EP4689664A1

EP4689664A1 - Method of treatment with mpo inhibitors

Info

Publication number: EP4689664A1
Application number: EP24715231.7A
Authority: EP
Inventors: Erik Michaëlsson
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2023-04-06
Filing date: 2024-04-05
Publication date: 2026-02-11
Also published as: WO2024209075A1; CN120898134A

Abstract

The present disclosure relates to methods of identifying subjects likely to respond to treatment with a myeloperoxidase (MPO) inhibitor based on their neutrophil levels and/or the concentration of at least one protein biomarker. The present disclosure also relates to methods of selecting subjects for treatment with an MPO inhibitor, methods of predicting whether a subject will respond to treatment with an MPO inhibitor and methods of treating subjects likely to respond to treatment with an MPO inhibitor. The present disclosure also relates to a method of predicting an improved clinical response in a subject having an MPO-related disorder following treatment with an MPO inhibitor.

Description

METHOD OF TREATMENT WITH MPO INHIBITORS

Field of the Invention

The present disclosure relates to methods of identifying subjects likely to respond to treatment with a myeloperoxidase (MPO) inhibitor based on their neutrophil levels and/or the concentration of at least one biomarker selected from the group consisting of: CXCL1 1 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, STK4, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 . The present disclosure also relates to methods of selecting subjects for treatment with an MPO inhibitor, methods of predicting whether a subject will respond to treatment with an MPO inhibitor and methods of treating subjects likely to respond to treatment with an MPO inhibitor.

Background

Myeloperoxidase (MPO) is a heme-containing enzyme found in neutrophilic granulocytes (neutrophils) and monocytes. MPO is one member of a diverse protein family of mammalian peroxidases that also includes eosinophil peroxidase (EPO), thyroid peroxidase (TPO), salivary peroxidase (SPS), lactoperoxidase (LPO), prostaglandin H synthase (PGHS), and others. The mature enzyme is a dimer of identical halves. Each half molecule contains a covalently bound heme that exhibits unusual spectral properties responsible for the characteristic green color of MPO. Cleavage of the disulphide bridge linking the two halves of MPO yields the hemi-enzyme that exhibits spectral and catalytic properties indistinguishable from those of the intact enzyme. The enzyme is activated by hydrogen peroxide, the source of which can be superoxide dismuatase (SOD)-catalyzed NADPH-derived superoxide anion and xanthine oxidase-derived superoxide anion and hydrogen peroxide formed upon purine oxidation. The main physiological substrates of MPO are halides (e.g. chloride) and pseudohalides (like thiocyanate), forming microbicidal hypohalous acids like hypochlorous acid (bleach) and hypothiocyanous acid {J. Clin. Biochem. Nutr., 2011 , 48, 8-19).

Neutrophils play an important microbicidal role by phagocytosing (engulfing) and killing microorganisms. The engulfed load is incorporated into vacuoles, termed phagosomes, which fuse with granules containing myeloperoxidase to form phagolysosomes. In phagolysosomes the enzymatic activity of the myeloperoxidase leads to the formation of hypochlorous acid, a potent bactericidal compound {Free Radical Biology & Medicine, 2010, 49, 1834-1845). Hypochlorous acid is oxidizing in itself, and reacts most avidly with thiols and thioethers, but also converts amines into chloramines, and chlorinates aromatic amino acids. MPO can also be released to the outside of the cells where the reaction with chloride can induce damage to adjacent tissue. In addition to this controlled release of MPO, neutrophils can also cast webs of decondensed DNA interspersed with intracellular proteins such as MPO into the extracellular space, so called neutrophil extracellular traps (NET). These NETs are thought to play a role in host defence towards extracellular microbes and has also been suggested to be an important pathophysiological mechanism in acute inflammatory diseases such as the immunothrombosis occurring in sepsis (Nature Rev. Immunol, 2013, 13, 34) and in autoimmunity, such as in systemic lupus erythematousus (SLE) (J. Immunol., 2011 , 187, 538-552). Notably, MPO is required for NET formation (Blood, 2011 , 117, 953).

Heart failure (HF) is a major and growing syndrome worldwide, and morbidity and mortality rates remain high despite recent advances in treatments. The increase in HF is partly explained by an ageing population with rising prevalence of chronic conditions, such as hypertension, renal failure, diabetes mellitus, and metabolic syndrome. In addition, improved treatment of ischemic heart disease has increased the number of surviving HF. The syndrome comprises a wide spectrum of patients with symptoms and/or signs caused by structural or functional cardiac abnormality, and left ventricular (LV) function ranging from preserved (HFpEF), mildly reduced (HFmrEF) or reduced ejection fraction (HFrEF) (McDonagh et al 2022).

The goals of HF treatment are to improve the patient’s clinical status, functional capacity, and prevent hospital admission and mortality. Recommendations for pharmacological treatment for HFrEF consist of 4 major classes of medications: ARBs/ACE inhibitors/ARNIs, beta blockers, MRAs, and SGLT2 inhibitors. For patients with HFpEF, diagnosis and treatment of comorbidities and use of diuretics are recommended (McDonagh et al 2022). For patients with HFmrEF and HFpEF, treatments that improve morbidity and mortality are more limited. Recently however, SGLT2 inhibitors have been shown to reduce CV death and hospitalisation for HF also in these patients (Vaduganathan et al 2022).

Summary of the Invention

The present inventor sought to stratify patients who would respond well to treatment with an MPO inhibitor.

Accordingly, provided herein is a method of selecting a subject having a myeloperoxidase (MPO)- related disorder for treatment with an MPO inhibitor, the method comprising (i) determining the neutrophil level in a blood sample from said subject and selecting the subject for treatment if the neutrophil level is increased relative to a control neutrophil level and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample from said subject and selecting the subject for treatment if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

Provided herein is a method of predicting whether a subject having an MPO-related disorder is likely to respond to treatment with an MPO inhibitor, the method comprising (i) determining the neutrophil level in a blood sample from said subject and selecting the subject for treatment if the neutrophil level is increased relative to a control neutrophil level and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample from said subject, wherein the subject is likely to respond to treatment with an MPO inhibitor if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

Provided herein is a method for identifying a subject with an MPO-related disorder who is likely to respond to treatment with an MPO inhibitor, the method comprising (i) obtaining a blood sample from the subject and determining the neutrophil level in said blood sample, wherein the subject is likely to respond to treatment with an MPO inhibitor if the neutrophil level is increased relative to a control neutrophil level and/or (ii) obtaining a plasma or serum sample from the subject and determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in said plasma or serum sample, wherein the subject is likely to respond to treatment with an MPO inhibitor if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

Provided herein is a method of treating or preventing an MPO-related disorder in a subject in whom (i) the neutrophil level in a blood sample has been shown to be higher than a control neutrophil level and /or (ii) the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample has been shown to be increased relative to the concentration of the at least one biomarker in a reference sample or in a reference population, wherein the method comprises administering an MPO inhibitor to the subject. Provided herein is a method of treating or preventing an MPO-related disorder in a subject, wherein the method comprises: (i) determining the neutrophil level in a blood sample from said subject and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample from said subject; and administering an MPO inhibitor to a subject having a higher neutrophil level than a control neutrophil level and/or an increased concentration of the at least one biomarker is relative to its concentration in a reference sample or in a reference population.

Provided herein is a method of treating or preventing an MPO-related disorder in a subject, the method comprising administering an MPO inhibitor to the subject, wherein the subject has been selected for treatment with an MPO inhibitor on the basis of exhibiting (i) a higher neutrophil level in a blood sample compared to a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

Provided herein is a method of identifying and treating a subject suitable for treatment of an MPO- related disorder, the method comprising: a) obtaining a blood sample and/or a plasma or serum sample from the subject; b) measuring the neutrophil level in the blood sample and/or the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in the plasma or serum sample; c) identifying the subject as being suitable for treatment of an MPO-related disorder when the neutrophil level in the blood sample is increased relative to a control neutrophil level and/or the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , is increased compared to the concentration of the at least one biomarker in a reference sample or in a reference population; and d) administering an effective amount of an MPO inhibitor to the subject.

Provided herein is a method of predicting an improved clinical response in a subject having an MPO- related disorder following treatment with an MPO inhibitor, wherein a decreased concentration of at least one biomarker selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4 following treatment with an MPO inhibitor is predictive of an improved clinical response.

Provided herein is an MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject having (i) a higher neutrophil level in a blood sample compared to a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

Provided herein is the use of an MPO inhibitor in the manufacture of a medicament for the treatment or prevention of an MPO-related disorder in a subject having (i) a higher neutrophil level in a blood sample compared to a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNY, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

Provided herein is an MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject, the method comprising:

(i) determining the neutrophil level in a blood sample from said subject and administering the MPO inhibitor to the subject if the neutrophil level is higher than a control neutrophil level; and/or

(ii) determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in a plasma or serum sample from said subject and administering the MPO inhibitor to a subject if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

Provided herein is an MPO inhibitor for use in a method of treating or preventing an MPO-related disorder, the method comprising administering the MPO inhibitor to a subject having (i) a higher neutrophil level in a blood sample than a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNY, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a tissue sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNY, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be selected from the group consisting of: ANGPT1 , CXCL11 , CXCL5, Dkk1 , IL7, OSM, PDGFA and PDGFB.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be selected from the group consisting of: CXCL11 , HBEGF, AXIN1 , CXCL10, CCL4, CD40L, NEMO and ITGB1 BP2.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CXCL11 .

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be HGF.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be 4EBP1 .

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be ACE2. In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be ANGPT1 .

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be AXIN1 .

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CASP3.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CCL17.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CCL3.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CCL4.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CD40L.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CST5.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CXCL1 .

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CXCL10.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CXCL5.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CXCL6.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be Dkk1 . In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be HBEGF.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be HSP27.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be IFNy.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be IL-1 Ra.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be IL7.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be IL8.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be ITGB1 BP2.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be MCP3.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be MMP1 .

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be NEMO.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be OSM.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be PDGF-A.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be PDGF-B. In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be PTX3.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be SIRT2.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be SRC.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be STAMBP.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be STK4

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be LOX1 .

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be MMP9.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be CEACAM8.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be MPO.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be PGLYRP1.

In any of the aspects or disclosures above or throughout this specification, the at least one biomarker may be AZU1 .

Provided herein is a method of selecting a subject having a myeloperoxidase (MPO)-related disorder for treatment with an MPO inhibitor, the method comprising determining the neutrophil level in a blood sample from said subject and selecting the subject for treatment if the neutrophil level is increased relative to a control neutrophil level.

Provided herein is a method of predicting whether a subject having an MPO-related disorder is likely to respond to treatment with an MPO inhibitor, the method comprising determining the neutrophil level in a blood sample from said subject and selecting the subject for treatment if the neutrophil level is increased relative to a control neutrophil level.

Provided herein is a method for identifying a subject with an MPO-related disorder who is likely to respond to treatment with an MPO inhibitor, the method comprising obtaining a blood sample from the subject and determining the neutrophil level in said blood sample, wherein the subject is likely to respond to treatment with an MPO inhibitor if the neutrophil level is increased relative to a control neutrophil level.

Provided herein is a method of treating or preventing an MPO-related disorder in a subject in whom the neutrophil level in a blood sample has been shown to be higher than a control neutrophil level and, wherein the method comprises administering an MPO inhibitor to the subject.

Provided herein is a method of treating or preventing an MPO-related disorder in a subject, wherein the method comprises determining the neutrophil level in a blood sample from said subject and administering an MPO inhibitor to a subject having a higher neutrophil level than a control neutrophil level.

Provided herein is a method of treating or preventing an MPO-related disorder in a subject, the method comprising administering an MPO inhibitor to the subject, wherein the subject has been selected for treatment with an MPO inhibitor on the basis of exhibiting a higher neutrophil level in a blood sample compared to a control neutrophil level.

Provided herein is a method of identifying and treating a subject suitable for treatment of an MPO- related disorder, the method comprising: a) obtaining a blood sample from the subject; b) measuring the neutrophil level in the blood sample; c) identifying the subject as being suitable for treatment of an MPO-related disorder when the neutrophil level in the blood sample is increased relative to a control neutrophil level; and d) administering an effective amount of an MPO inhibitor to the subject.

Provided herein is an MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject having a higher neutrophil level in a blood sample compared to a control neutrophil level.

Provided herein is the use of an MPO inhibitor in the manufacture of a medicament for the treatment or prevention of an MPO-related disorder in a subject having a higher neutrophil level in a blood sample compared to a control neutrophil level. Provided herein is an MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject, the method comprising determining the neutrophil level in a blood sample from said subject and administering the MPO inhibitor to the subject if the neutrophil level is higher than a control neutrophil level.

Provided herein is an MPO inhibitor for use in a method of treating or preventing an MPO-related disorder, the method comprising administering the MPO inhibitor to a subject having a higher neutrophil level in a blood sample than a control neutrophil level.

In any of the aspects or disclosures described above, the method may relate to treating an MPO- related disorder.

In some instances of any of the aspects or disclosures described above or herein, the MPO-related disorder may be heart failure (e.g. heart failure with reduced ejection fraction or heart failure with preserved ejection fraction), myocardial infarction, coronary artery disease (CAD), peripheral artery disease, AAA or stroke. For example, the MPO-related disorder may be heart failure with reduced (HFrEF), mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF). In such instances, the treatment may result in an improvement from baseline in Kansas City Cardiomyopathy Questionnaire Total Symptoms Score (KCCQ-TSS) and/or an improvement from baseline in 6-minute walk distance (6MWD).

