PF-6425090(PF-6425090) - 药物靶点：TcdA x toxB_在研适应症：艰难梭菌感染_专利_临床

概要

基本信息

药物类型

预防性疫苗

别名

Clostridium difficile vaccine、Toxoid-based Clostridium difficile vaccine、PF 6425090

+ [1]

靶点

TcdA x toxB

作用机制

TcdA抑制剂(TcdA inhibitors)、toxB抑制剂(艰难梭菌毒素B抑制剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构

最高研发阶段临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

Sequence Code 4709750

Sequence Code 4709758

关联

10

项与 PF-6425090 相关的临床试验

NCT03918629

/ Completed临床3期

A PHASE 3, RANDOMIZED OBSERVER-BLINDED STUDY TO EVALUATE THE IMMUNOGENICITY, SAFETY, AND TOLERABILITY OF 2 DOSES COMPARED TO 3 DOSES OF CLOSTRIDIUM DIFFICILE VACCINE IN ADULTS 50 YEARS OF AGE AND OLDER

This study will investigate a Clostridium difficile vaccine in adults 50 years of age and older. In half the adults, all 3 doses given are the Clostridium difficile vaccine, and in half the adults, 2 of the 3 doses are the Clostridium difficile vaccine with the other dose containing no active ingredients. The study will look at the subjects' immune response to the vaccine and assess the safety and tolerability of a 2-dose regimen of Clostridium difficile vaccine compared to a 3-dose regimen of Clostridium difficile vaccine.

开始日期2019-04-01

申办/合作机构

Pfizer Inc.

NCT03579459

/ Completed临床3期

A PHASE 3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLINDED STUDY TO EVALUATE THE LOT CONSISTENCY, SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF A CLOSTRIDIUM DIFFICILE VACCINE IN HEALTHY ADULTS 65 TO 85 YEARS OF AGE

This study will investigate a Clostridium difficile vaccine in healthy adults 65 to 85 years of age, who will each receive 3 doses of vaccine. The study will assess the lot consistency, safety, and tolerability of the vaccine, and also look at the subjects' immune response to the vaccine.

开始日期2018-07-31

申办/合作机构

Pfizer Inc.

NCT03090191

/ Completed临床3期

A PHASE 3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLINDED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF A CLOSTRIDIUM DIFFICILE VACCINE IN ADULTS 50 YEARS OF AGE AND OLDER

The Clover trial is evaluating an investigational vaccine that may help to prevent Clostridium difficile infection. Participants in the study are adults 50 years of age and older, who are at risk of developing Clostridium difficile infection. The study will assess whether the vaccine prevents the disease, and whether it is safe and well tolerated.
Each subject will receive 3 doses of Clostridium difficile vaccine or placebo and be followed for up to 3 years after vaccination for potential Clostridium difficile infection.

开始日期2017-03-29

申办/合作机构

Pfizer Inc.

100 项与 PF-6425090 相关的临床结果

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100 项与 PF-6425090 相关的转化医学

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100 项与 PF-6425090 相关的专利（医药）

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19

项与 PF-6425090 相关的文献（医药）

2024-12-17·CLINICAL INFECTIOUS DISEASES

CLOVER (CLOstridium difficile Vaccine Efficacy tRial) Study: A Phase 3, Randomized Trial Investigating the Efficacy and Safety of a Detoxified Toxin A/B Vaccine in Adults 50 Years and Older at Increased Risk of Clostridioides difficile Infection

Article

作者: Dubberke, Erik R ; Zhang, Haiying ; Kitchin, Nicholas ; Donskey, Curtis J ; Wilcox, Mark H ; Koury, Kenneth ; Klein, Nicola P ; Lamberth, Erik ; Webber, Chris ; Smith, Helen M ; Bailey, Ruth ; Szymkowiak, Katarzyna ; Bouguermouh, Salim ; Gruber, William C ; Liles, Elizabeth G ; Jansen, Kathrin U ; Lawrence, Jody ; Pride, Michael W ; Anderson, Annaliesa S ; Lockhart, Stephen ; Kalina, Warren V

Abstract:

Background:

Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention.

