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WO2024068848A1 - Methods for treating obesity - Google Patents

Methods for treating obesity Download PDF

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Publication number
WO2024068848A1
WO2024068848A1 PCT/EP2023/076908 EP2023076908W WO2024068848A1 WO 2024068848 A1 WO2024068848 A1 WO 2024068848A1 EP 2023076908 W EP2023076908 W EP 2023076908W WO 2024068848 A1 WO2024068848 A1 WO 2024068848A1
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subject
agonist
glp
peg3
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French (fr)
Inventor
Jolanta SKARBALIENE
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Zealand Pharma AS
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Zealand Pharma AS
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Priority to EP23783327.2A priority Critical patent/EP4593864A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the invention features combination therapies for promoting weight loss.
  • Background of the Invention Obesity is a chronic disease associated with many complications. Weight loss of 5–15% can improve many obesity-related complications. Despite the benefits of weight reduction, there are many challenges in losing weight and maintaining long-term weight loss. Achieving and maintaining weight loss is challenging for many individuals. There is therefore a need for some patients to take medications to help them lose weight and prevent weight regain.
  • GLP-1RA GLP-1 receptor agonist
  • the present invention features methods for treating obesity and promoting weight loss by administering to a subject a combination of a GLP-1 agonist and a GIP agonist.
  • the invention features a method of increasing weight loss in a subject in need thereof, the method including: (i) providing a subject undergoing treatment with a GLP- 1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant, and (ii) following step (i), administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject.
  • the invention features a method of increasing weight loss in a subject in need thereof, the method including: (i) providing a subject who fails to respond to treatment with a GLP-1 agonist, and (ii) administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject.
  • the invention features a method of increasing weight loss in a subject in need thereof, the method including: (i) providing a subject undergoing treatment with a GLP- 1 agonist for a period of at least 1 month (e.g., at least one month, two months, three months, four months, five months or six months), and (ii) following step (i), administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject.
  • a GLP-1 agonist e.g., at least one month, two months, three months, four months, five months or six months
  • the invention features a method of maintaining weight loss in a subject in need thereof, the method including: (i) providing a subject undergoing treatment with a GLP- 1 agonist, wherein the subject has experience weight loss, and (ii) following step (i), administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject.
  • the subject s weight loss is maintained for a period of at least 1 month (e.g., at least one month, two months, three months, four months, five months or six months).
  • the subject has a BMI of >30 kg/m2, >35 kg/m2, >40 kg/m2, >45 kg/m2, or >50 kg/m2.
  • the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide, and taspoglutide.
  • the GIP agonist is any GIP agonist described herein.
  • the GIP agonist is H-Y-Aib- EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)- AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
  • the subject is not receiving any other weight loss drug other than the GLP-1 agonist.
  • the term “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.
  • the terms “patient,” “subject,” and “individual” may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats).
  • the term “agonist” as employed in the context of the invention refers to a substance (ligand) that activates signaling by the receptor type in question.
  • sequences disclosed herein are sequences incorporating an “H-“ moiety at the amino terminus (N-terminus) of the sequence, and either an “-OH” moiety or an “–NH 2 ” moiety at the carboxy terminus (C-terminus) of the sequence.
  • R 2 OH or NH 2 ) indicates a carboxy (COOH) group or an amido (CONH 2 ) group at the C-terminus, respectively.
  • pharmaceutically acceptable salt refers to a salt of the compound. Salts include pharmaceutically acceptable salts, such as, e.g., acid addition salts and basic salts. Examples of an acid addition salt includes hydrochloride salts. Examples of basic salts include salts where the cation is selected from, e.g., an alkali metal. Other examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences” ,17th edition. Ed. Alfonso R.
  • Treatment is an approach for obtaining beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment may also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Treatment is an intervention performed with the intention of preventing the development or altering the pathology of a disorder. Accordingly, “treatment” refers to both therapeutic treatment and prophylactic or preventative measures in certain embodiments. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. By treatment is meant inhibiting or reducing an increase in pathology or symptoms (e.g. weight gain) when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant condition.
  • plateau refers to patients undergoing GLP-1 monotherapy for a period of time during which the subject’s weight is unchanged, or there is weight gain in the subject.
  • a subject experiencing a plateau can be identified when their weight loss is less than 1% of their body weight over a period of at least two weeks, three weeks, one month, or two months.
  • GLP-1 treatment resistant refers to patients undergoing GLP-1 monotherapy for a period of time during which the subject’s weight is unchanged, or there is weight gain in the subject.
  • a subject experiencing such a resistance can be identified as any one or more of the following weight characteristics of the subject over a period of any of: at least about one week, or at least about two weeks, or at least about three weeks, or at least about one month, or at least about two months, about one week, or about two weeks, or about three weeks, or about one month, or about two months: when their weight loss is less than about 3%, or when their weight loss is less than about 2%, or when their weight loss is less than about 1% of their body weight, or when there is a substantially constant body weight, or when there is an increase in body weight of about at least 1%.
  • patients that experience a plateau may be a sub- group of patients who are GLP-1 treatment resistant.
  • the term “fails to respond to treatment with a GLP-1 agonist” refers to patients undergoing GLP-1 monotherapy for a period of at least 1 month or at least 2 months without experiencing a loss of at least 1% of their body weight.
  • the effect of treatment according to the methods of the present invention may be superior to that obtained GLP-1 agonist monotherapy or GIP agonist monotherapy in comparable subjects.
  • Figure 1 is a graph showing that the combination therapy of semaglutide + compound 41, achieved a significant, sustained and greater body weight reduction in obese mice (DIO mice) compared to vehicle- and each monotherapy group (-24.5% ⁇ 2.4 combination therapy from day 14; -24.1% ⁇ 1.3 combination therapy from day 0; -0.8% ⁇ 0.9 compound 41 from day 0; 2.0% ⁇ 0.8 compound 41 from day 14 days; -13.7% ⁇ 2.3 semaglutide; 3.1% ⁇ 0.8, vehicle; relative to initial body weights).
  • the effects on body weight loss in combination groups of semaglutide + compound 41 were similar at the end of the study irrespective of the pretreatment with semaglutide. The results were obtained as described in Example 1.
  • the present invention features methods for treating obesity and promoting weight loss by administering to a subject a combination of an GLP-1 agonist and a GIP agonist.
  • the methods of the invention can be useful for promoting weight loss in (i) subjects who are refractory to GLP-1 monotherapy, and (ii) subjects experiencing a plateau in weight loss in response to ongoing GLP-1 monotherapy and/or subjects that are or become GLP-1 treatment resistant.
  • GLP-1 receptor agonists The combination therapies of the present invention may be particular effective in improving glycaemic control and reducing body weight.
  • Glucagon-like peptide-1 receptor agonists also known as GLP-1 receptor agonists or incretin mimetics are agonists of the GLP-1 receptor.
  • GLP-1 agonists that can be used in the methods of the invention include but are not limited to exenatide (BYETTA®/BYDUREON®), liraglutide (VICTOZA®), semaglutide, lixisenatide (LYXUMIA®), dulaglutide (TRULICITY®), albiglutide (TANZENUM®) and Taspoglutide.
  • the GLP-1 agonist used in the combination therapy of the invention can be a peptide having the sequence of any one of exenatide, liraglutide, semaglutide, lixisenatide, dulaglutide, albiglutide, or taspoglutide, or a pharmaceutically acceptable salt thereof.
  • the GLP-1 agonist may be any GLP-1 agonist described herein or a pharmaceutically acceptable salt thereof.
  • Exenatide is a synthetic version of exendin-4, a peptide found in the venom of the Gila monster, described in Fig.2 of WO 99/07404 and has the formula: Hy-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPP-NH 2 (SEQ ID NO: 89).
  • Liraglutide is a derivative of GLP-1 described in Example 37 of US patent no.6,268,343 and has the formula: Hy-HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG-OH (SEQ ID NO: 90), wherein the side- chain amino group of the lysine at position 20 is linked to the lipohilic moiety hexadecanoyl (i.e. palmitoyl) via a ⁇ -Glu linker.
  • Semaglutide is a derivative of GLP-1 described in Example 4 of WO 2006/097537 and has the formula: Hy-HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRG-OH (SEQ ID NO: 91), wherein X at position 2 is 2-aminoisobutyric acid (Aib) and the side-chain amino group of the lysine at position 20 is linked to the lipohilic moiety [2-(2-[2-(2-[2-[2-[2-[2-[2-[2-[4-(17- Carboxyheptadecanoylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl].
  • Dulaglutide is a fusion protein of a GLP-1 variant and an IgG4 Fc region described in WO 2005/000892 (compound named “Gly 8 -Glu 22 -Gly 36 -GLP-1(7-37)-L- IgG4(S228P,F234A,L235A)”) and has the sequence: HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSAESKYGPPCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT VDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLG
  • Lixisenatide is a derivative of exendin-4, presented as Compound 2 in WO 01/04156 and has the formula: Hy-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH 2 (SEQ ID NO: 93).
  • Albiglutide is Construct 3438 in WO 2005/003296 and has the formula: HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRHGEGTFTSDVSSYLEGQAAKEFIAWLVKGR DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAEN CDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVD VMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLD ELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTE CCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLA ADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETT
  • Albiglutide is a fusion protein of two copies of a derivative of GLP-1 fused in series, fused to human serum albumin at their C-terminus.
  • Taspoglutide is a GLP-1 variant described in Example 1 of WO 2000/34331 and has the formula: Hy-HXEGTFTSDVSSYLEGQAAKEFIAWLVKXR-NH 2 (SEQ ID NO: 95), wherein X at positions 2 and 29 is 2-aminoisobutyric acid (Aib).
  • Route of administration of GLP-1 agonist The administration to a subject of the GLP-1 agonist may be by any mode of administration common or standard in the art, e.g.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray.
  • injection including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection
  • infusion pump such as subcutaneous infusion pump
  • nasal such as by nasal spray
  • pulmonary spray such as by nasal spray
  • the GLP-1 agonist may be administered by subcutaneous injection.
  • GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of up to about 50 mg, such as up to about 40 mg, up to about 30 mg, up to about 20 mg or up to about 10 mg.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of from of from about 0.25 mg to about 100 mg, such as from about 0.25 mg to about 90 mg, such as from about 0.25 mg to about 80 mg, such as from about 0.25 mg to about 70 mg, such as from about 0.25 mg to about 60 mg,about 0.25 mg to about 50 mg, such as from about 0.25 mg to about 40 mg, such as from about 0.25 mg to about 30 mg, from about 0.25 mg to about 20 mg, from about 0.25 mg to about 14 mg or from about 0.25 mg to about 10 mg.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of from about 1 mg to about 50 mg, such as from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 14 mg or from about 1 mg to about 10 mg.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of about 0.25 mg, about 0.5 mg, about 0.6 mg, about 1 mg, about 1.2 mg, about 1.5 mg, about 1.8 mg, about 2 mg, about 3 mg, about 4.5 mg, about 5 mg, about 7 mg, about 10 mg, about 14 mg, about 20 mg, about 30 mg or about 50 mg.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of up to about 10 mg/kg body weight of the subject, such as up to about 5 mg/kg body weight or up to about 1 mg/kg body weight.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of from about 0.01 to about 10 mg/kg body weight of the subject, such as from about 0.01 to about 5 mg/kg body weight, from about 0.01 to about 1 mg/kg body weight, from about 0.05 to about 10 mg/kg body weight, from about 0.05 to about 5 mg/kg body weight, from about 0.05 to about 1 mg/kg body weight or from about 0.05 to about 0.5 mg/kg body weight.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered to the subject at least once, twice, or three times daily.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered to the subject once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days or more such as every 28 days or every month.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered to the subject once a day (i.e. daily or once daily).
  • the GLP-1 agonist of step (i) and step (ii) may be administered to the subject once a week (i.e weekly or once weekly).
  • Exenatide is preferably administered by subcutaneous injection twice daily, at least 6 hours apart and each time before a main meal. Initially, 5 mg are administered twice daily for at least 1 month, then the dose may be increased to 10 mg twice daily if necessary.
  • exenatide may be administered by subcutaneous injection once weekly at a dose of 2 mg.
  • Liraglutide is preferably administered by subcutaneous injection once daily. Initially, 0.6 mg are administered once daily for at least 1 week, then the dose is increased to 1.2 mg once daily for at least 1 week, and then the dose may be increased to 1.8 mg once daily if necessary.
  • Semaglutide is preferably administered by subcutaneous injection once weekly. Semaglutide may be administered subuctaneously at a dose of up to about 7.2 mg. In a preferred embodiment, 0.25 mg are initially administered once weekly for at least 4 weeks, then the dose is increased to 0.5 mg once weekly for at least 4 weeks, then the dose is increased to 1 mg once weekly for at least 4 weeks, then the dose is increased to 1.7 mg once weekly for at least 4 weeks, and then the dose is increased to 2.4 mg once weekly; the dose is maintained at 2.4 mg for the course of the treatment. Alternatively, semaglutide may be administered orally once daily on an empty stomach.
  • Semaglutide may be administered orally once daily at a dose of up to about 50 mg, such as about 50 mg, about 40 mg, about 30 mg, about 20 mg or about 10 mg. In a preferred embodiment, 3 mg are initially administered once daily for at least 1 month, then the dose is increased to 7 mg once daily for at least 1 month, and then the dose may be increased to 14 mg once daily if necessary.
  • Dulaglutide is preferably administered by subcutaneous injection once weekly at a dose of 0.75 mg.
  • dulaglutide is preferably administered initially at 1.5 mg once weekly for at least 4 weeks, then the dose is increased to 3 mg once weekly for at least 4 weeks, and then the dose may be increased to 4.5 mg once weekly if necessary.
  • Lixisenatide is preferably administered by subcutaneous injection once daily, taken within 1 hour before a meal. Initially, 10 mg are administered once daily for 2 weeks, then the dose is increased to 20 mg once daily.
  • Albiglutide is preferably administered by subcutaneous injection once weekly at a dose of 30 mg. The dose may be increased to 50 mg if the glycaemic response is inadequate.
  • Taspoglutide is preferably administered by subcutaneous injection once weekly.
  • GIP receptor agonists The combination therapies of the invention include a GIP analogue (also referred to as a “GIP agonist” or a “GIP receptor agonist” herein).
  • GIP analogue also referred to as a “GIP agonist” or a “GIP receptor agonist” herein.
  • the GIP agonist may be any GIP agonist described herein or a pharmaceutically acceptable salt thereof.
  • the combination therapies of the invention can include a GIP analogue represented by the general Formula I: R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y1-Y2-R 2 (I) (SEQ ID NO: 42) wherein R 1 is H-, Ac or pGlu pyroglutamic acid (pGlu; (S)-(-)-2-pyrrolidone-5-carboxylic acid), C 1-4 alkyl, acetyl, formyl, benzoyl and trifluoroacetyl, X2 is Aib, Ala, D-Ala, Gly, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c; X10 is Tyr,
  • a GIP analogue according to Formula I may be any of the following: R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Lys-Gly-Y2-R 2 (SEQ ID NO: 115); R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-Y2-R 2 (SEQ ID NO:
  • R 1 is H-, Ac or pGlu.