In some instances of any of the aspects or disclosures described above or herein, the MPO inhibitor may be mitiperstat.

In some instances of any of the aspects or disclosures described above or herein, the neutrophil level is the absolute neutrophil count (ANC) and the control neutrophil level is a reference ANC value of about 4 million cells/mL.

Summary of the Figures

Figure 1 illustrates neutrophil-associated risk among UK Biobank heart failure patients. Heart failure was defined by the ICD10 codes for dilated cardiomyopathy, heart failure or ischaemic heart disease and risk for all-cause mortality (A) or cardiovascular mortality (B) was determined by univariate Cox regression using bins of million/mL neutrophils as subgroups and the group having 2-3 million neutrophils/mL as reference group.

Figure 2 illustrates the neutrophil-to-lymphocyte ratio (NLR) associated risk among UK Biobank heart failure patients. Heart failure was defined by the ICD10 codes for dilated cardiomyopathy, heart failure or ischaemic heart disease and risk for all-cause mortality (A) or cardiovascular mortality (B) was determined by univariate Cox regression using bins of NLR of 1 as subgroups and the group having NLR of 1 to 2 as reference group.

Figure 3 illustrates the ENDEAVOR study design (phase 2b part). ^aTo be completed by participant at home on the tablet provided during 3 consecutive days in study weeks -1 and 15 ^b If not possible on same day as screening visit, then within 1-2 days for screening or 7 days for follow-up visits. 6MWT, 6-minute walk test; Echo, echocardiography; EoS, end of study; HF, heart failure; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire - total summary score; LVEF, left ventricular ejection fraction; NT- proBNP, N-terminal pro B-type natriuretic peptide.

Figure 4 illustrates the baseline-adjusted 90-day effects of mitiperstat- as compared to placebotreatment in the SATELLITE study (NCT03756285), when stratified for > (=cat 1 ) or <= (= cat 0) absolute neutrophil counts >4*10⁶/mL at randomization. Panel A shows NT-proBNP levels, panel B the 6-minute walk distance and panel C the Kansas City Cardiomyopathy Questionaire-Overall Symptoms Score.

Figure 5 illustrates the correlation between absolute neutrophil counts and total white blood cell counts (leukocytes) (A) and NLR (B) at baseline in the two HFpEF cohorts PROMIS-HfpEF (Shah et al., 2018) and ENDEAVOR (NCT04986202). Each participant is represented by a symbol and the line represents the straight line fit with the following equations: “neutrophils = 0.78*total leukocytes - 0.8” and “NLR = 0.57*neutrophils + 0.5”. In A, the dotted horizontal and vertical lines represent 4*106/mL neutrophils, and 6.2*106/mL leukocytes, respectively and in B, 4*106/mL neutrophils, and NLR=2.8, respectively.

Figure 6 illustrates the baseline characteristics of ENDEAVOR participants stratified by neutrophil counts >4 million/mL. A discriminant analysis (OPLS-DA, umetrics.com) was performed on the baseline patient features in ENDEAVOR to illustrate how the features associated with the neutrophil strata (> or <=4) and what features mapped orthogonally to such a comparison. The X axis (predictive component) of the figure A shows how the different features (each symbol) contributes to the discrimination of the two groups (higher numerical values along the X-axis represents better specificity) and the Y-axis (orthogonal component) how much of the variation is independent of the group belonging. Abbreviations for key features are highlighted (BMI, Body mass index; eGFR, estimated glomerular filtration rate; CrCI, creatinine clearance; KCCQ, Quality of Life score; MCV, red blood cell mean corpsular volume; RBC, red blood cell; Tfsat; transferrin saturation; T2D, type 2 diabetes; 6MWD, 6min walk distance). Figure B shows how the 699 participants (all available at the time of the analysis) distribute along these components, depending on their characteristics. Each symbol (sized for the actual neutrophil count) represents a participant, and darker symbols represent the high neutrophil stratum clustering to the left in the figure. Figure 7 shows Volcano plots showing 16-week baseline-adjusted changes in Olink biomarkers in ENDEAVOR. The Olink Target Inflammation; cardiovascular"; cardiovascular¹¹¹ panels, representing 266 unique biomarkers were applied to baseline and 16-week samples in the ENDEAVOR trial at an interim analysis, representing paired data from approximately one third of the cohort of 711 participants. Panel A shows the effects in allcomers; and in panels B and C, the cohort is stratified for neutrophil counts at baseline above 4 million/mL (Stratum 1 , panel B) or equal to or below 4 million/mL (stratum 2, panel C). The 35 biomarkers significantly (unadjusted p value <0.05) reduced by mitiperstat in allcomers versus placebo-treated participants were 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL11 , CXCL5, CXCL6, Dkk1 , HBEGF, HGF, HSP27, IFNgamma, IL1 ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF- A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, STK4.

Figure 8 illustrates an association between 16-week effects of mitiperstat on biomarkers, function and symptoms in ENDEAVOR. The figure shows how placebo-adjusted reduction (X-axis) or increase (Y- axis) in the 37 biomarkers (described in Figure 7) associated with placebo-adjusted changes in A symptoms (KCCQ-TSS) and B function (6MWD). The lower right quadrants thus represent the biomarker changes associated with a placebo-corrected, baseline-adjusted change in symptoms and function, so that an improvement was associated with reduced and worsening was associated with an increase of the indicated biomarker. C is a Venn diagram showing the overlap of the 8 biomarkers (ANGPT1 , CXCL11 , CXCL5, Dkk1 , IL-7, OSM, PDGF-A, PDGF-B) in lower right quadrant of panel A and B, i.e. the reduction of which were associated with a placebo-adjusted improvement, and the increase of which was associated with a deterioration of KCCQ-TSS as well as 6MWD. The data represent participants for which Olink data were available at an interim analysis (approximately 1/3 of the cohort).

Figure 9 illustrates an association between 16-week effects of mitiperstat on CXCL11 and primary endpoints in ENDEAVOR. The subcohort represented by Olink data (1/3 of cohort) was stratified on the participants that had a 16-week decrease vs increase of CXCL11 . The figures show the change from baseline (CFB) of mitiperstat-treated (A) and placebo-treated (P) on 6MWD (A) and KCCQ-TSS (B). Boxes and whiskers represent Q1 -Q3 and max/min and the distribution of participants illustrated by single symbols. Statistics was calculated using Mann-Whitney U test.

Figure 10 illustrates an association between 16-week effects of mitiperstat on HGF and primary endpoints in ENDEAVOR. The subcohort represented by Olink data (1/3 of cohort) was stratified on the participants that had a 16-week decrease vs increase of HGF. The figures show the change from baseline (CFB) of mitiperstat-treated (A) and placebo-treated (P) on 6MWD (A) and KCCQ-TSS (B). Boxes and whiskers represent Q1 -Q3 and max/min and the distribution of participants illustrated by single symbols. Statistics was calculated using Mann-Whitney U test. Figure 11 shows an interaction between 16-week Olink biomarker effects and baseline neutrophil counts in ENDEAVOR. The individual plots show the 10 biomarkers having the largest effect vs placebo among the subpopulation analyzed for these biomarkers (approximately one third of the cohort). Thin line and shaded areas represent the linear regression of neutrophil counts and biomarker change from baseline among participants treated with mitiperstat (A) or placebo (P). The thick lines represent the corresponding regression using a spline analysis. The dashed arrow and the numbers indicate where the confidence intervals for the active and placebo arms diverge, thus approximating a cutpoint for efficacy on the biomarker.

Detailed description

Aspects and embodiments disclosed herein will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

The present disclosure relates to methods of identifying subjects more likely to respond to treatment with a MPO inhibitor based on their neutrophil levels and/or the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4 and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 . Identifying patients with elevated neutrophil counts represents a patient enrichment strategy, i.e. the identification of patients more likely to respond to the treatment. The present disclosure also relates to methods of selecting subjects for treatment with an MPO inhibitor, methods of predicting whether a subject will respond to treatment with an MPO inhibitor and methods of treating subjects likely to respond to treatment with an MPO inhibitor.

Subject

The disclosure relates to identifying a subject with an MPO-related disorder as being likely to respond to treatment with an MPO inhibitor and/or treating such a subject with an MPO inhibitor. MPO-related disorders are described in more detail below. The subject may be a mammal and in certain embodiments is a human subject.

MPO-related disorders

MPO-related disorders are diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable. In particular, linkage of MPO activity to disease has been implicated in numerous diseases, including diseases with inflammatory, cardiovascular, respiratory, renal, metabolic, hepatic and/or neurological components, as well as neutrophil-driven diseases. The present disclosure may be used for the treatment or prevention of MPO-related disorders with a cardiovascular component. Such disorders (e.g. diseases or conditions) include, but are not limited to, heart failure (e.g. heart failure with reduced ejection fraction, heart failure with mildly reduced or heart failure with preserved ejection fraction), acute coronary syndrome, myocardial infarction, coronary artery disease (CAD), peripheral artery disease, arrhythmia, cardiomyopathy, dilated and hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), stress-induced cardiomyopathy, unclassified cardiomyopathies, left ventricular noncompaction, valvular disease, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm (AAA), chemotherapy-induced cardiotoxicity or stroke. For example, the present disclosure may be used for the treatment or prevention of heart failure (e.g. heart failure with reduced ejection fraction or heart failure with preserved ejection fraction), myocardial infarction, coronary artery disease (CAD), peripheral artery disease, AAA or stroke. For example, the MPO-related disorder may be heart failure with reduced (HFrEF), mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF). In HFrEF, the left ventricular ejection fraction (LVEF) is below 40%. In HFmrEF, the LVEF is 40-50%. In HFpEF, the LVEF is greater than 50%. LVEF is calculated by subtracting the end- systolic left ventricular (LV) volume from the end-diastolic LV volume and dividing it by the end- diastolic LV volume. LVEF can be measured by non-invasive methods, such as echocardiography, magnetic resonance imaging (MRI), computed tomography (CT), gated equilibrium radionuclide angiography (commonly referred to as multiple-gated acquisition [MUGA] scan) and gated myocardial perfusion imaging with either single-photon emission computed tomography (SPECT) or positron emission tomography (PET).

The disclosed compounds are indicated for use in the treatment or prophylaxis of cardiovascular diseases or conditions in mammals, including humans, which are responsive to inhibition of MPO. Such cardiovascular diseases or conditions include, but are not limited to, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial fibrillation/flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and/or non-ST segment elevation myocardial infarction.

The present disclosure may be used for the treatment or prevention of MPO-related disorders with an inflammatory component. Such disorders (e.g. diseases or conditions) include, but are not limited to, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-related vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, and/or diabetes. For example, the present disclosure may be used for the treatment or prevention of COPD, NASH, MASH (metabolic- associated steatohepatitis) or CKD.

The disclosed compounds are indicated for use in the treatment or prophylaxis of inflammatory diseases or conditions, or diseases or conditions with an inflammatory component, in mammals, including humans, which are responsive to inhibition of MPO. Such diseases or conditions include, but are not limited to, autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch-Schonlein Purpura), Immunoglobulin A nephropathy (Ig AN) , lupus nephritis, diabetic CKD, hypertensive CKD, and/or obesity with CKD.

In some instances, the disclosed compounds are also indicated for use in the treatment or prophylaxis of COPD.

In some instances, the disclosed compounds are also indicated for use in the treatment or prophylaxis of bronchiectasis.

The disclosed compounds are also indicated for use in the treatment or prophylaxis of neurological diseases and conditions in mammals, including humans, which are responsive to inhibition of MPO. Such diseases and conditions include, but are not limited to diseases with a neuroinflammatory response. These diseases and conditions include, but are not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischaemic stroke, and /or subarachnoid haemorrhage.

The disclosed compounds are also indicated for use in the treatment or prophylaxis of neutrophilic driven diseases and conditions in mammals, including humans. Such diseases and conditions include, but are not limited to chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF) , neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).

The disclosed compounds are indicated for use in the treatment of cancer.

For the avoidance of doubt, as used herein, the term “treatment” includes therapeutic and/or prophylactic treatment. In some instances, “treatment” may refer to therapeutic treatment only.

Prophylaxis is expected to be particularly relevant to the treatment of patients who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Patients at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening or identified through a specific biomarker pattern to be particularly susceptible to developing the disease or condition.

MPO inhibitors

The MPO inhibitor for use as described herein may be any compound that inhibits the activity of MPO. Non-limiting examples of such MPO inhibitors are provided below. Examples of MPO inhibitors are also provided in WO 2016/087338 as shown below.

For example, the MPO inhibitor may be a compound having formula (I), or pharmaceutically acceptable salts thereof, wherein R"* represents H, F, Cl or CF3. In a further embodiment, R"* represents Cl.

In one embodiment, R² represents H, CH3 or C2H5.

R² may represent CH3 or C2H5.

R² may represent CH3.

R² may represent H, CH3, C2H5, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl or cyclopentyl.

R² may represent H.

The carbon atom to which R² is attached may have the R-configuration when R² represents CH3 or C₂H₅.

