mitiperstat (AZD4831) / AstraZeneca - LARVOL DELTA

A Phase 2a Trial of Myeloperoxidase Inhibitor Mitiperstat in Non-Cirrhotic Metabolic Dysfunction-Associated Steatohepatitis. (PubMed, Liver Int) - P2 | "This study does not provide proof of concept that mitiperstat 5 mg exerts an anti-inflammatory/anti-fibrotic effect in MASH."

Biomarker • Clinical • Journal • P2a data • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • MPO

Phase 2a, Randomized Trial of Mitiperstat Versus Placebo in Patients with COPD at High Risk of Exacerbation (CRESCENDO). (PubMed, Int J Chron Obstruct Pulmon Dis) - "The study period is planned to take between 18 and 30 weeks for each patient. CRESCENDO will assess efficacy and safety of mitiperstat using a novel, patient-centric trial design to enhance participant recruitment, partially via community-based facilities, helping to overcome restrictive trial designs and better reflect the real-world population with COPD, as well as reducing its environmental impact."

Clinical protocol • Journal • P2a data • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • MPO

Anti-inflammatory Treatment For Heart Failure With Reduced And Preserved Ejection Fraction: A Meta‑Analysis Of Randomized Controlled Trials (HFSA 2025) - "The anti-inflammatory treatment in the RCTs included colchicine, verinurad, mitiperstat, and anakinra. The anti-inflammatory treatment had a tendency toward improved clinical outcomes compared with placebo, which was consistent in the subgroup analysis of HFrEF and HFpEF. Further research is warranted to assess the efficacy of anti-inflammatory treatment for patients with heart failure."

Retrospective data • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation

Quantitative CT biomarkers reveal COPD subtypes with distinct lung function profiles (ERS 2025) - P2 | " CRESCENDO was arandomized, double-blind, placebo-controlled study of mitiperstat, an oral MPO- inhibitor, in adults with moderate-to-severe COPD (FEV1/FVC <0.7) at high risk of exacerbations... COPD subtypes based on CT biomarkers show differential lung function impairment. This subtyping approach holds potential to identify differential treatment responses."

Biomarker • Chronic Obstructive Pulmonary Disease • Immunology • Respiratory Diseases

From proteomics to precision: protein signatures as surrogate markers in phase II heart failure trials. A subanalysis from MYSTERY-HF (ESC-WCC 2025) - P2 | "MYSTERY-HF (Myeloperoxidase inhibition in patients with ischemic or non-ischemic cardiomyopathy and heart failure with reduced ejection fraction (HFrEF), EudraCT: 2022-003797-23) was a phase II multicenter randomized, double-blind placebo-controlled trial: Patients diagnosed for HFrEF with an LVEF ≤40% were randomized 1:1 to receive either the MPO inhibitor mitiperstat or matching placebo for 12 weeks... We integrated the proteomics datasets from a phase II trial into a rigorously characterized, much larger cohort of similar patients with available long-term follow-up. Using this -omics approach to create digital twins has the potential to supersede classical phase II surrogate markers and thereby reduce the risk for unsuccessful phase II/III translation of clinical trials."

P2 data • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • MPO

Acute Effects of Myeloperoxidase Inhibition on Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial. (PubMed, Mayo Clin Proc) - "Acute MPO inhibition with mitiperstat did not reduce exertional hemodynamic congestion in patients with HFpEF."

Clinical • Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • MPO

Myeloperoxidase inhibition in the landscape of anti-inflammatory therapies for heart failure with preserved ejection fraction: the ENDEAVOR trial. (PubMed, Heart Fail Rev) - "While inflammation has been investigated as a potential therapeutic target in HFpEF, previous trials evaluating treatments targeting various inflammatory pathways such as interleukin-1 (IL-1) inhibitors or colchicine have largely yielded neutral effects on clinical outcomes. This review summarizes the findings of the ENDEAVOR trial evaluating the efficacy and safety of mitiperstat, a selective MPO inhibitor, in patients with symptomatic HF with ejection fraction > 40%. We will discuss these results within the context of previous anti-inflammatory trials in HF and explore the challenges in developing effective anti-inflammatory therapies for this complex condition."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • MPO

