The present invention relates to GLP-1 /Glucagon dual agonist prodrugs, pharmaceutical compositions comprising said prodrugs as well as their use as a medicament for treating or preventing diseases or disorders which can be treated by a GLP-1 /Glucagon dual agonist, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.

BACKGROUND OF THE INVENTION

GLP-1 agonists

Exendin-4 is a 39-amino acid peptide, isolated from the salivary secretions of the venomous Gila monster (Heloderma suspectum). It has some sequence similarity to several members of the glucagon-like peptide family, with the highest homology of 53% being to glucagon-like peptide-1 [7-36]-amide (GLP-1 ). Exendin-4 acts as a agonist on the GLP-1 receptor and bears GLP-1 -like insulin sectretagogue action in isolated rat islets. Exendin-4 is a high potency agonist and truncated GLP-1 agonist-(9-39)-amide is an antagonist at the glucagon-like peptide 1 -(7-36)-amide receptor of insulin-secreting beta-cells, (see e.g. J. Biol. Chem. 268(26):19650-19655). Exendin-4 ("exenatide") was approved recently in the US and EU for improving glycemic control in patients with type 2 diabetes taking metformin and/or a sulfonylurea but have not achieved adequate glycemic control.

The amino acid sequence of exendin-4 is shown as SEQ ID NO: 1

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

The amino acid sequence of GLP-1 (7-36)-amide is shown as SEQ ID NO 2

HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2

Glucagon is a 29-amino acid peptide which is released into the bloodstream when circulating glucose is low. Glucagon's amino acid sequence is shown in SEQ ID NO 3.

HSQGTFTSDYSKYLDSRRAQDFVQWLMNT-OH

During hypoglycemia, when blood glucose levels drop below normal, glucagon signals the liver to break down glycogen and release glucose, causing an increase of blood glucose levels to reach a normal level. Hypoglycemia is a common side effect of insulin treated patients with hyperglycemia (elevated blood glucose levels) due to diabetes. Thus, glucagon's most predominant role in glucose regulation is to counteract insulin action and maintain blood glucose levels.

Hoist (Hoist, J. J. Physiol. Rev. 2007, 87, 1409) and Meier (Meier, J. J. Nat. Rev.

Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1 , liraglutide and exendin-4, have 3 major pharmacological activities to improve glycemic control in patients with T2DM by reducing fasting and postprandial glucose (FPG and PPG): (i) increased glucose-dependent insulin secretion (improved first- and second-phase), (ii) glucagon suppressing activity under hyperglycemic conditions, (iii) delay of gastric emptying rate resulting in retarded absorption of meal-derived glucose.

GLP-1/Glucagon (Glc) agonists

Pocai et al (Obesity. 2012;20:1566-1571 ; Diabetes 2009, 58, 2258) and Day et al. (Nat Chem Biol 2009;5:749) describe that dual activation of the GLP-1 and glucagon receptors, e.g., by combining the actions of GLP-1 and glucagon in one molecule leads to a therapeutic principle with anti-diabetic action and a pronounced weight lowering effect.

Peptides which bind and activate both the glucagon and the GLP-1 receptor (Hjort et al. Journal of Biological Chemistry, 269, 30121 -30124,1994; Day JW et al, Nature Chem Biol, 5: 749-757, 2009) and suppress body weight gain and reduce food intake are described in patent applications WO 2008/071972, WO 2008/101017, WO

2009/155258, WO 2010/096052, WO 2010/096142, WO 201 1/075393, WO

2008/152403, WO 2010/070251, WO 2010/070252, WO 2010/070253, WO

2010/070255, WO 201 11 \ 60630, WO 201 1/006497, WO 201 1/152181, WO

201 1 /1 521 82, WO201 11λ 1741 5, WO201 11λ 1 741 6, and WO 2006/134340, the contents of which are herein incorporated by reference.

In addition, triple co-agonist peptides which not only activate the GLP-1 and the glucagon receptor, but also the GI P receptor (Gastric inhibitory polypeptide) are described in WO 2012/0881 1 6 and by VA Gault et al (Biochem Pharmacol, 85, 1 6655-1 6662, 201 3; Diabetologia, 56, 141 7-1424, 201 3).

Bloom et al. (WO 2006/1 34340) disclose that peptides which bind and activate both the glucagon and the GLP-1 receptor can be constructed as hybrid molecules from glucagon and exendin-4, where the N-terminal part (e.g. residues 1 -14 or 1 -24) originate from glucagon and the C-terminal part (e.g. residues 1 5-39 or 25-39) originate from exendin-4.

Otzen et al (Biochemistry, 45, 14503-1451 2, 2006) disclose that N- and C-terminal hydrophobic patches are involved in fibrillation of glucagon, due to the hydrophobicity and/or high β-sheet propensity of the underlying residues.

WO2014/056872 discloses peptides which bind and activate both the glucagon and the GLP-1 receptor that are derived from exendin-4 wherein at least the aminoacid at position 14 bear a side chain for a prolonged half life.

Peptides used in this invention are exendin-4 peptide analogues comprising leucine in position 1 0 and glutamine in position 1 3 and are described in WO201 5/086731 , WO201 5/086732, WO201 5/086733.

Peptides also used in this invention are exendin-4 peptide analogues comprising beta-alanine in position 28 and are described in EP1 5305899.5.

Further a peptide is used in this invention which is a exendin-4 peptide analogue comprising glutamine at position 3, beta-alanine in position 28 and D-alanines in position 29 and 34.

Peptides used in this invention preferably are soluble not only at neutral pH, but also at pH 4.5. Also the chemical stability at pH values of 4.5 to 5 is an important criterion for the long acting prodrug product. The prodrug is preferably formulated in this pH range in order to obtain a shelflife from at least 6 month at 4°C.

Longacting GLP-1 /Glucagon agonists

Ideally, the peptide is formulated in a fashion that provides for a sustained plasma level in human for at least one week after application to a human body resulting in a once-weekly or longer injection frequency.

Current therapy with a long acting GLP-1 agonists is Bydureon® which is exendin-4 in a depot suspension for a once weekly injection based on poly(glycol-co lactic acid) using a 23 gauge needle.

WO2012/173422 describes a GLP-1 /Glucagon agonist conjugated to the Fc region of an immunoglobulin for weekly administration wherein the peptide is derived from oxyntomodulin.

Carrier linked prodrugs

To enhance physicochemical or pharmacokinetic properties of a drug in vivo, such as its half-live, such drug can be conjugated with a carrier. If the drug is transiently bound to a carrier and/or a linker, such systems are commonly assigned as carrier-linked prodrugs. According to the definitions provided by lUPAC (as given under

http://www.chem.qmul.ac.uk/iupac.medchem, accessed on July 22, 2009), a carrier-linked prodrug is a prodrug that contains a temporary linkage of a given active substance with a transient carrier group that produces improved physicochemical or pharmacokinetic properties and that can be easily removed in vivo, usually by a hydrolytic cleavage.

The linkers employed in such carrier-linked prodrugs may be transient, meaning that they are non-enzymatically hydrolytically degradable (cleavable) under physiological conditions (aqueous buffer at pH 7.4, 37°C) with half-lives ranging from, for example, one hour to three months. Suitable carriers are polymers and can either be directly conjugated to the linker or via a non-cleavable spacer.

Transient polymer conjugation through traceless prodrug linkers combines the advantages of prolonged residence time due to polymer attachment and the recovery of the original pharmacology of the native peptide after release from the polymer conjugate.

