A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, CROSSOVER STUDY TO DETERMINE THE BE OF NIRMATRELVIR FOLLOWING ORAL ADMINISTRATION OF FDC TABLETS RELATIVE TO THE PAXLOVID® COMMERCIAL TABLETS IN HEALTHY ADULT PARTICIPANTS UNDER FASTED CONDITIONS

Medicines that may have different names or be made in different ways but have the same effect on the body are called bioequivalent.
The purpose of this study is to learn about the bioequivalence of nirmatrelvir plus ritonavir after taking 2 different combination tablet forms by mouth. These combination tablets are compared to the tablet formulation that is already in the market. This study will be done under fasted conditions in healthy adult participants.
This study is seeking participants who are:
Male and non-pregnant female participants aged 18 years and above.
with a body weight of more than 50 kilograms and Body Mass Index (BMI) between 16 to 32 kilograms per meter squared.
are healthy as confirmed by medical history, physical examination, laboratory tests.
The study will also look at the safety and tolerability of nirmatrelvir plus ritonavir combination tablet and marketed tablet formulations in healthy adult participants.
The study will consist of 4 treatments:
Treatment A: Single oral dose of nirmatrelvir plus ritonavir 150 (1 × 150)/100 milligrams marketed tablets under fasted conditions (Reference 1) Treatment B (low dose strength): Single oral dose of nirmatrelvir plus ritonavir 150/100 milligrams (2 × [75/50 milligrams]) combination tablets under fasted conditions (Test 1) Treatment C: Single oral dose of nirmatrelvir/ritonavir 300 (2 × 150)/100 milligrams marketed tablets under fasted conditions (Reference 2) Treatment D (high dose strength): Single oral dose of nirmatrelvir/ritonavir 300/100 milligrams (2 × [150/50 milligrams]) combination tablets under fasted conditions (Test 2)
All treatments will be given under fasted conditions. Fasted condition means the participants would not have had anything to eat before taking the medicines.
Around 28 participants will be enrolled in the study. Healthy participants will be tested to see if they can be in the study within 28 days before receiving the study medicine. Selected participants will be admitted to the clinical research unit (CRU) one day before receiving the study medicine and will remain in the CRU until discharge after completing all the treatment periods.
On Day 1 of each period, participants will be given a single dose of study medicine nirmatrelvir/ritonavir 300/100 mg or 150/100 mg by mouth by chance. Study medicine will be given with approximately 240 milliliters of room temperature water under fasted conditions (overnight fast of at least 10 hours and no food until 4 hours after receiving the study medicine). Blood samples will be collected at different times of the day up to 48 hours after taking the study medicine. Participants will be discharged from the CRU on Day 3 of Period 4, after all the study related procedures have been completed.
A follow-up call will be made to participants around 28 to 35 days from receiving the final dose of the study medicine. The study will look at the experiences of participants receiving the study medicine. This will help to understand if the study medicine is safe and effective.

开始日期2025-02-14

申办/合作机构

Pfizer Inc.

NCT05997485 / WithdrawnN/A

A Retrospective Observational Non-Interventional Study (NIS) to Assess Patient Characteristics Among COVID-19 Patients Receiving Treatment With Nirmatrelvir/Ritonavir (PAXLOVIDTM) in Morocco.

The purpose of this study is to collect information on the:
general information of a group of people such as their age, sex, and other facts.
clinical information of the patients such as any other illness before having COVID 19.
In adult patients with COVID-19 who have been prescribed nirmatrelvir and ritonavir treatment.
This study will be conducted in Morocco. The study will capture information of the adult COVID-19 outpatients and inpatients who have been prescribed nirmatrelvir, ritonavir treatment. The inpatients will be admitted in the hospital for other reasons than COVID-19.
This study will have about 150 patients. The study will involve collection of patient information from medical records. The information collected can be either from papers or from computers.
The study will include patient information of those who:
are confirmed to have COVID-19 infection during the study period from 01 June 2022 to 30 June 2023.
are 18 years of age or older.
are prescribed Nirmatrelvir and ritonavir. This study will help to inform decision-making on use of Paxlovid at the national level.

开始日期2024-03-30

申办/合作机构

Pfizer Inc.

NCT06291831 / CompletedN/A

A Retrospective Observational Non-Interventional Study (NIS) to Assess Patient Characteristics and Healthcare Resource Use (HRU) Among COVID-19 Patients With or Without Nirmatrelvir/Ritonavir (PAXLOVID™) Treatment in the Kingdom of Bahrain.

The purpose of this study is to collect information on the:
general information of a group of people such as their age, sex
clinical information of the patients such as any other illness before having COVID 19.
the number of COVID-19 patients who meet and follow the most up to date World Health Organization (WHO) recommendations for medication to treat COVID-19 (such as version 14, published 10Nov2023) compared to Kingdom of Bahrain national recommendations
adult COVID-19 patients' health care resource use and outcomes within the 28-day period In adult patients with COVID-19 who have been prescribed nirmatrelvir and ritonavir treatment.
This study will be conducted in the Kingdom of Bahrain. The study will capture information of the adult COVID-19 outpatients and inpatients who have been prescribed nirmatrelvir, ritonavir treatment and those not treated with nirmatrelvir, ritonavir.
This study will have about 3000 patients treated with Paxlovid™ therapy and 1000 were not. The study will involve collection of patient information from medical records. The information collected can be either from papers or from computers.
The study will include patient information of those who:
had COVID-19 infection during the study period from 16 February 2022 to 30 November 2022.
are 18 years of age or older. This study will help to inform decision-making on use of Paxlovid at the national level.

开始日期2024-03-13

申办/合作机构

Pfizer Inc.

