WO2024027901A1 - Biomarqueur prédictif de réponse clinique à un inhibiteur de pde4 - Google Patents

Biomarqueur prédictif de réponse clinique à un inhibiteur de pde4 Download PDF

Info

Publication number
WO2024027901A1
WO2024027901A1 PCT/EP2022/071618 EP2022071618W WO2024027901A1 WO 2024027901 A1 WO2024027901 A1 WO 2024027901A1 EP 2022071618 W EP2022071618 W EP 2022071618W WO 2024027901 A1 WO2024027901 A1 WO 2024027901A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
value
subject
treatment
Prior art date
Application number
PCT/EP2022/071618
Other languages
English (en)
Inventor
Mirco GOVONI
Debora Santoro
Original Assignee
Chiesi Farmaceutici S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chiesi Farmaceutici S.P.A. filed Critical Chiesi Farmaceutici S.P.A.
Priority to PCT/EP2022/071618 priority Critical patent/WO2024027901A1/fr
Publication of WO2024027901A1 publication Critical patent/WO2024027901A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to the use of IL-8 as a biomarker of clinical response to a compound of formula (I). It refers to a compound of formula (I) or a pharmaceutical composition thereof for use in a method of treatment of a disorder susceptible to treatment with a PDE4 inhibitor, wherein the method comprises the step of measuring the value of IL-8 in the blood of a subject and to a method to identify a subject to be treated with a compound of formula (I) or a pharmaceutical composition.
  • Interleukin-8 is a chemoattractant cytokine produced by a variety of tissue and blood cells. Unlike many other cytokines, it has a distinct target specificity for the neutrophil, with only weak effects on other blood cells. Interleukin-8 attracts and activates neutrophils in inflammatory regions. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms.
  • Interleukin-8 is a member of the Interleukin-8 supergene family that includes other small chemotactic peptides with structural homology. It also shares with other cytokines DNA sequence features that suggest common regulatory pathways. In humans, the interleukin-8 protein is encoded by the CXCL8 gene.
  • IL-8 In vivo intracutaneous application of IL-8 induces local exudation and a massive, long-lasting accumulation of neutrophils. Although IL-8 plays a role in the cytokine network, its major pathophysiological role lies in affecting neutrophils.
  • Airway obstruction characterizes a number of severe respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include oedema of airway walls, increased mucous production and inflammation.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic respiratory disorder that progresses slowly and is characterised by an obstructive ventilatory pattern, which is rarely reversible, very often related to tobacco smoking and which can lead to chronic respiratory failure.
  • This definition covers chronic bronchitis, with an obstructive ventilatory pattern that is defined by the existence of chronic bronchitis with permanent obstruction of airways.
  • COPD is currently ranked as the fourth leading cause of death in the US and is predicted to become the third leading cause of death worldwide by 2030. More than 16.4 million people in the US have been diagnosed with COPD, but it is estimated that millions more have yet to be diagnosed (American Lung Association. How serious is COPD; 2019). The global COPD burden is projected to increase (Mathers C, Loncar D.
  • biomarkers have long been used in drug development, and the discovery and validation of new efficacy biomarkers is expected to improve the predictive disease models, reduce the time and cost associated with drug development, and increase the success rate of translating experimental drugs into clinical therapeutics.
  • biomarkers are valuable in early detection of disease development, changes in disease status, and effectiveness of behavioral modifications and therapeutics in disease control.
  • PDE4 phosphodiesterase enzymes
  • the compound of formula (I) also named Tanimilast or CHF6001 or CHF-6001, with INN (3,5-dichloro-4-[(2S)- 2-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2- ⁇ [3-(cyclopropylmethoxy)- 4-(methanesulfonamido)benzoyl]oxy ⁇ ethyl]pyridinel -oxide), is an highly potent and selective PDE4 inhibitor with robust anti-inflammatory activity, currently under clinical development.
  • Roflumilast is Among other PDE4 inhibitors, Roflumilast is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD and method for selecting patients suffering from COPD with rare exacerbations to be treated with Roflumilast is known in the art and disclosed in RU2726228.
  • the method comprises assessing a patient's quality of life using a CAT test and sampling blood to measure serum levels of tumor necrosis factor-alpha and interleukin-8.
  • blood IL-8 value represents a predictive biomarker of enhanced clinical response to the compound of formula (I).
  • COPD patients with a blood IL-8 value lower or equal to a reference value are shown to have an increased response to the compound of formula (I) treatment in terms of moderate-to-severe exacerbation rate reduction as well as in delay of time to first moderate-to-severe exacerbation.
  • the present invention relates to a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for use in a method of treatment of a disorder susceptible to treatment with a PDE4 inhibitor, wherein the method comprises the step of measuring the value of IL-8 in the blood of a subject, and comparing the measured value to a reference IL-8 value wherein if the measured value is lower or equal to said reference value the subject is treated.
  • the present invention refers to a method to identify a subject to be treated with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier wherein said subject is afflicted with a disorder susceptible to treatment with a PDE4 inhibitor, the method comprising the step of measuring the value of IL-8 in the blood of the subject, and comparing the measured value to a reference IL-8 value, wherein, if the measured value is lower or equal to said reference value, then the subject is identified.
  • the present invention refers to a method for treating a subject with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier wherein the subject afflicted with a disorder susceptible to treatment with a PDE4 inhibitor, the method comprising the steps of: a) identifying a subject to be treated with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier according to the method defined above and b) administering a therapeutic amount of a compound of formula (I) or the pharmaceutical composition to the subject.
  • Fig. 1 A -Adjusted annualised moderate-to-severe exacerbation rate (with 95% CI) in the overall population and in subgroups of patients characterised by low serum interleukin-8 levels at baseline ⁇ statistically significantly different versus placebo, p ⁇ 0.05).
  • B Adjusted annualised moderate-to-severe exacerbation rate (with 95% CI) in patients with a chronic bronchitis phenotype (CB) and with different serum interleukin- 8 levels at baseline ⁇ statistically significantly different versus placebo, p ⁇ 0.05).
  • CB chronic bronchitis phenotype
  • Fig. 2 A -Adjusted % reduction vs placebo of the moderate-to-severe exacerbation rate in the overall population and in subgroups of patients characterised by low serum interleukin-8 levels at baseline (* exacerbation rate statistically significantly different versus placebo, p ⁇ 0.05).