Methods:

This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N = 17 535) to receive 3 PF-06425090 or placebo doses (0, 1, and 6 months). Primary end points were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary end points), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability and safety were assessed.

Results:

The primary end point was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE) = 31.0% (96.4% confidence interval [CI], −38.7% to 66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE = 28.6% (96.4% CI, −28.4% to 61.0%)]. Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P = .02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE = 100%; 95% CI, 59.6% to 100.0%) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE = 100%; 95% CI, 54.8% to 100.0%). Local reactions were more frequent in PF-06425090 recipients, and systemic events were generally similar between groups; most were mild to moderate. Adverse event rates were similar between groups.

Conclusions:

Three PF-06425090 doses were safe and well tolerated. Although the primary end point was not met, PF-06425090 reduced symptom duration, CDI that required medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden.

Clinical Trials Registration:

NCT03090191.

2024-11-01·TOXICON

Protection efficacy and immunogenicity of Clostridium chauvoei proteins as a subunit blackleg vaccine or an adjuvant for Clostridium perfringens epsilon toxoid

Article

作者: Paradise, Alireza ; Hamzavipour, Roxana ; Zahmatkesh, Azadeh ; Hosseini, Farzaneh

Potential application of Clostridium chauvoei proteins was studied as a subunit blackleg vaccine or a biological adjuvant for Clostridium perfringens epsilon toxoid vaccine. Extracellular and cell surface proteins were extracted from C. chauvoei culture, and their protective efficacy was evaluated by potency test in guinea pigs. In order to investigate the effect of cell surface proteins on C. perfringens epsilon toxoid immunogenicity, rabbits were inoculated subcutaneously twice with: C. perfringens type D toxoid supernatant +200 μg C. chauvoei cell surface proteins (PR-200), toxoid supernatant + 400 μg cell surface proteins (PR-400), inactivated C. perfringens type D vaccine (Vac), toxoid supernatant (Tox), or PBS. Isolation of cell surface proteins yielded about 2.5 mg/L culture protein with a sharp band at 43 kDa probably corresponding to flagellin. Potency test demonstrated the protection ability of both cellular and extracellular proteins of C. chauvoei. ELISA showed that the highest antibody titers against epsilon toxoid belonged to PR-400 and Vac groups. The effect of days post immunization on antibody response was not significant. No significant difference was observed between PR-400 and Vac, as well as PR-200 and Tox groups. Clostridium chauvoei cell surface proteins may have the potential for application as a blackleg disease vaccine and an adjuvant for clostridial toxoids.

2024-01-01·Advances in Experimental Medicine and Biology

Clostridioides difficile Infections: Prevention and Treatment Strategies

Review

作者: Levy, Elvira Ingrid ; Vandenplas, Yvan ; Dinleyici, Meltem ; Dinleyici, Ener

Clostridioides difficile is the most common causative agent of antibiotic-associated diarrhea. This spore forming, obligate anaerobic, gram-positive bacillus is becoming responsible for an increasing number of infections worldwide, both in community and in hospital settings, whose severity can vary widely from an asymptomatic infection to a lethal disease. While discontinuation of antimicrobial agents and antibiotic treatment of the infection remain the cornerstone of therapy, more recent fecal microbiota transplantation has also been valid as a therapy. The use of probiotics, especially Saccharomyces boulardii CNCM I-745 have become valid forms of prevention therapy. Although there are studies in adults with microbiota-targeted new generation therapies and Clostridium difficile vaccines, there are no data in the paediatric age group yet.