100 项与奈玛特韦/利托那韦相关的临床结果

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100 项与奈玛特韦/利托那韦相关的转化医学

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100 项与奈玛特韦/利托那韦相关的专利（医药）

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374

项与奈玛特韦/利托那韦相关的文献（医药）

2024-04-10·Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Review: The Landscape of Antiviral Therapy for COVID-19 in the Era of Widespread Population Immunity and Omicron-Lineage Viruses

Review

作者: Meyerowitz, Eric A ; Li, Yijia

Abstract:

The goals of coronavirus disease 2019 (COVID-19) antiviral therapy early in the pandemic were to prevent severe disease, hospitalization, and death. As these outcomes have become infrequent in the age of widespread population immunity, the objectives have shifted. For the general population, COVID-19–directed antiviral therapy should decrease symptom severity and duration and minimize infectiousness, and for immunocompromised individuals, antiviral therapy should reduce severe outcomes and persistent infection. The increased recognition of virologic rebound following ritonavir-boosted nirmatrelvir (NMV/r) and the lack of randomized controlled trial data showing benefit of antiviral therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for standard-risk, vaccinated individuals remain major knowledge gaps. Here, we review data for selected antiviral agents and immunomodulators currently available or in late-stage clinical trials for use in outpatients. We do not review antibody products, convalescent plasma, systemic corticosteroids, IL-6 inhibitors, Janus kinase inhibitors, or agents that lack Food and Drug Administration approval or emergency use authorization or are not appropriate for outpatients.

2024-04-01·Journal of peptide science : an official publication of the European Peptide Society

Antiviral peptides inhibiting the main protease of SARS‐CoV‐2 investigated by computational screening and in vitro protease assay

Article

作者: Stewart, James ; Sufian, Md Abu ; McShan, Andrew C ; Faddis, Ryan ; Jia, Ruoqing ; Rupa, Sharmin Akther ; Shahinuzzaman, A D A ; Rahman, Khondaker Miraz ; Bourque, Cole ; Al-Adhami, Taha ; Islam, Rajib ; Halim, Mohammad A ; Ali, Md Ackas ; Stone, Kaylee ; Shawon, Jakaria ; Williams, Blaise

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) plays an important role in viral replication and transcription and received great attention as a vital target for drug/peptide development. Therapeutic agents such as small‐molecule drugs or peptides that interact with the Cys–His present in the catalytic site of Mpro are an efficient way to inhibit the protease. Although several emergency‐approved vaccines showed good efficacy and drastically dropped the infection rate, evolving variants are still infecting and killing millions of people globally. While a small‐molecule drug (Paxlovid) received emergency approval, small‐molecule drugs have low target specificity and higher toxicity. Besides small‐molecule drugs, peptide therapeutics are thus gaining increasing popularity as they are easy to synthesize and highly selective and have limited side effects. In this study, we investigated the therapeutic value of 67 peptides targeting Mpro using molecular docking. Subsequently, molecular dynamics (MD) simulations were implemented on eight protein–peptide complexes to obtain molecular‐level information on the interaction between these peptides and the Mpro active site, which revealed that temporin L, indolicidin, and lymphocytic choriomeningitis virus (LCMV) GP1 are the best candidates in terms of stability, interaction, and structural compactness. These peptides were synthesized using the solid‐phase peptide synthesis protocol, purified by reversed‐phase high‐performance liquid chromatography (RP‐HPLC), and authenticated by mass spectrometry (MS). The in vitro fluorometric Mpro activity assay was used to validate the computational results, where temporin L and indolicidin were observed to be very active against SARS‐CoV‐2 Mpro with IC50 values of 38.80 and 87.23 μM, respectively. A liquid chromatography–MS (LC–MS) assay was developed, and the IC50 value of temporin L was measured at 23.8 μM. The solution‐state nuclear magnetic resonance (NMR) structure of temporin L was determined in the absence of sodium dodecyl sulfate (SDS) micelles and was compared to previous temporin structures. This combined investigation provides critical insights and assists us to further develop peptide inhibitors of SARS‐CoV‐2 Mpro through structural guided investigation.

2024-03-01·Journal of molecular graphics & modelling

Discovery of pyrimidoindol and benzylpyrrolyl inhibitors targeting SARS-CoV-2 main protease (Mpro) through pharmacophore modelling, covalent docking, and biological evaluation

Article

作者: Rabeh, Wael M ; Atatreh, Noor ; Mohamed, Feda E ; Mahgoub, Radwa E ; Ferreira, Juliana ; Ali, Bassam R ; Ghattas, Mohammad A

The main protease (M^pro) enzyme has an imperative function in disease progression and the life cycle of the SARS-CoV-2 virus. Although the orally active drug nirmatrelvir (co-administered with ritonavir as paxlovid) has been approved for emergency use as the frontline antiviral agent, there are a number of limitations that necessitate the discovery of new drug scaffolds, such as poor pharmacokinetics and susceptibility to proteolytic degradation due to its peptidomimetic nature. This study utilized a novel virtual screening workflow that combines pharmacophore modelling, multiple-receptor covalent docking, and biological evaluation in order to find new M^pro inhibitors. After filtering and analysing ∼66,000 ligands from three different electrophilic libraries, 29 compounds were shortlisted for experimental testing, and two of them exhibited ≥20% inhibition at 100 μM. Our top candidate, GF04, is a benzylpyrrolyl compound that exhibited the highest inhibition activity of 38.3%, with a relatively small size (<350 Da) and leadlike character. Interestingly, our approach also identified another hit, DR07, a pyrimidoindol with a non-peptide character, and a molecular weight of 438.9 Da, reporting an inhibition of 26.3%. The established approach detailed in this study, in conjunction with the discovered inhibitors, has the capacity to yield novel perspectives for devising covalent inhibitors targeting the COVID-19 M^pro enzyme and other comparable targets.

