A Phase 3 Study to Evaluate Cefepime-taniborbactam Compared to Meropenem in Adults with Ventilator Associated Bacterial Pneumonia (VABP) or Ventilated Hospital Acquired Bacterial Pneumonia (vHABP)

This is a Phase 3, randomized, multicenter, double-blind, non-inferiority study to evaluate the efficacy and safety of cefepime-taniborbactam compared to meropenem in patients ≥ 18 years of age with ventilated HABP or VABP.

开始日期2025-06-01

申办/合作机构

Venatorx Pharmaceuticals, Inc.

[+1]

NCT04951505

/ Completed临床1期

A Phase 1 Study to Evaluate the Safety and Intrapulmonary Pharmacokinetics of Cefepime and Taniborbactam in Healthy Subjects

This is a single-center, open-label study to assess the safety and intrapulmonary pharmacokinetics of cefepime and taniborbactam in healthy adult male and female subjects. Thirty subjects will receive a total of 6 doses of cefepime-taniborbactam (2 g cefepime/0.5g taniborbactam) administered intravenously every 8 hours. Following the sixth dose of cefepime-taniborbactam, subjects will be assigned to one of six bronchoscopy sampling times.

开始日期2021-06-29

申办/合作机构

Venatorx Pharmaceuticals, Inc.

CTR20191681

/ Completed临床1期

头孢吡肟/VNRX-5133在中国健康受试者中单剂和多剂静脉输注给药的药代动力学、安全性和耐受性的1期临床试验

1. 评价中国健康受试者中头孢吡肟/VNRX-5133单剂和多剂静脉（IV）输注给药的药代动力学。 2. 评价中国健康受试者中头孢吡肟/VNRX-5133单剂和多剂静脉输注给药的安全性和耐受性。

开始日期2020-06-06

申办/合作机构

Lyophilization Services of New England, Inc.

[+2]

100 项与头孢吡肟/他尼硼巴坦相关的临床结果

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100 项与头孢吡肟/他尼硼巴坦相关的转化医学

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100 项与头孢吡肟/他尼硼巴坦相关的专利（医药）

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3,279

项与头孢吡肟/他尼硼巴坦相关的文献（医药）

2025-02-11·Journal of biomolecular structure & dynamics

Mutations in V84I & A184V of bla _TEM cluster plays a pivotal role in the dynamics of Ω-loop leading to genesis of IR-TEM

Article

作者: Rath, Soumya Lipsa ; Banerjee, Devjani ; Darji, Siddhi A. ; Mandal, Nabanita

The Enterobacteriaceae family exhibits resistance to antibiotics by producing β-Lactamase. Mutations in β-Lactamase, have led to the generation of inhibitor resistant variants known as IR-TEM. In the present study, IR-TEM β-Lactamase of Enterobacter hormaechei and Enterobacter asburiae was compared. To investigate the mechanism behind the conferred mutation, we studied its interaction with Clavulanic acid, (β-Lactamase inhibitor) with different lineages of TEM and IR-TEM. We found that Clavulanic acid quickly left the binding pockets of both variants using molecular dynamics (MD) simulations. Interestingly, mutations at the V84I and A184V positions were found to drastically influence the protein dynamics. Mutating the residues at V84I and A184V positions by computational mutagenesis in Enterobacter hormaechei, it was observed that the residues on the Ω-loop as well as a few downstream residues were primarily involved in generating resistance towards inhibitors by conferring increased flexibility to the loop. This further strongly supports the notion that inhibitor resistance in β-Lactamase is conferred through allosteric regulation, wherein mutations in positions 84 and 184 may play an important role in regulating the movement of the Ω-loop. These two positions determine the lineage pattern between two clusters in TEM-1 and TEM-116. To date, no reports have been made regarding the importance of these mutations and their dynamics in Ω-loop.Communicated by Ramaswamy H. Sarma.

2025-02-01·JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

Chronic activation of β-adrenergic receptors leads to tissue water and electrolyte retention

Article

作者: Akumwami, Steeve ; Rahman, Md Moshiur ; Rahman, Asadur ; Nishiyama, Akira ; Kitamura, Hiroaki ; Fujisawa, Yoshihide ; Kitada, Kento ; Morishita, Asahiro ; Kundo, Netish Kumar ; Ogino, Yuichi