The MPO inhibitor may be selected from:

1 -{2-[(1 R)-1 -aminopropyl]-4-chlorobenzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4- one;

1 -[2-(1 -aminoethyl)-4-chlorobenzyl]-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one;

1 -{2-[(1 R)-1 -aminoethyl]-4-chlorobenzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one;

1 -{2-[(1 S)-1 -aminoethyl]-4-chlorobenzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one;

1 -{4-chloro-2-[1 -(methylamino)ethyl]benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4- one;

1 -{4-chloro-2-[(ethylamino)methyl]benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4- one;

1 -[2-(aminomethyl)-4-chlorobenzyl]-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one;

1 -{4-chloro-2-[(methylamino)methyl]benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4- one;

1 -(2-{[(cyclobutylmethyl)amino]methyl}benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin- 4-one;

1 -{2-[(cyclobutylamino)methyl]benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one;

1 -{2-[(cyclopentylamino)methyl]benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one;

1 -(2-{[(2-methylpropyl)amino]methyl}benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4- one;

1 -{2-[(propan-2-ylamino)methyl]benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one;

1 -[2-(aminomethyl)-4-(trifluoromethyl)benzyl]-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4- one;

1 -{2-[(methylamino)methyl]-4-(trifluoromethyl)benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d]pyrimidin-4-one; and pharmaceutically acceptable salts thereof. In certain embodiments, the MPO inhibitor is mitiperstat (1 -{2-[(1 F?)-1 -aminoethyl]-4-chlorobenzyl}-2- thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one), which is shown below:

Further examples of MPO inhibitors can be found in US provisional application 63/398,939, which was filed on 18 August 2022. These MPO inhibitors are shown below.

The MPO inhibitor may be a compound having formula (II) wherein

X = CH or N

Y¹ = CZ¹ or N, Y² = CZ² or N, Y³ = CZ³ or N, Y⁴ = CZ⁴ or N, and Y⁵ = CZ⁵ or N

Z¹, Z², Z³, Z⁴ , and Z⁵, are, if present, independently, H, halo, CF3, Q or T, provided that no more than one of Y¹, Y²,Y³, Y⁴, or Y⁵ is N, at least two of Y¹ , Y²,Y³, Y⁴, or Y⁵ are CH, no more than one of Z¹, Z², Z³, Z⁴ , and Z⁵ is halo or CF3, and one, and only one, of Z¹ , Z², Z³, Z⁴ , and Z⁵ is Q or T, , wherein m is 0, 1 , 2, or 3, p is 0 or 1 , s is 0, 1 or 2, n is 0, 1 or 2,

A is CH₂, CF₂, CHF, CHR², CFR², NR³, or O, wherein;

R¹ and R², if present, are independently CH₂F, CHF₂, or CF3

R³, if present, is independently H or CH3, or any stereoisomer thereof or pharmaceutically acceptable salt thereof.

The term “halo” means fluoro, chloro, bromo or iodo. In some instances, “halo” may be fluoro or chloro in any of the relevant MPO inhibitors disclosed herein.

The MPO inhibitor may be a compound having the structure: or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein X, Y¹ , Y²,Y³, Y⁴ , A, R¹ , n, p, and s, are defined as above for formula (II).

The MPO inhibitor may be a compound: or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein X, Y¹ , Y²,Y³, Y⁴ , A, R¹, n, p, and s, are defined as above for formula (II).

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y¹ is N and Y²,Y³, are Y⁴ are CH.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y² is N and Y¹ , Y³, are Y⁴ are CH. The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y³ is N and Y¹ , Y², are Y⁴ are CH.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y⁴ is N and Y¹ , Y², are Y³ are CH. The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein n is 0.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein n is 1 .

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein n is 2.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is NR³.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is NR³ and R³ is CH3.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is NR³ and R³ is H.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is CH2, CF2,CHF, CHR², or CFR².

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is CH2.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is CHF.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is CF2.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is CHR².

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is CHR² and R² is CH2F.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is CHR² and R² is CHF2.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein A is CHR² and R² is CF3.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein s is 0.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein s is 1 .

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein s is 2. The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein p is 0.

The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein p is 1 .

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y⁵ is CZ⁵, and Z⁵ is T or Q.

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y⁵ is CZ⁵, and Z⁵ is T.

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y⁵ is CZ⁵, and Z⁵ is T and T is

In some instances, p may be 0.

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y⁵ is CZ⁵, Z⁵ is T or Q, and Y¹, Y², Y³ and Y⁴ are CH.

In some instances, Z⁵ may be T.

In some instances, p may be 0.

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y⁵ is CZ⁵, Z⁵ is T or Q, and one of Y¹, Y², Y³ and Y⁴ is N.

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y⁵ is CZ⁵, Z⁵ is T or Q, and two of Y¹, Y², Y³ and Y⁴ are CH, one of Y¹, Y², Y³ and Y⁴ is N, and one of Y¹, Y², Y³ and Y⁴ is CCI.

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Z¹ and Z⁵ , together with the atoms they are bound to, form a five-or six-membered N-heterocycle. In some instances, Y², Y³, and Y⁴ may be CH.

The term “N-heterocycle” refers to a partially or completely saturated hydrocarbon ring system, i.e., non-aromatic, wherein at least one of the ring carbon atoms is replaced with a nitrogen. The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Z² and Z³ , together with the atoms they are bound to, form a five- or six-membered N-heterocycle. In further embodiments, Y¹ , Y⁴, and Y⁵ are CH.

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y² is Q. In some instances, m = 1 .

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y³ is Q. In some instances, m = 1 .

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y⁴ is Q. In some instances, m = 1 .

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein X is CH.

The MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein X is N.

The MPO inhibitor, or any stereoisomer thereof or pharmaceutically acceptable salt thereof, of a compound selected from:

1 -(2-(Piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-1 -(2-(piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1 -(2-(piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4 /-pyrrolo[3,2-d]pyrimidin-4-one,

1 -(4-Chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4- one,

(R)-1 -(4-Chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- c(|pyrimidin-4-one,

(S)-1 -(4-Chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4 /-pyrrolo[3,2- c(|pyrimidin-4-one,

1 -(4-Chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4- one,

(R)-1 -(4-Chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- c(|pyrimidin-4-one,

(S)-1 -(4-Chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- c(|pyrimidin-4-one,

1 -(4-Chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin- 4-one,

(R)-1 -(4-Chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- c(|pyrimidin-4-one, (S)-1 -(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one,

3-(4-Chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,7-tetrahydro-6/7-purin-6-one,

1 -(2-(Azepan-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4-one,

(R)-1 -(2-(Azepan-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4H-pyrrolo[3,2-d|pyrimidin-4-one,

(S)-1 -(2-(Azepan-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4-one,

(R)-3-(2-(Azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1 ,2,3,7-tetrahydro-6/7-purin-6-one,

(S)-3-(2-(Azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1 ,2,3,7-tetrahydro-6/7-purin-6-one,

(R)-1 -(2-(Morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1 -(2-(Morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one

1 -(2-(4-Methylpiperazin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4- one, rac-2-Thioxo-1 -(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -(2-(5-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one,

1 -(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin- 4-one,

(R)-1 -(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one,

(S)-1 -(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one, rac-2-Thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,7-tetrahydro-6H- purin-6-one,

2-Thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,7-tetrahydro-6/7-purin-6- one,

2-Thioxo-3-(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,7-tetrahydro-6/7-purin-6- one,

3-(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,7-tetrahydro-6/7-purin-6-one, 3-(2-(5-Fluoropiperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,7-tetrahydro-6/7-purin-6-one,

2-Thioxo-1 -((2-(-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one, rac-2-Thioxo-1 -((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((2-((cis)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro- 4/7-pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one, rao2-Thioxo-1 -(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -(2-((2R,4/^:?)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one, rac-2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,7-tetrahydro-6/7- purin-6-one,

2-thioxo-3-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,7-tetrahydro-6/7-purin-6- one,

2-Thioxo-3-(2-((2R,4/^:?)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,7-tetrahydro-6/7-purin-6- one,

2-Thioxo-3-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,7-tetrahydro-6/7-purin-6- one, rac-1 -(2-((2R,4S)-4-(Difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

1 -(2-((2R,4S)-4-(Difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

1 -(2-((2S,4R>4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one, 1 -((2-(Piperidin-2-yl)pyridin-3-yl)methyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one, rac-2-Thioxo-1 -((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((3-((cis)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1 ,2,3,5-tetrahydro- 4/7-pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((3-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-Thioxo-1 -((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((3-((cis)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1 ,2,3,5-tetrahydro- 4/7-pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((3-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

1 -(4-(1 -Aminocyclobutyl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

1 -(3-(1 -Aminocyclobutyl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

1 -(2-(Piperidin-3-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4-one,

1 -(2-(morpholin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4-one,

(R)-1 -(2-(Morpholin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

(SJ-1 -(2-(morpholin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

1 -(2-(Piperidin-4-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4-one, rac-2-Thioxo-1 -((2-((2^4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((2-((trans)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro- 4/7-pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -((2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one, and pharmaceutically acceptable salts thereof.

The MPO inhibitor may be a compound having formula (Ila) wherein, X¹ = CH or N, each X² is, independently, CH, CF, or CCI, and r and q are 0, 1 , or 2, provided r + q = 2 or 3, or any stereoisomer thereof or pharmaceutically acceptable salt thereof.

The MPO inhibitor may be a compound having formula (lib) wherein,

X¹ = CH or N, each X² is, independently, CH, CF, or CCI, and r and q are 0, 1 , or 2, provided that r + q = 2 or 3 or any stereoisomer thereof or pharmaceutically acceptable salt thereof. The MPO inhibitor may be a compound having formula (Ila) or (lib), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein each X² are CH.

The MPO inhibitor may be a compound having formula (Ila) or (lib), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein r is 1 and q is 1 .

The MPO inhibitor may be a compound having formula (Ila) or (lib), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein r is 1 and q is 2 or r is 2 and q is 1 .

The MPO inhibitor may be a compound having formula (Ila) or (lib), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein r is 0 and q is 2 or r is 2 and q is 0.

The MPO inhibitor may be a compound having formula (Ila) or (lib), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein X¹ is CH.

The MPO inhibitor may be a compound having formula (Ila) or (lib), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein X¹ is N.

The MPO inhibitor may be a compound selected from:

1 -((1 ,2,3,4-Tetrahydroisoquinolin-8-yl)methyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- c(|pyrimidin-4-one,

1 -(lsoindolin-5-ylmethyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-c(|pyrimidin-4-one,

1 -(lsoindolin-4-ylmethyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-c(|pyrimidin-4-one, and any stereoisomers thereof or pharmaceutically acceptable salts thereof.

The MPO inhibitor may be a compound having the structure: (Illb), wherein X, Y¹ , Y²,Y³, Y⁴ , A, R¹, n, p, and s, are defined as above for formula (III).

The MPO inhibitor may be a compound having the structure: and s, a

The MPO inhibitor may be a compound having the structure: and s, are defined as above for formula (V).

When an MPO inhibitor or salt described herein is administered as therapy for treating a disorder, it is administered in a “therapeutically effective amount”, which is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder, cure the disorder, reverse, completely stop, or slow the progress of the disorder or reduce the risk of the disorder getting worse.

The dosage of the MPO inhibitor for use as described herein will vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds are administered at a dosage of the solid form of between 1 mg and 2000 mg per day. For example, the MPO inhibitor mitiperstat may be administered once daily at a dose of 2.5mg or 5mg. In certain embodiments, the MPO is administered orally

The MPO inhibitors defined herein, and pharmaceutically acceptable derivatives thereof, may be used on their own, or in the form of appropriate pharmaceutical compositions in which the compound or derivative is in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Thus, the MPO inhibitor may be present in a pharmaceutical composition comprising the MPO inhibitor, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, inhalation, intravenous, topical or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage Form Designs, M. E. Aulton, Churchill Livingstone, 2^nd Ed. 2002.

The MPO inhibitors defined herein may also be administered in conjunction with other compounds used for the treatment of the MPO-related disorders defined herein.

Other compounds that may be used in combination with an MPO inhibitor (by concurrent or sequential administration, or in admixture) include agents that are:

• cardiac therapies,

• anti-hypertensives,

• diuretics,

• peripheral vasodilators,

• lipid modifying agents,

• anti-diabetics,

• anti-inflammatories, or

• anti-coagulants.

Examples of the above include, but are not restricted to, digitalis glycosides, anti-arrhythmics, calcium channel antagonists, ACE inhibitors, angiotensin receptor blockers (e.g. Valsartan), endothelin receptor blockers, p-blockers, thiazide diuretics, loop diuretics, cholesterol synthesis inhibitors such as statins (e.g. Rosuvastatin), cholesterol absorption inhibitors, cholesterylester transfer protein (CETP) inhibitors, anti-diabetic drugs such as insulin and analogues, GLP-1 analogues, sulphonamides, dipeptidyl peptidase 4 inhibitors, thiazolidinediones, SGLT-2 inhibitors, and antiinflammatory drugs such as NSAID’s and CCR2 antagonists, anti-coagulants such as heparins, thrombin inhibitors and inhibitors of factor Xa, platelet aggregation inhibitors, P2X7 antagonists and neprilysin inhibitors (e.g. Sacubitril).