  • B Adjusted % reduction vs placebo of the moderate-to-severe exacerbation rate in patients with a chronic bronchitis phenotype and with different serum interleukin-8 levels at baseline (*exacerbation rate statistically significantly different versus placebo, p ⁇ 0.05).
  • Fig. 3 Al A2, A3, A4 - Kaplan-Meier curve for time to first moderate-to-severe exacerbation event during the 24-week treatment period in the overall population and in subgroups of patients characterised by lower serum interleukin-8 levels at baseline (*risk of experiencing a moderate-to-severe exacerbation over time statistically significantly different versus placebo, p ⁇ 0.05).
  • Bl, B2, B3, B4 - Kaplan-Meier curve for time to first moderate-to-severe exacerbation event during the 24-week treatment period in patients with a chronic bronchitis phenotype and with different serum interleukin-8 levels at baseline (*risk of experiencing a moderate-to-severe exacerbation over time statistically significantly different versus placebo, p ⁇ 0.05).
  • the compound of formula (I) of the present invention is intended to include also stereoisomers, tautomers or pharmaceutically acceptable salts or solvates thereof.
  • pharmaceutically acceptable salts refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable.
  • Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups.
  • Cations of inorganic bases which can be suitably used to prepare salts comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.
  • Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.
  • solvate means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • stereoisomer refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.
  • racemate or “racemic mixture” refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.
  • tautomer refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by migration of an atom or group within the molecule.
  • biomarker or “marker” refers to an objectively measured indicator that reflects the successful treatment of a particular condition.
  • IL-8 refers to Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8), preferably human IL-8.
  • the sequence of the protein is well-known in the art and is, for example, accessible via Uni-Prot (UniProtKB - P10145 (IL8 HLTMAN) or via GenBank (NCBI Reference Sequence: NM_000584.4)).
  • blood refers to serum, plasma, whole blood or PBMCs derived from the subject's blood.
  • sample refers to the liquid fraction of whole blood that is obtained after the blood is allowed to clot.
  • measuring the amount of a biomarker or “measuring the biomarker” as referred to herein refers to the quantification of the biomarker, e.g. to determining the level of the biomarker in the sample, employing appropriate methods of detection described herein below.
  • the terms “measuring” and “determining” are used herein interchangeably.
  • binding agent binds to a biomarker
  • binding agent relates to an agent that comprises a binding moiety which specifically binds the corresponding biomarker.
  • binding agents or “agents” are a nucleic acid probe, nucleic acid primer, DNA molecule, RNA molecule, aptamer, antibody, antibody fragment, peptide, peptide nucleic acid (PNA) or chemical compound.
  • a preferred agent is an antibody which specifically binds to the biomarker to be measured.
  • antibody herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multi- specific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity (i.e. antigen-binding fragments thereof).
  • the antibody is a polyclonal antibody. More preferably, the antibody is a monoclonal antibody.
  • binding refers to a binding reaction wherein binding pair molecules exhibit a binding to each other under conditions where they do not significantly bind to other molecules.
  • the term “specific binding” or “specifically binds” preferably refers to an affinity of at least 1 O' 8 M or even more preferred of at least 1 O' 9 M for its target molecule.
  • the term “specific” or “specifically” is used to indicate that other molecules present in the sample do not significantly bind to the binding agent specific for the target molecule.
  • the “value” or “expression” or “level” or “amount” of IL-8 relates to the amount of IL-8 polypeptide present in a sample or the amount of mRNA encoding IL-8 present in a sample.
  • amount encompasses the absolute amount of a biomarker as referred to herein, the relative amount or concentration of the said biomarker as well as any value or parameter which correlates thereto or can be derived therefrom.
  • comparing refers to comparing the amount of the biomarker in the sample from the subject with the reference amount of the biomarker specified elsewhere in this description. It is to be understood that comparing as used herein usually refers to a comparison of corresponding parameters or values, e.g., an absolute amount is compared to an absolute reference amount while a concentration is compared to a reference concentration or an intensity signal obtained from the biomarker in a sample is compared to the same type of intensity signal obtained from a reference sample.
  • reference IL-8 amount or “reference IL-8 value” or “reference eosinophil amount” or “reference eosinophil value” as used herein refer to an amount which allows to identify a subject with enhanced response to compound of formula (I) and therefore to be treated with the same. Such terms may also refer to a predetermined value. Said predetermined value shall allow to identify a subject with enhanced response to compound of formula (I) and therefore to be treated with the same.
  • An amount of IL- 8 in the sample of the test subject at or below the reference IL-8 amount indicates that the subject is lilely to have an enhanced response to the compound of formula (I).
  • An amount of eosinophils in the sample of the test subject at or above the reference eosinophil amount indicates that the subject is lilely to have an enhanced response to compound of formula (I).
  • Low or lower serum IL-8 levels means a serum level lower than or equal to about 23 pg/ml.
  • “High or higher blood eosinophil count” means a blood eosinophil count higher than about 150 cells/pl.
  • subject refers to a specific individual, preferably a mammal, more preferably a human, who is diagnosed with, or suspected of having, a disease or disorder and/or is under treatment for a disease or disorder susceptible of treatment with a PDE4 inhibitor.
  • subject and patient are used interchangeably in this application.
  • baseline or a subject at “baseline” is a subject prior to administration of the compound of formula (I).
  • a “pharmaceutically acceptable carrier” refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject.
  • a “PDE4 inhibitor” is any molecule that blocks the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP), it prevents the breakdown of cAMP.
  • a disorder susceptible to treatment with a PDE4 inhibitor is any disease wherein the activity of PDE4 receptors is implicated and inhibition of PDE4 receptor activity is desired or a disease state which is mediated by PDE4 activity, for instance a disease state in which PDE4 is overexpressed or overactive.