1,336

项与奈玛特韦/利托那韦相关的新闻（医药）

2024-06-17

·赛柏蓝

全球制药企业TOP50公布，4家中国药企上榜

编者按：本文来自药智头条，作者在水；赛柏蓝授权转载，编辑凯西近日，美国《制药经理人》杂志（Pharm Exec）官网公布了2024年全球制药企业TOP50榜单。 01 4家中国企业上榜 2024年Pharm Exec 50 榜单基于全球药企处方药销售额的最新排名，结合了Evaluate Pharma 网站发布的2023年全球畅销药品收入数据，该榜单还涵盖了各企业2023年畅销药销售额以及全年研发投入数据。从总体上看，全球bigpharma仍然保持着强劲和稳定的发展势头，今年Top 10依旧是全球第一梯队企业间的角逐。由于新冠相关产品营收大跳水，辉瑞结束了连续两年的“领头羊”地位，全球排名从榜首跌至第六位。强生则得益于其多样化的产品组合推动，以534.6亿美元的处方药销售额登顶Top 1宝座。此外，纵观榜单，有4家中国企业上榜，排名最高的为云南白药，位列第33位，中国生物制药位于第38位，上海医药排名第42位，而恒瑞医药则排在第48位。落榜两年后，云南白药重新回归，且在中国药企中排名第一。2023年，云南白药实现了391.11亿元的营收，同比增长7.19%，扣非净利润达到37.64亿元，同比增长16.45%，创下了同期的历史新高。中国生物制药连续第六年上榜，且排名稳步上升，全球排名第38位。 2023年，中国生物制药研发投入达44亿元，占比达到16.8%。其中，创新药投入占总研发费用的77%。全年创新产品收入达98.9亿元，创新产品数量由2015年的2个快速攀升至2023年末的11个，创新收入占比从11%迅速提升至38%。虽排名较去年下降一位，但今年上海医药连续第五年上榜，同中国生物制药排名稳定。2023年，上海医药医药工业板块营收超260亿元，主要得益于参麦注射液、丹参酮ⅡA磺酸钠注射液和硫酸羟氯喹片等产品的贡献。恒瑞医药今年的排名也略有下滑，从2023年第43位降至第48位。值得注意的是，2023年还入围榜单的石药集团，在本年度未能继续入围。 02 新冠泡沫重塑竞争格局今年的榜单数据中最引人注目的莫过于辉瑞结束了两年的榜首蝉联，遗憾跌出前五。随着 COVID-19 疫苗和疗法需求的急剧下降，2023 年辉瑞处方药收入骤降47.2%。尽管其mRNA疫苗Comirnaty的总收入仍达到112亿美元，但与2022年的峰值相比大幅下滑了70.3%，而其抗病毒药物Paxlovid在2022年创造了189.3亿美元的收入后，2023年也出现了大幅下滑。不过，辉瑞在 2023 年 12 月以 430 亿美元的价格完成了对ADC先驱 Seagen 的收购，有望使得辉瑞在2025年排名中略有上升。此外，辉瑞高管曾公开表示，到 2030 年公司将至少开发出八种抗癌新药。而其他以 COVID 产品为核心的企业也面临同样的命运。如 Moderna，该公司的排名从去年的第 18 位下降到了今年的第 29 位，COVID-19 疫苗Spikevax 销售额下降了 63. 8%。辉瑞 Comirnaty 合作伙伴 BioNTech今年更是退出了50 强，2023年曾排名第 47 位。曾凭借新冠疫苗自救的Novavax 公司2023年成功占据最后一席，但今年同样无缘榜单。此外，阿斯利康于 5 月初宣布在全球范围内撤出其 COVID 疫苗，不过此举可能不会对其未来的发展产生太大影响，今年的排名与去年持平，依旧稳居第八位。凭借其多样化产品组合的亮眼表现，强生今年取代辉瑞一举夺魁。2023年处方药销售额达 534.6 亿美元，其中有两种治疗药物跻身2023年畅销药Top 10，包括需长期使用的IL-12/23抑制剂 Stelara，该药专利已于2023年过期，不过直到 2025 年才会在市场上面临与生物类似药展开竞争；另一款为单克隆抗体 Darzalex，该药的销售额飙升了 39.7%，巩固了该药在多发性骨髓瘤领域的地位。艾伯维再次蝉联第二，尽管销售额下降了6.1%，降至 527.3 亿美元。全年销售额的下降反映了美国市场推出的 Humira 生物类似药所带来的影响。尽管两款接力产品Skyrizi和Rinvoq继续保持良好表现，分别增长了50.3%和57.4%，但原研药的销售额还是下降了32.2%，使得艾伯维在连续数年蝉联全球第一后丢掉了第一的宝座。跻身Top 5行列的还有诺华、默沙东和罗氏。诺华名次较2023年上升一位，位列探花之位；默沙东也取得了2.5%的总体增长，其PD-1抗体Keytruda（已获批用于治疗17种癌症）销售额增长了19.5%，从Humira手中抢走了药王的衣钵。排在辉瑞之后的第7位是百时美施贵宝，阿斯利康排在第8位，赛诺菲和葛兰素史克分别位列第9和第10位。 03 GLP-1继续搅动风云 Pharm Exec 在2023年发布榜单报告时就曾指出，诺和诺德和礼来在GLP-1 受体激动剂千亿蓝海展开了强强对决，并成为全球市值最高的两大药企，在今年的50强榜单中排名也有所提升。诺和诺德2023年处方药销售额激增 32.8%，达到 337 亿美元，其排名从第 13 位跃升至第 11 位。Ozempic（司美格鲁肽降糖注射版）已获批用于治疗2型糖尿病，2023年销售额飙升62.1%，达到139亿美元，成功跻身百亿美元药物的行列。Wegovy（司美格鲁肽减重注射版）于2021年6月获准用于治疗肥胖症，2023年营收达到45.5亿美元。礼来虽然排名落后于诺和诺德，但今年排名依旧上升一位，升至第 12 位，2023年产品销售额猛增 25.2%，高达319亿美元。同为GLP-1 受体激动剂的Mounjaro（替尔泊肽）于 2022 年 5 月获得 FDA 批准用于治疗糖尿病，并于 2023 年 11 月获得批准用于减肥（品牌名称为 Zepbound），上市后的第一个完整年度就创造了 52 亿美元的销售额，并迅速成长为礼来第二大畅销药。据Evaluate Pharma网站预测，到 2028 年，替尔泊肽的总销售额将达到 170 亿美元。虽然准入、报销和供应问题在一定程度上给GLP-1产品市场蒙上了阴影，但Wegovy和Zepbound在减肥领域如日中天的崛起和吸收率却有目共睹。据报道，基于这两款药物在呼吸系统疾病、心力衰竭和睡眠呼吸暂停等一系列其他适应症上的前景，以及其他新一代 GLP-1 激动剂的潜力，部分专家预测，到 2030 年代初，这些疗法的全球销售额将达到约 1500 亿美元。同时，预计该领域的合作和交易活动也将升温。在《通货膨胀削减法》，药品定价审查、供应链中断和畅销药专利到期，以及生物类似药竞争等多重因素影响下，2024的Top 50排名经历了大洗牌。无论是实力强大的big pharma还是迅速崛起的潜力biotech，都需要采取新的战略决策和行动应对挑战。附：2023年全球畅销药Top 10 附2024年全球制药企业Top 50 END 内容沟通：13810174402 医药代表交流群扫描下方二维码加入银发经济市场机遇交流群扫描下方二维码加入左下角「关注账号」，右下角「在看」，防止失联