Neutrophil level

As explained above, elevated neutrophil counts (e.g. in patients with HFpEF) are associated with an increased propensity for the neutrophils to degranulate and cast neutrophil extracellular traps and therefore, to release MPO (Bai et al, 2021 ; Bjornsdottir et al, 2015). In the present disclosure, elevated neutrophil levels are used as a patient enrichment strategy, i.e. to identify subjects more likely to respond to treatment with an MPO inhibitor.

Neutrophil levels in a subject can be determined in various ways, for example by determining the subject’s (i) absolute neutrophil count (ANC), (ii) neutrophil-to-lymphocyte ratio (NLR) and/or (iii) total white blood cell (WBC) count. Each of the subject’s ANC, NLR and/or WBC count may be determined in a blood sample that has been taken from the subject.

ANC is the total number of neutrophils in a subject’s white blood cell (WBC) count and can be calculated by multiplying the total number of WBCs by the percentage of neutrophilic granulocytes (i.e. neutrophils) and dividing by 100 (see Coates, 2000).

A subject’s ANC may be determined by routine hematological analysis of a subject’s complete blood count using a hematology analyzer machine. Hematology analyzers are used to count and identify blood cells accurately at high speed. They conduct a complete blood count, which includes red blood cell (RBC), WBC, hemoglobin, and platelet counts, as well as hematocrit levels. Other analyses include: RBC distribution width, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentrations, WBC differential count in percentage and absolute value (including ANC), platelet distribution width, platelet mean volume, large platelet cell ratio and platelet criteria. The hematology analyzer machine used for the analysis may differ between hospitals, depending on the specific manufacturer. Examples of manufacturers include Abbott Diagnostics, Beckman Coulter, Erba Diagnostics, Horiba, Idexx, Siemens, Sysmex, Diagnostica Stago and Clinical Diagnosticis Solutions (CDS).

NLR is the neutrophil to lymphocyte ratio in a blood sample from a subject and is calculated by dividing the number of neutrophils by the number of lymphocytes in a blood sample from the subject. Numbers of neutrophils and lymphocytes in a blood sample from a subject can be determined by routine hematological analysis of a subject’s complete blood count using a hematology analyzer machine as described above.

Total WBC count can be used as a surrogate measure for neutrophil level as neutrophils are the most abundant types of white blood cell (i.e. leukocytes) in blood and neutrophil count correlates well with total WBC count. Typically, neutrophil count = (WBC*0.8)-1. This is based on a correlation between ANC and WBC of neutrophil count = 0.78*total leukocytes (i.e. WBC) - 0.8 as derived from Figure 5. To capture subjects with lower levels of neutrophils, ANC may be calculated by (WBC*0.8)-1 , although this will exclude some subjects having an ANC > 4million cells/mL. Using total WBC count as a surrogate measure for neutrophil level can be useful if a complete blood cell count has been performed on a subject’s blood sample, but not a differential count.

In certain embodiments, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has a higher neutrophil level in a blood sample than a control neutrophil level. The control neutrophil level may be the mean or median neutrophil level in a population, e.g. the mean or median neutrophil level in a population of the same ethnic group as the subject. For example, the control neutrophil level may be the mean or median neutrophil level in a population of healthy subjects, e.g. the mean or median neutrophil level in a population of healthy subjects of the same ethnic group as the subject. The population may, for example, be an adult population or an adolescent population, e.g. 12-18 years old.

When the neutrophil level in a blood sample from a subject is measured as the ANC, the control neutrophil level is a reference ANC value. The reference ANC value may be the mean or median ANC in a population, e.g. the mean or median ANC in a population of the same ethnic group as the subject. For example, the reference ANC value may be the mean or median ANC in a population of healthy subjects, e.g. the mean or median ANC in a population of healthy subjects of the same ethnic group as the subject. The mean ANC value in various ethnic populations is shown in Table 1 below. Further median values for ANC in various ethnic populations are shown in Table 2 of Lim et al., 2010. The reference ANC value may be 4 million cells /mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2% or ±1%. The reference ANC value may be about 4 million cells /mL or 4 million cells/mL.

When the neutrophil level in a plasma sample from a subject is measured as the NLR, the control neutrophil level is a reference NLR value. The reference NLR value may be the mean or median NLR value in a population, e.g. the mean or median NLR value in a population of the same ethnic group as the subject. For example, the reference NLR value may be the mean or median NLR value in a population of healthy subjects, e.g. the mean or median NLR value in a population of healthy subjects of the same ethnic group as the subject. The reference NLR value may be about 2.21 (see Table 1 of Bai et al., 2010) or about 2.3 (based on an ANC of 4 million cells/mL; see Figure 5 correlation). The reference NLR value may be 3 ±20%, ±10%, ±5%, ±4%, ±3%, ±2% or ±1%. The reference NLR value may be about 3 or 3.

When the neutrophil level in a blood sample from a subject is measured as the total WBC count, the control neutrophil level is a reference total WBC count. The reference total WBC count may be the mean or median total WBC count in a population, e.g. the mean or median total WBC count in a population of the same ethnic group as the subject. For example, the reference total WBC count may be the mean or median total WBC count in a population of healthy subjects, e.g. the mean or median total WBC count in a population of healthy subjects of the same ethnic group as the subject. The mean WBC count in various ethnic populations is shown in Table 1 below. Further median values for WBC in various ethnic populations are shown in Table 1 of Lim et al., 2010 and in Table 2 of Lim et al., 2015. The reference total WBC count may be 6.25 million cells /mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2% or ±1%. The reference WBC count may be about 6.25 million cells /mL or 6.25 million cells.

Table 1

Data obtained from Table 3 of Lim etal., 2010

Predictive and predictive response biomarkers

In some instances, a subject having an MPO-related disorder is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of a biomarker selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CXCL11 .

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of HGF.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of 4EBP1 . In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of ACE2.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of ANGPT1 .

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of AXIN1 .

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CASP3.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CCL17.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CCL3.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CCL4.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CD40L.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CST5.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CXCL1 .

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CXCL10.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CXCL5.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CXCL6. In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of Dkk1 .

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of HBEGF.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of HSP27.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of IFNy.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of IL-1 Ra.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of IL7.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of IL8.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of ITGB1 BP2.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of MCP3.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of MMP1 .

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of NEMO.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of OSM.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of PDGF-A. In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of PDGF-B.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of PTX3.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of SIRT2.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of SRC.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of STAMBP.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of STK4.

In some instances a subject having an MPO-related disorder is more likely to have an improved clinical response following treatment with an MPO inhibitor if the subject has a decreased concentration of at least one biomarker selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4 following treatment with the MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CXCL11 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of HGF following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of 4EBP1 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of ACE2 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of ANGPT 1 following treatment with an MPO inhibitor. In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of AXIN1 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CASP3 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CCL17 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CCL3 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CCL4 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CD40L following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CST5 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CXCL1 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CXCL10 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CXCL5 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of CXCL6 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of Dkk1 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of HBEGF following treatment with an MPO inhibitor. In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of HSP27 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of IFNy following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of IL-1 Ra following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of IL7 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of IL8 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of ITGB1 BP2 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of MCP3 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of MMP1 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of NEMO following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of OSM following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of PDGF-A following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of PDGF-B following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of PTX3 following treatment with an MPO inhibitor. In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of SIRT2 following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of SRC following treatment with an MPO inhibitor.

In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of STAMBP following treatment with an MPO inhibitor. In some instances, a subject is identified as more likely to have an improved clinical response if the subject has a decreased concentration of STK4 following treatment with an MPO inhibitor.

Table 2 Predictive and predictive response biomarkers for use as described herein PDGF-A Platelet-derived growth factor subunit A P04085 PDGFA

PDGF-B Platelet-derived growth factor subunit B P01127 PDGFB

PTX3 Pentraxin-related protein PTX3 P26022 PTX3

SIRT2 NAD-dependent protein deacetylase sirtuin-2 Q8IXJ6 SIRT2

SRC Proto-oncogene tyrosine-protein kinase Src P12931 SRC

STAMBP STAM-binding protein 095630 STAMBP

STK4 Serine/threonine-protein kinase 4 Q13043 STK4

The concentration of these biomarkers in a sample from the subject, e.g. a plasma or serum sample, may be assessed at the protein level and may be measured by any suitable method known in the art, such as ELISA.

The concentration of any of the biomarkers described above can be determined in a sample obtained from a subject, such as a plasma sample, serum sample, urine sample or a sputum sample.

In some instances, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the concentration of at least one of the biomarkers selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4 is increased relative to its concentration in a reference sample or in a reference population.

The reference sample may be a corresponding sample type (e.g. the same type of tissue) from a normal, healthy individual, e.g. an individual that does not have or is not suspected to have an MPO- related disorder. For example, the reference sample may be a corresponding sample type (e.g. the same type of tissue) from a normal, healthy individual of the same ethnic group as the subject. The reference population may be a population of healthy subjects. The reference population may a population of subjects, e.g. healthy subjects, of the same ethnic group as the subject.

Inflammatory risk biomarkers

In certain embodiments, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of an inflammatory risk biomarker and/or a biomarker annotated to neutrophil degranulation, such as OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and/or AZU1 (see Table 3). Out of these, OSM is highly correlated to neutrophil counts and LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 are all markers annotated to neutrophil degranulation (see https://reactome.org/content/detail/R-HSA-6798695) and could thus be used as surrogates for neutrophil levels and degranulation, respectively.

Table 3 Inflammatory risk biomarkers for use as described herein

The concentration of these biomarkers in a sample from the subject, e.g. a plasma or serum sample, may be assessed at the protein level and may be measured by any suitable method known in the art, such as ELISA. Methods for measuring levels of these biomarkers are shown in Table 4 below: Table 4

Analyte Example of ELISA kit

AZU1 https ://www. biocomDare.com/25138-Assav-Kit/18382288-Human-AZU1 -

Azurocidin-ELISA-Kit/?Dda=9956|18382288 1 013681 IIAZU1 &dfp=true

OSM https ://www. biocomDare.com/25138-Assav-Kit/18381054-Human-Qncostatin-M-

OSM-CLIA-Kit/?Dda=9956|18381054 3 013681 IIOSM&dfp=true

OLR1 /LOX1 https://www.biocompare.com/9956-Assav-Kit/551632-Human-LOX10LR1 - DuoSet/?pda=9956l551632 1 013681 IIOLR1 &dfp=true

MMP9 https://www.biocompare.com/25138-Assav-Kit/13709524-MMP-9- ELISA/?pda=9956l 13709524 15 013681 IIMMP9

CAECAM8 https://www.biocompare.com/25138-Assav-Kit/18391970-Human-CEACAM8-

Carcinoembryonic-Antiqen-Related-Cell-Adhesion-Molecule-8-ELISA- Kit/?pda=9956|18391970 0 1 ||4|CEACAM8&dfp=true MPO httDs://www.biocomDare.com/9956-Assav-Kit/2341485-Human-MyeloDeroxidase-

DuoSet/?pda=9956|2341485 6 013681 IIMPO

P G L Y R P 1 https://www.biocompare.com/9956-Assav-Kit/887431 -Human-PGRPS-

DuoSet/?pda=9956l887431 3 013681 IIPGLYRP1 &dfp=true

In one embodiment, a subject is identified as more likely to respond to treatment with an MPO inhibitor if the concentration of at least one of the biomarkers described above is increased relative to its concentration in a reference sample or in a reference population. The reference sample may be a corresponding sample type (e.g. the same type of tissue) from a normal, healthy individual, e.g. an individual that does not have or is not suspected to have an MPO-related disorder. For example, the reference sample may be a corresponding sample type (e.g. the same type of tissue) from a normal, healthy individual of the same ethnic group as the subject. The reference population may be a population of healthy subjects. The reference population may a population of subjects, e.g. healthy subjects, of the same ethnic group as the subject.

Outcomes following treatment

Treatment as described herein with an MPO inhibitor may result in an improvement in symptoms experienced by the subject, i.e. an improved clinical response. For example, when the MPO-related disorder is a cardiovascular disorder, the treatment may result in an improvement from baseline in Kansas City Cardiomyopathy Questionnaire Overall Symptoms Score (KCCQ-OSS) and/or an improvement from baseline in 6-minute walk distance (6MWD)An improvement from baseline in Kansas City Cardiomyopathy Questionnaire Overall Symptoms Score (KCCQ-OSS) and/or an improvement from baseline in 6-minute walk distance (6MWD) represent an improved clinical response.

The improvement in KCCQ-OSS or 6MWD is measured relative to baseline. Typically, the baseline is the subject’s KCCQ-OSS or 6MWD before treatment with the MPO inhibitor or at randomization to treatment.

The KCCQ is a psychometrically validated questionnaire developed for patients with congestive HF (Green et al., 2000). It is a 23-item, self-administered health status measure that quantifies physical limitations, symptoms, social interference, self-efficacy, and quality of life. Results for each domain are summarised and transformed to a score of 0 to 100; higher scores indicate better health status. An improvement may be at least a 1 -point increase, at least a 2-point increase, at least a 3-point increase, at least a 4-point increase, at least a 5-point increase or at least a 10-point increase in KCCQ-OSS from baseline, for example. In some instances, an improvement may be at least a 5% increase, at least a 10% increase, at least a 15% increase, at least a 20% increase or at least a 25% increase in KCCQ-OSS from baseline.