  • Combinations of residues which may be present at some of the variable positions of Formula I include: Aib2, Asp15, Lys20; Aib2, Asp15, Arg20; Aib2, Asp15, Arg20, Ile23; Aib2, Ile12, Asp15, Arg20, Ile23, Glu24; Ile12, Asp15, Ile23; Ile12, Asp15, Ile23, Glu24; Ile12, Asp15, Ala21, Ile23; Aib2, Ala21, Ile23, Glu24; Aib2, Asp15, Ile23; Aib2, Asp15, Arg20, Ile23, Gln29; Aib2, Asp15, Arg20, Gly29; Aib2, Asp15, Ile17, Arg20, Gly29; Aib2, Asp15, Ile17, Lys20, Gly29; DAla2, Asp
  • the combination therapies of the invention can include a GIP analogue represented by the general Formula II: R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y1-Y2-R 2 (II) (SEQ ID NO: 48) wherein R 1 is H-, Ac or pGlu; X2 is Aib, Ala, D-Ala or Gly; X12 is Lys, ⁇ or Ile; X15 is Asp or Glu; X16 is Ser, Glu, Lys or ⁇ ; X17 is Ile, Lys, Gln, Arg X18 is His, Arg or Ala; X19 is Gln or Ala; X20 is Gln, Lys, Al
  • a GIP analogue according to Formula II may be any of the following: R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Lys-Gly-Y2-R 2 (SEQ ID NO: 116); R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-Y2-R 2 (SEQ
  • Combinations of residues which may be present at some of the variable positions of Formula II include: Aib2, Lys12, Asp15, Lys20; Aib2, Lys12, Asp15, Arg20; Aib2, Asp15, Arg20; Aib2, Ile12, Asp15, Arg20, Glu24; Ile12, Asp15, Ile23; Ile12, Asp15, Glu24; Ile12, Asp15, Ala21; Aib2, Lys12, Ala21, Glu24; Aib2, Lys12, Asp15; Aib2, Lys,12, Asp15, Arg20, Gln29; Aib2, Lys, 12, Asp15, Arg20, Gly29; Aib2, Lys12, Asp15, Ile17, Arg20, Gly29; Aib2, Asp15, Ile17, Lys20, Gly29; DAla2, Asp15; DAla2, Asp15, Ala28;
  • the combination therapies of the invention can include a GIP analogue represented by the general Formula III: R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Y1-Y2-R 2 (III) (SEQ ID NO: 50) wherein R 1 is H-, Ac or pGlu; X15 is Asp or Glu; X16 is Lys or ⁇ ; X17 is Ile or ⁇ ; X18 is His or Ala; X19 is Gln or Ala; X20 is Gln, Lys or Arg; X21 is Ala, Asp or Glu; X24 is Asn or Glu; X25 is Tyr or Trp; X28 is Ala, Ser or Arg;
  • a GIP analogue according to Formula III may be any of the following: R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Lys-Gly-Y2-R 2 (SEQ ID NO: 117); R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro- Ser-Y2-R 2 (S
  • Combinations of residues which may be present at some of the variable positions of Formula III include: Asp15, Lys20; Asp15, Arg20; Asp15, Arg20, Glu24; Asp15, Lys 16; Asp15, Lys 16, Glu24; Asp15, ⁇ 16, Ala21; Ala21, Glu24; Asp15, Arg20, Gln29; Asp15, Arg20, Gly29; Asp15, Ile17, Arg20, Gly29; Asp15, Ile17, Lys20, Gly29; Asp15, Ala28; Asp15, Ile17, Lys20, Ala28; Asp15, Ile23, Glu24; Asp15, ⁇ 17, Lys20; Asp15, ⁇ 17, Arg20; Asp15, ⁇ 17, Arg20 Asp15, ⁇ 17, Arg20 Asp15, ⁇ 17, Arg20, Glu24; Asp15, Lys16, ⁇ 17;
  • the GIP-analogue useful in the combination therapies of the invention may have the formula R1-Z-R2 where R1 and R2 are as defined above and Z has the sequence: Y-Aib-EGTFISDYSIELDK ⁇ HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 51); Y-Aib-EGTFISDYSIELD ⁇ IHQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 52); Y-Aib-EGTFISDYSIELEK ⁇ HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 53); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS ⁇ (SEQ ID NO: 54); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS ⁇ (SEQ ID NO: 96); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSG
  • the GIP-analogue useful in the combination therapies of the invention may have the formula R1-Z-R2 where R1 and R2 are as defined above and Z has the sequence Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 1); Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-isoGlu)- IHQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 2); Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 3); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-P
  • the GIP-analogue used in the combination therapy may be any of the following, or a pharmaceutically acceptable salt thereof: H-Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS-NH 2 (Compound 1) (SEQ ID NO: 1); H-Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-isoGlu)- IHQQDFVNWLLAQGPSSGAPPPS-NH 2 (Compound 2) (SEQ ID NO: 2); H-Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS-NH 2 (Compound 3) (SEQ ID NO: 3); H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K([19-carboxy- non
  • compound 41 for use in the combination therapies of the invention, compound 41, or a salt thereof, is the preferred GIP agonist.
  • Compound 41 is also described in WO 2016/066744 as compound 41.
  • Route of administration of GIP agonist The administration to a subject of the GIP agonist may be by any mode of administration common or standard in the art, e.g. oral, intravenous, intramuscular, subcutaneous, sublingual, intranasal, intradermal, suppository routes or implanting.
  • the GIP agonist may be administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray.
  • injection including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection
  • infusion pump such as subcutaneous infusion pump
  • oral sublingual, rectal, vaginal, parenteral
  • topical such as by dermal
  • dermal such as by transdermal patch
  • nasal such as by nasal spray
  • pulmonary spray pulmonary spray.
  • the GIP agonist may be administered by injection.
  • the GIP agonist may be administered by subcutaneous injection.
  • the GIP agonist may be administered at a dose of up to about 100 mg, such as up to about 90 mg, up to about 80 mg, up to about 70 mg, up to about 60 mg, up to about 50 mg, up to about 40 mg, up to about 30 mg, up to about 20 mg, up to about 15 mg, up to about 12.5 mg, up to about 10 mg, up to about 7.5 mg, up to about 5 mg, up to about 2.5 mg, up to about 2 mg, up to about 1 mg, up to about 0.5 mg or up to about 0.1 mg.
  • up to about 100 mg such as up to about 90 mg, up to about 80 mg, up to about 70 mg, up to about 60 mg, up to about 50 mg, up to about 40 mg, up to about 30 mg, up to about 20 mg, up to about 15 mg, up to about 12.5 mg, up to about 10 mg, up to about 7.5 mg, up to about 5 mg, up to about 2.5 mg, up to about 2 mg, up to about 1 mg, up to about 0.5 mg or up to about 0.1 mg.
  • the GIP agonist may be administered at a dose of from about 0.1 mg to about 100 mg, from about 0.5 mg to about 100 mg, from about 1 mg to about 100 mg, from about 2.5 mg to about 100 mg, from about 5 mg to about 100 mg, from about 7.5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 12.5 mg to about 100 mg, from about 15 mg to about 100 mg, from about 20 mg to about 100 mg, from about 30 mg to about 100 mg, from about 40 mg to about 100 mg, from about 50 mg to about 100 mg, from about 60 mg to about 100 mg, from about 70 mg to about 100 mg, from about 80 mg to about 100 mg, or from about 90 mg to about 100 mg.
  • the GIP agonist may be administered at a dose of from about 0.1 mg to about 80 mg, from about 0.5 mg to about 80 mg, from about 1 mg to about 80 mg, from about 2.5 mg to about 80 mg, from about 5 mg to about 80 mg, from about 7.5 mg to about 80 mg, from about 10 mg to about 80 mg, from about 12.5 mg to about 80 mg, from about 15 mg to about 80 mg, from about 20 mg to about 80 mg, from about 30 mg to about 80 mg, from about 40 mg to about 80 mg, from about 50 mg to about 80 mg, from about 60 mg to about 80 mg, or from about 70 mg to about 80 mg.
  • the GIP agonist may be administered at a dose of from about 0.1 mg to about 50 mg, from about 0.5 mg to about 50 mg, from about 1 mg to about 50 mg, from about 2.5 mg to about 50 mg, from about 5 mg to about 50 mg, from about 7.5 mg to about 50 mg, from about 10 mg to about 50 mg, from about 12.5 mg to about 50 mg, from about 15 mg to about 50 mg, from about 20 mg to about 50 mg, from about 30 mg to about 50 mg, or from about 40 mg to about 50 mg.
  • the GIP agonist may be administered at a dose of from about 0.1 mg to about 15 mg, from about 0.5 mg to about 15 mg, from about 1 mg to about 15 mg, from about 2.5 mg to about 15 mg, from about 5 mg to about 15 mg, from about 7.5 mg to about 15 mg, from about 10 mg to about 15 mg, or from about 12.5 mg to about 15 mg.
  • the GIP agonist may be administered at a dose of from about 0.5 mg to about 10 mg, about 1 mg to about 10 mg, from about 2.5 mg to about 10 mg, from about 5 mg to about 10 mg, or from about 7.5 mg to about 10 mg.
  • the GIP agonist may be administered at a dose of from about 1 mg to about 5 mg, or from about 2.5 mg to about 5 mg.
  • the GIP agonist may be administered at a dose of about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 15 mg, about 12.5 mg, about 10 mg, about 7.5 mg, about 5 mg, about 2.5 mg, or about 1 mg.
  • the GIP agonist may be administered to the subject at a dose of up to about 500 nmol/kg body weight, such as up to about 400 nmol/kg body weight, or up to about 300 nmol/kg body weight.
  • the GIP agonist may be administered to the subject at a dose of from about 10 to about 500 nmol/kg body weight, such as from about 50 to about 500 nmol/kg body weight, from about 100 to about 500 nmol/kg body weight, or from about 200 to about 500 nmol/kg body weight.
  • the GIP agonist may be administered to the subject at a dose of from about 10 to about 400 nmol/kg body weight, such as from about 50 to about 400 nmol/kg body weight, from about 100 to about 400 nmol/kg body weigh, or from about 200 to about 400 nmol/kg body weight.
  • the GIP agonist may be administered to the subject at a dose of from about 250 to about 350 nmol/kg body weight.
  • the GIP agonist may be administered at a dose of about 300 nmol/kg body weight. Timing of administration of GIP agonist
  • the GIP agonist may be administered to the subject at least once, twice, or three times daily.
  • the GIP agonist may be administered to the subject once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days or more such as every 28 days or every month.
  • the GLP-1 agonist of step (i) and/or step (ii) may be administered to the subject once a day (i.e. daily or once daily).
  • the GLP-1 agonist of step (i) and step (ii) may be administered to the subject once a week (i.e weekly or once weekly).
  • the GIP agonist may be administered at the same time or at a different time as the administration of the GLP-1 agonist of step (ii).
  • Lipophilic groups The GIP analogue used in the methods of the invention can comprise a residue i.e. a residue selected from Lys, Arg, Orn and Cys in which the side chain is conjugated to a lipophilic substituent. Without wishing to be bound by any particular theory, it is thought that the substituent binds plasma proteins (e.g.
  • the substituent is conjugated to the functional group at the distal end of the side chain from the alpha-carbon.
  • the normal ability of the Lys, Arg, Orn or Cys side chain to participate in interactions mediated by that functional group may therefore be reduced or completely eliminated by the presence of the substituent.
  • the overall properties of the compound may be relatively insensitive to changes in the actual amino acid present as residue Consequently, it is believed that any of the residues Lys, Arg, Orn and Cys may be present at any position where ⁇ is permitted. However, in certain embodiments, it may be advantageous that the amino acid component of ⁇ is Lys.
  • ⁇ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula –Z 1 or –Z 2 –Z 1 .
  • –Z 1 is a fatty chain having at a terminus a connection –X– to ⁇ or to Z 2 ; wherein —X– is a bond, –CO–, –SO–, or –SO 2 –; and, optionally, Z 1 has a polar group at the end of the chain distal from connection –X–; said polar group comprising a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; and wherein –Z 2 –, if present, is a spacer of formula: connecting wherein: each Y is independently –NH, –NR, –S or –O, where R is alkyl, a protecting group or forms a linkage to another part of the spacer Z 2 ; each X is independently a bond, CO–, SO–, or SO 2 –; with the proviso that when Y is –S, the X to which it is bound is a bond
  • the group Z 1 Z 1 is a fatty chain having a connection to ⁇ or to Z 2 , referred to herein as –X–.
  • –X— may be, for example, a bond, acyl (–CO–), sulfinyl (–SO–), or sulfonyl (–SO 2 –).
  • Z 1 is bound directly to ⁇ , that is, when Z 2 is not present, preferably –X– is acyl (–CO–), sulfinyl (–SO–), or sulfonyl (–SO 2 –).
  • –X– is acyl (–CO–).
  • Z 1 may further have a polar group, said polar group being located at the end of the chain distal from the connection –X–.
  • the connection is located at the ⁇ -position with respect to the polar group.
  • the polar group may be bound directly to the terminus of the fatty chain, or may be bound via a linker.
  • the polar group is an acidic or weakly acid group, for example a carboxylic acid or a carboxylic acid bioisostere, a phosphonate, or a sulfonate.
  • the polar group may have a pK a of between –2 and 12 in water, more preferably between 1 and 7, more preferably between 3 and 6.
  • the polar group may comprise a carboxylic acid (– COOH) or a carboxylic acid bioisostere, a phosphonic acid (–P(O)(OH) 2 ), or a sulfonic acid (–SO 2 OH) group.
  • the polar group if present, comprises a carboxylic acid or carboxylic acid bioisostere. Suitable carboxylic acid bioisosteres are known in the art.
  • the bioisostere has a proton having a pK a similar to the corresponding carboxylic acid.
  • suitable bioisoteres may include, not by way of limitation, tetrazole, acylsulfomides, acylhydroxylamine, and squaric acid derivatives, as shown below (--- indicates the point of attachment):
  • Fatty chain as used herein refers to a moiety comprising a chain of carbon atoms, the carbon atoms being predominantly substituted with hydrogen or hydrogen-like atoms, for example, a hydrocarbon chain.
  • Such fatty chains are often referred to as lipophilic, although it will be appreciated that substitution may alter the lipophilic properties of the overall molecule.
  • the fatty chain may by aliphatic. It may be entirely saturated or may include one or more double or triple bonds.
  • the fatty chain may also have one or more cycloalkylene or heterocycloalkylene moieties in its length, and additionally or alternatively may have one or more arylene or heteroarylene moieties in its length.
  • the fatty chain may incorporate a phenylene or piperazinylene moiety in its length as, for example, shown below (wherein --- represents the points of attachment within the chain).
  • the fatty chain may be derived from a fatty acid, for example, it may be derived from a medium-chain fatty acid (MCFA) with an aliphatic tail of 6–12 carbon atoms, a long-chain fatty acid (LCFA) with an aliphatic tail of 13–21 carbon atoms, or a very long-chain fatty acid (LCFA) with an aliphatic tail of 22 carbon atoms or more.
  • MCFA medium-chain fatty acid
  • LCFA long-chain fatty acid
  • LCFA very long-chain fatty acid
  • linear saturated fatty acids from which suitable fatty chains may be derived include tridecylic (tridecanoic) acid, myristic (tetradecanoic) acid, pentadecylic (pentadecanoic) acid, palmitic (hexadecanoic) acid, and margaric (heptadecanoic) acid.
  • linear unsaturated fatty acids from which suitable fatty chains may be derived include myristoleic acid, palmitoleic acid, sapienic acid and oleic acid.
  • the fatty chain may be connected to or to Z 2 by an amide linkage, a sulfinamide linkage, a sulfonamide linkage, or by an ester linkage, or by an ether, thioether or amine linkage. Accordingly, the fatty chain may have, a bond to or to Z 2 or an acyl (–CO–), sulfinyl (–SO– ), or sulfonyl (–SO 2 –) group. Preferably, the fatty chain has a terminus having an acyl (– CO–) group and is connected to ⁇ or Z 2 by an amide or ester linkage.
  • Z 1 is a group of formula: A–B–Alk–X– wherein A is hydrogen or a carboxylic acid, a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; B is a bond or a linker; X is a bond, acyl (–CO–), sulfinyl (–SO–), or sulfonyl (–SO 2 –); and Alk is a fatty chain that may be optionally substituted with one or more substituents.
  • the fatty chain is preferably 6 to 28 carbon atoms in length (e.g. a C 6-28 alkylene), more preferably, 12 to 26 carbons in length (e.g.
  • a C 12-26 alkylene more preferably, 16 to 22 carbons in length (e.g. C 16-22 alkylene), and may be saturated or unsaturated.
  • Alk is saturated, that is, preferably Alk is alkylene.
  • Optional substituents on the fatty chain may be independently selected from fluoro, C 1-4 alkyl, preferably methyl; trifluoromethyl, hydroxymethyl, amino, hydroxyl, C 1-4 alkoxy, preferably methoxy; oxo, and carboxyl, and may be independently located at any point along the chain.
  • each optional substituent is selected from fluoro, methyl, and hydroxyl. Where more than one substituent is present, substituents may be the same or different.
  • the number of substituents is 0 to 3; more preferably the fatty chain is unsubstituted.
  • B may be a bond or a linker. When B is a linker, it may be a cycloalkylene, heterocycloalkylene, C 6 arylene, or C 5-6 heteroarylene, or C 6 arylene–O– or C 5-6 heteroarylene– O–.
  • B When B is phenylene it may, for example, be selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, preferably 1,4-phenylene (so that A–B– is a 4-benzoic acid substituent or 4-benzoic acid bioisostere).
  • B When B is phenylene–O–, it may, for example, be selected from 1,2-phenylene–O–, 1,3-phenylene–O–, 1,4-phenylene–O–, preferably 1,4-phenylene–O.
  • Each phenylene of B may be optionally substituted with one or more substituents selected from fluoro, methyl, trifluoromethyl, amino, hydroxyl, and C 1-4 alkoxy, preferably methoxy. It will be appreciated that substituent identity and position may be selected to subtly alter the pK a of the polar group. Suitable inductively or mesomerically electron-withdrawing or donating groups and their positional effects are known in the art.
  • B may be C 5-6 heteroarylene, for example, pyridinylene or thiofuranylene, and may be optionally substituted as described.
  • A–B– may be selected from: A .
  • A is H– or HOOC— and B is a bond. It will be understood that when A is hydrogen, B is a bond and Alk is unsubstituted alkylene, A–B–Alk– is an alkyl chain of formula H 3 C–(CH 2 ) n –.
  • Z 1 is an acyl group of formula: A–B–Alk–(CO)– or a sulfonyl group of formula: A–B–Alk–(SO 2 )–.
  • Z 1 is an acyl group of formula: A–B–alkylene–(CO)– where A and B are as defined above.
  • A is –COOH and B is a bond.
  • certain preferred Z 1 are derived from long-chain saturated ⁇ , ⁇ -dicarboxylic acids of formula HOOC–(CH 2 ) 12-22 – COOH, preferably, long-chain saturated ⁇ , ⁇ -dicarboxylic acids having an even number of carbon atoms in the aliphatic chain.
  • A is H and B is a bond.
  • certain preferred Z 1 are derived from long-chain saturated carboxylic acids of formula HOOC–(CH 2 ) 12-22 –CH 3 , preferably, long-chain saturated carboxylic acids having an even number of carbon atoms in the aliphatic chain.
  • Z 1 may be: A–B–C 16-20 alkylene–(CO)– wherein A is H or –COOH and B is a bond, for example: 17-carboxy-heptadecanoyl HOOC–(CH 2 ) 16 –(CO)–; 19-carboxy-nonadecanoyl HOOC–(CH 2 ) 18 –(CO)–; Octadecanoyl H 3 C–(CH 2 ) 16 –(CO)–; Eicosanoyl H 3 C–(CH 2 ) 18 –(CO)–;
  • the carboxylic acid group if present, may be replaced by a bioisotere as detailed herein.