  • COPD exacerbation is defined as a sustained worsening of the patient’s condition (dyspnoea, cough and/or sputum product! on/purulence), from the stable state and beyond normal day-to-day variations, that was acute in onset and necessitated a change in regular medication in a patient with underlying COPD that required prescriptions of systemic corticosteroids (oral/intravenous [IV]/intramuscular [IM] corticosteroids) and/or antibiotics (for a moderate exacerbation) or hospitalisation or leading to death (for severe exacerbation).
  • systemic corticosteroids oral/intravenous [IV]/intramuscular [IM] corticosteroids
  • antibiotics for a moderate exacerbation
  • hospitalisation or leading to death for severe exacerbation
  • “Mild exacerbation” is defined as exacerbations described as an increase in respiratory symptoms that can be controlled by the patient with an increase in usual medication;
  • Modeerate exacerbation represents exacerbations that require treatment with systemic (oral/IV/IM corticosteroids) corticosteroids and/or antibiotics;
  • Rate ratio refers to the ratio between annualised rate in the compound of formula (I) arm and annualised rate in the placebo arm. Percent reduction is derived as (1 - rate ratio) x 100. Adjusted rates are those derived from the negative binomial models.
  • “Hazard ratio” is the conditional probability that the event will occur at time t given that it has not occurred prior to time t and it is computed as ratio between density function f(t) and survivor function S(t).
  • the present invention refers to a method to identify a subject to be treated with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier wherein said subject is afflicted with a disorder susceptible to treatment with a PDE4 inhibitor, and wherein the method is characterized by the steps of:
  • the inventors conducted a study to investigate the effect of said compound in comparison to placebo over 24 weeks in terms of rate of moderate-to-severe exacerbations and time to first moderate or severe exacerbation in groups of patients characterized by different serum interleukin-8 levels at baseline.
  • Said patients were also characterized by different blood eosinophil count (number of eosinophil s/pl).
  • the present invention relates to the use of blood IL-8 amount as a biomarker of response to a compound of formula (I).
  • blood IL-8 value represents a predictive biomarker of enhanced clinical response to the compound of formula (I).
  • Patients with a blood IL-8 value lower or equal to about 23 pg/ml are shown to have a higher clinical response to compound of formula (I) treatment as evidenced by a significant reduction of moderate- to-severe exacerbation rate and/or increased time to first moderate-to-severe exacerbation.
  • the exacerbation rate reduction due to compound of formula I treatment in the overall population is -18%, while in patients with IL8 less or equal to about 23 pg/ml it is -27%, with IL8 less or equal to about 20 pg/ml it is -36 % and in patients with IL8 less than or equal to about 17 pg/ml it is -34%.
  • Patient with lower serum IL-8 levels at baseline show augmented response to the compound of formula (I); the HR [95% CI] compared to placebo was 0.64 [0.41-1.01] for patients with IL8 lower than or equal to about 17 (17.3 pg/mL), 0.61 [0.40-0.93] for patients with IL8 lower than or equal to about 20 pg/mL, and 0.67 [0.46-0.97]; for patients with IL8 lower than or equal to about 23 pg/mL (Fig.3Al, A2, A3, respectively).
  • IL-8 may be combined with at least one other biomarker, preferably blood eosinophils count.
  • Patients with blood IL-8 value lower or equal to about 23 pg/ml and with blood eosinophil count higher or equal to about 150 cells/pl are shown to have a further enhanced response to the compound of formula (I), as demonstrated by a reduction of moderate-to-severe exacerbation rate and increased time to first moderate-to-severe exacerbation as shown in Fig 3C1-C3.
  • the invention refers a method to identify a subject to be treated with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier wherein said subject is afflicted with a disorder susceptible to treatment with a PDE4 inhibitor, the method comprising the step of measuring the value of IL-8 and eosinophils value in the blood of the subject, and comparing the measured IL- 8 value and measured eosinophils value to a reference IL-8 and reference eosinophils value, respectively, wherein, if the IL-8 measured value is lower than or equal to the reference IL-8 value and the measured eosinophil value is higher than or equal to the reference eosinophil value, then the subject is identified.
  • Inventors have also surprisingly found that patients with a chronic bronchitis phenotype and blood IL-8 value lower or equal to a reference value, have a further enhanced response to the compound of formula (I) as demonstrated by a reduction of moderate-to-severe exacerbation rate and by increased time to first moderate-to-severe exacerbation as shown in Fig. 3B1-B3.
  • blood IL-8 as a biomarker provides a robust and reliable method to identify subjects with enhanced response to the compound of formula (I).
  • the method of the present invention is particularly appreciated by the skilled person when looking at a suitable and efficacious way to personalize treatment with a PDE4 inhibitor, such as the compound of formula (I).
  • the present invention relates to method for treating a subject with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier wherein the subject afflicted with a disorder susceptible to treatment with a PDE4 inhibitor, the method comprising the steps of: a) identifying a subject to be treated with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier according to the method as defined above and b) administering a therapeutic amount of a compound of formula (I) or the pharmaceutical composition to the subject.
  • the disorder susceptible to treatment with a PDE4 inhibitor is a disease of the respiratory tract, preferably the disease is characterized by airway obstruction, still preferably the disease is asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the disorder susceptible to treatment with a PDE4 inhibitor is COPD.
  • the value of IL-8 is a serum, plasma or PBMC concentration.
  • the value of IL-8 is measured beforhands, i.e before starting the administration of the compound of formula (I), in order to better identify a suitable patient with higher likelihood to respond to the treatment.
  • the measured value is lower than or equal to about 23 pg/ml.
  • the measured value is lower than or equal to about 20 pg/ml.
  • the measured value is lower than or equal to about 17 pg/ml.
  • the method of the invention comprises a further step of measuring the value of eosinophils in the blood and comparing the measured value to a reference eosinophils value, wherein, if the measured eosinophils value is higher or equal to the reference eosinophils value, then the subject is identified or treated.
  • the value of eosinophil is measured before starting the administration of the compound of formula (I).
  • the eosinophils’ measured value is higher or equal to about 150 cells/pl.
  • the method of the present invention is suitable to identify a patient population with enhanced response to compound of formula (I), said population being characterized by a serum IL-8 amount lower than or equal to about 23 pg/ml and a blood eosinophil count higher than or equal to about 150 cells/pl.
  • the subject to be treated with the compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) and a pharmaceutically acceptable carrier is affected by COPD.