The 6MWD test involves the subject walking as far as they can in 6 minutes. An improvement may be at least a 5m increase, at least a 10m increase, at least a 20m increase, at least a 30m increase, at least a 40m increase, at least a 50m increase, at least a 60m increase or at least a 70m increase in 6MWD from baseline, for example. In some instances, an improvement may be at least a 5% increase, at least a 10% increase, at least a 15% increase, at least a 20% increase or at least a 25% increase in 6MWD from baseline.

In some instances, KCCQ-OSS or 6MWD may be determined at 16 weeks, 24 weeks or 48 weeks after baseline, i.e. at 16 weeks, 24 weeks or 48 weeks after the start of treatment with an MPO inhibitor. Therefore, an improvement in KCCQ-OSS or 6MWD from baseline may be seen at 16 weeks, 24 weeks or 48 weeks.

Treatment with an MPO inhibitor as described herein may result in a decrease from baseline in plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP) and/or interleukin-6 (IL-6). Typically, the baseline is the subject’s plasma level of plasma levels of NT-proBNP, hsCRP and/or IL-6 before treatment with the MPO inhibitor or at randomization to treatment. Plasma levels of NT-proBNP, hsCRP and/or IL-6 may be measured by any suitable technique known in the art. Typically, plasma levels of NT-proBNP, hsCRP and/or IL-6 are measured by ELISA or by proteomic methods, such as mass spectrometry or SOMAscan. In some instances, a decrease in plasma levels from baseline of NT-proBNP, hsCRP and/or IL-6 by at least 5%, at least 10%, at least 15%, at least 20% or at least 25% may represent an improvement.

In some instances, plasma levels of NT-proBNP, hsCRP and/or IL-6 may be determined at 16 weeks, 24 weeks or 48 weeks after baseline, i.e. at 16 weeks, 24 weeks or 48 weeks after the start of treatment with an MPO inhibitor. Therefore, a decrease in plasma levels NT-proBNP, hsCRP and/or IL-6 from baseline may be seen at 16 weeks, 24 weeks or 48 weeks.

Treatment with an MPO inhibitor as described herein may result in an improvement from baseline in left ventricular global longitudinal strain (LV-GLS), left atrial volume index (LAVI) and/or left ventricular mass index (LVMI). LV/GLS, LAVI and/or LNMI may be assessed by echocardiography. Typically, the baseline LV-GLS, LAVI and/or LVMI is the subject’s LV-GLS, LAVI and/or LVMI before treatment with an MPO inhibitor. In some instances, an increase of LV-GLS from baseline by at least 5%, at least 10%, at least 15%, at least 20% or at least 25% may represent an improvement. In some instances, a decrease of LAVI and/or LVMI from baseline by at least 5%, at least 10%, at least 15%, at least 20% or at least 25% may represent an improvement.

In some instances, LV-GLS, LAVI and/or LVMI may be determined at 16 weeks, 24 weeks or 48 weeks after baseline, i.e. at 16 weeks, 24 weeks or 48 weeks after the start of treatment with an MPO inhibitor. Therefore, an improvement in LV-GLS, LAVI and/or LVMI from baseline may be seen at 16 weeks, 24 weeks or 48 weeks.

Treatment with an MPO inhibitor as described herein may result in a decreased risk of hospitalisation, a decreased risk of urgent heart failure visits to the hospital with a requirement for additional loop diuretic treatment, a decreased risk of myocardial infarction, a decreased risk of major adverse cardiovascular events (MACE) and/or a decreased risk of cardiovascular death compared to if said treatment is not administered to the subject. MACE may be determined as the time to any of the components of a 5-point MACE (death, myocardial infarction, stroke, heart failure hospitalisation, revascularisation).

Treatment with an MPO inhibitor as described herein may result in an improvement in Patient Global Impression of Severity in Heart Failure Symptoms (PGIS-HF), Patient Global Impression of Severity in Walking Difficulties (PGIS-WD), Patient Rating of Dyspnoea, Acute Version (PRD-acute version), EuroQol Five-dimensional Five-level Questionnaire (EQ-5D-5L) and/or New York Heart Association (NYHA) Class compared to baseline. Typically, the baseline PGIS-HF, PGIS-WD, PRD-acute version, EQ-5D-5L and/or New York Heart Association Class is the subject’s PGIS-HF, PGIS-WD, PRD-acute version, EQ-5D-5L and/or NYHA Class before treatment with an MPO inhibitor.

The PGIS-HF assesses how a participant perceives his or her overall severity of HF symptoms over the past two weeks and is used to enable anchor-based assessments of within-participant clinically meaningful change. Participants choose from 6 response options ranging from ‘no symptoms’ to ‘very severe’.

The PGIS-WD assesses how a participant perceives his or her current overall limitation in walking ability and is used to enable anchor-based assessments of within-participant clinically meaningful change for 6MWD. Participants choose from 6 response options ranging from ‘no limitations’ to ‘very severe limitations’.

The PRD-acute version is a single question item asking the participant to rate his or her shortness of breath right now on a scale from 0 to 10, where 0 indicates 'No shortness of breath' and 10 ‘As bad as you can imagine’.

The EQ-5D-5L developed by the EuroQol Group is a self-reported questionnaire that is used to derive a standardised measure of health status, also referred to as a utility score. The EQ-5D-5L utility scores are widely accepted by reimbursement authorities and will be used to support health economic evaluations.

This detailed description and its specific examples, while indicating embodiments, are intended for purposes of illustration only. Therefore, there is no limitation to the illustrative embodiments described in this specification. In addition, it is to be appreciated that various features that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

For the avoidance of doubt, it is to be understood that where in this specification a group is qualified by “defined herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group. It is to be understood that any definitions, claims, aspects or embodiments of the variable groups of the formulae disclosed herein, may be combined with any other definitions, claims, aspects or embodiments herein (unless the context does not permit) to provide further embodiments of the specification.

The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the disclosure in diverse forms thereof.

While the embodiments disclosed herein have been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the disclosure.

For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example +/- 10%.

Examples

Binary analyses for UK Biobank heart failure patients having neutrophil counts >4 million/mL resulted in a hazard ratio of 1 .46 for all cause-mortality and 1 .49 for cardiovascular (CV) mortality (p<2E-16) (see Figure 1 ).

Binary analyses for UK Biobank heart failure patients having NLR>2.27 resulted in a hazard ratio of 1 .52 for all cause-mortality and 1 .55 for CV mortality (p<2E-16) (see Figure 2).

Neutrophil enrichment in the SATELLITE study

SATELLITE (NCT03756285) was a randomized, double-blind, placebo-controlled phase 2a trial evaluating target engagement and safety of mitiperstat in patients with heart failure and ejection fraction >=40%. In addition, the effect of mitiperstat on heart wall stress (assessed by plasma NT- proBNP levels), exercise capacity (assessed by the 6-minute walk distance, 6MWD), and quality-of- life (assessed by the Kansas City Cardiomyopathy Questionnaire overall summary score, KCCQ- OSS) were assessed as exploratory endpoints after 1 and 3 months of treatment. As a post-hoc analysis, the baseline-adjusted effect on these variables were assessed in subgroups stratified for absolute neutrophil counts at baseline (> or <= 4 million neutrophils/mL). Figure 4 shows the effects (max, min, median and Q1 -Q3) of 3-month mitiperstat vs placebo treatment on baseline-adjusted NT- proBNP, 6MWD and KCCQ-OSS. The median absolute change in the >4 vs <= 4 neutrophil subgroups placebo were -204 vs 28 pg/mL NT-proBNP; +17 vs 41 m 6MWD; and +4.9 vs 0 points in KCCQ-OSS score. Corresponding placebo-corrected data were: -439 vs +2 pg/mL NTproBNP; +27 vs -3m 6MWD; and 9.1 vs -6.5 points in KCCQ-OSS score for >4 vs <= 4 neutrophil subgroups, respectively.

ENDEAVOR study

Here, we present the design of part A of ENDEAVOR (NCT04986202), a sequential phase 2b-3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction. ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.

Overview

ENDEAVOR is a randomized, double-blind, parallel-group, placebo-controlled, multi-centre, sequential phase 2b and phase 3 study of the efficacy and safety of mitiperstat on top of optimal background therapy for up to 48 weeks in patients with heart failure and LVEF above 40%. The study consists of two parts. Part A is a phase 2b efficacy, safety/tolerability and dose-finding study with a planned randomization of approximately 660 patients. Results from part A will determine the dose of mitiperstat for part B, a phase 3 study with a planned randomization of approximately 820 patients.

Patient inclusion and exclusion criteria

Eligible patients are aged 40-85 years, with a body mass index of 18.0-45.0 kg/m² and documented stable symptomatic heart failure (New York Heart Association Class 11— IV) with LVEF above 40% for at least 1 month. Eligible patients also have a KCCQ total symptom score (TSS) below or equal to 90 points and a 6MWD of at least 30 m and at most 400 m at both screening and randomization, with a difference between the two 6MWD measurements of less than 50 m. Eligible patients also have structural heart disease, signs of increased left ventricular filling pressure, signs of significant diastolic dysfunction or recent hospitalization for decompensated heart failure (Table 5).

The key exclusion criteria are estimated glomerular filtration rate below 30 mL/min/1 .73m² at screening, systolic blood pressure below 90 mmHg at randomization (or >160 mmHg if not on treatment with >3 blood pressure-lowering medications, or >180 mmHg irrespective of treatment), heart rate greater than 110 bpm or less than 50 bpm at randomization, life expectancy less than 3 years for reasons other than cardiovascular disease, or a documented history of LVEF below 40% (Table 5).

Randomization and treatment

Eligible patients are randomized 1 :1 :1 to receive once-daily oral doses of mitiperstat 2.5 mg, mitiperstat 5 mg or matching placebo tablets for 48 weeks. Patients are randomized using interactive response technology to allocate treatments and conceal allocations (Figure 3). Randomization is stratified by baseline absolute neutrophil count (>4 x 10⁶/mL vs <4 x lO⁶/mL) with capping rules based on neutrophil count, exercise capacity (6MWD) and symptom status (KCCQ-TSS). The 48- week double-blind treatment period comprises a 16-week period followed by a 32-week safety extension.

Endpoints

Efficacy

The dual primary endpoints are the change from baseline to 16 weeks in KCCQ-TSS and 6MWD (Table 7). The KCCQ is a validated patient-reported instrument for quantifying heart failure symptoms, heart failure-related physical limitations and health-related quality of life, and the KCCQ-TSS is the domain measuring heart failure symptoms only, on a scale of 0-100 (with higher scores indicating worse symptoms) (Spertus et al, 2020). KCCQ-TSS was chosen because the rationale for myeloperoxidase inhibition improvement of symptoms and because results of the phase 2a SATELLITE that preceded ENDEAVOR suggested that the trend towards improvement in KCCQ- OSS was driven by improvement in KCCQ-TSS (Lam et al, 2021 ). The 6MWD is a standardized selfpaced measure of exercise capacity that reflects usual activities of daily living in people with moderate to severe cardiac disease (Holland et al, 2014). Secondary endpoints include change from baseline to 24 and 48 weeks in KCCQ-TSS and 6MWD; to 16, 24 and 48 weeks in plasma levels of the biomarkers N-terminal pro B-type natriuretic peptide, high-sensitivity C-reactive protein and interleukin-6; and to 16 and 24 weeks in the echocardiographic parameters left ventricular global longitudinal strain, left atrial volume index and left ventricular mass index.

Safety

Safety and tolerability outcomes include adverse events, vital signs, clinical laboratory tests and electrocardiograms. Adverse events of special interest include infections and skin reactions, including maculopapular rash. Maculopapular rash is graded using the Common Terminology Criteria for Adverse Events (Table 7). Vital sign parameters include blood pressure, pulse rate, body temperature and orthostatic blood pressure (Table 6).

Statistical methods

Sample size estimation

Approximately 660 patients are expected to be randomized, and it is estimated that 600 will have complete efficacy data (allowing for 10% dropout). With 85% power at an overall significance level of a = 0.05, a sample size of 200 patients per arm (1 :1 :1) will allow detection of a difference of 6.0 points in mean change from baseline in KCCQ-TSS when comparing mitiperstat with placebo. For 6MWD, this sample size will allow detection of a difference of 21 m. Change from baseline in KCCQ-TSS and 6MWD were assumed to be approximately normally distributed with standard deviations of 20 points and 70 m respectively, and calculations were based on analysis of covariance (ANCOVA).

Interim analysis

One or more interim analyses will be performed in the phase 2b part of the study to inform further development of the clinical study programme, including but not limited to dose selection for the phase 3 part of the study. The last interim analysis will be performed when all patients in the phase 2b part of the study have completed the last protocol-specified visit or assessment. All members of the study team will remain blinded throughout phase 2b. If phase 3 were not to start or progress, then the last interim phase 2b analysis would be the final analysis.

Efficacy analyses

Efficacy endpoints will be analysed in the full analysis set, comprising all randomized participants who received at least one dose of mitiperstat or placebo. Endpoints will be analysed by randomized treatment assignment comparing mitiperstat versus placebo. Nominal significance levels are 5%, all tests are two sided, and all confidence intervals are 95%. An ANCOVA model will be used with treatment group, neutrophil count stratum and the baseline value of the efficacy variable as covariates. The null hypothesis is a zero difference in mean change from baseline between mitiperstat (pooled doses) and placebo for the dual primary endpoints, and the alternative hypothesis is a nonzero difference. Missing data will not be imputed. Multiplicity of testing across primary and secondary endpoints will be accounted for using a pre-specified testing procedure with alpha recycling. The strategy will control the type I error rate at 5% for erroneous rejection of the null hypothesis.