  • the group Z 2 Z 2 is an optional spacer that connects Z 1 to the side chain of the amino acid component of ⁇ .
  • Z 2 if present, is a spacer bound at one terminus by Y, which may be a nitrogen, oxygen or sulfur atom, and at the other terminus by X, which may be a bond or an acyl (–CO–), sulfinyl (–SO–), sulfonyl (–SO 2 –)or absent.
  • Z 2 may be a spacer of formula (--- indicate points of attachment): wherein: Y may be –NH, –NR, –S or –O, where R may be alkyl, a protecting group or may form a linkage to another part of the spacer, with the remaining valency forming a linkage to Z 1 ; X may be a bond, CO–, SO–, or SO 2 –, with the remaining valency forming a linkage to the side chain of the amino acid component of V is a bivalent organic moiety linking Y and X; and n may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • each Y, V, and X is independent of every other Y, V, and X. Accordingly, Z 2 may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z 1 and the side chain. Where n is 2 or greater, each V may also be bound to each adjacent V by linkages as described. Preferably, linkages are amides, esters or sulfonamides, most preferably amides. Accordingly, in some embodiments, each Y is –NH or –NR and each X is CO– or SO 2 –.
  • –X– is acyl (–CO–).
  • Z 2 is a spacer of formula –S A –, –S B –, –S A –S B – or –S B –S A –, wherein S A and S B are as defined below.
  • Z 2 is selected from –S A – or –S B –S A –, that is, [side chain]–Z 2
  • Z 1 is [side chain]–S A –Z 1 or [side chain]–S B –S A –Z 1 .
  • the group S A S A may be a single amino acid residue or a residue of an amino acid derivative, especially an amino acid derivative residue having a sulfinyl or sulfonyl in place of the carboxy moiety at the C terminus. Additionally or alternatively, the single amino acid residue may have an oxygen or sulfur atom in place of the nitrogen atom at the N terminus.
  • S A may be or may comprise a nitrogen-containing heterocycle, said nitrogen-containing heterocycle being bound within the lipophilic group at one end via a bond, a carboxy, a sulfinyl, or a sulfonyl group and at the other via a ring nitrogen atom.
  • S A may comprise a piperazine ring.
  • S A is a 5-8-membered heterocycle having 1 or 2 nitrogen atoms and substituted with an X group, where X is a bond, CO–, SO–, or SO 2 –, and where L, if present, is C 1-4 alkylene (– denotes a point of attachment within the lipophilic group).
  • S A is a 6-membered heterocycle having 1 or 2 nitrogen atoms, preferably 2, and substituted with a -CH 2 CO–, -CH 2 SO–, or -CH 2 SO 2 – group.
  • S A may be:
  • S A may be: (referred to herein as piperazine-1-yl-acetyl).
  • S A is a single amino acid residue or piperazine-1-yl-acetyl. More preferably S A is a single amino acid residue.
  • the amino acid may be selected from ⁇ -Glu, ⁇ -Glu, ⁇ -Asp, ⁇ -Asp, Ala, ⁇ -Ala (3-aminopropanoic acid), Dapa (2,3-diaminopropanoic acid), Dab (2,4- diaminobutanoic acid), and Gaba (4-aminobutanoic acid). It will be understood that where more than one carboxylic acid or amino moiety is present, connection may be at any moiety as appropriate.
  • carboxylic acid or amino resides not bound within the residue may be free, that is, present as a free carboxylic acid or primary amine, or may be derivatised. Suitable derivatisation is known in the art.
  • carboxylic acid moieties may be present in S A amino acid residues as esters, for example, as methyl esters.
  • Amino moieties may be present as alkylated amines, for example, methylated, or may be protected as amide or carbamate moieties.
  • Other suitable amino acids include ⁇ -Ala (3-aminopropanoic acid) and Gaba (4-aminobutanoic acid) and similar ⁇ amino acids.
  • amino acids may be D or L, or a racemic or enantioenriched mixture.
  • the amino acid is an L-amino acid.
  • the amino acid is a D-amino acid.
  • S A has a carboxylic acid substituent, with ⁇ -Glu, ⁇ -Glu, ⁇ - Asp, and ⁇ -Asp, and sulfinyl and sulfonyl derivatives thereof, being preferred.
  • the amino acid residue is: , where –X– is –CO–, –SO–, –SO 2 –, preferably –CO–, and a is 1 or 2, preferably 2.
  • the carboxylic acid is an ester, and the amino acid residue is: where –X– is –CO–, –SO–, –SO 2 –, preferably –CO–, and a is 1 or 2, preferably 2, and R is C 1-4 alkyl or C 6 aryl.
  • R is C 1-4 alkyl, preferably methyl or ethyl, more preferably ethyl.
  • a preferred S A group bearing a carboxylic acid is ⁇ -Glu.
  • S A is selected from Dapa or ⁇ -Glu. Most preferably, S A is ⁇ -Glu.
  • the group S B S B may be a linker of general formula: wherein P U is a polymeric unit and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • One terminus of the linker S B is an —NH, –NR, –S or –O, wherein R may be alkyl, a protecting group or may form a linkage to another part of the polymeric unit; while the other is a bond or CO–, SO– or SO 2 – .
  • each polymeric unit P U may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z 1 , S A , and Lys.
  • each P U may be independently a unit of formula: wherein: Y may be –NH, –NR, –S or –O, wherein R may be alkyl, a protecting group or may form a linkage to another part of the spacer, with the remaining valency forming a linkage to Z 1 ; X may be a bond, CO–, SO–, or SO 2 –, with the remaining valency forming a linkage to the side chain; and V is a bivalent organic moiety linking Y and X.
  • V is the ⁇ -carbon of a natural or unnatural amino acid, that is V is – CHR AA –, wherein R AA is an amino acid side chain; or V is an optionally substituted C 1-6 alkylene, or V is a chain comprising one or more units of ethylene glycol in series, also known as PEG chain, for example, –CH 2 CH 2 –(OCH 2 CH 2 ) m –O–(CH 2 ) p –, where m is 0, 1, 2, 3, 4, or 5, and p is 1, 2, 3, 4, or 5; when X is CO–, p is preferably 1, 3, 4, or 5.
  • Optional alkylene substituents include fluoro, methyl, hydroxy, hydroxymethy, and amino.
  • Preferred P U units include: (i). Single amino acid residues: P U i ; (ii). Dipeptide residues: P U ii ; and (iii). Amino-(PEG) m -carboxylic acid residues: P U iii , and may be present in any combination or order.
  • S B may comprise one or more of each of P U i , P U ii , and P U iii in any order, or may comprise one or more units of P U i , P U ii , and P U iii only, or one of more units selected from P U i and P U ii , P U i and P U iii , or P U ii and P U iii . (i).
  • Each P U i may be independently selected from any natural or unnatural amino acid residue and, for example, may be selected from Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, ⁇ -Glu, ⁇ -Glu, Asp, Ser Thr, Dapa, Gaba, Aib, ⁇ -Ala, 5- aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, and 10-aminodecanoyl.
  • P U i amino acid residues are selected from Gly, Ser, Ala, Thr, and Cys, more preferably from Gly and Ser.
  • S B is –(P U i ) n –, wherein n is 1 to 8, more preferably 5 to 7, most preferably 6.
  • S B is –(P U i ) n –, n is 6 and each P U i is independently selected from Gly or Ser, with a preferred sequence being -Gly-Ser-Gly-Ser- Gly-Gly-. (ii).
  • P U ii dipeptide residues Each P U ii may be independently selected from any dipeptide residue comprising two natural or unnatural amino acid residues bound by an amide linkage.
  • Preferred P U ii dipeptide residues include Gly-Gly, Gly-Ser, Ser-Gly, Gly-Ala, Ala-Gly, and Ala-Ala, more preferably Gly-Ser and Gly-Gly.
  • S B is –(P U ii ) n –, wherein n is 2 to 4, more preferably 3, and each P U ii is independently selected from Gly-Ser and Gly-Gly.
  • S B is – (P U ii ) n –, n is 3 and each P U ii is independently selected from Gly-Ser and Gly-Gly, with a preferred sequence being -(Gly-Ser)-(Gly-Ser)-(Gly-Gly) (SEQ ID NO: 85).
  • Amino acids having stereogenic centres within P U i and Pu ii may be racemic, enantioenriched, or enantiopure.
  • the or each amino acid is independently an L-amino acid.
  • the or each amino acid is independently a D-amino acid. (iii).
  • P U iii amino-(PEG) m -carboxylic acid residues Each P U iii may be independently a residue of general formula: O wherein m is 0, 1, 2, 3, 4, or 5, preferably 1 or 2, and p is 1, 3, 4, or 5, preferably 1.
  • m is 1 and p is 1, that is, P U iii is a residue of 8-amino-3,6- dioxaoctanoic acid (also known as ⁇ 2-[2-aminoethoxy]ethoxy ⁇ acetic acid and H 2 N-PEG 3 - COOH). This residue is referred to herein as –PEG 3 –.
  • Other, longer, PEG chains are also known in the art.
  • 11-amino-3,6,9- trioxaundecanoic acid also known as H 2 N-PEG 4 -COOH or –PEG 4 –.
  • S B is —(P U iii ) n –, wherein n is 1 to 3, more preferably 2. Most preferably, S B is –PEG 3 –PEG 3 –.
  • Preferred Combinations It will be understood that the above preferences may be independently combined to give preferred –Z 1 and –Z 2 –Z 1 moieties.
  • the methods of the invention can be particular effective in reducing body weight, maintaining weight loss, and treating obesity (e.g., by control of appetite, feeding, food intake, calorie intake, and/or energy expenditure and lipoiysis), including morbid obesity, as well as associated diseases and health conditions including but not limited to obesity linked conditions and symptoms.
  • Pharmaceutical compositions The GLP-1 agonists and GIP analogues (e.g., GIP agonist compounds) used in the methods of the present invention may be formulated separately as pharmaceutical compositions (and administered separately), each including a therapeutically effective amount of a compound employed in the context of the invention, or a salt thereof, in a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of the GIP analogue.
  • the therapeutically effective amount of each compound used in the method of the present invention will depend, e.g., on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy, and may depend on such factors as weight, diet, concurrent medication and other factors, well known to those skilled in the medical arts.
  • the dosage sizes and dosing regimen most appropriate for human use may be guided by the results obtained by the present invention, and may be confirmed in properly designed clinical trials.
  • An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are known to the skilled person.
  • pharmaceutically acceptable carrier includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit.1985).
  • Suitable pH buffering agents may be, e.g., phosphate, citrate, acetate, lactate, maleate, tris/hydroxymethyl)aminomethane (TRIS), N-Tris(hydroxymethyl)methyl-3- aminopropanesulphonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, which in certain embodiments is a preferred buffer, arginine, lysine, or acetate or mixtures thereof.
  • TIS tris/hydroxymethyl)aminomethane
  • TAPS N-Tris(hydroxymethyl)methyl-3- aminopropanesulphonic acid
  • ammonium bicarbonate diethanolamine
  • histidine which in certain embodiments is a preferred buffer, arginine, lysine, or acetate or mixtures thereof.
  • the term further encompasses any agents listed in the US Pharmacopeia for use in animals, including humans.
  • a nucleic acid molecule may encode the amino acid sequence of any of Formula I to III or a precursor thereof.
  • the amino acid sequence encoded can be regarded as a precursor of a compound of the invention.
  • nucleic acid sequences will be provided as expression constructs wherein the encoding nucleic acid is in functional linkage with appropriate control sequences to direct its expression.
  • the expression construct may be provided in the context of a host cell capable of expressing (and optionally also secreting) the amio acid precursor, or ina cell-free expression system.
  • the compounds used in the methods of the invention may also be manufactured by standard peptide synthetic methods, e.g. by standard solid-phase or liquid-phase methodology, either stepwise or by fragment assembly, and isolating and purifying the final peptide compound product, or by any combinations of recombinant and synthetic methods. It may be preferable to synthesize the peptide compounds of the invention by means of solid-phase or liquid-phase peptide synthesis.
  • Sequence listing Sequence identifier numbers are assigned to sequences herein as follows: SEQ ID NOs: 1-41 & 118 – GIP analogue sequences SEQ ID NOs: 42, 48 & 50 – GIP analogue Formulas I, II & III respectively SEQ ID NOs: 43-47 – Alternative sequences within GIP analogue Formulas I, II & III SEQ ID NO: 49 & 86-88 – skipped SEQ ID NOs: 51-84 & 96 – GIP analogue sequences wherein the substituent may be any substituent herein SEQ ID NO: 85 – Linker sequence SEQ ID NOs: 89-95 – Sequences of GLP-1 analogues exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide and taspoglutide respectively SEQ ID NOs: 97-102 & 115 – Embodiments of GIP analogue
  • a method of increasing weight loss in a subject in need thereof comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 2.
  • a method of increasing weight loss in a subject in need thereof comprising: (i) providing a subject who fails to respond to treatment with a GLP-1 agonist, and (ii) administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 3.
  • a method of increasing weight loss in a subject in need thereof the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of at least 1 month, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 4.
  • a method of maintaining weight loss in a subject in need thereof comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist, wherein the subject has experienced weight loss, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject. 5.
  • a method of increasing weight loss in a subject in need thereof comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 6.
  • a method of achieving additional weight loss in a subject in need thereof comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss is achieved and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 7.
  • a combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of at least 1 month, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 10.
  • a combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject.
  • a combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is for achieving additional weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss is achieved and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 13.
  • a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 14.
  • a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject who fails to respond to treatment with a GLP-1 agonist, and (ii) administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 15.
  • a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of at least 1 month, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 16.
  • a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for maintaining weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist, wherein the subject has experienced weight loss, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject. 17.
  • a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 18.
  • a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for achieving additional weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss is achieved and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 19.
  • the GIP agonist is selected from the following, and pharmaceutically acceptable salts thereof: H-Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS-NH 2 (Compound 1) (SEQ ID NO: 1); H-Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-isoGlu)- IHQQDFVNWLLAQGPSSGAPPPS-NH 2 (Compound 2) (SEQ ID NO: 2); H-Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS-NH 2 (Compound 3) (SEQ ID NO: 3); H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPP
  • the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)- acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41), or a pharmaceutically acceptable salt thereof.
  • the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)- acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41), or a pharmaceutically acceptable salt thereof.
  • the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine- 1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof; and wherein the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide, and taspoglutide. 27.
  • the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine- 1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof; and wherein the GLP-1 agonist is semaglutide.
  • the GLP-1 agonist is administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray. 29.
  • injection including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection
  • infusion pump such as subcutaneous infusion pump
  • oral sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch)
  • nasal such as by nasal spray
  • pulmonary spray such as by nasal spray
  • the GLP-1 agonist is administered at a dose of from about 0.25 mg to about 50 mg, such as from about 0.25 mg to about 30 mg, from about 0.25 mg to about 20 mg, from about 0.25 mg to about 14 mg, from about 0.25 mg to about 10 mg, from about 1 mg to about 50 mg, such as from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 14 mg, or from about 1 mg to about 10 mg. 32.
  • step (i) the GLP-1 agonist is administered to the subject as defined in any one of paragraphs 28-35.
  • step (i) the GLP-1 agonist is administered to the subject as defined in any one of paragraphs 28-35.
  • step (ii) the GLP-1 agonist is administered to the subject as defined in any one of paragraphs 28-35.
  • the GIP agonist is administered to the subject at a dose of up to about 15 mg, up to about 12.5 mg, up to about 10 mg, up to about 7.5 mg, up to about 5 mg, up to about 2.5 mg, up to about 2 mg, up to about 1 mg, up to about 0.5 mg or up to about 0.1 mg. 41.
  • the GIP agonist is administered to the subject at a dose of about 15 mg, about 12.5 mg, about 10 mg, about 7.5 mg, about 5 mg, about 2.5 mg, or about 1 mg. 43.
  • a method of increasing weight loss in a subject in need thereof comprising administering to the subject a GLP-1 agonist and a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject, wherein the GIP agonist is H-Y- Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 2.
  • a method of maintaining weight loss in a subject in need thereof comprising administering to the subject a GLP-1 agonist and a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject, wherein the GIP agonist is H- Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 3.
  • the GIP agonist is H- Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2 (
  • a method of increasing weight loss in a subject in need thereof comprising administering to the subject a GLP-1 agonist and a GIP agonist, each in an amount that together is sufficient to achieve additional weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 4.
  • the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41)
  • a method of achieving additional weight loss in a subject in need thereof comprising administering to the subject a GLP-1 agonist and a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine- 1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 5.
  • the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine- 1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2
  • a combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is as defined in any one of additional paragraphs 1-4
  • the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
  • GIP agonist H-Y-Aib- EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)- AAQAFIEWLLAQGPSSGAPPPS-NH 2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
  • the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide, and taspoglutide, preferably wherein the GLP-1 agonist is semaglutide.
  • the GLP-1 agonist and/or the GIP agonist is administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray, preferably by subcutaneous injection.
  • injection including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection
  • infusion pump such as subcutaneous infusion pump
  • oral sublingual, rectal, vaginal, parenteral
  • topical such as by transdermal patch
  • nasal such as by nasal spray
  • pulmonary spray preferably by subcutaneous injection.
  • the GLP-1 agonist is administered at a dose of up to about 50 mg, such as up to about 40 mg, up to about 30 mg, up to about 20 mg or up to about 10 mg.
  • the GLP-1 agonist is administered to the subject at least once, twice, or three times daily, or once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 28 days or every month, preferably wherein the GLP-1 agonist is administered to the subject once weekly. 12.