并购信使RNA疫苗财报抗体药物偶联物

2024-06-16

·AIDD Pro

【第一百三十一期】AI+药物研发领域一周资讯

前言 AIDD Pro 根据国内外各大网站以及人工智能药物设计主流新闻网站及公众号，从 AIDD会议、AIDD招聘，重大科研进展、行业动态、最新报告发布等角度，分析挖掘了每周人工智能辅助药物设计领域所发生的、对领域技术发展产生重大推动作用的事件，旨在帮助 AIDD领域研究人员和业内人士及时追踪最新科研动态、洞察前沿热点。如果您觉得符合以上要求的内容我们有遗漏或者更好建议，欢迎后台留言。科研进展2024年6月14日【图注意网络】J. Chem. Theory Comput. | 推进力场参数化：一种有向图注意网络方法2024年6月13日【药物发现】ACS Omega | 选定抗生素的药物再利用：癌症药物发现的一种新兴方法2024年6月13日【酶抑制剂】J. Med. Chem. | 含有芳基羧酸片段的1,2,4-恶二唑衍生物作为沙贝病毒木瓜蛋白酶样抑制剂的设计、合成和生物学评价2024年6月13日【化学空间】J. Chem. Inf. Model. | 隐式化学空间中的进化多目标分子优化2024年6月12日【强化学习】J. Med. Chem. | 基于强化学习模型的综合可行导联分子从头设计：人工智能辅助发现靶向CXCR4的抗IBD导联2024年6月12日【SARS-CoV-2】ACS Chem. Biol. | SARS-CoV-2 Mpro的高分辨率底物特异性分析与SARS-CoV Mpro的比较具体信息，请滑动下方文字 1.【图注意网络】力场(FFs)是一种成熟的模拟大型复杂分子系统的工具。然而，参数化FFs是一项具有挑战性且耗时的任务，它依赖于经验启发法、实验数据和计算数据。最近的努力旨在使用预先存在的数据库和动态从头算数据自动分配FF参数。在这项研究中，我们提出了一个基于图的力场(GB-FFs)模型，直接从化学环境中推导出广义琥珀力场(GAFF)的参数，并研究了功能形式的影响。我们的端到端参数化方法通过聚集定向分子图中的基本信息来预测参数，消除了对专家定义程序的需要，并提高了GAFF在更广泛的分子复合物中的准确性和可移植性。仿真结果与原GAFF参数化进行了比较。实际上，我们的研究结果表明，该模型的可转移性得到了改善，表明其在模拟分子间和扭转相互作用方面的准确性得到了提高，同时溶剂化自由能也得到了改善。本文提出的优化方法完全适用于其他非极化ff和极化ff。链接网址：https://pubs-acs-org.libproxy1.nus.edu.sg/doi/10.1021/acs.jctc.3c01421 DOI：https://doi-org.libproxy1.nus.edu.sg/10.1021/acs.jctc.3c01421 2.【药物发现】药物再利用是一种研究先前批准的药物的新治疗应用的方法。这种对“旧”药物进行再利用的方法现在非常有效，易于安排，具有成本效益，并且在治疗包括癌症在内的各种疾病方面几乎没有失败的风险。药物再利用是目前癌症治疗的一个重要研究课题。这是一种探索现有药物的最新治疗应用的方法。从理论上讲，与创造新分子实体的公认挑战相比，重新利用策略具有各种优势，包括更快、更安全、更容易、更便宜。在现实世界中，一些药物已经被重新利用，包括阿司匹林、二甲双胍和氯喹。然而，医生和科学家在重新利用药物时面临着许多挑战，比如大多数药物不具有成本效益，而且对细菌有抗药性。因此，这篇综述的目的是收集有关重新利用药物的信息，使其更具成本效益，使细菌更难抵抗。癌症患者更容易受到细菌感染。由于他们的免疫系统较弱，抗生素有助于保护他们免受各种传染病的侵害。虽然抗生素不是免疫增强剂，但它们确实通过杀死细菌和减缓癌细胞的生长而有益于防御系统。它们的使用也增加了治疗效果，并有助于避免复发。近年来，由于真核生物的原核基因组和线粒体DNA之间的进化关系，抗生素已被重新用作有效的抗癌药物。抗癌抗生素通过干扰癌细胞的DNA和阻断启动子的生长来阻止癌细胞的生长，包括蒽环类药物、柔红霉素、表柔红霉素、米托蒽醌、阿霉素和伊达柔红霉素，这是另一种经fda批准用于治疗癌症的抗生素。根据内共生假说，原核生物和真核生物被认为具有进化关系。因此，在这项研究中，我们正试图探索治疗疾病(包括癌症)所必需的抗生素，帮助人们减少与各种感染相关的死亡，并大幅延长人们的预期寿命和生活质量。链接网址：https://pubs-acs-org.libproxy1.nus.edu.sg/doi/10.1021/acsomega.4c00617 DOI：https://doi-org.libproxy1.nus.edu.sg/10.1021/acsomega.4c00617 3.