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WO2024209075A1 - Méthode de traitement avec des inhibiteurs de mpo - Google Patents

Méthode de traitement avec des inhibiteurs de mpo Download PDF

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Publication number
WO2024209075A1
WO2024209075A1 PCT/EP2024/059368 EP2024059368W WO2024209075A1 WO 2024209075 A1 WO2024209075 A1 WO 2024209075A1 EP 2024059368 W EP2024059368 W EP 2024059368W WO 2024209075 A1 WO2024209075 A1 WO 2024209075A1
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WIPO (PCT)
Prior art keywords
thioxo
tetrahydro
mpo
pyrrolo
pyrimidin
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PCT/EP2024/059368
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English (en)
Inventor
Erik Michaëlsson
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Astrazeneca Ab
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Publication of WO2024209075A1 publication Critical patent/WO2024209075A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G01N2333/908—Oxidoreductases (1.) acting on hydrogen peroxide as acceptor (1.11)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5094—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for blood cell populations

Definitions

  • 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 .
  • MPO myeloperoxidase
  • MPO Myeloperoxidase
  • EPO eosinophil peroxidase
  • TPO thyroid peroxidase
  • SPS salivary peroxidase
  • LPO lactoperoxidase
  • PGHS prostaglandin H synthase
  • 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.
  • 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.
  • SOD superoxide dismuatase
  • hypochlorous acid bleach
  • hypothiocyanous acid hypochlorous acid
  • the engulfed load is incorporated into vacuoles, termed phagosomes, which fuse with granules containing myeloperoxidase to form phagolysosomes.
  • phagosomes vacuoles
  • 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).
  • Heart failure 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.
  • 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).
  • HF treatment 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.
  • ARBs/ACE inhibitors/ARNIs ARBs/ACE inhibitors/ARNIs
  • beta blockers beta blockers
  • MRAs beta blockers
  • SGLT2 inhibitors For patients with HFpEF, diagnosis and treatment of comorbidities and use of diuretics are recommended (McDonagh et al 2022).
  • treatments that improve morbidity and mortality are more limited.
  • SGLT2 inhibitors have been shown to reduce CV death and hospitalisation for HF also in these patients (Vaduganathan et al 2022).
  • the present inventor sought to stratify patients who would respond well to treatment with an MPO inhibitor.
  • a method of selecting a subject having a myeloperoxidase (MPO)- related disorder for treatment with an MPO inhibitor 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,
  • MPO myeloperoxid
  • a method of predicting whether a subject having an MPO-related disorder is likely to respond to treatment with an MPO inhibitor 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
  • a method for identifying a subject with an MPO-related disorder who is likely to respond to treatment with an MPO inhibitor 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,
  • 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, PGLY
  • a method of treating or preventing an MPO-related disorder in a subject 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
  • a method of treating or preventing an MPO-related disorder in a subject 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 ST
  • a method of identifying and treating a subject suitable for treatment of an MPO- related disorder 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
  • 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.
  • a biomarker selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN
  • 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, M
  • 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, CE
  • an MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject, the method comprising:
  • 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 , M
  • 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.
  • the at least one biomarker may be selected from the group consisting of: ANGPT1 , CXCL11 , CXCL5, Dkk1 , IL7, OSM, PDGFA and PDGFB.
  • the at least one biomarker may be selected from the group consisting of: CXCL11 , HBEGF, AXIN1 , CXCL10, CCL4, CD40L, NEMO and ITGB1 BP2.
  • the at least one biomarker may be CXCL11 .
  • the at least one biomarker may be HGF.
  • the at least one biomarker may be 4EBP1 .
  • 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 .
  • the at least one biomarker may be AXIN1 .
  • the at least one biomarker may be CASP3.
  • the at least one biomarker may be CCL17.
  • the at least one biomarker may be CCL3.
  • the at least one biomarker may be CCL4.
  • the at least one biomarker may be CD40L.
  • the at least one biomarker may be CST5.
  • the at least one biomarker may be CXCL1 .
  • the at least one biomarker may be CXCL10.
  • the at least one biomarker may be CXCL5.
  • the at least one biomarker may be CXCL6.
  • 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.
  • the at least one biomarker may be HSP27.
  • the at least one biomarker may be IFNy.
  • the at least one biomarker may be IL-1 Ra.
  • the at least one biomarker may be IL7.
  • the at least one biomarker may be IL8.
  • the at least one biomarker may be ITGB1 BP2.
  • the at least one biomarker may be MCP3.
  • the at least one biomarker may be MMP1 .
  • the at least one biomarker may be NEMO.
  • the at least one biomarker may be OSM.
  • the at least one biomarker may be PDGF-A.
  • 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.
  • the at least one biomarker may be SIRT2.
  • the at least one biomarker may be SRC.
  • the at least one biomarker may be STAMBP.
  • the at least one biomarker may be STK4
  • the at least one biomarker may be LOX1 .
  • the at least one biomarker may be MMP9.
  • the at least one biomarker may be CEACAM8.
  • the at least one biomarker may be MPO.
  • the at least one biomarker may be PGLYRP1.
  • the at least one biomarker may be AZU1 .
  • a method of selecting a subject having a myeloperoxidase (MPO)-related disorder for treatment with an MPO inhibitor 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.
  • MPO myeloperoxidase
  • a method of predicting whether a subject having an MPO-related disorder is likely to respond to treatment with an MPO inhibitor 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.
  • a method for identifying a subject with an MPO-related disorder who is likely to respond to treatment with an MPO inhibitor 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.
  • 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 comprises administering an MPO inhibitor to the subject.
  • a method of treating or preventing an MPO-related disorder in a subject 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.
  • a method of treating or preventing an MPO-related disorder in a subject 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.
  • a method of identifying and treating a subject suitable for treatment of an MPO- related disorder 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.
  • 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.
  • 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.
  • an MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject 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.
  • 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.
  • the method may relate to treating an MPO-related disorder.
  • 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.
  • the MPO-related disorder may be heart failure with reduced (HFrEF), mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF).
  • 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).
  • the MPO inhibitor may be mitiperstat.
  • 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.