  • the GIP agonist is administered to the subject at a dose of up to about 15 mg, up to about 12.5 mg, up to about 10 mg, up to about 7.5 mg, up to about 5 mg, up to about 2.5 mg, up to about 2 mg, up to about 1 mg, up to about 0.5 mg or up to about 0.1 mg. 13.
  • Compound 41 is a long-acting gastric inhibitory peptide (GIP) analogue with a predicted half-life supporting once-weekly dosing in humans.
  • GIP gastric inhibitory peptide
  • GLP-1 glucagon-like peptide 1
  • a DIO (diet induced obese) mouse is a C57BL/6 - "Black 6" - mouse which has been made obese through conditioning with a special diet.
  • Methods DIO mice were treated for 2 weeks by sc injection either with vehicle (qd), compound 41 (300 nmol/kg, ev.2nd day), semaglutide (Sema, 10 nmol/kg, qd) or combination of sema + compound 41 (10 nmol/kg, qd and 300 nmol/kg, ev.2nd, respectively).
  • mice dosed with vehicle either continued on vehicle or switched to compound 41 mice dosed with compound 41 continued on compound 41 therapy, mice dosed with sema continued on sema or switched to the combination therapy of sema + compound 41.

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Abstract

The present invention features methods for treating obesity and promoting weight loss by administering to a subject a combination of a GLP-1 agonist and a GIP agonist.

Description

METHODS FOR TREATING OBESITY Field of the Invention The invention features combination therapies for promoting weight loss. Background of the Invention Obesity is a chronic disease associated with many complications. Weight loss of 5–15% can improve many obesity-related complications. Despite the benefits of weight reduction, there are many challenges in losing weight and maintaining long-term weight loss. Achieving and maintaining weight loss is challenging for many individuals. There is therefore a need for some patients to take medications to help them lose weight and prevent weight regain. GLP-1RA (GLP-1 receptor agonist) therapy was initially developed to treat type 2 diabetes. For example, owing to their effectiveness in reducing body weight, once-daily subcutaneous administration of liraglutide 3.0 mg and once weekly subcutaneous administration of semaglutide 2.4 mg have both been improved for weight management in people with obesity. New approaches are needed for patients who fail to respond to GLP-1RA monotherapy, or who become refractory to GLP-1RA monotherapy during treatment, plateau in their weight loss, and/or are or become GLP-1 treatment resistant, while undergoing GLP-1RA treatment, or who wish to maintain weight loss following GLP-1RA monotherapy. Summary of the Invention The present invention features methods for treating obesity and promoting weight loss by administering to a subject a combination of a GLP-1 agonist and a GIP agonist. Applicants have observed that it is possible to continue weight loss in subjects undergoing GLP-1RA monotherapy reaching a weight loss plateau, and/or the subjects are or become GLP-1 treatment resistant, by adding a GIP agonist to their treatment regimen. In a first aspect, the invention features a method of increasing weight loss in a subject in need thereof, the method including: (i) providing a subject undergoing treatment with a GLP- 1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant, and (ii) following step (i), administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. In a related aspect, the invention features a method of increasing weight loss in a subject in need thereof, the method including: (i) providing a subject who fails to respond to treatment with a GLP-1 agonist, and (ii) administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. In a related aspect, the invention features a method of increasing weight loss in a subject in need thereof, the method including: (i) providing a subject undergoing treatment with a GLP- 1 agonist for a period of at least 1 month (e.g., at least one month, two months, three months, four months, five months or six months), and (ii) following step (i), administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. In a related aspect, the invention features a method of maintaining weight loss in a subject in need thereof, the method including: (i) providing a subject undergoing treatment with a GLP- 1 agonist, wherein the subject has experience weight loss, and (ii) following step (i), administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject. In particular embodiments, the subject’s weight loss is maintained for a period of at least 1 month (e.g., at least one month, two months, three months, four months, five months or six months). In an embodiment of any of the methods of the invention, the subject has a BMI of >30 kg/m2, >35 kg/m2, >40 kg/m2, >45 kg/m2, or >50 kg/m2. In another embodiment of any of the methods of the invention, the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide, and taspoglutide. In another embodiment of any of the methods of the invention, the GIP agonist is any GIP agonist described herein. In particular embodiments, the GIP agonist is H-Y-Aib- EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)- AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. In particular embodiments of any of the methods of the invention, during part (i) of the method the subject is not receiving any other weight loss drug other than the GLP-1 agonist. Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art. Unless specified otherwise, the following definitions are provided for specific terms, which are used in the above written description. Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components). The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictates otherwise. The term “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably. The terms “patient,” “subject,” and “individual” may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats). The term “agonist” as employed in the context of the invention refers to a substance (ligand) that activates signaling by the receptor type in question. Throughout the description and claims the conventional one-letter and three-letter codes for natural (or “proteinogenic”) amino acids are used, as well as generally accepted three letter codes for other (non-natural or “non-proteinogenic”) α-amino acids, such as Aib (α- aminoisobutyric acid), Orn (ornithine) and D-Ala (D-alanine). All amino acid residues in peptides of the invention are preferably of the L-configuration except where explicitly stated. Among sequences disclosed herein are sequences incorporating an “H-“ moiety at the amino terminus (N-terminus) of the sequence, and either an “-OH” moiety or an “–NH2” moiety at the carboxy terminus (C-terminus) of the sequence. In such cases, and unless otherwise indicated, an “H-” or “Hy-” moiety at the N-terminus of the sequence in question indicates a hydrogen atom (i.e. R1 = H), corresponding to the presence of a free primary or secondary amino group at the N-terminus, while an “-OH” or an “–NH2” moiety at the C- terminus of the sequence (i.e. R2 = OH or NH2) indicates a carboxy (COOH) group or an amido (CONH2) group at the C-terminus, respectively. The term "pharmaceutically acceptable salt" refers to a salt of the compound. Salts include pharmaceutically acceptable salts, such as, e.g., acid addition salts and basic salts. Examples of an acid addition salt includes hydrochloride salts. Examples of basic salts include salts where the cation is selected from, e.g., an alkali metal. Other examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences" ,17th edition. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, U.S.A., 1985 and more recent editions, and in the Encyclopaedia of Pharmaceutical Technology. "Treatment" is an approach for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment. "Treatment" is an intervention performed with the intention of preventing the development or altering the pathology of a disorder. Accordingly, "treatment" refers to both therapeutic treatment and prophylactic or preventative measures in certain embodiments. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. By treatment is meant inhibiting or reducing an increase in pathology or symptoms (e.g. weight gain) when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant condition. As used herein, the term “plateau” refers to patients undergoing GLP-1 monotherapy for a period of time during which the subject’s weight is unchanged, or there is weight gain in the subject. A subject experiencing a plateau can be identified when their weight loss is less than 1% of their body weight over a period of at least two weeks, three weeks, one month, or two months. As used herein, the term “GLP-1 treatment resistant” refers to patients undergoing GLP-1 monotherapy for a period of time during which the subject’s weight is unchanged, or there is weight gain in the subject. For some asepcts of the invention, a subject experiencing such a resistance can be identified as any one or more of the following weight characteristics of the subject over a period of any of: at least about one week, or at least about two weeks, or at least about three weeks, or at least about one month, or at least about two months, about one week, or about two weeks, or about three weeks, or about one month, or about two months: when their weight loss is less than about 3%, or when their weight loss is less than about 2%, or when their weight loss is less than about 1% of their body weight, or when there is a substantially constant body weight, or when there is an increase in body weight of about at least 1%. In some instances, patients that experience a plateau may be a sub- group of patients who are GLP-1 treatment resistant. As used herein, the term “fails to respond to treatment with a GLP-1 agonist” refers to patients undergoing GLP-1 monotherapy for a period of at least 1 month or at least 2 months without experiencing a loss of at least 1% of their body weight. In either the treatment of an overweight or obese subject, the effect of treatment according to the methods of the present invention may be superior to that obtained GLP-1 agonist monotherapy or GIP agonist monotherapy in comparable subjects. Brief Description of the Drawings Figure 1 is a graph showing that the combination therapy of semaglutide + compound 41, achieved a significant, sustained and greater body weight reduction in obese mice (DIO mice) compared to vehicle- and each monotherapy group (-24.5% ± 2.4 combination therapy from day 14; -24.1% ± 1.3 combination therapy from day 0; -0.8% ±0.9 compound 41 from day 0; 2.0% ±0.8 compound 41 from day 14 days; -13.7% ± 2.3 semaglutide; 3.1% ± 0.8, vehicle; relative to initial body weights). The effects on body weight loss in combination groups of semaglutide + compound 41 were similar at the end of the study irrespective of the pretreatment with semaglutide. The results were obtained as described in Example 1. Detailed Description The present invention features methods for treating obesity and promoting weight loss by administering to a subject a combination of an GLP-1 agonist and a GIP agonist. The methods of the invention can be useful for promoting weight loss in (i) subjects who are refractory to GLP-1 monotherapy, and (ii) subjects experiencing a plateau in weight loss in response to ongoing GLP-1 monotherapy and/or subjects that are or become GLP-1 treatment resistant. GLP-1 receptor agonists The combination therapies of the present invention may be particular effective in improving glycaemic control and reducing body weight. Glucagon-like peptide-1 receptor agonists also known as GLP-1 receptor agonists or incretin mimetics are agonists of the GLP-1 receptor. One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia. Examples of GLP-1 agonists that can be used in the methods of the invention include but are not limited to exenatide (BYETTA®/BYDUREON®), liraglutide (VICTOZA®), semaglutide, lixisenatide (LYXUMIA®), dulaglutide (TRULICITY®), albiglutide (TANZENUM®) and Taspoglutide. The GLP-1 agonist used in the combination therapy of the invention can be a peptide having the sequence of any one of exenatide, liraglutide, semaglutide, lixisenatide, dulaglutide, albiglutide, or taspoglutide, or a pharmaceutically acceptable salt thereof. The GLP-1 agonist may be any GLP-1 agonist described herein or a pharmaceutically acceptable salt thereof. Exenatide is a synthetic version of exendin-4, a peptide found in the venom of the Gila monster, described in Fig.2 of WO 99/07404 and has the formula: Hy-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPP-NH2 (SEQ ID NO: 89). Liraglutide is a derivative of GLP-1 described in Example 37 of US patent no.6,268,343 and has the formula: Hy-HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG-OH (SEQ ID NO: 90), wherein the side- chain amino group of the lysine at position 20 is linked to the lipohilic moiety hexadecanoyl (i.e. palmitoyl) via a γ-Glu linker. Semaglutide is a derivative of GLP-1 described in Example 4 of WO 2006/097537 and has the formula: Hy-HXEGTFTSDVSSYLEGQAAKEFIAWLVRGRG-OH (SEQ ID NO: 91), wherein X at position 2 is 2-aminoisobutyric acid (Aib) and the side-chain amino group of the lysine at position 20 is linked to the lipohilic moiety [2-(2-[2-(2-[2-(2-[4-(17- Carboxyheptadecanoylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]. Dulaglutide is a fusion protein of a GLP-1 variant and an IgG4 Fc region described in WO 2005/000892 (compound named “Gly8-Glu22-Gly36-GLP-1(7-37)-L- IgG4(S228P,F234A,L235A)”) and has the sequence: HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSAESKYGPPCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT VDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 92). Lixisenatide is a derivative of exendin-4, presented as Compound 2 in WO 01/04156 and has the formula: Hy-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2 (SEQ ID NO: 93). Albiglutide is Construct 3438 in WO 2005/003296 and has the formula: HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRHGEGTFTSDVSSYLEGQAAKEFIAWLVKGR DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAEN CDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVD VMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLD ELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTE CCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLA ADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPH ECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRN LGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFS ALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDF AAFVEKCCKADDKETCFAEEGKKLVAASQAALGL (SEQ ID NO: 94). Albiglutide is a fusion protein of two copies of a derivative of GLP-1 fused in series, fused to human serum albumin at their C-terminus. Taspoglutide is a GLP-1 variant described in Example 1 of WO 2000/34331 and has the formula: Hy-HXEGTFTSDVSSYLEGQAAKEFIAWLVKXR-NH2 (SEQ ID NO: 95), wherein X at positions 2 and 29 is 2-aminoisobutyric acid (Aib). Route of administration of GLP-1 agonist The administration to a subject of the GLP-1 agonist may be by any mode of administration common or standard in the art, e.g. oral, intravenous, intramuscular, subcutaneous, sublingual, intranasal, intradermal, suppository routes or implanting. The GLP-1 agonist of step (i) and/or step (ii) may be administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray. In certain embodiments the GLP-1 agonist may be administered by subcutaneous injection. Dose of GLP-1 agonist The GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of up to about 50 mg, such as up to about 40 mg, up to about 30 mg, up to about 20 mg or up to about 10 mg. The GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of from of from about 0.25 mg to about 100 mg, such as from about 0.25 mg to about 90 mg, such as from about 0.25 mg to about 80 mg, such as from about 0.25 mg to about 70 mg, such as from about 0.25 mg to about 60 mg,about 0.25 mg to about 50 mg, such as from about 0.25 mg to about 40 mg, such as from about 0.25 mg to about 30 mg, from about 0.25 mg to about 20 mg, from about 0.25 mg to about 14 mg or from about 0.25 mg to about 10 mg. The GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of from about 1 mg to about 50 mg, such as from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 14 mg or from about 1 mg to about 10 mg. The GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of about 0.25 mg, about 0.5 mg, about 0.6 mg, about 1 mg, about 1.2 mg, about 1.5 mg, about 1.8 mg, about 2 mg, about 3 mg, about 4.5 mg, about 5 mg, about 7 mg, about 10 mg, about 14 mg, about 20 mg, about 30 mg or about 50 mg. The GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of up to about 10 mg/kg body weight of the subject, such as up to about 5 mg/kg body weight or up to about 1 mg/kg body weight. The GLP-1 agonist of step (i) and/or step (ii) may be administered at a dose of from about 0.01 to about 10 mg/kg body weight of the subject, such as from about 0.01 to about 5 mg/kg body weight, from about 0.01 to about 1 mg/kg body weight, from about 0.05 to about 10 mg/kg