PBPs x β-lactamase x Enzymes

EMBLAVEO® is the first β-lactam/β-lactamase inhibitor antibiotic combination approved in the European Union for treating serious infections in adult patients caused by multidrug-resistant Gram-negative bacteria, including metallo-β-lactamase-producing bacteria EMBLAVEO® was reviewed under European Medicines Agency accelerated assessment procedure, used when a pharmaceutical product is of major interest for public health and therapeutic innovation NEW YORK--(BUSINESS WIRE)-- Pfizer Inc. (NYSE: PFE) today announced that the European Commission (EC) has granted marketing authorization for EMBLAVEO® (aztreonam-avibactam) for the treatment of adult patients with complicated intra-abdominal infections (cIAI), hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), and complicated urinary tract infections (cUTI), including pyelonephritis. It is also indicated for the treatment of infections due to aerobic Gram-negative organisms in adult patients with limited treatment options. “For healthcare teams treating patients with serious Gram-negative bacterial infections, the prospect of running out of effective treatment options is a daunting but very real threat,” said Yehuda Carmeli, Head, National Institute for Antibiotic Resistance and Infection Control, Tel Aviv Medical Center, Israel, and an investigator in the REVISIT study. “The approval of EMBLAVEO is welcome news for the infectious disease community and provides new hope to critically ill patients affected by antimicrobial resistance.” Antimicrobial resistance (AMR) – when bacteria, viruses, fungi, and parasites change and find ways to resist the effects of antimicrobial drugs – is recognized as one of the biggest threats to global health.1 If AMR continues to rise unchecked, minor infections could become life-threatening, and many routine medical procedures such as caesarean sections and hip replacements could become too risky to perform.1 Multidrug-resistant Gram-negative bacteria are of particular concern due to the high rates of morbidity and mortality they cause.2,3 Metallo-β-lactamases (MBLs) are a type of enzyme produced by certain bacteria that can result in resistance to antibiotics, and MBL-producing Gram-negative bacteria are on the rise globally.4 Developing new treatments for infections caused by Gram-negative bacteria has been prioritized by the World Health Organization (WHO) as a critical area of focus due to their increasing spread.1,5 “The European Medicines Agency’s accelerated review of EMBLAVEO reflects the urgent need for new treatments to address the threat of antimicrobial resistance,” said Alexandre de Germay, Chief International Commercial Officer, Executive Vice President, Pfizer. “With this approval, Pfizer is proud to take another step forward in its commitment to developing and bringing breakthrough health solutions to patients impacted by serious infectious diseases around the world.” This approval is based on results from the previously reported Phase 3 program comprising the REVISIT (NCT03329092) and ASSEMBLE (NCT03580044) studies evaluating the efficacy, safety, and tolerability of EMBLAVEO in treating serious bacterial infections due to Gram-negative bacteria, including MBL-producing multidrug-resistant pathogens for which there are limited or no treatment options.6,7 Data support that EMBLAVEO is effective and well-tolerated, with no new safety findings and a similar safety pro aztreonam alone.8 The marketing authorization of EMBLAVEO is valid in all 27 European Union (EU) member states, as well as in Iceland, Liechtenstein, and Norway. Marketing authorization applications for EMBLAVEO are planned for submission in other countries. About EMBLAVEO® (aztreonam-avibactam) EMBLAVEO® is indicated for the treatment of adult patients with complicated intra-abdominal infections (cIAI), hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), complicated urinary tract infections (cUTI), including pyelonephritis, and infections due to aerobic Gram-negative organisms with limited treatment options. It combines aztreonam, a monobactam β-lactam, with avibactam, a recent broad-spectrum β-lactamase inhibitor.9,10 MBLs are a class of β-lactamase enzymes that are not inhibited by current β-lactamase inhibitors and hydrolyze nearly all β-lactam antibiotics, with an exception being monobactams such as aztreonam. However, monobactams are degraded by other β-lactamases that are frequently co-produced with MBLs, limiting the clinical usefulness of aztreonam monotherapy.9 The combination of aztreonam with avibactam restores aztreonam’s activity against bacteria that co-produce MBLs and other β-lactamases and provides a well-tolerated and effective treatment option against multidrug-resistant Gram-negative bacteria.9 These multidrug-resistant Gram-negative bacteria include MBL-producing Enterobacterales, which have been highlighted as a critical priority pathogen by the WHO, and S. maltophilia.4,11 EMBLAVEO is the first β-lactam/β-lactamase inhibitor combination for treating serious bacterial infections in adult patients caused by multidrug-resistant Gram-negative bacteria, including MBL-producing bacteria, approved for use in the EU. EMBLAVEO was jointly developed with AbbVie. Pfizer holds the global rights to commercialize this therapy outside of the U.S. and Canada, where the rights are held by AbbVie. Development of EMBLAVEO was also supported by public-private partnerships between Pfizer and the U.S. Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA) under OTA number HHSO100201500029C; and through the EU’s Innovative Medicines Initiative (IMI) – a partnership between the EU and the European pharmaceutical industry – under a project called COMBACTE-CARE (Combatting Bacterial Resistance in Europe – Carbapenem Resistance). The COMBACTE-CARE consortium is a unique public-private collaboration that unites the knowledge and capabilities of leading drug-resistant bacterial infection experts and is supported by the COMBACTE pan-European clinical and laboratory networks. About Pfizer: Breakthroughs That Change Patients’ Lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development, and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at . In addition, to learn more, please visit us on and follow us on X at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer/. Category: Prescription Medicines Disclosure Notice The information contained in this statement is as of April 22, 2024. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. This release contains forward-looking information about EMBLAVEO (aztreonam-avibactam), including its potential benefits, a marketing authorization granted by the European Commission, and planned regulatory submissions in other countries, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of EMBLAVEO; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when any drug applications may be filed in any other jurisdictions for EMBLAVEO; whether and when regulatory authorities in any such other jurisdictions where applications may be filed or pending may approve such applications, which will depend on myriad factors, including making a determination as to whether the product’s benefits outweigh its known risks and determination of the product’s efficacy, and whether EMBLAVEO will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of EMBLAVEO; the impact of COVID-19 on our business, operations and financial results; and competitive developments. A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results,” as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at and . _________________ 1 World Health Organization. Antimicrobial resistance. November 2023. Available at: . Last accessed April 2024. 2 Review on Antimicrobial Resistance. Tackling drug-resistant infections globally: final report and recommendations. May 2016. Available at: . Last accessed April 2024. 3 Oliveira J, Reygaert WC. Gram-Negative Bacteria. [Updated August 8, 2023]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. January 2024. Available at: . Last accessed April 2024. 4 Boyd SE, Livermore DM, Hooper DC, et al. Metallo-β-lactamases: Structure, function, epidemiology, treatment options, and the development pipeline. Antimicrob Agents Chemother. 2020;64(10):e00397-20. 5 World Health Organization. Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug-resistant bacterial infections, including tuberculosis. September 2017. Available at: . Last accessed April 2024. 6 Pfizer. Phase 3 studies of Pfizer’s novel antibiotic combination offer new treatment hope for patients with multidrug-resistant infections and limited treatment options. June 2023. Available at: . Last accessed April 2024. 7 Carmeli Y. Efficacy and safety of aztreonam-avibactam for the treatment of serious infections due to gram-negative bacteria, including metallo-β-lactamase-producing pathogens: phase 3 REVISIT study. Presented as oral session (abstract 2893) at IDWeek 2023; 11–15 October, 2023; Boston MA. 2893. 8 Pfizer data on file. ATM-AVI Top-Line Report C3601009. 9 Rossolini GM, Stone G, Kantecki M, et al. In vitro activity of aztreonam/avibactam against isolates of Enterobacterales collected globally from ATLAS in 2019. J Glob Antimicrob Resist. 2022;30:214–221. 10 Cornely OA, Cisneros JM, Torre-Cisneros J, et al. Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study. J Antimicrob Chemother. 2020;75(3):618–627. 11 World Health Organization. WHO publishes list of bacteria for which new antibiotics are urgently needed. February 2017. Available at: . Last accessed April 2024.

