Delving into the Latest Updates on AZD-2373 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [5]

Target

APOL1 x FOXP3

Action

inhibitors

Mechanism

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

Therapeutic Areas

NeoplasmsDigestive System DisordersRespiratory Diseases+ [3]

Active Indication

Apolipoprotein L1-mediated Kidney DiseaseNeoplasmsAdvanced Malignant Solid Neoplasm+ [9]

Inactive Indication-

Originator Organization

Ionis Pharmaceuticals, Inc.

Active Organization

AstraZeneca PLC

AstraZeneca Pharmaceuticals Co. Ltd.

Ionis Pharmaceuticals, Inc.

Inactive Organization-

License Organization

Ionis Pharmaceuticals, Inc.

AstraZeneca PLC

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Sequence Code 719606449

Source: *****

The purpose of this study is to assess the efficacy and safety of AZD2373 in participants diagnosed with APOL1-Mediated Kidney Disease (AMKD) who are homozygotes or compound heterozygotes for APOL1 high-risk genotypes (G1 and G2). The primary hypothesis to be evaluated is that AZD2373, compared with placebo, will result in a greater reduction in UACR as assessed by the relative change from Baseline in UACR at Week 30.

Start Date05 Mar 2025

Sponsor / Collaborator

AstraZeneca PLC

NCT05351047

/ CompletedPhase 1

A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD2373 Following Multiple Ascending Dose Administration to Healthy Male Participants of Sub-Saharan West African Ancestry

This is a Phase 1 study to assess the the safety, tolerability and pharmacokinetics (PK) of AZD2373, following subcutaneous (SC) administration of multiple ascending doses (MAD) of AZD2373 in healthy male participants of sub-Saharan West African ancestry.

Start Date04 Apr 2022

Sponsor / Collaborator

AstraZeneca PLC

[+1]

NCT04504669

/ CompletedPhase 1

A Phase I First-in-Human Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of AZD8701 Administered Intravenously as Monotherapy and in Combination With Durvaluamb (MEDI4736) in Participants With Advanced Solid Tumours.

The purpose of this study is to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Antitumor Activity of AZD8701 Alone and in Combination with Durvalumab (MEDI4736) in Adult Subjects with Select Advanced Solid Tumors

Start Date18 Aug 2020

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-2373

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100 Translational Medicine associated with AZD-2373

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100 Patents (Medical) associated with AZD-2373

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2

Literatures (Medical) associated with AZD-2373

14 Apr 2025·Clinical Cancer Research

AZD8701, an Antisense Oligonucleotide Targeting FOXP3 mRNA, as Monotherapy and in Combination with Durvalumab: A Phase I Trial in Patients with Advanced Solid Tumors

Article

Author: Siu, Lillian L. ; Roy, Archana ; Stone, John ; Saran, Shashank ; Castanon Alvarez, Eduardo ; Lambert, Arthur W. ; Massard, Christophe ; Villanueva-Vázquez, Rafael ; Ng, Felicia ; Cho, Song ; Johnson, Melissa ; Miller, Neil ; Postel-Vinay, Sophie ; Ouali, Kaïssa ; Bayat, Mahdiye ; Collins, Teresa ; Petruzzelli, Michele ; McMorn, Stephen ; Angell, Helen K. ; de Velasco, Guillermo ; Kyriakopoulos, Christos E.

AbstractPurpose:AZD8701 uses next-generation antisense oligonucleotide (ASO) technology to selectively reduce human forkhead box P3 (FOXP3) expression in regulatory T cells, reversing their immunosuppressive function. FOXP3 ASO alone or with PD-(L)1 inhibition attenuated tumor growth in mice. We report a phase I study of AZD8701 alone or combined with durvalumab in patients with advanced solid tumors.Patients and Methods:Eligible patients had solid tumors and received prior standard-of-care treatment, including anti–PD-(L)1 therapy. Patient cohorts were treated with AZD8701 intravenously weekly at escalating doses, either alone (60–960 mg) or combined (240–720 mg) with durvalumab 1,500 mg intravenous every 4 weeks. The primary objective was safety and tolerability, with the aim of determining the MTD.Results:Forty-five patients received AZD8701 monotherapy, and 18 received AZD8701 with durvalumab. One dose-limiting toxicity (increased alanine aminotransferase) occurred with AZD8701 960 mg. The most common adverse events related to AZD8701 monotherapy were fatigue (22.2%), asthenia, pyrexia, and increased alanine aminotransferase (20% each); the safety profile was similar when combined with durvalumab. With AZD8701 monotherapy, 24.4% and 15.6% of the patients had stable disease for ≥16 and ≥24 weeks, respectively; one patient treated with AZD8701 720 mg and durvalumab had a partial response. FOXP3 mRNA changes were heterogeneous (8/13 patients showed a reduction), with no clear dose relationship. ASO accumulated in the tumor epithelium and stroma.Conclusions:This study demonstrates the clinical feasibility of ASO therapy, with generally manageable adverse events, FOXP3 knockdown, and ASO delivery to the tumor.

01 Apr 2022·Journal for ImmunoTherapy of CancerQ2 · MEDICINE

Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer

Q2 · MEDICINE

ArticleOA

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 ; Chapman, Melissa ; Peter, Alison ; 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
Apolipoprotein L1-mediated Kidney Disease	Phase 2	United States	AstraZeneca PLC	05 Mar 2025
Apolipoprotein L1-mediated Kidney Disease	Phase 2	United Kingdom	AstraZeneca PLC	05 Mar 2025
Neoplasms	Phase 2	-	Ionis Pharmaceuticals, Inc.	-
Neoplasms	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Squamous Cell Carcinoma of Head and Neck	Phase 1	Spain	AstraZeneca PLC	18 Aug 2020
Squamous Cell Carcinoma of Head and Neck	Phase 1	United States	AstraZeneca PLC	18 Aug 2020
Squamous Cell Carcinoma of Head and Neck	Phase 1	Canada	AstraZeneca PLC	18 Aug 2020
Chronic Kidney Diseases	Phase 1	-	Ionis Pharmaceuticals, Inc.	-
Chronic Kidney Diseases	Phase 1	-	AstraZeneca PLC	-