body weight, from about 0.05 to about 5 mg/kg body weight, from about 0.05 to about 1 mg/kg body weight or from about 0.05 to about 0.5 mg/kg body weight. Timing of administration of GLP-1 agonist The GLP-1 agonist of step (i) and/or step (ii) may be administered to the subject at least once, twice, or three times daily. The GLP-1 agonist of step (i) and/or step (ii) may be administered to the subject once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days or more such as every 28 days or every month. For certain embodiments, the GLP-1 agonist of step (i) and/or step (ii) may be administered to the subject once a day (i.e. daily or once daily). For certain embodiments, the GLP-1 agonist of step (i) and step (ii) may be administered to the subject once a week (i.e weekly or once weekly). Exenatide is preferably administered by subcutaneous injection twice daily, at least 6 hours apart and each time before a main meal. Initially, 5 mg are administered twice daily for at least 1 month, then the dose may be increased to 10 mg twice daily if necessary. Alternatively, exenatide may be administered by subcutaneous injection once weekly at a dose of 2 mg. Liraglutide is preferably administered by subcutaneous injection once daily. Initially, 0.6 mg are administered once daily for at least 1 week, then the dose is increased to 1.2 mg once daily for at least 1 week, and then the dose may be increased to 1.8 mg once daily if necessary. Semaglutide is preferably administered by subcutaneous injection once weekly. Semaglutide may be administered subuctaneously at a dose of up to about 7.2 mg. In a preferred embodiment, 0.25 mg are initially administered once weekly for at least 4 weeks, then the dose is increased to 0.5 mg once weekly for at least 4 weeks, then the dose is increased to 1 mg once weekly for at least 4 weeks, then the dose is increased to 1.7 mg once weekly for at least 4 weeks, and then the dose is increased to 2.4 mg once weekly; the dose is maintained at 2.4 mg for the course of the treatment. Alternatively, semaglutide may be administered orally once daily on an empty stomach. Semaglutide may be administered orally once daily at a dose of up to about 50 mg, such as about 50 mg, about 40 mg, about 30 mg, about 20 mg or about 10 mg. In a preferred embodiment, 3 mg are initially administered once daily for at least 1 month, then the dose is increased to 7 mg once daily for at least 1 month, and then the dose may be increased to 14 mg once daily if necessary. Dulaglutide is preferably administered by subcutaneous injection once weekly at a dose of 0.75 mg. Alternatively, if dulaglutide is administered in combination with another drug (such as a GIP agonist), dulaglutide is preferably administered initially at 1.5 mg once weekly for at least 4 weeks, then the dose is increased to 3 mg once weekly for at least 4 weeks, and then the dose may be increased to 4.5 mg once weekly if necessary. Lixisenatide is preferably administered by subcutaneous injection once daily, taken within 1 hour before a meal. Initially, 10 mg are administered once daily for 2 weeks, then the dose is increased to 20 mg once daily. Albiglutide is preferably administered by subcutaneous injection once weekly at a dose of 30 mg. The dose may be increased to 50 mg if the glycaemic response is inadequate. Taspoglutide is preferably administered by subcutaneous injection once weekly. GIP receptor agonists The combination therapies of the invention include a GIP analogue (also referred to as a “GIP agonist” or a “GIP receptor agonist” herein). The GIP agonist may be any GIP agonist described herein or a pharmaceutically acceptable salt thereof. The combination therapies of the invention can include a GIP analogue represented by the general Formula I: R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y1-Y2-R2 (I) (SEQ ID NO: 42) wherein R1 is H-, Ac or pGlu pyroglutamic acid (pGlu; (S)-(-)-2-pyrrolidone-5-carboxylic acid), C1-4 alkyl, acetyl, formyl, benzoyl and trifluoroacetyl, X2 is Aib, Ala, D-Ala, Gly, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c; X10 is Tyr, Leu or Ser; X11 is Ser or Leu;
Figure imgf000012_0001
Ile; X15 is Asp or Glu; X16 is Ser, Glu, Lys or Ψ; X17 is Ile, Lys, Gln, Arg or Ψ; X18 is His, Arg or Ala; X19 is Gln, Lys, Ala or Glu; X20 is Gln, Lys, Ala, His or Arg; X21 is Ala, Leu, Asp or Glu; X23 is Val or Ile; X24 is Asn or Glu; X25 is Tyr or Trp; X27 is Leu, Glu, Ser, Lys or Val; X28 is Ala, Ser or Arg; X29 is Aib, Gly, Ala, Gln, Thr, Ser or Lys or is absent; Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 43), Gly-Pro- Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 46), Gly-Lys-Lys- Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln (SEQ ID NO: 47) or absent; Y2 is Ψ or is absent; R2 is –NH2 or –OH; wherein
Figure imgf000012_0002
is a residue independently selected from Lys, Arg, Orn and Cys and wherein the side chain of said residue is conjugated to a lipophilic substituent; and wherein the GIP analogue contains one and only one residue ψ; or a pharmaceutically acceptable salt thereof. Thus, a GIP analogue according to Formula I may be any of the following: R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Lys-Gly-Y2-R2 (SEQ ID NO: 115); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-Y2-R2 (SEQ ID NO: 97); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Ser-Y2-R2 (SEQ ID NO: 98); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Pro-Ser-Ser-Gly-Ala-Pro-Pro- Pro-Ser-Y2-R2 (SEQ ID NO: 99); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Pro-Ser-Ser-Gly-Ala-Pro-Pro- Ser-Y2-R2 (SEQ ID NO: 100); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Gly-Lys-Lys-Asn-Asp-Trp-Lys- His-Asn-Ile-Thr-Gln-Y2-R2 (SEQ ID NO: 101); or R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y2-R2 (SEQ ID NO: 102). In one aspect, R1 is H-, Ac or pGlu. Combinations of residues which may be present at some of the variable positions of Formula I include: Aib2, Asp15, Lys20; Aib2, Asp15, Arg20; Aib2, Asp15, Arg20, Ile23; Aib2, Ile12, Asp15, Arg20, Ile23, Glu24; Ile12, Asp15, Ile23; Ile12, Asp15, Ile23, Glu24; Ile12, Asp15, Ala21, Ile23; Aib2, Ala21, Ile23, Glu24; Aib2, Asp15, Ile23; Aib2, Asp15, Arg20, Ile23, Gln29; Aib2, Asp15, Arg20, Gly29; Aib2, Asp15, Ile17, Arg20, Gly29; Aib2, Asp15, Ile17, Lys20, Gly29; DAla2, Asp15, Ile23; DAla2, Asp15, Ile23, Ala28; Aib2, Asp15, Ile17, Lys20, Ala28; Asp15, Ile23, Glu24; N-Me-Ser2, Asp15, Lys20; N-Me-Ser2, Asp15, Arg20; N-Me-Ser2, Asp15, Arg20, Ile23; N-Me-Ser2, Ile12, Asp15, Arg20, Ile23, Glu24; N-Me-Ser2, Ala21, Ile23, Glu24; N-Me-Ser2, Asp15, Ile23; N-Me-Ser2, Asp15, Arg20, Ile23, Gln29; N-Me-Ser2, Asp15, Arg20, Gly29; N-Me-Ser2, Asp15, Ile17, Arg20, Gly29; N-Me-Ser2, Asp15, Ile17, Lys20, Gly29; N-Me-Ser2, Asp15, Ile23; N-Me-Ser2, Asp15, Ile23, Ala28; Ac3c2, Asp15, Lys20; Ac3c2, Asp15, Arg20; Ac3c2, Asp15, Arg20, Ile23; Ac3c2, Ile12, Asp15, Arg20, Ile23, Glu24; Ac3c2, Ala21, Ile23, Glu24; Ac3c2, Asp15, Ile23; Ac3c2, Asp15, Arg20, Ile23, Gln29; Ac3c2, Asp15, Arg20, Gly29; Ac3c2, Asp15, Ile17, Arg20, Gly29; Ac3c2, Asp15, Ile17, Lys20, Gly29; Ac3c2, Asp15, Ile23; Ac3c2, Asp15, Ile23, Ala28; Ac4c2, Asp15, Lys20; Ac4c2, Asp15, Arg20; Ac4c2, Asp15, Arg20, Ile23; Ac4c2, Ile12, Asp15, Arg20, Ile23, Glu24; Ac4c2, Ala21, Ile23, Glu24; Ac4c2, Asp15, Ile23; Ac4c2, Asp15, Arg20, Ile23, Gln29; Ac4c2, Asp15, Arg20, Gly29; Ac4c2, Asp15, Ile17, Arg20, Gly29; Ac4c2, Asp15, Ile17, Lys20, Gly29; Ac4c2, Asp15, Ile23; Ac4c2, Asp15, Ile23, Ala28; Ac5c2, Asp15, Lys20; Ac5c2, Asp15, Arg20; Ac5c2, Asp15, Arg20, Ile23; Ac5c2, Ile12, Asp15, Arg20, Ile23, Glu24; Ac5c2, Ala21, Ile23, Glu24; Ac5c2, Asp15, Ile23; Ac5c2, Asp15, Arg20, Ile23, Gln29; Ac5c2, Asp15, Arg20, Gly29; Ac5c2, Asp15, Ile17, Arg20, Gly29; Ac5c2, Asp15, Ile17, Lys20, Gly29; Ac5c2, Asp15, Ile23; or Ac5c2, Asp15, Ile23, Ala28. The combination therapies of the invention can include a GIP analogue represented by the general Formula II: R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y1-Y2-R2 (II) (SEQ ID NO: 48) wherein R1 is H-, Ac or pGlu; X2 is Aib, Ala, D-Ala or Gly; X12 is Lys, Ψ or Ile; X15 is Asp or Glu; X16 is Ser, Glu, Lys or Ψ; X17 is Ile, Lys, Gln, Arg
Figure imgf000015_0001
X18 is His, Arg or Ala; X19 is Gln or Ala; X20 is Gln, Lys, Ala, His or Arg; X21 is Ala, Asp or Glu; X23 is Ile or Val; X24 is Asn or Glu; X25 is Tyr or Trp; X27 is Leu, Glu, Ser, Lys or Val; X28 is Ala, Ser or Arg; X29 is Aib, Gly, Ala, Gln, Thr, Ser or Lys or is absent; Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 43), Gly-Pro- Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 46), Gly-Lys-Lys- Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln (SEQ ID NO: 47) or absent; absent; R2 is –NH2 or –OH; wherein Ψ is a Lys residue wherein the side chain of said Lys residue is conjugated to a lipophilic substituent; and wherein the GIP analogue contains one and only one residue ψ; or a pharmaceutically acceptable salt thereof. Thus, a GIP analogue according to Formula II may be any of the following: R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Lys-Gly-Y2-R2 (SEQ ID NO: 116); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-Y2-R2 (SEQ ID NO: 103); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Ser-Y2-R2 (SEQ ID NO: 104); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Pro-Ser-Ser-Gly-Ala-Pro-Pro- Pro-Ser-Y2-R2 (SEQ ID NO: 105); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Pro-Ser-Ser-Gly-Ala-Pro-Pro- Ser-Y2-R2 (SEQ ID NO: 106); R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Gly-Lys-Lys-Asn-Asp-Trp-Lys- His-Asn-Ile-Thr-Gln-Y2-R2 (SEQ ID NO: 107); or R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-Glu-Leu-X15-X16-X17-X18- X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y2-R2 (SEQ ID NO: 108). Combinations of residues which may be present at some of the variable positions of Formula II include: Aib2, Lys12, Asp15, Lys20; Aib2, Lys12, Asp15, Arg20; Aib2, Asp15, Arg20; Aib2, Ile12, Asp15, Arg20, Glu24; Ile12, Asp15, Ile23; Ile12, Asp15, Glu24; Ile12, Asp15, Ala21; Aib2, Lys12, Ala21, Glu24; Aib2, Lys12, Asp15; Aib2, Lys,12, Asp15, Arg20, Gln29; Aib2, Lys, 12, Asp15, Arg20, Gly29; Aib2, Lys12, Asp15, Ile17, Arg20, Gly29; Aib2, Asp15, Ile17, Lys20, Gly29; DAla2, Asp15; DAla2, Asp15, Ala28; Aib2, Asp15, Ile17, Lys20, Ala28; Asp15, Glu24; Ala2, Lys12, Asp15, Lys20; Ala2, Lys12, Asp15, Arg20; Ala2, Asp15, Arg20; Ala2, Ile12, Asp15, Arg20, Glu24; Ala2, Ile12, Asp15, Ile23; Ala2, Ile12, Asp15, Glu24; Ala2, Ile12, Asp15, Ala21; Ala2, Lys12, Ala21, Glu24; Ala2, lys12, Asp15; Ala2, Lys12, Asp15, Arg20, Gln29; Ala2, Lys12, Asp15, Arg20, Gly29; Ala2, Lys12, Asp15, Ile17, Arg20, Gly29; Ala2, Asp15, Ile17, Lys20, Gly29; Ala2, Asp15; Ala2, Asp15, Ala28; Ala2, Asp15, Ile17, Lys20, Ala28; Gly2, Lys12, Asp15, Lys20; Gly2, Lys12, Asp15, Arg20; Gly2, Asp15, Arg20; Gly2, Ile12, Asp15, Arg20, Glu24; Gly2, Ile12, Asp15, Ile23; Gly2, Ile12, Asp15, Glu24; Gly2, Ile12, Asp15, Ala21; Gly2, Lys12, Ala21, Glu24; Gly2, Lys12, Asp15; Gly2, Lys12, Asp15, Arg20, Gln29; Gly2, Lys 12, Asp15, Arg20, Gly29; Gly2, Lys12, Asp15, Ile17, Arg20, Gly29; Gly2, Asp15, Ile17, Lys20, Gly29; Gly2, Asp15; Gly2, Asp15, Ala28; Gly2, Asp15, Ile17, Lys20, Ala28; or Gly2, Asp15, Glu24. The combination therapies of the invention can include a GIP analogue represented by the general Formula III: R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Y1-Y2-R2 (III) (SEQ ID NO: 50) wherein R1 is H-, Ac or pGlu; X15 is Asp or Glu; X16 is Lys or Ψ; X17 is Ile or Ψ; X18 is His or Ala; X19 is Gln or Ala; X20 is Gln, Lys or Arg; X21 is Ala, Asp or Glu; X24 is Asn or Glu; X25 is Tyr or Trp; X28 is Ala, Ser or Arg; X29 is Gln or is absent; Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 43), Gly-Pro- Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 46), Gly-Lys-Lys- Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln (SEQ ID NO: 47) or absent; Y2 is Ψ or is absent; R2 is –NH2 or –OH; wherein Ψ is a residue independently selected from Lys, Arg, Orn and Cys and wherein the side chain of said residue is conjugated to a lipophilic substituent; and wherein the GIP analogue contains one and only one residue ψ; or a pharmaceutically acceptable salt thereof. Thus, a GIP analogue according to Formula III may be any of the following: R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Lys-Gly-Y2-R2 (SEQ ID NO: 117); R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro- Ser-Y2-R2 (SEQ ID NO: 109); R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser- Y2-R2 (SEQ ID NO: 110); R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser- Y2-R2 (SEQ ID NO: 111); R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Y2- R2 (SEQ ID NO: 112); R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn- Ile-Thr-Gln-Y2-R2 (SEQ ID NO: 113); or R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19- X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Y2-R2 (SEQ ID NO: 114). Combinations of residues which may be present at some of the variable positions of Formula III include: Asp15, Lys20; Asp15, Arg20; Asp15, Arg20, Glu24; Asp15, Lys 16; Asp15, Lys 16, Glu24; Asp15, Ψ16, Ala21; Ala21, Glu24; Asp15, Arg20, Gln29; Asp15, Arg20, Gly29; Asp15, Ile17, Arg20, Gly29; Asp15, Ile17, Lys20, Gly29; Asp15, Ala28; Asp15, Ile17, Lys20, Ala28; Asp15, Ile23, Glu24; Asp15, Ψ17, Lys20; Asp15, Ψ17, Arg20; Asp15, Ψ17, Arg20 Asp15, Ψ17, Arg20, Glu24; Asp15, Lys16, Ψ17; Asp15, Lys16, Ψ17, Glu24; Asp15, Ψ17, Ala21; Ala21, Ψ17, Glu24; Asp15, Asp15, Ψ17, Arg20, Gln29; Asp15, Ψ17, Arg20, Gly29; Asp15, Ile17, Arg20, Gly29; Asp15, Ile17, Lys20, Gly29; Asp15; Ψ17; Asp15, Ψ17, Ala28; Asp15, Ile17, Lys20, Ala28; or Asp15, Ψ17, Ile23, Glu24. The GIP-analogue useful in the combination therapies of the invention may have the formula R1-Z-R2 where R1 and R2 are as defined above and Z has the sequence: Y-Aib-EGTFISDYSIELDKΨHQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 51); Y-Aib-EGTFISDYSIELDΨIHQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 52); Y-Aib-EGTFISDYSIELEKΨHQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 53); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPSΨ (SEQ ID NO: 54); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPSΨ (SEQ ID NO: 96); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQΨ (SEQ ID NO: 55); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKGΨ (SEQ ID NO: 56); Y-Aib-EGTFISDYSIELDKΨHQQDFVNYLLAQGPSSGAPPPS (SEQ ID NO: 57); Y-Aib-EGTFISDYSIELDKΨHQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 58); Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 59); Y-Aib-EGTFISDYSIELEKΨAAKEFVNWLLAQGPSSGAPPPS (SEQ ID NO: 60); Y-Aib-EGTFISDYSIELEKΨAQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 61); Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPSΨ (SEQ ID NO: 62); Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQΨ (SEQ ID NO: 63); Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAGPSSGAPPPS (SEQ ID NO: 64); Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPSΨ (SEQ ID NO: 65); Y-Aib-EGTFISDYSIELDKΨAQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 66); Y-Aib-EGTFISDYSIELDKΨAQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 67); Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPSKΨ (SEQ ID NO: 68); Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPSKΨ (SEQ ID NO: 69); Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKΨ (SEQ ID NO: 70); Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPSKΨ (SEQ ID NO: 71); Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPSKΨ (SEQ ID NO: 72); Y-Aib-EGTFISDYSIELDKΨAAQAFVNWLLAGPSSGAPPPS (SEQ ID NO: 73); Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAAGPSSGAPPPS (SEQ ID NO: 74); Y-Aib-EGTFISDYSIELDKΨAAQDFINWLLAGPSSGAPPPS (SEQ ID NO: 75); Y-Aib-EGTFISDYSIELDKΨAAQDFIEWLLAGPSSGAPPPS (SEQ ID NO: 76); Y-Aib-EGTFISDYSIELDKΨAAQDFIEWLLAGPSSGAPPPS (SEQ ID NO: 77); Y-Aib-EGTFISDYSIELDKΨIAQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 78); Y-Aib-EGTFISDYSΨELDKIAQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 79); Y-DAla-EGTFISDYSIELDKΨAQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 80); Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKΨ (SEQ ID NO: 81); Y-Aib-EGTFISDYSIELDKΨAAQDFIEWLLAQGPSSGAPPPS (SEQ ID NO: 82); Y-Aib-EGTFISDYSIELDKΨAAQDFINWLLAQGPSSGAPPPS (SEQ ID NO: 83); or Y-Aib-EGTFISDYSIELDKΨAAQAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 84). The GIP-analogue useful in the combination therapies of the invention may have the formula R1-Z-R2 where R1 and R2 are as defined above and Z has the sequence Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 1); Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-isoGlu)- IHQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 2); Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 3); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3) (SEQ ID NO: 4); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K(Hexadecanoyl- isoGlu) (SEQ ID NO: 5); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQ-K(Hexadecanoyl-isoGlu) (SEQ ID NO: 6); Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKG-K(Hexadecanoyl-isoGlu) (SEQ ID NO: 7); Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- HQQDFVNYLLAQGPSSGAPPPS (SEQ ID NO: 8); Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- HQQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 9); Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAQGPSSGAPPPS (SEQ ID NO: 10); Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAKEFVNWLLAQGPSSGAPPPS (SEQ ID NO: 11); Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 12); Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3) (SEQ ID NO: 13); Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQ-K([19-carboxy-nonadecanoyl]-isoGlu- Peg3-Peg3) (SEQ ID NO: 14); Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAGPSSGAPPPS (SEQ ID NO: 15); H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAGPSSGAPPPS (SEQ ID NO: 118); Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3) (SEQ ID NO: 16); Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 17); Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 18); Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 19); Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO: 20); Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AQKEFVEWLLAAGPSSGAPPPS (SEQ ID NO: 21); Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQKEFVEWLLAAGPSSGAPPPS (SEQ ID NO: 22); Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3) (SEQ ID NO: 23); Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3) (SEQ ID NO: 24); Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3) (SEQ ID NO: 25); Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-Peg3) (SEQ ID NO: 26); Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3) (SEQ ID NO: 27); Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3) (SEQ ID NO: 28); Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQAFVNWLLAGPSSGAPPPS (SEQ ID NO: 29); Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAAGPSSGAPPPS (SEQ ID NO: 30); Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFINWLLAGPSSGAPPPS (SEQ ID NO: 31); Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFIEWLLAGPSSGAPPPS (SEQ ID NO: 32); Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AAQDFIEWLLAGPSSGAPPPS (SEQ ID NO: 33); Y-Aib-EGTFISDYSIELD-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- IAQRAFIEWLLAQGPSSGAPPPS; (SEQ ID NO: 34) Y-Aib-EGTFISDYS-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- ELDKIAQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 35); Y-DAla-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 36); Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-Peg3) (SEQ ID NO: 37); Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFIEWLLAQGPSSGAPPPS; (SEQ ID NO: 38) Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFINWLLAQGPSSGAPPPS (SEQ ID NO: 39); Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 40); or Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AAQAFIEWLLAQGPSSGAPPPS (SEQ ID NO: 41). The GIP-analogue used in the combination therapy may be any of the following, or a pharmaceutically acceptable salt thereof: H-Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 1) (SEQ ID NO: 1); H-Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-isoGlu)- IHQQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 2) (SEQ ID NO: 2); H-Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 3) (SEQ ID NO: 3); H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 4); (SEQ ID NO: 4) H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K(Hexadecanoyl- isoGlu)-NH2 (Compound 5) (SEQ ID NO: 5); H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQ-K(Hexadecanoyl-isoGlu)-NH2 (Compound 6); (SEQ ID NO: 6); H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKG-K(Hexadecanoyl-isoGlu)-NH2 (Compound 7) (SEQ ID NO: 7); H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- HQQDFVNYLLAQGPSSGAPPPS-NH2 (Compound 8) (SEQ ID NO: 8); H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- HQQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 9) (SEQ ID NO: 9); H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 10) (SEQ ID NO: 10); H-Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAKEFVNWLLAQGPSSGAPPPS-NH2 (Compound 11) (SEQ ID NO: 11); H-Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQGPSSGAPPPS-NH2 (Compound 12) (SEQ ID NO: 12); H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 13) (SEQ ID NO: 13); H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQ-K([19-carboxy-nonadecanoyl]- isoGlu-Peg3-Peg3)-NH2 (Compound 14) (SEQ ID NO: 14); H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAGPSSGAPPPS-NH2 (Compound 15) (SEQ ID NO: 15); H-Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 16) (SEQ ID NO: 16); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQGPSSGAPPPS-NH2 (Compound 17) (SEQ ID NO: 17); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFIEWLLAQGPSSGAPPPS-NH2 (Compound 18) (SEQ ID NO: 18); H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS-NH2 (Compound 19) (SEQ ID NO: 19); H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-NH2 (Compound 20) (SEQ ID NO: 20); H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AQKEFVEWLLAAGPSSGAPPPS-NH2 (Compound 21) (SEQ ID NO: 21); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQKEFVEWLLAAGPSSGAPPPS-NH2 (Compound 22) (SEQ ID NO: 22); H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 23) (SEQ ID NO: 23); H-Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 24) (SEQ ID NO: 24); H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 25) (SEQ ID NO: 25); H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-Peg3)-NH2 (Compound 26) (SEQ ID NO: 26); H-Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 27) (SEQ ID NO: 27); H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 28) (SEQ ID NO: 28); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQAFVNWLLAGPSSGAPPPS-NH2 (Compound 29) (SEQ ID NO: 29); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAAGPSSGAPPPS-NH2 (Compound 30) (SEQ ID NO: 30); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFINWLLAGPSSGAPPPS-NH2 (Compound 31) (SEQ ID NO: 31); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFIEWLLAGPSSGAPPPS-NH2 (Compound 32) (SEQ ID NO: 32); H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AAQDFIEWLLAGPSSGAPPPS-NH2 (Compound 33) (SEQ ID NO: 33); H-Y-Aib-EGTFISDYSIELD-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- IAQRAFIEWLLAQGPSSGAPPPS-NH2 (Compound 34) (SEQ ID NO: 34); H-Y-Aib-EGTFISDYS-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- ELDKIAQRAFIEWLLAQGPSSGAPPPS-NH2; ; (Compound 35) (SEQ ID NO: 35); H-Y-DAla-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFIEWLLAQGPSSGAPPPS-NH2 (Compound 36) (SEQ ID NO: 36); H-Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-Peg3)-NH2 (Compound 37) (SEQ ID NO: 37); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFIEWLLAQGPSSGAPPPS-NH2 (Compound 38) (SEQ ID NO: 38); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFINWLLAQGPSSGAPPPS-NH2 (Compound 39) (SEQ ID NO: 39); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQAFIEWLLAQGPSSGAPPPS-NH2 (Compound 40) (SEQ ID NO: 40); or H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (Compound 41) (SEQ ID NO: 41). For use in the combination therapies of the invention, compound 41, or a salt thereof, is the preferred GIP agonist. Compound 41 is also described in WO 2016/066744 as compound 41. Route of administration of GIP agonist The administration to a subject of the GIP agonist may be by any mode of administration common or standard in the art, e.g. oral, intravenous, intramuscular, subcutaneous, sublingual, intranasal, intradermal, suppository routes or implanting. The GIP agonist may be administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray. The GIP agonist may be administered by injection. For certain embodiments, the GIP agonist may be administered by subcutaneous injection. Dose of GIP agonist The GIP agonist may be administered at a dose of up to about 100 mg, such as up to about 90 mg, up to about 80 mg, up to about 70 mg, up to about 60 mg, up to about 50 mg, up to about 40 mg, up to about 30 mg, up to about 20 mg, up to about 15 mg, up to about 12.5 mg, up to about 10 mg, up to about 7.5 mg, up to about 5 mg, up to about 2.5 mg, up to about 2 mg, up to about 1 mg, up to about 0.5 mg or up to about 0.1 mg. The GIP agonist may be administered at a dose of from about 0.1 mg to about 100 mg, from about 0.5 mg to about 100 mg, from about 1 mg to about 100 mg, from about 2.5 mg to about 100 mg, from about 5 mg to about 100 mg, from about 7.5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 12.5 mg to about 100 mg, from about 15 mg to about 100 mg, from about 20 mg to about 100 mg, from about 30 mg to about 100 mg, from about 40 mg to about 100 mg, from about 50 mg to about 100 mg, from about 60 mg to about 100 mg, from about 70 mg to about 100 mg, from about 80 mg to about 100 mg, or from about 90 mg to about 100 mg. The GIP agonist may be administered at a dose of from about 0.1 mg to about 80 mg, from about 0.5 mg to about 80 mg, from about 1 mg to about 80 mg, from about 2.5 mg to about 80 mg, from about 5 mg to about 80 mg, from about 7.5 mg to about 80 mg, from about 10 mg to about 80 mg, from about 12.5 mg to about 80 mg, from about 15 mg to about 80 mg, from about 20 mg to about 80 mg, from about 30 mg to about 80 mg, from about 40 mg to about 80 mg, from about 50 mg to about 80 mg, from about 60 mg to about 80 mg, or from about 70 mg to about 80 mg. The GIP agonist may be administered at a dose of from about 0.1 mg to about 50 mg, from about 0.5 mg to about 50 mg, from about 1 mg to about 50 mg, from about 2.5 mg to about 50 mg, from about 5 mg to about 50 mg, from about 7.5 mg to about 50 mg, from about 10 mg to about 50 mg, from about 12.5 mg to about 50 mg, from about 15 mg to about 50 mg, from about 20 mg to about 50 mg, from about 30 mg to about 50 mg, or from about 40 mg to about 50 mg. The GIP agonist may be administered at a dose of from about 0.1 mg to about 15 mg, from about 0.5 mg to about 15 mg, from about 1 mg to about 15 mg, from about 2.5 mg to about 15 mg, from about 5 mg to about 15 mg, from about 7.5 mg to about 15 mg, from about 10 mg to about 15 mg, or from about 12.5 mg to about 15 mg. The GIP agonist may be administered at a dose of from about 0.5 mg to about 10 mg, about 1 mg to about 10 mg, from about 2.5 mg to about 10 mg, from about 5 mg to about 10 mg, or from about 7.5 mg to about 10 mg. The GIP agonist may be administered at a dose of from about 1 mg to about 5 mg, or from about 2.5 mg to about 5 mg. The GIP agonist may be administered at a dose of about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 15 mg, about 12.5 mg, about 10 mg, about 7.5 mg, about 5 mg, about 2.5 mg, or about 1 mg. The GIP agonist may be administered to the subject at a dose of up to about 500 nmol/kg body weight, such as up to about 400 nmol/kg body weight, or up to about 300 nmol/kg body weight. The GIP agonist may be administered to the subject at a dose of from about 10 to about 500 nmol/kg body weight, such as from about 50 to about 500 nmol/kg body weight, from about 100 to about 500 nmol/kg body weight, or from about 200 to about 500 nmol/kg body weight. The GIP agonist may be administered to the subject at a dose of from about 10 to about 400 nmol/kg body weight, such as from about 50 to about 400 nmol/kg body weight, from about 100 to about 400 nmol/kg body weigh, or from about 200 to about 400 nmol/kg body weight. The GIP agonist may be administered to the subject at a dose of from about 250 to about 350 nmol/kg body weight. For certain embodiments, the GIP agonist may be administered at a dose of about 300 nmol/kg body weight. Timing of administration of GIP agonist The GIP agonist may be administered to the subject at least once, twice, or three times daily. The GIP agonist may be administered to the subject once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days or more such as every 28 days or every month. For certain embodiments, the GLP-1 agonist of step (i) and/or step (ii) may be administered to the subject once a day (i.e. daily or once daily). For certain embodiments, the GLP-1 agonist of step (i) and step (ii) may be administered to the subject once a week (i.e weekly or once weekly). The GIP agonist may be administered at the same time or at a different time as the administration of the GLP-1 agonist of step (ii). Lipophilic groups The GIP analogue used in the methods of the invention can comprise a residue
Figure imgf000028_0001
i.e. a residue selected from Lys, Arg, Orn and Cys in which the side chain is conjugated to a lipophilic substituent. Without wishing to be bound by any particular theory, it is thought that the substituent binds plasma proteins (e.g. albumin) in the blood stream, thus shielding the compounds of the invention from enzymatic degradation and thereby enhancing the half-life of the compounds. It may also modulate the potency of the compound, e.g. with respect to the GIP receptor. The substituent is conjugated to the functional group at the distal end of the side chain from the alpha-carbon. The normal ability of the Lys, Arg, Orn or Cys side chain to participate in interactions mediated by that functional group (e.g. intra- and inter-molecular interactions) may therefore be reduced or completely eliminated by the presence of the substituent. Thus, the overall properties of the compound may be relatively insensitive to changes in the actual amino acid present as residue
Figure imgf000029_0001
Consequently, it is believed that any of the residues Lys, Arg, Orn and Cys may be present at any position where Ψ is permitted. However, in certain embodiments, it may be advantageous that the amino acid component of Ψ is Lys. Thus, Ψ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula –Z1 or –Z2–Z1. –Z1 is a fatty chain having at a terminus a connection –X– to Ψ or to Z2; wherein –X– is a bond, –CO–, –SO–, or –SO2–; and, optionally, Z1 has a polar group at the end of the chain distal from connection –X–; said polar group comprising a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; and wherein –Z2–, if present, is a spacer of formula:
Figure imgf000029_0002
connecting wherein: each Y is independently –NH, –NR, –S or –O, where R is alkyl, a protecting group or forms a linkage to another part of the spacer Z2; each X is independently a bond, CO–, SO–, or SO2–; with the proviso that when Y is –S, the X to which it is bound is a bond; each V is independently a bivalent organic moiety linking Y and X; and n is 1-10. The group Z1 Z1 is a fatty chain having a connection to Ψ or to Z2, referred to herein as –X–. –X– may be, for example, a bond, acyl (–CO–), sulfinyl (–SO–), or sulfonyl (–SO2–). When Z1 is bound directly to Ψ, that is, when Z2 is not present, preferably –X– is acyl (–CO–), sulfinyl (–SO–), or sulfonyl (–SO2–). Most preferably, –X– is acyl (–CO–). Z1 may further have a polar group, said polar group being located at the end of the chain distal from the connection –X–. In other words, the connection is located at the ω-position with respect to the polar group. The polar group may be bound directly to the terminus of the fatty chain, or may be bound via a linker. Preferably, the polar group is an acidic or weakly acid group, for example a carboxylic acid or a carboxylic acid bioisostere, a phosphonate, or a sulfonate. The polar group may have a pKa of between –2 and 12 in water, more preferably between 1 and 7, more preferably between 3 and 6. Certain preferred polar groups have a pKa of between 4 and 5. For example, and not by way of limitation, the polar group may comprise a carboxylic acid (– COOH) or a carboxylic acid bioisostere, a phosphonic acid (–P(O)(OH)2), or a sulfonic acid (–SO2OH) group. Preferably the polar group, if present, comprises a carboxylic acid or carboxylic acid bioisostere. Suitable carboxylic acid bioisosteres are known in the art. Preferably the bioisostere has a proton having a pKa similar to the corresponding carboxylic acid. Examples of suitable bioisoteres may include, not by way of limitation, tetrazole, acylsulfomides, acylhydroxylamine, and squaric acid derivatives, as shown below (--- indicates the point of attachment):
Figure imgf000030_0001
Fatty chain as used herein refers to a moiety comprising a chain of carbon atoms, the carbon atoms being predominantly substituted with hydrogen or hydrogen-like atoms, for example, a hydrocarbon chain. Such fatty chains are often referred to as lipophilic, although it will be appreciated that substitution may alter the lipophilic properties of the overall molecule. The fatty chain may by aliphatic. It may be entirely saturated or may include one or more double or triple bonds. Each double bond, if present, may be in the E or Z configuration. The fatty chain may also have one or more cycloalkylene or heterocycloalkylene moieties in its length, and additionally or alternatively may have one or more arylene or heteroarylene moieties in its length. For example, the fatty chain may incorporate a phenylene or piperazinylene moiety in its length as, for example, shown below (wherein --- represents the points of attachment within the chain).