Beta-adrenergic receptors (β-AR) are expressed on the membranes of various cell types and their activation affects body water balance by modulating renal sodium and water excretion, cardiovascular function and metabolic processes. However, β-AR-associated body fluid imbalance has not been well characterised. In the present study, we hypothesized that chronic β-AR stimulation increases electrolyte and water content at the tissue level. We evaluated the effects of isoproterenol, a non-selective β-AR agonist, on electrolyte and water balance at the tissue level. Continuous isoproterenol administration for 14 days induced cardiac hypertrophy, associated with sodium-driven water retention in the heart, increased the total body sodium, potassium and water contents at the tissue level, and increased the water intake and blood pressure of the mice. There was greater urine output in response to the isoproterenol-induced body water retention. These isoproterenol-induced changes were reduced by propranolol, a non-selective beta-receptor inhibitor. Isoproterenol-treated mice even without excessive water intake had higher total body electrolyte and water contents, and this tissue water retention was associated with lower dry body mass, suggesting that β-AR stimulation in the absence of excess water intake induces catabolism and water retention. These findings suggest that β-AR activation induces tissue sodium and potassium retention, leading to body fluid retention, with or without excess water intake. This characterisation of β-AR-induced electrolyte and fluid abnormalities improves our understanding of the pharmacological effects of β-AR inhibitors. Significance Statement We have shown that chronic β-AR stimulation causes cardiac hypertrophy associated with sodium-driven water retention in the heart and increases the accumulation of body sodium, potassium and water at the tissue level. This characterisation of the β-AR-induced abnormalities in electrolyte and water balance at the tissue level improves our understanding of the roles of β-AR in physiology and pathophysiology and the pharmacological effects of β-AR inhibitors.

2025-02-01·ANNALS OF PHARMACOTHERAPY

Decreased Hepatic Functional Reserve Increases the Risk of Piperacillin/Tazobactam-Induced Abnormal Liver Enzyme Levels: A Retrospective Case-Control Study

Article

作者: Asai, Yuki ; Takahashi, Masaaki ; Koriyama, Yoshiki ; Ooi, Hayahide

Background::

Piperacillin/tazobactam (PIPC/TAZ), which is a combination of a beta-lactam/beta-lactamase inhibitor, often causes liver enzyme abnormalities. The albumin-bilirubin (ALBI) score is a simple index that uses the serum albumin and total bilirubin levels for estimating hepatic functional reserve. Although patients with low hepatic reserve may be at high risk for drug-induced liver enzyme abnormalities, the relationship between PIPC/TAZ-induced abnormal liver enzymes levels and the ALBI score remains unknown.

Objective::

This study aimed to elucidate the relationship between PIPC/TAZ-induced abnormal liver enzyme levels and the ALBI score.

Methods::

This single-center retrospective case-control study included 335 patients. The primary outcome was PIPC/TAZ-induced abnormal liver enzyme levels. We performed COX regression analysis with male gender, age (≥75 years), alanine aminotransferase level (≥20 IU/L), and ALBI score (≥−2.00) as explanatory factors. To investigate the influence of the ALBI score on the development of abnormal liver enzyme levels, 1:1 propensity score matching between the ≤−2.00 and ≥−2.00 ALBI score groups was performed using the risk factors for drug-induced abnormal liver enzyme levels.

Results::

The incidence of abnormal liver enzyme levels was 14.0% (47/335). COX regression analysis revealed that an ALBI score ≥−2.00 was an independent risk factor for PIPC/TAZ-induced abnormal liver enzyme levels (adjusted hazard ratio: 3.08, 95% coefficient interval: 1.207-7.835, P = 0.019). After 1:1 propensity score matching, the Kaplan-Meier curve revealed that the cumulative risk for PIPC/TAZ-induced abnormal liver enzyme levels was significantly higher in the ALBI score ≥−2.00 group (n = 76) than in the <−2.00 group (n = 76) ( P = 0.033).

Conclusion and relevance::

An ALBI score ≥−2.00 may predict the development of PIPC/TAZ-induced abnormal liver enzyme levels. Therefore, frequent monitoring of liver enzymes should be conducted to minimize the risk of severe PIPC/TAZ-induced abnormal liver enzyme levels in patients with low hepatic functional reserve.

项与头孢吡肟/他尼硼巴坦相关的新闻（医药）

2024-09-04

·Business Wire

Shionogi Continues Global Commitment to Advances in Infectious Disease with Key Data Presentations from Its Expanding Product Portfolio at IDWeek 2024