2022年11月30日，Innoviva宣布，FDA已接受SUL-DUR的NDA并将其纳入优先审评，处方药使用者费用法案（PDUFA）的目标行动日期为2023年5月29日。SUL-DUR是一款静脉输注的处于研究阶段的创新药物，用于治疗包括碳青霉烯类耐药菌株在内的鲍曼不动杆菌引起的感染。来源：Innoviva官网此次向FDA递交NDA是基于具有里程碑意义的III期临床研究ATTACK的积极结果。01关于ATTACK研究ATTACK是一项关键III期注册性研究（CTR20191711），旨在评估SUL-DUR对比多黏菌素用于治疗鲍曼不动杆菌-醋酸钙复合体（ABC）感染患者（包括碳青霉烯类耐药和多药耐药菌株）的疗效和安全性，两者均以联合亚胺培南/西司他丁作为背景疗法。本研究共有207名患者入组。研究分为两部分，A部分为随机对照部分（SUL-DUR对比多黏菌素），针对鲍曼不动杆菌院内感染的细菌性肺炎（HABP）、呼吸机相关细菌性肺炎（VABP）、通气性肺炎（VP）或菌血症的患者。B部分为开放标签部分（仅SUL-DUR）入选对多黏菌素或多黏菌素B治疗耐药或失败的ABC感染。所有患者均接受亚胺培南/西司他丁作为背景治疗。该研究的主要疗效终点是28天全因死亡率。该研究的主要安全目标是肾毒性的发生率（根据修改后的RIFLE标准衡量）。来源：药渡数据库研究结果显示，在碳青霉烯耐药ABC感染患者中，与多粘菌素相比，SUL-DUR在主要研究终点“28天全因死亡率”方面，具有统计学意义上的非劣效性，并且临床治愈率存在显著差异。SUL-DUR还表现出良好的安全性，其肾毒性对比多黏菌素具有统计学意义上的显著降低。 02关于SUL-DUR舒巴坦是一种青霉素衍生物，作为β内酰胺酶抑制剂得到广泛应用，对鲍曼不动杆菌具有内在抗菌活性。然而，鲍曼不动杆菌容易以从未见过的速度获得多重耐药性，导致舒巴坦耐药问题越来越严重，很大程度上限制了舒巴坦在治疗鲍曼不动杆菌感染中的应用。 Durlobactam是一款新型的广谱静脉A、C和D类β-内酰胺酶抑制剂。Durlobactam可恢复多种β-内酰胺类抗生素对革兰氏阴性菌、多药耐药病原体的体外活性。SUL-DUR是舒巴坦（一种静脉输注的β-内酰胺类抗生素）和Durlobactam（一种新型广谱静脉输注的β-内酰胺酶抑制剂）的创新型组合型药物。FDA已经授予SUL-DUR合格传染病产品（QIDP）认证和快速审批通道资格。 青霉素结合蛋白(PBPs)是β-内酰胺类抗菌药物作用的靶点，鲍曼不动杆菌对舒巴坦产生耐药突变时，可改变PBPs与药物结合的能力，降低药物效力。临床前研究发现，Durlobactam可抑制鲍曼不动杆菌中常见的β-内酰胺酶，从而恢复舒巴坦的抗菌活性。二者组合用于治疗包括碳青霉烯类耐药菌株在内的鲍曼不动杆菌（无论是否耐药）引起的感染。来源：DOI: https://doi.org/10.1128/AAC.01576-1703交易进展SUL-DUR（原研代号：ETX2514SUL）是Entasis Therapeutics原研开发的创新药组合药物，是Durlobactam和舒巴坦固定剂量组合。再鼎医药&Entasis2018年4月23日，再鼎医药与Entasis Therapeutics就Durlobactam达成亚太地区的独家许可协议和全球战略发展合作。根据协议条款，再鼎医药向Entasis Therapeutics支付500万美元的预付款，取得包括日本在内的亚太地区特定国家开发和商业化SUL-DUR的独家许可。除了首付款外，Entasis Therapeutics有资格获得高达760万美元的近期发展里程碑和高达9100万美元的与SUL-DUR和其他组合相关的额外开发、监管和销售里程碑付款和版权费用。双方将合作在中国开展关键的III期试验，再鼎医药将牵头进行患者的筛选、入组和治疗，并协调SUL-DUR在该地区的开发、注册和商业化。Innoviva&Entasis2022年5月23日，Innoviva和Entasis Therapeutics达成最终收购协议，Innoviva将以每股2.20美元的现金价格收购Entasis剩余的所有流通股。此前，Innoviva已拥有Entasis约60%的流通股，至此，Innoviva完成对Entasis Therapeutics的全面收购和享有包括SUL-DUR在内所有产品的开发、商业化推广权利。04临床进展根据药渡数据调研，目前全球15+国家和地区范围内，SUL-DUR针对不动杆菌感染、细菌性肺炎、胰腺癌、菌血症等多个适应症的临床研究正在开展中。来源：药渡数据库 鲍曼不动杆菌-醋酸钙复合体（ABC）是革兰氏阴性、机会性人类病原体，主要感染重症患者，通常会导致严重的肺炎和血流感染。ABC被认为是一种全球性的公共卫生威胁，部分原因是其能够获得多重耐药性。根据目前的碳青霉烯类耐药率，全球每年有超过300,000例住院治疗的碳青霉烯类耐药ABC感染病例，由于治疗选择有限，其发病率和死亡率都很高。期望SUL-DUR早日获批上市，为耐药菌感染患者带来更多治疗选择。参考来源Innoviva、Entasis、再鼎医药官网、公告药渡数据库END对啦对啦~还有一件重要事情需要预告！！‍💚药渡数据双12福利再升级；免费为您开放“药学人员必备的5大数据库”之一【药典库】7天试用权限！‍💚转发朋友圈集够12个咱即可免费获取四国药典资料（印度药典、韩国药典、日本药典、欧洲药典）！扫码文首二维码加入社群了解一手活动福利！👇欢迎关注药渡数据媒体矩阵

Venatorx President and CEO Christopher J. Burns, Ph.D./Courtesy Venatorx Pharmaceuticals On an annual basis in the U.S., at least 2.8 million people have an antibiotic-resistant infection, and more than 35,000 people die from those infections, according to the U.S. Centers for Disease Control and Prevention. Drug-resistant pathogens have helped create an antibiotic-resistance crisis. Those magic bullets – antibiotics – aren’t as resilient as they used to be. A Critical Lack of Funding Compounding the problem, many pharmaceutical companies have exited the antibiotic business because financial incentive is lacking. Essentially, less private investment and innovation in the development of new antibiotics are impeding efforts to combat drug-resistant infections. To help rectify this problem, Malvern, PA-based Venatorx Pharmaceuticals, a clinical-stage pharmaceutical company, is developing treatments for patients with multi-drug-resistant (MDR) bacterial infections. “Making a new drug to treat a bacteria has historically been very difficult. Bacteria are living organisms. They’ve been around for billions of years. They’ve learned how to fight off an attack from just about any front. Bacteria are clever; you can put them under pressure with an antibiotic, but eventually, they’ll find a way to circumvent it and decrease its effectiveness,” said Venatorx President and CEO Christopher J. Burns, Ph.D. in an email. “There’s an inevitability to antimicrobial resistance (AMR), which is why