Using polymer-linker peptide conjugates, native unchanged peptide is slowly released after application to a patient, governed only by release kinetics of the linker and pharmacokinetics of the polymer carrier. Ideally, release kinetics would be independent from the presence of enzymes like proteases or esterases in body fluids to guarantee a consistent and homogenous release pattern.

WO2008/148839, WO2009/095479 and WO2012/035139 refer to prodrugs comprising drug linker conjugates, where the linker is covalently attached via a cleavable bond to a biologically active moiety, such as the GLP 1 - agonist exendin-4. The biologically active moiety is released from the prodrug upon cyclization-activation by cyclic imide formation. The release kinetic is dependent on the pH value and is minimum for storage of the prodrug at pH values from 4.5 to 5 and reach its intended release rate at physiological pH of around 7.4 to 7.5. An GLP-1 agonist-prodrug is described in which the linker is based on L-alanine and the polymeric carrier is a PEG-lysine based hydrogel. Not described are dual GLP-1 /Glucagon agonist-prodrugs.

Hyaluronic acid (HA)

Dhal et al (Journal of Biomedical Nanotechnology, vol 9, 2013, 1 - 13) report hyaluronic acid as a suitable carrier for drug conjugates. Kong et al. (Biomaterials 31 (2010), 4121 -4128) report an exendin-4-hyaluronic acid conjugate which showed an glucose lowering effect over 3 days in mice. The used HA was a linear polymer with a drug load ranging from about 2.4 to 12.%.

In the present invention hydrogels of crosslinked hyaluronic acid are chosen due to their longer residence time as a local depot at the application site than soluble HA.

Important criteria for the use of hyaluronic acid (HA) as a carrier polymer is the achievable drug load in the final drug product which is determined by the drug load on the polymer itself and the concentration of the final solution/suspension. Giving the fact that the injection volume for subcutaneous drug depots is practically limited to

equal/less than 1 mL, preferably equal/less than 0.6 mL.

The more concentrated the polymer solutions/suspensions of HA is, the more viscous is the formulation which has a negative impact on the syringability of the prodrug formulation. Viscous solutions need injection needles of a larger diameter to limit the force on the plunger of which the syringe is pressed. Also the time for injection is longer.

It is an object of the present invention to provide a GLP-1 /Glucagon agonist prodrug for administering as a subcutaneous depot which releases a GLP-1 /Glucagon agonist in an active form over the time period of at least 6 days between administrations and which can be injected through 26 gauge needles or even needles of smaller inner diameter for good patient compliance.

An object of the invention is a prodrug or a pharmaceutically acceptable salt thereof comprising a drug linker conjugate of formula (I)

The Z - L' 1 -L 2 - L'- the Y - the R : 20

(I)

wherein Y is a peptide moiety having the formula (II)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Lys

X20 represents an amino acid residue selected from Lys, Gin and His,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val,

or wherein Y is a peptide moiety having the formula (III)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (III)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Leu and His

X20 represents an amino acid residue selected from His, Arg, Lys, and Gin, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Lys, Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val,

or

wherein Y is a peptide moiety having the formula (IV)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Leu-Leu-Asp-Glu-Gln-X18-Ala- Lys-Asp-Phe-lle-Glu-Trp-Leu-lle-Ala-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (IV)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Leu,

X32 represents an amino acid residue selected from Ser and Val,

or

wherein Y is a peptide moiety having the formula (IVa)

H2N-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-X15-Glu-Gln-Leu-Ala- Arg-Asp-Phe-lle-Glu-Trp-Leu-lle-Bal-X29-Gly-X31 -X32-Ser-X34-X35-Pro-Pro-Pro- X39-R20 (IVa)

X15 represents an amino acid residue selected from Asp and Glu, (pref. Asp) X29 represents an amino acid residue selected from Gly, D-Ala and Pro, (pref) Gly, D-Ala

X31 represents an amino acid residue selected from Pro, His and Trp, (pref. Pro)

X32 represents an amino acid residue selected from Ser, His, Pro and Arg, (pref.

Ser, His, Pro),

X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents an amino acid residue selected from Ala, Pro and Lys, (pref. Ala, Pro)

X39 represents Ser or Pro-Pro-Pro,

or

wherein Y is a peptide moiety having the formula (IVb)

H2N-His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Leu-Leu-Glu-Glu-Gln-Arg- Ala-Arg-Glu-Phe-lle-Glu-Trp-Leu-lle-Bal-D-Ala-Gly-Pro-Pro-Ser-D-Ala -Ala- Pro-Pro-Pro-Ser-R20;

or a salt or solvate thereof;

R20 is OH or NH2;

L is a linker of formula (la),

wherein the dashed line indicates the attachment to the N-Terminus of Y by forming an amide bond;

X is C(R4R4a); N(R4);

R1, R1a, are independently selected from the group consisting of H; and Ci 4 alky I;

R2, R2a, are independently selected from the group consisting of H; and Ci 4 alky I;

R4, R4a, are independently selected from the group consisting of H; and Ci 4 alky I;

wherein R2 , R2a, R4 or R4a is substituted with one group L2-L1-Z; wherein

L2 is a single chemical bond or is a Ci-2o alkyl chain, which is optionally interrupted by one or more groups independently selected from -O- and C(O)N(R3aa) and is optionally substituted with one or more groups independently selected from OH and C(O)N(R3aaR3aaa), wherein R3aa and R3aaa are independently selected from the group consisting of H and Ci-4 alkyl; and

L2 is attached to L1 via a terminal group selected from the group consisting of

wherein L2 is attached to the one position indicated with the dashed line and and L1 is attached to the position indicated with the other dashed line; and

L1 is a C-i-20 alkyl chain, which is optionally interrupted by one or more groups

independently selected from -O- and C(O)N(R5aa) and is optionally substituted with one or more groups independently selected from OH and C(O)N(R5aaR5aaa), wherein R5aa and R5aaa are independently selected from the group consisting of H and Ci-4 alkyl; and

L1 is attached to Z via a terminal amino group forming an amide bond with the carboxy group of the beta-1 ,3-D-glucuronic acid of the hyaluronic acid of Z;

Z is a crosslinked hyaluronic acid hydrogel, in which

0.05 to 20 % of the monomeric disaccharide units are crosslinked by a crosslinker; and 0.2 to 8.5 % of the monomeric disaccharide units bear L1-L2 -L-Y-R20. groups.

The present invention relates to a prodrug which provides a GLP-1 /Glucagon agonist release from a subcutaneous depot in an active form over the time period of at least 6 days between administrations

This helps patients to reduce the frequency of injections, while being able to maintain optimal control the plasma levels of GLP-1 /Glucagon agonist and consequently blood glucose.

Further advantages of the crosslinked hyaluronic acid carrier of the invention are the good injectability through a 26 gauge needle or even a needle of a smaller inner diameter.

LEGENDS TO THE FIGURES

Figure 1 a, Figure 1 b, Figure 1 c show various crosslinking chemistries to synthesize hyaluronic acid hydrogels.

Figure 2a. Magnetic Resonance (MR) images of the HA hydrogel at the injection site, taken at different time points.

Figure 2b. Magnetic Resonance (MR) images of the polymer suspension containing 1 :1 (w/w) HA hydrogel- 800 kDa soluble HA at the injection site, taken at different time points.