FLORHAM PARK, N.J.--( BUSINESS WIRE )--Shionogi Inc., the United States subsidiary of Shionogi & Co., Ltd., (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.) will have 22 scientific presentations across the company’s infectious disease portfolio at IDWeek 2024 (October 16-19, 2024) in Los Angeles, California. Key among Shionogi’s 13 data presentations for Fetroja® (cefiderocol) will be a new real-world evidence study including approximately 1,000 patients treated with cefiderocol from across the U.S. and Europe. This trial, known as PROVE, is the largest study to evaluate cefiderocol use in hospitalized patients with serious Gram-negative infections, the majority of whom were resistant to carbapenem antibiotics. Notably, Shionogi will have two oral presentations featuring nonclinical data evaluating cefiderocol activity against some of the most difficult-to-treat bacterial strains that were resistant to antibiotics, alone and in combination with xeruborbactam, an investigational beta-lactamase inhibitor that became part of the Shionogi pipeline with the acquisition of Qpex Biopharma, Inc. (hereafter “Qpex”) by Shionogi Inc. in 2023. “Here in the U.S., a core focus of our work includes continuing to evaluate real-world outcomes associated with the use of our antibiotic for the treatment of certain Gram-negative infections and ensuring we’re meeting the educational and practical needs of our customers and their patients,” said Nate McCutcheon, President and Chief Executive Officer, Shionogi Inc. “We’re proud to make this important medication available and we also recognize that ongoing innovation is critical in infectious disease. That’s why we recently announced plans to expand our global infectious disease and antimicrobial research operations in the U.S. through Qpex with the establishment of our first U.S.-based discovery laboratory in San Diego.” Shionogi is honored to announce that Michael N. Dudley, PharmD, President and CEO of Qpex will deliver the keynote address at the Society of Infectious Diseases Pharmacists (SIDP) Annual Meeting, taking place in conjunction with IDWeek. In addition to numerous scientific presentations at IDWeek, Shionogi will once again enable the infectious disease community to join the fight and take a stand against the global public health threat of antimicrobial resistance (AMR) with a new version of its award-winning AMR Warrior experience. All visitors to Shionogi’s Booth #322 will have the opportunity to create their own AMR Warrior and use the image to spread awareness amongst their own networks and communities. Shionogi’s presence at IDWeek will also include a sponsored Learning Lounge on Friday, October 18, at 10:15 AM PT, featuring Thomas Lodise, PharmD, PhD, Professor at the Albany College of Pharmacy and Health Sciences, entitled “Fetroja® (cefiderocol): An Overview of In Vitro, Clinical, and Real-world Data.” Summary of Presentations Cefiderocol data presentations at IDWeek will include: Oral #513: Cefiderocol Retains in vitro Activity Against Enterobacterales Non-Susceptible to beta-lactam-beta-lactamase Inhibitor Combinations Poster #650: In vitro Activity of Cefiderocol and Comparator Agents Against Global Enterobacterales Isolates from Hospitalized Patients with Pneumonia Collected as Part of the SENTRY Surveillance Program (2020-2022) Poster #1099: Correlation Analysis of Cefiderocol in vitro Activity and in vivo Efficacy Against Acinetobacter baumannii Strains with Difficult-to-Read MIC Endpoints Poster #1100: Activity of Cefiderocol and Comparator Agents Against Global Isolates of Stenotrophomonas maltophilia from the SENTRY Antimicrobial Surveillance Program (2020–2023) Poster #1360: Activity of Cefiderocol Against Carbapenem Non-susceptible Enterobacterales, Including Molecularly Characterized Multidrug-resistant Clinical Isolates, Causing Infections in United States Hospitals (2020–2023) Poster #1361: Cefiderocol Activity Against Pseudomonas aeruginosa , Including Resistant Subsets and Isolates Carrying Carbapenemase beta-lactamase Genes, from United States Hospitals (2020–2023) Poster #1362: Cefiderocol Activity Against Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex, Including Molecularly Characterized Clinical Isolates, Causing Infections in United States Hospitals (2020–2023) Poster #1363: Cefiderocol Activity Against Clinical Enterobacterales Isolates Carrying Metallo-beta-lactamase Genes in United States and European Hospitals (2020–2023) Poster #1364: Cefiderocol Activity Against Pseudomonas aeruginosa Clinical Isolates Carrying Metallo-beta-lactamase Genes in United States and European Hospitals (2020–2023) Poster #1472: Cefiderocol Remains Highly Active Against Carbapenemase-Producing Enterobacterales Poster #1475: Real-World Effectiveness and Safety of Cefiderocol in the Treatment of Patients with Serious Gram-negative Bacterial Infections: Results of the PROVE Chart Review Study Poster #1484: In vitro Activity of Cefiderocol and Comparator Agents Against Non-fermentative Gram-negative Bacilli Isolated from Patients Hospitalized with Pneumonia as part of the SENTRY Global Surveillance Program (2020-2022) Poster #1530: Evaluation of Phenotypic Cross-Resistance Between Cefiderocol and beta-lactam/beta-lactamase Inhibitor Combinations Against Pseudomonas aeruginosa Isolates from US Medical Centers Xeruborbactam data presentations at IDWeek will include: Oral #514: The Impact of Xeruborbactam on in vitro Activity of Cefiderocol Against a Panel of Acinetobacter baumannii Enriched in Isolates with Reduced Cefiderocol Susceptibility Poster #1110: The Impact of Xeruborbactam on in vitro Activity of Cefiderocol Against a Panel of Enterobacterales Enriched with Isolates with Reduced Cefiderocol Susceptibility For Full Prescribing Information for Fetroja® (cefiderocol), including approved Indications and Safety Information, please visit https://www.shionogi.com/content/dam/shionogi/si/products/pdf/fetroja.pdf . Shionogi’s scientific contributions at IDWeek will also include seven poster presentations featuring clinical, nonclinical and real-world evidence from its COVID-19 franchise. For more information, including a complete list of abstracts, please visit https://idweek.org/program/ . IDWeek attendees can learn more about Shionogi at Booth #322. About Shionogi in Infectious Disease Since 1953, Shionogi has been a leader in infectious disease discovery and commercialization. Our R&D story extends beyond antibiotics to include novel medications for HIV and influenza. Today, our global pipeline includes investigational agents developed to address global health challenges including antimicrobial resistance, COVID-19, influenza, rare fungal diseases and respiratory syncytial virus. As part of our commitment to addressing unmet medical needs, Shionogi is partnering with several non-governmental organizations to increase equitable access to our medications worldwide. Shionogi has a landmark license and technology transfer agreement for cefiderocol with Global Antibiotic Research and Development Partnership (GARDP) and a collaboration agreement with the Clinton Health Access Initiative (CHAI) to transform the landscape of access to antibiotics in many low-income countries, most lower middle- and upper middle-income countries, and select high-income countries. About Shionogi Inc. Shionogi Inc. is a U.S. subsidiary of Shionogi & Co., Ltd., a Japanese research-driven pharmaceutical company committed to developing innovative medicines that address unmet medical needs for people worldwide. Since 1878, we have been harnessing the full potential of science to address global health challenges. Over the past six decades, we have discovered several novel antibiotics and medications for HIV and influenza. Today, we’ve focused on developing antibiotics for infections due to serious Gram-negative bacteria and antivirals for COVID-19. In addition to infectious disease, we are also advancing rare disease clinical programs in Fragile X syndrome and Pompe disease. Learn more at Shionogi.com . About Qpex Biopharma Inc., a Shionogi Group Company Qpex Biopharma, Inc. is a resistance-focused infectious disease company on a mission to make both a dramatic and sustainable improvement in patient care across both inpatient and outpatient settings. Advancing a robust portfolio of best-in-class, clinical-stage products, the company’s lead program is based on xeruborbactam, an investigational beta-lactamase inhibitor discovered by Qpex scientists. For more information, please visit www.qpexbio.com . Forward-Looking Statements This announcement contains forward-looking statements. These statements are based on expectations in light of the information currently available, assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from these statements. Risks and uncertainties include general domestic and international economic conditions such as general industry and market conditions, and changes of interest rate and currency exchange rate. These risks and uncertainties particularly apply with respect to product-related forward-looking statements. Product risks and uncertainties include, but are not limited to, completion and discontinuation of clinical trials; obtaining regulatory approvals; claims and concerns about product safety and efficacy; technological advances; adverse outcome of important litigation; domestic and foreign healthcare reforms and changes of laws and regulations. Also for existing products, there are manufacturing and marketing risks, which include, but are not limited to, inability to build production capacity to meet demand, lack of availability of raw materials and entry of competitive products. The company disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events or otherwise.

