PF-4878691(PF-4878691) - 药物靶点：TLR7_专利_临床

概要

基本信息

药物类型

小分子化药

别名

IMDZQ

+ [2]

靶点

TLR7

作用机制

TLR7激动剂(Toll样受体7激动剂)

治疗领域

肿瘤免疫系统疾病感染+ [6]

在研适应症-

非在研适应症

急性淋巴细胞白血病急性髓性白血病巴雷特食管+ [12]

原研机构

3M Health Care, Inc.

在研机构-

非在研机构

Pfizer Inc.

Kindeva Drug Delivery LP

3M Health Care, Inc.

最高研发阶段终止临床2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

分子式C17H23N5O2S

InChIKeyYZOQZEXYFLXNKA-UHFFFAOYSA-N

CAS号532959-63-0

关联

8

项与 PF-4878691 相关的临床试验

NCT00810758 / Completed临床1期

A Phase 1, Randomized, Placebo Controlled, Blinded (3rd Party Open), Sequential, Multiple-Dose Escalation Study To Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PF-04878691 In Healthy Volunteers

To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple oral doses of PF-04878691.

开始日期2009-01-01

申办/合作机构

Pfizer Inc.

NCT00386594 / TerminatedN/AIIT

Pilot Study of Oral 852A for Elimination of High-Grade Dysplasia in Barrett's Esophagus

Barrett's esophagus with high-grade dysplasia is a premalignant condition caused by chronic reflux of gastric contents into the esophagus. High-grade dysplasia is the same as carcinoma-in-situ. If untreated, patients with this condition are at high risk for developing cancer of the esophagus. Cancer of the esophagus is a miserable disease that is difficult to treat and about 95% fatal after 5 years. To prevent progession to cancer of the esophagus several interventions are available and they include surgery, Photofrin photodynamic therapy, endoscopic mucosal resection and endoscopic thermal therapy. All of these modalities are uncomfortable, expensive and have associated risks. The oral agent, 852A stimulates the innate immune system in such a way as to eliminate early cancer. A similar dermatologic drug(imiquimod) is approved for treating the premalignant condition, actinic keratosis. If local therapy with imiquimod can eliminate a premalignant lesion in the skin, a similar acting drug should be able to do the same for a premalignant lesion in the lining of the esophagus. This study is designed to test that hypothesis.

开始日期2006-10-01

申办/合作机构

3M Co.

NCT00319748 / Completed临床2期IIT

Phase II Study of 852A Administered Subcutaneously in Patients With Metastatic Refractory Breast, Ovarian, Endometrial and Cervical Cancers

The purpose of this study is to evaluate the anti-tumor activity of 852A when used to treat metastatic breast, ovarian, endometrial or cervical cancer not responding to standard treatment.

开始日期2006-04-01

申办/合作机构

University of Minnesota Masonic Cancer Center

[+1]

100 项与 PF-4878691 相关的临床结果

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100 项与 PF-4878691 相关的转化医学

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100 项与 PF-4878691 相关的专利（医药）

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12

项与 PF-4878691 相关的文献（医药）

2012-10-01·Journal of Clinical Immunology2区 · 医学

Therapy with TLR7 Agonists Induces Lymphopenia: Correlating Pharmacology to Mechanism in a Mouse Model

2区 · 医学

Article

作者: Tansi Khodai ; Jaiessh Rawal ; Carl Laxton ; Hannah Perkins ; Helen Bright ; Houria Mechiche ; Frances Burden ; Jonathan Heyen ; Tom Corey ; Peter Colman ; Mike Westby ; Nigel Horscroft ; Deborah Rodrigues ; Mark Fidock

