Use of glp-2 analogues in patients with renal failure

Abstract

FIELD: pharmaceuticals.SUBSTANCE: method is provided for preventing or treating a condition responsive to ZP1848 in a subject with at least severe renal failure, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein said disease is selected from ulcers, indigestion, malabsorption syndrome, short bowel syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small intestinal injury, or short bowel syndrome (SBS).EFFECT: effective treatment of the said conditions in patients with severe renal failure without the need for dose adjustment of ZP1848.10 cl, 1 tbl, 1 ex

Description

[0001] Technical field

[0002] The present invention relates to dosage regimens for the administration of glucagon-like peptide-2 (GLP-2) analogues, and in particular ZP1848 (glepaglutide), to patients with renal failure.

[0003] Technology Level

[0004] Human GLP-2 is a 33-amino acid peptide with the following sequence: Hy-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-lle-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-lle-Gln-Thr-Lys-Ile-Thr-Asp-OH. It is formed as a result of specific post-translational processing of proglucagon in enteroendocrine L cells of the intestine and in certain areas of the brainstem. GLP-2 binds to a single G protein-coupled receptor belonging to the glucagon-secretin class II family.

[0005] GLP-2 has been reported to induce significant growth of small intestinal mucosal epithelium by stimulating stem cell proliferation in crypts and inhibiting apoptosis in villi (Drucker et al., 1996, Proc. Natl. Acad. Sci. USA 93: 7911-7916). GLP-2 also affects colonic growth. In addition, GLP-2 inhibits gastric emptying and gastric acid secretion (Wojdemann et al., 1999, J. Clin. Endocrinol. Metab. 84: 2513–2517), enhances intestinal barrier function (Benjamin et al., 2000, Gut 47: 112–119), stimulates intestinal hexose transport by activating glucose transporters (Cheeseman, 1997, Am. J. Physiol. R1965–71), and increases intestinal blood flow (Guan et al., 2003, Gastroenterology, 125:136–147). For a review of GLP-2 and its properties, see Burrin et al., 2001, The Journal of Nutrition, 131(3), March 2001, 709–712.

[0006] In the art, glucagon-like peptide-2 receptor analogs are considered to have therapeutic potential for the treatment of intestinal diseases. However, native hGLP-2, a 33-amino acid gastrointestinal peptide, is not suitable for clinical use due to its very short half-life in humans, which is approximately 7 minutes for full-length GLP-2 [1-33] and 27 minutes for truncated GLP-2 [3-33]. The short half-life is largely due to degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). Accordingly, efforts have been made in the art to develop GLP-2 receptor agonists with improved pharmacokinetic properties, in particular to improve the half-life of GLP-2 molecules.For example, GLP-2 analogs with substitutions have been proposed, such as GLP-2 analogs containing a Gly substitution at position 2 ([hGly2] GLP-2, teduglutide), which increases the half-life from seven minutes (native GLP-2) to approximately two hours. Teduglutide is approved for the treatment of short bowel syndrome under the names Gattex (in the US) and Revestive (in Europe).

[0007] WO 2006 / 117565 (Zealand Pharma A / S) describes GLP-2 analogues that contain one of several substitutions compared to [hGly2]GLP-2 and that have improved in vivo biological activity and / or improved chemical stability, for example, as assessed in in vitro stability assays.

[0008] Among the molecules described in WO 2006 / 117565 is ZP1848 (glepaglutide), which was developed to provide stability in liquid formulations. Dosage regimens for GLP-2 analogs, including ZP1848 and its metabolites, are described in WO 2018 / 229252, which also demonstrates that these compounds are effective in increasing intestinal longitudinal growth.

[0009] The use of GLP-2 analogues, including ZP1848, for the treatment of conditions associated with bile acid synthesis, hepatic bile acid content, or intestinal bile acid content is described in WO 2020 / 020904.

[0010] Ready-to-use formulations of ZP1848 are described in WO 2020 / 065064.

[0011] Brief description of the invention

[0012] Teduglutide clearance is reduced in patients with renal dysfunction, and in particular in patients with moderate or severe renal impairment or end-stage renal disease (ESRD). Therefore, it is recommended to reduce the normal dose of teduglutide by 50% in patients with moderate renal impairment, severe renal impairment, or ESRD. See, e.g., Nave, R et al., Eur. J. Clin. Pharmacol. 2013, 69(5): 1149–1155, Summary of Product Characteristics of Revestive® (European Medicines Agency), European Medicines Agency (2012) European Public Assessment Report of Revestive®.

[0013] Since ZP1848 is also a GLP-2 analogue, similar considerations can be expected to apply.

[0014] Surprisingly, ZP1848 was found to be eliminated in patients with renal impairment. As a result, there is no need to adjust the dosage of ZP1848 based on the patient's renal function. This offers several advantages. Firstly, it means that patients with impaired renal function can receive the full therapeutically effective dose without unwanted side effects, such as those caused by excessive exposure to the active agent. Furthermore, it eliminates the need to check the patient's renal function before prescribing ZP1848, resulting in more effective and cost-effective treatment. Furthermore, safety should be enhanced if a patient already receiving ZP1848 develops renal impairment, as there is no need to adjust their dosage based on the renal event.

[0015] Thus, in a first aspect, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a condition responsive thereto in a subject with at least moderate renal failure, wherein no dosage adjustment of ZP1848 or said salt is required.

[0016] Furthermore, a method for preventing or treating a condition responsive thereto in a subject with at least moderate renal failure is provided, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein no dose adjustment of ZP1848 or said salt is required.

[0017] The present invention also provides the use of ZP1848 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a condition responsive thereto in a subject with at least moderate renal failure, without requiring a dose adjustment of ZP1848 or said salt.

[0018] The term “at least moderate” renal impairment is used in this description to refer to patients with moderate renal impairment, severe renal impairment, or ESRD.

[0019] Therefore, a subject typically requires an adjusted teduglutide dose if teduglutide is prescribed for the same condition. The subject may or may not have previously received teduglutide therapy, for example, at an adjusted dose.

[0020] In a further aspect, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a pathological condition responsive thereto in a subject for whom an adjusted dose of teduglutide would be indicated due to renal failure, wherein no dose adjustment of ZP1848 or said salt is required.

[0021] Furthermore, the present invention provides a method for preventing or treating a ZP1848-responsive condition in a subject for whom an adjusted dose of teduglutide would be indicated due to renal failure, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein no dose adjustment of ZP1848 or said salt is required.

[0022] The present invention also provides the use of ZP1848 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a condition responsive thereto in a subject for whom an adjusted dose of teduglutide would be indicated due to renal failure, wherein no dose adjustment of ZP1848 or said salt is required.

[0023] Thus, the subject may have at least moderate renal impairment, such as moderate renal impairment, severe renal impairment, or ESRD.

[0024] The subject typically requires an adjusted teduglutide dose if teduglutide is prescribed for the same condition. The subject may or may not have previously received teduglutide therapy, such as at an adjusted dose.

[0025] In a further aspect, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a pathological condition responsive thereto in a subject who has received an adjusted dose of teduglutide due to renal failure, wherein no dose adjustment of ZP1848 or said salt is required.

