# US 2019/0376985 A1 · Adrenomedullin for assessing congestion in a subject with acute heart failure

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- Number: US 2019/0376985 A1
- Document ID: US20190376985A1
- Status: Published application
- Kind: A1
- Application number: 16/315,805
- Filed: 2017-07-07
- Published: 2019-12-12
- Earliest claimed: 2016-07-08
- Assignees: Sphingotec GmbH
- Applicants: Sphingotec GmbH
- Inventors: Andreas BERGMANN; Adriaan VOORS
- Web page: https://patentgrep.com/patent/US20190376985A1

## CPC

- G01N 33/74: involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- C07K 16/22: against growth factors {; against growth regulators}
- G01N 33/6893: {related to diseases not provided for elsewhere}
- G01N 2800/325: Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

A method in a subject for a) diagnosing congestion or assessing or monitoring the extent of congestion or, b) predicting or determining or monitoring need of therapy or intervention or predicting or determining or monitoring the success of a therapy or intervention of congestion or guiding a therapy or intervention or, c) predicting decongestion or residual congestion after therapy or intervention of congestion or, d) assessing decongestion or residual congestion after therapy or intervention of congestion or, e) assessing the decision on hospital discharge of a subject, wherein the subject is having acute heart failure that is either new-onset AHF or acute decompensated HF or acute decompensated chronic HF or wherein the subject is having chronic heart failure with worsening signs/symptoms of chronic heart failure and wherein Pro-Adrenomedullin or fragments thereof of at least 5 amino acids is an early surrogate marker for congestion.

## Claims

### Claim at position 1

-16. (canceled)

### Claim 17

A method for
a) diagnosing congestion or assessing or monitoring the extent of congestion in a subject or,
b) predicting or determining or monitoring need of therapy or intervention of congestion or predicting or determining or monitoring the success of a therapy or intervention of congestion or guiding a therapy or intervention of congestion in a subject or,
c) predicting decongestion or residual congestion after therapy or intervention of congestion in a subject or,
d) assessing decongestion or residual congestion after therapy or intervention of congestion in a subject or,
e) assessing the decision on hospital discharge of a subject,
wherein said subject is subject having acute heart failure that is either new-onset AHF or acute decompensated HF or acute decompensated chronic HF or wherein said subject is a subject having chronic heart failure with worsening signs/symptoms of chronic heart failure and
wherein Pro-Adrenomedullin or fragments thereof of at least 5 amino acids is used as an early surrogate marker for congestion and
wherein said Pro-Adrenomedullin or fragment is selected from the group comprising Pro-Adrenomedullin according to SEQ ID No. 1 or PAMP according to SEQ ID No.: 2 or MR-proADM according to SEQ ID No.: 3 or mature ADM-NH2 according to SEQ ID No.: 4 or ADM-Gly according to SEQ ID No.: 5 or CT-proADM according to SEQ ID No.: 6.

### Claim 18 (depends on 17)

A method of claim 17 comprising the steps:
Determining the level of Pro-Adrenomedullin or fragments thereof of at least 5 amino acids in a bodily fluid obtained from said subject; and
a) Correlating said level of Pro-Adrenomedullin or fragments thereof with the extent of congestion in said subject or diagnosing congestion, wherein an elevated level above a certain threshold is indicative of congestion or the extent of congestion or,
b) Correlating said level of Pro-Adrenomedullin or fragments thereof with success of a therapy or intervention of congestion in said subject, wherein a level below a certain threshold is predictive for a success of therapy or intervention of congestion, and wherein a level above a certain threshold is indicative for need of therapy or intervention of congestion or,
c) Correlating said level of Pro-Adrenomedullin or fragments thereof with a prediction of decongestion or residual congestion after therapy or intervention of congestion, wherein an elevated level above a certain threshold predicts residual congestion after therapy or intervention of congestion whereas a level below a certain threshold predicts decongestion after therapy or intervention of congestion, or
d) Correlating said level of Pro-Adrenomedullin or fragments thereof with decongestion or residual congestion after therapy or intervention of congestion, wherein an elevated level above a certain threshold indicates residual congestion after therapy or intervention of congestion whereas a level below a certain threshold indicates decongestion after therapy or intervention of congestion, or
e) Correlating said level of Pro-Adrenomedullin or fragments thereof with the assessment of the decision on hospital discharge, wherein an elevated level above a certain threshold means that the subject shall not be discharged and wherein a level below a certain threshold means that the subject may be discharged,
wherein said Pro-Adrenomedullin or fragment is selected from the group comprising Pro-Adrenomedullin according to SEQ ID No. 1 or PAMP according to SEQ ID No.: 2 or MR-proADM according to SEQ ID No.: 3 or mature ADM-NH2 according to SEQ ID No.: 4 or ADM-Gly according to SEQ ID No.: 5 or CT-proADM according to SEQ ID No.: 6.

