AZD1981 / AstraZeneca - LARVOL DELTA

FROM BIOMARKER TO DISEASE MAKER: CHI3L1/YKL-40 ASTROCYTE CIRCUITS AS DRIVERS AND THERAPEUTIC TARGETS IN ALZHEIMER'S AND CNS INFLAMMATORY DISORDERS (ADPD 2026) - "Second, cross-validate this axis in neuromyelitis optica (NMO)—a primary astrocytopathy—to isolate astrocyte-first mechanisms and minimize microglial confounds. Human AD re-analysis and IHC; iPSC-derived human astrocytes/NSCs with co-culture, conditioned media, and CHI3L1 immunodepletion; amyloid mouse models (including dentate Aβ42 infusion); astrocyte-specific Chi3l1 knockout and dentate CHI3L1 overexpression with neurogenesis (EdU/BrdU) and memory readouts; receptor/pathway mapping (CRTH2, GSK-3β/β-catenin), si/shRNA; and pharmacology with the CRTH2 antagonist AZD1981... Across human tissue and AD models, activated astrocytes release CHI3L1 that shuts down adult neurogenesis via a CRTH2 → GSK-3β → β-catenin cascade, driving cognitive impairment. Genetic or pharmacologic interruption—especially CRTH2 antagonism—reopens neurogenesis, recasting CHI3L1 from biomarker to disease driver and nominating the CHI3L1–CRTH2 pathway as a repurposing-ready AD target. Independent..."

Biomarker • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Neuromyelitis Optica Spectrum Disorder • Rare Diseases • Aβ42 • CHI3L1

Pharmacologic activation of Δ133p53α reduces cellular senescence in progeria patients-derived cells. (PubMed, Aging Pathobiol Ther) - "We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate Δ133p53α protein levels...Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which Δ133p53α-regulated senescence plays a role."

Journal • CDKN1A • IL6

Pharmacologic activation of Δ133p53α reduces cellular senescence in progeria patients-derived cells. (PubMed, bioRxiv) - "We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate Δ133p53α protein levels...Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which Δ133p53α-regulated senescence plays a role."

Journal • CDKN1A • IL6

A Quantitative High-Throughput Screen Identifies Compounds that Upregulate the p53 Isoform Δ133p53α and Inhibit Cellular Senescence. (PubMed, ACS Pharmacol Transl Sci) - "We successfully identified two candidate compounds, AZD1981 and celastrol, which were shown to upregulate the fluorescently labeled Δ133p53α protein, as well as the endogenous Δ133p53α protein in primary human astrocytes and the normal lung fibroblasts MRC-5, leading to reduced induction of cellular senescence and SASP factor secretion...Together with our previous findings of Δ133p53α overexpression-induced restoration of cell proliferation and function in cells otherwise approaching senescence, we propose that these two compounds may have therapeutic potential in senescence- and aging-associated diseases. The qHTS assay developed in this study could be used to identify new therapies for these diseases."

Journal • CNS Disorders • Targeted Protein Degradation • CD8 • TP53

PGD2 displays distinct effects in diffuse large B-cell lymphoma depending on different concentrations. (PubMed, Cell Death Discov) - "Besides, high-concentration PGD2 could induce ROS-mediated DNA damage and enhance the cytotoxicity of adriamycin, bendamustine and venetoclax. Furthermore, HDAC inhibitors, vorinostat (SAHA) and panobinostat (LBH589) regulated CRTH2 expression and PGD2 production, and CRTH2 inhibitor AZD1981 and high-concentration PGD2 enhanced their anti-tumor effects in DLBCL. Altogether, our findings demonstrated PGD2 and CRTH2 as novel prognostic biomarkers and therapeutic targets in DLBCL, and highlighted the potency of high-concentration PGD2 as a promising therapeutic strategy for DLBCL patients."

Journal • Allergy • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • PTGDR

Efficacy of an oral CRTH2 antagonist (AZD1981) in the treatment of chronic rhinosinusitis with nasal polyps in adults: a randomized controlled clinical trial. (PubMed, Clin Exp Allergy) - "In patients with CRSwNP, the addition of AZD1981 to intranasal corticosteroids did not change nasal polyp size, radiographic scores, symptoms or disease-specific quality of life."

Clinical • Journal • Allergy • Chronic Rhinosinusitis With Nasal Polyps • Immunology • Inflammation • Nasal Polyps • Otorhinolaryngology • Respiratory Diseases • Sinusitis

Current and EmergingTreatments for Chronic Spontaneous Urticaria. (PubMed, Ann Allergy Asthma Immunol) - "The development of new treatments for CSU will importantly lead to improved options for patients and may assist with improving our understanding of disease pathophysiology."

Journal • Review • Dermatology • Urticaria

Looking forward to new targeted treatments for chronic spontaneous urticaria. (PubMed) - Clin Transl Allergy - "Ligelizumab (anti-IgE), canakinumab (anti-IL-1), AZD1981 (a PGD2 receptor antagonist) and GSK 2646264 (a selective Syk inhibitor) are currently in clinical trials for CSU. The introduction of omalizumab to the management of chronic spontaneous urticaria (CSU) has markedly improved the therapeutic possibilities for both, patients and physicians dealing with this disabling disease. Off-licence uses of currently available drugs include rituximab and tumour necrosis factor inhibitors. Other mediators and receptors of likely pathogenic relevance should be explored in skin profiling and functional proof of concept studies. The exploration of novel therapeutic targets for their role and relevance in CSU should help to achieve a better understanding of its etiopathogenesis."

Journal • Review • Biosimilar • Immunology

A Drug-Drug Interaction Study Between AZD1981 and Pravastatin to Study the Effect of AZD1981 on the Kinetics of Pravastatin -

AZ; P1, N=30

Investigation of efficacy, safety and tolerability of once and twice daily doses of AZD1981 in asthmatic patients (Sweapea) (clinicaltrials.gov) - P2, N=1,120; Recruiting

Protocol • Asthma • Immunology

A bioavailability study comparing 3 different AZD1981 tablets (clinicaltrials.gov) - P1; N=16; Completion date: July '11 → Jun ‘11; Active, not recruiting → Completed

Completion date • Trial completion • Immunology

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria. (PubMed, Int Arch Allergy Immunol) - "This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD2-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD2/CRTh2 pathway will be an -effective treatment for CSU."

Journal