AZD8154 / AstraZeneca - LARVOL DELTA

PI3Kγδ inhibition suppresses key disease features in a rat model of asthma. (PubMed, Respir Res) - "These data show that a dual PI3Kγδ inhibitor suppress key features of disease in a rat model of asthma to a similar degree as budesonide and indicate that dual PI3Kγδ inhibition may be an effective treatment for people suffering from allergic asthma."

Journal • Preclinical • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • PIK3CG

PI3Kγd inhibition suppresses key disease features in a rat model of asthma (ERS 2023) - "Furthermore, AZD8154 administration was associated with an inhibition of airway inflammation and penh to a similar degree as budesonide. These data show that a dual PI3Kγδ inhibitor suppress key features of disease in a rat model of asthma to a similar degree as budesonide and indicate that dual PI3Kγδ inhibition may be an effective treatment for people suffering from asthma if an optimal safety profile can be achieved.; Epidemiology; Pulmonary function testing; Pulmonary rehabilitation; Cell and molecular biology; Physiology; General respiratory patient care"

Preclinical • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • PIK3CG

Diurnal variation in DLCO and non-standardized study procedures may cause a false positive safety signal in clinical trials. (PubMed, Respir Med) - "Diffusing capacity for carbon monoxide (DLCO) was measured in a phase I single ascending dose study after inhalation of AZD8154 or placebo in healthy participants at baseline (DLCO) and follow-up (DLCO) 6 days after dosing...The observed reduction in DLCO was confirmed as a false positive finding after alignment of DLCO timings. As a consequence, when DLCO is used in clinical studies, measurements should be strictly standardized in relation to time of the day."

Clinical • Journal • Inflammation • Pneumonia

[VIRTUAL] Exploring a dual PI3Kgd inhibitor, AZD8154, in COPD pathogenesis (ERS 2021) - No abstract available

Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease. (PubMed, Br J Clin Pharmacol) - P1 | "AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events and no clinically significant drug-associated safety concerns reported in healthy volunteers. AZD8154 demonstrated prolonged lung retention and a half-life supporting once-daily dosing."

Clinical • Journal • P1 data • PK/PD data • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • PIK3CG

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma. (PubMed, J Med Chem) - "We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] PI3Kγd Inhibitor, AZD8154, Demonstrates Improved Efficacious Profile Over PI3Kd Selective Inhibitor, GSK2269557, in a Rat Model of Asthma (ATS 2021) - "These data suggest that a dual PI3Kγδ inhibitor has an improved therapeutic profile compared to the selective PI3Kδ inhibitor, GSK557. Furthermore, these data suggest that AZD8154 may not trigger the increase in coughing which was observed for GSK557. Together these data indicate that AZD8154 may be an effective treatment for people suffering from asthma."

Preclinical • Asthma • Eosinophilia • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Product discontinued (AstraZeneca Press Release) - Asthma

Asthma • Respiratory Diseases

Evaluation of AZD8154 Concentrations in Blood (clinicaltrials.gov) - P1; N=10; Terminated; Sponsor: AstraZeneca; N=15 ➔ 10; Suspended ➔ Terminated; Need for evaluation of emerging pre-clinical toxicology findings

Clinical • Enrollment change • Trial termination • Asthma • Immunology • Respiratory Diseases • CRP

A Study to Evaluate the Effect of AZD8154 Administered Via Nebulizer Once Daily in Subjects With Mild Allergic Asthma Challenged With an Inhaled Allergen (clinicaltrials.gov) - P2a; N=0; Withdrawn; Sponsor: AstraZeneca; N=200 ➔ 0; Suspended ➔ Withdrawn

Clinical • Enrollment change • Trial withdrawal • Asthma • Immunology • Inflammation • Respiratory Diseases

Evaluation of AZD8154 Concentrations in Blood (clinicaltrials.gov) - P1; N=15; Suspended; Sponsor: AstraZeneca; Recruiting ➔ Suspended

Clinical • Trial suspension • Asthma • Respiratory Diseases • CRP

A Study to Evaluate the Effect of AZD8154 Administered Via Nebulizer Once Daily in Subjects With Mild Allergic Asthma Challenged With an Inhaled Allergen (clinicaltrials.gov) - P2a; N=200; Suspended; Sponsor: AstraZeneca; N=36 ➔ 200; Active, not recruiting ➔ Suspended

Clinical • Enrollment change • Trial suspension • Asthma • Immunology • Inflammation • Respiratory Diseases

[VIRTUAL] Discovery of AZD8154, a dual PI3Kγδ inhibitor, as an inhaled treatment for asthma (ACS-Fall 2020) - P1 | "In vivo studies in a rat ovalbumin challenge model of allergic asthma showed target engagement through inhibition of the phosphorylation of S6 ribosomal protein, inhibition of the release of key cytokines (IL-5, IL-13, IL-17) and inhibition of the influx of eosinophils, lymphocytes and neutrophils into the lung as measured in BAL. These effects were long-lasting with inhibition still significant from a challenge 7h after dosing.AZD8154 is currently undergoing Phase 1 clinical studies (NCT03436316); details of the initial human PK will be shown."