[0026] Furthermore, the present invention provides a method for preventing or treating a ZP1848-responsive condition in a subject who has received an adjusted dose of teduglutide due to renal failure, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein no dose adjustment of ZP1848 or said salt is required.

[0027] The present invention also provides the use of ZP1848 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a condition responsive thereto in a subject who has received an adjusted dose of teduglutide due to renal failure, wherein no dose adjustment of ZP1848 or said salt is required.

[0028] Thus, the subject previously received teduglutide at an adjusted dose for the same condition. Typically, the subject has at least moderate renal impairment, such as moderate renal impairment, severe renal impairment, or ESRD.

[0029] The condition being treated may be any condition that is therapeutically responsive to treatment with a GLP-2 analogue, for example, when treatment results in relief of one or more symptoms, alleviation of the underlying pathology, delay of onset, and / or inhibition of progression. Thus, prevention may be considered either treatment or therapy.

[0030] Such conditions include disorders related to the stomach and intestines such as ulcers, digestive disorders, malabsorption syndromes, short bowel syndrome, inflammatory bowel disease, non-tropical sprue (such as that caused by gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small intestinal injury, or short bowel syndrome (SBS).

[0031] The use in the treatment of short bowel syndrome (SBS) may be of particular interest, especially in a subject receiving parenteral support (PN).

[0032] Additional conditions include disorders involving the stomach and intestines, such as radiation enteritis, infectious or post-infectious enteritis, or small intestinal injury caused by toxic or other chemotherapeutic agents. In this case, treatment with a GLP-2 analogue may optionally be combined with one or more types of anticancer therapy and, therefore, may include administering one or more chemotherapeutic agents to the subject or treating the subject with radiation therapy.

[0033] Thus, the condition may be a side effect of chemotherapy or radiotherapy in a human subject.

[0034] The terms "subject" and "patient" are used interchangeably in this description. It is understood that a subject (or patient) is a mammal and, typically, a human.

[0035] ZP1848 is also effective in increasing intestinal mass and longitudinal growth of the intestine, especially the small intestine.

[0036] Thus, in a further aspect, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject with at least moderate renal failure, wherein no dosage adjustment of ZP1848 or said salt is required.

[0037] Furthermore, a method for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject with at least moderate renal failure is provided, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein no dosage adjustment of ZP1848 or said salt is required.

[0038] The present invention also provides the use of ZP1848 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject with at least moderate renal failure, wherein no dose adjustment of ZP1848 or said salt is required.

[0039] Thus, the subject typically requires an adjusted teduglutide dose if teduglutide has been used for the same purpose. The subject may or may not have previously received teduglutide therapy, for example, at an adjusted dose.

[0040] In a further aspect, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject for whom an adjusted dose of teduglutide would be indicated due to renal failure, wherein no dose adjustment of ZP1848 or said salt is required.

[0041] Furthermore, a method is provided for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject for whom an adjusted dose of teduglutide would be indicated due to renal failure, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein no dose adjustment of ZP1848 or said salt is required.

[0042] The present invention also provides the use of ZP1848 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject for whom an adjusted dose of teduglutide would be indicated due to renal failure, wherein no dose adjustment of ZP1848 or said salt is required.

[0043] Thus, the subject may have at least moderate renal impairment, such as moderate renal impairment, severe renal impairment, or ESRD.

[0044] The subject typically requires an adjusted teduglutide dose if teduglutide was prescribed for the same purpose. The subject may or may not have previously received teduglutide therapy, such as at an adjusted dose.

[0045] In a further aspect, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject who has received an adjusted dose of teduglutide due to renal failure, wherein no dose adjustment of ZP1848 or said salt is required.

[0046] Furthermore, a method is provided for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject who has received an adjusted dose of teduglutide due to renal failure, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein no dose adjustment of ZP1848 or said salt is required.

[0047] The present invention also provides the use of ZP1848 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject who has received an adjusted dose of teduglutide due to renal failure, wherein no dose adjustment of ZP1848 or said salt is required.

[0048] Thus, the subject has previously received teduglutide at an adjusted dose, for example, for the same purpose. Typically, the subject has at least moderate renal impairment, such as moderate renal impairment, severe renal impairment, or ESRD.

[0049] In such aspects, the subject may suffer from a condition in which an increase in intestinal mass and / or stimulation or enhancement of longitudinal intestinal growth, such as therapeutic, is desirable. This may include any of the conditions described elsewhere herein, but is particularly true for subjects suffering from short bowel syndrome (SBS), such as those receiving parenteral support.

[0050] In a further aspect, the present invention provides a pharmaceutical kit comprising ZP1848 or a pharmaceutically acceptable salt thereof, and information that no dosage adjustment of ZP1848 is required for subjects with at least moderate renal impairment.

[0051] ZP1848 or a pharmaceutically acceptable salt is typically provided as a pharmaceutical composition comprising ZP1848 or said salt in combination with a pharmaceutically acceptable carrier or excipient.

[0052] The kit may contain one or more individual measured doses of ZP1848 or the specified salt, wherein each individual measured dose is an adjusted dose as described elsewhere herein.

[0053] Individual doses may be intended to be administered via a dosing regimen as described elsewhere herein.

[0054] The kit may further contain one or more chemotherapeutic agents, which may be provided in a separate pharmaceutical composition from ZP1848 or a salt thereof.

[0055] It should be understood that subjects receiving treatment in accordance with any aspect of the invention will typically receive ZP1848 or a pharmaceutically acceptable salt thereof in place of teduglutide (and any other GLP-2 receptor agonist), i.e., ZP1848 or a corresponding salt will typically be the only GLP-2 receptor agonist used to treat the subject. Similarly, the compositions and kits defined herein typically comprise ZP1848 or a corresponding salt as the sole GLP-2 receptor agonist.

[0056] In the context of the present invention, an "adjusted" dose is a dose that has been reduced to account for renal impairment. Thus, the teduglutide dose is reduced by 50% when administered to subjects with at least moderate renal impairment to account for impaired drug clearance from the system of such patients and to avoid excessive drug exposure.

[0057] For ZP1848 and its salts, no dosage adjustment is necessary for renal impairment. Therefore, the dose for such subjects may be the same as the dose that would be administered to an equivalent subject with normal renal function. This may be referred to as the "normal," "standard," or "unadjusted" dose. It should be understood that a small amount of variation, for example, ±10%, may nevertheless be permitted without regard to the "adjusted" dose. Typically, the "adjusted" dose varies by more than 30%, for example, more than 40%, for example, approximately 50%.

[0058] It should be understood, of course, that a "normal" dose may be determined depending on the individual subject, for example, based on their age, gender, body weight, disease status, etc., and / or the intended dosing regimen. Again, such variations should not be construed as resulting in an "adjusted" dose within the meaning of the present invention. Rather, "adjusted" should be interpreted to mean "adjusted for renal function considerations" or similar terms, unless the context otherwise requires.

[0059] Administration may be carried out according to any suitable dosage regimen.

[0060] For example, the administration can be once a day.