【酶抑制剂】木瓜蛋白酶(PLpro)因其在SARS-CoV-2生命周期中的关键作用而成为一个有希望的治疗靶点。基于SARS-CoV-2 PLpro-GRL0617配合物结构，通过成环策略设计合成了一系列1,2,4-恶二唑衍生物。系统构效关系研究表明，在GRL0617中引入恶二唑和芳基羧酸基团增强了GRL0617对PLpro的酶抑制活性、亲和力和去泛素化能力。1,2,4- oxadiazole化合物13f和26r具有PLpro抑制活性(IC50分别为1.8和1.0 μM)和抗病毒活性(EC50分别为5.4和4.3 μM)，在小鼠体内具有良好的代谢稳定性(t1/2 > 93.2 min)和较高的血浆暴露量(AUC0-t分别为17,380.08和24,289.76 ng·h/mL)。特别是化合物26r具有39.1%的中等口服生物利用度和较强的抗病毒活性，值得进一步的体内研究。我们的发现为发现靶向PLpro的抗病毒药物提供了新的见解。链接网址：https://pubs-acs-org.libproxy1.nus.edu.sg/doi/10.1021/acs.jmedchem.4c00534 DOI：https://doi-org.libproxy1.nus.edu.sg/10.1021/acs.jmedchem.4c00534 4.【化学空间】优化技术在推进药物开发中发挥着关键作用，作为许多生成方法的基础，可以有效地设计从现有先导化合物衍生的优化分子。然而，现有的方法在生成同时优化多种药物性质的多样化、新颖和高性质的分子时经常遇到困难。为了克服这个瓶颈，我们提出了一个多目标分子优化框架(MOMO)。MOMO在分子序列水平上采用了一种特别设计的基于帕累托的多属性评估策略来指导隐式化学空间中的进化搜索。通过对MOMO与五种最先进的方法在两个基准多性质分子优化任务中的比较分析表明，MOMO在多样性、新颖性和优化性质方面明显优于它们。MOMO在药物发现中的实际适用性也在现实世界发现问题中的四个具有挑战性的任务中得到了验证。这些结果表明，MOMO可以为解决具有多种性质的分子优化问题提供一个有用的工具。链接网址：https://pubs-acs-org.libproxy1.nus.edu.sg/doi/10.1021/acs.jcim.4c00031 DOI：https://doi-org.libproxy1.nus.edu.sg/10.1021/acs.jcim.4c00031 5.【强化学习】人工智能(AI)从头分子生成为药物发现提供了新结构的线索。然而，所生成分子的靶亲和力和可合成性对人工智能技术的成功应用提出了关键挑战。因此，我们开发了一种先进的强化学习模型，以弥合从头分子生成理论与药物发现实际方面之间的差距。该模型以化学反应模板和市售积木为起点，采用正向反应预测生成分子，同时进行实时对接和药物相似度预测，确保可合成性和药物相似度。我们应用该模型设计了靶向炎症相关受体CXCR4的活性分子，并根据ai提出的合成路线成功制备了活性分子。在随后的体外和体内实验中，一些分子表现出有效的抗cxcr4和抗炎活性。表现最好的化合物XVI缓解了炎症性肠病的相关症状，并表现出合理的药代动力学特性。链接网址：https://pubs-acs-org.libproxy1.nus.edu.sg/doi/10.1021/acs.jmedchem.4c00184 DOI：https://doi-org.libproxy1.nus.edu.sg/10.1021/acs.jmedchem.4c00184 6.【SARS-CoV-2】来自COVID-19的SARS-CoV-2 Mpro蛋白酶在病毒成熟过程中在11个位点切割pp1a和pp2b多蛋白，是Nirmatrelvir的靶标，Nirmatrelvir是一线治疗药物Paxlovid的两种成分之一。我们利用YESS 2.0平台，结合蛋白酶和底物在酵母内质网中的表达、荧光活化细胞分选和下一代测序，对SARS-CoV-2 Mpro以及SARS 2003中相关的SARS- CoV Mpro进行了高分辨率底物特异性分析。即使在如此高的分辨率下，这两种酶的底物特异性特征基本上是相同的。在我们的分类中分离的裂解底物的种群是如此之深，以至于对SARS-CoV-2多蛋白pp1a和pp2b上不同裂解位点的相对催化效率进行了定性预测。这些结果不仅证明了YESS 2.0/NGS方法在蛋白酶底物特异性分析方面的精确性和可重复性，而且应该有助于设计下一代SARS-CoV-2 Mpro抑制剂，以及类似的SARS-CoV Mpro抑制剂。