引进/卖出并购临床研究

2024-07-19

·上海市生物医药科技发展中心

2024年上半年FDA拒批16款药物

据不完全统计，2024年上半年FDA拒批了16款新药，涉及ADC药物、细胞疗法、基因疗法、抗体和组合疗法。小编汇总如下：六月： Rocket:KRESLADI 2024年6月28日，Rocket Pharmaceuticals宣布美国食品和药物管理局（FDA）针对其公司在研基因疗法KRESLADI™ （marnegragene autotemcel; marne-cel）的生物制剂许可申请发出了一份完整答复函 (CRL)，其中FDA要求提供有限的额外化学制造和控制 (CMC) 信息以完成审查。此前，该机构以需要更多时间审查生产过程为由，将其决定推迟了三个月。 Kresladi（曾用名RP-L201）是一款用以治疗严重白细胞粘附缺陷-I（LAD-I）的在研基因疗法，该疗法通过慢病毒对患者的自体造血干细胞进行基因工程化改造，以递送ITGB2基因的功能性拷贝。该基因编码β-2整合素成分CD18，这是一种促进白细胞粘附并使其从血管中渗出以抵抗感染的关键蛋白质。默沙东/第一三共:HER3-DXd 6月26日，FDA 已对第一三共和默沙东提交的加速批准Patritumab Deruxtecan（HER3-DXd）生物制品许可申请（BLA）发出完全回复信（CRL），该药物用于治疗先前接受过两种或两种以上系统疗法的成人局部晚期或转移性EGFR突变非小细胞肺癌（NSCLC）患者。该完全回复信是由于对第三方制造设施的检查发现的问题。信函中未发现提交的疗效或安全性数据存在任何问题，这也意味HER3-DXd仍有望成为首款获批上市的HER3 ADC。 Patritumab Deruxtecan是一种专门设计的潜在首创的HER3靶向DXd抗体药物偶联物（ADC），目前正由第一三共和默沙东联合开发。去年10月，默沙东与第一三共达成合作协议，以220亿美元的总交易额获得该产品以及另外两款ADC在日本以外的全球开发和商业化权益。艾伯维:ABBV-951 6月25日，艾伯维（AbbVie）公司表示已收到美国FDA关于帕金森病候选药物ABBV-951新药申请的完整回应函。这是FDA自去年以来针对该药物发布的第二封完整回应函，这次是因为第三方供应商出现的问题。对该工厂的检查不涉及ABBV-951或任何艾伯维药品。CRL没有发现任何与ABBV-951的安全性、有效性或标签（包括设备）有关的问题。CRL没有要求艾伯维进行更多与药物或设备相关的疗效和安全性试验。 ABBV-951复方中的两种成分foslevodopa / foscarbidopa分别是左旋多巴和卡比多巴的前药，具有较高水溶性，可以通过一个连接到皮下的泵实现持续24小时皮下输注给药，从而使体内的左旋多巴和卡比多巴浓度在24h内保持稳定，改善晚期帕金森病患者的药效波动。五月：江苏恒瑞/HLB:“双艾”疗法 5月17日，Elevar Therapeutics子公司HLB及其在中国的合作伙伴江苏恒瑞医药宣布收到FDA对于注射用卡瑞利珠单抗联合甲磺酸阿帕替尼片用于不可切除或转移性肝细胞癌患者的一线治疗的BLA申请的完整回复信（CRL），在CRL中FDA表示会对恒瑞提交的生产现场检查缺陷完整回复进行全面评估，以及由于部分国家的旅行限制，无法在审查周期内完成必需的生物学研究监测计划(BIMO)临床检查，因此该产品的BLA申请将被拒绝。对此，恒瑞表示将尽快重新提交申请。卡瑞利珠单抗（camrelizumab）是恒瑞医药研发的人源化抗PD-1单克隆抗体，于2019年5月在中国获批上市，此前已在肺癌、肝癌、食管癌、鼻咽癌以及淋巴瘤五大瘤种中获批了9个适应症。阿帕替尼（rivoceranib）是恒瑞医药开发的一款针对血管内皮生长因子受体（VEGFR）的小分子酪氨酸激酶抑制剂，于2014年10月在中国获批上市，目前有3个适应症获批，分别为单药用于晚期胃腺癌或胃食管结合部腺癌、既往接受过至少一线系统性治疗后失败或不可耐受的晚期肝细胞癌、联合卡瑞利珠单抗用于不可切除或转移性肝细胞癌。 Dynavax：Heplisav-B 5月14日，Dynavax Technologies 宣布FDA拒绝了其重组蛋白乙型肝炎疫苗用于在血液透析中患者的补充生物制品许可证申请。这家加州生物制药公司表示，它收到了监管机构关于其sBLA的完整回复函（CRL），其中包括来自119名接受血液透析的成人的四剂量Heplisav-B方案的I期HBV-24研究的临床免疫原性和安全性数据。根据CRL，“申请没有提供足够的数据来支持对有效性或安全性的全面评估。” FDA 认为该申请没有提供足够的数据来支持有效性或安全性的全面评估。CRL表示，HBV-24的数据不足，因为第三方临床试验现场运营商销毁了大约一半参加试验的受试者的数据源文件。该公司还透露，FDA发现单臂研究中的受试者总数“不足以评估四剂方案的安全性”。 