[0061] However, as described in WO 2018 / 229252, ZP1848 has an unexpectedly long half-life, which may allow for alternative regimens, such as once- or twice-weekly administration, particularly when delivered by subcutaneous injection. Without being bound by any theory, it is believed that the half-life of ZP1848 may be due to a combination of the formation of a subcutaneous depot and the formation of metabolites that are slowly released from the subcutaneous depot and that are also agonistic to the GLP-2 receptor. The subcutaneous depot may be formed upon administration as a result of a reaction between the lysine tail of ZP1848 and hyaluronic acid in the subcutaneous compartment.

[0062] Thus, the dosing regimen may include multiple doses or a course of doses separated in time by an interval of 2 days, 2.5 days, 3 days, 3.5 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days. According to a preferred embodiment of the present invention, the doses are separated in time by 3 days, 3.5 days, 4 days, 5 days, 6 days, 7 days, or 8 days. According to a preferred embodiment of the present invention, the doses are separated in time by 3 days, 3.5 days, 4 days, or 7 days. As will be understood in the art, the time between doses may vary to some extent so that each and every dose is not separated by exactly the same time interval. The interval will often be set at the discretion of the physician. Thus, the doses may be separated in time by a clinically acceptable time interval, for example, from about 2 days to about 10 days or from about 3 or 4 days to about 7 or 8 days.

[0063] A typical "normal" or "unadjusted" dose may range from 0.5 mg to 25 mg, inclusive, per subject per administration.

[0064] For example, it may be from 1 mg to 20 mg inclusive per subject per dose, such as from 1 mg to 10 mg inclusive per subject per dose, such as from 2 mg to 7 mg inclusive per subject per dose, such as from 5 mg to 7 mg inclusive per subject per dose, or from 2 mg to 5 mg inclusive per subject per dose.

[0065] Alternatively, it may be from 5 mg to 15 mg inclusive per subject per dose, such as from 7 mg to 12 mg inclusive per subject per dose, such as from 9 mg to 11 mg inclusive per subject per dose.

[0066] In some embodiments, the dose of GLP-2 analogs used in accordance with the present invention is about 10 mg per subject per dose (where “about” means ±10%).

[0067] In some embodiments, the dose of the GLP-2 analogs used in accordance with the present invention is a fixed dose of 10 mg per subject.

[0068] These doses may be suitable for any dosing regimen, but are especially suitable for a once or twice weekly regimen.

[0069] During treatment, the doses taken by the patient may be the same or different in accordance with the doctor's instructions.

[0070] In some cases, it may be desirable to divide the total dose into multiple (e.g., two or three) separate doses or administrations, for example, for administration at spatially separated injection sites, for example, at injection sites that are at least 5 cm apart. Such spatially separated administrations are typically carried out at substantially the same time, for example, on the same day, within one hour of each other, or even closer in time.

[0071] The embodiments of the present invention will be described below by way of example and are not intended to be limiting. However, various additional aspects and embodiments of the present invention will be apparent to those skilled in the art given the present description.

[0072] Unless the context otherwise requires, the descriptions and definitions of the features set forth above are not limited to any particular aspect or embodiment of the present invention and are equally applicable to all aspects and embodiments described.

[0073] Detailed description of the invention

[0074] Throughout the description and claims, conventional single- and three-letter codes are used for naturally occurring amino acids. All amino acid residues in the described compounds typically have the L-configuration.

[0075] Connections

[0076] ZP1848 is a peptide with the formula:

[0077] H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2

[0078] as described, for example, in WO 2006 / 117565. It should be understood that the N-terminal "H-" denotes the free N-terminal amino group (NH2-). The C-terminal "NH2-" denotes the C-terminal amide group. The terms ZP1848 and glepaglutide can be used interchangeably.

[0079] The present invention includes the use of pharmaceutically acceptable salts of ZP1848, described in more detail below. Any suitable salt can be used, although the acetate may be preferred.

[0080] When ZP1848 is administered by injection into the subcutaneous (s.c.) compartment, two functionally active metabolites, ZP2469 and ZP2711, are formed. Both are C-terminally truncated analogs of ZP1848. Thus, the overall PK profile of ZP1848 includes the effects of ZP1848 and its two major metabolites.

[0081] ZP2469 is a peptide with the formula:

[0082] H-HGEGTFSSELATILDALAARDFIAWLIATKITDK-OH

[0083] ZP2711 is a peptide with the formula:

[0084] H-HGEGTFSSELATILDALAARDFIAWLIATKITDKK-OH

[0085] where the N-terminal “H-” is as described above, and the C-terminal “-OH” indicates the free C-terminal carboxylic acid group.

[0086] Teduglutide is a peptide with the formula:

[0087] H-HGDGSFSDEMNTILDNLAARDFINWLIQTKITD-OH

[0088] where the N-terminal “H-” and C-terminal “-OH” are as described above.

[0089] Kidney function and its definition

[0090] Kidney function is usually determined by reference to the glomerular filtration rate (GFR) or estimated glomerular filtration rate (eGFR).

[0091] GFR (units ml / min) can be determined using any suitable filtration marker such as inulin, 51 Cr-EDTA, 99mTc-DTPA, iothalamate, or iohexol. Suitable methods are well known to those skilled in the art, for example, those based on monitoring the excretion of the relevant marker in urine over a predetermined period of time, such as 24 hours.

[0092] eGFR can be calculated based on standardized serum creatinine (SSC) values. For example, it can be calculated according to the Modification of Diet in Renal Disease (MDRD) equation (Levey AS et al., Clin Chem. Apr 2007;53(4):766-772), which provides a value normalized to a body surface area of ​​1.73 m 2 , in units of ml / min / 1.73 m 2 :

[0093] eGFR=175×standardized SFR -1,154 ×age -0,203 ×1.212 [if black]×0.742 [if female]

[0094] [TFR in mg / dl]

[0095] or

[0096] eSCF=30849×standardized SCF -1,154 ×age -0,203 ×1.212 [if black]×0.742 [if female]

[0097] [TFR in µmol / l]

[0098] Alternatively, renal function can be determined by creatinine clearance (Ccr using the Cockcroft-Gault equation (Cockcroft DWand Gault MN, Nephron 16: 31-41 (1976)):

[0099] Ccr=[(140-age)(mass. kg)] / [72×CCR(mg / 100 ml)]

[0100] for adult males; 15% less for adult females.

[0101] Alternative formulas can be used to calculate eGFR for children and adolescents (aged 1–18 years), such as the creatinine-based “bedside Schwartz equation” (Schwartz GJ and Work DF, J Am Soc Nephrol. 2009; Nov; 4(11): 1832–643; Schwartz GJ et al., J Am Soc Nephrol. 2009; 20: 629–637):

[0102] eGFR=0.413x(height / TFR) [height expressed in cm; TFR mg / 100 ml]

[0103] For adults, it may be preferable to calculate eGFR using the MDRD equation.

[0104] For the purpose of calculating eGFR, standardized serum creatinine levels can be determined using isotope dilution gas chromatography / mass spectrometry (ID-GC / MS), such as described by Stoeckl and Reinauer, Clin. Chem. 1993;39:993-1000, which represents the “gold standard” for creatinine measurement.