链接网址：https://pubs-acs-org.libproxy1.nus.edu.sg/doi/10.1021/acschembio.4c00096 DOI：https://doi-org.libproxy1.nus.edu.sg/10.1021/acschembio.4c00096 上下滚动查看更多药企动态2024年6月14日【信诺维】信诺维创新ADC获FDA快速通道资格，治疗胃癌2024年6月13日【晶泰科技】晶泰科技在港交所主板挂牌上市，AI+机器人打造18C第一股2024年6月13日【BMS】BMS新一代ROS1/NTRK抑制剂获FDA批准新适应症2024年6月13日【艾伯维】17.1亿美元！明济生物与艾伯维达成授权协议2024年6月12日【君实生物】全球首个达预设PFS和OS双主要终点阳性！君实PD-1单抗第9项适应症获批！2024年6月12日【诺华】诺华「卡马替尼」在华获批上市各动态具体信息，请滑动下方文字 1.【信诺维】 6月14日，信诺维宣布其研发的靶向Claudin18.2的新一代抗体偶联药物（ADC） XNW27011获得美国FDA授予快速通道资格，用于治疗胃癌。链接网址请戳我 2.【晶泰科技】 2024年6月13日，晶泰科技（2228.HK）正式在香港交易所主板挂牌上市，上市股票发行价格为5.28港元/股，净募集资金约8.96亿港元。香港特别行政区财政司司长陈茂波，香港特别行政区政府创新科技及工业局局长孙东、副局长张曼莉，香港交易所集团主席唐家成、行政总裁陈翊庭出席上市仪式，与晶泰科技联合创始人温书豪、马健、赖力鹏一起，共同见证港交所18C第一股诞生的历史性时刻。链接网址请戳我 3.【BMS】 6月13日，BMS宣布FDA已经加速批准Augtyro（repotrectinib）新适应症，用于12岁及以上儿童和成人神经营养因子受体络氨酸激酶（NTRK）基因融合突变局部晚期或转移性实体瘤患者。链接网址请戳我 4.【艾伯维】 6月13日，明济生物制药（北京）有限公司和艾伯维共同宣布一项开发FG-M701的许可协议。FG-M701是一种用于治疗炎症性肠病的下一代TL1A抗体，目前正处于临床前开发阶段。（去年Sanofi、Roche和Merck均花重金布局TL1A抗体）链接网址请戳我 5.【君实生物】 6月12日，君实生物宣布，已收到国家药品监督管理局核准签发的《药品注册证书》，特瑞普利单抗联合依托泊苷和铂类用于广泛期小细胞肺癌（ES-SCLC）的一线治疗的新适应症上市申请获得批准。链接网址请戳我 6.【诺华】6月12日，诺华宣布，该公司盐酸卡马替尼片（妥瑞达®）获得中国国家药品监督管理局批准上市，用于未经系统治疗的携带间质上皮转化因子（MET）外显子14跳跃突变的局部晚期或转移性非小细胞肺癌（NSCLC）成人患者。链接网址请戳我上下滚动查看更多会议信息 2024年6月20-21日智药邦举办2024人工智能与生物医药生态大会2024年6月27-28日上海求实医药咨询有限公司举办ING 2024第七届免疫及基因治疗论坛2024年8月29-30日上海求实医药咨询有限公司举办ICNS 2024 第四届中枢神经系统药物深度聚焦论坛各会议具体详情和参会方式，请滑动下方文字 2024人工智能与生物医药生态大会主办方：智药邦会议时间：2024年6月20日-21日会议地点：上海会议主旨：充分介绍和讨论AI赋能生物医药领域的前沿进展、重要案例、关键问题和各方思考，加强交流与合作，加速生物制药相关技术和产业的发展。链接网址请戳我 ING 2024第七届免疫及基因治疗论坛主办方：上海求实医药咨询有限公司会议时间：2024年6月27日-28日会议地点：北京会议主旨：聚焦CGT领域开发的核心问题，破除技术壁垒，推动产业不断前进，开启生物医药产业下一个风口！链接网址请戳我 ICNS 2024 第四届中枢神经系统药物深度聚焦论坛主办方：上海求实医药咨询有限公司会议时间：2024年8月29日-30日会议地点：南京会议主旨：深化基础研究，提升药物开发成功率，突破技术瓶颈，并探索新疗法的前沿进展。链接网址请戳我上下滚动查看更多版权信息本文内容均由小编收集于公开的各个网络平台，发布的目的仅为了方便大家一站式了解AIDD行业信息，并未对发布源头进行真实性验证。如您发现相关信息有任何版权侵扰或者信息错误，请及时联系AIDD Pro（请添加微信号sixiali_fox59）进行删改处理。原创内容未经授权，禁止转载至其他平台。有问题可发邮件至sixiali@stonewise.cn 关注我，更多资讯早知道↓↓↓