Figure 3. In vitro release kinetics of Exendin-4 Seq ID No. 26 dual agonist with weekly linker from the HA hydrogel (example 18). The half-life is 5 days.

Figure 4 In vivo Effect of HA Hydrogel - Dual Agonist (Seq ID No. 26) Conjugate on Non-fasting Blood Glucose in db/db Mice: shown is the the difference level of blood glucose in mmol/L versus the treatment time of the animals for different doses .

Figure 4b In vivo Effect of HA Hydrogel - Dual Agonist (Seq ID No. 26) Conjugate on Non-fasting Blood Glucose in db/db Mice: shown is the the difference level of blood glucose in mmol/L versus the treatment time of the animals for different hydrogel constructs: soluble and crosslinked hyaluronic acid.

Figure 4c In vivo Effect of HA Hydrogel - Dual agonists (Seq ID No. 45, 46 and 48) Conjugates on Non-fasting Blood Glucose in db/db Mice: shown is the level of blood glucose in mmol/L versus the treatment time of the animals.

Figure 4d In vivo Effect of HA Hydrogel - Dual Agonist (Seq ID No. 49) Conjugate on Non-fasting Blood Glucose in db/db Mice: shown is the level of blood glucose in mmol/L versus the treatment time of the animals.

Figure 5 Injectability study: Extrusion Force on syringe plunger for HA hydrogels of different peptide loading.

Detailed Description

The amino acid sequences of the present invention contain the conventional one letter and three letter codes for naturally occurring amino acids, as well as generally accepted three letter codes for other amino acids, such as Aib (a-aminoisobutyric acid).

Furthermore, the following code was used for the amino acid shown in the table below.

GLP-1/Glucagon agonist bound to linker is referred to as "GLP-1/Glucagon agonist moiety".

"Protective groups" refers to a moiety which temporarily protects a chemical functional group of a molecule during synthesis to obtain chemoselectivity in subsequent chemical reactions. Protective groups for alcohols are, for example, benzyl and trityl, protective groups for amines are, for example, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and benzyl and for thiols examples of protective groups are 2,4,6-trimethoxybenzyl, phenylthiomethyl, acetamidomethyl, p-methoxybenzyloxycarbonyl, tert-butylthio, triphenylmethyl, 3-nitro-2-pyridylthio, 4-methyltrityl.

"Protected functional groups" means a chemical functional group protected by a protective group.

"Acylating agent" means a moiety of the structure R-(C=0)-, providing the acyl group in an acylation reaction, optionally connected to a leaving group, such as acid chloride, N-hydroxy succinimide, pentafluorphenol and para-nitrophenol.

"Alkyl" means a straight-chain or branched carbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent.

"Aryl" refers to any substituent derived from a monocyclic or polycyclic or fused aromatic ring, including heterocyclic rings, e.g. phenyl, thiophene, indolyl, napthyl, pyridyl, which may optionally be further substituted.

"Acyl" means a chemical functional group of the structure R-(C=0)-, wherein R is an alkyl or aryl.

"C-1 -4 alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl tert-butyl, or e.g. -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci-4 alkyl carbon may be replaced by a substituent.

"C1-6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, n-hexyl, or e.g. -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, - CH(C2H5)-, -C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci-6 alkyl carbon may be replaced by a substituent.

Accordingly, "CMS alkyl" means an alkyl chain having 1 to 18 carbon atoms and "C8-is alkyl" means an alkyl chain having 8 to 18 carbon atoms. Accordingly, "Ci-5o alkyl" means an alkyl chain having 1 to 50 carbon atoms.

"Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.

"Hyaluronic acid" means a polymer of a disaccharide composed of of beta-1 ,3-D-glucuronic acid and beta-1 ,4-N-acetyl-D-glucosamine and their respective sodium salts. These polymers are linear.

"Disaccharide unit" means the disaccharide composed of beta-1 ,3-D-glucuronic acid and beta-1 ,4-N-acetyl-D-glucosamine and their respective sodium salts and is the monomeric building block for HA.

"Crosslinked hyaluronic acid" means a polymer of hyaluronic acid" wherein different chains of HA are covalently connected by a crosslinker, forming a 3-dimensional polymer network. The degree of crosslinking refers the molar ratio of disaccharide units to crosslinker units in the polymer network.

Crosslinked hyaluronic acid" may be derived by different methods. Reaction of HA with the crosslinker, reaction of modified (activated) HA with the crosslinker, reaction of two different modified HA with the crosslinker. Examples may be described in Oh et al, Journal of Controlled Release 141 (2010), 2-12. Example 1 1 decribes the crosslinking of unmodified HA with divinylsulfone. Further methods for preparing crosslinked HA are also depicted in Figure 1 a, Figure 1 b and Figure 1 c: aldehyde (diol oxidation) and subsequent amine reductive amination, hydroxyl mediated alkylation, amide formation

reaction, Michael Addition Crosslinking (Thiol - maleimide), diol - epoxide chemistry and others.

"Crosslinker" may be a linear or branched molecule or chemical group, preferably is a linear molecule with at least chemical functional groups on each distal ends

"functionalized hyaluronic acid" means a polymer of hyaluronic acid" wherein HA is chemically modified with a group L1 which bears a chemical functional chemical group at its distal end. The degree of functionalization refers the molar ratio of disaccharide units to L1 units in the polymer.

The term "chemical functional group" refers to but not limited to carboxylic acid and activated derivatives, amino, maleimide, thiol and derivatives, sulfonic acid and derivatives, carbonate and derivatives, carbamate and derivatives, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid and derivatives, phosphonic acid and derivatives, haloacetyl, alkyl halides, acryloyi and other alpha-beta unsaturated michael acceptors, arylating agents like aryl fluorides, hydroxylamine, disulfides like pyridyl disulfide, vinyl sulfone, vinyl ketone, diazoalkanes, diazoacetyl compounds, oxirane, and aziridine.

If a chemical functional group is coupled to another chemical functional group, the resulting chemical structure is referred to as "linkage". For example, the reaction of an amine group with a carboxyl group results in an amide linkage.

"Reactive functional groups" are chemical functional groups of the backbone moiety, which are connected to the hyperbranched moiety.

"Functional group" is the collective term used for "reactive functional group",

"degradable interconnected functional group", or "conjugate functional group".

The terms "blocking group" or "capping group" are used synonymously and refer to moieties which are irreversibly connected to reactive functional groups to render them incapable of reacting with for example chemical functional groups.

The terms "protecting group" or "protective group" refers to a moiety which is reversibly connected to reactive functional groups to render them incapable of reacting with for example other chemical functional groups under specific conditions.

The term "derivatives" refers to chemical functional groups suitably substituted with protecting and/or activation groups or to activated forms of a corresponding chemical functional group which are known to the person skilled in the art. For example, activated forms of carboxyl groups include but are not limited to active esters, such as

succinimidyl ester, benzotriazyl ester, nitrophenyl ester, pentafluorophenyl ester, azabenzotriazyl ester, acyl halogenides, mixed or symmetrical anhydrides, acyl imidazole.

The term "non-enzymatically cleavable linker" refers to linkers that are hydrolytically degradable under physiological conditions without enzymatic activity.

The terms "spacer", "spacer group", "spacer molecule", and "spacer moiety" are used interchangeably and if used to describe a moiety present in the hydrogel carrier of the invention, refer to any moiety suitable for connecting two moieties, such as C-i-5o alkyl. which fragment is optionally interrupted by one or more groups selected from -NH-, -N(Ci-4 alkyl)-, -0-, -S-, -C(O)-, -C(0)NH-, -C(0)N(Ci-4 alkyl)-, -O-C(O)-, -S(O)-, -S(0)2-.

