Ensitrelvir Fumaric Acid in Health care workers with SARS-CoV-2 Retrospective Chart Review - Tokyo Rinkai Hospital - - Ensitrelvir Fumaric Acid in Health care workers with SARS-CoV-2 Retrospective Chart Review - Tokyo Rinkai Hospital -

开始日期2024-04-12

申办/合作机构

Shionogi & Co., Ltd.

NCT06161688 / Recruiting临床2期IIT

Placebo-Controlled, Randomized Trial of Ensitrelvir (S-217622) for Viral Persistence and Inflammation in People Experiencing Long COVID (PREVAIL-LC)

Persistent viral infection with viral reservoirs and detection of circulating spike protein after the initial acute illness is one potential pathogenic mechanism for Long COVID. This mechanism may be susceptible to antiviral therapy that blocks viral replication, which has the potential to alleviate long COVID symptoms. This trial will study the safety and efficacy of Ensitrelvir (S-217622), an antiviral, to treat individuals with Long COVID in an adult population.

开始日期2024-04-09

申办/合作机构

The University of California, San Francisco

[+1]

CTR20240600 / CompletedN/A

富马酸恩昔特韦片人体生物等效性试验

采用单中心、随机、开放、两制剂、两周期交叉、单剂量给药设计比较空腹和餐后给药条件下，远大医药（中国）有限公司提供的富马酸恩昔特韦片（规格：125 mg）与盐野义制药株式会社持证的富马酸恩昔特韦片（规格：125 mg，XOCOVA® Tablets）在中国健康人群中吸收程度和吸收速度的差异，并评价远大医药（中国）有限公司提供的富马酸恩昔特韦片的安全性

开始日期2024-03-21

申办/合作机构

远大医药（中国）有限公司

100 项与恩赛特韦相关的临床结果

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100 项与恩赛特韦相关的转化医学

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100 项与恩赛特韦相关的专利（医药）

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项与恩赛特韦相关的文献（医药）

2025-01-01·BIOORGANIC CHEMISTRY

Development of pyrimidone derivatives as nonpeptidic and noncovalent 3-chymotrypsin-like protease (3CLpro) inhibitors with anti-coronavirus activities

Article

作者: Ou, Weixin ; Yang, Sidi ; Zhang, Hongmin ; Chen, Yongzhi ; Xie, Cailing ; Li, Yingjun ; Zhang, Xumu ; Guo, Deyin ; Hu, Ruiyu ; Chao, Yang ; Pan, Fan ; Yan, Ming ; Zhou, Qifan ; Wen, Yuanmei

3CL^Pro is crucial to the life cycle of SARS-CoV-2 and exhibits high sequence similarity with other coronaviruses, while being absent in human proteases. This makes it an ideal target for developing broad-spectrum antiviral drugs. Ensitrelvir (S-217622) is the only launched non-covalent, non-peptidomimetic 3CL^Pro inhibitor, offering certain advantages in terms of dosage and metabolism. Using S-217622 as the lead, we designed and synthesized 43 pyrimidone derivatives and conducted a systematic evaluation of their structure-activity relationships. Among them, A36 exhibited strong inhibitory activity against several β-coronaviruses and demonstrated low cytotoxicity. A36 also displayed moderate stability in mouse liver microsomes. Co-crystal structure analysis of 3CL^Pro in complex with A36 revealed the similar binding mode with S-217622. A36 shows strong potential as a promising lead for broad-spectrum anti-coronavirus therapy, warranting further investigation.

2024-12-06·Journal of biomolecular structure & dynamics

The binding mechanism of failed, in processing and succeed inhibitors target SARS-CoV-2 main protease

Article

作者: Wu, Tong ; Huang, Junjie ; Niu, Zhangming ; Tang, Bowen ; He, Fengming ; Wang, Xiaofeng ; Hongyu, Hu ; Chao, Ma

Since the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several variants have caused a persistent pandemic. Consequently, it is crucial to develop new potential anti-SARS-CoV-2 drugs with specificity. To minimize potential failures and preserve valuable clinical resources for the development of other useful drugs, researchers must enhance their understanding of the interactions between drugs and SARS-CoV-2. While numerous crystal structures of the SARS-CoV-2 main protease (SCM) and its inhibitors have been reported, they provide only static snapshots and fail to capture the dynamic nature of SCM/inhibitor interactions. Herein, we conducted molecular dynamics simulations for five SCM complexes: ritonavir (SCM/RTV), lopinavir (SCM/LPV), the identified inhibitor N3 (SCM/N3), the approved inhibitor ensitrelvir (SCM/ESV), and the approved drug nirmatrelvir (SCM/NMV). Additionally, we explored the potential for covalent bond formation in the N3 and NMV inhibitors through QM/MM calculations using Umbrella sampling. The results show that the binding site is highly flexible to fit those five different inhibitors and each compound has its unique binding mode at the same binding site. Moreover, the binding affinities of positive and negative inhibitors to SCM exhibit significant differences. By gaining insights into the dynamics, we can potentially elucidate why lopinavir/ritonavir, initially considered promising, failed to effectively treat COVID-19. Furthermore, understanding the mechanistic aspects of N3 and NMV inhibition on SCM not only contributes to rational drug discovery against COVID-19 but also aids future studies on the catalytic mechanisms of main proteases in other novel coronaviruses.Communicated by Ramaswamy H. Sarma.

