(PF-6425090) - 药物靶点：TcdA x toxB_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

感染

在研适应症-

非在研适应症

艰难梭菌结肠炎艰难梭菌感染

原研机构

Pfizer Inc.

在研机构-

非在研机构

Pfizer Inc.

最高研发阶段无进展临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

序列信息

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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15

项与 PF-6425090 相关的文献（医药）

2023-12-01·Vaccine

A phase 3 study evaluating the lot consistency, immunogenicity, safety, and tolerability of a Clostridioides difficile vaccine in healthy adults 65 to 85 years of age

Article

作者: Shah, Rupal ; Lockhart, Stephen P ; Gruber, William C ; Brock, Linda ; Bouguermouh, Salim ; Anderson, Annaliesa S ; Zhang, Haiying ; Christensen, Shane ; Pride, Michael W ; Ilangovan, Kumar ; Lamberth, Erik ; Webber, Chris ; Gao, Qi ; Kitchin, Nicholas

BACKGROUND:

A toxoid-based Clostridioides difficile vaccine is currently in development. Here, we report lot-to-lot consistency, immunogenicity, safety, and tolerability of 3 C difficile vaccine doses in healthy older adults.

METHODS:

This phase 3, placebo-controlled study randomized (1:1:1:1) healthy adults 65 to 85 years of age to 1 of 3 C difficile vaccine lots or placebo. Participants received C difficile vaccine (200 μg total toxoid) or placebo (Months 0, 1, 6). The primary immunogenicity objective was lot-to-lot consistency (2-sided 95 % CIs within 0.5 and 2 for comparisons of geometric mean concentration [GMC] ratios) for toxins A- and B-specific neutralizing antibody levels 1 month after Dose 3. Safety outcomes included local reactions and systemic events ≤7 days after vaccination, adverse events (AEs), and serious AEs (SAEs).

RESULTS:

Of 1317 enrolled participants, 1218 completed the study. C difficile vaccine immunogenicity was consistent across lots, with neutralizing antibody responses 1 month after Dose 3 for both toxin A (GMC [95 % CI]: lot 1, 878.8 [786.3, 982.2]; lot 2, 873.0 [779.2, 978.1]; lot 3, 872.9 [782.6, 973.5]) and toxin B (lot 1, 5823.9 [5041.0, 6728.4]; lot 2, 5462.8 [4733.4, 6304.7]; lot 3, 5426.0 [4724.4, 6231.8]). Two-sided 95 % CIs for GMC ratios were within 0.5 and 2 for toxins A and B, indicating lot-to-lot consistency was achieved. C difficile vaccine was well tolerated, with similar rates of local reactions and systemic events among vaccine lots. AE and SAE rates were similar across C difficile vaccine (36.5 % and 4.5 %, respectively) and placebo (35.3 % and 6 %).

CONCLUSIONS:

Three doses (Months 0,1,6) of toxoid-based C difficile vaccine induced robust neutralizing antibody responses and were well tolerated in healthy participants 65 to 85 years of age. Lot-to-lot consistency was excellent, indicating the manufacturing process for this C difficile vaccine formulation was well controlled.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov identifier: NCT03579459.

2023-02-01·Drugs

Emerging Options for the Prevention and Management of Clostridioides difficile Infection

Review

作者: Garey, Kevin W ; Gonzales-Luna, Anne J ; Carlson, Travis J

Agents in development for the prevention or treatment of Clostridioides difficile infection can be split into three broad categories: antibiotics, microbiome restoration, and vaccines. Given the extensive list of agents currently in development, this narrative review will focus on agents that have progressed into late-stage clinical trials, defined as having a Phase III clinical trial registered on ClinicalTrials.gov. These agents include one antibiotic (ridinilazole), three live biotherapeutic products (LBPs) (CP101, RBX2660, and SER109), and two toxoid vaccines (PF06425090 and a second toxoid vaccine). As new prevention and treatment strategies enter the market, clinicians and administrators will need knowledge of these products to make rational decisions on how best to adopt them into clinical practice.

2020-12-01·BMC infectious diseases3区 · 医学

Non-toxigenic Corynebacterium diphtheriae infective endocarditis with embolic events: a case report

3区 · 医学

ArticleOA

作者: Rosa, Vitor E E ; de Santis, Antonio ; Veronese, Elinthon T ; Sampaio, Roney Orismar ; Accorsi, Tarso A D ; de Almeida Magalhaes, Francisco Monteiro ; Siciliano, Rinaldo Focaccia ; Nastri, Ana Catharina ; Akamine, Masahiko ; Titinger, David Provenzale ; Spina, Guilherme S ; Rossi, Flavia ; Araújo, Maria Rita Elmor ; Tarasoutchi, Flavio ; Magri, Marcelo M C

Abstract:

Background:

Corynebacterium diphtheriae (C. diphtheriae) infections, usually related to upper airways involvement, could be highly invasive. Especially in developing countries, non-toxigenic C. diphtheriae strains are now emerging as cause of invasive disease like endocarditis. The present case stands out for reinforcing the high virulence of this pathogen, demonstrated by the multiple systemic embolism and severe valve deterioration. It also emphasizes the importance of a coordinated interdisciplinary work to address all these challenges related to infectious endocarditis.