Pharmacokinetics of Mitiperstat in Participants With Hepatic Impairment (clinicaltrials.gov) - P1 | N=31 | Completed | Sponsor: AstraZeneca | Recruiting ➔ Completed | Trial primary completion date: Aug 2024 ➔ Nov 2024

Trial completion • Trial primary completion date • Hepatology

LBS 06: Medical therapy for heart failure (American Heart Association) - "Overall, mitiperstat was safe, with few serious adverse events, but it did not improve symptoms or exercise function over 16 weeks in patients with HFpEF. 'But mitiperstat did result in reduced heart failure hospitalization,' said Sanjiv Shah, MD...noted that the potential beneficial longer-term effect of mitiperstat on reducing heart failure hospitalization and death requires further investigation."

Media quote

Myeloperoxidase Inhibition with Mitiperstat in Heart Failure with Preserved and Mildly Reduced Ejection Fraction: Primary Results from the ENDEAVOR Randomized Clinical Trial (AHA 2024) - P2/3 | "Mitiperstat was safe but did not improve symptoms or exercise function over 16 weeks in HFpEF. The potential beneficial longer-term effect of mitiperstat on reducing HF hospitalization and death requires further investigation."

Clinical • Late-breaking abstract • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • IL6 • MPO

Pharmacokinetics and Tolerability of the Novel Myeloperoxidase Inhibitor Mitiperstat in Healthy Japanese and Chinese Volunteers. (PubMed, Clin Drug Investig) - P1 | "The pharmacokinetics of mitiperstat were similar among Japanese and Chinese participants. These characteristics were similar to those in a previous multiple ascending-dose study in healthy primarily white and Black/African American volunteers. Therefore, the pharmacokinetics of mitiperstat do not affect dosing regimens in these different populations."

Journal • PK/PD data • Cardiovascular • Chronic Obstructive Pulmonary Disease • Congestive Heart Failure • Heart Failure • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Pulmonary Disease • Respiratory Diseases • MPO

CRESCENDO: An Efficacy and Safety Study of Mitiperstat (AZD4831) (MPO Inhibitor) vs Placebo in the Treatment of Moderate to Severe COPD. (clinicaltrials.gov) - P2 | N=381 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

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

Reducing CO2 and improving clinical delivery with novel study designs (ERS 2024) - "AstraZeneca Sustainability in Clinical Trials Initiative developed a framework to optimize CO2e in clinical trial design.1 AstraZeneca used CRESCENDO, a Phase 2a clinical trial of the myeloperoxidase (MPO) inhibitor mitiperstat in patients with chronic obstructive pulmonary disease (COPD)as a proof of principle to apply the framework to optimize CO2e...Vogelmeier C et al. Respir Med 2020; 173:106175"

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

Early clinical drug product shelf-life setting using accelerated predictive stability and metabolite data for impurity qualification: A case study. (PubMed, J Pharm Sci) - "Applying all available data for AZD4831, (R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidin-4(5H)-one, a reliable predictive model was developed despite minor differences in technical batch tablet compositions...Hence, it was possible to guide the development stability activities and set an initial shelf-life of a tablet formulation. The presented study displays the importance of combining several sources of information in drug development, e.g., potential degradation pathways, accelerated stability, stability program design, metabolite data, and specification limits."

Journal

Role of Myeloperoxidase, Oxidative Stress, and Inflammation in Bronchopulmonary Dysplasia. (PubMed, Antioxidants (Basel)) - "In contrast, the irreversible MPO inhibitor-AZD4831-failed to provide similar efficacy. Interestingly, KYC cannot offer its effectiveness without the existence of MPO. We review the mechanisms by which this anti-MPO agent attenuates BPD."

Journal • Review • Bronchopulmonary Dysplasia • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • MPO

The effect of severe renal impairment on the pharmacokinetics, safety and tolerability of mitiperstat. (PubMed, Br J Clin Pharmacol) - "Mitiperstat apparent clearance was approximately twofold lower in individuals with severe renal impairment than in those with normal renal function. Lower clearance was driven by reduced renal clearance; non-renal clearance was similar. Mitiperstat was generally well tolerated by participants with severe renal impairment and normal renal function. These findings, together with efficacy and safety/tolerability data from phase 2b, will guide the dosing regimen for phase 3."