The terms "terminal", "terminus" or "distal end" refer to the position of a functional group or linkage within a molecule or moiety, whereby such functional group may be a chemical functional group and the linkage may be a degradable or permanent linkage, characterized by being located adjacent to or within a linkage between two moieties or at the end of an oligomeric or polymeric chain.

The phrases "in bound form" or "moiety" refer to sub-structures which are part of a larger molecule. The phrase "in bound form" is used to simplify reference to moieties by naming or listing reagents, starting materials or hypothetical starting materials well known in the art, and whereby "in bound form" means that for example one or more hydrogen radicals (-H), or one or more activating or protecting groups present in the reagents or starting materials are not present in the moiety.

It is understood that all reagents and moieties comprising polymeric moieties refer to macromolecular entities known to exhibit variabilities with respect to molecular weight, chain lengths or degree of polymerization, or the number of functional groups.

Structures shown for crosslinking reagents, and crosslinked moieties are thus only representative examples.

A reagent or moiety may be linear or branched. If the reagent or moiety has two terminal groups, it is referred to as a linear reagent or moiety. If the reagent or moiety has more than two terminal groups, it is considered to be a branched or multi-functional reagent or moiety.

The linkers employed in such carrier-linked prodrugs are transient, meaning that they are non-enzymatically hydrolytically degradable (cleavable) under physiological conditions (aqueous buffer at pH 7.4, 37°C) with half-lives ranging from, for example, one hour to three months.

The term "GLP-1 /Glucagon agonist hydrogel prodrug" refers to carrier-linked prodrugs of GLP-1 /Glucagon agonist, wherein the carrier is a hydrogel. The terms "hydrogel prodrug" and "hydrogel-linked prodrug" refer to prodrugs of biologically active agents transiently linked to a hydrogel and are used synonymously.

A "hydrogel" may be defined as a three-dimensional, hydrophilic or amphiphilic polymeric network capable of taking up large quantities of water. The networks are composed of homopolymers or copolymers, are insoluble due to the presence of covalent chemical or physical (ionic, hydrophobic interactions, entanglements) crosslinks. The crosslinks provide the network structure and physical integrity.

Hydrogels exhibit a thermodynamic compatibility with water which allows them to swell in aqueous media. The chains of the network are connected in such a fashion that pores exist and that a substantial fraction of these pores are of dimensions between 1 nm and 1000 nm.

"Free form" of a drug refers to a drug, specifically to GLP-1 /Glucagon agonist, in its unmodified, pharmacologically active form, such as after being released from a polymer conjugate.

The terms "drug", "biologically active molecule", "biologically active moiety", "biologically active agent", "active agent", are used synonymously and refer to GLP-1 /Glucagon agonist, either in its bound or free form.

A "therapeutically effective amount" of GLP-1 /Glucagon agonist as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which are all within the ordinary skills of a trained physician.

"Stable" and "stability" means that within the indicated storage time the hydrogel conjugates remain conjugated and do not hydrolyze to a substantial extent and exhibit an acceptable impurity profile relating to GLP-1 /Glucagon agonist. To be considered stable, the composition contains less than 5% of the drug in its free form.

The term "pharmaceutically acceptable" means approved by a regulatory agency such as the EMEA (Europe) and/or the FDA (US) and/or any other national regulatory agenciesy for use in animals, preferably in humans.

"Pharmaceutical composition" or "composition" means one or more active ingredients, and one or more inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the

pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable excipient (pharmaceutically acceptable carrier).

"Dry composition" means that the GLP-1 /Glucagon agonist hydrogel prodrug

composition is provided in a dry form in a container. Suitable methods for drying are for example spray-drying and lyophilization (freeze-drying). Such dry composition of GLP-1/Glucagon agonist hydrogel prodrug has a residual water content of a maximum of 10 %, preferably less than 5% and more preferably less than 2% (determined according to Karl Fischer method). The preferred method of drying is lyophilization. "Lyophilized composition" means that the GLP-1/Glucagon agonist hydrogel polymer prodrug composition was first frozen and subsequently subjected to water reduction by means of reduced pressure. This terminology does not exclude additional drying steps which occur in the manufacturing process prior to filling the composition into the final container.

"Lyophilization" (freeze-drying) is a dehydration process, characterized by freezing a composition and then reducing the surrounding pressure and, optionally, adding heat to allow the frozen water in the composition to sublime directly from the solid phase to gas. Typically, the sublimed water is collected by desublimation.

"Reconstitution" means the addition of a liquid to a dry composition to bring it into the form of a liquid or suspension composition. It is understood that the term "reconstitution" is not limited to the addition of water, but refers to the addition of any liquid, including for example buffers or other aqueous solutions.

"Reconstitution solution" refers to the liquid used to reconstitute the dry composition of an GLP-1 /Glucagon agonist hydrogel prodrug prior to administration to a patient in need thereof.

"Container" means any container in which the GLP-1/Glucagon agonist hydrogel prodrug composition is comprised and can be stored until reconstitution.

"Buffer" or "buffering agent" refers to chemical compounds that maintain the pH in a desired range. Physiologically tolerated buffers are, for example, sodium phosphate, succinate, histidine, bicarbonate, citrate and acetate, pyruvate. Antacids such as

Mg(OH)2 or ZnC03 may be also used. Buffering capacity may be adjusted to match the conditions most sensitive to pH stability.

"Excipients" refers to compounds administered together with the therapeutic agent, for example, buffering agents, isotonicity modifiers, preservatives, stabilizers, anti-adsorption agents, oxidation protection agents, or other auxiliary agents. However, in some cases, one excipient may have dual or triple functions.

A "lyoprotectant" is a molecule which, when combined with a protein of interest, significantly prevents or reduces chemical and/or physical instability of the protein upon drying in general and especially during lyophilization and subsequent storage.

Exemplary lyoprotectants include sugars, such as sucrose or trehalose; amino acids such as arginine, glycine, glutamate or histidine; methylamines such as betaine;

lyotropic salts such as magnesium sulfate; polyols such as trihydric or higher sugar alcohols, e.g. glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol;

ethylene glycol; propylene glycol; polyethylene glycol; pluronics; hydroxyalkyl starches, e.g. hydroxyethyl starch (HES), and combinations thereof.

"Surfactant" refers to wetting agents that lower the surface tension of a liquid.

"Isotonicity modifiers" refer to compounds which minimize pain that can result from cell damage due to osmotic pressure differences at the injection depot.

The term "stabilizers" refers to compouds used to stabilize the polymer prodrug.

Stabilisation is achieved by strengthening of the protein-stabilising forces, by

destabilisation of the denatured state, or by direct binding of excipients to the protein.

"Anti-adsorption agents" refers to mainly ionic or non-ionic surfactants or other proteins or soluble polymers used to coat or adsorb competitively to the inner surface of the composition's container. Chosen concentration and type of excipient depends on the effect to be avoided but typically a monolayer of surfactant is formed at the interface just above the CMC value.

"Oxidation protection agents" refers to antioxidants such as ascorbic acid, ectoine, glutathione, methionine, monothioglycerol, morin, polyethylenimine (PEI), propyl gallate, vitamin E, chelating agents such aus citric acid, EDTA, hexaphosphate, thioglycolic acid.

