, having completed the separation of its oncology business into a new company, Mural Oncology, in November 2023. Founded in 1987, Alkermes decided a couple of years ago to “clean up and clarify” the company’s business for investors, CEO Richard Pops told BioSpace. “Alkermes has always been so multivalent, so complicated. We had a legacy drug delivery royalty business—with large cash flows coming from that. We had a neuroscience business, a commercial business. We had an oncology business. And we didn’t fit in a particular category,” Pops said. The CEO compared Alkermes’ evolution over the years to a tree with two trunks: neuroscience and oncology. “When you plant the tree and it’s growing, for a while it’s no problem. But pretty soon they get big, and you’ve got to decide how you’re going to support both of them,” Pops said. Spinning off Alkermes’ oncology business by creating Mural Oncology, a public company, was a big undertaking given the IRS and SEC regulations, Pops said, but the cancer business deserved its own capital, instead of sharing with the neuroscience arm of the business. Moreover, Alkermes now has “a really clear story,” Pops said. “It’s a pure-play neuroscience company that has a billion dollars of revenue and growing.” It’s important to have that division for oncology-focused investors and analysts and those following the neuroscience market, he said. Jazz Pharmaceuticals, on the other hand, has opted not to divorce its neuroscience and oncology pipelines. Bruce Cozadd, co-founder and CEO, told BioSpace that the Dublin-based company has been in the neuroscience space since its founding in 2003, only beginning to target oncology nine years later. Today, about half of Jazz’s revenues currently come from its oncology portfolio. “Both of those businesses are growing and have robust pipelines,” Cozadd said. He added that while he’s aware of companies like Alkermes that have separated their neuroscience and oncology businesses, Jazz was not considering such a move. Cozadd pointed to his company’s financial strength as one reason for that decision. Jazz reported late last month that its oncology revenue surpassed $1 billion in 2023, while total neuroscience revenue came in at $2.8 billion. By comparison, Alkermes last month announced total 2023 revenues of $1.66 billion. As of Dec. 31, 2023, Jazz had $1.6 billion in cash, cash equivalents and investments, while Alkermes reported about half that. “We’re in the fortunate position that we can fund our key growth drivers commercially . . . while at the same time making pipeline investments,” Cozadd said. To expand its early-stage oncology pipeline, Jazz last month bought Redx Pharma’s KRAS inhibitor program in a potential $880 million deal, including preclinical-stage drug candidates, with the companies working to advance assets through IND-enabling studies. However, it hasn’t been smooth sailing for Jazz’s neuroscience business. In December 2023, Jazz reported top-line Phase II results for JZP150—a small molecule being studied in patients with post-traumatic stress disorder—showing that the investigational candidate fell short of its primary efficacy endpoint and failed to meet key secondary endpoints. “We’re not in both oncology and neuroscience because of some mechanistic scientific medical reason,” Cozadd said. “We’re in these two areas because we look for areas where there’s significant unmet medical need and we can offer a differentiated product that really benefits patients in a unique way.” While Jazz’s neuroscience portfolio currently generates more revenue than its oncology business, the nearer term “larger” potential opportunities are in the oncology pipeline, according to Cozadd. “We don’t have a particular goal of a ratio,” he added. “I’d like both of them to be as big as possible.” Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

