Use of GLP-2 analogs in patients with renal failure

Abstract

The present invention relates to dosage regimes for the administration of glucagon-like peptide-2 (GLP-2) analogs, and in particular ZP1848 (grepaglutide), in patients with renal failure. Unlike other GLP-2 analogs, such as teduglutide, ZP1848 has been found to be normally cleared in patients with renal impairment. As a result, there is no need to adjust the dosage of ZP1848 depending on the patient's renal function.

Description

[Technical Field]

[0001] This invention relates to dosage regimes for the administration of glucagon-like peptide-2 (GLP-2) analogs, and in particular ZP1848 (glepaglutide), in patients with renal failure. [Background technology]

[0002] 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-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-OH. It derives from specific post-translational processing of proglucagon in enteroendocrine L cells of the intestine and in specific regions of the brainstem. GLP-2 binds to a single G protein-coupled receptor belonging to the class II glucagon secretin family.

[0003] GLP-2 has been reported to induce significant growth of the 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 has a growth effect on the colon. Furthermore, GLP-2 inhibits gastric emptying and gastric acid secretion (Wojdemann et al., 1999, J. Clin. Endocrinol. Metab. 84:2513-2517), enhances the intestinal barrier function (Benjamin et al., 2000, Gut 47:112-119), stimulates intestinal hexose transport via upregulation of glucose transporters (Cheeseman, 1997, Am. J. Physiol. R 1965-71), 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.

[0004] The potential of glucagon-like peptide-2 receptor analogs for treating intestinal diseases is recognized in this art. However, native hGLP-2, a 33-amino acid gastrointestinal peptide, is not useful in clinical practice because its half-life in humans is very short: approximately 7 minutes for full-length GLP-2[1~33] and approximately 27 minutes for shortened GLP-2[3~33]. This short half-life is mainly due to degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). Therefore, in this art, attempts have been made to develop GLP-2 receptor agonists with better pharmacokinetic properties, particularly to improve the half-life of the GLP-2 molecule. For example, GLP-2 analogs with substitutions, such as GLP-2 analogs containing a Gly substitution at position 2 ([hGly2]GLP-2, teduglutide) that increases the half-life from 7 minutes (native GLP-2) to approximately 2 hours, have been proposed. Teduglutide is approved as a treatment for short bowel disease under the names Gatex (USA) and Revestive (Europe).

[0005] International Publication No. 2006 / 117565 (Zealand Pharma A / S) describes a GLP-2 analog comprising one or more substitutions compared to [hGly2]GLP-2, which enhances in vivo bioactivity and / or chemical stability as assessed, for example, by in vitro stability assays.

[0006] Among the molecules disclosed in International Publication No. 2006 / 117565 is ZP1848 (glepaglutide), which is designed to be stable in liquid formulations. A dosing regimen for GLP-2 analogs containing ZP1848 and its metabolites is described in International Publication No. 2018 / 229252, which also shows that these compounds are effective in increasing longitudinal growth of the intestine.

[0007] The use of GLP-2 analogs, including ZP1848, for the treatment of conditions related to bile acid synthesis, hepatic bile acid content, or intestinal bile acid content is described in International Publication No. 2020 / 020904.

[0008] A ready-to-use formulation of ZP1848 is described in International Publication No. 2020 / 065064. [Overview of the project]

[0009] Teduglutide clearance is impaired in patients with renal impairment, particularly those with moderate or severe renal impairment or end-stage renal disease (ESRD). Therefore, a 50% reduction in the usual dose of teduglutide is recommended for patients with moderate or severe renal impairment or ESRD. See, for example, Nave, R et al., Eur.J.Clin.Pharmacol.2013,69(5):1149-1155, Summary of Product Characteristics of Revestive® (European Medicines Agency), and the European Public Assessment Report of Revestive® (2012) by the European Medicines Agency.

[0010] Since the ZP1848 is also a GLP-2 analog, it would be reasonable to expect that similar considerations apply.

[0011] Surprisingly, however, it was found that ZP1848 is normally eliminated in patients with renal impairment. As a result, there is no need to adjust the dosage of ZP1848 according to the patient's renal function. This offers several advantages. Firstly, it means that patients with impaired renal function can fully receive a therapeutically effective dose without causing undesirable side effects, such as those caused by excessive exposure to the active drug. Furthermore, it eliminates the need to test the patient's renal function before prescribing ZP1848, resulting in more efficient and economical treatment. In addition, even if a patient already receiving ZP1848 develops a type of renal impairment, there is no need to adjust the dosage in consideration of renal events, which should improve safety.

