Delving into the Latest Updates on AZD-8848 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

AZD-3025, DSP 3025, DSP-3025

Target

TLR7

Action

agonists

Mechanism

TLR7 agonists(Toll like receptor 7 agonists)

Therapeutic Areas

Immune System DiseasesInfectious DiseasesOtorhinolaryngologic Diseases+ [4]

Active Indication-

Inactive Indication

Allergic asthmaButyrylcholinesterase DeficiencyRhinitis, Allergic, Seasonal

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization-

Inactive Organization

Sumitomo Pharma Co., Ltd.

AstraZeneca PLC

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC29H43N7O5

InChIKeyFEFIBEHSXLKJGI-UHFFFAOYSA-N

CAS Registry866269-28-5

Conjunctival epithelia cells play an important role in the development of allergic reactions. TLR7 agonists have been shown in studies to increase the body's immunological tolerance by controlling the proportion of Th1/Th2 cells, although it is still unknown what impact this has on conjunctival epithelial cells. In this study, we examined the effect of TLR7 agonists on the inflammatory-activation of conjunctival epithelial cells induced by IL-1β. Quantitative PCR and ELISA analysis confirmed that TLR7 agonists could impair the proinflammatory cytokines released by the epithelia cells, whereas pro-inflammatory cytokines led to subsequent reactive oxygen species and neutrophil chemotaxis. Phosphorylation analysis and nucleocytoplasmic separation further confirmed that TLR7 agonists inhibit IL-1β-induced epithelia cells activation and ATP depletion via modulating the cytoplasmic residence of ERK1/2. Our finding indicated that TLR7 of conjunctival epithelia cells could be as a potent anti-inflammatory target for the ocular surface. And TLR7 agonists may become potential new drug for the treatment of allergic conjunctivitis.

01 Dec 2019·Respiratory researchQ2 · MEDICINE

Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study

Q2 · MEDICINE

ArticleOA

Author: Eriksson, Leif ; Lindgren, Sam ; Almqvist, Gun ; O'Connor, Brian ; Singh, Dave ; Leaker, Brian R ; Young, Barbara

Abstract:

Background:

Although allergic asthma is a complex area with many interacting factors involved, the ‘hygiene hypothesis’ proposes that a lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals. Toll-like receptors (TLRs) play a key role within the innate immune system and TLR7 agonists have previously been shown to up-regulate Th1 responses and down-regulate Th2 responses to allergens in murine models of allergic or chronic asthma. This study aimed to examine the efficacy and safety of the novel TRL7 agonist AZD8848, which has been developed as an antedrug.

Methods:

In this double-blind, randomised, parallel-group study, AZD8848 60 μg or placebo was administered intranasally once-weekly for 8 weeks in patients with mild-to-moderate allergic asthma (NCT00999466). Efficacy assessments were performed at 1 and 4 weeks after the last dose. The primary outcome was the late asthmatic response (LAR) fall in forced expiratory volume in 1 s (FEV1) after allergen challenge at 1-week post-treatment.

Results:

AZD8848 significantly reduced average LAR fall in FEV1by 27% vs. placebo at 1 week after treatment (p = 0.035). This effect was sustained at 4 weeks post-treatment; however, it did not reach clinical significance. AZD8848 reduced post-allergen challenge methacholine-induced airway hyper-responsiveness (AHR) vs. placebo at 1 week post-dosing (treatment ratio: 2.20,p = 0.024), with no effect at 4 weeks. There was no significant difference between the two groups in plasma cytokine, sputum Th2 cytokine or eosinophil responses post-allergen challenge at 1 week after treatment. The incidence of adverse events was similar in the two groups. AZD8848 was generally well tolerated.

Conclusions and clinical relevance:

In patients with allergic asthma, TLR7 agonists could potentially reduce allergen responsiveness by stimulating Type 1 interferon responses to down-regulate the dominant Th2 responses.

Trial registration:

clinicaltrials.govidentifier NCT00999466.

01 Dec 2019·Cell reportsQ1 · BIOLOGY

Discovery of Small Molecules for the Reversal of T Cell Exhaustion

Q1 · BIOLOGY

ArticleOA

Author: Zavareh, Reza Beheshti ; Marro, Brett S ; Zak, Jaroslav ; Teijaro, John R ; Lairson, Luke L ; Oldstone, Michael B A

Inhibitory receptors (IRs) function as critical regulators of immune responses by tempering T cell activity. In humans, several persisting viruses as well as cancers exploit IR signaling by upregulating IR ligands, resulting in suppression of T cell function (i.e., exhaustion). This allows escape from immune surveillance and continuation of disease. Here, we report the design, implementation, and results of a phenotypic high-throughput screen for molecules that modulate CD8⁺ T cell activity. We identify 19 compounds from the ReFRAME drug-repurposing collection that restore cytokine production and enhance the proliferation of exhausted T cells. Analysis of our top hit, ingenol mebutate, a protein kinase C (PKC) inducing diterpene ester, reveals a role for this molecule in overriding the suppressive signaling cascade mediated by IR signaling on T cells. Collectively, these results demonstrate a disease-relevant methodology for identifying modulators of T cell function and reveal new targets for immunotherapy.

100 Deals associated with AZD-8848

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14868

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Rhinitis, Allergic, Seasonal	Phase 2	Sweden	AstraZeneca PLC	01 Sep 2010
Allergic asthma	Phase 2	United Kingdom	AstraZeneca PLC	01 Oct 2009
Butyrylcholinesterase Deficiency	Phase 1	Denmark	AstraZeneca PLC	01 Sep 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01560234 (CTgov)	Phase 1	-	47	Placebo	ktjlapzyuc = nyxczonyfm gdpcrivjzf (ykhhxvagzg, qeutchswwr - fygzsywaal) View more	-	06 Jun 2016
NCT00999466 (CTgov)	Phase 2	Allergic asthma	60	AZD8848 (AZD8848, 30 μg)	ddpbvojfhg(oekedizhmz) = pozcgmfwwl ohgtpnmyhu (rmdzetxbff, pxboisdbkq - ldiaxcvsik) View more	-	26 Jan 2016
				AZD8848 (AZD8848, 60 μg)	hxtbibkzeu(iybbnuqbrh) = dlqnfeoqht ctpgfglbgu (wrzuqjelkg, 0.450) View more
NCT01185080 (CTgov)	Phase 2	Rhinitis, Allergic, Seasonal	93	AZD8848 (AZD8848 20 μg x3)	oksbogwjvc(lsuvgvsuek) = jnquujziwb uwzebzzoua (jcnnleavie, ngjkbciely - qtwyampfsv) View more	-	07 Jan 2016
				Placebo (Placebo)	oksbogwjvc(lsuvgvsuek) = jkxuynbcvz uwzebzzoua (jcnnleavie, jjwedbtvjg - wkzuhfxavz) View more
NCT01185080 (Pubmed \| Inflamm Res) Manual	Phase 2	Rhinitis, Allergic, Seasonal	83	AZD8848	mvdhbncxwn(qntxxtewsf) = Symptoms recorded soon after allergen challenge were reduced up to eight days after the final dose of AZD8848. knlqvabihz (bbjizkpgoa ) View more	Positive	01 Nov 2015
				Placebo