[0105] It should be understood that other methods and commercial kits for measuring serum creatinine are available, including enzymatic methods or colorimetric methods such as the Jaffe reaction, in which creatinine forms a colored product after reaction with an alkaline picrate. Such methods typically use various compensation or correction factors to more accurately reflect the gold standard results, for example, by minimizing interference from bilirubin and pseudocreatinine chromogens such as proteins and ketones. Examples include the Cobas® CREJ2 (Second-Generation Creatinine Jaffe) kit (Roche).

[0106] Current classifications of renal function for specialized studies of renal impairment can be found in the “Guidance for Industry Pharmacokinetics in Patients with Impaired Renal Function - Study Design, Data Analysis, and Impact on Dosing, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), September 2020” or in the corresponding European “Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function, European Medicines Agency, 2015”.

[0107] According to current clinical guidelines, normal renal function can be defined as SCF (or Ccr)≥90 ml / min or eSCF≥90 ml / min / 1.73 m 2 .

[0108] Mild renal impairment can be defined as a SCF (or Ccr) of 60 to <90 mL / min or an eSCF of 60 to <90 mL / min / 1.73 m 2 .

[0109] Moderate renal impairment can be defined as a SCF (or Ccr) of 30 to <60 mL / min or an eSCF of 30 to <60 mL / min / 1.73 m 2 .

[0110] Severe renal impairment can be defined as SCF (or Ccr) of 15 to <30 mL / min or eGFR of 15 to <30 mL / min / 1.73 m 2 .

[0111] End-stage kidney disease (ESRD) is typically characterized by a SCF (or Ccr)<15 mL / min or eSCF<15 mL / min / 1.73 m 2 .

[0112] Previous guidelines set the threshold for moderate renal impairment at <50 mL / min rather than <60 mL / min, and the original guidelines for teduglutide therefore recommended a 50% dose reduction for patients with an SCF <50 mL / min. Therefore, it should be understood that no dose adjustment is required for subjects with an SCF (or Ccr) <50 mL / min or an eSCF <50 mL / min / 1.73 m 2In some cases, it may be appropriate to consider this value as a threshold for moderate renal impairment. Thus, subjects with at least moderate renal impairment may be considered to have a SCF (or Ccr) <50 mL / min or an eSCF <50 mL / min / 1.73 m 2 .

[0113] For the purposes of the present invention, it may be preferable to base the classification of a subject on the measurement of eGFR, calculated, for example, using the MDRD equation, based on the measurement of standardized SCr. SCr is preferably determined using ID-GC / MS, for example, as described above.

[0114] Pharmaceutical compositions and administration

[0115] The active agents described can be formulated as pharmaceutical compositions prepared for storage or administration that contain a therapeutically effective amount of the active agent in a pharmaceutically acceptable carrier.

[0116] The therapeutically effective amount of the respective active agent will depend on the route of administration, the type of mammal being treated (usually humans), and the physical characteristics of the particular mammal in question. These factors and their relationship to the determination of such an amount are well known to those skilled in the art. This amount and route of administration can be adapted to achieve optimal efficacy by delivering the peptide to the intestine, but will be influenced by factors such as body weight, diet, concomitant medications, and other factors well known to those skilled in the art.

[0117] The active agent is typically present in an amount effective to prevent or treat the relevant condition, such as to treat or prevent disorders related to the stomach and intestines, to increase intestinal mass and / or to promote or increase longitudinal intestinal growth in a subject.

[0118] Examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences,”17 th edition. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 and later editions, and in the Encyclopaedia of Pharmaceutical Technology.

[0119] Suitable salts include acid addition salts and basic salts. Examples of acid addition salts include hydrochloride salts, citrate salts, chloride salts, and acetate salts. Preferably, the salt is acetate. In general, it is preferable that the salt not be a chloride salt. Examples of basic salts include salts in which the cation is selected from alkali metals such as sodium and potassium, alkaline earth metals such as calcium, and ammonium ions. + N(R 3 )3(R 4 ), where R 3 and R 4 independently denote optionally substituted C 1-6 -alkyl, optionally substituted with C 2-6-alkenyl, optionally substituted aryl or optionally substituted heteroaryl.

[0120] Acetate salts may be particularly preferred. In the present context, the term "ZP1848 acetate" refers to a ZP1848 molecule in the form of an acetate salt. Acetate salts of ZP1848 may be represented by the formula (ZP1848), x(CH3COOH), where x is from 1.0 to 8.0, i.e., where x is 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, or 8.0. In any composition, there may be molecules with different numbers of acetate molecules, so that x is not necessarily an integer. In some cases, x is from 4.0 to 8.0, x is from 6.0 to 8.0, or x is from 4.0 to 6.5. In some cases, x is between 4.0 and 6.0, x is between 2.0 and 7.0, x is between 3.0 and 6.0, x is between 4.0 and 6.0, or x is between 4.0 and 8.0.

[0121] A person skilled in the art will understand that a "therapeutically effective amount" of the peptides or pharmaceutical compositions according to the present invention may vary depending on the age, weight and species of the mammal being treated, the specific compounds used, the specific route of administration and the target effects and therapeutic indication. Since these factors and their relationship to the determination of this amount are well known in the medical field, the determination of therapeutically effective dosage levels, the amount necessary to achieve the desired result (e.g., the prevention and / or treatment of diseases related to the intestine and stomach described in this application, as well as other medical indications described in this application, or an increase in intestinal mass and / or the induction or increase in longitudinal intestinal growth in a subject), will be within the competence of a person skilled in the art.

[0122] In the present application, the term "therapeutically effective amount" means an amount that reduces the symptoms of a particular condition or pathology and that preferably normalizes physiological responses in an individual suffering from the condition or pathology. The reduction of symptoms or normalization of physiological responses can be determined using conventional methods in the art and can vary depending on the particular condition or pathology. According to one aspect, a therapeutically effective amount is an amount that restores a measurable physiological parameter to a substantially similar value (preferably within +30%, more preferably within +20%, and even more preferably within 10% of the value) of the parameter in an individual not suffering from the condition or pathology.

[0123] According to one embodiment of the present invention, administration of the compounds or pharmaceutical composition of the present invention begins at lower dosage levels, with dosage levels being increased until the target effect of preventing / treating the relevant medical indications, such as diseases associated with the intestines and stomach, or until an increase in longitudinal intestinal growth is achieved. This will determine the therapeutically effective amount. Recommendations for appropriate individual doses are provided elsewhere in this description. However, one skilled in the art will be able to adjust these doses if an alternative dosing regimen is selected.

[0124] For therapeutic use, the active agent is formulated with a carrier that is pharmaceutically acceptable and suitable for delivery of the peptide via the selected route of administration. For the purposes of the present invention, peripheral parenteral routes include intravenous, intramuscular, subcutaneous, and intraperitoneal administration. According to one embodiment of the present invention, the route of administration is the subcutaneous route or subcutaneous administration.

[0125] When administration is to be parenteral, such as intravenous, subcutaneous or intramuscular, injectable pharmaceutical compositions may be prepared in conventional forms, either as aqueous solutions or suspensions; lyophilized, solid forms suitable for reconstitution immediately before use, or suspension in liquid before injection, or as emulsions.