2024-06-11

·FiercePharma

After M&A stretch, Pfizer CEO says company needs 'breathing period' from large deals

“I don’t foresee ourselves going and buying something sizeable now because I don’t want to disrupt our commercial operations, our research operations or our manufacturing operations,” Pfizer CEO Albert Bourla told investors this week. Amid a recent biopharma M&A resurgence, one major player plans to stay out of the waters after making multiple recent splashes. Though not for lack of business development capacity, Pfizer is currently taking a large dealmaking “breathing period,” CEO Albert Bourla told investors this week at Goldman Sachs’ 2024 annual Global Healthcare Conference in Miami. After spending tens of billions of dollars on Arena Pharmaceuticals, Biohaven Pharma, Global Blood Therapeutics (GBT) and, most recently, Seagen, “[w]e need to catch our breath and make sure that we execute well on those [companies] that we have right now,” Bourla explained. Speaking to some of those recent deals—which Pfizer struck thanks to its trove of COVID pandemic cash—the CEO added that Seagen’s integration into the company is going well and that Biohaven’s migraine med Nurtec ODT has the potential to “surprise us very positively going forward.” “I don’t foresee ourselves going and buying something sizeable now because I don’t want to disrupt our commercial operations, our research operations or our manufacturing operations,” Bourla said. The large M&A pause comes at a crucial time for Pfizer, which said in December that it expects to bring home revenues between $58.5 billion and $61.5 billion this year. That target fell short of analyst consensus of $63.2 billion, with the projected gap largely attributable to plunging demand for the company’s COVID-19 products Comirnaty and Paxlovid. Still, Pfizer’s COVID fortune has helped the company chart a number of high-profile buyouts in recent years, starting with its $6.7 billion deal for immune-inflammatory biotech Arena in December of 2021. The following year, Pfizer acquired much of its migraine partner Biohaven and sickle cell disease-focused GBT for $11.6 billion and $5.4 billion, respectively. That trio of biotech grabs pales in comparison however to Pfizer’s $43 billion buyout of antibody-drug conjugate (ADC) specialist Seagen, which became the largest biopharma M&A transaction since AbbVie’s $63 billion deal for Allergan when it wrapped up in December. The move doubled Pfizer’s pipeline to 60 programs and added four FDA-approved cancer meds in Adcetris, Padcev, Tivdak and Tukysa—giving Pfizer a total of nine oncology drugs that are already blockbusters or have blockbuster potential, Pfizer said late last year. Pfizer has said it expects the Seagen acquisition to tack on an additional $3.1 billion in revenue in 2024 and $10 billion by 2030. That said—in a move familiar to those who track large pharma buyouts—Pfizer has already put the kibosh on a planned Seagen factory, putting more than 100 jobs on the line. In March, the company said it was shutting down construction on a 270,000-square-foot manufacturing plant being built by Seagen in Everett, Washington, some 13 miles north of the Seattle-based company’s current headquarters. Still, Pfizer remains “highly committed to the Seattle side” of Seagen and plans to “develop it even further,” Bourla said during Goldman Sachs’ event. Meanwhile, Pfizer's companywide savings drive went largely undiscussed during the Goldman Sachs conference. After the company spent tens of billions of dollars on M&A in recent years, it's now working to rein in costs through a pair of cost-cutting initiatives. In one campaign, revealed last year, Pfizer aims to achieve $4 billion in savings by the end of 2024. In another, rolled out last month, the company is working to realize $1.5 billion in savings by 2027. Pfizer's downsizing efforts have affected its operations in many places, including in Connecticut, New Jersey, Michigan, California, the U.K., Ireland and beyond. Bourla made his comments this week after heralding 2024 as a “year of execution” earlier this year at the J.P. Morgan Healthcare Conference. At the time, the CEO mentioned that Pfizer this year will “try to consolidate what we already acquired,” noting that the company would stay away from another big acquisition. Pfizer isn’t the only Big Pharma company taking a break from major business development deals, as AstraZeneca looks to slow its roll on technology platform deals in the coming months. “I think we have acquired and built most of what we need for now and we need to execute on what we’ve got,” AZ CEO Pascal Soriot said on a recent earnings call. “But it doesn’t mean, of course, BD will come down to zero.”

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100 项与奈玛特韦/利托那韦相关的药物交易

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适应症	国家/地区	公司	日期
新型冠状病毒感染	韩国	Pfizer Inc.	2021-12-27

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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