"Antimicrobial" refers to a chemical substance that kills or inhibits the growth of microorganisms, such as bacteria, fungi, yeasts, protozoans and/or destroys viruses.

"Sealing a container" means that the container is closed in such way that it is airtight, allowing no gas exchange between the outside and the inside and keeping the content sterile.

The term "reagent" or "precursor" refers to an intermediate or starting material used in the assembly process leading to a prodrug of the present invention.

An object of the invention is a prodrug or a pharmaceutically acceptable salt thereof comprising a drug linker conjugate of formula (I)

The Z - L' 1 -L 2 - L'- the Y - the R 20 ( the I)

wherein Y is a peptide moiety having the formula (II)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (II)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Lys

X20 represents an amino acid residue selected from Lys, Gin and His,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val,

or wherein Y is a peptide moiety having the formula (III)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (III)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Leu and His

X20 represents an amino acid residue selected from His, Arg, Lys, and Gin, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Lys, Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val,

or

wherein Y is a peptide moiety having the formula (IV)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Leu-Leu-Asp-Glu-Gln-X18-Ala- Lys-Asp-Phe-lle-Glu-Trp-Leu-lle-Ala-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (IV)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Leu,

X32 represents an amino acid residue selected from Ser and Val,

or a salt or solvate thereof;

or a salt or solvate thereof;

R20 is OH or NH2;

L is a linker of formula (la),

wherein the dashed line indicates the attachment to the N-Terminus of Y by forming an amide bond;

X is C(R4R4a); N(R4);

R1, R1a, are independently selected from the group consisting of H; and Ci 4 alky I;

R2, R2a, are independently selected from the group consisting of H; and Ci 4 alky I;

R4, R4a, are independently selected from the group consisting of H; and Ci 4 alky I;

wherein R2 , R2a, R4 or R4a is substituted with one group L2-L1-Z; wherein

L2 is a single chemical bond or is a Ci-2o alkyl chain, which is optionally interrupted by one or more groups independently selected from -O- and C(O)N(R3aa) and is optionally substituted with one or more groups independently selected from OH and

C(O)N(R3aaR3aaa), wherein R3aa and R3aaa are independently selected from the group consisting of H and C1-4 alkyl; and

L2 is attached to L1 via a terminal group selected from the group consisting of

wherein L2 is attached to the one position indicated with the dashed line and and L1 is attached to the position indicated with the other dashed line; and

L1 is a C-i-20 alkyl chain, which is optionally interrupted by one or more groups

independently selected from -O- and C(0)N(R5aa) and is optionally substituted with one or more groups independently selected from OH and C(O)N(R5aaR5aaa), wherein R5aa and R5aaa are independently selected from the group consisting of H and Ci-4 alkyl; and

L1 is attached to Z via a terminal amino group forming an amide bond with the carboxy group of the beta-1 ,3-D-glucuronic acid of the hyaluronic acid of Z;

Z is a crosslinked hyaluronic acid hydrogel, in which

0.05 to 20 % of the monomeric disaccharide units are crosslinked by a crosslinker; and 0.2 to 8.5 % of the monomeric disaccharide units bear L1-L2 -L-Y-R20. groups.

Further embodiments of L, L1 , L2, Z and Y.

In another embodiment

L is a linker moiety of formula (lb),

(lb),

wherein the dashed line indicates attachment to Y by forming an amide bond;

R1, R1a, R2a are selected independently from the group consisting of H and Ci-4 alkyl;

L2-L1-Z is defined as described above.

In another embodiment

L is a linker moiety of formula (lb), wherein

R1 is CH3;

R1a is H;

R2a is H; and

L2-L1-Z is defined as described above.

In another embodiment

L is a linker moiety of formula (lb), wherein

R is H;

R a is CH3;

R2a is H; and

L2-L1-Z is defined as described above.

In another embodiment

L is a linker moiety of formula (lb), wherein

R1 is CH3;

R1a is CH3;

R2a is H; and

L2-L1-Z is defined as described above.

In another embodiment

L is a linker moiety -L of formula (lc),

L (Ic)

wherein the dashed line indicates attachment to Y by forming an amide bond; R1 is selected from H or Ci-4 alkyl, preferably H;

R1a is selected from H or Ci-4 alkyl, preferably H;

R2, R2a are independently selected from the group consisting of H and Ci-4 alkyl; wherein L2-L1-Z is defined as described above.

In another embodiment

L is a linker moiety -L of formula (lc),

Z (lc)

wherein the dashed line indicates attachment to Y by forming an amide bond;

Ft1 and Ft1a are H;

Ft2, Ft2a are independently selected from the group consisting of H and CH3;

wherein L2-L1-Z is defined as described above.

In another embodiment

L is a linker moiety -L of formula (lc), wherein

Ft1 and Ft1a are H;

Ft2 is H and Ft2a is CH3;

wherein L2-L1-Z is defined as described above.

In another embodiment

L2 is a C-i-10 alkyl chain, which is optionally interrupted by one or two groups

independently selected from -O- and C(0)N(Ft3aa) and, wherein Ft3aa is independently selected from the group consisting of H and Ci-4 alkyl; and

L2 is attached to L1 via a terminal group selected from the group consisting of

wherein L2 is attached to the one position indicated with the dashed line and and L1 is attached to the position indicated with the other dashed line; and

In another embodiment

L2 is a C-i-6 alkyl chain, which is optionally interrupted by one group selected from -O-and C(0)N(R3aa) and, wherein R3aa is independently selected from the group consisting of H and Ci-4 alkyl; and

L2 is attached to L1 via a terminal group selected from the group consisting of

wherein L2 is attached to the one position indicated with the dashed line and and L1 is attached to the position indicated with the other dashed line.

In another embodiment

L' 2 Is -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -C (0) NH- Or -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - And

is attached to L1 via the terminal group

wherein wherein L2 is attached to the Sulfur atom indicated with the dashed line and and L1 is attached to nitrogen atom indicated with the dashed line.

In another embodiment

L1 is a C1-10 alkyl chain, with an amino group on one distal end, which is optionally interrupted by one or two groups independently selected from -O- and C(0)N(R5aa) and, wherein R5aa is independently selected from the group consisting of H and Ci- alkyl.

A further embodiment relates to prodrugs, wherein

Z is a crosslinked hyaluronic acid hydrogel, in which

0.05 to 15 % of the monomeric disaccharide units are crosslinked by a crosslinker.

A further embodiment relates to prodrugs, wherein

Z is a crosslinked hyaluronic acid hydrogel, in which

1 to 10 % of the monomeric disaccharide units are crosslinked by a crosslinker.

A further embodiment relates to prodrugs, wherein

Z is a crosslinked hyaluronic acid hydrogel, in which

0.2 to 8.5 % of the monomeric disaccharide units bear L1-L2 -L-Y-R20. groups.

A further embodiment relates to prodrugs, wherein

Z is a crosslinked hyaluronic acid hydrogel, in which

0.2 to 6 % of the monomeric disaccharide units bear L1-L2 -L-Y-R20. groups.

A further embodiment relates to prodrugs, wherein

Z is a crosslinked hyaluronic acid hydrogel, in which

0.2 to 5 % of the monomeric disaccharide units bear L1-L2 -L-Y-R20. groups.