[0126] Diluents for reconstituting the lyophilized product may be a suitable buffer such as a histidine buffer, a mesylate buffer, an acetate buffer, a glycine buffer, a lysine buffer, a Tris buffer, a Bis-Tris buffer, and a MOPS buffer, water, saline, dextrose, mannitol, lactose, trehalose, sucrose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride; or water for injection with the addition of detergents such as Tween 20, Tween 80, poloxamers such as pluronic F-68 or pluronic F-127, polyethylene glycol, and / or with the addition of preservatives such as para-, meta- and ortho-cresol, methyl- and propylparaben, phenol, benzyl alcohol, sodium benzoate, benzoic acid, benzyl benzoate, sorbic acid, propanoic acid, esters of p-hydroxybenzoic acid, and / or with the addition of an organic modifier such as ethanol, acetic acid, citric acid, lactic acid or their salts.

[0127] In addition, if necessary, injectable pharmaceutical compositions may contain minor amounts of non-toxic excipients, such as wetting agents or pH buffering agents. Drugs that enhance absorption (e.g., liposomes, detergents, and organic acids) may be used.

[0128] According to one embodiment of the present invention, the compounds are formulated for administration by infusion, for example, when used as liquid nutritional supplements for patients receiving total parenteral nutrition therapy (e.g., neonates or patients suffering from cachexia or anorexia), or by injection, for example, subcutaneously, intraperitoneally or intravenously, and are accordingly used in the form of aqueous solutions in a sterile and pyrogen-free form and optionally buffered to a physiologically tolerable pH, for example, slightly acidic or physiological pH. The formulation for intramuscular administration can be based on solutions or suspensions in vegetable oil, for example, canola oil, corn oil or soybean oil. These oil-based formulations can be stabilized with antioxidants, for example, BHA (butylated hydroxyanisole) and BHT (butylated hydroxytoluene).

[0129] Thus, the peptide compounds of the present invention can be administered in a vehicle such as distilled water or saline, phosphate-buffered saline, 5% dextrose solutions, or oils. The solubility of the active agent can be increased, if necessary, by including a solubility enhancer, such as detergents and emulsifiers.

[0130] For use as injectables, the aqueous carrier or excipient may be supplemented with a small amount of gelatin, which serves to deposit the active agent at or near the injection site for slow release to the target site. Other gelling agents, such as hyaluronic acid, can also be used as depot agents.

[0131] Subcutaneous administration may be particularly preferable, such as by injection.

[0132] Active agents can also be formulated as slow-release implant devices for prolonged and extended administration. Such sustained-release formulations can be in the form of a patch applied externally to the body. Examples of sustained-release formulations include composites of biocompatible polymers such as polylactic acid, poly(lactic acid-co-glycolic acid), methylcellulose, hyaluronic acid, sialic acid, silicate, collagen, liposomes, and the like. Sustained-release formulations may be of particular interest when high local concentrations of the active agent are desired.

[0133] The therapeutic dosage and regimen most suitable for treating a patient will vary depending on the disease or condition being treated and the patient's parameters. Without being bound by any particular theory, it is expected that doses of 0.1 to 25 mg per patient and shorter or longer durations or frequency of treatment can lead to therapeutically beneficial results, such as a statistically significant increase, in particular, in small intestinal weight. In some cases, the therapeutic regimen may include the administration of maintenance doses suitable for preventing tissue regression that occurs after cessation of initial treatment. The dosage sizes and dosing regimens most suitable for use in humans can be based on the results obtained with the present invention and can be confirmed in further clinical studies.

[0134] In humans, ZP1848 can be administered at a dose of about 0.01 mg / kg to 100 mg / kg body weight, such as about 0.01 mg / kg to 10 mg / kg body weight, such as 10-100 μg / kg body weight. According to further embodiments of the present invention, the dose (total dose) of ZP1848 in a human may be in the range of or about 0.1 mg to 25 mg per patient, may be in the range of or about 0.5 mg to 20 mg per patient, such as may be in the range of or about 1 mg to 15 mg per patient, such as may be in the range of or about 1 mg to 10 mg per patient, once or twice a week or in multiple doses as defined herein spaced over a period of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days. In some cases, a fixed dose of ZP1848 may be administered according to the dosing pattern described herein, i.e.A fixed dose that is the same regardless of the patient's body weight and is administered once or twice a week. For example, a fixed dose may be 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg. A fixed dose of 10 mg is convenient to administer. The advantage of using a fixed dose is increased patient compliance and a reduced risk of dosing errors, including the risk of incorrectly calculating the dose to be administered based on weight.

[0135] In preferred embodiments, the formulation is a ready-to-use formulation as described in WO 2020 / 065064. The term "ready to use" as used herein refers to a formulation that does not require reconstitution or dilution with a prescribed amount of a diluent, such as water for injection or other suitable diluent, prior to use by the specified route of administration.

[0136] As described herein, the liquid formulations of the GLP-2 analogs of the present invention comprise a buffer, a non-ionic tonicity modifier, and arginine in an amount sufficient to provide the pH of the final formulation. In accordance with standard pharmaceutical practice, the formulations of the present invention are sterile and / or free of reducing agents. In some cases, the liquid formulations of the present invention are aqueous liquid formulations. In some cases, the liquid formulations of the present invention are non-aqueous liquid formulations.

[0137] The term "buffer" as used herein refers to a pharmaceutically acceptable excipient that stabilizes the pH of a pharmaceutical composition. Suitable buffers are well known in the art and can be found in the literature. Screening experiments in the examples show that the formulations of the present invention preferably contain a buffer selected from a histidine buffer, a mesylate buffer, an acetate buffer, a glycine buffer, a lysine buffer, a Tris buffer, a Bis-Tris buffer, and a MOPS buffer, since these buffers provide stable formulations in which the GLP-2 analogs are dissolved and do not become viscous, turbid, or precipitate the peptide drug. In preferred embodiments, the buffer is a histidine buffer, such as L-histidine.Typically, the buffer will be present at a concentration of about 5 mM to about 50 mM, more preferably at a concentration of about 5 mM to about 25 mM, and most preferably at a concentration of about 15 mM. Preferably, the buffer is not a phosphate buffer, citrate buffer, citrate / Tris buffer, and / or succinate buffer.

[0138] The term "tonicity modifier" as used herein refers to pharmaceutically acceptable tonicity agents that are used to modulate the tonicity of a formulation. The compositions of the present invention are preferably isosmotic, i.e., have an osmotic pressure substantially the same as that of human serum. The tonicity modifiers used in the formulations are preferably non-ionic tonicity modifiers and are preferably selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose. A preferred non-ionic tonicity modification is mannitol, such as D-mannitol. The concentration of the tonicity modifier will depend on the concentration of the other components of the formulation, especially in cases where the formulation is intended to be isosmotic.Typically, the non-ionic tonicity modifier is used at a concentration of from about 90 mM to about 360 mM, more preferably at a concentration of from about 150 mM to about 250 mM, and most preferably at a concentration of about 230 mM.

