Gip activity modulators and orthostatic intolerance

A method of reducing heart rate and/or preventing an increase in heart rate, in an individual with orthostatic challenges, such as an individual with orthostatic intolerance, said method comprising one or more steps of administering to said individual a therapeutically effective amount of a GIP activity modulator.

A method of increasing blood pressure and/or preventing a reduction in blood pressure, such as in diastolic and/or in systolic blood pressure, in an individual with orthostatic challenges, such as an individual with orthostatic intolerance, said method comprising one or more steps of administering to said individual a therapeutically effective amount of a GIP activity modulator.

A method of reducing or preventing one or more of syncope, presyncope, dizziness or light-headedness, heart palpitations, problems with thinking, memory and concentration, in an individual with orthostatic challenges, such as an individual with orthostatic intolerance, said method comprising one or more steps of administering to said individual a therapeutically effective amount of a GIP activity modulator.

The method according to any one of the preceding claims, wherein said individual with orthostatic challenges is an individual moving from a supine position to a standing position;

• or an individual moving from a supine position to a sitting position;
• or an individual tilting up their head at least 60 degrees.

The method according to any one of the preceding claims, wherein said individual with orthostatic intolerance or orthostatic hypotension has a sustained reduction of systolic BP of at least 20 mmHg;

• a sustained reduction of diastolic BP of at least 10 mmHg, and/or a sustained decrease in systolic BP to an absolute value 90 mmHg or lower after standing, or after a head-up tilt of at least 60 degrees.

The method according to any one of the preceding claims, wherein said individual with orthostatic intolerance has a heart rate increase of more than 30 bpm, for adults and/or a heart rate increase of more than 40 bpm for adolescents, and/or a heart rate of at least 120 bpm within 10 minutes of standing, or within a head-up tilt of at least 60 degrees.

The method according to any one of the preceding claims, wherein said individual with orthostatic challenges or orthostatic intolerance is a female individual.

The method according to any one of the preceding claims, wherein said orthostatic intolerance is postprandial orthostatic intolerance.

The method according to any one of the preceding claims, wherein said orthostatic intolerance is POTS.

The method according to any one of the preceding claims, wherein said individual is diagnosed with POTS.

The method according to any one of the preceding claims, wherein said orthostatic intolerance is orthostatic hypotension.

The method according to any one of the preceding claims, wherein said orthostatic intolerance is postprandial orthostatic hypotension.

The method according to any one of the preceding claims, wherein said orthostatic intolerance is orthostatic syncope.

The method according to any one of the preceding claims, wherein said orthostatic intolerance is postprandial orthostatic syncope.

method according to any one of the preceding claims, wherein said orthostatic intolerance is orthostatic intolerance with hypermobility spectrum disorders/hypermobile Ehlers-Danlos syndrome (HSD/hEDS).

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP receptor (GIPR) ligand.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIPR activity modulator.

The method according to any one of the preceding claims, wherein said GIP activity modulator or said GIPR activity modulator is a GIP and/or GIPR inhibitor.

The method according to any one of the preceding claims, wherein said GIP activity modulator is an agonist of a GIPR, such as hGIPR.

The method according to any one of the preceding claims, wherein said GIP activity modulator is an antagonist of a GIPR, such as hGIPR.

The method according to any one of the preceding claims, wherein said GIP activity modulator is an antibody.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a small molecule.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a peptide.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP antibody.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIPR antibody.

The method according to any one of the preceding claims, wherein said GIP antibody or GIPR antibody is an antibody or an antigen-binding fragment thereof, such as an anti-GIPR antibody and/or an anti-GIPR antibody fragment or an anti-GIP antibody and/or an anti-GIP antibody fragment.

The method according to any one of the preceding claims, wherein said GIP antibody or GIPR antibody is a monoclonal antibody or an antigen binding fragment thereof.

The method according to any one of the preceding claims, wherein said GIP antibody or GIPR antibody is a polyclonal antibody or an antigen binding fragment thereof.

The method according to any one of the preceding claims, wherein the GIP activity modulator is an agonist or an antagonist of the GIPR and an agonist or an antagonist of one or more targets such as protein targets.

The method according to any one of the preceding claims, wherein the GIP activity modulator is a GIP/GIPR activity modulator and one or more of a GLP-1/GLP-1R modulator, a GLP-2/GLP-2R modulator, a glucagon/glucagon receptor modulator and a Cholecystokinin (CCK) modulator.

The method according to any one of the preceding claims, wherein the GIP activity modulator is an agonist or an antagonist of the GIPR and an agonist or antagonist of one or more of GLP-1R, GLP-2R and glucagon receptor.

The method according to any one of the preceding claims, wherein the GIP activity modulator is a GIPR agonist and an agonist of GLP-1R and/or GLP-2R.

The method according to any one of the preceding claims, wherein the GIP activity modulator is tirzepatide.

The method according to any one of the preceding claims, wherein the GIP activity modulator is capable of modulating the expression of GIP or GIPR.

The method according to any one of the preceding claims, wherein the GIP activity modulator is an antisense oligonucleotide (ASO) or an RNAi oligonucleotide targeting GIP or a GIPR.

The method according to any one of the preceding claims, wherein the GIP activity modulator is capable of modulating GIP secretion and/or release.

The method according to any one of the preceding claims, wherein the GIP activity modulator is capable of inhibiting GIP secretion and/or release.