1

项与 PF-6425090 相关的新闻（医药）

2022-06-16

·CPhI制药在线

研发 | 艰难梭菌感染药物研究进展：辉瑞艰难梭菌疫苗折戟，微生物疗法SER-109未来可期

点击关注，星标CPhI制药在线艰难梭菌（CD）又称难辨棱状芽孢杆菌，是一种革兰阳性厌氧芽孢杆菌，是引起院内肠道感染的主要致病菌之一。临床上，约15%-25% 的抗菌药物相关性腹泻(AAD) 、50% ～ 75% 的抗菌药物相关性结肠炎和95% ～ 100% 的伪膜性肠炎( PMC) 是由艰难梭菌感染（CDI）引起。 CDI 主要是由产毒素CD 过度繁殖导致肠道菌群失调并释放毒素所引起，主要临床症状为发热、腹痛、水样便腹泻。CDI 通常由长期或不规范使用抗菌药物引起，轻者引起腹泻，严重者引发伪膜性肠炎，且常伴有中毒性巨结肠、肠穿孔、感染性休克等并发症，甚至最终导致死亡。据疾病预防控制中心（CDC）报告显示，美国每年约有70万人感染CDI，50万人接受CDI抗生素治疗，复发率约在20%至30%，其中近60%的患者会存在多次复发的风险。此外，美国每年因CDI死亡的人数高达2.9万人，国家投入的CDI急诊设施近48亿美元，被DOC列为紧急公共卫生威胁。目前，CDI治疗领域还存在很大需求，已获批治疗药物有限，其中万古霉素（vancomycin）和非达霉素（fidaxomicin）是CDI的主流治疗药物。此外，默沙东的Zinplava（bezlotoxumab）于2016被FDA批准用于因感染已在接受抗菌药物治疗及处于高风险CDI的成年患者，以减少CDI复发。值得一提的是，Zinplava是一种单克隆抗体，通过中和CD的毒素B，阻断毒素与细胞结合的能力发挥作用。随着对CDI的关注，目前全球已出现多款在研CDI新疗法，详见下表。其中SER-109进展较快，已开始滚动递交BLA。 ♦ SER-109是来自于健康人粪便中约50种细菌孢子的组合物，旨在减少CDI的复发，曾被FDA授予治疗CDI的突破性疗法认定和孤儿药资格。2020年8月，该药在治疗复发性CDI的关键3期临床试验ECOSPOR III中获得积极顶线结果：与安慰剂相比，SER-109导致给药8周内CDI出现复发的患者比例显著下降，疗效结果超过之前与美国FDA协商确定的阈值。近日，Seres Therapeutics宣布该药在ECOSPOR IV临床试验中取得积极结果：以SER-109治疗的受试者在第8周时有8.7%的复发率。此外，第8周时，CDI首次复发受试者的复发率为6.5%，曾发生2次或以上CDI受试者的复发率为9.7%。基于这些研究结果，公司已开始滚动递交SER-109的BLA。 ♦ RBX2660是首个在3期试验中取得积极初步结果的微生物治疗，旨在阻止CDI的复发，已被FDA授予快速通道资格、孤儿药资格和突破性疗法认定。 ♦ CP101是一种研究性口服微生物组药物，以口服肠溶胶囊形式递送完整的微生物群落，旨在通过恢复定植抗性，或健康的微生物组，来防止潜在病原体定植的能力，从而预防复发性CDI，被FDA授予用于预防复发性CDI的快速通道资格和突破性疗法认定。