[0139] Typically, the components and amounts of the liquid formulations are selected to provide a formulation with a pH of about 6.6 to about 7.4, more preferably with a pH of about 6.8 to about 7.2, and most preferably with a pH of about 7.0. Arginine can be added in a sufficient amount (qs) to adjust the pH so that it is within the desired pH range. From the experiments shown in the examples, it is preferable that the pH adjustment not be performed using hydrochloric acid or sodium hydroxide.

[0140] In one embodiment, the liquid formulations consist of ZP1848, such as its acetate salt, at a concentration of about 2 mg / mL to about 30 mg / mL, a buffer selected from the group consisting of a histidine buffer, a mesylate buffer, an acetate buffer, a glycine buffer, a lysine buffer, a Tris buffer, a Bis-Tris buffer, and a MOPS buffer, wherein the buffer is present at a concentration of about 5 mM to about 50 mM, a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose at a concentration of about 90 mM to about 360 mM, arginine in a sufficient amount to provide a pH of about 6.6 to about 7.4.

[0141] In one embodiment, the liquid formulations consist of ZP1848, such as its acetate salt, at a concentration of about 2 mg / mL to about 30 mg / mL, a buffer selected from the group consisting of a histidine buffer, a mesylate buffer, and an acetate buffer, wherein the buffer is present at a concentration of about 5 mM to about 50 mM, a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, and sorbitol at a concentration of about 90 mM to about 360 mM, arginine in a sufficient amount to provide a pH of about 6.6 to about 7.4.

[0142] In a further embodiment, the liquid formulations comprise ZP1848, such as its acetate salt, at a concentration of about 20 mg / mL, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and arginine in a sufficient amount to provide a pH of about 7.0.

[0143] In a further embodiment, the liquid formulations comprise ZP1848, such as its acetate salt, at a concentration of about 20 mg / mL, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and have a pH of about 7.0.

[0144] In a further embodiment, the liquid formulations comprise ZP1848 acetate or H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2(SEQ ID NO: 1) at a concentration of about 20 mg / mL, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and arginine in a sufficient amount to provide a pH of about 7.0.

[0145] In a further embodiment, the liquid formulations comprise ZP1848 acetate or H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2(SEQ ID NO: 1) at a concentration of about 20 mg / mL, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM and have a pH of about 7.0.

[0146] In another embodiment, the liquid formulations comprise an acetate salt of a glucagon-like peptide 2 (GLP-2) analog having the formula:

[0147] (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH), where x is from 1.0 to 8.0, at a concentration of about 20 mg / mL, histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM and have a pH of about 7.0.

[0148] In another embodiment, the liquid formulations comprise an acetate salt of a glucagon-like peptide 2 (GLP-2) analog having the formula:

[0149] (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH), where x is from 1.0 to 8.0, at a concentration of about 20 mg / mL, histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM and have a pH of about 7.0, at a dosing regimen of once or twice a day.

[0150] In another embodiment, the liquid formulations comprise the acetate salt of a glucagon-like peptide 2 (GLP-2) analog having the formula: (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH), where x is from 1.0 to 8.0, at a concentration of about 20 mg / mL, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM and have a pH of about 7.0, in a dosing regimen of once or twice a week.

[0151] In some cases, the liquid formulations of the present invention additionally contain a preservative. In some cases, the preservative is a preservative selected from the group consisting of benzalkonium chloride, chlorobutanol, methylparaben, and potassium sorbate. Typically, the preservative is present at a concentration of from about 0.1% to about 1% of the final volume of the formulation.

[0152] Medical indications

[0153] The peptides of the present invention can be used as a pharmaceutical agent for preventing or treating a subject suffering from gastrointestinal disorders, including the upper gastrointestinal tract in the esophagus region, by administering an effective amount of ZP1848 or a salt thereof described in the present application. Disorders involving the stomach and intestine include ulcers of any etiology (e.g., peptide ulcers, drug-induced ulcers, ulcers associated with infections or other pathogens), digestive disorders, malabsorption syndromes, short bowel syndrome, inflammatory bowel disease, sprue-celiac disease (e.g., caused by gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, enteritis, ulcerative colitis, small intestinal injury, and chemotherapy-induced diarrhea / mucositis (CID).

[0154] As generally mentioned above, individuals who would benefit from an increase in small intestinal mass and the results thereof and / or maintenance of the normal structure and function of the small intestinal mucosa are candidates for treatment with ZP1848 or its salt. Specific conditions that can be treated with ZP1848 include various forms of sprue, including celiac sprue, which develops as a result of a toxic reaction to alpha-gliadin from wheat and can be caused by gluten-induced enteropathy or celiac disease and is characterized by a significant loss of small intestinal villi; tropical sprue, which occurs as a result of infection and is characterized by partial flattening of the villi; hypogammaglobulinemic sprue, which is usually observed in patients with unclassifiable variable immunodeficiency or hypogammaglobulinemia and is characterized by a significant decrease in villus height.The therapeutic efficacy of treatment with ZP1848 or its salt can be monitored by intestinal biopsy to examine villus morphology, biochemical assessment of nutrient absorption, patient weight gain, or reduction in symptoms associated with these conditions.

[0155] Another specific condition that can be treated using ZP1848 or a salt thereof according to the present invention or for which ZP1848 or a salt thereof can be used for therapeutic and / or prophylactic purposes is short bowel syndrome (SBS), also known as short bowel syndrome or simply short bowel, which occurs as a result of surgical resection, a congenital defect, or disease-associated intestinal absorption loss, in which patients are subsequently unable to maintain fluid, electrolyte, and nutrient balance with a normal diet. Despite adaptation, which typically occurs two years after resection, patients with SBS have reduced alimentary intake and fluid loss.

[0156] The class of human patients suffering from SBS includes patients suffering from SBS-intestinal failure syndrome (SBS-IFS) and patients whose condition is intermediate between SBS-intestinal failure (SBS-IFS) and SBS-intestinal failure syndrome (SBS-IFS). In some cases, patients suffering from SBS-intestinal failure syndrome (SBS-IFS) are also called SBS-PP if they depend on parenteral nutrition, and patients suffering from SBS-intestinal failure (SBS-IFS) are also called SBS without PP if they do not depend on parenteral nutrition.

[0157] The spectrum of SBS patient types is reviewed in Jeppensen, Journal of Parenteral and Enteral Nutrition, 38(1), 8S-13S, May 2014, doi: 10.1177 / 0148607114520994. Further subdivision of SBS patient types can be made according to the principles described in Schwartz et al., Clinical and Translational Gastroenterology (2016) 7, e142; doi:10.1038 / ctg.2015.69. This allows subdivision of SBS patients into early responders and late / slow responders. It is currently believed that early responders are those who demonstrate an early response to treatment with a GLP-2 analogue such as ZP1848 due to, among other effects, an increase in small intestinal width / diameter, while late or slow responders are those who primarily or mainly benefit from treatment with a GLP-2 analogue due to an increase in small intestinal length.Determining whether a subject is an early responder or a late responder can be used to determine the duration of the GLP-2 analog treatment regimen, the timing of any clinical decision to reduce parenteral nutrition, and the interval between tests to determine whether parenteral nutrition can be reduced. Accordingly, in one embodiment of the present invention, the patient is a late responder or a slow responder. Small intestinal length can be measured, for example, using CT scanning (computed tomography), MRI (magnetic resonance imaging), histology, laparoscopic, or other measurements or techniques known in the art.

