atuliflapon (AZD-5718) / AstraZeneca - LARVOL DELTA

PASSIVATE: PASSIvation of Vulnerable Plaque With AZD5718 in AcuTe Coronary syndromE (clinicaltrials.gov) - P2 | N=243 | Terminated | Sponsor: National University Heart Centre, Singapore | N=360 ➔ 243 | Recruiting ➔ Terminated | Trial primary completion date: Mar 2023 ➔ May 2024; The study was terminated early on 14th September 2023 by the main funding company because of financial futility. We were able to enroll 243 of the initial planned 360 participants and randomised 209 participants of the intial planned 286.

Enrollment change • Trial primary completion date • Trial termination • Acute Coronary Syndrome • Cardiovascular

FLASH: Study to Assess the Efficacy and Safety of Atuliflapon in Moderate-to-Severe Uncontrolled Asthma (clinicaltrials.gov) - P2 | N=666 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jan 2025 ➔ Jan 2026 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Disposition of orally administered atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor in healthy participants. (PubMed, Pharmacol Res Perspect) - "Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications."

Journal • Cardiovascular

Atomic-level structure of the amorphous drug atuliflapon via NMR crystallography. (PubMed, Faraday Discuss) - "The ensemble of preferred structures allows us to identify a number of specific conformations and interactions that stabilize the amorphous structure. These include preferred hydrogen-bonding motifs with water and with other drug molecules, as well as conformations of the cyclohexane and pyrazole rings that stabilize structure by indirectly allowing for optimization of hydrogen bonding."

Journal

A drug-drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5-lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam. (PubMed, Br J Clin Pharmacol) - "Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs."

Journal • PK/PD data

FLASH: Study to Assess the Efficacy and Safety of Atuliflapon in Moderate-to-Severe Uncontrolled Asthma (clinicaltrials.gov) - P2 | N=1102 | Recruiting | Sponsor: AstraZeneca | N=667 ➔ 1102

Enrollment change • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

FLASH: Study to Assess the Efficacy and Safety of Atuliflapon in Moderate-to-Severe Uncontrolled Asthma (clinicaltrials.gov) - P2 | N=667 | Recruiting | Sponsor: AstraZeneca | N=1102 ➔ 667

Enrollment change • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

A Study to Evaluate the Safety and Efficacy of AZD5718 in Participants With Proteinuric Chronic Kidney Disease (clinicaltrials.gov) - P2 | N=613 | Terminated | Sponsor: AstraZeneca | Phase classification: P2b ➔ P2 | Completed ➔ Terminated; The Sponsor decided to terminate the study early due to lack of efficacy. There were no safety concerns related to the study.

Phase classification • Trial termination • Chronic Kidney Disease • Nephrology • Renal Disease

A Phase IIb Randomized, Double-Blind, Placebo-Controlled, Multi-Centre, Dose Ranging Study of Atuliflapon in Participants with Proteinuric CKD (KIDNEY WEEK 2023) - "Atuliflapon did not significantly reduce uACR in any of the treatment groups compared to placebo."

Clinical • P2b data • Inflammation • Renal Disease

FLASH: Study to Assess the Efficacy and Safety of Atuliflapon in Moderate-to-Severe Uncontrolled Asthma (clinicaltrials.gov) - P2 | N=1102 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2025 ➔ Jan 2025 | Trial primary completion date: Dec 2025 ➔ Jan 2025

Trial completion date • Trial primary completion date • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

FLASH: Study to Assess the Efficacy and Safety of Atuliflapon in Moderate-to-Severe Uncontrolled Asthma (clinicaltrials.gov) - P2 | N=1102 | Recruiting | Sponsor: AstraZeneca | N=1928 ➔ 1102 | Trial completion date: Aug 2025 ➔ Dec 2025 | Trial primary completion date: Aug 2025 ➔ Dec 2025

Enrollment change • Trial completion date • Trial primary completion date • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • CORIN

FLASH: Study to Assess the Efficacy and Safety of AZD5718 in Moderate-to-Severe Uncontrolled Asthma (clinicaltrials.gov) - P2 | N=1928 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Feb 2024 ➔ Aug 2025 | Trial primary completion date: Feb 2024 ➔ Aug 2025

Trial completion date • Trial primary completion date • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • CORIN

PASSIVATE: PASSIvation of Vulnerable Plaque With AZD5718 in AcuTe Coronary syndromE (clinicaltrials.gov) - P2 | N=360 | Recruiting | Sponsor: National University Heart Centre, Singapore | Not yet recruiting ➔ Recruiting | Trial completion date: Sep 2023 ➔ Sep 2024

Enrollment open • Trial completion date • Acute Coronary Syndrome • Cardiovascular

A Study to Evaluate the Safety and Efficacy of AZD5718 in Participants With Proteinuric Chronic Kidney Disease (clinicaltrials.gov) - P2b | N=613 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Chronic Kidney Disease • Nephrology • Renal Disease