2期临床试验PRISM3结果显示：接受CP101单次给药的复发性CDI患者中74.5%在第8周达到了持续的临床治愈，与对照组患者的61.5%相比，改善具有统计学意义，达到主要疗效终点。 ♦ MGB-BP-3是一种抗菌剂，对多种重要的多重耐药和敏感的革兰氏阳性病原菌具有抗菌活性，曾被FDA授予合格传染病产品（QIDP）资格认定。据悉，MGB-BP-3有非常快的杀菌效果，能在艰难梭菌形成孢子之前杀死其营养体，从而通过减少艰难梭菌的总负荷达到初步治愈和防止疾病复发的目的，对目前抗药性最强的的BI/NAP1/027菌株具有很强的杀菌活性。2020年5月，该药一线治疗CDI的2期研究达到安全性、疗效、剂量选择终点，具体数据为：每天2次、连续10天服用250mg剂量MGB-BP-3，可获得100%的初步治愈、100%的持续治愈。 ♦ Ibezapolstat是一款DNA聚合酶IIIC抑制剂，曾被FDA授予治疗CDI的合格传染病产品（QIDP）资格和快速通道资格。2020年11月，该药在一项治疗轻中度CDI的开放标签2a期临床试验中达到研究的主要和次要疗效终点：入组试验的所有10名患者治疗结束时均获得临床治愈，而且获得28天随访时CDI无复发的持续性临床治愈。 ♦ SYN-004（ribaxamase）是公司开发的同类首个旨在保护肠道微生物群体免受某些由静脉注射的β-内酰胺抗生素破坏的口服型酶剂，曾被FDA授予治疗CDI的突破性疗法认定。评估该药预防原发性CDI、抗生素相关性腹泻和抗生素耐药性出现的有效性的2b期验证性临床试验结果显示：与接受安慰剂的患者相比，接受 SYN-004的患者的CDI发生率相对降低了71.4％（p=0.045）。 ♦ DNV3837 是一种水溶性前药，在人体静脉内给药后会迅速去磷酸化，从而产生药物的活性形式 DNV3681。其结构由两个活性部分组合而成，即抑制细菌 DNA 促旋酶以干扰细菌基因组复制的氟喹诺酮和抑制细菌蛋白质合成起始的恶唑烷酮。 ♦ Ridinilazole是一种双苯并咪唑类化合物，X衍射结果显示，Ridinilazole以特定序列的方式与 DNA 的小沟直接结合。2021年12月，Summit Therapeutics宣布该药治疗CDI的3期临床研究失败：与万古霉素相比，ridinilazole的SCR率（SCR定义为治疗CDI的临床反应，并且治疗结束后30天内无感染复发）更高，但未达到该研究的主要优势终点。 ♦ PF-06425090是一款CD候选疫苗，旨在通过触发来自这种细菌的两种主要致病毒素的抗体反应，以预防经常发生在医院或长期护理设施中的艰难梭菌感染。今年3月，辉瑞宣布PF-06425090在一项关键性3期试验中未能达到预防感染的主要终点，但在次要终点方面，PF-06425090已被证明具有减少疾病持续时间和改善疾病严重程度的潜力。整体来看，CDI在研药物种类还是比较多样的，而且部分产品已进入临床后期。期待随着新产品的获批上市，CDI治疗可以迎来新局面。智药研习社小程序上线，三重福利扫码领取！来源：CPhI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多精彩制药资讯，请关注CPhI制药在线▼点击阅读原文，进入智药研习社~