A further embodiment relates to prodrugs, wherein

Z is a crosslinked hyaluronic acid hydrogel, in which

0.4 to 4 % of the monomeric disaccharide units bear L1-L2 -L-Y-R20. groups.

In another embodiment the GLP-1 /Glucagon agonist prodrug has a structure as represented by formula (V)

In another embodiment the GLP-1 /Glucagon agonist prodrug has a structure as represented by formula (VI) (Aib-linker)

In another embodiment the GLP-1 /Glucagon agonist prodrug has a structure as represented by formula (VII)

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (II), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib, X3 represents an amino acid residue selected from Gin and His,

X18 represents Arg

X20 represents an amino acid residue selected from Lys, Gin and His, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (II), wherein

X2 represents an D-Ser

X3 represents His,

X18 represents Arg

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (II), wherein

Represents X2 D-Ser,

X3 represents an amino acid residue selected from Gin and His,

X18 represents Arg,

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (II), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents His,

X18 represents Arg,

X20 represents Lys,

X21 represents Asp,

X28 represents Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (II), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Lys,

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (II), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid selected from Arg and Lys,

X20 represents an amino acid residue selected from Lys, Gin and His,

X21 represents Asp,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (II), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib, X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid selected from Arg and Lys,

X20 represents an amino acid residue selected from Lys, Gin and His, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety Y formula (II), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents Arg

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents Ala,

X32 represents Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib, X3 represents an amino acid residue selected from Gin and His,

X18 represents Leu

X20 represents an amino acid residue selected from His, Arg, Lys and Gin, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Lys, Ser and Ala, X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from His and Leu;

X20 represents an amino acid residue selected from His, Arg, Lys and Gin, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Lys, Ser and Ala, X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents Aib,

X3 represents His,

X18 represents Leu,

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents His,

X18 represents an amino acid residue selected from His and Leu,

X20 represents an amino acid residue selected from His, Arg, Lys and Gin,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Lys, Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents Gin,

X18 represents Leu,

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents Ala,

X32 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib, X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from His and Leu,

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Lys, Ser and Ala, X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from His and Leu,

X20 represents an amino acid residue selected from His, Arg, Lys and Gin,

X21 represents Asp,

X28 represents an amino acid residue selected from Lys, Ser and Ala, X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents Leu,

X20 represents an amino acid residue selected from Lys and Gin,

X21 represents Glu,

X28 represents Ala,

X32 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib, X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from His and Leu,

X20 represents an amino acid residue selected from His, Arg, Lys and Gin, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (III), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib, X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from His and Leu,

X20 represents an amino acid residue selected from His, Arg, Lys and Gin, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Lys, Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety Y of formula (II) or (III), wherein

X2 represents an amino acid residue selected from Aib and D-Ser,

X3 represents His,

X18 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Leu and Arg,

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IV), wherein

Represents X2 D-Ser,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Leu,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IV), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents His,

X18 represents an amino acid residue selected from Arg and Leu, particularly Leu, X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IV), wherein

Represents X2 D-Ser,

X3 represents Gin,

X18 represents Arg,

X32 represents an amino acid residue selected from Ser and Val.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IV), wherein

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Leu,

X32 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa)

H2N-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-X15-Glu-Gln-Leu-Ala- Arg-Asp-Phe-lle-Glu-Trp-Leu-lle-Bal-X29-Gly-X31 -X32-Ser-X34-X35-Pro-Pro-Pro- X39-R20 (IVa)

wherein

X15 represents an amino acid residue selected from Asp and Glu, (pref. Asp) X29 represents an amino acid residue selected from Gly, D-Ala and Pro, (pref) Gly, D-Ala

X31 represents an amino acid residue selected from Pro, His and Trp, (pref. Pro) X32 represents an amino acid residue selected from Ser, His, Pro and Arg, (pref.

Ser, His, Pro),

X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents an amino acid residue selected from Ala, Pro and Lys, (pref. Ala,

Pro)

X39 represents Ser or Pro-Pro-Pro,

or a salt or solvate thereof.

A further embodiment relates to a group of prodrugs having a peptide moiety of fo (IVa), wherein

X15 represents Asp,

X29 represents an amino acid residue selected from Gly, D-Ala and Pro,

X31 represents an amino acid residue selected from Pro, His and Trp,

X32 represents an amino acid residue selected from Ser, His, Pro and Arg, X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents an amino acid residue selected from Ala, Pro and Lys,

X39 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety of fo (IVa), wherein

X15 represents an amino acid residue selected from Asp and Glu,

X29 represents Gly,

X31 represents an amino acid residue selected from Pro, His and Trp,

X32 represents an amino acid residue selected from Ser, His, Pro and Arg, X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents an amino acid residue selected from Ala, Pro and Lys,

X39 represents Ser or Pro-Pro-Pro.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents an amino acid residue selected from Asp and Glu,

X29 represents Gly,

X31 represents Pro,

X32 represents an amino acid residue selected from Ser, His and Pro,

X34 represents Gly,

X35 represents Ala,

X39 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents Asp,

X29 represents D-Ala,

X31 represents Pro,

X32 represents Pro,

X34 represents D-Ala,

X35 represents an amino acid residue selected from Ala and Pro,

X39 represents Ser or Pro-Pro-Pro.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents an amino acid residue selected from Asp and Glu,

X29 represents an amino acid residue selected from Gly, D-Ala and Pro,

X31 represents Pro,

X32 represents an amino acid residue selected from Ser, His, Pro and Arg, X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents an amino acid residue selected from Ala, Pro and Lys,

X39 represents Ser or Pro-Pro-Pro.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents Asp,

X29 represents Gly,

X31 represents His,

X32 represents Pro,

X34 represents Gly,

X35 represents an amino acid residue selected from Ala and Lys,

X39 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents Asp,

X29 represents an amino acid residue selected from Gly and Pro,

X31 represents Pro,

X32 represents Ser,

X34 represents Gly,

X35 represents Ala,

X39 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents an amino acid residue selected from Asp and Glu,

X29 represents an amino acid residue selected from Gly, D-Ala and Pro,

X31 represents an amino acid residue selected from Pro, His and Trp,

X32 represents Pro,

X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents an amino acid residue selected from Ala, Pro and Lys,

X39 represents Ser or Pro-Pro-Pro.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents Asp,

X29 represents an amino acid residue selected from Gly and Pro,

X31 represents Pro,

X32 represents His, ,

X34 represents Gly,

X35 represents Ala,

X39 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents an amino acid residue selected from Asp and Glu,

X29 represents an amino acid residue selected from Gly, D-Ala and Pro,

X31 represents an amino acid residue selected from Pro, His and Trp, X32 represents an amino acid residue selected from Ser, His, Pro and Arg, X34 represents Gly,

X35 represents an amino acid residue selected from Ala, Pro and Lys,

X39 represents Ser or Pro-Pro-Pro.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents Asp,

X29 represents D-Ala,

X31 represents Pro,

X32 represents an amino acid residue selected from Ser and Pro,

X34 represents D-Ala,

X35 represents an amino acid residue selected from Ala and Pro,

X39 represents Ser or Pro-Pro-Pro.