Dynavax在其新闻稿中表示，FDA拒绝其sBLA不会影响欧盟委员会于2023年10月批准血液透析患者四剂量方案的决定，或Heplisav-B在美国、欧盟和英国被批准用于预防所有已知乙型肝炎病毒亚型引起的成人感染的适应症。四月： Abeona：pz-cel 4月22日，Abeona Therapeutics宣布FDA针对其细胞疗法 prademagene zamikeracel (pz-cel，EB-101)的完整回复信 (CRL)，FDA拒绝了该疗法上市，并要求其提供治疗的有效信息，以及满足额外的CMC 要求才能批准申请。受此消息影响，Abeona股价大跌53%。 Pz-cel是一种体外基因校正的自体细胞疗法，用于治疗RDEB患者。该疗法由表皮片组成，旨在将功能性COL7A1基因传递到患者自身的皮肤细胞中，以实现正常的VII型胶原蛋白表达，并促进伤口愈合。试验表明，pz-cel可以帮助治愈伤口，并减轻RDEB患者的疼痛。然而，FDA对其位于俄亥俄州克利夫兰的制造工厂进行检查，因pz-cel制造相关的问题，FDA驳回了pz-cel的上市申请，但没有要求提供额外的试验或数据来支持后续申请。pz-cel原定PDUFA 日期是2024年5月25日，现在将有所推迟。 Supernus：SPN-830 4月8日，FDA宣布Supernus Pharmaceuticals治疗帕金森病的药物SPN-830第二次被拒，原因是质量和设备问题。SPN-830是一种阿朴吗啡注射剂，用于持续治疗帕金森病（PD）的运动波动（间歇性发作）。受此影响，Supernus股价在盘前下跌了10%。 CRL中表示有两个方面需要FDA进行更多审查。第一个问题是Supernus需要提供更多信息，包括有关产品质量的更多信息。Supernus指出最近向监管机构提交了更多的产品质量数据，但尚未得到审查。FDA 提出的另一个问题与输液设备的主文件有关。Supernus 表示，主文件是专有的，并计划与设备制造商讨论监管机构要求的信息和重新提交 NDA 所需的步骤。与此同时，Supernus公司表示，没有发现任何临床安全性或有效性问题需要获得批准。三月： Vanda：Hetlioz 3月6日，Vanda Pharmaceuticals宣布，已经收到FDA就Hetlioz（他司美琼）治疗失眠补充新药申请（sNDA）发出的完整回应函。FDA表示发现了标签和上市后要求/保证之外的缺陷，不能批准目前的sNDA。Vanda正在对其进行审查，并评估下一步行动。 Hetlioz是一款褪黑素受体激动剂，2014年1月在美国获批治疗非24小时睡眠觉醒障碍。2020年12月，该产品拓展新适应症，获FDA批准治疗史密斯-马吉利综合征 (SMS) 夜间睡眠障碍。 Viatris/Mapi Pharma：GA Depot 3月11日，晖致（Viatris）和Mapi Pharma共同宣布收到FDA就GA Depot（醋酸格拉替雷，40mg）用于治疗复发型多发性硬化症的新药申请（NDA）发出的完整回复函（CRL）。关于FDA拒绝的具体细节很少，这两家公司仅表示，他们目前正在审查完整回复函，以更好地确定GA Depot 40的“适当下一步”。 GA Depot 40的活性成分醋酸格拉替雷是一种免疫调节剂，1996年在美国获批用于治疗多发性硬化症（MS），商品名为Copaxone。2023年6月，格拉替雷在中国获批上市。GA Depot的NDA主要是基于一项III期研究的积极结果。该研究评估了GA Depot对比安慰剂治疗RMS患者的有效性、安全性和耐受性。结果显示，GA Depot组患者的年复发率相比安慰剂组降低了30.1%（P=0.0066）。 Regeneron：Odronextamab 3月25日，再生元宣布，FDA拒绝其CD3/CD20双抗Odronextamab治疗复发性或转移性滤泡淋巴瘤（FL）和弥漫大B细胞淋巴瘤的上市申请，再生元表示唯一原因是确证临床的入组状态问题，FDA在完整的回复函（CRL）中没有发现任何与有效性、安全性、试验设计、标签或制造有关的问题。这款CD3/CD20双抗已在复发/难治性滤泡性淋巴瘤以及复发／难治弥漫大B细胞淋巴瘤( DLBCL )中获得批准，均经过2线或2线以上的系统治疗。在12月的ASH上，Regeneron报告了DLBCL的2期数据，显示52%的反应率。如果上市成功，Odronextamab将是继基因泰克(Genentech)的Lunsumio和Genmab/艾伯维(AbbVie)的Epkinly之后，市场上第三种CD20xCD3双特异性抗体。二月： Venatorx/Melinta：cefepime-taniborbactam 2月23日，Venatorx和Melinta共同宣布，FDA发布了关于头孢吡肟-他尼波巴坦（cefepime-taniborbactam）新药申请的完整回应函。 CRL没有发现NDA中的临床安全性或有效性问题，FDA也没有要求任何新的临床试验来支持头孢吡肟-他尼波巴坦的批准。FDA要求提供额外的化学、生产和控制(CMC)以及有关药物、测试方法和生产工艺的相关数据。