every 15 to 20 years, the world needs a new wave of antibiotics. Without them infections are becoming harder, and inevitably impossible, to treat.” All of the company’s therapeutic candidates were discovered internally, according to Venatorx. Its most advanced development-stage product is taniborbactam, an injectable beta-lactamase inhibitor (BLI). Beta-lactamase inhibitors block the activity of beta-lactamase enzymes and keep beta-lactam antibiotics from degrading. Venatorx executives believe that taniborbactam, in combination with cefepime, the fourth generation cephalosporin, could provide a broad-spectrum treatment option to meet unmet medical needs in patients with infections caused by carbapenem-resistant pathogens, including carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA); suspected polymicrobial infections caused by both gram-negative and gram-positive susceptible pathogens; and engineerable bioterror pathogens, such as Burkholderia. Venatorx is currently enrolling a Phase III clinical trial of cefepime-taniborbactam in patients with complicated urinary tract infections (cUTIs). The trial will assess the safety and efficacy of cefepime-taniborbactam compared with meropenem (another antibiotic) in adults with cUTI, including acute pyelonephritis. Cefepime-taniborbactam is also under development for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). Venatorx’s second development-stage product is VNRX-7145, an orally bioavailable BLI that, in combination with the third generation orally bioavailable cephalosporin, ceftibuten, has the potential to protect the partner antibiotic against extended spectrum beta-lactamases and key CRE – including those expressing Klebsiella pneumoniae carbapenemase and Oxacillinase carbapenemases. The candidate is intended to treat patients with infections caused by MDR gram-negative pathogens that are resistant to current standard-of-care oral and intravenous antibiotics, including fluoroquinolones, cephalosporins and carbapenems. In July, Venatorx announced positive top line results for its Phase I single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial of VNRX-7145. The Phase I study was a two-part, first-in-human dose-ranging study intended to evaluate the safety and pharmacokinetics of escalating oral doses of the drug. In part one, subjects received single ascending doses of VNRX-7145. In part two, subjects received multiple escalating doses of VNRX-7145 for 10 days. There were no serious adverse events, and VNRX-7145 was well-tolerated up to the highest single or multiple doses administered, the company said. VNRX-7145 had excellent oral bioavailability, dose-proportional pharmacokinetics across the doses studied and readily achieved efficacy exposure targets identified in non-clinical studies. Venatorx is continuing the development of VNRX-7145 with a Phase I drug-drug interaction study, which will provide an initial assessment of the safety and pharmacokinetics of single and multiple doses of VNRX-7145 and ceftibuten, when co-administered. Top line results are expected during the fourth quarter of 2021. Hope for Hepatitis B Sufferers On another front, more than 250 million individuals chronically infected with chronic Hepatitis B Virus (HBV) worldwide are at risk from complications due to liver disease and liver cancer. Venatorx is developing VNRX-9945, a core protein allosteric modulator (CpAM), for the treatment of chronic HBV infection. VNRX-9945 is a third-generation, highly potent dual-mechanism viral replication inhibitor with activity against both nucleocapsid assembly and formation of cccDNA. In preclinical studies, it demonstrated broad antiviral activity against multiple HBV genotypes in vitro and suppresses HBV DNA to below the lower limit of qualification in a mouse model of HBV