Subgroup analyses

Subgroup analyses of the primary endpoints based on baseline demographics and disease characteristics are planned to assess the consistency of effects (Table 8).

Discussion

ENDEAVOR is the first sequential phase 2b-3 clinical trial in patients with heart failure and LVEF above 40%, to our knowledge. The study aims to compare the efficacy of mitiperstat versus placebo, with dual primary endpoints of physical functioning (6MWD) and patient-reported heart failure symptoms (KCCQ-TSS).

Mitiperstat has previously been assessed in healthy volunteers (Gan et al, 2019; Nelander et al,

2021 ), and in patients with HFpEF/HFmrEF in the SATELLITE study (Lam et al, 2021 ). In SATELLITE, plasma myeloperoxidase activity was inhibited by 75% (95% confidence interval [Cl]: 48, 88; nominal p < 0.001 ) from baseline to end-of-treatment in the mitiperstat 5 mg group (n = 27) versus placebo (n = 14), and was generally well tolerated, except for maculopapular rash in one patient (Lam et al, 2021 ). There was a trend towards improvement in KCCQ-OSS in patients receiving mitiperstat versus placebo, with a placebo-adjusted change of +6.283 points (95% Cl: -0.461 , +13.027; nominal p = 0.067), but no placebo-adjusted improvements were noted in coronary flow reserve or 6MWD.

The study was, however, underpowered for these efficacy outcomes because of early termination due to COVID-19.

Despite recent advances, new therapies are still needed for patients with HFpEF/HFmrEF. The EMPEROR-Preserved and DELIVER trials demonstrated the efficacy of sodium-glucose cotransporter-2 inhibitors in a broad spectrum of patients with HFpEF/HFmrEF (Vaduganathan et al,

2022). However the absolute risk reduction in both of these large randomized-controlled trials was only approximately 3%, and the residual risk of cardiovascular death and hospitalization for heart failure remained high. Improvements in KCCQ-TSS were modest at best, with placebo-adjusted increases of only 1 .5 to 2.5 points (on a 0-100 scale). Larger improvements have been reported in only one trial, PRESERVED-HF, which was conducted only in the US and reported placebo-adjusted improvements of 5.8 points in KCCQ-TSS and 20.8 m in 6MWD (Nassif et al, 2021 ). Conversely, other trials have reported no improvement in health status or exercise capacity in patients with HFpEF and HFmrEF (Abraham et al, 2021 ). In the PARALLAX trial of sacubitril/valsartan in patients with heart failure and LVEF above 40%, there was no improvement in KCCQ scores or 6MWD (Pieske et al, 2021 ). Furthermore, mineralocorticoid receptor antagonists are not associated with improvements in exercise capacity in patients with HFpEF (Edelmann et al, 2013). A large unmet need therefore remains for therapies that can improve health status (symptoms and/or health-related quality of life) and exercise capacity in patients with HFpEF and HFmrEF. ENDEAVOR was designed to investigate a novel therapeutic pathway that is unrelated to bloodpressure lowering, heart-rate lowering and decongestion. Myeloperoxidase inhibition with mitiperstat specifically targets pathophysiology hypothesized to be relevant to HFpEF and HFmrEF. Interstitial myeloperoxidase modulates myofibroblast function and fibrosis, and elevated circulating myeloperoxidase levels are associated with chronic heart failure and poor clinical outcomes (Hawkins et al, 2021 ; Tang et al, 2006; Tang et al, 2007). ENDEAVOR is designed and sufficiently powered to test the hypothesis that ameliorating myeloperoxidase-related microvascular dysfunction and fibrosis results in clinical benefits, as assessed using the KCCQ-TSS and 6MWD as dual primary efficacy endpoints, plus biomarkers and echocardiographic measurements as secondary endpoints.

Strengths of the ENDEAVOR study design include the careful selection of patients with HFpEF and HFmrEF, with exclusion of patients with conditions that may mimic heart failure when LVEF is above 40%. The selection criteria also ensure that a large proportion of the study population have high absolute neutrophil counts, which is important because neutrophils are the primary source of myeloperoxidase. Neutrophil count is a feasible way of enriching for patients with more prominent neutrophil degranulation, and those with increased neutrophil-to-lymphocyte ratio are at higher risk of poor outcomes (Bai et al, 2021 ). In addition, increased neutrophil-to-lymphocyte ratio has been associated with reduced 6MWD, although this was in the setting of pulmonary hypertension (Harbaum et al, 2017). Repetition of the 6MWD before randomization aims to reduce both heterogeneity in the enrolled population and variability in the assessments. Furthermore, the seamless design between phase 2b and phase 3 of ENDEAVOR allows rapid transition from the dose selection study to the pivotal trial and may enable early regulatory approval of myeloperoxidase inhibition for patients with HFpEF and HFmrEF, if mitiperstat is proven effective.

The strengths of all study designs are tempered by their limitations. The phase 3 part of ENDEAVOR may not continue if the phase 2b efficacy or safety results are unfavourable, or, conversely, if the results show significant benefit indicating a potential for moving directly to a large cardiovascular outcomes trial. The 6MWD is a measure of exercise capacity, but not of general daily activity or maximal capacity (as assessed using cardiopulmonary exercise testing). Furthermore, 6MWD provides no insight into the mechanisms of exercise limitation because results can be affected by age, sex, height, weight and orthopaedic issues. The KCCQ-TSS captures clinically meaningful changes in patient-reported heart failure symptoms, but is not sensitive to changes in the domains of physical, social and emotional functioning and health-related quality of life, although these will be captured via other KCCQ domains (Spertus et al, 2020). These domains will be assessed as exploratory efficacy outcomes. ENDEAVOR is not examining major adverse cardiac events or other event-driven outcomes as a primary or secondary measure of efficacy (deaths and serious adverse events are safety outcomes). Although the FDA has indicated that treatments for HFpEF can be approved based on improvements in symptoms or functional capacity, it is unclear whether such treatments will be covered by payers and, therefore, may not be available to patients. In summary, ENDEAVOR is designed for the most rapid achievable pivotal efficacy evaluation of mitiperstat to enable potential early approval for treatment of patients with HFpEF/HFmrEF based on improvements in physical functioning and self-reported heart failure symptoms. This approach is warranted for a novel selective myeloperoxidase inhibitor that targets a previously untested pathophysiological pathway.

Interim analysis

The baseline characteristics of ENDEAVOR participants stratified by neutrophil counts >4 million/mL are shown in Figure 6 and confirm a neutrophil association to morbidity, i.e. poor function (shorter 6MWD) and symptoms (lower KCCQ), bodymass index (BMI), signs of anemia (lower transferrin saturation, Tfsat) along with higher level of acute phase proteins and neutrophil- and obesity-related cytokines (adipokines), some of which are associated to clinical events in observational cohorts.

Interim analysis of approximately one third of a cohort of 711 participants in the ENDEAVOR trial identified 35 biomarkers that were significantly reduced by mitiperstat versus placebo-treated participants following stratification for neutrophil counts at a baseline of above 4 million/mL (see Figure 7). These were 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL11 , CXCL5, CXCL6, Dkk1 , HBEGF, HGF, HSP27, IFNgamma, IL1 ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, STK4. As an example, among participants having reduced CXCL11 , mitiperstat-treatment was associated with a 3.7 point increase in KCCQ-TSS and 24m longer 6MWD. Among participants having increased CXCL11 , mitiperstat-treatment was associated with a 1 .2 point decrease in KCCQ- TSS and 6.4m shorter 6MWD (see Figure 8A&B). Eight biomarkers (ANGPT1 , CXCL11 , CXCL5, Dkk1 , IL-7, OSM, PDGF-A, PDGF-B) were associated with a placebo-adjusted improvement, and the increase of these eight biomarkers was associated with a deterioration of KCCQ-TSS as well as 6MWD.

These findings are confirmed for CXCL11 by the data provided in Figure 9. As shown in Figure 9A, a mitiperstat-induced decrease in CXCL11 resulted in a significant increase in 6MWD. Figure 9B shows a similar effect for KCCQ-TSS; a mitiperstat-induced decrease in CXCL11 resulted in an increase in KCCQ-TSS. Similarly, a mitiperstat-induced decrease in HGF resulted in an increase in 6MWD and KCCQ-TSS (see Figures 10A&B).

For the 10 biomarkers having the largest effect versus placebo, the mean cut-point for 8 of the biomarkers (CXCL11 , HBEGF, AXIN1 , CXCL10, CCL4, CD40L, NEMO and ITGB1 BP2) was 4.1 million neutrophils/ml (see Figure 11 ). For two of the biomarkers, STAMBP and HGF, no separation of the confidence intervals was observed. Table 5. Inclusion and exclusion criteria in phase 2b of ENDEAVOR

6MWD, 6-minute walk distance; ALT, alanine aminotransferase; AST, aspartate aminotransferase;

AZ, AstraZeneca; BP, blood pressure; bpm, beats per minute; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CYP3A4, cytochrome P450 3A4; E/e’, ratio between early mitral inflow velocity and mitral annular early diastolic velocity; ePRO, electronic patient reported outcome; Hb, haemoglobin; HF, heart failure; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; IV, intravenous; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire total symptom score; eGFR, estimated glomerular filtration rate; HFpEF, heart failure with preserved ejection fraction; LAVI, left atrial volume index; LVMI, left ventricular mass index; Ml, myocardial infarction; NT- proBNP, N-terminal pro B-type natriuretic peptide, PASP, pulmonary artery systolic pressure; PI, principal investigator; TRmax, tricuspid regurgitation maximum flow rate; TSS, total symptom score; ULN, upper limit of normal.

Table 6. Outcomes in phase 2b of ENDEAVOR

6MWD, 6-minute walk distance; AE, adverse event; AEoSI, adverse event of special interest; CTCAE, Common Terminology Criteria for Adverse Events; ECG, electrocardiogram; hsCRP, high-sensitivity C-reactive protein; KCCQ, Kansas City Cardiomyopathy Questionnaire; HF, heart failure; IL6, interleukin 6; LAVI, left atrial volume index; LV-GLS, left ventricular global longitudinal strain; LVMI, left ventricular mass index; NT-proBNP, N-terminal pro-brain natriuretic peptide; TSS, total symptom score.

Table 7. CTCAE grading for maculopapular rash

Notes: Also known as morbilliform rash, maculopapular rash is one of the most common cutaneous adverse events. It is defined as a disorder characterized by the presence of macules (flat) and papules (elevated) frequently affecting the upper trunk, spreading centripetally and associated with pruritis.

From National Cancer Institute CTCAE v5.0, 27 November 2017

(httDs://cteD.cancer.qov/DrotocoldeveloDment/electronic aDDlications/ctc.htm#ctc 50)

CTCAE, Common Terminology Criteria for Adverse Events.

Table 8. Prespecified subgroups for analysis

Baseline variable Categories

Age (years) <65 / 65-75 / >75

Sex Male / Female

Race Black or African American / Native Hawaiian or other

Pacific Islander / American Indian or Alaska Native / Asian

/ White / Other

Hispanic/Latino Yes / No

Geographic region Europe / North America / South America / Asia / Australia

BMI (kg/m²) <30 / >30

Alcohol consumption Never / Former / Current

Nicotine consumption Never / Former / Current

KCCQ-TSS (points) <80 / >80

6MWD (m) <350 / >350

Hospitalization for HF before Yes / No randomization

NYHA functional classification II / III / IV

LVEF (%) <median / >median

LVEF (%) <50 / >50

History of atrial fibrillation Yes / No

History of atrial flutter Yes / No

History of hypertension Yes / No

NT-proBNP level <median / >median

Neutrophil count at baseline (x >4 / < 4

10⁶/mL)

T2DM at randomization Yes / No eGFR by CKD-EPI (mUmin/1 ,73m²) <60 / >60

6MWD, 6-minute walk distance; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; HF, heart failure; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide, NYHA, New York Heart Association; T2DM, type 2 diabetes mellitus. The following numbered clauses, describing aspects of the invention, are part of the description.

1 . A method of selecting a subject having a myeloperoxidase (MPO)-related disorder for treatment with an MPO inhibitor, the method comprising (i) determining the neutrophil level in a blood sample from said subject and selecting the subject for treatment if the neutrophil level is increased relative to a control neutrophil level and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in a plasma or serum sample from said subject and selecting the subject for treatment if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

2. A method of predicting whether a subject having an MPO-related disorder is likely to respond to treatment with an MPO inhibitor, the method comprising (i) determining the neutrophil level in a blood sample from said subject and selecting the subject for treatment if the neutrophil level is increased relative to a control neutrophil level and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in a plasma or serum sample from said subject, wherein the subject is likely to respond to treatment with an MPO inhibitor if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

3. A method for identifying a subject with an MPO-related disorder who is likely to respond to treatment with an MPO inhibitor, the method comprising (i) obtaining a blood sample from the subject and determining the neutrophil level in said blood sample, wherein the subject is likely to respond to treatment with an MPO inhibitor if the neutrophil level is increased relative to a control neutrophil level and/or (ii) obtaining a plasma or serum sample from the subject and determining the concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in said plasma or serum sample, wherein the subject is likely to respond to treatment with an MPO inhibitor if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

4. A method of treating or preventing an MPO-related disorder in a subject in whom (i) the neutrophil level in a blood sample has been shown to be higher than a control neutrophil level and /or (ii) the concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in a plasma or serum sample has been shown to be increased relative to the concentration of the at least one biomarker in a reference sample or in a reference population, wherein the method comprises administering an MPO inhibitor to the subject.