[0158] As used herein, the term "parenteral nutrition" or "PN" includes the administration of nutrients and / or fluids to a subject receiving GLP-2 therapy as a means of providing the subject with nutrients and / or fluids that the subject needs but cannot fully absorb due to the subject's condition.

[0159] Other conditions that may be treated or for which ZP1848 or its salt may be used prophylactically include radiation enteritis, infectious or post-infectious enteritis, and small intestinal injury caused by anticancer chemotherapeutic or toxic agents.

[0160] This may require the administration of ZP1848 or its salt before, simultaneously with, or after a course of chemotherapy or radiation therapy to reduce the side effects of chemotherapy, such as diarrhea, abdominal cramps, and vomiting, and to reduce subsequent structural and functional damage to the intestinal epithelium caused by chemotherapy or radiation therapy. Preferably, administration begins 1, 2, 3, 4, 5, 6, or 7 days before the start of a chemotherapy or radiation cycle. Preferably, administration begins the day before or on the day of the start of treatment using a chemotherapy or radiation cycle, and once or twice a week thereafter.

[0161] Intestinal damage and dysfunction are a well-known side effect of chemotherapy treatment for cancer. Chemotherapy is often associated with undesirable gastrointestinal side effects, such as mucositis, diarrhea, bacterial translocation, malabsorption, abdominal cramps, gastrointestinal bleeding, and vomiting. These side effects are clinical consequences of structural and functional damage to the intestinal epithelium and often lead to the need to reduce the dose and frequency of chemotherapy. Administration of ZP1848 or its salt can enhance the trophic effect in intestinal crypts and quickly provide new cells to replace damaged intestinal epithelium after chemotherapy. The ultimate goal is to reduce gastrointestinal morbidity in patients undergoing chemotherapy while simultaneously creating the most optimal chemotherapy regimen for cancer treatment.Concomitant prophylactic or therapeutic treatment may be provided in accordance with the present invention to patients undergoing or about to undergo radiation therapy.

[0162] Small intestinal mucosal stem cells are particularly sensitive to the cytotoxic effects of chemotherapy due to their high proliferation rate (Keefe et al., Gut 2000; 47: 632-7). Chemotherapy-induced damage to the small intestinal mucosa is clinically often referred to as gastrointestinal mucositis and is characterized by impaired absorption and barrier function of the small intestine. For example, the widely used chemotherapeutic agents 5-FU, irinotecan, and methotrexate have been shown to enhance apoptosis, leading to villous atrophy and crypt hypoplasia in the small intestine of rodents (Keefe et al., Gut 47: 632-7, 2000; Gibson et al., J Gastroenterol Hepatol. Sep;18(9):1095-1100, 2003; Tamaki et al., J Int Med Res. 31(1):6-16, 2003).In humans, chemotherapeutic agents have been shown to increase apoptosis in intestinal crypts 24 hours after administration and subsequently decrease villus area, crypt length, mitotic index per crypt, and enterocyte height three days after chemotherapy (Keefe et al., Gut 2000; 47: 632-7). Thus, structural changes in the small intestine directly lead to intestinal dysfunction and, in some cases, diarrhea.

[0163] Gastrointestinal mucositis after cancer chemotherapy is an increasingly common problem that is essentially untreatable once it occurs, although it gradually improves. Studies with commonly used cytostatic anticancer drugs, 5-FU and irinotecan, have demonstrated that effective chemotherapy with these drugs predominantly negatively affects the structural integrity and function of the small intestine, while the large intestine is less sensitive and mainly responds with increased mucus production (Gibson et al., J Gastroenterol Hepatol. Sep; 18(9): 1095-1100, 2003; Tamaki et al., J Int Med Res. 31(1):6-16, 2003).

[0164] ZP1848 can be used to prevent and / or treat gastrointestinal damage and side effects of chemotherapeutic agents. This potentially important therapeutic application applies to currently used chemotherapeutic agents such as, but not limited to: 5-FU, altretamine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, liposomal doxorubicin, leucovorin, lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone, Oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, raltitrexed, streptozocin, te ga fur-ura cil, temozolomide, thiotepa, thioguanine / thioguanine, topotecan, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, bleomycin,Busulfan, Capecitabine, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Docetaxel, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Liposomal Doxorubicin, Leucovorin, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Pentostatin, Procarbazine, Raltitrexed, Streptozocin, Tegafur-uracil, Temozolomide, thiotepa, thioguanine / thioguanine, topotecan, treosulfan, vinblastine, vincristine, vindesine, vinorelbine.,

[0165] Additional aspects of the present invention relate to increasing intestinal mass or longitudinal intestinal growth in a patient, for example, a human patient, particularly the small intestine. ZP1848 or its salt is capable of increasing longitudinal intestinal growth relative to a control treatment, as shown in WO 2018 / 229252.

[0166] This option is particularly important for patients with SBS, as it will lead to increased absorptive capacity even after treatment is discontinued. Such patients will receive treatment for at least 1 to 3 years, such as at least 1 to 4 years, such as 1 to 10 years, such as 1 to 20 years, such as 1 to 35 years, to induce longitudinal intestinal growth.

[0167] As described in this application, patients with SBS whose condition is intermediate between intestinal failure (SBS-CI) and SBS-PP and intestinal failure syndrome (SBS-IPS) or SBS without PP, respectively, may benefit from lengthening their intestines over a course of treatment of 1 to 3 years, after which the risk of developing intestinal failure syndrome is reduced, for example, with once-weekly or twice-weekly administration during the treatment period. This includes a reduced risk associated with the need for central catheter insertion and the risk of sepsis associated with its use.

[0168] Active agents can also be used to treat malnutrition such as that resulting from cachexia and anorexia.

[0169] Examples

[0170] The following examples are provided to illustrate preferred aspects of the present invention and are not intended to limit the scope of the present invention. GLP-2 analogs administered according to the dosage regimens described herein can be prepared according to methods such as the solid-phase peptide synthesis described in WO 2006 / 117565, the contents of which are expressly incorporated by reference in their entirety.

[0171] Example 1: Pharmacokinetic (PK) profile of glepaglutide and its two major active metabolites in patients with different degrees of renal function

[0172] Problem

[0173] Glepaglutide (ZP1848, glepaglutide 1-39Glepaglutide is a potent, long-acting GLP-2 analogue currently in Phase 3 for the treatment of short bowel syndrome (SBS). Glepaglutide consists of 39 L-amino acids, all of which are naturally occurring. Glepaglutide has nine amino acid substitutions compared to native GLP-2 and a C-terminal tail consisting of six lysine residues, providing a stable, long-lasting liquid formulation.

[0174] After subcutaneous injection of glepaglutide, two functionally active metabolites are formed from cleavages at the C-terminus, namely ZP2469 (1848 1-34 ) and ZP2711 (ZP1848 1-35 ).