Case presentation:

A 21-year-old male cocaine drug abuser presented to the emergency department with a 1-week history of fever, asthenia and dyspnea. His physical examination revealed a mitral systolic murmur, signs of acute arterial occlusion of the left lower limb, severe arterial hypotension and acute respiratory failure, with need of vasoactive drugs, orotracheal intubation/mechanical ventilation, empiric antimicrobial therapy and emergent endovascular treatment. The clinical suspicion of acute infective endocarditis was confirmed by transesophageal echocardiography, demonstrating a large vegetation on the mitral valve associated with severe valvular regurgitation. Abdominal ultrasound was normal with no hepatic, renal, or spleen abscess. Serial blood cultures and thrombus culture, obtained in the vascular procedure, identified non-toxigenic C. diphtheriae, with antibiotic therapy adjustment to monotherapy with ampicillin. Since the patient had a severe septic shock with sustained fever, despite antimicrobial therapy, urgent cardiac surgical intervention was planned. Anatomical findings were compatible with an aggressive endocarditis, requiring mitral valve replacement for a biological prosthesis. During the postoperative period, despite an initial clinical recovery and successfully weaning from mechanical ventilation, the patient presented with a recrudescent daily fever. Computed tomography of the abdomen revealed a hypoattenuating and extensive splenic lesion suggestive of abscess. After sonographically guided bridging percutaneous catheter drainage, surgical splenectomy was performed. Despite left limb revascularization, a forefoot amputation was required due to gangrene. The patient had a good clinical recovery, fulfilling 4-weeks of antimicrobial treatment.

Conclusion:

Despite the effectiveness of toxoid-based vaccines, recent global outbreaks of invasive C. diphtheriae infectious related to non-toxigenic strains have been described. These infectious could be highly invasive as demonstrated in this case. Interdisciplinary work with an institutional “endocarditis team” is essential to achieve favorable clinical outcomes in such defiant scenarios.

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

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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.	2019-04-01
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	日本	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

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临床结果

适应症

分期

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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)	鹽簾襯廠鬱蓋鏇顧憲夢(艱繭淵窪鏇衊觸襯鏇製): Adjusted Geometric Mean Ratio = 0.82 (95.0% CI, 0.74 ~ 0.9); Adjusted Geometric Mean Ratio = 0.57 (95.0% CI, 0.49 ~ 0.66) 更多	-	2024-01-10
				Clostridium Difficile Vaccine (3-Dose Clostridium Difficile Vaccine)
EASL2023	N/A	非酒精性脂肪性肝炎 \| 代谢功能障碍相关的脂肪肝病	-	Clostridium difficile (CDI and NASH)	餘衊構範簾鹹壓獵齋鹹(衊鏇蓋齋獵壓壓選淵襯) = 膚壓蓋簾構鹹糧選鑰網襯鑰醖衊願遞餘簾鏇齋 (衊鏇繭繭壓蓋鹽網簾鑰 )	-	2023-06-21
				Clostridium difficile (CDI and NAFLD)	餘衊構範簾鹹壓獵齋鹹(衊鏇蓋齋獵壓壓選淵襯) = 醖願膚襯簾鏇襯壓鹹醖襯鑰醖衊願遞餘簾鏇齋 (衊鏇繭繭壓蓋鹽網簾鑰 )
NCT03090191 (CTgov)	临床3期	艰难梭菌感染	17,535	Clostridium difficile vaccine (Clostridium Difficile Vaccine)	醖鹹構餘鹹範網壓襯遞(範淵鹹蓋廠積選顧構製) = 鏇壓顧製衊築繭觸糧獵齋製築衊積鹽範獵鏇糧 (艱顧願鑰範築齋艱鏇獵, 醖膚獵艱蓋範醖窪壓蓋 ~ 淵鬱壓獵鏇獵繭膚範齋) 更多	-	2023-02-13
				Placebo (Placebo)	醖鹹構餘鹹範網壓襯遞(範淵鹹蓋廠積選顧構製) = 衊觸齋製壓範鑰襯獵窪齋製築衊積鹽範獵鏇糧 (艱顧願鑰範築齋艱鏇獵, 窪鹽鬱鬱範鬱窪鑰鹹鏇 ~ 窪襯襯糧夢夢繭壓鑰壓) 更多
NCT03579459 (CTgov)	临床3期	艰难梭菌结肠炎	1,317	placebo	遞齋鏇觸獵淵觸繭獵鹽(醖觸憲獵範夢鑰願範夢) = 鏇獵積製艱壓壓醖獵築鑰獵壓衊糧鏇鏇蓋範夢 (餘選夢醖壓艱構選衊壓, 觸齋餘顧鹹積窪網衊鑰 ~ 蓋糧憲觸鹹網糧鏇築範) 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	鬱製簾簾構製鑰糧餘夢(願積糧夢衊艱網鬱鹹廠) = 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. 艱築蓋觸壓簾醖製窪醖 (憲願醖艱襯簾製襯艱鏇 )	不佳	2022-03-01
				Placebo
NCT02117570 (CTgov)	临床2期	艰难梭菌结肠炎	185	Placebo	膚選積襯膚觸選憲淵艱(築蓋夢窪範夢簾積壓艱) = 網築繭願鏇醖簾餘襯壓製壓範夢願願艱襯獵選 (壓衊襯窪選鑰鏇積糧鑰, 獵夢淵鹹願鬱醖艱廠壓 ~ 網鑰廠窪繭顧鏇範鬱醖) 更多	-	2017-01-30