5. A method of treating or preventing an MPO-related disorder in a subject, wherein the method comprises: (i) determining the neutrophil level in a blood sample from said subject and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in a plasma or serum sample from said subject; and administering an MPO inhibitor to a subject having a higher neutrophil level than a control neutrophil level and/or an increased concentration of the at least one biomarker is relative to its concentration in a reference sample or in a reference population.

6. A method of treating or preventing an MPO-related disorder in a subject, the method comprising administering an MPO inhibitor to the subject, wherein the subject has been selected for treatment with an MPO inhibitor on the basis of exhibiting (i) a higher neutrophil level in a blood sample compared to a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in a plasma or serum sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

7. A method of identifying and treating a subject suitable for treatment of an MPO-related disorder, the method comprising: a) obtaining a blood sample and/or a plasma or serum sample from the subject; b) measuring the neutrophil level in the blood sample and/or the concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in the plasma or serum sample; c) identifying the subject as being suitable for treatment of an MPO-related disorder when the neutrophil level in the blood sample is increased relative to a control neutrophil level and/or the concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 is increased compared to the concentration of the at least one biomarker in a reference sample or in a reference population; and d) administering an effective amount of an MPO inhibitor to the subject.

8. An MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject having (i) a higher neutrophil level in a blood sample compared to a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in a plasma or serum sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

9. An MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject, the method comprising:

(i) determining the neutrophil level in a blood sample from said subject and administering the MPO inhibitor to the subject if the neutrophil level is higher than a control neutrophil level; and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in a plasma or serum sample from said subject and administering the MPO inhibitor to a subject if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

10. An MPO inhibitor for use in a method of treating or preventing an MPO-related disorder, the method comprising administering the MPO inhibitor to a subject having (i) a higher neutrophil level in a blood sample than a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 in a tissue sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

11 . The method according to any one of clauses 1 -7 or the MPO inhibitor for use according to any one of clauses 8-10, wherein (i) the neutrophil level is the absolute neutrophil count (ANC) and the control neutrophil level is a reference ANC value, (ii) the neutrophil level is the neutrophil-to- lymphocyte ratio (NLR) and the control neutrophil level is a reference NLR value and/or (Hi) the neutrophil level is determined by the total white blood cell (WBC) count and the control neutrophil level is a reference total WBC count.

12. The method or the MPO inhibitor for use according clause 11 , wherein (i) the reference ANC value is the median or mean ANC in a population of subjects of the same ethnic group as said subject, (ii) the reference NLR value is the median or mean NLR in a population of subjects of the same ethnic group as said subject and/or (iii) the reference total WBC count is the median or mean total WBC count in a population of subjects of the same ethnic group as said subject.

13. The method or the MPO inhibitor for use according to clause 11 or 12, wherein the reference ANC value is 4 million cells /mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2% or ±1%.

14. The method or the MPO inhibitor for use according to clause 13, wherein the reference ANC value is about 4 million cells /mL.

15. The method or the MPO inhibitor for use according to any one of clauses 11 -14, wherein the reference NLR value is 3 ±20%, ±10%, ±5%, ±4%, ±3%, ±2% or ±1%.

16. The method of the MPO inhibitor for use according to clause 15, wherein the reference NLR value is about 3.

17. The method or the MPO inhibitor for use according to any one of clauses 11 -16, wherein the reference total WBC count is 6.25 million cells /mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2% or ±1%. 18. The method of the MPO inhibitor for use according to clause 17, wherein the reference total WBC count is about 6.25 million cells /ml_.

19. The method or the MPO inhibitor for use according to any one of the preceding clauses, wherein the reference sample is from a normal, healthy individual.

20. The method or the MPO inhibitor for use according to clause 19, wherein the reference sample is from a population of subjects of the same ethnic group as said subject.

21 . The method or the MPO inhibitor for use according to any one of the preceding clauses, wherein the reference population is a population of subjects of the same ethnic group as said subject and wherein the concentration of the at least one biomarker in the reference population is the median or mean concentration of the at least one biomarker in a population of healthy subjects of the same ethnic group as said subject.

22. The method or the MPO inhibitor for use according to any one of the preceding clauses, wherein the MPO-related disorder has an inflammatory, cardiovascular, respiratory, renal, metabolic, hepatic and/or neurological component, and/or is a neutrophil-driven disorder.

23. The method or the MPO inhibitor for use according to clause 22, wherein the MPO-related disorder is chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), alcoholic and non-alcoholic steatohepatitis (ASH/NASH), alcoholic and non-alcoholic fatty liver disease (AFLD/NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti- neutrophilic cytoplasmic autoantibody (ANCA)-related vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, and/or type 2 diabetes.

24. The method or the MPO inhibitor for use according to clause 23, wherein the MPO-related disorder is COPD, NASH or CKD.

25. The method or the MPO inhibitor for use according to clause 22, wherein the MPO-related disorder is a cardiovascular disorder, such as heart failure (e.g. heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction), acute coronary syndrome, myocardial infarction, coronary artery disease (CAD), peripheral artery disease, arrhythmia, cardiomyopathy, dilated and hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), stress-induced cardiomyopathy, unclassified cardiomyopathies, left ventricular noncompaction, valvular disease, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm (AAA), chemotherapy-induced cardiotoxicity or stroke.

26. The method or the MPO inhibitor for use according to clause 25, wherein the MPO-related disorder is heart failure (e.g. heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction), myocardial infarction, coronary artery disease (CAD), peripheral artery disease, AAA or stroke.

27. The method or the MPO inhibitor for use according to clause 26, wherein the MPO-related disorder is heart failure with reduced ejection fraction (HFrEF), mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF).

28. The method or the MPO inhibitor for use according to any one of clauses 25-27, wherein the treatment results in an improvement from baseline in Kansas City Cardiomyopathy Questionnaire Overall Symptoms Score (KCCQ-OSS) and/or an improvement from baseline in 6-minute walk distance (6MWD).

29. The method or the MPO inhibitor for use according to clause 28, wherein the improvement in KCCQ-OSS and/or 6MWD is from baseline to 16 weeks, 24 weeks or 48 weeks.

30. The method or the MPO inhibitor for use according to any one of the preceding clauses, wherein the treatment results in a decrease from baseline in plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP) and/or interleukin-6 (IL- 6).

31 . The method or the MPO inhibitor for use according to clause 30, wherein the decrease in plasma levels of NT-proBNP, hsCRP and/or IL-6 is from baseline to 16 weeks, 24 weeks or 48 weeks.

32. The method or the MPO inhibitor for use according to any one of the preceding clauses, wherein the treatment results in an improvement from baseline in left ventricular global longitudinal strain (LV-GLS), left atrial volume index (LAVI) and/or left ventricular mass index (LVMI).

33. The method or the MPO inhibitor for use according to clause 32 wherein the improvement in LV-GLS, LAVI and/or LVMI is from baseline to 16 weeks or 24 weeks.

34. The method or the MPO inhibitor for use according to any one of the preceding clauses, wherein the treatment results in a decreased risk of hospitalisation, a decreased risk of urgent heart failure visits to the hospital with a requirement for additional loop diuretic treatment, a decreased risk of myocardial infarction, a decreased risk of major adverse cardiovascular events (MACE) and/or a decreased risk of cardiovascular death compared to if said treatment is not administered to the subject.

35. The method or the MPO inhibitor for use according to any one of the preceding clauses, wherein the MPO inhibitor is a compound of formula (I)

R3 is H, CH3, C2H5, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutyl methyl or cyclopentyl; or a pharmaceutically acceptable salt thereof.

36. The method or the MPO inhibitor for use according to clause 35, selected from

1 -{2-[(1 F?)-1 -aminopropyl]-4-chlorobenzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4- one;

1 -{2-[(1 F?)-1 -aminoethyl]-4-chlorobenzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one;

1 -{2-[(cyclopentylamino)methyl]benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one; 1 -(2-{[(2-methylpropyl)amino]methyl}benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4- one;

1 -{2-[(methylamino)methyl]-4-(trifluoromethyl)benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d]pyrimidin-4-one; or a pharmaceutically acceptable salts thereof.

37. The method or the MPO inhibitor for use according to any one of clauses 1 -34, wherein the MPO inhibitor is a compound of formula (II) wherein

X = CH or N

Y¹ = CZ¹ or N, Y² = CZ² or N, Y³ = CZ³ or N, Y⁴ = CZ⁴ or N, and Y⁵ = CZ⁵ or N Z¹, Z², Z³, Z⁴ , and Z⁵, are, if present, independently, H, halo, CF3, Q or T, provided that no more than one of Y¹, Y², Y³, Y⁴, or Y⁵ is N, at least two of Y¹ , Y²,Y³, Y⁴, or Y⁵ are CH, no more than one of Z¹, Z², Z³, Z⁴ , and Z⁵ is halo or CF3, and one, and only one, of Z¹ , Z², Z³, Z⁴ , and Z⁵ is Q or T, , wherein m is 0, 1 , 2, or 3, p is 0 or 1 , s is 0, 1 or 2, n is 0, 1 or 2, A is CH₂, CF₂, CHF, CHR², CFR², NR³, or O, wherein;

R¹ and R², if present, are independently CH2F, CHF2, or CF3

R³, if present, is independently H or CH3, or any stereoisomer thereof or pharmaceutically acceptable salt thereof. 38. The method or the MPO inhibitor for use according to clause 37, wherein the MPO inhibitor has the structure:

39. The method or the MPO inhibitor for use according to clause 37, wherein the MPO inhibitor is selected from: 1 -(2-(Piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

(F?)-1 -(2-(piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1 -(2-(piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4 /-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-1 -(4-Chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one,

(S)-1 -(4-Chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4 /-pyrrolo[3,2- d|pyrimidin-4-one,

(R)-1 -(4-Chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one,

(S)-1 -(4-Chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one,

(R)-1 -(4-Chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one,

(S)-1 -(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one,

(S)-1 -(2-(Azepan-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4H-pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one, 2-Thioxo-1 -(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

3-(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,7-tetrahydro-6/7-purin-6-one,

3-(2-(5-Fluoropiperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,7-tetrahydro-6/7-purin-6-one,

2-Thioxo-1 -((2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-Thioxo-1 -(2-((2^4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -(2-((2R,4/^:?)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one, 2-Thioxo-1 -(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one, rac-2-thioxo-3-(2-((2R,4/^:?)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1 ,2,3,7-tetrahydro-6/7- purin-6-one,

1 -(2-((2S,4R>4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one,

1 -((2-(Piperidin-2-yl)pyridin-3-yl)methyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one, rac-2-Thioxo-1 -((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-2-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((3-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-4-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one, 1 -(4-(1 -Aminocyclobutyl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1 -((2-((trans)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-

4/7-pyrrolo[3,2-d|pyrimidin-4-one,

2-Thioxo-1 -((2-((2F?,4F?)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

40. The method or the MPO inhibitor for use according to any one of clauses 1 -34, wherein the MPO inhibitor is a compound having formula (Ila): wherein,

X¹ = CH or N, each X² is, independently, CH, CF, or CCI, and r and q are 0, 1 , or 2, provided r + q = 2 or 3, or any stereoisomer thereof or pharmaceutically acceptable salt thereof.

41 . The method or the MPO inhibitor for use according to any one of clauses 1 -34, wherein the MPO inhibitor is a compound having formula (lib): wherein,

X¹ = CH or N, each X² is, independently, CH, CF, or CCI, and r and q are 0, 1 , or 2, provided that r + q = 2 or 3 or any stereoisomer thereof or pharmaceutically acceptable salt thereof.

42. The method or the MPO inhibitor for use according to clause 37, wherein the MPO inhibitor is selected from:

1 -((1 ,2,3,4-Tetrahydroisoquinolin-8-yl)methyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one,

1 -(lsoindolin-5-ylmethyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4-one,

1 -(lsoindolin-4-ylmethyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d|pyrimidin-4-one, and pharmaceutically acceptable salts thereof.