A Study to Evaluate the Safety and Efficacy of AZD5718 in Participants With Proteinuric Chronic Kidney Disease (clinicaltrials.gov) - P2b | N=613 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2023 ➔ Aug 2022 | Trial primary completion date: Feb 2023 ➔ Aug 2022

Enrollment closed • Trial completion date • Trial primary completion date • Chronic Kidney Disease • Nephrology • Renal Disease

Safety and efficacy of the 5-lipoxygenase-activating protein inhibitor AZD5718 in patients with recent myocardial infarction: The phase 2a FLAVOUR study. (PubMed, Int J Cardiol) - P2a | "In patients with recent myocardial infarction, AZD5718 was well tolerated, and leukotriene biosynthesis was dose-dependently inhibited. No significant changes in CFVR were detected."

Journal • P2a data • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction

FLASH: Study to Assess the Efficacy and Safety of AZD5718 in Moderate-to-Severe Uncontrolled Asthma (clinicaltrials.gov) - P2 | N=1900 | Recruiting | Sponsor: AstraZeneca | Trial primary completion date: Feb 2023 ➔ Feb 2024

Trial primary completion date • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Study to Assess the Efficacy and Safety of AZD5718 in Moderate-to-Severe Uncontrolled Asthma Vizsgálat az AZD5718 hatásosságának és biztonságosságának értékelésére mérsékelten súlyos–súlyos, kontrollálatlan asztmában szenvedőknél (clinicaltrialsregister.eu) - P2 | N=1928 | Ongoing | Sponsor: AstraZeneca AB

New P2 trial • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

FLASH: Study to Assess the Efficacy and Safety of AZD5718 in Moderate-to-Severe Uncontrolled Asthma (clinicaltrials.gov) - P2 | N=1928 | Recruiting | Sponsor: AstraZeneca

New P2 trial • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Design of FLAIR: a Phase 2b Study of the 5-Lipoxygenase Activating Protein Inhibitor AZD5718 in Patients With Proteinuric CKD. (PubMed, Kidney Int Rep) - P2b | "Participants receive AZD5718 at 3 different doses or placebo once daily for 12 weeks, followed by an 8-week extension in which they also receive dapagliflozin (10 mg/d) as anticipated future standard of care. Safety, tolerability, AZD5718 pharmacokinetics, and analyses of biomarkers that may predict or reflect response to AZD5718 are additional objectives. FLAIR will provide data on the effects of 5-lipoxygenase pathway inhibition in patients with proteinuric CKD with or without type 2 diabetes, and will form the basis for future clinical trials (ClinicalTrials.gov: NCT04492722)."

Clinical • Journal • P2b data • Cardiovascular • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Pharmacokinetics, Pharmacodynamics, and Tolerability of AZD5718, an Oral 5-Lipoxygenase-Activating Protein (FLAP) Inhibitor, in Healthy Japanese Male Subjects. (PubMed, Clin Drug Investig) - "The observed pharmacokinetics and pharmacodynamics were similar to reported data for non-Japanese healthy subjects, which support further evaluation of AZD5718 at similar doses/exposures in Japanese and non-Japanese subjects for future evaluation in patients with CAD and CKD."

Clinical • Journal • PK/PD data • Cardiovascular • Chronic Kidney Disease • Coronary Artery Disease • Nephrology • Renal Disease

Structure determination of an amorphous drug through large-scale NMR predictions. (PubMed, Nat Commun) - "Here, using a machine learning model of chemical shifts, we determine the atomic-level structure of the hydrated amorphous drug AZD5718 by combining dynamic nuclear polarization-enhanced solid-state NMR experiments with predicted chemical shifts for MD simulations of large systems. From these amorphous structures we then identify H-bonding motifs and relate them to local intermolecular complex formation energies."

Journal

[VIRTUAL] EFFICACY, SAFETY AND TOLERABILITY OF THE 5-LIPOXYGENASE-ACTIVATING PROTEIN INHIBITOR AZD5718 IN PATIENTS WITH RECENT MYOCARDIAL INFARCTION: A PHASE 2A STUDY (FLAVOUR) (ACC 2021) - "In patients with recent MI, AZD5718 was well tolerated and dose-dependently inhibited leukotriene biosynthesis. No significant improvement in coronary microvascular function was detected by echocardiography."

Clinical • P2a data • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction

Study to Assess Relative Bioavailability and Safety of AZD5718 in Healthy Volunteers (clinicaltrials.gov) - P1; N=16; Completed; Sponsor: AstraZeneca; Active, not recruiting ➔ Completed

Trial completion • Chronic Kidney Disease • Nephrology • Renal Disease

Study to Assess Relative Bioavailability and Safety of AZD5718 in Healthy Volunteers (clinicaltrials.gov) - P1; N=16; Active, not recruiting; Sponsor: AstraZeneca; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Chronic Kidney Disease • Nephrology • Renal Disease