Delving into the Latest Updates on AZD-2373 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [5]

Target

APOL1 x FOXP3

Mechanism

APOL1 inhibitors(Apolipoprotein L1 inhibitors), FOXP3 inhibitors(forkhead box P3 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersRespiratory Diseases+ [3]

Active Indication

NeoplasmsAdvanced Malignant Solid NeoplasmMalignant neoplasm of gastro-oesophageal junction+ [8]

Inactive Indication-

Originator Organization

Ionis Pharmaceuticals, Inc.

Active Organization

AstraZeneca PLC

AstraZeneca Pharmaceuticals Co. Ltd.

Ionis Pharmaceuticals, Inc.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Author: Taylor, Molly ; Magiera, Lukasz ; Barry, Simon T ; Kar, Gozde ; Hettrick, Lisa ; Sinclair, Charles ; Lyne, Paul ; Singh, Maneesh ; Gattis, Danielle ; King, Matthew ; MacLeod, A Robert ; Klein, Stephanie ; Mele, Deanna A ; Sah, Vasu ; Fawell, Stephen ; Hughes, Adina M ; Walton, Josephine ; Goldberg, Frederick W ; Ireland, Lucy ; Edbrooke, Mark ; Johnson, Ben ; Watt, Andrew ; Mairesse, Maelle ; Solanki, Anisha ; Revenko, Alexey ; Peter, Alison ; Chapman, Melissa ; Carnevalli, Larissa S

BackgroundThe Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to the tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 by systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate the activity of Tregs and augment antitumor immunity providing therapeutic benefit in cancer models and potentially in man.MethodsWe have identified murine Foxp3 antisense oligonucleotides (ASOs) and clinical candidate human FOXP3 ASO AZD8701. Pharmacology and biological effects of FOXP3 inhibitors on Treg function and antitumor immunity were tested in cultured Tregs and mouse syngeneic tumor models. Experiments were controlled by vehicle and non-targeting control ASO groups as well as by use of multiple independent FOXP3 ASOs. Statistical significance of biological effects was evaluated by one or two-way analysis of variance with multiple comparisons.ResultsAZD8701 demonstrated a dose-dependent knockdown of FOXP3 in primary Tregs, reduction of suppressive function and efficient target downregulation in humanized mice at clinically relevant doses. Surrogate murine FOXP3 ASO, which efficiently downregulated Foxp3 messenger RNA and protein levels in primary Tregs, reduced Treg suppressive function in immune suppression assays in vitro. FOXP3 ASO promoted more than 70% reduction in FOXP3 levels in Tregs in vitro and in vivo, strongly modulated Treg effector molecules (eg, ICOS, CTLA-4, CD25 and 4-1BB), and augmented CD8+ T cell activation and produced antitumor activity in syngeneic tumor models. The combination of FOXP3 ASOs with immune checkpoint blockade further enhanced antitumor efficacy.ConclusionsAntisense inhibitors of FOXP3 offer a promising novel cancer immunotherapy approach. AZD8701 is being developed clinically as a first-in-class FOXP3 inhibitor for the treatment of cancer currently in Ph1a/b clinical trial (NCT04504669).

100 Deals associated with AZD-2373

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 2	-	Ionis Pharmaceuticals, Inc.	-
Neoplasms	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Small Cell Lung Cancer	Phase 1	CA	AstraZeneca PLC	18 Aug 2020
Small Cell Lung Cancer	Phase 1	US	AstraZeneca PLC	18 Aug 2020
Small Cell Lung Cancer	Phase 1	FR	AstraZeneca PLC	18 Aug 2020
Small Cell Lung Cancer	Phase 1	ES	AstraZeneca PLC	18 Aug 2020
Triple Negative Breast Cancer	Phase 1	CA	AstraZeneca PLC	18 Aug 2020
Chronic Kidney Diseases	Phase 1	-	AstraZeneca PLC	-
Chronic Kidney Diseases	Phase 1	-	Ionis Pharmaceuticals, Inc.	-