[0175] Patients with short bowel syndrome are at risk of developing renal impairment, which may require dose adjustment of glepaglutide, so a phase 1 clinical study was conducted to investigate the pharmacokinetics of glepaglutide after a single dose in patients with renal impairment compared with patients with normal renal function.

[0176] The clinical trial protocol, its amendments / updates, informed consent forms (ICFs) and their amendments before screening were reviewed and approved by the Independent Ethics Committee (IEC).

[0177] Methods

[0178] The study was designed as a two-stage, open-label, multicenter, non-randomized trial to evaluate the pharmacokinetic properties of a single subcutaneous dose of 10 mg glepaglutide in subjects with varying degrees of renal function. Renal function was calculated using the estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) equation.

[0179] Sixteen Caucasian patients were included in the study, 4 patients with end-stage renal disease (ESRD) not on dialysis (eGFR<15 mL / min), 4 patients with severe renal impairment (eGFR<30 mL / min), and 8 matched controls with normal renal function (eGFR>90 mL / min) (Table 1). Demographic data, except for eGFR, were similar between groups (Table 1).

[0180] Glepaglutide (ZP1848, 10 mg) was provided in a single-use vial containing 1 mL (0.5 mL withdrawable volume) of clear, colorless solution for subcutaneous injection at a concentration of 20 mg / mL glepaglutide.

[0181] Blood PK samples were collected for 14 days following a single 10 mg intra-abdominal injection of glepaglutide. PK samples were analyzed for glepaglutide, ZP2469, and ZP2711 using a validated GLP-compliant LC / MS / MS assay.

[0182] The primary PK parameters were the area under the curve between the dose and the last measurable concentration (AUGt) extrapolated to infinity (AUC inf ) and calculated from 0 to 168 hours (AUC 0-168 ) and maximum plasma concentration (C max ), which were calculated for glepaglutide, ZP2469, ZP2711. For the primary endpoint, a designed analyte of “glepaglutide-total” (glepaglutide + ZP2469 + ZP2711) was used and analyzed using a non-compartmental approach.

[0183] Results

[0184] No statistically significant differences in primary PK parameters were observed in patients with severe renal impairment and ESRD compared to healthy matched subjects. In particular, there was no clinically significant difference between patients with severe renal impairment / ESRD and normal renal function in terms of total exposure (AUC 0-168ч ) and peak plasma concentration (C max) glepaglutide after a single subcutaneous dose.

[0185] Geometric mean ratios for glepaglutide итого were 0.96 [90%Cl: 0.69-1.35] for AUC 0-168ч 0.90 [90%Cl: 0.62-1.31] for C max . Therefore, the exposure of glepaglutide итого In patients with renal impairment, the two PK parameters were 4% and 10% lower compared to healthy patients, respectively, which is not considered clinically significant.

[0186] Glepaglutide exposure итого was similar in patients with renal impairment and in healthy subjects with normal renal function. This suggests that renal function does not influence the systemic exposure of glepaglutide, and therefore, no dose adjustment of glepaglutide is required in patients with renal impairment.

[0187] The geometric mean ratios for ZP2469 were 0.96 [90%Cl:0.667-1.38] for AUC 0-168 and 0.91 [90%Cl: 0.595-1.39] for C max .

[0188] The geometric mean ratios for ZP2711 were 0.89 [90%CI: 0.616-1.29] for AUC 0-168 and 0.81 [90%Cl: 0.572-1.15] for C max .

[0189]

[0190] eGFR was calculated according to the Modification of Diet in Renal Disease (MDRD) equation (Levey AS et al., Clin Chem. Apr 2007;53(4):766-772).

[0191] ***

[0192] Although the present invention has been described with respect to the exemplary embodiments described above, many equivalent modifications and changes will be apparent to those skilled in the art upon consideration of this description. Accordingly, the described exemplary embodiments of the present invention are considered illustrative and not restrictive. Various changes in the described embodiments can be made without departing from the spirit and scope of the present invention. All documents cited in this application are expressly incorporated by reference.

[0193] --->

[0194] SEQUENCE LISTING

[0195] <110> ZEALAND PHARMA A / S

[0196] <120> USE OF GLP-2 ANALOGUES IN PATIENTS WITH RENAL FAILURE

[0197] <130> 008160723

[0198] <140> PCT / EP2021 / 085846

[0199] <141> December 15, 2021

[0200] <160> 5

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[0234] His Gly Glu Gly Thr Phe Ser Ser Glu Leu Ala Thr Ile Leu Asp Ala

[0235] 1 5 10 15

[0236] Leu Ala Ala Arg Asp Phe Ile Ala Trp Leu Ile Ala Thr Lys Ile Thr

[0237] 20 25 30

[0238] Asp Lys Lys

[0239] 35

[0240] <210> 4

[0241] <211> 33

[0242] <212> PRT

[0243] <213> Artificial sequence

[0244] <220>

[0245] <223> Synthetic construction

[0246] <400> 4

[0247] His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn

[0248] 1 5 10 15

[0249] Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr

[0250] 20 25 30

[0251] Asp

[0252] <210> 5

[0253] <211> 33

[0254] <212> PRT

[0255] <213> Artificial sequence

[0256] <220>

[0257] <223> Synthetic construction

[0258] <400> 5

[0259] His Ala Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn

[0260] 1 5 10 15

[0261] Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr

[0262] 20 25 30

[0263] Asp

[0264] <---

Claims

1. A method for preventing or treating a ZP1848-responsive condition in a subject with at least severe renal impairment, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein no dose adjustment of ZP1848 or said salt is required and wherein said disease is selected from ulcers, indigestion, malabsorption syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small intestinal injury, or short bowel syndrome (SBS).

2. The method of claim 1, wherein the subject has previously been treated with teduglutide at an adjusted dose.

3. The method according to any one of claims 1, 2, wherein the subject has severe renal failure or end-stage renal disease (ESRD).

4. The method according to any one of claims 1-3, wherein said condition is short bowel syndrome (SBS) in a subject receiving parenteral nutrition (PN).

5. The method according to any one of claims 1-3, wherein said condition is radiation enteritis, infectious or post-infectious enteritis, or small intestinal injury caused by toxic or other chemotherapeutic agents.

6. The method according to any one of claims 1-3, wherein said condition is a side effect of chemotherapy or radiation therapy in a human subject.

7. The method according to any one of claims 1 to 6, wherein said ZP1848 or a pharmaceutically acceptable salt thereof is administered by a dosing regimen comprising a plurality of doses or a course of doses separated in time by an interval of 2 days, 2.5 days, 3 days, 3.5 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days or 12 days, for example separated in time by an interval of 3 days, 3.5 days, 4 days, 5 days, 6 days, 7 days or 8 days, for example separated in time by an interval of 3 days, 3.5 days, 4 days or 7 days.

8. The method of claim 7, wherein said dosing regimen is a once or twice weekly dosing regimen.

9. The method according to any one of claims 1 to 8, characterized in that each individual unadjusted dose is from 1 to 20 mg, inclusive, per subject per dose, for example from 5 to 15 mg, from 7 to 12 mg, or from 9 to 11 mg, inclusive, per subject per dose.

10. The method of claim 9, wherein each individual unadjusted dose is 10 mg ±10% per subject per dose.

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