头孢吡肟-他尼波巴坦是一种实验性静脉注射(IV) β-内酰胺/ β-内酰胺酶抑制剂(BL/BLI)抗生素组合，用于治疗成人复杂尿路感染(cUTIs)，包括肾盂肾炎、医院获得性细菌性肺炎和呼吸机相关细菌性肺炎(HABP/VABP)。 Minerva：Roluperidone 2月27日，Minerva Neurosciences宣布收到FDA就5-HT2A受体和σ2受体拮抗剂Roluperidone用于治疗精神分裂症阴性症状的新药申请（NDA）发出的完整回复函（CRL），表示拒批其精神分裂症新药。受此消息影响，Minerva股价大跌59%。在CRL中，FDA 指出了以下四点拒批理由：虽然MIN-101C03研究在主要疗效终点上显示出统计学意义，但其本身不足以确立实质性的有效性证据；提交的NDA缺乏有关同时服用抗精神病药物的数据；NDA材料缺乏证明Roluperidone对改善精神分裂症阴性症状具有临床意义的必要数据；在已提交的安全性数据中，至少服用12个月拟议剂量（64mg）Roluperidone的患者数量不足。为了解决这些缺陷，FDA规定Minerva必须至少再提交一项积极、充分和对照良好的研究，以支持Roluperidone治疗阴性症状的安全性和有效性。Minerva还必须提供额外的数据来证明Roluperidone与其它抗精神病药物联合用药的安全性和有效性，以进一步支持Roluperidone的有效性并证明拟议剂量的长期安全性。 Theratechnologies：Trogarzo 2月27日，Theratechnologies宣布，美国食品和药物管理局（FDA）已就该公司关于Trogarzo®（ibalizumab-uiyk）维持剂量的肌肉注射（IM）给药方法的补充生物制品许可申请（sBLA）发出了拒绝备案函（RTF）。经初步审查，FDA认定该sBLA不够完整，无法进行实质性审查。RTF指出，sBLA没有包含建立Trogarzo® IM给药途径与静脉输注给药途径之间药代动力学桥梁所需的数据。 Trogarzo®（ibalizumab-uiyk）是一种长效、CD4导向、附着后HIV-1抑制剂。在美国，Trogarzo®与其他抗逆转录病毒药物联用，适用于治疗目前抗逆转录病毒疗法无效的多重耐药HIV-1感染的重度治疗经验成人的1型人类免疫缺陷病毒（HIV-1）感染。Trogarzo® 在加拿大未获批准。一月：安斯泰来：zolbetuximab 2024年1月9日，安斯泰来宣布其收到FDA就CLDN18.2单抗zolbetuximab上市申请发出的完整回复函（CRL），暂时拒绝批准上市，作为Claudin18.2阳性、HER2阴性的局部晚期不可切除或转移性胃或胃食管交界处（G/GEJ）腺癌的一线治疗方案。在CRL信函中，FDA指出了zolbetuximab第三方生产工厂未解决的缺陷，表示不能在原定的PDUFA日期前批准该药上市。其中，FDA未对zolbetuximab的临床数据提出任何疑问，也没有要求开展额外的临床试验。安斯泰来表示，这些生产缺陷不会造成任何安全性和有效性数据的隐患，公司正在与FDA和第三方制造商密切合作，以尽快解决该生产缺陷。 Venatorx/Melinta：cefepime-taniborbactam 2024年1月18日，FDA 拒绝批准日本SNBL旗下Satsuma Pharmaceuticals用于治疗急性偏头痛的双氢麦角胺鼻粉产品 STS101上市。STS101 是鼻腔给药偏头痛药物甲磺酸双氢麦角胺 (DHE) 的重新配制版本，利用 Satsuma 的专有设备进行递送，整体只有口红大小，方便携带和使用。完整回应函 (CRL) 中指出了STS101的化学、制造和控制 (CMC) 方面的问题。CRL 没有指出STS101有任何安全问题，也没有要求进行额外的研究。Satsuma 将与 FDA 讨论拒绝事宜，以重新提交上市申请。 Defender：DPI-386鼻用凝胶 1月30日，Defender Pharmaceuticals宣布FDA签发了一份完整答复函（CRL），拒批了该公司用于预防晕动病引起的恶心和呕吐的鼻内东莨菪碱凝胶（DPI-386鼻用凝胶）NDA。该公司没有说明监管机构拒绝该药物的原因。 DPI-386凝胶在一项3期、双盲、安慰剂对照研究(NCT05548270)中进行了评估，该研究包括约500名在海上航行中暴露于运动的成年人。研究参与者被随机分配到自行服用东莨菪碱鼻用凝胶(每0.12克凝胶含0.2毫克东莨菪碱HBr)或安慰剂组。研究结果显示，与安慰剂组相比，鼻内东莨菪碱组未报告呕吐和未请求抢救药物(主要终点)的患者比例显著更高。总结被美国FDA批准上市往往相当于拿到了全球通行证。但近年来FDA在创新药的上市审批上日渐趋严，以高标准、高要求将多款创新药被拒之门外。从这半年的拒批理由来看，CMC问题是FDA新药拒绝占比最大因素，其次第三方问题也愈发普遍，这提示药企需高度重视对第三方的监管和核查，审慎避坑。参考资料：各公司公告来源 | 生物药大时代