Figure imgf000031_0001
The fatty chain may be derived from a fatty acid, for example, it may be derived from a medium-chain fatty acid (MCFA) with an aliphatic tail of 6–12 carbon atoms, a long-chain fatty acid (LCFA) with an aliphatic tail of 13–21 carbon atoms, or a very long-chain fatty acid (LCFA) with an aliphatic tail of 22 carbon atoms or more. Examples of linear saturated fatty acids from which suitable fatty chains may be derived include tridecylic (tridecanoic) acid, myristic (tetradecanoic) acid, pentadecylic (pentadecanoic) acid, palmitic (hexadecanoic) acid, and margaric (heptadecanoic) acid. Examples of linear unsaturated fatty acids from which suitable fatty chains may be derived include myristoleic acid, palmitoleic acid, sapienic acid and oleic acid. The fatty chain may be connected to
Figure imgf000031_0002
or to Z2 by an amide linkage, a sulfinamide linkage, a sulfonamide linkage, or by an ester linkage, or by an ether, thioether or amine linkage. Accordingly, the fatty chain may have, a bond to
Figure imgf000031_0003
or to Z2 or an acyl (–CO–), sulfinyl (–SO– ), or sulfonyl (–SO2–) group. Preferably, the fatty chain has a terminus having an acyl (– CO–) group and is connected to Ψ or Z2 by an amide or ester linkage. In some embodiments, Z1 is a group of formula: A–B–Alk–X– wherein A is hydrogen or a carboxylic acid, a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; B is a bond or a linker; X is a bond, acyl (–CO–), sulfinyl (–SO–), or sulfonyl (–SO2–); and Alk is a fatty chain that may be optionally substituted with one or more substituents. The fatty chain is preferably 6 to 28 carbon atoms in length (e.g. a C6-28alkylene), more preferably, 12 to 26 carbons in length (e.g. a C12-26alkylene), more preferably, 16 to 22 carbons in length (e.g. C16-22alkylene), and may be saturated or unsaturated. Preferably, Alk is saturated, that is, preferably Alk is alkylene. Optional substituents on the fatty chain may be independently selected from fluoro, C1-4alkyl, preferably methyl; trifluoromethyl, hydroxymethyl, amino, hydroxyl, C1-4alkoxy, preferably methoxy; oxo, and carboxyl, and may be independently located at any point along the chain. In some embodiments, each optional substituent is selected from fluoro, methyl, and hydroxyl. Where more than one substituent is present, substituents may be the same or different. Preferably, the number of substituents is 0 to 3; more preferably the fatty chain is unsubstituted. B may be a bond or a linker. When B is a linker, it may be a cycloalkylene, heterocycloalkylene, C6arylene, or C5-6heteroarylene, or C6arylene–O– or C5-6heteroarylene– O–. When B is phenylene it may, for example, be selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, preferably 1,4-phenylene (so that A–B– is a 4-benzoic acid substituent or 4-benzoic acid bioisostere). When B is phenylene–O–, it may, for example, be selected from 1,2-phenylene–O–, 1,3-phenylene–O–, 1,4-phenylene–O–, preferably 1,4-phenylene–O. Each phenylene of B may be optionally substituted with one or more substituents selected from fluoro, methyl, trifluoromethyl, amino, hydroxyl, and C1-4alkoxy, preferably methoxy. It will be appreciated that substituent identity and position may be selected to subtly alter the pKa of the polar group. Suitable inductively or mesomerically electron-withdrawing or donating groups and their positional effects are known in the art. In some embodiments, B may be C5-6heteroarylene, for example, pyridinylene or thiofuranylene, and may be optionally substituted as described. For example, in some embodiments, A–B– may be selected from: A
Figure imgf000032_0001
. Preferably, A is H– or HOOC– and B is a bond. It will be understood that when A is hydrogen, B is a bond and Alk is unsubstituted alkylene, A–B–Alk– is an alkyl chain of formula H3C–(CH2)n–. In some embodiments, Z1 is an acyl group of formula: A–B–Alk–(CO)– or a sulfonyl group of formula: A–B–Alk–(SO2)–. Preferably, Z1 is an acyl group of formula: A–B–alkylene–(CO)– where A and B are as defined above. In some embodiments, A is –COOH and B is a bond. Accordingly, certain preferred Z1 are derived from long-chain saturated α,ω-dicarboxylic acids of formula HOOC–(CH2)12-22– COOH, preferably, long-chain saturated α,ω-dicarboxylic acids having an even number of carbon atoms in the aliphatic chain. In some other embodiments, A is H and B is a bond. Accordingly, certain preferred Z1 are derived from long-chain saturated carboxylic acids of formula HOOC–(CH2)12-22–CH3, preferably, long-chain saturated carboxylic acids having an even number of carbon atoms in the aliphatic chain. For example, and not by way of limitation, Z1 may be: A–B–C16-20alkylene–(CO)– wherein A is H or –COOH and B is a bond, for example: 17-carboxy-heptadecanoyl HOOC–(CH2)16–(CO)–; 19-carboxy-nonadecanoyl HOOC–(CH2)18–(CO)–; Octadecanoyl H3C–(CH2)16–(CO)–; Eicosanoyl H3C–(CH2)18–(CO)–; The carboxylic acid group, if present, may be replaced by a bioisotere as detailed herein. The group Z2 Z2 is an optional spacer that connects Z1 to the side chain of the amino acid component of Ψ. At its most general, Z2, if present, is a spacer bound at one terminus by Y, which may be a nitrogen, oxygen or sulfur atom, and at the other terminus by X, which may be a bond or an acyl (–CO–), sulfinyl (–SO–), sulfonyl (–SO2–)or absent. Accordingly, Z2 may be a spacer of formula (--- indicate points of attachment):
Figure imgf000034_0001
wherein: Y may be –NH, –NR, –S or –O, where R may be alkyl, a protecting group or may form a linkage to another part of the spacer, with the remaining valency forming a linkage to Z1; X may be a bond, CO–, SO–, or SO2–, with the remaining valency forming a linkage to the side chain of the amino acid component of
Figure imgf000034_0002
V is a bivalent organic moiety linking Y and X; and n may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Where n is 2 or more, each Y, V, and X is independent of every other Y, V, and X. Accordingly, Z2 may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z1 and the side chain. Where n is 2 or greater, each V may also be bound to each adjacent V by linkages as described. Preferably, linkages are amides, esters or sulfonamides, most preferably amides. Accordingly, in some embodiments, each Y is –NH or –NR and each X is CO– or SO2–. Most preferably, –X– is acyl (–CO–). In some embodiments, Z2 is a spacer of formula –SA–, –SB–, –SA–SB– or –SB–SA–, wherein SA and SB are as defined below. In some embodiments, Z2 is selected from –SA– or –SB–SA–, that is, [side chain]–Z2Z1 is [side chain]–SA–Z1 or [side chain]–SB–SA–Z1. The group SA SA may be a single amino acid residue or a residue of an amino acid derivative, especially an amino acid derivative residue having a sulfinyl or sulfonyl in place of the carboxy moiety at the C terminus. Additionally or alternatively, the single amino acid residue may have an oxygen or sulfur atom in place of the nitrogen atom at the N terminus. SA may be or may comprise a nitrogen-containing heterocycle, said nitrogen-containing heterocycle being bound within the lipophilic group at one end via a bond, a carboxy, a sulfinyl, or a sulfonyl group and at the other via a ring nitrogen atom. For example, SA may comprise a piperazine ring. Suitably, SA is a 5-8-membered heterocycle having 1 or 2 nitrogen atoms and substituted with an X group, where X is a bond, CO–, SO–, or SO2–, and where L, if present, is C1-4alkylene (– denotes a point of attachment within the lipophilic group). Preferably, SA is a 6-membered heterocycle having 1 or 2 nitrogen atoms, preferably 2, and substituted with a -CH2CO–, -CH2SO–, or -CH2SO2– group. For example, SA may be:
Figure imgf000035_0001
For example, SA may be:
Figure imgf000035_0002
(referred to herein as piperazine-1-yl-acetyl). Preferably, SA is a single amino acid residue or piperazine-1-yl-acetyl. More preferably SA is a single amino acid residue. In some embodiments, the amino acid may be selected from γ-Glu, α-Glu, α-Asp, β-Asp, Ala, β-Ala (3-aminopropanoic acid), Dapa (2,3-diaminopropanoic acid), Dab (2,4- diaminobutanoic acid), and Gaba (4-aminobutanoic acid). It will be understood that where more than one carboxylic acid or amino moiety is present, connection may be at any moiety as appropriate. Any carboxylic acid or amino resides not bound within the residue may be free, that is, present as a free carboxylic acid or primary amine, or may be derivatised. Suitable derivatisation is known in the art. For example, carboxylic acid moieties may be present in SA amino acid residues as esters, for example, as methyl esters. Amino moieties may be present as alkylated amines, for example, methylated, or may be protected as amide or carbamate moieties. Other suitable amino acids include β-Ala (3-aminopropanoic acid) and Gaba (4-aminobutanoic acid) and similar ω amino acids. It will be understood that amino acids may be D or L, or a racemic or enantioenriched mixture. In some embodiments, the amino acid is an L-amino acid. In some embodiments, the amino acid is a D-amino acid. In some preferred embodiments, SA has a carboxylic acid substituent, with γ-Glu, α-Glu, α- Asp, and β-Asp, and sulfinyl and sulfonyl derivatives thereof, being preferred. Accordingly, in some embodiments, the amino acid residue is:
Figure imgf000036_0001
, where –X– is –CO–, –SO–, –SO2–, preferably –CO–, and a is 1 or 2, preferably 2. In some embodiments, the carboxylic acid is an ester, and the amino acid residue is:
Figure imgf000036_0002
where –X– is –CO–, –SO–, –SO2–, preferably –CO–, and a is 1 or 2, preferably 2, and R is C1-4alkyl or C6aryl. Preferably R is C1-4alkyl, preferably methyl or ethyl, more preferably ethyl. A preferred SA group bearing a carboxylic acid is γ-Glu. Preferably, SA is selected from Dapa or γ-Glu. Most preferably, SA is γ-Glu. The group SB SB may be a linker of general formula:
Figure imgf000037_0001
wherein PU is a polymeric unit and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. One terminus of the linker SB is an –NH, –NR, –S or –O, wherein R may be alkyl, a protecting group or may form a linkage to another part of the polymeric unit; while the other is a bond or CO–, SO– or SO2– . Accordingly, each polymeric unit PU may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z1, SA, and Lys. In some embodiments, each PU may be independently a unit of formula:
Figure imgf000037_0002
wherein: Y may be –NH, –NR, –S or –O, wherein R may be alkyl, a protecting group or may form a linkage to another part of the spacer, with the remaining valency forming a linkage to Z1; X may be a bond, CO–, SO–, or SO2–, with the remaining valency forming a linkage to the side chain; and V is a bivalent organic moiety linking Y and X. In some embodiments, V is the α-carbon of a natural or unnatural amino acid, that is V is – CHRAA–, wherein RAA is an amino acid side chain; or V is an optionally substituted C1-6alkylene, or V is a chain comprising one or more units of ethylene glycol in series, also known as PEG chain, for example, –CH2CH2–(OCH2CH2)m–O–(CH2)p–, where m is 0, 1, 2, 3, 4, or 5, and p is 1, 2, 3, 4, or 5; when X is CO–, p is preferably 1, 3, 4, or 5. Optional alkylene substituents include fluoro, methyl, hydroxy, hydroxymethy, and amino. Preferred PU units include: (i). Single amino acid residues: PU i ; (ii). Dipeptide residues: PU ii; and (iii). Amino-(PEG)m-carboxylic acid residues: PU iii, and may be present in any combination or order. For example, SB may comprise one or more of each of PU i, PU ii, and PU iii in any order, or may comprise one or more units of PU i, PU ii, and PU iii only, or one of more units selected from PU i and PU ii, PU i and PU iii, or PU ii and PU iii. (i). PU i single amino acid residues Each PU i may be independently selected from any natural or unnatural amino acid residue and, for example, may be selected from Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, α-Glu, γ-Glu, Asp, Ser Thr, Dapa, Gaba, Aib, β-Ala, 5- aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, and 10-aminodecanoyl. Preferably, PU i amino acid residues are selected from Gly, Ser, Ala, Thr, and Cys, more preferably from Gly and Ser. In some embodiments, SB is –(PU i)n–, wherein n is 1 to 8, more preferably 5 to 7, most preferably 6. In some preferred embodiments, SB is –(PU i)n–, n is 6 and each PU i is independently selected from Gly or Ser, with a preferred sequence being -Gly-Ser-Gly-Ser- Gly-Gly-. (ii). PU ii dipeptide residues Each PU ii may be independently selected from any dipeptide residue comprising two natural or unnatural amino acid residues bound by an amide linkage. Preferred PU ii dipeptide residues include Gly-Gly, Gly-Ser, Ser-Gly, Gly-Ala, Ala-Gly, and Ala-Ala, more preferably Gly-Ser and Gly-Gly. In some embodiments, SB is –(PU ii)n–, wherein n is 2 to 4, more preferably 3, and each PU ii is independently selected from Gly-Ser and Gly-Gly. In some preferred embodiments SB is – (PU ii)n–, n is 3 and each PU ii is independently selected from Gly-Ser and Gly-Gly, with a preferred sequence being -(Gly-Ser)-(Gly-Ser)-(Gly-Gly) (SEQ ID NO: 85). Amino acids having stereogenic centres within PU i and Puii may be racemic, enantioenriched, or enantiopure. In some embodiments, the or each amino acid is independently an L-amino acid. In some embodiments, the or each amino acid is independently a D-amino acid. (iii). PU iii amino-(PEG)m-carboxylic acid residues Each PU iii may be independently a residue of general formula: O
Figure imgf000039_0001
wherein m is 0, 1, 2, 3, 4, or 5, preferably 1 or 2, and p is 1, 3, 4, or 5, preferably 1. In some embodiments, m is 1 and p is 1, that is, PU iii is a residue of 8-amino-3,6- dioxaoctanoic acid (also known as {2-[2-aminoethoxy]ethoxy}acetic acid and H2N-PEG3- COOH). This residue is referred to herein as –PEG3–. Other, longer, PEG chains are also known in the art. For example, 11-amino-3,6,9- trioxaundecanoic acid (also known as H2N-PEG4-COOH or –PEG4–). In some embodiments, SB is –(PU iii)n–, wherein n is 1 to 3, more preferably 2. Most preferably, SB is –PEG3–PEG3–. Preferred Combinations It will be understood that the above preferences may be independently combined to give preferred –Z1 and –Z2–Z1 moieties. Some preferred –Z1 and –Z2–Z1 moieties are shown below (in each case, --- indicates the point of attachment to the side chain of the amino acid component of Ψ: (i) [17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3
Figure imgf000040_0001
(ii) [17-carboxy-heptadecanoyl]-isoGlu
Figure imgf000040_0002
(iii) Octadecanoyl-isoGlu-Peg3-Peg3
Figure imgf000040_0003
(iv) Eicosanoyl-isoGlu-Peg3-Peg3
Figure imgf000040_0004
(v) [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3
Figure imgf000041_0001
(vi) Octadecanoyl-Dapa-Peg3-Peg3
Figure imgf000041_0002
(vii) Hexadecanoyl-isoGlu
Figure imgf000041_0003
(viii) (19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-Peg3 O
Figure imgf000041_0004
In particular embodiments, the GIP analogue used in the methods of the invention is selected from those listed in Table 1. Table 1
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Clinical utility The methods of the invention can be particular effective in reducing body weight, maintaining weight loss, and treating obesity (e.g., by control of appetite, feeding, food intake, calorie intake, and/or energy expenditure and lipoiysis), including morbid obesity, as well as associated diseases and health conditions including but not limited to obesity linked conditions and symptoms. Pharmaceutical compositions The GLP-1 agonists and GIP analogues (e.g., GIP agonist compounds) used in the methods of the present invention may be formulated separately as pharmaceutical compositions (and administered separately), each including a therapeutically effective amount of a compound employed in the context of the invention, or a salt thereof, in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of the GIP analogue. The therapeutically effective amount of each compound used in the method of the present invention will depend, e.g., on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy, and may depend on such factors as weight, diet, concurrent medication and other factors, well known to those skilled in the medical arts. The dosage sizes and dosing regimen most appropriate for human use may be guided by the results obtained by the present invention, and may be confirmed in properly designed clinical trials. An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are known to the skilled person. The term "pharmaceutically acceptable carrier" includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit.1985). For example, sterile saline and phosphate- buffered saline at slightly acidic or physiological pH may be used. Suitable pH buffering agents may be, e.g., phosphate, citrate, acetate, lactate, maleate, tris/hydroxymethyl)aminomethane (TRIS), N-Tris(hydroxymethyl)methyl-3- aminopropanesulphonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, which in certain embodiments is a preferred buffer, arginine, lysine, or acetate or mixtures thereof. The term further encompasses any agents listed in the US Pharmacopeia for use in animals, including humans. Synthesis of compounds used in the methods of the invention The skilled person will be well aware of suitable techniques for preparing the compounds employed in the context of the invention. For examples of suitable chemistry, see, e.g., WO98/08871, WO2016/066744, WO00/55184, WO00/55119, Madsen et al. (J. Med. Chem. 2007, 50, 6126-32), and Knudsen et al.2000 (J. Med Chem.43, 1664-1669). A nucleic acid molecule may encode the amino acid sequence of any of Formula I to III or a precursor thereof. The amino acid sequence encoded can be regarded as a precursor of a compound of the invention. Typically, such nucleic acid sequences will be provided as expression constructs wherein the encoding nucleic acid is in functional linkage with appropriate control sequences to direct its expression. The expression construct may be provided in the context of a host cell capable of expressing (and optionally also secreting) the amio acid precursor, or ina cell-free expression system. The compounds used in the methods of the invention may also be manufactured by standard peptide synthetic methods, e.g. by standard solid-phase or liquid-phase methodology, either stepwise or by fragment assembly, and isolating and purifying the final peptide compound product, or by any combinations of recombinant and synthetic methods. It may be preferable to synthesize the peptide compounds of the invention by means of solid-phase or liquid-phase peptide synthesis. In this context, reference may be made to WO 98/11125 or, inter alia, Fields, G.B. et al., “Principles and Practice of Solid-Phase Peptide Synthesis”; in: Synthetic Peptides, Gregory A. Grant (ed.), Oxford University Press (2nd edition, 2002) and the synthesis examples herein. Sequence listing Sequence identifier numbers (SEQ ID NOs) are assigned to sequences herein as follows: SEQ ID NOs: 1-41 & 118 – GIP analogue sequences SEQ ID NOs: 42, 48 & 50 – GIP analogue Formulas I, II & III respectively SEQ ID NOs: 43-47 – Alternative sequences within GIP analogue Formulas I, II & III SEQ ID NO: 49 & 86-88 – skipped SEQ ID NOs: 51-84 & 96 – GIP analogue sequences wherein the substituent may be any substituent herein SEQ ID NO: 85 – Linker sequence SEQ ID NOs: 89-95 – Sequences of GLP-1 analogues exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide and taspoglutide respectively SEQ ID NOs: 97-102 & 115 – Embodiments of GIP analogue Formula I SEQ ID NOs: 103-108 & 116 – Embodiments of GIP analogue Formula II SEQ ID NOs: 109-114 & 117 – Embodiments of GIP analogue Formula III Numbered Paragraphs The present invention will now be described by way of numbered paragraphs. 1. A method of increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 2. A method of increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject who fails to respond to treatment with a GLP-1 agonist, and (ii) administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 3. A method of increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of at least 1 month, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 4. A method of maintaining weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist, wherein the subject has experienced weight loss, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject. 5. A method of increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 6. A method of achieving additional weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss is achieved and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 7. A combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject, wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 8. A combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject, wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject who fails to respond to treatment with a GLP-1 agonist, and (ii) administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 9. A combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject, wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of at least 1 month, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 10. A combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject, wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is for maintaining weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist, wherein the subject has experienced weight loss, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject. 11. A combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject, wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 12. A combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject, wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is for achieving additional weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss is achieved and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 13. Use of a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 14. Use of a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject who fails to respond to treatment with a GLP-1 agonist, and (ii) administering to the subject (a) the GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 15. Use of a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of at least 1 month, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject. 16. Use of a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for maintaining weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist, wherein the subject has experienced weight loss, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject. 17. Use of a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 18. Use of a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is for achieving additional weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss is achieved and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject. 19. The method or the combination for use of any one of paragraphs 1-18, wherein the subject has a BMI of >30 kg/m2, such as an initial BMI of >30 kg/m2 before the method is used on the subject. 