A further embodiment relates to a group of prodrugs having a peptide moiety of fo (IVa), wherein

X15 represents an amino acid residue selected from Asp and Glu,

X29 represents an amino acid residue selected from Gly, D-Ala and Pro,

X31 represents an amino acid residue selected from Pro, His and Trp,

X32 represents an amino acid residue selected from Ser, His, Pro and Arg,

X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents Ala,

X39 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents Asp,

X29 represents Gly,

X31 represents an amino acid residue selected from Pro and His,

X32 represents Pro,

X34 represents Gly,

X35 represents Lys,

X39 represents Ser.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents Asp,

X29 represents an amino acid residue selected from Gly and D-Ala,

X31 represents Pro,

X32 represents Pro,

X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents Pro,

X39 represents Pro-Pro-Pro.

A further embodiment relates to a group of prodrugs having a peptide moiety of formula (IVa), wherein

X15 represents an amino acid residue selected from Asp and Glu,

X29 represents an amino acid residue selected from Gly, D-Ala and Pro,

X31 represents an amino acid residue selected from Pro, His and Trp,

X32 represents an amino acid residue selected from Ser, His, Pro and Arg,

X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents an amino acid residue selected from Ala, Pro and Lys,

X39 represents Ser.

In one embodiment Y refers to an GLP-1/Glucagon agonist of Seq. ID No 60.

In one embodiment Y refers to an GLP-1 /Glucagon agonist selected from sequences Seq. ID No 4 to 60.

In one embodiment Y refers to an GLP-1 /Glucagon agonist selected from sequences Seq. ID No 4 to 44.

In one embodiment Y refers to an GLP-1 /Glucagon agonist selected from sequences Seq. ID No 4 to 22.

In one embodiment Y refers to an GLP-1 /Glucagon agonist selected from sequences Seq. ID No 23 to 39.

In one embodiment Y refers to an GLP-1 /Glucagon agonist selected from sequences Seq. ID No 40 to 44.

Claims

1 . A prodrug or a pharmaceutically acceptable salt thereof comprising a drug linker conjugate of formula (I)

The Z - L' 1 -L 2 - L'- the Y - the R 20 ( the I)

wherein Y is a peptide moiety having the formula (II)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (II)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Lys

X20 represents an amino acid residue selected from Lys, Gin and His,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val,

or wherein Y is a peptide moiety having the formula (III)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (III)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Leu and His

X20 represents an amino acid residue selected from His, Arg, Lys, and Gin, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Lys, Ser and Ala, X32 represents an amino acid residue selected from Ser and Val,

or

wherein Y is a peptide moiety having the formula (IV)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Leu-Leu-Asp-Glu-Gln-X18-Ala- Lys-Asp-Phe-lle-Glu-Trp-Leu-lle-Ala-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (IV)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Leu,

X32 represents an amino acid residue selected from Ser and Val,

or

wherein Y is a peptide moiety having the formula (IVa)

H2N-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-X15-Glu-Gln-Leu-Ala- Arg-Asp-Phe-lle-Glu-Trp-Leu-lle-Bal-X29-Gly-X31 -X32-Ser-X34-X35-Pro-Pro-Pro- X39-R20 (V)

X15 represents an amino acid residue selected from Asp and Glu, (pref. Asp) X29 represents an amino acid residue selected from Gly, D-Ala and Pro, (pref) Gly, D-Ala

X31 represents an amino acid residue selected from Pro, His and Trp, (pref. Pro)

X32 represents an amino acid residue selected from Ser, His, Pro and Arg, (pref.

Ser, His, Pro),

X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents an amino acid residue selected from Ala, Pro and Lys, (pref. Ala, Pro)

X39 represents Ser or Pro-Pro-Pro,

or

wherein Y is a peptide moiety having the formula (IVb)

H2N-His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Leu-Leu-Glu-Glu-Gln-Arg- Ala-Arg-Glu-Phe-lle-Glu-Trp-Leu-lle-Bal-D-Ala-Gly-Pro-Pro-Ser-D-Ala -Ala- Pro-Pro-Pro-Ser-R20;

or a salt or solvate thereof ;

R20 is OH or NH2;

L is a linker of formula (la),

wherein the dashed line indicates the attachment to the N-Terminus of Y by forming an amide bond;

X is C(R4R4a); N(R4);

R1 , R1a, are independently selected from the group consisting of H; and Ci 4 alky I ;

R2, R2a, are independently selected from the group consisting of H; and Ci 4 alky I ;

R4, R4a, are independently selected from the group consisting of H; and Ci 4 alky I ;

wherein R2 , R2a, R4 or R4a is substituted with one group L2-L1-Z; wherein

L2 is a single chemical bond or is a Ci-2o alkyl chain, which is optionally interrupted by one or more groups independently selected from -O- and C(O)N(R3aa) and is optionally substituted with one or more groups independently selected from OH and

C(O)N(R3aaR3aaa), wherein R3aa and R3aaa are independently selected from the group consisting of H and C1-4 alkyl ; and

L2 is attached to L1 via a terminal group selected from the group consisting of

wherein L2 is attached to the one position indicated with the dashed line and and L1 is attached to the position indicated with the other dashed line; and

L1 is a C-i-20 alkyl chain, which is optionally interrupted by one or more groups

independently selected from -O- and C(0)N(R5aa) and is optionally substituted with one or more groups independently selected from OH and C(O)N(R5aaR5aaa), wherein R5aa and R5aaa are independently selected from the group consisting of H and Ci-4 alkyl; and

L1 is attached to Z via a terminal amino group forming an amide bond with the carboxy group of the beta-1 ,3-D-glucuronic acid of the hyaluronic acid of Z;

Z is a crosslinked hyaluronic acid hydrogel, in which

0.05 to 20 % of the monomeric disaccharide units are crosslinked by a crosslinker; and 0.2 to 8.5 % of the monomeric disaccharide units bear L1-L2 -L-Y-R20. groups.

2. A prodrug or a pharmaceutically acceptable salt thereof comprising a drug linker conjugate of formula (I) as claimed in claim 1

The Z - L' 1 -L 2 - L'- the Y - the R 20 ( the I)

wherein Y is a peptide moiety having the formula (II)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (II)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Lys

X20 represents an amino acid residue selected from Lys, Gin and His,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val,

or wherein Y is a peptide moiety having the formula (III)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (III)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Leu and His

X20 represents an amino acid residue selected from His, Arg, Lys, and Gin, X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Lys, Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val,

or

wherein Y is a peptide moiety having the formula (IV)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Leu-Leu-Asp-Glu-Gln-X18-Ala- Lys-Asp-Phe-lle-Glu-Trp-Leu-lle-Ala-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (IV)

X2 represents an amino acid residue selected from Ser, D-Ser and Aib,

X3 represents an amino acid residue selected from Gin and His,

X18 represents an amino acid residue selected from Arg and Leu,

X32 represents an amino acid residue selected from Ser and Val,

or a salt or solvate thereof;

R20 is OH or NH2;

L is a linker of formula (la),

wherein the dashed line indicates the attachment to the N-Terminus of Y by forming an amide bond;

X is C(R4R4a); N(R4);

R1, R1a, are independently selected from the group consisting of H; and Ci- 4 alky I;

R2, R2a, are independently selected from the group consisting of H; and C-i- 4 alky I;

R4, R4a, are independently selected from the group consisting of H; and C-i- 4 alky I;

wherein R2 , R2a, R4 or R4a is substituted with one group L2-L1-Z; wherein

L2 is a single chemical bond or is a Ci-2o alkyl chain, which is optionally interrupted by one or more groups independently selected from -O- and C(O)N(R3aa) and is optionally substituted with one or more groups independently selected from OH and

C(O)N(R3aaR3aaa), wherein R3aa and R3aaa are independently selected from the group consisting of H and Ci-4 alkyl; and

L2 is attached to L1 via a terminal group selected from the group consisting of

wherein L2 is attached to the one position indicated with the dashed line and and L1 is attached to the position indicated with the other dashed line; and

L1 is a C-i-20 alkyl chain, which is optionally interrupted by one or more groups

independently selected from -O- and C(0)N(R5aa) and is optionally substituted with one or more groups independently selected from OH and C(O)N(R5aaR5aaa), wherein R5aa and R5aaa are independently selected from the group consisting of H and Ci-4 alkyl; and

L1 is attached to Z via a terminal amino group forming an amide bond with the carboxy group of the beta-1 ,3-D-glucuronic acid of the hyaluronic acid of Z;

Z is a crosslinked hyaluronic acid hydrogel, in which

0.05 to 20 % of the monomeric disaccharide units are crosslinked by a crosslinker; and 0.2 to 8.5 % of the monomeric disaccharide units bear L1-L2 -L-Y-R20. groups.

