Delving into the Latest Updates on PF-4878691 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

IMDZQ

+ [2]

Target

TLR7

Mechanism

TLR7 agonists(Toll like receptor 7 agonists)

Therapeutic Areas

NeoplasmsImmune System DiseasesInfectious Diseases+ [6]

Active Indication-

Inactive Indication

Acute Lymphoblastic LeukemiaAcute Myeloid LeukemiaBarrett Esophagus+ [12]

Originator Organization

3M Health Care, Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Kindeva Drug Delivery LP

3M Health Care, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC17H23N5O2S

InChIKeyYZOQZEXYFLXNKA-UHFFFAOYSA-N

CAS Registry532959-63-0

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.

Start Date01 Oct 2006

Sponsor / Collaborator

3M Co.

NCT00319748 / CompletedPhase 2IIT

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.

Start Date01 Apr 2006

Sponsor / Collaborator

University of Minnesota Masonic Cancer Center

[+1]

100 Clinical Results associated with PF-4878691

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100 Translational Medicine associated with PF-4878691

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100 Patents (Medical) associated with PF-4878691

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12

Literatures (Medical) associated with PF-4878691

01 Oct 2012·Journal of Clinical ImmunologyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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.

01 Oct 2012·American Journal of HematologyQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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.

01 Jun 2011·Clinical Pharmacology & TherapeuticsQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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 Deals associated with PF-4878691

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12476

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	Phase 2	US	Pfizer Inc.	01 Jan 2006
Acute Myeloid Leukemia	Phase 2	US	Pfizer Inc.	01 Jan 2006
Melanoma, Cutaneous Malignant	Phase 2	CH	Pfizer Inc.	01 Feb 2005
Melanoma, Cutaneous Malignant	Phase 2	FR	Pfizer Inc.	01 Feb 2005
Melanoma, Cutaneous Malignant	Phase 2	DE	Pfizer Inc.	01 Feb 2005
Unresectable Melanoma	Phase 2	DE	Pfizer Inc.	01 Feb 2005
Unresectable Melanoma	Phase 2	FR	Pfizer Inc.	01 Feb 2005
Unresectable Melanoma	Phase 2	CH	Pfizer Inc.	01 Feb 2005
Hepatitis C	Phase 2	-	3M Health Care, Inc.	-
Hepatitis C	Phase 2	-	3M Health Care, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00276159 (CTgov)	Phase 2	Acute Myeloid Leukemia \| Hodgkin's Lymphoma \| Acute Lymphoblastic Leukemia \| Chronic Lymphocytic Leukemia \| Multiple Myeloma	6	852A	mtarutyfrb(lwevkarjhd) = vkdsuhgsha zwibfejekn (noqjbaajns, zgyxuwdriw - vuvzyfhjlk) View more	-	05 May 2010
NCT00319748 (CTgov)	Phase 2	Ovarian Cancer \| Endometrial Carcinoma \| Breast Cancer \| Uterine Cervical Cancer	15	852A (Patients With Ovarian Cancer)	gsjodsbhqy(kjcfigfcpe) = nyrwqksqio szfwkoorzu (ufocegvphd, pxlzxotzzl - lpdzeinhpd) View more	-	25 Sep 2009
NCT00319748 (CTgov)	Phase 2		15	852A (Patients Treated With 852A)	wdnvbljgwg(mmcyagzknk) = qxbbrtbzqu cfuogxieor (creofforky, hbcvptbsrf - uhkuywgxkb) View more	-	25 Sep 2009