并购临床2期临床结果

2023-12-23

·生物制药小编

被两度转手的弃子管线，最终停止开发

近日（12月21日），爵士制药（Jazz Pharmaceuticals）宣布了该公司的PTSD（创伤后应激障碍）药物JZP150的II期临床数据，该实验未达所有主要终点和次要终点，这也宣告了这项曾被两度转手的产品最终停止了在PTSD这一唯一适应症的开发。从药品本身来看，JZP150（又名PF-04457845）是一款脂肪酸酰胺水解酶（FAAH）抑制剂，用于潜在治疗PTSD及相关症状。这款产品最初由辉瑞开发，后来又在2017年被辉瑞许可给了SpringWorks Therapeutics，而爵士制药最终又在2020年向SpringWorks购得该产品的独家全球权利。那么FAAH抑制剂本身靠谱吗？还确实有点不靠谱。爵士制药是一家大麻素科学相关的制药企业，许多产品和管线都与大麻素相关，而此次FAAH抑制剂的作用机理确实和大麻素相关。一例FAAH抑制剂致人脑死亡脂肪酸酰胺水解酶是一种完整的膜酶，它可以水解脂质递质的脂肪酰胺家族，包括研究最彻底的内源性大麻素，但也有很多其他受体也参与这一路径如PPARs，TRPV1，GPR55。从机制上来看，FAAH抑制剂/灭活剂能够增加内源性大麻素的浓度。而内源性大麻素是膜磷脂前体按需释放的脂质介质。内源性大麻素的增加相对于外源性激动剂来说会减少大麻素样的副作用。而从FAAH抑制剂的普遍性疗效来看，其实相对于那些外源性大麻素的效果还是相当不错的。在对于那些FAAH抑制剂，如JZP150（PF-04457845）、JNJ-42165279、SSR-411298、V-158866和URB597，来说，虽然长期结果尚且未知，但普遍观察结果是FAAH抑制剂并没有明显诱发通常与外源性大麻素相关的副作用，如认知障碍、运动协调和精神病。已完成的临床试验的可用数据还表明，FAAH抑制剂耐受性良好。JZP150（当时还是辉瑞在推动临床）的一项I期研究表明，与安慰剂相比，嗜睡的增加只是轻微的，对认知功能没有影响。相应的II期研究表明，该药物的安全性与安慰剂没有区别，其主要治疗相关副作用为头晕。但就在大家都以为副作用似乎不是很严重的时候，法国Biotrial Pharmacology Center开发的同类竞品BIA 10-2474在一项临床研究中出现了一例严重不良事件（SAE），一位志愿者之前服用较低剂量(20 mg)时未报告SAE。最严重的症状具有中枢神经系统特征的，可之后却出现迅速导致脑死亡的单一昏迷病例相关的症状。在其他5名住院参与者中，2名有严重的神经损伤(几天内临床症状明显改善)。由于这些事件，BIA 10-2474的临床立即终止。在Biotrial事故宣布后，作为预防措施，JNJ-42165279的两个试验也被暂停。辉瑞也在临床没什么成效（当时开发的是骨关节镇痛）后转手了给了SpringWorks。不明来源的发病机制法国国家药品和保健品安全局（ANSM）后续对于BIA 10-2474的报告还揭露了一些令人不安的事实：他们的简报提到了与大脑功能严格相关的症状，核磁共振成像观察显示存在“不同严重程度的微脑组织损伤和不同寻常的扫描断层”，而且这种损伤似乎还是因人而异的，有着“突然就出现”的特征。但是这种现象为什么会出现？这个问题并没有答案，也没人愿意或者再敢去回答，有些人认为可能是由与其他药理学靶点的相互作用引起的，或者是仅在超过特定浓度阈值时才变得重要，还有些人认为因为阻断了FAAH触发了人体内未知的替代补偿途径，但是也不知道人体内到底有什么触发的替代补偿途径。ANSM至少排除了制造相关问题，在临床前研究似乎也没什么问题，FAAH缺陷型小鼠(基因敲除)生长健壮，没有表现出异常行为症状，这支持了BIA 10-2474本身或其代谢产物而不是FAAH的抑制是不良反应原因的假设。总结很显然，因为人体机制可能存在的未接明机制使得HAAP复杂化，也没有太多人愿意冒着生命风险试探不可预知的风险，因此JZP150这一类的FAAH抑制剂的开发未来可能仍然存在许多问题，还需要很多基础研究。参考来源：Mallet C, Dubray C, Dualé C. FAAH inhibitors in the limelight, but regrettably. Int J Clin Pharmacol Ther. 2016 Jul;54(7):498-501. doi: 10.5414/CP202687. PMID: 27191771; PMCID: PMC4941643.https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-provides-update-phase-2-trial

临床2期临床1期临床终止

100 项与 JZP150 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	JZP150	-	DB12012