微生物疗法疫苗抗体突破性疗法孤儿药

100 项与 PF-6425090 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
艰难梭菌结肠炎	临床3期	美国	Pfizer Inc.	2018-07-31
艰难梭菌感染	临床3期	美国	Pfizer Inc.	2017-03-29
艰难梭菌感染	临床3期	阿根廷	Pfizer Inc.	2017-03-29
艰难梭菌感染	临床3期	澳大利亚	Pfizer Inc.	2017-03-29
艰难梭菌感染	临床3期	比利时	Pfizer Inc.	2017-03-29
艰难梭菌感染	临床3期	保加利亚	Pfizer Inc.	2017-03-29
艰难梭菌感染	临床3期	加拿大	Pfizer Inc.	2017-03-29
艰难梭菌感染	临床3期	智利	Pfizer Inc.	2017-03-29
艰难梭菌感染	临床3期	哥伦比亚	Pfizer Inc.	2017-03-29
艰难梭菌感染	临床3期	捷克	Pfizer Inc.	2017-03-29

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临床结果

适应症

分期

评价

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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


NCT03918629 (CTgov)	临床3期	艰难梭菌结肠炎	1,994	Clostridium Difficile Vaccine (2-Dose Clostridium Difficile Vaccine)	選蓋簾願蓋襯積壓窪艱(膚餘網製鏇衊鬱膚鏇鏇) = 製齋網廠繭衊範壓糧襯鏇淵餘簾築繭餘淵夢鏇 (窪壓製鑰齋網餘積積糧, 壓淵願範夢衊醖鏇願醖 ~ 顧憲鹽顧衊鹽築鏇鏇網) 更多	-	2024-01-10
				Clostridium Difficile Vaccine (3-Dose Clostridium Difficile Vaccine)	選蓋簾願蓋襯積壓窪艱(膚餘網製鏇衊鬱膚鏇鏇) = 鬱餘築餘鏇範齋鏇淵窪鏇淵餘簾築繭餘淵夢鏇 (窪壓製鑰齋網餘積積糧, 齋鑰獵鏇膚網獵築衊觸 ~ 廠餘築製範壓繭鹹壓廠) 更多
NCT03090191 (CLOVER, CTgov)	临床3期	艰难梭菌感染	17,535	Clostridium difficile vaccine (Clostridium Difficile Vaccine)	糧廠夢獵繭鹹範壓製夢(繭獵齋齋構衊繭獵製獵) = 糧襯獵鏇願範廠齋網淵願蓋窪糧蓋簾積衊淵淵 (艱糧選壓襯鬱鹹繭襯構, 襯壓憲齋齋遞糧醖鑰糧 ~ 艱膚顧願壓夢衊襯構壓) 更多	-	2023-02-13
				Placebo (Placebo)	糧廠夢獵繭鹹範壓製夢(繭獵齋齋構衊繭獵製獵) = 糧襯廠構齋窪製廠鬱鏇願蓋窪糧蓋簾積衊淵淵 (艱糧選壓襯鬱鹹繭襯構, 鏇壓糧選選憲鏇觸鬱鏇 ~ 壓淵構觸繭憲獵簾製廠) 更多
NCT03579459 (CTgov)	临床3期	艰难梭菌结肠炎	1,317	placebo	構齋窪廠廠鹹膚艱膚艱(膚窪憲憲鹹鬱壓觸鏇齋) = 鏇鑰夢憲壓齋網遞簾艱網廠憲淵廠繭範襯簾鏇 (艱夢顧鹽衊積選壓遞構, 憲齋憲壓製襯糧廠願淵 ~ 憲繭憲獵簾膚糧願繭壓) 更多	-	2023-01-19
NCT03090191 (CLOVER, BusinessWire) 人工标引	临床3期	艰难梭菌感染	17,500	PF-6425090	鏇壓遞鬱鹽壓糧衊築製(築膚鏇鏇獵齋願壓鏇製) = Local and systemic reactions were mild to moderate, with mostly pain at the injection site with higher incidence after the second and third doses. The number of participants reporting overall adverse events (AEs), serious AEs (SAEs), withdrawals and deaths were similar between the two groups. 顧鑰壓壓夢壓網夢廠鹹 (鑰鏇餘願憲選構憲糧鏇 )	不佳	2022-03-01
				Placebo
NCT02117570 (CTgov)	临床2期	艰难梭菌结肠炎	185	Placebo	遞醖鬱糧壓選製網顧獵(襯襯鹹積夢窪製遞壓壓) = 齋願廠範繭鹽網選簾築膚鹽觸觸蓋艱餘選繭積 (築艱遞鑰憲衊艱襯衊壓, 衊選餘積艱簾簾壓獵鹽 ~ 醖積顧襯鹽範鹽繭鹹觸) 更多	-	2017-01-30