43. The method or the MPO inhibitor for use according to any one of clauses 1 -34, wherein the MPO inhibitor is mitiperstat. References

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Claims

1 . A method of selecting a subject having a myeloperoxidase (MPO)-related disorder for treatment with an MPO inhibitor, the method comprising (i) determining the neutrophil level in a blood sample from said subject and selecting the subject for treatment if the neutrophil level is increased relative to a control neutrophil level and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample from said subject and selecting the subject for treatment if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

2. A method of predicting whether a subject having an MPO-related disorder is likely to respond to treatment with an MPO inhibitor, the method comprising (i) determining the neutrophil level in a blood sample from said subject and selecting the subject for treatment if the neutrophil level is increased relative to a control neutrophil level and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample from said subject, wherein the subject is likely to respond to treatment with an MPO inhibitor if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

3. A method for identifying a subject with an MPO-related disorder who is likely to respond to treatment with an MPO inhibitor, the method comprising (i) obtaining a blood sample from the subject and determining the neutrophil level in said blood sample, wherein the subject is likely to respond to treatment with an MPO inhibitor if the neutrophil level is increased relative to a control neutrophil level and/or (ii) obtaining a plasma or serum sample from the subject and determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in said plasma or serum sample, wherein the subject is likely to respond to treatment with an MPO inhibitor if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

4. A method of treating or preventing an MPO-related disorder in a subject in whom (i) the neutrophil level in a blood sample has been shown to be higher than a control neutrophil level and /or (ii) the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNY, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample has been shown to be increased relative to the concentration of the at least one biomarker in a reference sample or in a reference population, wherein the method comprises administering an MPO inhibitor to the subject.

5. A method of treating or preventing an MPO-related disorder in a subject, wherein the method comprises: (i) determining the neutrophil level in a blood sample from said subject and/or (ii) determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNY, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample from said subject; and administering an MPO inhibitor to a subject having a higher neutrophil level than a control neutrophil level and/or an increased concentration of the at least one biomarker is relative to its concentration in a reference sample or in a reference population.

6. A method of treating or preventing an MPO-related disorder in a subject, the method comprising administering an MPO inhibitor to the subject, wherein the subject has been selected for treatment with an MPO inhibitor on the basis of exhibiting (i) a higher neutrophil level in a blood sample compared to a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNY, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

7. A method of identifying and treating a subject suitable for treatment of an MPO-related disorder, the method comprising: a) obtaining a blood sample and/or a plasma or serum sample from the subject; b) measuring the neutrophil level in the blood sample and/or the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNY, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in the plasma or serum sample; c) identifying the subject as being suitable for treatment of an MPO-related disorder when the neutrophil level in the blood sample is increased relative to a control neutrophil level and/or the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , is increased compared to the concentration of the at least one biomarker in a reference sample or in a reference population; and d) administering an effective amount of an MPO inhibitor to the subject.

8. A method of predicting an improved clinical response in a subject having an MPO-related disorder following treatment with an MPO inhibitor, wherein a decreased concentration of at least one biomarker selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4 following treatment with an MPO inhibitor is predictive of an improved clinical response.

9. An MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject having (i) a higher neutrophil level in a blood sample compared to a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

10. An MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject, the method comprising:

(ii) determining the concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample from said subject and administering the MPO inhibitor to a subject if the concentration of the at least one biomarker is increased relative to its concentration in a reference sample or in a reference population.

11. An MPO inhibitor for use in a method of treating or preventing an MPO-related disorder, the method comprising administering the MPO inhibitor to a subject having (i) a higher neutrophil level in a blood sample than a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNY, IL-1Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a tissue sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

12. Use of an MPO inhibitor in the manufacture of a medicament for the treatment or prevention of an MPO-related disorder in a subject having (i) a higher neutrophil level in a blood sample compared to a control neutrophil level and/or (ii) an increased concentration of at least one biomarker selected from the group consisting of: (a) CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1 , CXCL10, CXCL5, CXCL6, Dkk1 , HBEGF, HSP27, IFNy, IL-1 Ra, IL7, IL8, ITGB1 BP2, MCP3, MMP1 , NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and/or (b) OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 , in a plasma or serum sample compared to the concentration of the at least one biomarker in a reference sample or in a reference population.

13. The method according to any one of claims 1 -8, the MPO inhibitor for use according to any one of claims 9-11 or the use according to claim 12, wherein (i) the neutrophil level is the absolute neutrophil count (ANC) and the control neutrophil level is a reference ANC value, (ii) the neutrophil level is the neutrophil-to-lymphocyte ratio (NLR) and the control neutrophil level is a reference NLR value and/or (Hi) the neutrophil level is determined by the total white blood cell (WBC) count and the control neutrophil level is a reference total WBC count.

14. The method, the MPO inhibitor for use or the use according claim 13, wherein (i) the reference ANC value is the median or mean ANC in a population of subjects of the same ethnic group as said subject, (ii) the reference NLR value is the median or mean NLR in a population of subjects of the same ethnic group as said subject and/or (iii) the reference total WBC count is the median or mean total WBC count in a population of subjects of the same ethnic group as said subject.

15. The method, the MPO inhibitor for use or the use according to claim 13 or 14, wherein the reference ANC value is 4 million cells /mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2% or ±1%.

16. The method, the MPO inhibitor for use or the use according to claim 15, wherein the reference ANC value is about 4 million cells /mL.

17. The method, the MPO inhibitor for use or the use according to any one of claims 13-16, wherein the reference NLR value is 3 ±20%, ±10%, ±5%, ±4%, ±3%, ±2% or ±1 %.

18. The method, the MPO inhibitor for use or the use according to claim 17, wherein the reference NLR value is about 3.

19. The method, the MPO inhibitor for use or the use according to any one of claims 13-18, wherein the reference total WBC count is 6.25 million cells /mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2% or ±1 %.

20. The method, the MPO inhibitor for use or the use according to claim 19, wherein the reference total WBC count is about 6.25 million cells /mL.

21 . The method, the MPO inhibitor for use or the use according to any one of the preceding claims, wherein the reference sample is from a normal, healthy individual.

22. The method, the MPO inhibitor for use or the use according to claim 21 , wherein the reference sample is from a population of subjects of the same ethnic group as said subject.

23. The method, the MPO inhibitor for use or the use according to any one of the preceding claims, wherein the reference population is a population of subjects of the same ethnic group as said subject and wherein the concentration of the at least one biomarker in the reference population is the median or mean concentration of the at least one biomarker in a population of healthy subjects of the same ethnic group as said subject.

24. The method, the MPO inhibitor for use or the use according to any one of the preceding claims, wherein the MPO-related disorder has an inflammatory, cardiovascular, respiratory, renal, metabolic, hepatic and/or neurological component, and/or is a neutrophil-driven disorder.

25. The method, the MPO inhibitor for use or the use according to claim 24, wherein the MPO- related disorder is chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), alcoholic and non-alcoholic steatohepatitis (ASH/NASH), alcoholic and non-alcoholic fatty liver disease (AFLD/NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti- neutrophilic cytoplasmic autoantibody (ANCA)-related vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, and/or type 2 diabetes.

26. The method, the MPO inhibitor for use or the use according to claim 24, wherein the MPO- related disorder is chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular damage, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophilic cytoplasmic autoantibody (ANCA)- associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, type 2 diabetes, bronchiectasis, COVID-19 (or SARS CoV2) induced renal failure, diabetic kidney disease (DKD), endometriosis, endstage kidney disease (ESKD), Immunoglobulin A vasculitis (Henoch-Schonlein Purpura), Immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and/or obesity with CKD.

27. The method, the MPO inhibitor for use or the use according to claim 25 or 26, wherein the MPO-related disorder is COPD, bronchiectasis, NASH or CKD.

28. The method, the MPO inhibitor for use or the use according to claim 27, wherein the MPO- related disorder is COPD.

29. The method, the MPO inhibitor for use or the use according to claim 27, wherein the MPO- related disorder is bronchiectasis.

30. The method, the MPO inhibitor for use or the use according to claim 24, wherein the MPO- related disorder is a cardiovascular disorder, such as heart failure (e.g. heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction), acute coronary syndrome, myocardial infarction, coronary artery disease (CAD), peripheral artery disease, arrhythmia, cardiomyopathy, dilated and hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), stress-induced cardiomyopathy, unclassified cardiomyopathies, left ventricular noncompaction, valvular disease, hypertension, pulmonary arterial hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm (AAA), chemotherapy-induced cardiotoxicity or stroke.

31 . The method, the MPO inhibitor for use or the use according to claim 24, wherein the MPO- related disorder is coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolonging the time to/prevention of reoccurrence of Atrial fibrillation/flutter after cardioversion, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), halting the progression and/or causing regression of atheroma, COVID-19 (or SARS CoV2) induced heart failure, COVID-19 (or SARS CoV2) induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF) renal crossover, first or recurrent myocardial infarction, peripheral arterial disease, restrictive cardiomyopathy, unclassified cardiomyopathy, inhibition of plaque rupture, amelioration of the inflammation associated with plaque rupture, secondary myocardial infarction, ST segment elevation myocardial infarction, and/or non-ST segment elevation myocardial infarction.

32. The method, the MPO inhibitor for use or the use according to claim 30, wherein the MPO- related disorder is heart failure (e.g. heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction), myocardial infarction, coronary artery disease (CAD), peripheral artery disease, AAA or stroke.

33. The method, the MPO inhibitor for use or the use according to claim 32, wherein the MPO- related disorder is heart failure with reduced ejection fraction (HFrEF), mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF).

34. The method, the MPO inhibitor for use or the use according to any one of claims 30-33, wherein the treatment results in an improvement from baseline in Kansas City Cardiomyopathy Questionnaire Overall Symptoms Score (KCCQ-OSS) and/or an improvement from baseline in 6- minute walk distance (6MWD).

35. The method, the MPO inhibitor for use or the use according to claim 34, wherein the improvement in KCCQ-OSS and/or 6MWD is from baseline to 16 weeks, 24 weeks or 48 weeks.

36. The method, the MPO inhibitor for use or the use according to any one of the preceding claims, wherein the treatment results in a decrease from baseline in plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP) and/or interleukin- 6 (IL-6).

37. The method, the MPO inhibitor for use or the use according to claim 36, wherein the decrease in plasma levels of NT-proBNP, hsCRP and/or IL-6 is from baseline to 16 weeks, 24 weeks or 48 weeks.

38. The method, the MPO inhibitor for use or the use according to any one of the preceding claims, wherein the treatment results in an improvement from baseline in left ventricular global longitudinal strain (LV-GLS), left atrial volume index (LAVI) and/or left ventricular mass index (LVMI).

39. The method, the MPO inhibitor for use or the use according to claim 38 wherein the improvement in LV-GLS, LAVI and/or LVMI is from baseline to 16 weeks or 24 weeks.

40. The method, the MPO inhibitor for use or the use according to any one of the preceding claims, wherein the treatment results in a decreased risk of hospitalisation, a decreased risk of urgent heart failure visits to the hospital with a requirement for additional loop diuretic treatment, a decreased risk of myocardial infarction, a decreased risk of major adverse cardiovascular events (MACE) and/or a decreased risk of cardiovascular death compared to if said treatment is not administered to the subject.

41 . The method, the MPO inhibitor for use or the use according to any one of the preceding claims, wherein the MPO inhibitor is a compound of formula (I)

R3 is H, CH₃, C2H5, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutyl methyl or cyclopentyl; or a pharmaceutically acceptable salt thereof.

42. The method, the MPO inhibitor for use or the use according to claim 41 , selected from

1 -{2-[(1 S)-1 -aminoethyl]-4-chlorobenzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one; 1 -{4-chloro-2-[1 -(methylamino)ethyl]benzyl}-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4- one;

43. The method, the MPO inhibitor for use or the use according to any one of claims 1 -40, wherein the MPO inhibitor is a compound of formula (II) wherein

X = CH or N

Z¹, Z², Z³, Z⁴ , and Z⁵, are, if present, independently, H, halo, CF3, Q or T, provided that no more than one of Y¹, Y², Y³, Y⁴, or Y⁵ is N, at least two of Y¹ , Y²,Y³, Y⁴, or Y⁵ are CH, no more than one of Z¹, Z², Z³, Z⁴ , and Z⁵ is halo or CF3, and one, and only one, of Z¹ , Z², Z³, Z⁴ , and Z⁵ is Q or T, wherein m is 0, 1 , 2, or 3, p is 0 or 1 , s is 0, 1 or 2, n is 0, 1 or 2,

A is CH₂, CF₂, CHF, CHR², CFR², NR³, or O, wherein;

R¹ and R², if present, are independently CH₂F, CHF₂, or CF3

44. The method, the MPO inhibitor for use or the use according to claim 43, wherein the MPO inhibitor has the structure:

45. The method, the MPO inhibitor for use or the use according to claim 43, wherein the MPO inhibitor is selected from:

(S)-1 -(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,5-tetrahydro-4/7-pyrrolo[3,2- d|pyrimidin-4-one, 3-(4-Chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1 ,2,3,7-tetrahydro-6/7-purin-6-one,

3-(2-(5-Fluoropiperidin-2-yl)benzyl)-2-thioxo-1 ,2,3,7-tetrahydro-6/7-purin-6-one, 2-Thioxo-1 -((2-(-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5-tetrahydro-4/7- pyrrolo[3,2-d|pyrimidin-4-one, rac-2-Thioxo-1 -((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1 ,2,3,5- tetrahydro-4/7-pyrrolo[3,2-d]pyrimidin-4-one,

46. The method, the MPO inhibitor for use or the use according to any one of claims 1 -40, wherein the MPO inhibitor is a compound having formula (Ila): wherein,

47. The method, the MPO inhibitor for use or the use according to any one of claims 1 -40, wherein the MPO inhibitor is a compound having formula (lib): wherein,

48. The method, the MPO inhibitor for use or the use according to claim 43, wherein the MPO inhibitor is selected from:

49. The method, the MPO inhibitor for use or the use according to any one of claims 1 -40, wherein the MPO inhibitor is mitiperstat.