### Claim 19 (depends on 17)

A method according to claim 17 comprising the steps:
Determining the level of immunoreactive analyte by using at least one binder that binds to a region within the amino acid sequence of Pro-Adrenomedullin or fragments thereof of at least 5 amino acids in a bodily fluid obtained from said subject; and
a) Correlating said level of immunoreactive analyte with the extent of congestion in said subject or diagnosing congestion, wherein an elevated level above a certain threshold is indicative of congestion or the extent of congestion or,
b) Correlating said level of immunoreactive analyte with success of a therapy or intervention of congestion in said subject, wherein a level below a certain threshold is predictive for a success of therapy or intervention of congestion, and wherein a level above a certain threshold is indicative for need of therapy or intervention of congestion or
c) Correlating said level of immunoreactive analyte with a prediction of decongestion or residual congestion after therapy or intervention of congestion, wherein an elevated level above a certain threshold predicts residual congestion after therapy or intervention of congestion whereas a level below a certain threshold predicts decongestion after therapy or
d) Correlating said level of immunoreactive analyte with decongestion or residual congestion after therapy or intervention of congestion, wherein an elevated level above a certain threshold indicates residual congestion after therapy or intervention of congestion whereas a level below a certain threshold indicates decongestion after therapy or intervention of congestion, or
e) Correlating said level of immunoreactive analyte with the assessment of the decision on hospital discharge wherein an elevated level above a certain threshold means that the subject shall not be discharged and wherein a level below a certain threshold means that the subject may be discharged,
wherein said Pro-Adrenomedullin or fragment is selected from the group comprising Pro-Adrenomedullin according to SEQ ID No. 1 or PAMP according to SEQ ID No.: 2 or MR-proADM according to SEQ ID No.: 3 or mature ADM-NH2 according to SEQ ID No.: 4 or ADM-Gly according to SEQ ID No.: 5 or CT-proADM according to SEQ ID No.: 6.

### Claim 20 (depends on 17)

A method according to claim 17, wherein said extent of congestion is expressed as congestion score, in particular a clinical congestion score.

### Claim 21 (depends on 17)

A method of claim 17, wherein said subject is stratified
a) into groups of grades of congestion or,
b) into non-responder and/or responder, and/or bad responder to therapy or intervention of congestion or,
c) into a group with decongestion or into a group of residual congestion after therapy or intervention of congestion.

### Claim 22 (depends on 17)

A method according to claim 17 wherein said fragment may be selected from MR-proADM according to SEQ ID No.: 3 or mature ADM-NH2 according to SEQ ID No.: 4.

### Claim 23 (depends on 17)

A method according to claim 17, wherein the level of Pro-Adrenomedullin or fragments thereof of at least 5 amino acids is determined by using a binder to Pro-Adrenomedullin or fragments thereof of at least 5 amino acids.

### Claim 24 (depends on 22)

A method according to claim 22, wherein the binder is selected from the group comprising an antibody, an antibody fragment or a non-Ig-Scaffold binding to Pro-Adrenomedullin or fragments thereof of at least 5 amino acids.

### Claim 25 (depends on 17)

A method according to claim 17, wherein said threshold is within a threshold range that is a threshold range for plasma mature ADM-NH2 according to SEQ ID No.: 4 between 50 and 100 pg/ml and for plasma MR-proADM between 0.5 and 1.5 nmol/L, and for plasma CT-proADM between 85 and 350 pmol/L.

### Claim 26 (depends on 17)

A method according to claim 17, wherein said determination of Pro-Adrenomedullin or fragments thereof of at least 5 amino acids is performed more than once in one patient.

### Claim 27 (depends on 17)

A method according to claim 17, wherein the sample is taken at admission to a hospital or discharge of hospital.

### Claim 28 (depends on 17)

A method according to claim 17, wherein said monitoring is performed in order to evaluate the response of said subject to preventive and/or therapeutic measures taken.

### Claim 29 (depends on 17)

A method according to claim 17 in order to stratify said subjects into congestion grade groups.

### Claim 30 (depends on 17)

A method according to claim 17 wherein said level of Pro-Adrenomedullin or fragments thereof or said level of immunoreactive analyte is correlated with a risk of death or an adverse event in subject having acute heart failure, wherein an elevated level above a certain threshold is predictive for an enhanced risk of death or adverse events.

### Claim 31 (depends on 17)

A method according to claim 17 wherein said level of Pro-Adrenomedullin or fragments thereof or said level of immunoreactive analyte is used for guidance of therapy or intervention of congestion, wherein therapy or intervention is indicated if said level of Pro-Adrenomedullin or fragments is above a certain threshold and wherein-, therapy or intervention of congestion is not indicated if said level of Pro-Adrenomedullin or fragments is below a certain threshold.

### Claim 32 (depends on 17)

A method according to claim 17 wherein said level of Pro-Adrenomedullin or fragments thereof or said level of immunoreactive analyte is used for determining the need of therapy or intervention of congestion.

### Claim 33 (depends on 17)

A method according to claim 17 wherein said intervention or therapy is selected from the group comprising administration of diuretics, administration of inotropes, administration of vasodilators, ultrafiltration.