  • 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). a To 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.
  • 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
  • Panel A shows NT-proBNP levels
  • panel B the 6-minute walk distance
  • 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).
  • Figure 6 illustrates the baseline characteristics of ENDEAVOR participants stratified by neutrophil counts >4 million/mL.
  • 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.
  • 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.
  • cardiovascular cardiovascular 111 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.
  • FIG 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 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 .
  • biomarker selected from the group consisting of: (a
  • 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 are diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable.
  • MPO activity 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
  • disorders include, but are not limited to, heart failure (e.g.
  • 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.
  • the MPO-related disorder may be heart failure with reduced (HFrEF), mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF).
  • HFrEF heart failure with reduced
  • HFmrEF mildly reduced
  • HFpEF preserved ejection fraction
  • LVEF left ventricular ejection fraction
  • the LVEF is 40-50%.
  • HFpEF the LVEF is greater than 50%.
  • the present disclosure may be used for the treatment or prevention of MPO-related disorders with an inflammatory component.
  • disorders e.g. diseases or conditions
  • disorders 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 autoanti
  • 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.
  • diseases and conditions include, but are not limited to diseases with a neuroinflammatory response.
  • 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.
  • 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.
  • 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.
  • the MPO inhibitor for use as described herein may be any compound that inhibits the activity of MPO.
  • MPO inhibitors are provided below.
  • MPO inhibitors are also provided in WO 2016/087338 as shown below.
  • 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.
  • R 2 represents H, CH3 or C2H5.
  • R 2 may represent CH3 or C2H5.
  • R 2 may represent CH3.
  • R 2 may represent H, CH3, C2H5, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl or cyclopentyl.
  • R 2 may represent H.
  • the carbon atom to which R 2 is attached may have the R-configuration when R 2 represents CH3 or C 2 H 5 .
  • the MPO inhibitor may be selected from:
  • 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:
  • 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
  • Y 1 CZ 1 or N
  • Y 2 CZ 2 or N
  • Y 3 CZ 3 or N
  • Y 4 CZ 4 or N
  • Y 5 CZ 5 or N
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are, if present, independently, H, halo, CF3, Q or T, provided that no more than one of Y 1 , Y 2 ,Y 3 , Y 4 , or Y 5 is N, at least two of Y 1 , Y 2 ,Y 3 , Y 4 , or Y 5 are CH, no more than one of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is halo or CF3, and one, and only one, of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 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 CH 2 , CF 2 , CHF, CHR 2 , CFR 2 , NR 3 , or O, wherein;
  • R 1 and R 2 are independently CH 2 F, CHF 2 , or CF3
  • R 3 if present, is independently H or CH3, or any stereoisomer thereof or pharmaceutically acceptable salt thereof.
  • 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, Y 1 , Y 2 ,Y 3 , Y 4 , A, R 1 , 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, Y 1 , Y 2 ,Y 3 , Y 4 , A, R 1 , 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 Y 4 is N and Y 1 , Y 2 , are Y 3 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 A is NR 3 .
  • 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 NR 3 and R 3 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 NR 3 and R 3 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, CHR 2 , or CFR 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 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 CHR 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 CHR 2 and R 2 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 CHR 2 and R 2 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 CHR 2 and R 2 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 Y 5 is CZ 5 , and Z 5 is T or Q.
  • the MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 , and Z 5 is T.
  • the MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 , and Z 5 is T and T is
  • p may be 0.
  • the MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 , Z 5 is T or Q, and Y 1 , Y 2 , Y 3 and Y 4 are CH.
  • Z 5 may be T.
  • p may be 0.
  • the MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 , Z 5 is T or Q, and one of Y 1 , Y 2 , Y 3 and Y 4 is N.
  • the MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y 5 is CZ 5 , Z 5 is T or Q, and two of Y 1 , Y 2 , Y 3 and Y 4 are CH, one of Y 1 , Y 2 , Y 3 and Y 4 is N, and one of Y 1 , Y 2 , Y 3 and Y 4 is CCI.
  • the MPO inhibitor may be a compound of formula (II), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Z 1 and Z 5 , together with the atoms they are bound to, form a five-or six-membered N-heterocycle.
  • Y 2 , Y 3 , and Y 4 may be CH.
  • 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 Z 2 and Z 3 , together with the atoms they are bound to, form a five- or six-membered N-heterocycle.
  • Y 1 , Y 4 , and Y 5 are CH.
  • 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:
  • the MPO inhibitor may be a compound having formula (lib) wherein,
  • X 1 CH or N
  • each X 2 is, independently, CH, CF, or CCI
  • the MPO inhibitor may be a compound having formula (Ila) or (lib), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein each X 2 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 X 1 is CH.
  • the MPO inhibitor may be a compound having formula (Ila) or (lib), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein X 1 is N.
  • the MPO inhibitor may be a compound selected from:
  • the MPO inhibitor may be a compound having the structure: (Illb), wherein X, Y 1 , Y 2 ,Y 3 , Y 4 , A, R 1 , 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).
  • an MPO inhibitor or salt described herein When 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.
  • 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.
  • 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.
  • agents that are:
  • 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).
  • CETP cholesterylester transfer protein
  • elevated neutrophil counts 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).
  • 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.
  • ANC absolute neutrophil count
  • NLR neutrophil-to-lymphocyte ratio
  • WBC total white blood cell 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).
  • WBC white blood cell
  • 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.
  • RBC red blood cell
  • WBC hemoglobin
  • 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.
  • WBC total leukocytes
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a biomarker selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL17, CCL3, CCL4, CD40
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CXCL11 .
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of HGF.
  • 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.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of ANGPT1 .
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of AXIN1 .
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CASP3.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CCL17.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CCL3.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CCL4.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CD40L.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CST5.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CXCL1 .