  • the subject to be treated with the compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) and a pharmaceutically acceptable carrier is affected by COPD with a chronic bronchitis phenotype.
  • the biomarkers as referred to herein can be detected using methods generally known in the art.
  • the amount of a biomarker may be measured by contacting the sample with an agent that specifically binds to the biomarker, thereby forming a complex between the agent and said biomarker, detecting the amount of complex formed, and thereby measuring the amount of said biomarker.
  • Methods of detection generally encompass methods to quantify the amount of a biomarker in the sample (quantitative method). It is generally known to the skilled artisan which of the following methods are suitable for qualitative and/or for quantitative detection of a biomarker. Samples can be conveniently assayed for, e.g., proteins using Westerns and immunoassays, like ELISAs, RIAs, fluorescence- and luminescence-based immunoassays, which are commercially available. Further suitable methods to detect biomarkers include measuring a physical or chemical property specific for the peptide or polypeptide such as its precise molecular mass or NMR spectrum.
  • Said methods comprise, e.g., biosensors, optical devices coupled to immunoassays, biochips, analytical devices such as mass- spectrometers, NMR- analyzers, or chromatography devices.
  • methods include microplate ELISA-based methods, fully-automated or robotic immunoassays (available for example on ElecsysTM analyzers), CBA (an enzymatic Cobalt Binding Assay, available for example on Roche-HitachiTM analyzers), and latex agglutination assays (available for ex- ample on Roche-HitachiTM analyzers).
  • Examples of such methods include immuno-based assays, tandem Mass Spectrometry, isotopecoded protein labeling, protein microarrays, Proximity Extension Assays, immunoblotting, RN A- Sequencing, Microarray Gene Expression, real-time PCR, NanoString's nCounter.
  • biomarker proteins For the detection of biomarker proteins as referred to herein a wide range of immunoassay techniques using such an assay format are available. These include both single-site and two-site or “sandwich” assays of the non-competitive types, as well as in the traditional competitive binding assays. These assays also include direct binding of a labeled antibody to a target biomarker.
  • IL-8 is a biomarker and its amount shall be measured.
  • the amount of the IL-8 polypeptide is measured.
  • Seven isoforms are produced by proteolytic cleavage after cells secretion, namely:
  • IL-8 may be measured by any method known in the art as protein or product of gene expression (mRNA) (Gene: CXCL8 ENSG00000169429) with different technologies.
  • mRNA product of gene expression
  • Measuring the amount of a polypeptide may, preferably, comprise the steps of (a) contacting the polypeptide with an agent that specifically binds said polypeptide (b) (optionally) removing non-bound agent, (c) measuring the amount of bound binding agent, i.e. the complex of the agent formed in step (a).
  • said steps of contacting, removing and measuring may be performed by an analyzer unit.
  • said steps may be performed by a single analyzer unit of said system or by more than one analyzer unit in operable communication with each other.
  • said system disclosed herein may include a first analyzer unit for performing said steps of contacting and removing and a second analyzer unit, operably connected to said first analyzer unit by a transport unit (for example, a robotic arm), which performs said step of measuring.
  • a transport unit for example, a robotic arm
  • binding agent The agent which specifically binds the biomarker
  • labeling agent may be coupled covalently or non-covalently to a label allowing detection and measurement of the bound agent.
  • Labeling may be done by direct or indirect methods. Direct labeling involves coupling of the label directly (covalently or non- covalently) to the binding agent. Indirect labeling involves binding (covalently or non- covalently) of a secondary binding agent to the first binding agent.
  • the secondary binding agent should specifically bind to the first binding agent.
  • Said secondary binding agent may be coupled with a suitable label and/or be the target (receptor) of tertiary binding agent binding to the secondary binding agent.
  • Suitable secondary and higher order binding agents may include antibodies, secondary antibodies, and the well-known streptavidin-biotin system (Vector Laboratories, Inc.).
  • the binding agent or substrate may also be “tagged” with one or more tags as known in the art. Such tags may then be targets for higher order binding agents.
  • Suitable tags include biotin, digoxygenin, His-Tag, Glutathion-S-Transferase, FLAG, GFP, myc-tag, influenza A virus haemagglutinin (HA), maltose binding protein, and the like.
  • the tag is preferably at the N-terminus and/or C- terminus.
  • Suitable labels are any labels detectable by an appropriate detection method.
  • Typical labels include gold particles, latex beads, acridan ester, luminol, ruthenium complexes, iridium complexes, enzymatically active labels, radioactive labels, magnetic labels (“e.g. magnetic beads”, including paramagnetic and superparamagnetic labels), and fluo- rescent labels.
  • Enzymatically active labels include e.g. horseradish peroxidase, alkaline phosphatase, beta-Galactosidase, Luciferase, and derivatives thereof.
  • Suitable substrates for detection include di-amino- benzidine (DAB), 3,3'-5,5'-tetramethylbenzidine, NBT- BCIP (4-nitro blue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl-phosphate, available as ready-made stock solution from Roche Diagnostics), CDP-StarTM (Amersham Bio- sciences), ECFTM (Amersham Biosciences).
  • a suitable enzyme-substrate combination may result in a colored reaction product, fluorescence or chemo luminescence, which can be measured according to methods known in the art (e.g. using a light-sensitive film or a suitable camera system). As for measuring the enzymatic reaction, the criteria given above apply analogously.
  • fluorescent labels include fluorescent proteins (such as GFP and its derivatives), Cy3, Cy5, Texas Red, Fluorescein, and the Alexa dyes (e.g. Alexa 568). Further fluorescent labels are available e.g. from Molecular Probes (Oregon). Also the use of quantum dots as fluorescent labels is contemplated.
  • a radioactive label can be detected by any method known and appropriate, e.g. a light-sensitive film or a phosphor imager.
  • the amount of a polypeptide may be, also preferably, measured as follows: (a) contacting a solid support comprising a binding agent for the polypeptide as described elsewhere herein with a sample comprising the peptide or polypeptide and (b) measuring the amount peptide or polypeptide which is bound to the support.
  • Materials for manufacturing supports are well-known in the art and include, inter alia, commercially available column materials, polystyrene beads, latex beads, magnetic beads, colloid metal particles, glass and/or silicon chips and surfaces, nitrocellulose strips, membranes, sheets, duracytes, wells and walls of reaction trays, plastic tubes etc.
  • the sample may be removed from the complex formed between the binding agent and the at least one marker prior to the measurement of the amount of formed complex.
  • the binding agent may be immobilized on a solid support.