抗体药物偶联物上市批准细胞疗法基因疗法加速审批

2024-05-23

·美通社

Access to Medicine Foundation的新报告显示，制药公司可以采取哪些措施来确保处于耐药性前线的患者能够获得正在开发的少数有前途的抗微生物药物

阿姆斯特丹 2024年5月23日 /美通社/ -- 开发替代抗生素和抗真菌药物来对抗超级细菌的竞赛严重不足，使世界各地的人们处于危险之中。但是，研发（R&D）的转变，包括对准入和管理规划的投资，可以对抗微生物药物耐药性（AMR）产生重大影响。由于大多数以研究为基础的大型制药公司不再活跃于抗微生物药物研发，因此上市的新疗法很少，这使得患者容易受到抗微生物药物耐药性快速传播的影响。尽管存在这种现实，但少数处于后期临床开发阶段的项目可能会产生重大影响。 A ccess to Medicine Foundation的新报告追踪了葛兰素史克、F2G、Innoviva、Venatorx（分别为gepotidacin、olorofim、zoliflodacin和cefepime-taniborbactam）和辉瑞最近批准的阿曲南阿维巴坦（Emblaveo®）管道中的五个此类项目。通过提供急需的药物来治疗耐药性淋病、尿路感染、腹腔内感染、呼吸道感染和侵入性真菌感染，这些项目每年总共可以挽救至少16万人的生命。尽管这些疾病影响着全球范围广泛的患者，但妇女和儿童，尤其是生活在低收入和中等收入国家（LMIC）的妇女和儿童，受到的影响尤其严重。 "在抗击耐药感染的竞赛中，我们的武器规模虽小但有效。我们在这场竞赛中获胜与失败的区别取决于公司如何为生活在耐药前线的人们提供机会。" — 医学准入基金会首席执行官贾亚斯里•艾耶。调查结果显示，各公司在其准入和管理计划中采用了多种策略，但结构化的预先计划尚未成为标准。令人鼓舞的是，在范围内的五家公司中，有四家——葛兰素史克、辉瑞、Innoviva和Venatorx——正在进行或启动直接针对儿童的临床试验，这表明在缩小成人和儿科准入差距方面取得了进展。五个低收入国家确定了注册承诺：中国、印度、墨西哥、南非和泰国。但是，对于范围内的113个中低收入国家中的108个，人们也面临着这些项目针对的疾病的沉重负担，目前尚不清楚在初步批准后是否会提供这些项目。该报告为重点公司确定了机遇和建议，并概述了全球利益相关者在抗微生物药物研发领域的可行措施，以促进广泛采用预先准入和管理规划。 "应对耐药性的巨大规模和速度是一个复杂的全球健康问题，需要制药公司在多个领域采取行动。这包括提供适当的准入和实施管理措施，以保障创新抗微生物药物的有效性。不这样做将限制解决耐药性的努力。"——准入医学基金会运营与研究总监玛丽恩•维尔霍夫。在全球卫生利益相关者为2024年联合国大会抗菌素耐药性高级别会议做准备之际，本报告是在关键时刻发布的，强调了需要注意的紧迫差距。在这里阅读报告。