Journal • PK/PD data • Cardiovascular • Congestive Heart Failure • Heart Failure • Metabolic Disorders • Nephrology • Renal Disease • MPO

CRESCENDO: An Efficacy and Safety Study of Mitiperstat (AZD4831) (MPO Inhibitor) vs Placebo in the Treatment of Moderate to Severe COPD. (clinicaltrials.gov) - P2 | N=380 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | Trial completion date: Nov 2024 ➔ Aug 2024 | Trial primary completion date: Nov 2024 ➔ Aug 2024

Enrollment closed • Trial completion date • Trial primary completion date • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

COSMOS: A Study in Participants With Non-cirrhotic NASH With Fibrosis (clinicaltrials.gov) - P2 | N=122 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

ENDEAVOR: Study to Evaluate the Efficacy and Safety of AZD4831 in Participants With Heart Failure With Left Ventricular Ejection Fraction > 40% (clinicaltrials.gov) - P2/3 | N=711 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Congestive Heart Failure • Heart Failure

The myeloperoxidase inhibitor mitiperstat (AZD4831) does not prolong the QT interval at expected therapeutic doses. (PubMed, Pharmacol Res Perspect) - P1 | "The 16-fold margin to the highest observed exposure was high enough to mean that a positive control was not needed. Mitiperstat is not associated with risk of QT-interval prolongation at expected therapeutic concentrations."

Journal • Addiction (Opioid and Alcohol) • Cardiovascular • Chronic Obstructive Pulmonary Disease • Congestive Heart Failure • Heart Failure • Immunology • Pulmonary Disease • Respiratory Diseases • MPO

ENDEAVOR: Study to Evaluate the Efficacy and Safety of AZD4831 in Participants With Heart Failure With Left Ventricular Ejection Fraction > 40% (clinicaltrials.gov) - P2/3 | N=711 | Active, not recruiting | Sponsor: AstraZeneca | Phase classification: P2b ➔ P2/3

Phase classification • Cardiovascular • Congestive Heart Failure • Heart Failure

COPD clinical trial of mitiperstat now recruiting adults in Oklahoma (COPD News Today) - " A Phase 2a clinical trial of AstraZeneca’s experimental therapy mitiperstat is now recruiting adults with moderate to severe chronic obstructive pulmonary disease (COPD) at a study site in Choctaw, Oklahoma...CRESCENDO will enroll up to 406 people with COPD, ages 40 to 80, who have a history of smoking and are at high risk of experiencing exacerbations, or flare-ups of symptoms, despite standard treatment for the chronic disease...The goal of CRESCENDO is to evaluate how safe mitiperstat is against a placebo in people with COPD."

Enrollment open • Chronic Obstructive Pulmonary Disease

CRESCENDO: An Efficacy and Safety Study of Mitiperstat (AZD4831) (MPO Inhibitor) vs Placebo in the Treatment of Moderate to Severe COPD. (clinicaltrials.gov) - P2 | N=406 | Recruiting | Sponsor: AstraZeneca | N=288 ➔ 406 | Trial completion date: May 2024 ➔ Nov 2024 | Trial primary completion date: May 2024 ➔ Nov 2024

Enrollment change • Trial completion date • Trial primary completion date • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

COSMOS: A Study in Participants With Non-cirrhotic NASH With Fibrosis (clinicaltrials.gov) - P2 | N=109 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | Phase classification: P2a ➔ P2 | Trial completion date: Jul 2024 ➔ Mar 2024 | Trial primary completion date: Jul 2024 ➔ Mar 2024

Enrollment closed • Phase classification • Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis

CRESCENDO: An Efficacy and Safety Study of Mitiperstat (AZD4831) (MPO Inhibitor) vs Placebo in the Treatment of Moderate to Severe COPD. (clinicaltrials.gov) - P2 | N=288 | Recruiting | Sponsor: AstraZeneca | Phase classification: P2a ➔ P2

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