BACKGROUND AND OBJECTIVESynthetic TLR7 agonists have been proposed as oral replacements for interferonα (IFNα) therapy in the treatment of hepatitis C virus infection. However, adverse effects, such as lymphopenia and cardiovascular irregularities, have been observed in the clinical following treatment with TLR7 agonists. We wished to understand and characterise the relationship between TLR7 agonism and adverse effects.METHODSWe compared responses to two prototypic TLR7 agonists (Resiquimod: R-848; and PF-04878691) in a mouse model and compared the responses to treatment with IFNα. We measured clinically relevant adverse effects such as lymphopenia and cardiovascular irregularities and related them to plasma drug levels and clinically relevant efficacy biomarkers such as the pro-inflammatory cytokine IP-10, 2'5'OAS and TLR7 receptor expression.RESULTSBy 2 h post dose all agents had induced a dose-dependent transient lymphopenia. IFNα increased heart rate immediately following dosing, persisting for 5 h, whilst PF-04878691 induced significant reductions in blood pressure. Lymphopenia co-incided with maximum plasma drug levels, raised levels of IP-10 and the auto-induction of TLR7 expression in the blood and lymph nodes. Peak levels of 2'5'OAS occurred at 24 h post-dose and only at doses which also induced lymphopenia.CONCLUSIONSWe conclude that systemic delivery of TLR7 agonists or IFNα induces similar exaggerated pharmacology, consistent with there being a narrow therapeutic window between efficacy and safety. This clinically validated mouse model will help to investigate whether more potent agonists or optimised dosing schedules, will be successful strategies for targeting TLR7 in patients.

2012-10-01·American Journal of Hematology1区 · 医学

Prolonged subcutaneous administration of 852A, a novel systemic toll‐like receptor 7 agonist, to activate innate immune responses in patients with advanced hematologic malignancies

1区 · 医学

Article

作者: Bruce R. Blazar ; Angela Panoskaltsis-Mortari ; Sarah Cooley ; Brenda J. Weigel ; Jeffrey S. Miller ; Wei Chen ; Todd DeFor ; Daniel J. Weisdorf

AbstractThe toll‐like receptor (TLR) 7 agonist 852A, a small‐molecule imidazoquinoline, stimulates plasmacytoid dendritic cells to produce multiple cytokines. We conducted a Phase II study of 852A in patients with recurrent hematologic malignancies. The primary objective was assessing the activity of 852A administered subcutaneously twice weekly for 12 weeks. Secondary objectives were assessing the safety of 852A and its ability to activate the immune system with prolonged dosing. Patients with relapsed hematologic malignancies of any age with adequate organ function were eligible. Patients initiated dosing at 0.6 mg/m2 twice weekly and escalated by 0.2 mg/m2 after every two doses as tolerated to a target dose of 1.2 mg/m2. Patients with responses or stable disease were eligible for additional cycles. Seventeen patients (15 males) entered the study: 6 with AML, 5 ALL, 4 NHL, 1 Hodgkin's lymphoma, and 1 multiple myeloma. The mean age was 41 years (12–71 years). The median number of prior chemotherapy regimens was 5 (range = 1–14). Thirteen patients completed all 24 injections. Grade 3‐4 toxicities included nausea, dyspnea, fever, myalgia, malaise, and cough. Responses included one complete response (ALL), one partial response (AML), two stable disease (AML and NHL), and 9 progressive disease. This is the first in‐human hematologic malignancy trial of a subcutaneously (SC) delivered TLR7 agonist using a prolonged dosing schedule. 852A was safely administered up to 1.2 mg/m2 twice weekly with evidence of sustained tolerability and clinical activity in hematologic malignancies. Systemic TLR agonists for the treatment of hematologic malignancies warrant further study. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.