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CXCL10.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of CXCL5.
  • 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 .
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of HBEGF.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of HSP27.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of IFNy.
  • 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.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of IL7.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of IL8.
  • 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.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of MCP3.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of MMP1 .
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of NEMO.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of OSM.
  • 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.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of PTX3.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of SIRT2.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of SRC.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of STAMBP.
  • a subject is identified as more likely to respond to treatment with an MPO inhibitor if the subject has an increased concentration of STK4.
  • 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.
  • biomarker selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • SIRT2 NAD-dependent protein deacetylase sirtuin-2 Q8IXJ6 SIRT2
  • concentration of these biomarkers in a sample from the subject 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.
  • 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 biomarkers selected from the group consisting of: CXCL11 , HGF, 4EBP1 , ACE2, ANGPT1 , AXIN1 , CASP3, CCL
  • 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.
  • 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.
  • 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).
  • an inflammatory risk biomarker such as OSM, LOX1 , MMP9, CEACAM8, MPO, PGLYRP1 and/or AZU1 (see Table 3).
  • 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.
  • concentration of these biomarkers in a sample from the subject 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • NT-proBNP N-terminal pro B-type natriuretic peptide
  • hsCRP high-sensitivity C-reactive protein
  • IL-6 interleukin-6
  • 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.
  • plasma levels of NT-proBNP, hsCRP and/or IL-6 are measured by ELISA or by proteomic methods, such as mass spectrometry or SOMAscan.
  • 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.
  • 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.
  • 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-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 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.
  • 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.
  • ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.
  • 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.
  • Eligible patients are aged 40-85 years, with a body mass index of 18.0-45.0 kg/m 2 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).
  • TSS KCCQ total symptom score
  • the key exclusion criteria are estimated glomerular filtration rate below 30 mL/min/1 .73m 2 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).
  • 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 10 6 /mL vs ⁇ 4 x lO 6 /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.
  • 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
  • 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.
  • 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).
  • 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 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.
  • 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,
  • KCCQ-TSS KCCQ-TSS 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 ).
  • 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 ).
  • increased neutrophil-to-lymphocyte ratio has been associated with reduced 6MWD, although this was in the setting of pulmonary hypertension (Harbaum et al, 2017).
  • 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).
  • 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.
  • 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.
  • mitiperstat-treatment was associated with a 3.7 point increase in KCCQ-TSS and 24m longer 6MWD.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • a method of selecting a subject having a myeloperoxidase (MPO)-related disorder for treatment with an MPO inhibitor 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.
  • MPO myeloperoxidase
  • a method of predicting whether a subject having an MPO-related disorder is likely to respond to treatment with an MPO inhibitor 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.
  • a method for identifying a subject with an MPO-related disorder who is likely to respond to treatment with an MPO inhibitor 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.
  • a method of treating or preventing an MPO-related disorder in a subject 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.
  • a method of treating or preventing an MPO-related disorder in a subject 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.
  • a method of identifying and treating a subject suitable for treatment of an MPO-related disorder 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.
  • 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.
  • An MPO inhibitor for use in a method of treating or preventing an MPO-related disorder in a subject comprising:
  • 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.
  • the reference ANC value is the median or mean ANC in a population of subjects of the same ethnic group as said subject
  • the reference NLR value is the median or mean NLR in a population of subjects of the same ethnic group as said subject
  • 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.
  • 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.
  • 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,
  • CKD chronic kidney disease
  • AKI acute kidney injury
  • 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.
  • heart failure e.g. heart failure with reduced ejection fraction,
  • 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.
  • 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 CAD
  • coronary artery disease CAD
  • peripheral artery disease AAA or stroke.
  • NT-proBNP N-terminal pro B-type natriuretic peptide
  • hsCRP high-sensitivity C-reactive protein
  • IL-6 interleukin-6
  • LV-GLS left ventricular global longitudinal strain
  • LAVI left atrial volume index
  • LVMI left ventricular mass index
  • 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.
  • Y 1 CZ 1 or N
  • Y 2 CZ 2 or N
  • Y 3 CZ 3 or N
  • Y 4 CZ 4 or N
  • Y 5 CZ 5 or N Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , are, if present, independently, H, halo, CF3, Q or T, provided that no more than one of Y 1 , Y 2 , Y 3 , Y 4 , or Y 5 is N, at least two of Y 1 , Y 2 ,Y 3 , Y 4 , or Y 5 are CH, no more than one of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is halo or CF3, and one, and only one, of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 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
  • R 1 and R 2 are independently CH2F, CHF2, or CF3
  • R 3 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:
  • X 1 CH or N
  • each X 2 is, independently, CH, CF, or CCI
  • X 1 CH or N
  • each X 2 is, independently, CH, CF, or CCI
  • Lam CSP CVoors AA, Shah SJ, Erlinge D, Saraste A, Pirazzi C, Grove EL, Barasa A, Schou M, Aziz A, Gustavsson A, Garkaviy O, Gan LM, Gabrielsen A, Lund LH.
  • Myeloperoxidase inhibitor AZD4831 target engagement and safety in a phase2a study in patients with heart failure with preserved ejection fraction (SATELLITE). European Journal of Heart Failure 23, 129 (2021 ).