2024-12-02·MOLECULAR PHARMACEUTICS

Cocrystallization Enables Ensitrelvir to Overcome Anomalous Low Solubility Caused by Strong Intermolecular Interactions between Triazine–Triazole Groups in Stable Crystal Form

Article

作者: Ando, Shigeru ; Nagamatsu, Daiki ; Miyano, Tetsuya ; Watanabe, Yui ; Ueda, Hiroshi ; Sawada, Daichi

Ensitrelvir is a nonpeptide 3CL protease inhibitor used for coronavirus disease 2019 treatment. Four crystalline forms of ensitrelvir, metastable (Form I), acetonate (Form II), stable (Form III), and hydrate (Form IV), have been analyzed as pharmaceutical crystals. Their rank order of solubility is Form I > IV > III. Form III is the stable crystal with a significantly lower solubility than that predicted from its log P value of 2.7. Here, single-crystal structural analysis revealed strong intermolecular interactions between the triazine (acidic) and triazole (basic) groups of Form III not Forms I and IV. Multicomponent crystals were also designed to improve the solubility by altering the intermolecular interactions in Form III. Slurry conversion with equal molar ratios of ensitrelvir and fumaric acid successfully induced the formation of a novel cocrystal (Form V). Fumaric acid inhibited the triazine-triazole interactions, and dissolution of Form V was approximately 8- and 13-fold higher than that of Form III in pH 1.2 and 6.8 media, respectively. Furthermore, Form V exhibited an approximately 16-fold higher flux value than that of Form III. Therefore, alterations in intermolecular interactions via cocrystallization significantly enhance the dissolution and permeation of ensitrelvir.

154

项与恩赛特韦相关的新闻（医药）

2024-11-11

·SYNAPSE

Shionogi Expands its COVID-19 Product Portfolio by Initiating a Phase 1 Clinical Trial in Japan for a Second COVID-19 Antiviral

OSAKA, Japan, May 17, 2023 - Shionogi & Co., Ltd. (Head Office: Osaka, Japan; President and CEO: Isao Teshirogi, Ph.D.; hereinafter “Shionogi”) today announced the initiation of a Phase 1 clinical trial in Japan of S-892216, an investigational agent which is being developed as an antiviral against COVID-19, caused by SARS-CoV-2 infection. The first dose in this Phase 1 clinical trial was administered successfully and no safety concerns have been identified. S-892216 is a 3CL protease inhibitor discovered by Shionogi and its research and development is supported by Japan Agency for Medical Research and Development (AMED) under Grant Number JP21fk0108584. In addition to S-892216, Shionogi continues its extensive global development program for the novel COVID-19 oral antiviral ensitrelvir (generic name: ensitrelvir fumaric acid, Code No.: S-217622), known as Xocova® 125 mg tablet in Japan. 1-5In pre-clinical trials, S-892216 demonstrated strong antiviral effect as well as ensitrelvir. In the Phase 1 clinical trial, Shionogi will evaluate the pharmacokinetics, safety, and tolerability of this agent in healthy adults. Since the start of the COVID-19 pandemic, the emergence of new variants has often signaled the onset of a new wave of infection worldwide.6,7While the rate of severe cases of COVID-19 leading to hospitalization has decreased due to vaccination programs, natural immunity and possibly less virulent variants, COVID-19 remains an ongoing health concern and future waves of infection are likely.6,8-12Therefore, the development of additional antiviral drugs is needed. 13Shionogi is committed to the principle “Protecting people worldwide from the threat of infectious diseases” as our key focus, and is working on the realization of total care for infectious diseases. Shionogi will seek to contribute to re-establishing the safety and security of society by developing new products and services to address COVID-19, which continues to affect many individuals around the world, and continue to focus on research and development for COVID-19 so as to be prepared for the swift provision of therapeutic drugs and vaccines as necessary depending on the situation, such as the emergence of new variants or the future prevalence of the disease. Ensitrelvir (known in Japan as Xocova®), an oral antiviral drug for COVID-19 currently approved under the emergency regulatory approval system in Japan, is a 3CL protease inhibitor created through joint research between Hokkaido University and Shionogi. SARS-CoV-2 has an enzyme called 3CL protease, which is essential for the replication of the virus. Ensitrelvir suppresses the replication of SARS-CoV-2 by selectively inhibiting 3CL protease. Ensitrelvir is the first antiviral agent to show both clinical symptomatic efficacy for five typical Omicron-related symptoms (primary endpoint) and antiviral efficacy (key secondary endpoint) in a predominantly vaccinated population of patients with mild to moderate SARS-CoV-2 infection, regardless of risk factors, in the Phase 3 part of the Phase 2/3 study conducted during the Omicron-dominant phase of the epidemic. With regard to safety, most adverse events were mild in severity and no deaths were seen in the study. Among the most common treatment-related adverse events were temporary decreases in high-density lipoprotein and increased blood triglycerides, as observed in previous studies. Currently, the Phase 2b/3 part of the Phase 2/3 study targeting SARS-CoV-2 infected persons who were asymptomatic or only had mild symptoms is being conducted in Asia, mainly in Japan. Recently, the U.S. Food and Drug Administration (FDA) grantedFast Trackdesignation to ensitrelvir for COVID-19. FDAFast Trackdesignation is designed to facilitate the development and expedite the review of potential new therapies that treat serious conditions and fulfill an unmet medical need. Ensitrelvir remains an investigational drug outside of Japan and has not been approved outside of Japan. In addition, the brand name Xocova® has not been approved for use outside of Japan and pertains only to the approved drug in Japan. SHIONOGI Website Inquiry Form :https://www.shionogi.com/global/en/contact.html