The prodrug of claim 1 , wherein

L is a linker moiety of formula (lb),

wherein the dashed line indicates attachment to Y by forming an amide bond;

R , R1a, R2a are selected independently from the group consisting of H and Ci-4 alkyl; L2-L1-Z is defined as in claim 1 .

4. The prodrug of claim 1 , wherein

L is a linker moiety -L of formula (lc),

Z (lc)

wherein the dashed line indicates attachment to Y by forming an amide bond;

R and R1a are H;

R2, R2a are independently selected from the group consisting of H and CH3;

wherein L2-L1-Z is defined as in claim 1 .

5. The prodrug of any of claims 1 to 4, wherein

L2 is a C-i-6 alkyl chain, which is optionally interrupted by one group selected from -O-and C(0)N(R3aa) and, wherein R3aa is independently selected from the group consisting of H and Ci-4 alkyl; and

L2 is attached to L1 via a terminal group selected from the group consisting of

wherein L2 is attached to the one position indicated with the dashed line and and L1 is attached to the position indicated with the other dashed line.

6. The prodrug of any of claims 1 to 5, wherein

wherein Y is a peptide moiety having the formula (II)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (II)

wherein

X2 represents an D-Ser

X3 represents His,

X18 represents Arg

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val;

or wherein Y is a peptide moiety having the formula (III)

His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-Asp-Glu-Gln-X18-Ala- X20-X21 -Phe-lle-Glu-Trp-Leu-lle-X28-Gly-Gly-Pro-X32-Ser-Gly-Ala-Pro-Pro-Pro- Ser (III)

wherein

X2 represents Aib,

X3 represents His,

X18 represents Leu,

X20 represents Lys,

X21 represents an amino acid residue selected from Asp and Glu,

X28 represents an amino acid residue selected from Ser and Ala,

X32 represents an amino acid residue selected from Ser and Val.

7. The prodrug of any of claims 1 to 5, wherein Y is a peptide moiety having the formula (IVa)

H2N-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu-X15-Glu-Gln-Leu- Ala-Arg-Asp-Phe-lle-Glu-Trp-Leu-lle-Bal-X29-Gly-X31 -X32-Ser-X34-X35-Pro-Pro- Pro-X39-R20 (IVa)

X15 represents an amino acid residue selected from Asp and Glu, (pref. Asp) X29 represents an amino acid residue selected from Gly, D-Ala and Pro, (pref) Gly, D-Ala

X31 represents an amino acid residue selected from Pro, His and Trp, (pref. Pro) X32 represents an amino acid residue selected from Ser, His, Pro and Arg, (pref.

Ser, His, Pro),

X34 represents an amino acid residue selected from Gly and D-Ala,

X35 represents an amino acid residue selected from Ala, Pro and Lys, (pref. Ala, Pro)

X39 represents Ser or Pro-Pro-Pro.

8. The prodrug of any of claims 1 to 5, wherein Y is a peptide moiety having the formula (IVb)

H2N-His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Leu-Leu-Glu-Glu-Gln-Arg- Ala-Arg-Glu-Phe-lle-Glu-Trp-Leu-lle-Bal-D-Ala-Gly-Pro-Pro-Ser-D-Ala -Ala- Pro-Pro-Pro-Ser-R20.

9. The prodrug of any of claims 1 to 8, wherein

Y is GLP-1 /Glucagon agonist selected from sequences Seq. ID No 4 to 60.

10. A pharmaceutical composition comprising a prodrug of any of claims 1 to 9 or a pharmaceutical salt thereof together with at least one pharmaceutically

acceptable excipient.

1 1 . A pharmaceutical composition comprising a prodrug of any of claims 1 to 9 or a pharmaceutical salt thereof together with at least one pharmaceutically

acceptable excipient and a viscosity modifier.

12. A pharmaceutical composition as claimed in claim 1 1 ,

wherein the viscosity modifier is hyaluronic acid.

13. A pharmaceutical composition as claimed in claims 10 to 12 in form of an

injectable formulation.

14. A pharmaceutical composition as claimed in claims 10 to 13 in form of a

suspension.

15. A pharmaceutical composition as claimed in claims 10 to 14 in form of a

suspension, wherein a prodrug of any of claims 1 to 6 has a concentration of 0.5 to 8 weight/volume percent.

1 6. A pharmaceutical composition as claimed in claims 10 to 14 in form of a

suspension, wherein a prodrug of any of claims 1 to 6 has a concentration of 1 .5 to 3 weight/volume percent.

17. A composition according to any of claims 10 to 16, wherein the prodrug is sufficiently dosed in the composition to provide a therapeutically effective amount of GLP1 /Glucagon agonist for at least 6 days in one application.

18. A composition according to any of claims 10 to 17, wherein it is a single dose composition.

19. The prodrug of any of claims 1 to 9 or the pharmaceutical composition of claims 10 to 18 for use as a medicament.

20. The prodrug of any of claims 1 to 9 or the pharmaceutical composition of claims 10 to 18 for use in a method of treating or preventing diseases or disorders which can be treated by GLP-1 /Glucagon agonist.

21 . The prodrug of any of claims 1 to 9 or the pharmaceutical composition of claims 10 to 18 for use in a method of treating or preventing diabetes.

22. The prodrug of any of claims 1 to 7 or the pharmaceutical composition of claims 10 to 18 for use in a method of treating or preventing dyslipemia.

23. The prodrug of any of claims 1 to 9 or the pharmaceutical composition of claims 10 to 1 6 for use in a method of treating or preventing metabolic syndrom.

24. The prodrug of any of claims 1 to 9 or the pharmaceutical composition of claims 10 to 18 for use in a method of treating or preventing of hepatosteatosis, preferably nonalcoholic liver-disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

25. -1 /Glucagon agonist-linker conjugate intermediate L2*-L-Y of formula (VIII)

wherein Y is a peptide of Seq ID 4 to 60.

26. -1 /Glucagon agonist-linker conjugate intermediate L2*-L-Y of formula (IX)

wherein Y is a peptide of Seq ID 4 to 60.

27. An GLP-1 /Glucagon agonist-linker conjugate intermediate L2*-L-Y of formula (X)

wherein Y is a peptide of Seq ID 4 to 60.

The composition of claim 18, wherein the prodrug suspension can be administered by injection through a needle smaller than 0.26 mm inner diameter.