  • the sample can be removed from the formed complex on the solid support by applying a washing solution.
  • Sandwich assays are among the most useful and commonly used assays encompassing a number of variations of the sandwich assay technique, including immune assays. Briefly, in a typical assay, an unlabeled (capture) binding agent is immobilized or can be immobilized on a solid substrate, and the sample to be tested is brought into contact with the capture binding agent. After a suitable period of incubation, for a period of time sufficient to allow formation of a binding agent-biomarker complex, a second (detection) binding agent labeled with a reporter molecule capable of producing a detectable signal is then added and incubated, allowing time sufficient for the formation of another complex of binding agent-biomarker-labeled bind- ing agent.
  • any unreacted material may be washed away, and the presence of the biomarker is determined by observation of a signal produced by the reporter molecule bound to the detection binding agent.
  • the results may either be qualitative, by simple observation of a visible signal, or may be quantitated by comparison with a control sample containing known amounts of bio marker.
  • the incubation steps of a typical sandwich assays can be varied as required and appropriate. Such variations include for example simultaneous incubations, in which two or more of binding agent and biomarker are co-incubated. For example, both, the sample to be analyzed and a labeled binding agent are added simultaneously to an immobilized capture binding agent.
  • the formed complex between a specific binding agent and the biomarker shall be proportional to the amount of the biomarker present in the sample. It will be understood that the specificity and/or sensitivity of the binding agent to be applied defines the degree of proportion of at least one marker comprised in the sample which is capable of being specifically bound. Further details on how the measurement can be carried out are also found elsewhere herein.
  • the amount of formed complex shall be transformed into an amount of the biomarker reflecting the amount indeed present in the sample.
  • Values or parameters which correlate with the amount comprise intensity signal values from all specific physical or chemical properties obtained from the said peptides by direct measurements, e.g., intensity values in mass spectra or NMR spectra. Moreover, encompassed are all values or parameters which are obtained by indirect measurements specified elsewhere in this description, e.g., response amounts measured from biological read out systems in response to the peptides or intensity signals obtained from specifically bound ligands. It is to be understood that values correlating to the aforementioned amounts or parameters can also be obtained by all standard mathematical operations.
  • the comparison may be carried out manually or computer-assisted.
  • the comparison may be carried out by a computing device.
  • the value of the measured or detected amount of the biomarker in the sample from the subject and the reference amount can be, e.g., compared to each other and the said comparison can be automatically carried out by a computer program executing an algorithm for the comparison.
  • the computer program carrying out the said evaluation will provide the desired assessment in a suitable output format.
  • the value of the measured amount may be compared to values corresponding to suitable references which are stored in a database by a computer program.
  • the computer program may further evaluate the result of the comparison, i.e. automatically provide the desired assessment in a suitable output format.
  • the value of the measured amount may be compared to values corresponding to suitable references which are stored in a database by a computer program.
  • the computer program may further evaluate the result of the comparison, i.e. automatically provides the desired assessment in a suitable output format.
  • the amount of the biomarker IL-8 is compared to a reference.
  • the reference is preferably a reference amount.
  • a suitable reference amount may be determined from a reference sample to be analyzed together, i.e. simultaneously or subsequently, with the test sample.
  • IL-8 may be measured in different biological samples such as blood, serum, plasma and PBMC.
  • Samples of blood, plasma, serum, or derivative thereof can be obtained by well- known techniques. Separated cells may be obtained from blood, plasma, serum, or derivative thereof by separating techniques such as centrifugation or cell sorting.
  • the sample may be frozen, fresh, centrifuged, etc.
  • the sample can, of course, be subjected to a variety of well-known post-collection preparative and storage techniques (e.g., nucleic acid and/or protein extraction, storage, freezing, ultrafiltration, concentration, evaporation, centrifugation, etc.) prior to assessing the amount of the marker in the sample.
  • IL-8 biomarker may be combined with at least another biomarker of response to the compound of formula (I): the blood eosinophils count.
  • the blood eosinophils count is compared to a reference eosinophil value.
  • Reference IL-8 value and reference eosinophil value are values measured before the beginning of administration of compound of formula (I) or a pharmaceutical composition thereof to a subject afflicted with a disorder susceptible to treatment with a PDE4 inhibitor.
  • Eosinophils value or count may be measured by any method known in the art.
  • eosinophils may be evaluated as part of standard hematology assessments by using Sysmex XT2000i analysers to provide results for all automated complete blood count testing (CBC).
  • the Sysmex XT performs an automated white cell differential via flow cytometry methodology. Forward scattered light, lateral scattered light band lateral fluorescent light are detected via flow cytometry method utilizing a semiconductor laser and two dimensional scattergrams are drawn.
  • the Sysmex analysers provide a 5-part white blood cell differential (neutrophils, lymphocytes, monocytes, eosinophils and basophils) reported in both percentages and absolutes.
  • the Sysmex analysers utilise fluorescence flow cytometry. The sub-populations are separated on the basis of nucleic acid content and internal structure or complexity.
  • Eosinophils in blood may also be measured with HemoCue® WBC Diff System (HemoCue AB, Angelholm, Sweden).
  • the compound of formula (I) may be in the form of an inhalable dry powder formulation comprising particles of said compound and particles of a carrier made of a physiologically acceptable pharmacologically-inert material.
  • patients may receive 1600 pg of the compound in the morning and 1600 pg in the evening for one year.
  • Pharmaceutical acceptable carrier comprises a crystalline sugar selected from the group consisting of glucose, arabinose, maltose, saccharose, dextrose and lactose or a polyalcohol selected from the group consisting of mannitol, maltitol, lactitol and sorbitol, preferably lactose, even more preferably a-lactose monohydrate.
  • composition may further comprise one or more additive materials selected form the group consisting of amino acids, water soluble surface active agents, lubricants and glidants, preferably magnesium stearate.