2011-06-01·Clinical Pharmacology & Therapeutics2区 · 医学

The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF-4878691)

2区 · 医学

Article

作者: TP Corey ; BE Souberbielle ; V Kumar ; C Laxton ; K Wright ; S Srinivasan ; O Delpuech‐Adams ; N Horscroft ; J Rawal ; M Perros ; K Rana ; M Westby ; JB Cheng ; P Colman ; Fidock ; C Craig ; R Webster ; E van der Ryst

Hepatitis C virus (HCV) infection is an issue of global concern, and studies are ongoing to identify new therapies that are both effective and safe. PF-4878691 is a Toll-like receptor 7 (TLR7) agonist modeled so as to dissociate its antiviral activities from its inflammatory activities. In a proof-of-mechanism study in healthy volunteers who received doses of 3, 6, and 9 mg of PF-4878691 twice a week for 2 weeks, PF-4878691 induced biomarkers of the immune and interferon (IFN) responses in a dose-dependent and dose-frequency-related manner. A novel finding was induction of TLR7 expression in vivo in response to PF-4878691, leading to an amplified biomarker response. A nonresponder at the 9-mg dose had a polymorphism in the IFN-α receptor 1 subunit (Val168Leu). Two subjects who had received 9-mg doses experienced serious adverse events (SAEs), characterized by flu-like symptoms, hypotension, and lymphopenia, leading to early termination of the study. TLR7 stimulation results in a pharmacologic response at levels commensurate with predicted antiviral efficacy, but these doses are associated with SAEs, raising concerns about the therapeutic window of this class of compounds for the treatment of HCV infection.

100 项与 PF-4878691 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12476

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
急性淋巴细胞白血病	临床2期	美国	Pfizer Inc.	2006-01-01
急性髓性白血病	临床2期	美国	Pfizer Inc.	2006-01-01
皮肤黑色素瘤	临床2期	瑞士	Pfizer Inc.	2005-02-01
皮肤黑色素瘤	临床2期	法国	Pfizer Inc.	2005-02-01
皮肤黑色素瘤	临床2期	德国	Pfizer Inc.	2005-02-01
不可切除的黑色素瘤	临床2期	德国	Pfizer Inc.	2005-02-01
不可切除的黑色素瘤	临床2期	法国	Pfizer Inc.	2005-02-01
不可切除的黑色素瘤	临床2期	瑞士	Pfizer Inc.	2005-02-01
丙型肝炎	临床2期	-	3M Health Care, Inc.	-
丙型肝炎	临床2期	-	3M Health Care, Inc.	-

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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


NCT00276159 (CTgov)	临床2期	急性髓性白血病 \| 霍奇金淋巴瘤 \| 急性淋巴细胞白血病 \| 慢性淋巴细胞白血病 \| 多发性骨髓瘤	6	852A	壓遞鏇齋餘繭襯艱選鹽(憲糧衊鹽壓衊壓廠餘窪) = 憲膚廠選糧衊糧夢蓋糧鑰鏇醖遞壓積餘網顧獵 (顧鑰衊獵淵遞衊繭築繭, 築構襯積築襯蓋積蓋窪 ~ 齋鑰醖築觸鑰願壓製糧) 更多	-	2010-05-05
NCT00319748 (CTgov)	临床2期	卵巢癌 \| 子宫内膜癌 \| 乳腺癌 \| 宫颈癌	15	852A (Patients With Ovarian Cancer)	蓋夢鏇簾鹽鬱觸餘糧艱(鏇鹹範繭鏇鹹網觸觸構) = 淵憲鹹構艱齋積齋選鬱壓鏇繭積廠鬱顧鬱鹹顧 (夢鹹簾糧艱製膚鏇膚衊, 廠鹹鹽鹹鏇繭壓範衊製 ~ 艱鑰構憲顧積糧壓憲艱) 更多	-	2009-09-25
NCT00319748 (CTgov)	临床2期	卵巢癌 \| 子宫内膜癌 \| 乳腺癌 \| 宫颈癌	15	852A (Patients Treated With 852A)	鏇鹽顧網選鏇醖鑰餘製(選夢淵鑰積築蓋構鏇衊) = 淵積醖蓋鑰夢醖醖鑰艱襯淵鬱網窪鹽鏇鹹鏇鹽 (觸齋選襯壓壓糧鏇鏇蓋, 築選網鹽鏇鏇範鹹齋顧 ~ 網糧餘壓糧膚齋繭鑰蓋) 更多	-	2009-09-25