The method according to any one of the preceding claims, wherein the GIP activity modulator capable of inhibiting GIP secretion is selected from the group consisting of GLP-1, a GLP-1 analogue, a GLP-1R agonist and somatostatin.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue.

The method according to any one of the preceding claims, wherein the GIP activity modulator is a GIP peptide analogue capable of binding to and antagonising a GIPR (GIPR peptide antagonist).

The method according to any one of the preceding claims, wherein the GIP activity modulator is a GIP peptide analogue capable of binding to and promoting activity of a GIPR (GIPR peptide agonist).

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue of sequence hGIP (1-42) as set forth in SEQ ID NO:1, or a functional variant thereof having at least 75% sequence identity to said hGIP (1-42).

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue of sequence hGIP (1-42) as set forth in SEQ ID NO:1, or a functional variant thereof having 1 to 6 individual amino acid substitutions compared to said hGIP (1-42).

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue which is a functional fragment of hGIP (1-42) (SEQ ID NO:1) wherein said functional fragment comprises 20 to 40 amino acids of said GIP (1-42);

• and is capable of binding a GIPR.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue of sequence hGIP (3-30) as set forth in SEQ ID NO:

• 3, or a functional variant thereof having at least 70% sequence identity to said hGIP (3-30) as set forth in SEQ ID NO:
• 3.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue of sequence hGIP (3-30) as set forth in SEQ ID NO:

• 3, or a functional variant thereof having 1 to 8 individual amino acid substitutions compared to said hGIP (3-30) as set forth in SEQ ID NO:
• 3.

The method according to any one of the preceding claims, wherein the GIP activity modulator is a GIP peptide analogue of sequence hGIP (3-30) as set forth in SEQ ID NO:

• 3, or a functional variant thereof capable of binding to a GIPR.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue which is a functional fragment of hGIP (3-30) as set forth in SEQ ID NO:3, wherein said functional fragment comprises 20 to 28 amino acids of said GIP (3-30);

• and is capable of binding a GIPR.

The method according to any one of the preceding claims, wherein the functional fragment comprises 22 to 28 amino acids of GIP (3-30), such as 22 to 26 amino acids, such as 22 to 24 amino acids, such as 24 to 28 amino acids, such as 24 to 26 amino acids, such as 26 to 28 amino acids of GIP (3-30).

The method according to any one of the preceding claims, wherein the GIP activity modulator is a GIP peptide analogue of sequence hGIP (5-30) as set forth in SEQ ID NO:

• 7, or a functional variant thereof capable of binding to a GIPR.

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue which is a functional fragment of hGIP (5-30) as set forth in SEQ ID NO:7, wherein said functional fragment comprises 20 to 26 amino acids of said GIP (5-30);

• and is capable of binding a GIPR.

The method according to any one of the preceding claims, wherein the functional fragment comprises 22 to 26 amino acids of GIP (3-30), such as 22 to 26 amino acids, such as 22 to 24 amino acids, such as 20 to 24 amino acids of GIP (3-30).

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue which is modified by attaching at least one fatty acid molecule at one or more amino acid residues of said peptide, or a functional variant thereof.

The method according to any one of the preceding claims, wherein the GIP activity modulator is a GIP peptide analogue which is C-terminally amidated (—NH2).

The method according to any one of the preceding claims, wherein said GIP activity modulator is a GIP peptide analogue which is C-terminally elongated.

The method according to any one of the preceding claims, wherein at least one of said at least one fatty acid molecule is a straight-chain fatty acid.

The method according to any one of the preceding claims, wherein at least one of said at least one fatty acid molecule is a branched fatty acid.

The method according to any one of the preceding claims, wherein at least one of said at least one fatty acid molecule is a monoacyl fatty acid molecule, comprising one fatty acid.

The method according to any one of the preceding claims, wherein at least one of said at least one fatty acid molecule is a diacyl fatty acid molecule.

The method according to any one of the preceding claims, wherein at least one of said at least one fatty acid molecule is attached to an amino acid residue directly.

The method according to any one of the preceding claims, wherein at least one of said at least one fatty acid molecule is attached to an amino acid residue via a linker.

The method according to any one of the preceding claims, wherein said GIP activity modulator reduces the heart rate, such as the fasting heart rate, of an individual during and/or after an orthostatic challenge.

The method according to any one of the preceding claims, wherein said GIP activity modulator increases the blood pressure of an individual during and/or after an orthostatic challenge.

The method according to any one of the preceding claims, wherein said GIP activity modulator increases the systolic blood pressure and/or the diastolic blood pressure, of an individual during and/or after an orthostatic challenge.

The method according to any one of the preceding claims, wherein said GIP activity modulator reduces the blood flow in superior mesenteric artery, such as reduces the fasting blood flow in superior mesenteric artery of an individual during and/or after an orthostatic challenge.

The method according to any one of the preceding claims, wherein said GIP activity modulator inhibits GIP activity at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as about 100%.

The method according to any one of the preceding claims, wherein said GIP activity modulator inhibits GIPR activity at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as about 100%;

• such as wherein said inhibition of GIPR activity is determined as a decrease in intracellular cAMP.

A method of treating orthostatic intolerance, the method comprising one or more steps of administering a pharmaceutical composition, such as a pharmaceutically acceptable composition, comprising a GIP activity modulator according to any of the preceding claims and a pharmaceutically acceptable carrier, and further comprising one or more steps of administering one or more additional therapeutic agents for use in the treatment of orthostatic intolerance.