  • disorders susceptible to treatment with a PDE4 inhibitor include: atopic dermatitis, allergic rhinitis, psoriasis and diseases of the respiratory tract, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and bronchiectasis.
  • atopic dermatitis atopic dermatitis, allergic rhinitis, psoriasis and diseases of the respiratory tract, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and bronchiectasis.
  • COPD chronic obstructive pulmonary disease
  • COPD refers to a group of diseases that cause airflow blockage and breathing- related problems. It includes emphysema and chronic bronchitis or a mixed of both. COPD patients may have a emphysema phenotype, a chronic bronchitis phenotype or a mixed phenotype.
  • the following examples illustrate the invention without limiting its scope.
  • the compound of formula (I) was synthetized according to the methods as defined in WO 2015/059050, incorporated by reference. It can also be synthetized by any known method in the art.
  • Objective of the present invention is to investigate the effect of the compound of formula (I) in comparison to placebo over 24 weeks in terms of rate of moderate-to-severe exacerbations and time to first moderate or severe exacerbation in groups of patients characterized by different serum interleukin-8 (IL-8) levels at baseline (randomization visit, prior to study treatment first intake) alone or within a group of patients characterized by a chronic bronchitis phenotype or patients characterized by different blood eosinophils count at baseline (randomization visit, prior to study treatment first intake)
  • IL-8 serum interleukin-8
  • IL-8 Blood for IL-8 determination was collected in the morning prior to the first treatment dose administration into serum separator tubes and kept at room temperature for 30-60 minutes to allow clotting. Samples were then centrifuged at 2000 g for 5 min at +4°C and serum transferred to the central laboratory at -60 to -90°C for analysis. IL- 8 was measured in serum with a validated Meso Scale Diagnostics (MSD) method using the MSD v-PLEX Plus kits (plate reader Mesoscale Discovery sector Imager 6000). The validation procedures followed was based upon those outlined in the ‘Guideline on Bioanalytical Method Validation’, EMA, CHMP, EWP, July 2011.
  • MSD Meso Scale Diagnostics
  • Assay validation comprised assessment of the calibration curve, establishment of endogenous concentration, validation control preparation, precision, parallelism/linearity of dilution, hook effect, stability and test article specificity.
  • Calibration curve ranged from 0.0743 pg/mL to 687 pg/mL with 16-fold times linearity for dilution. Precision and accuracy (intra- and inter-assay) were within acceptance criteria. Stability in serum was demonstrated for up to 24 h at room temperature, after 4 freeze thaw cycles and up to 90 days, at nominally -80°C. All samples were analysed within 90 days from collection. The assay method was found to be accurate and precise and deemed suitable for measuring concentrations of IL-8 in human serum from regulatory studies.
  • Eosinophils in blood may be measured by any method known in the art. Specifically eosinophils were evaluated as part of standard hematology assessments by using Sysmex XT2000i analysers to provide results for all automated complete blood count testing (CBC).
  • CBC complete blood count testing
  • the Sysmex XT performs an automated white cell differential via flow cytometry methodology. Forward scattered light, lateral scattered light band lateral fluorescent light are detected via flow cytometry method utilizing a semiconductor laser and two dimensional scattergrams are drawn.
  • the Sysmex analysers provide a 5-part white blood cell differential (neutrophils, lymphocytes, monocytes, eosinophils and basophils) reported in both percentages and absolutes.
  • the Sysmex analysers utilise fluorescence flow cytometry. The sub-populations are separated on the basis of nucleic acid content and internal structure or complexity.
  • the rate of moderate or severe COPD exacerbation per patient per year was calculated for each treatment using a weighted approach (which consists of pooling all patients of a treatment group and dividing the total number of moderate or severe COPD exacerbations by the total follow-up time).
  • the follow-up time in years was calculated using the following formula:
  • Min minimum; Discontinued patients: patients who didn’t complete the study (i.e. 24 week observation).
  • the moderate-to-severe COPD exacerbation rate and time to first moderate or severe exacerbation were analyzed in the overall population (including chronic bronchitis, emphysema and mixed phenotype) or in the chronic bronchitis phenotype (characterised by persistent cough and expectoration) only or in patients with higher blood eosinophil counts (EOS > 150 cells/ l).
  • the analyses were repeated in subgroups of patients defined based on different IL-8 levels at baseline (e.g., patients with IL-8 value ⁇ threshold). Three different IL-8 thresholds were considered: about 17 pg/mL (17.3 pg/mL), about 20 pg/mL and about 23 pg/mL. Comparisons were performed using a significance level alpha of 0.05. All data were analysed using Statistical Analysis System software Version 9.4.
  • the effect of the compound of formula (I) treatment is enhanced in patients having low serum IL-8 levels at baseline, specifically serum IL-8 levels at baseline below 23 pg/mL or below 20 pg /mL or below 17.3 pg/mL.
  • the adjusted annualised moderate-to-severe exacerbation rates for patients with chronic bronchitis and serum IL-8 ⁇ 17.3 pg/mL, 20 pg/mL or 23 pg/mL ranged from 0.67 to 0.72 for placebo and from 0.36 to 0.43 for the compound of formula (I) (Fig.
  • subjects with a chronic bronchitis phenotype and lower serum IL-8 concentration display a further increment of response to the compound of formula (I) also in terms of risk of experiencing a moderate-to-severe exacerbation over time.
  • subjects with higher blood eosinophil count and lower serum IL-8 concentration display a further increment of response to the compound of formula (I) also in terms of risk of experiencing a moderate-to-severe exacerbation over time.
  • blood IL-8 value represents a predictive biomarker of enhanced clinical response to the compound of formula (I).
  • COPD patients with a blood IL-8 value lower or equal to a reference value are shown to have an increased response to the compound of formula (I) treatment in terms of moderate-to-severe exacerbation rate reduction as well as in the delay of the time to first moderate-to-severe exacerbation.
  • biomarker may be combined with blood eosinophils counts.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention concerne l'utilisation de l'IL-8 comme biomarqueur de réponse clinique à un composé de formule (I), (I). L'invention concerne un composé de formule (I) ou une composition pharmaceutique associée destiné(e) à être utilisé(e) dans une méthode de traitement d'un trouble sensible au traitement avec un inhibiteur de PDE4, ladite méthode comprenant l'étape de mesure de la valeur de l'IL-8 dans le sang d'un sujet, ainsi qu'une méthode d'identification d'un sujet à traiter avec un composé de formule (I) ou une composition pharmaceutique.
PCT/EP2022/071618 2022-08-02 2022-08-02 Biomarqueur prédictif de réponse clinique à un inhibiteur de pde4 WO2024027901A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2022/071618 WO2024027901A1 (fr) 2022-08-02 2022-08-02 Biomarqueur prédictif de réponse clinique à un inhibiteur de pde4