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Abstract

La présente divulgation concerne des procédés d'identification de sujets susceptibles de répondre à un traitement avec un inhibiteur de myéloperoxydase (MPO) sur la base de leurs taux de neutrophiles et/ou de la concentration d'au moins un biomarqueur de protéine. La présente divulgation concerne également des procédés de sélection de sujets pour un traitement avec un inhibiteur de MPO, des procédés pour prédire si un sujet répondra à un traitement avec un inhibiteur de MPO et des méthodes de traitement de sujets susceptibles de répondre à un traitement avec un inhibiteur de MPO. La présente divulgation concerne également un procédé de prédiction d'une réponse clinique améliorée chez un sujet ayant un trouble lié à la MPO après traitement avec un inhibiteur de MPO.
PCT/EP2024/059368 2023-04-06 2024-04-05 Méthode de traitement avec des inhibiteurs de mpo WO2024209075A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160152623A1 (en) * 2014-12-01 2016-06-02 Astrazeneca Ab 1-[2-(AMINOMETHYL)BENZYL]-2-THIOXO-1,2,3,5-TETRAHYDRO-4H-PYRROLO[3,2-d]PYRIMIDIN-4-ONES AS INHIBITORS OF MYELOPEROXIDASE

Patent Citations (2)

* Cited by examiner, † Cited by third party
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US20160152623A1 (en) * 2014-12-01 2016-06-02 Astrazeneca Ab 1-[2-(AMINOMETHYL)BENZYL]-2-THIOXO-1,2,3,5-TETRAHYDRO-4H-PYRROLO[3,2-d]PYRIMIDIN-4-ONES AS INHIBITORS OF MYELOPEROXIDASE
WO2016087338A1 (fr) 2014-12-01 2016-06-09 Astrazeneca Ab 1-[2-(aminométhyl)benzyl]-2-thioxo-1,2,3,5-tétrahydro-4h-pyrrolo[3,2-d]pyrimidin-4-ones en tant qu'inhibiteurs de la myéloperoxydase

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