2024-10-29

·EndPoints

Shionogi touts topline data for Covid-19 antiviral for post-exposure treatment

Shionogi’s once-daily 3CL protease inhibitor hit on a primary endpoint in a late-stage trial as a post-exposure prophylaxis treatment for Covid-19 after failing a Phase 3 study in May. The oral antiviral, ensitrelvir, showed a statistically significant decrease in the proportion of patients with a symptomatic infection through 10 days after being exposed to household members with Covid-19 when compared to placebo. The company described the drug as well-tolerated with no new safety signals. Shionogi’s senior VP and head of clinical development Simon Portsmouth said in a statement that “there are currently no oral antiviral medications approved for post-exposure prophylactic use,” adding that “there is a need for convenient, preventive approaches to protect ourselves and those close to us from contracting SARS-CoV-2.” Ensitrelvir, marketed as Xocova and developed in a joint research collaboration with Hokkaido University, scored an emergency regulatory approval in Japan in 2022 before garnering a full approval in March for the treatment of Covid-19. But the drug failed in the NIH-partnered SCORPIO-HR study when it didn’t show a statistically significant reduction in patients being completely clear of symptoms for at least two days when the drug was given within three days of symptoms starting. However, a separate analysis showed that patients had no sign of six different symptoms for at least one day, earning a p-value of 0.05 compared to placebo. The trial showed other positives, according to the company, including a reduction from baseline in viral RNA levels and no symptomatic viral rebounds in patients.

临床结果临床3期上市批准

2024-10-29

·echemi

Shionogi’s COVID-19 Oral Medication Shows Significant Efficacy, but Faces a Crisis with 2 Million Treatment Courses Being Destroyed!

Shionogi & Co., one of Japan's leading drugmakers, said in a statement Tuesday that the results of an ongoing late-stage global clinical trial showed that its oral pill treatment for COVID-19 was significantly effective in reducing the spread of the virus. The drug, Ensitrelvir, which is commercially known as Xocova, showed a statistically significant reduction in patients who developed symptoms after home contact with COVID-19, Shionoi said in its statement. The Phase 3 trial, known as SCORPIO-PEP, involved about 2,400 participants in several countries in the U.S., South America, Africa and Asia. The trial results showed that Ensitrelvir was significantly effective in preventing COVID-19 transmission, especially among participants who developed symptoms after close contact with an infected person. It is worth noting, however, that in May this year, Shionogi Pharma had commented that Ensitrelvir had failed to show a significant effect in reducing common COVID-19 disease symptoms compared to a placebo. The results of this study, known as the SCORPIO-HR trial, are in stark contrast to the SCORPIO-PEP trial. Still, in March, the Japanese government fully approved the use of Ensitrelvir. However, while the government bought two million courses of treatment during the pandemic, most of the drugs went unused and will eventually be destroyed, according to media reports. This situation has led to public questioning and discussion about government decision-making and resource allocation.

临床3期临床结果紧急使用授权

100 项与恩赛特韦相关的药物交易

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研发状态

批准上市

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适应症	国家/地区	公司	日期
新型冠状病毒感染	日本	Shionogi & Co., Ltd.	2022-11-22

未上市

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适应症	最高研发状态	国家/地区	公司	日期
炎症	临床2期	美国	Shionogi, Inc.	2024-04-09
新冠肺炎后遗症	临床2期	美国	Shionogi, Inc.	2024-04-09
肝病	临床1期	美国	Shionogi, Inc.	2022-09-13

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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


Corporate Publications 人工标引	临床2/3期	新型冠状病毒感染	-	S-217622	鹽鹽糧餘膚鏇艱膚鏇顧(鹹鑰蓋蓋襯製膚積製遞) = On day four of treatment (following the third dose), the proportion of patients with positive viral titer decreased by approximately 90% versus placebo. 選壓鑰糧壓壓觸觸願鬱 (壓廠鑰憲鏇衊醖構鹽夢 ) 更多	积极	2022-04-24
				Placebo