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2022/071618 WO2024027901A1 (fr) 2022-08-02 2022-08-02 Biomarqueur prédictif de réponse clinique à un inhibiteur de pde4

Publications (1)

Publication Number Publication Date
WO2024027901A1 true WO2024027901A1 (fr) 2024-02-08

Family

ID=83149022

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/071618 WO2024027901A1 (fr) 2022-08-02 2022-08-02 Biomarqueur prédictif de réponse clinique à un inhibiteur de pde4

Country Status (1)

Country Link
WO (1) WO2024027901A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009018909A2 (fr) 2007-08-08 2009-02-12 Chiesi Farmaceutici S.P.A. Dérivés d'alcools alkyliques de 1-phényl-2-pyridinyle en tant qu'inhibiteurs de la phosphodiestérase
WO2010089107A1 (fr) 2009-02-06 2010-08-12 Chiesi Farmaceutici S.P.A. Esters (1-phényl-2-pyridin-4-yl) éthyliques d'acide benzoïque en tant qu'inhibiteurs de la phosphodiestérase
WO2012016889A2 (fr) 2010-08-03 2012-02-09 Chiesi Farmaceutici S.P.A. Formulation de poudre sèche comprenant un inhibiteur de phosphodiestérase
WO2015059050A1 (fr) 2013-10-22 2015-04-30 Chiesi Farmaceutici S.P.A. Procédé de préparation d'un inhibiteur de la pde4
WO2020081866A1 (fr) * 2018-10-18 2020-04-23 Proterixbio, Inc. Procédés d'évaluation et de traitement ciblés d'une maladie pulmonaire obstructive chronique et d'événements aigus et de la mortalité associés à ceux-ci
RU2726228C1 (ru) 2019-07-25 2020-07-10 Федеральное государственное бюджетное образовательное учреждение высшего образования "Амурская государственная медицинская академия" Министерства здравоохранения Российской Федерации Способ отбора больных хронической обструктивной болезнью легких фенотипа "с редкими обострениями" для лечения рофлумиластом