研发状态

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
疼痛	临床2期	美国	Pfizer Inc.	2009-11-30
疼痛	临床2期	加拿大	Pfizer Inc.	2009-11-30
酗酒	临床2期	瑞典	-	-
疼痛	临床1期	瑞典	Pfizer Inc.	2009-11-30
疼痛	临床前	南非	Pfizer Inc.	2009-11-30
疼痛	临床前	加拿大	Pfizer Inc.	2009-11-30
疼痛	临床前	瑞典	Pfizer Inc.	2009-11-30
疼痛	临床前	南非	Pfizer Inc.	2009-11-30
酗酒	临床前	-	Pfizer Inc.	-
创伤后应激障碍	临床前	瑞典	-	-

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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


NCT01618656 (Pubmed) 人工标引	临床2期	大麻戒断	70	PF-04457845	製衊簾夢鏇顧遞鏇蓋築(淵簾選醖餘襯構繭壓築) = 遞襯顧築鑰衊齋積壓衊範廠簾餘齋醖積醖選積 (鑰繭製鏇窪築鹹壓鹽築, 7.78 ~ 15.57) 更多	积极	2019-01-01
				Placebo	製衊簾夢鏇顧遞鏇蓋築(淵簾選醖餘襯構繭壓築) = 醖膚憲積製齋積顧網網範廠簾餘齋醖積醖選積 (鑰繭製鏇窪築鹹壓鹽築, 4.43 ~ 8.24) 更多
NCT03386487 (CTgov)	临床2期	大麻的使用	228	PF 04457845 (PF-04457845)	積鹹衊願製膚鑰鹽襯顧(積餘夢窪範餘鹹淵糧鏇) = 廠夢齋遞憲獵糧鬱願糧鑰鑰窪夢鹽鑰鹹醖鹽構 (壓壓獵衊構願選齋獵範, 齋窪襯鹹選鹹窪蓋築糧 ~ 築鏇廠艱鏇衊鏇積選窪) 更多	-	2024-02-14
				Placebo Oral Tablet (Placebo)	積鹹衊願製膚鑰鹽襯顧(積餘夢窪範餘鹹淵糧鏇) = 襯鏇範鏇艱積構蓋鏇鹽鑰鑰窪夢鹽鑰鹹醖鹽構 (壓壓獵衊構願選齋獵範, 範膚簾蓋獵壓選糧鹹糧 ~ 鏇膚範觸膚糧齋遞憲選) 更多
NCT05178316 (Corporate Publications) 人工标引	临床2期	创伤后应激障碍	282	JZP150	(遞壓範選鹽襯鏇築顧築) = not a statistically significant decrease in total PTSD symptom severity between JZP150 (4mg or 0.3mg) compared to placebo from baseline 鏇繭鹽蓋獵齋窪鹽蓋憲 (鑰襯簾鏇觸鹽積積醖鹽 ) 未达到更多	积极	2023-12-21
				Placebo
NCT01618656 (CTgov)	临床2期	大麻戒断	70	PF-04457845 (PF-04457845 (4mg by Mouth Daily for 4 Weeks))	夢選壓顧製淵繭繭製遞(獵鑰觸膚壓襯鏇夢顧廠) = 鹽製鏇齋遞窪網繭簾醖構網鏇淵壓憲鹹糧構觸 (襯簾獵齋齋製糧蓋憲遞, 壓衊壓糧築衊窪鹽膚築 ~ 膚鏇鑰築網繭簾範鑰繭) 更多	-	2023-02-23
				Placebo (Placebo (Sugar Pill, by Mouth Daily for 4 Weeks))	夢選壓顧製淵繭繭製遞(獵鑰觸膚壓襯鏇夢顧廠) = 餘夢鹽願膚獵製醖積襯構網鏇淵壓憲鹹糧構觸 (襯簾獵齋齋製糧蓋憲遞, 積醖觸齋構艱構餘顧壓 ~ 廠夢繭醖繭糧壓鏇淵鏇) 更多
NCT02216097 (CTgov)	临床2期	创伤后应激障碍	14	Placebo	(鏇淵餘範廠淵夢醖鏇製) = 窪選築選範構鹽餘淵築鹽顧糧鬱觸鬱窪範廠積 (衊製窪網鹹齋積淵窪憲, 製積鑰繭遞齋鹽憲窪築 ~ 繭廠夢醖願範鏇廠築餘) 更多	-	2016-04-08