ASCO2024	N/A	-	182	Nirmatrelvir/ritonavir	糧簾夢製鏇顧選範顧製(網網艱齋鹹願簾繭網製) = all mild/ moderate, mainly dysgeusia 齋壓醖夢鹹積獵顧願憲 (壓獵鏇艱選艱繭蓋艱憲 )	积极	2024-05-24
NCT04962230 (CTgov)	临床1期	-	12	PF-07321332+Ritonavir (Period1: PF-07321332 300 mg/Ritonavir 100 mg)	鏇憲壓選簾鹽餘蓋製襯(夢鑰觸構獵鹹艱遞鬱蓋) = 網築簾壓蓋鑰襯蓋願鹽餘觸繭選簾襯淵衊醖衊 (醖觸鏇夢衊壓範齋製衊, 積夢鏇衊顧衊鑰醖艱鬱 ~ 範鏇遞遞鑰簾餘獵淵鏇) 更多	-	2023-10-10
				PF-07321332+Carbamazepine+Ritonavir (Period2: Carbamazepine + PF-07321332 300 mg/Ritonavir 100 mg)	鏇憲壓選簾鹽餘蓋製襯(夢鑰觸構獵鹹艱遞鬱蓋) = 鹽衊醖顧餘淵餘積繭網餘觸繭選簾襯淵衊醖衊 (醖觸鏇夢衊壓範齋製衊, 壓觸鹽鬱蓋製願艱觸觸 ~ 簾衊顧淵遞網觸簾鏇遞) 更多
NCT05129475 (CTgov)	临床1期	-	12	PF-07321332+Ritonavir (PF-07321332 300 mg/Ritonavir 100 mg Fed)	簾選鏇築鹹廠齋網廠齋(夢齋鬱夢壓網糧壓窪夢) = 淵蓋鹹築顧築憲遞簾淵鑰選憲構遞範範鹹鹹廠 (窪鏇鹹願衊遞衊憲範鑰, 選淵鏇遞網鹹繭膚築築 ~ 範繭顧網衊選築構鬱鬱) 更多	-	2023-10-05
				PF-07321332+Ritonavir (PF-07321332 300 mg/Ritonavir 100 mg Fasted)	簾選鏇築鹹廠齋網廠齋(夢齋鬱夢壓網糧壓窪夢) = 獵壓願遞廠簾構糧鏇鹹鑰選憲構遞範範鹹鹹廠 (窪鏇鹹願衊遞衊憲範鑰, 餘廠顧築糧衊選憲衊鬱 ~ 餘鹽襯遞選艱鬱鏇醖築) 更多
NCT05032950 (CTgov)	临床1期	新型冠状病毒感染	12	Midazolam (Midazolam 2 mg)	製壓範築簾簾餘艱築膚(艱膚鑰鑰顧範簾構範衊) = 選願壓膚夢獵築蓋憲齋鑰鑰齋糧獵範鬱壓艱蓋 (淵鑰襯顧餘積衊衊構製, 窪網積壓遞襯憲齋淵蓋 ~ 鬱獵觸蓋遞廠積鹹夢壓) 更多	-	2023-10-04
				PF-07321332+Midazolam+Ritonavir (PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg)	製壓範築簾簾餘艱築膚(艱膚鑰鑰顧範簾構範衊) = 膚鏇糧壓鹽鹹鏇顧鬱壓鑰鑰齋糧獵範鬱壓艱蓋 (淵鑰襯顧餘積衊衊構製, 壓廠鹽獵夢蓋鹽廠餘餘 ~ 簾衊遞襯蓋膚窪顧餘獵) 更多
NCT04909853 (CTgov)	临床1期	肾功能不全	35	PF-07321332+ritonavir (Part 1: Normal Renal Function)	鑰製範醖夢鹹簾鏇製鹽(衊餘廠觸餘糧糧憲觸鏇) = 艱夢簾鏇壓夢壓築願鹽蓋窪醖鏇艱膚淵夢蓋醖 (範繭構簾遞積築糧簾蓋, 糧觸製壓簾願選夢廠廠 ~ 夢鹽衊築範壓鑰簾膚壓) 更多	-	2023-08-02
				PF-07321332+ritonavir (Part 1: Mild Renal Impairment)	鑰製範醖夢鹹簾鏇製鹽(衊餘廠觸餘糧糧憲觸鏇) = 範選繭獵網壓餘築齋糧蓋窪醖鏇艱膚淵夢蓋醖 (範繭構簾遞積築糧簾蓋, 衊選範鏇蓋襯選齋憲齋 ~ 鏇鏇蓋醖構餘壓醖積鹽) 更多
NCT04962022 (CTgov)	临床1期	新型冠状病毒感染	12	PF-07321332+Ritonavir (PF-07321332 (Suspension)/Ritonavir 300/100 mg BID, Fasted)	餘製範網構衊醖憲構繭(構鑰網鬱餘範鑰蓋壓顧) = 餘顧願鬱夢鑰淵遞壓範繭廠餘遞鬱顧糧襯憲衊 (範廠鑰範廠範範遞夢蓋, 鹽膚遞範壓簾範構願淵 ~ 廠醖遞鹹糧製鏇鏇廠齋) 更多	-	2023-07-13
				Itraconazole+PF-07321332+Ritonavir (Itraconazole 200 mg QD + PF-07321332(Suspension)/Ritonavir 300/100 mg BID, Fasted)	餘製範網構衊醖憲構繭(構鑰網鬱餘範鑰蓋壓顧) = 鏇鑰膚範餘蓋窪積襯襯繭廠餘遞鬱顧糧襯憲衊 (範廠鑰範廠範範遞夢蓋, 網繭艱積積蓋壓齋鏇膚 ~ 鬱觸選醖廠齋蓋獵膚積) 更多
EPICOVIDEHA (EHA2023)	N/A	血液肿瘤	108	Molnupiravir	襯膚獵醖糧製範艱鏇蓋(壓繭鬱構網構鏇鑰構壓) = 獵齋夢夢蓋廠衊積積淵鹹蓋積選艱網鬱衊範築 (窪願憲醖廠構夢艱鹽鏇 ) 更多	-	2023-06-08
				Nirmatrelvir/Ritonavir	襯膚獵醖糧製範艱鏇蓋(壓繭鬱構網構鏇鑰構壓) = 積餘築齋觸簾艱窪積膚鹹蓋積選艱網鬱衊範築 (窪願憲醖廠構夢艱鹽鏇 ) 更多
NCT04960202 (EPIC-HR, FDA) 人工标引	临床2/3期	新型冠状病毒感染	1,966	PAXLOVID	願蓋壓襯顧顧淵顧鏇選(鏇網醖夢遞壓觸淵淵簾) = 鹽襯憲廠鏇鹹繭鹹壓繭網觸艱顧廠構窪製衊夢 (醖鏇築糧鹽網築醖憲遞 ) 更多	积极	2023-05-25
				Placebo	願蓋壓襯顧顧淵顧鏇選(鏇網醖夢遞壓觸淵淵簾) = 製餘獵艱餘衊鹽淵壓夢網觸艱顧廠構窪製衊夢 (醖鏇築糧鹽網築醖憲遞 ) 更多
NCT04960202 (EPIC-HR, CTgov)	临床2/3期	新型冠状病毒感染	2,246	Placebo	築鹹衊壓獵鹽鏇憲窪蓋(鹽憲壓鬱衊夢衊餘鹹鹹) = 鏇鑰選願醖構簾鑰願壓繭選獵選艱廠鑰築構觸 (餘壓願鑰醖觸積積膚淵, 襯淵鹽簾膚艱醖獵衊廠 ~ 築鹽構獵鬱鬱廠廠願壓) 更多	-	2023-02-09
IMS2022	N/A	多发性骨髓瘤	64	ritonavir-nirmatrelvir	範壓醖淵選糧衊簾築選(廠憲積網製鹽遞鏇壓顧): P-Value = 0.44	-	2022-08-25
				molnupiravir