infection. In late June, Venatorx announced that the first patient was dosed in a Phase I clinical trial evaluating VNRX-9945, which will evaluate the safety and pharmacokinetics of single and multiple ascending doses of VNRX-9945, administered orally in healthy adult volunteers. “Current front-line therapies only partially suppress HBV replication, are not curative and require therapy for an indefinite duration, adding to patient burden,” explained Burns. “Novel inhibitors of HBV are required to further suppress viral replication and provide the conditions required to achieve immune control, termed a ‘functional cure’.” Concurrently, Venatorx is developing a novel class of non-beta-lactam molecules that kill bacteria by the same selective mechanism as beta-lactams, blocking cell wall synthesis via binding to the bacterial penicillin binding proteins (PBPs). These new molecules have been designed to be impervious to degradation by any beta-lactamases. Acinetobacter baumannii (A. baumannii) is ranked as a “Priority 1: Critical” carbapenem resistant pathogen on the World Health Organization’s list of bacteria for which new antibiotics are urgently needed. A. baumannii is primarily associated with hospital-acquired infections and has become resistant to a large number of antibiotics, including carbapenems and third generation cephalosporins – the best-known available antibiotics for treating MDR bacteria. In 2020, the National Institute of Allergy and Infectious Diseases awarded Venatorx $3.2 million to advance its novel series of PBP Inhibitors targeting MDR A. baumannii through Phase I clinical testing. There is the potential to receive up to $44.2 million, if all project milestones are met. Venatorx also is developing an oral penicillin-binding protein inhibitor (PBPi) to address the growing problem of resistance in Neisseria gonorrhoeae to the last resort antibiotic for outpatient use, ceftriaxone. Venatorx has identified non-beta-lactam transpeptidase inhibitors that are rapidly bactericidal, impervious to beta-lactamases, and show promising selective activity against gonococci, including both wild-type strains and isolates with PBP variants that confer ceftriaxone resistance. In 2019, the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) awarded Venatorx up to $4.1 million in non-dilutive funding, with the possibility of up to an additional $8.9 million if certain project milestones are met. CARB-X funding will help Venatorx progress these early molecules from hit-to-lead through IND-enabling studies. “Normally an unmet medical need is confronted by big pharma,” noted Burns. “But for antibiotics specifically, today's reimbursement rates effectively penalize physicians and hospitals for prescribing newer, more advanced antibiotics. Thus, pharma sees that the revenue and profit from investing 5 to 10 years to develop a new antibiotic will not yield a return on the investment, and have largely moved to the sidelines. Fixing a Broken Economic Model “An improved economic model is needed,” he continued, “one that incentivizes and supports antibiotic innovation and ensures that medicines are available when needed and new drugs are constantly in the pipeline. Burns highlighted two proposed remedies. “There are two obvious solutions that policymakers could implement with the stroke of a pen,” he said. “Pass the PASTEUR Act, a government subscription plan that incentivizes and rewards the small innovative biotech companies for investing years of blood, sweat and tears to solve this societal problem; and pass the DISARM Act (Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms Act) or an equivalent, that removes the economic noose from around the neck of physicians and hospitals when they want to prescribe a life-saving new antibiotic but are currently dissuaded.”