20. The method, the combination for use, or the use of any one of paragraphs 1-19, wherein the GLP-1 agonist in step (ii) is the same as the GLP-1 agonist in step (i). 21. The method, the combination for use, or the use of any one of paragraphs 1-20, wherein the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide, and taspoglutide. 22. The method, the combination for use, or the use of paragraph 21, wherein the GLP-1 agonist is semaglutide. 23. The method, the combination for use, or the use of any one of paragraphs 1-22, wherein the GIP agonist is any GIP agonist described herein. 24. The method, the combination for use, or the use of any one of paragraphs 1-23, wherein the GIP agonist is selected from the following, and pharmaceutically acceptable salts thereof: H-Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 1) (SEQ ID NO: 1); H-Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-isoGlu)- IHQQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 2) (SEQ ID NO: 2); H-Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-isoGlu)- HQQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 3) (SEQ ID NO: 3); H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 4); (SEQ ID NO: 4) H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-K(Hexadecanoyl- isoGlu)-NH2 (Compound 5) (SEQ ID NO: 5); H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQ-K(Hexadecanoyl-isoGlu)-NH2 (Compound 6); (SEQ ID NO: 6); H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKG-K(Hexadecanoyl-isoGlu)-NH2 (Compound 7) (SEQ ID NO: 7); H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- HQQDFVNYLLAQGPSSGAPPPS-NH2 (Compound 8) (SEQ ID NO: 8); H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- HQQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 9) (SEQ ID NO: 9); H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAQGPSSGAPPPS-NH2 (Compound 10) (SEQ ID NO: 10); H-Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAKEFVNWLLAQGPSSGAPPPS-NH2 (Compound 11) (SEQ ID NO: 11); H-Y-Aib-EGTFISDYSIELEK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQGPSSGAPPPS-NH2 (Compound 12) (SEQ ID NO: 12); H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 13) (SEQ ID NO: 13); H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQ-K([19-carboxy-nonadecanoyl]- isoGlu-Peg3-Peg3)-NH2 (Compound 14) (SEQ ID NO: 14); H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAGPSSGAPPPS-NH2 (Compound 15) (SEQ ID NO: 15); H-Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPS-K([19-carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 16) (SEQ ID NO: 16); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFVEWLLAQGPSSGAPPPS-NH2 (Compound 17) (SEQ ID NO: 17); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFIEWLLAQGPSSGAPPPS-NH2 (Compound 18) (SEQ ID NO: 18); H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS-NH2 (Compound 19) (SEQ ID NO: 19); H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-NH2 (Compound 20) (SEQ ID NO: 20); H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AQKEFVEWLLAAGPSSGAPPPS-NH2 (Compound 21) (SEQ ID NO: 21); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQKEFVEWLLAAGPSSGAPPPS-NH2 (Compound 22) (SEQ ID NO: 22); H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 23) (SEQ ID NO: 23); H-Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 24) (SEQ ID NO: 24); H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 25) (SEQ ID NO: 25); H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-Peg3)-NH2 (Compound 26) (SEQ ID NO: 26); H-Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 27) (SEQ ID NO: 27); H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPS-K([19-Carboxy- nonadecanoyl]-isoGlu-Peg3-Peg3)-NH2 (Compound 28) (SEQ ID NO: 28); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQAFVNWLLAGPSSGAPPPS-NH2 (Compound 29) (SEQ ID NO: 29); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFVNWLLAAGPSSGAPPPS-NH2 (Compound 30) (SEQ ID NO: 30); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFINWLLAGPSSGAPPPS-NH2 (Compound 31) (SEQ ID NO: 31); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFIEWLLAGPSSGAPPPS-NH2 (Compound 32) (SEQ ID NO: 32); H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AAQDFIEWLLAGPSSGAPPPS-NH2 (Compound 33) (SEQ ID NO: 33); H-Y-Aib-EGTFISDYSIELD-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- IAQRAFIEWLLAQGPSSGAPPPS-NH2 (Compound 34) (SEQ ID NO: 34); H-Y-Aib-EGTFISDYS-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- ELDKIAQRAFIEWLLAQGPSSGAPPPS-NH2; ; (Compound 35) (SEQ ID NO: 35); H-Y-DAla-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AQRAFIEWLLAQGPSSGAPPPS-NH2 (Compound 36) (SEQ ID NO: 36); H-Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPS-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3-Peg3)-NH2 (Compound 37) (SEQ ID NO: 37); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFIEWLLAQGPSSGAPPPS-NH2 (Compound 38) (SEQ ID NO: 38); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQDFINWLLAQGPSSGAPPPS-NH2 (Compound 39) (SEQ ID NO: 39); H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)- AAQAFIEWLLAQGPSSGAPPPS-NH2 (Compound 40) (SEQ ID NO: 40); or H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3-Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (Compound 41) (SEQ ID NO: 41). 25. The method, the combination for use, or the use of paragraph 24, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)- acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41), or a pharmaceutically acceptable salt thereof. 26. The method, the combination for use, or the use of any one of paragraphs 1-25, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine- 1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof; and wherein the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide, and taspoglutide. 27. The method, the combination for use, or the use of any one of paragraphs 1-26, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine- 1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof; and wherein the GLP-1 agonist is semaglutide. 28. The method, the combination for use, or the use of any one of paragraphs 1-27, wherein the GLP-1 agonist is administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray. 29. The method, the combination for use, or the use of paragraph 28, wherein the GLP-1 agonist is administered by subcutaneous injection. 30. The method, the combination for use, or the use of any one of paragraphs 1-29, wherein the GLP-1 agonist is administered at a dose of up to about 50 mg, such as up to about 40 mg, up to about 30 mg, up to about 20 mg or up to about 10 mg. 31. The method, the combination for use, or the use of any one of paragraphs 1-30, wherein the GLP-1 agonist is administered at a dose of from about 0.25 mg to about 50 mg, such as from about 0.25 mg to about 30 mg, from about 0.25 mg to about 20 mg, from about 0.25 mg to about 14 mg, from about 0.25 mg to about 10 mg, from about 1 mg to about 50 mg, such as from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 14 mg, or from about 1 mg to about 10 mg. 32. The method, the combination for use, or the use of any one of paragraphs 1-31, wherein the GLP-1 agonist is administered at a dose of about 0.25 mg, about 0.5 mg, about 0.6 mg, about 1 mg, about 1.2 mg, about 1.5 mg, about 1.8 mg, about 2 mg, about 3 mg, about 4.5 mg, about 5 mg, about 7 mg, about 10 mg, about 14 mg, about 20 mg, about 30 mg or about 50 mg. 33. The method, the combination for use, or the use of any one of paragraphs 1-32, wherein the GLP-1 agonist is administered to the subject at least once, twice, or three times daily, or once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 28 days or every month. 34. The method, the combination for use, or the use of paragraph 33, wherein the GLP-1 agonist is administered to the subject once daily. 35. The method, the combination for use, or the use of paragraph 33, wherein the GLP-1 agonist is administered to the subject once weekly. 36. The method, the combination for use, or the use of any one of paragraphs 1-35, wherein in step (i) the GLP-1 agonist is administered to the subject as defined in any one of paragraphs 28-35. 37. The method, the combination for use, or the use of any one of paragraphs 1-36, wherein in step (ii) the GLP-1 agonist is administered to the subject as defined in any one of paragraphs 28-35. 38. The method, the combination for use, or the use of any one of paragraphs 1-37, wherein the GIP agonist is administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray. 39. The method, the combination for use, or the use of paragraph 38, wherein the GIP agonist is administered by subcutaneous injection. 40. The method, the combination for use, or the use of any one of paragraphs 1-39, wherein the GIP agonist is administered to the subject at a dose of up to about 15 mg, up to about 12.5 mg, up to about 10 mg, up to about 7.5 mg, up to about 5 mg, up to about 2.5 mg, up to about 2 mg, up to about 1 mg, up to about 0.5 mg or up to about 0.1 mg. 41. The method, the combination for use, or the use of any one of paragraphs 1-40, wherein the GIP agonist is administered to the subject at a dose of from about 10 to about 500 nmol/kg body weight, such as from about 50 to about 500 nmol/kg body weight, from about 100 to about 500 nmol/kg body weigh, or from about 200 to about 500 nmol/kg body weight. 42. The method, the combination for use, or the use of any one of paragraphs 1-41, wherein the GIP agonist is administered to the subject at a dose of about 15 mg, about 12.5 mg, about 10 mg, about 7.5 mg, about 5 mg, about 2.5 mg, or about 1 mg. 43. The method, the combination for use, or the use of any one of paragraphs 1-42, wherein the GIP agonist is administered to the subject at least once, twice, or three times daily, or once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 28 days or every month. 44. The method, the combination for use, or the use of paragraph 43, wherein the GIP agonist is administered to the subject once daily. 45. The method, the combination for use, or the use of paragraph 44, wherein the GIP agonist is administered to the subject once weekly. Additional Numbered Paragraphs Other aspects of the present invention are now described by way of additional numbered paragraphs. 1. A method of increasing weight loss in a subject in need thereof, the method comprising administering to the subject a GLP-1 agonist and a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject, wherein the GIP agonist is H-Y- Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 2. A method of maintaining weight loss in a subject in need thereof, the method comprising administering to the subject a GLP-1 agonist and a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject, wherein the GIP agonist is H- Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 3. A method of increasing weight loss in a subject in need thereof, the method comprising administering to the subject a GLP-1 agonist and a GIP agonist, each in an amount that together is sufficient to achieve additional weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]- Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 4. A method of achieving additional weight loss in a subject in need thereof, the method comprising administering to the subject a GLP-1 agonist and a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine- 1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 5. A combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject, wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method is as defined in any one of additional paragraphs 1-4, and wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 6. Use of a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is as defined in any one of additional paragraphs 1-4, and wherein the GIP agonist is H-Y-Aib- EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)- AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof. 7. The method, the combination for use, or the use of any one of additional paragraphs 1-6, wherein the subject has a BMI of >30 kg/m2, such as an initial BMI of >30 kg/m2 before the method is used on the subject. 8. The method, the combination for use, or the use of any one of additional paragraphs 1-7, wherein the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide, and taspoglutide, preferably wherein the GLP-1 agonist is semaglutide. 9. The method, the combination for use, or the use of any one of additional paragraphs 1-8, wherein the GLP-1 agonist and/or the GIP agonist is administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray, preferably by subcutaneous injection. 10. The method, the combination for use, or the use of any one of additional paragraphs 1- 9, wherein the GLP-1 agonist is administered at a dose of up to about 50 mg, such as up to about 40 mg, up to about 30 mg, up to about 20 mg or up to about 10 mg. 11. The method, the combination for use, or the use of any one of additional paragraphs 1- 10, wherein the GLP-1 agonist is administered to the subject at least once, twice, or three times daily, or once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 28 days or every month, preferably wherein the GLP-1 agonist is administered to the subject once weekly. 12. The method, the combination for use, or the use of any one of additional paragraphs 1- 11, wherein the GIP agonist is administered to the subject at a dose of up to about 15 mg, up to about 12.5 mg, up to about 10 mg, up to about 7.5 mg, up to about 5 mg, up to about 2.5 mg, up to about 2 mg, up to about 1 mg, up to about 0.5 mg or up to about 0.1 mg. 13. The method, the combination for use, or the use of any one of additional paragraphs 1- 12, wherein the GIP agonist is administered to the subject at least once, twice, or three times daily, or once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 28 days or every month, preferably wherein the GIP agonist is administered to the subject once daily or once weekly. Examples The examples described herein serve to illustrate the present invention, and the invention is not limited to the examples given. Example 1. Anti-obesity Effects of GIP Analogue compound 41 in Combination with Semaglutide in DIO Mice. Current therapies for weight management are often associated with inadequate efficacy or complications and side effects. Therefore, combination therapy with complementary modes of action is warranted to maximize the effect on weight management while maintaining safety and tolerability. Compound 41 is a long-acting gastric inhibitory peptide (GIP) analogue with a predicted half-life supporting once-weekly dosing in humans. Here we investigated the combined anti-obesity effects of compound 41 and semaglutide, once- weekly glucagon-like peptide 1 (GLP-1) analogue in diet induced obese (DIO) mice. Compound 41 and semaglutide were administered by subcutaneous injection. Materials: Compound 41 is a GIP analogue described above. Semaglutide is a GLP-1 receptor agonist. A DIO (diet induced obese) mouse is a C57BL/6 - "Black 6" - mouse which has been made obese through conditioning with a special diet. Methods: DIO mice were treated for 2 weeks by sc injection either with vehicle (qd), compound 41 (300 nmol/kg, ev.2nd day), semaglutide (Sema, 10 nmol/kg, qd) or combination of sema + compound 41 (10 nmol/kg, qd and 300 nmol/kg, ev.2nd, respectively). From day 14 to day 34, mice dosed with vehicle either continued on vehicle or switched to compound 41, mice dosed with compound 41 continued on compound 41 therapy, mice dosed with sema continued on sema or switched to the combination therapy of sema + compound 41. Mice dosed with combination therapy of sema + compound 41 continued on the combination therapy. Results: Combination therapy of sema + compound 41, achieved a significant, sustained and greater body weight reduction in DIO mice compared to vehicle- and each monotherapy group (- 24.5% ± 2.4 combination therapy from day 14; -24.1% ± 1.3 combination therapy from day 0; -0.8% ±0.9 compound 41 from day 0; 2.0% ±0.8 compound 41 from day 14; -13.7% ± 2.3 sema; 3.1% ± 0.8, vehicle; relative to initial body weights). The effects on body weight loss in combination groups of sema + compound 41 were similar at the end of the study irrespective of the pretreatment with sema. The results are depicted in Figure 1. Conclusions: In DIO mice compound 41 potentiated the benefits of GLP-1 monotherapy on body weight loss despite compound 41 alone having negligible effect at the doses tested, suggesting the greater potential of this combination therapy in treating obesity and obesity-related comorbidities, especially in subjects where the weight loss plateaus, which may be due to for example the subjects becoming GLP-1 treatment resistant. Other Embodiments While the present invention has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the invention is not limited to the disclosed examples. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term. Other embodiments are in the claims. What is claimed is:

Claims

CLAIMS 1. A method of increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)- [(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
2. A method of increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject who fails to respond to treatment with a GLP-1 agonist, and (ii) administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)- acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
3. A method of increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of at least 1 month, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to increase weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)- [(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
4. A method of maintaining weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist, wherein the subject has experienced weight loss, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to maintain the weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
5. A method of increasing weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss in the subject plateaus and/or the subject is or becomes GLP-1 treatment resistant and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
6. A method of achieving additional weight loss in a subject in need thereof, the method comprising: (i) providing a subject undergoing treatment with a GLP-1 agonist for a period of time during which weight loss is achieved and there is a need to achieve additional weight loss in the subject, and (ii) following step (i), administering to the subject (a) a GLP-1 agonist and (b) a GIP agonist, each in an amount that together is sufficient to achieve the additional weight loss in the subject, wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy- nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
7. A combination of a GLP-1 agonist and a GIP agonist for use in achieving weight loss in a subject, wherein weight loss in the subject is achieved by use of the GLP-1 agonist and the GIP agonist in a method, wherein the method as defined in any one of claims 1-6, and wherein the GIP agonist is H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)- [(Piperazine-1-yl)-acetyl]-Peg3- Peg3)-AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
8. Use of a combination of a GLP-1 agonist and a GIP agonist for manufacture of a medicament for use in a method of achieving weight loss in a subject, wherein the method is as defined in any one of claims 1-6, and wherein the GIP agonist is H-Y-Aib- EGTFISDYSIELDK-K((19-Carboxy-nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-Peg3- Peg3)- AAQAFIEWLLAQGPSSGAPPPS-NH2 (compound 41) (SEQ ID NO: 41), or a pharmaceutically acceptable salt thereof.
9. The method, the combination for use, or the use of any one of claims 1-8, wherein the subject has a BMI of >30 kg/m2, such as an initial BMI of >30 kg/m2 before the method is used on the subject.
10. The method, the combination for use, or the use of any one of claims 1-9, wherein the GLP-1 agonist in step (ii) is the same as the GLP-1 agonist in step (i).
11. The method, the combination for use, or the use of any one of claims 1-10, wherein the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, albiglutide, and taspoglutide, preferably wherein the GLP-1 agonist is semaglutide.
12. The method, the combination for use, or the use of any one of claims 1-11, wherein the GLP-1 agonist and/or the GIP agonist is administered by one or more of the following routes of administration: injection (including subcutaneous injection, intramuscular injection, intravenous injection, epidural injection and intraperitoneal injection), infusion pump (such as subcutaneous infusion pump), oral, sublingual, rectal, vaginal, parenteral, topical, dermal (such as by transdermal patch), nasal (such as by nasal spray) and pulmonary spray, preferably by subcutaneous injection.
13. The method, the combination for use, or the use of any one of claims 1-12, wherein the GLP-1 agonist is administered at a dose of up to about 50 mg, such as up to about 40 mg, up to about 30 mg, up to about 20 mg or up to about 10 mg.
14. The method, the combination for use, or the use of any one of claims 1-13, wherein the GLP-1 agonist is administered to the subject at least once, twice, or three times daily, or once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 28 days or every month, preferably wherein the GLP-1 agonist is administered to the subject once weekly.
15. The method, the combination for use, or the use of any one of claims 1-14, wherein (a) in step (i) the GLP-1 agonist is administered to the subject as defined in any one of claims 12-14; and /or (b) in step (ii) the GLP-1 agonist is administered to the subject as defined in any one of claims 12-14.
16. The method, the combination for use, or the use of any one of claims 1-15, wherein the GIP agonist is administered to the subject at a dose of up to about 15 mg, up to about 12.5 mg, up to about 10 mg, up to about 7.5 mg, up to about 5 mg, up to about 2.5 mg, up to about 2 mg, up to about 1 mg, up to about 0.5 mg or up to about 0.1 mg.
17. The method, the combination for use, or the use of any one of claims 1-16, wherein the GIP agonist is administered to the subject at least once, twice, or three times daily, or once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 28 days or every month, preferably wherein the GIP agonist is administered to the subject once daily or once weekly.
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