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009018909A2 (fr) 2007-08-08 2009-02-12 Chiesi Farmaceutici S.P.A. Dérivés d'alcools alkyliques de 1-phényl-2-pyridinyle en tant qu'inhibiteurs de la phosphodiestérase
WO2010089107A1 (fr) 2009-02-06 2010-08-12 Chiesi Farmaceutici S.P.A. Esters (1-phényl-2-pyridin-4-yl) éthyliques d'acide benzoïque en tant qu'inhibiteurs de la phosphodiestérase
WO2012016889A2 (fr) 2010-08-03 2012-02-09 Chiesi Farmaceutici S.P.A. Formulation de poudre sèche comprenant un inhibiteur de phosphodiestérase
WO2015059050A1 (fr) 2013-10-22 2015-04-30 Chiesi Farmaceutici S.P.A. Procédé de préparation d'un inhibiteur de la pde4
WO2020081866A1 (fr) * 2018-10-18 2020-04-23 Proterixbio, Inc. Procédés d'évaluation et de traitement ciblés d'une maladie pulmonaire obstructive chronique et d'événements aigus et de la mortalité associés à ceux-ci
RU2726228C1 (ru) 2019-07-25 2020-07-10 Федеральное государственное бюджетное образовательное учреждение высшего образования "Амурская государственная медицинская академия" Министерства здравоохранения Российской Федерации Способ отбора больных хронической обструктивной болезнью легких фенотипа "с редкими обострениями" для лечения рофлумиластом

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"NCBI", Database accession no. NM_000584.4
"UniProtKB", Database accession no. P10145
FACCHINETTI FABRIZIO ET AL: "Tanimilast, A Novel Inhaled Pde4 Inhibitor for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease", FRONTIERS IN PHARMACOLOGY, vol. 12, 23 November 2021 (2021-11-23), XP093029049, DOI: 10.3389/fphar.2021.740803 *
KEATINGS ET AL., COMPARATIVE STUDY AM J RESPIR CRIT CARE MED, vol. 153, no. 2, February 1996 (1996-02-01), pages 530 - 4
SINGH DAVE ET AL: "Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD", RESPIRATORY RESEARCH, vol. 20, no. 1, 9 August 2019 (2019-08-09), XP055875532, Retrieved from the Internet <URL:http://link.springer.com/article/10.1186/s12931-019-1142-7/fulltext.html> DOI: 10.1186/s12931-019-1142-7 *

Similar Documents

Publication Publication Date Title
EP3577465B1 (fr) Proadm en tant que marqueur indiquant un événement indésirable
JP7104689B2 (ja) 有害事象を示すマーカーとしてのヒストンおよび／またはｐｒｏＡＤＭ
JP2008545139A (ja) 急性冠症候群の診断方法及び診断キット
JP7194673B2 (ja) 臓器障害を示すマーカーとしてのヒストンおよび／またはｐｒｏＡＤＭ
Veerappan et al. Mast cells and exosomes in hyperoxia-induced neonatal lung disease
CN115315523A (zh) 使用无细胞核小体水平的分诊方法
JP2023095851A (ja) 抗生物質治療をモニタリングするためのマーカーとしてのｐｃｔおよびｐｒｏ－ａｄｍ
Lepissier et al. Inflammation biomarkers in sputum for clinical trials in cystic fibrosis: current understanding and gaps in knowledge
JP2022521390A (ja) 術後有害事象の診断または予後
WO2024027901A1 (fr) Biomarqueur prédictif de réponse clinique à un inhibiteur de pde4
JP2021508045A (ja) 併存症を有する患者におけるプロカルシトニンに基づく抗生物質療法のガイダンス
US20230160893A1 (en) Pro-adrenomedullin for prognosing disease progression in severe acute respiratory syndrome (sars)
EP3861347B1 (fr) Biomarqueurs pour une polythérapie comprenant du lenvatinib et de l&#39;évérolimus
TW202406543A (zh) Pde4抑制劑臨床反應之預測性生物標記
JP2022512590A (ja) ソラフェニブ化合物を含む療法のためのバイオマーカー
RU2782305C2 (ru) Про-адм в качестве маркера мониторинга терапии для критически больных пациентов
EP3682236A1 (fr) Proadrénomédulline en tant qu&#39;indicateur pour thérapie de remplacement rénal chez des patients gravement malades
RU2775090C2 (ru) Проадреномедуллин в качестве маркера, указывающего на неблагоприятное событие
EP3985396A1 (fr) Méthode de prédiction de pronostic de fibrose pulmonaire idiopathique
CN111065927B (zh) 作为危重患者的治疗监测标记物的pro-adm
EP3928100B1 (fr) Stratification de traitement pour une exacerbation d&#39;inflammation
RU2788885C2 (ru) Прокальцитонин и про-адм в качестве маркеров для мониторинга лечения антибиотиками
TW201625946A (zh) ５-甲氧基色胺酸作為發炎疾病診斷試劑之用途
CN117529664A (zh) 用于预测脓毒症和脓毒性休克的方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22761442

Country of ref document: EP

Kind code of ref document: A1