微生物疗法临床研究

100 项与头孢吡肟/他尼硼巴坦相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
肾盂肾炎	申请上市	美国	Venatorx Pharmaceuticals, Inc.	2023-08-15
复杂的尿路感染	申请上市	美国	Venatorx Pharmaceuticals, Inc.	2023-08-15
医院获得性肺炎	临床3期	-	Venatorx Pharmaceuticals, Inc.	2025-06-01
呼吸机相关细菌性肺炎	临床3期	-	Venatorx Pharmaceuticals, Inc.	2025-06-01
急性肾盂肾炎	临床3期	美国	云济华美药业（北京）有限公司	2019-08-07
急性肾盂肾炎	临床3期	美国	Venatorx Pharmaceuticals, Inc.	2019-08-07
急性肾盂肾炎	临床3期	中国	Venatorx Pharmaceuticals, Inc.	2019-08-07
急性肾盂肾炎	临床3期	阿根廷	Venatorx Pharmaceuticals, Inc.	2019-08-07
急性肾盂肾炎	临床3期	阿根廷	云济华美药业（北京）有限公司	2019-08-07
急性肾盂肾炎	临床3期	巴西	Venatorx Pharmaceuticals, Inc.	2019-08-07

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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


NCT03840148 (CERTAIN-1, CTgov)	临床3期	泌尿道感染 \| 急性肾盂肾炎 \| 复杂的尿路感染	661	Cefepime/VNRX-5133 (taniborbactam) (Cefepime/VNRX-5133 (Taniborbactam))	衊夢築遞襯蓋襯憲壓夢(憲製範簾廠積襯憲觸糧) = 蓋憲積憲遞餘遞築鹽鹽範顧襯積鹹網夢淵製簾 (窪簾餘鏇範遞鬱餘鹽淵, 簾艱廠膚鹽糧襯廠範窪 ~ 餘鬱廠鑰顧願壓選襯獵) 更多	-	2024-05-29
				Meropenem (Meropenem)	衊夢築遞襯蓋襯憲壓夢(憲製範簾廠積襯憲觸糧) = 蓋鏇齋齋構醖糧蓋壓廠範顧襯積鹹網夢淵製簾 (窪簾餘鏇範遞鬱餘鹽淵, 壓鑰鬱醖艱壓範觸積鏇 ~ 構鹹遞壓築顧廠築觸鬱) 更多
NCT03840148 (CERTAIN-1, Pubmed \| Br Dent J \| N Engl J Med) 人工标引	临床3期	泌尿道感染	436	Cefepime/taniborbactam	鏇鬱蓋鑰鑰範簾壓醖獵(簾餘範簾網觸遞衊夢蓋) = 夢夢憲鬱簾醖糧壓醖齋蓋遞憲餘選憲淵獵網膚 (鏇鬱觸夢蓋構憲餘簾蓋 ) 更多	积极	2024-02-15
NCT03840148 (CERTAIN-1, Corporate Publications) 人工标引	临床3期	复杂的尿路感染	661	Cefepime/Taniborbactam	衊簾衊衊膚鹽網繭網鹽(觸遞鹽範鏇蓋淵窪遞醖) = 淵窪築獵積鏇齋顧壓壓糧鏇積積鑰繭醖鏇繭簾 (餘範廠範蓋憲簾遞鏇構 ) 更多	优效	2022-03-10
				meropenem	衊簾衊衊膚鹽網繭網鹽(觸遞鹽範鏇蓋淵窪遞醖) = 鹹憲蓋鑰糧網鏇獵簾蓋糧鏇積積鑰繭醖鏇繭簾 (餘範廠範蓋憲簾遞鏇構 ) 更多