Asthma • Immune Modulation • Immunology • Inflammation • Oncology • Respiratory Diseases • IL13 • IL17A • IL5

[VIRTUAL] Discovery of AZD8154, a dual PI3Kγδ inhibitor, as an inhaled treatment for asthma (ACS-Fall 2020) - P1 | "In vivo studies in a rat ovalbumin challenge model of allergic asthma showed target engagement through inhibition of the phosphorylation of S6 ribosomal protein, inhibition of the release of key cytokines (IL-5, IL-13, IL-17) and inhibition of the influx of eosinophils, lymphocytes and neutrophils into the lung as measured in BAL. These effects were long-lasting with inhibition still significant from a challenge 7h after dosing.AZD8154 is currently undergoing Phase 1 clinical studies (NCT03436316); details of the initial human PK will be shown."

Asthma • Immune Modulation • Immunology • Inflammation • Oncology • Respiratory Diseases • IL13 • IL17A • IL5

[VIRTUAL] Safety, Tolerability and Pharmacokinetics (PK) of AZD8154, A Selective PI3Kγδ Inhibitor, After Single and Multiple Ascending Inhaled Doses in Healthy Volunteers (ATS-I 2020) - P1 | "These data build confidence on inhaled delivery of AZD8154. Consistent absorption and dose proportional PK were observed following single doses in the dose range studied, with a half-life supporting once-daily dosing. These data support further clinical development of AZD8154."

Clinical • PK/PD data • Respiratory Diseases

Evaluation of AZD8154 Concentrations in Blood (clinicaltrials.gov) - P1; N=15; Recruiting; Sponsor: AstraZeneca; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Asthma • Respiratory Diseases • CRP

Evaluation of AZD8154 Concentrations in Blood (clinicaltrials.gov) - P1; N=15; Not yet recruiting; Sponsor: AstraZeneca

Clinical • New P1 trial • Asthma • Respiratory Diseases • CRP

A Study to Evaluate the Effect of AZD8154 Administered Via Nebulizer Once Daily in Subjects With Mild Allergic Asthma Challenged With an Inhaled Allergen (clinicaltrials.gov) - P2a; N=36; Active, not recruiting; Sponsor: AstraZeneca; Trial completion date: Jul 2021 ➔ Nov 2021; Trial primary completion date: Jul 2021 ➔ Nov 2021

Clinical • Trial completion date • Trial primary completion date • Asthma • Immunology • Respiratory Diseases

Safety, Tolerability and Pharmacokinetics (PK) of AZD8154, A Selective PI3Kγδ Inhibitor, After Single and Multiple Ascending Inhaled Doses in Healthy Volunteers (ATS 2020) - P1 | "These data build confidence on inhaled delivery of AZD8154. Consistent absorption and dose proportional PK were observed following single doses in the dose range studied, with a half-life supporting once-daily dosing. These data support further clinical development of AZD8154."

Clinical • PK/PD data

A Study to Evaluate the Effect of AZD8154 Administered Via Nebulizer Once Daily in Subjects With Mild Allergic Asthma Challenged With an Inhaled Allergen (clinicaltrials.gov) - P2a; N=36; Active, not recruiting; Sponsor: AstraZeneca; Suspended ➔ Active, not recruiting

Clinical • Enrollment closed

A Study to Evaluate the Effect of AZD8154 Administered Via Nebulizer Once Daily in Subjects With Mild Allergic Asthma Challenged With an Inhaled Allergen (clinicaltrials.gov) - P2a; N=36; Suspended; Sponsor: AstraZeneca; Trial completion date: Mar 2021 ➔ Jul 2021; Not yet recruiting ➔ Suspended; Trial primary completion date: Mar 2021 ➔ Jul 2021

Clinical • Trial completion date • Trial primary completion date • Trial suspension

PI3Kγδ Inhibitor, AZD8154, Demonstrates Improved Efficacious Profile Over PI3Kδ Selective Inhibitor, GSK2269557, in a Rat Model of Asthma (ATS 2020) - "Abstract embargoed at this time."

Preclinical

Discovery of AZD8154, a dual PI3Kγδ inhibitor, as an inhaled treatment for asthma (ACS-Sp 2020) - P1; "In vivo studies in a rat ovalbumin challenge model of allergic asthma showed target engagement through inhibition of the phosphorylation of S6 ribosomal protein, inhibition of the release of key cytokines (IL-5, IL-13, IL-17) and inhibition of the influx of eosinophils, lymphocytes and neutrophils into the lung as measured in BAL. These effects were long-lasting with inhibition still significant from a challenge 7h after dosing.AZD8154 is currently undergoing Phase 1 clinical studies (NCT03436316); details of the initial human PK will be shown."

IL13 • IL17A • IL5

A Study to Evaluate the Effect of AZD8154 Administered Via Nebulizer Once Daily in Subjects With Mild Allergic Asthma Challenged With an Inhaled Allergen (clinicaltrials.gov) - P2a; N=36; Not yet recruiting; Sponsor: AstraZeneca

Clinical • New P2a trial

Safety, tolerability and pharmacokinetics (PK) of AZD8154 (a selective PI3K?d inhibitor) after single ascending inhaled doses in healthy volunteers (ERS 2019) - "The terminal mean half-life was 18 to 29 h and the pulmonary bioavailability was on average 94%. In summary, AZD8154 displayed dose proportional PK characteristics in the dose range studied (0.1 to 7.7 mg) with a half-life potentially suitable for once-daily dosing and the data supports further evaluation in a multiple ascending dose study."

Clinical • PK/PD data