[0012] Accordingly, 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 having at least moderate renal impairment, wherein no dose adjustment of ZP1848 or said salt is required.

[0013] The present invention further provides a method for the prevention or treatment of a condition responsive thereto in a subject having at least moderate renal impairment, comprising the step of administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein no dose adjustment of ZP1848 or said salt is required.

[0014] The present invention further provides the use of ZP1848 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of a condition responsive thereto in a subject having at least moderate renal impairment, wherein no dose adjustment of ZP1848 or said salt is required.

[0015] The term "at least moderate" renal impairment is used herein to include subjects having moderate renal impairment, severe renal impairment, or ESRD.

[0016] Accordingly, when teduglutide is prescribed for the treatment of the same condition, the subject will normally require an adjusted dose of teduglutide. The subject may or may not have previously received treatment with, for example, an adjusted dose of teduglutide.

[0017] In a further 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 who requires an adjusted dose of teduglutide as a result of renal impairment, wherein no dose adjustment of ZP1848 or said salt is required.

[0018] The present invention further provides a method for preventing or treating a condition responsive to ZP1848 in a subject requiring a modified dose of teduglutide as a result of renal impairment, the method comprising the step of administering ZP1848 or a pharmaceutically acceptable salt thereof to the subject, wherein no dose adjustment of ZP1848 or the salt thereof is required.

[0019] The present invention further provides the use of ZP1848 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of a corresponding condition in subjects requiring a modified dose of teduglutide as a result of renal impairment, wherein no dose adjustment of ZP1848 or the salt is required.

[0020] Therefore, the subjects may have at least moderate renal impairment, such as moderate renal impairment, severe renal impairment, or ESRD.

[0021] When teduglutide is prescribed for the treatment of the same condition, the patient will usually require an adjusted dose of teduglutide. The patient may or may not have previously received treatment with an adjusted dose of teduglutide.

[0022] In a further embodiment, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a condition in response to teduglutide in a subject receiving a dose adjusted due to renal impairment, wherein no dose adjustment of ZP1848 or the salt is required.

[0023] The present invention further provides a method for preventing or treating a ZP1848-responsive condition in a subject who has received a modified dose of teduglutide due to renal impairment, the method comprising the step of administering ZP1848 or a pharmaceutically acceptable salt thereof to the subject, wherein no dose adjustment of ZP1848 or the salt thereof is required.

[0024] The present invention further provides the use of ZP1848 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of a condition in response to teduglutide in a subject who has received a dose adjusted due to renal impairment, wherein no dose adjustment of ZP1848 or the salt is required.

[0025] Therefore, the subjects would likely have previously received teduglutide at an adjusted dose for the treatment of the same condition. Typically, the subjects have at least moderate renal impairment, such as moderate renal impairment, severe renal impairment, or ESRD.

[0026] The condition being treated may be any condition that responds therapeutically to treatment with a GLP-2 analog, for example, treatment resulting in improvement of one or more symptoms, improvement of the underlying condition, delay of onset, and / or suppression of exacerbations. Therefore, prevention can be considered a treatment or therapy.

[0027] These conditions include gastrointestinal and intestinal disorders such as ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, inflammatory bowel disease, celiac sprue (e.g., resulting from gluten-sensitive bowel syndrome or celiac disease), tropical sprue, hypogammaglobulinemia sprue, enteritis, focal enteritis (Crohn's disease), ulcerative colitis, small intestine damage, or short bowel syndrome (SBS).

[0028] The use of this drug for the treatment of short bowel syndrome (SBS) could be particularly interesting, especially in patients receiving parenteral support (PS).

[0029] Further conditions include gastrointestinal and intestinal disorders such as radiation enteritis, infectious enteritis or post-infectious enteritis, or small intestinal damage caused by toxic agents or other chemotherapeutic agents. In this case, treatment with GLP-2 analogs may be combined with one or more anticancer therapies, and therefore may include administering one or more chemotherapeutic agents to the subject or treating the subject with radiotherapy.

[0030] Therefore, this condition may be a side effect of chemotherapy or radiation therapy in human subjects.

[0031] The terms “subject” and “patient” are used interchangeably herein. It will be understood that a subject (or patient) is a mammal, typically a human.

[0032] ZP1848 is particularly effective in increasing the mass of the intestinal tract and / or longitudinal growth of the intestinal tract, especially in the small intestine.

[0033] Accordingly, in a further embodiment, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in promoting or increasing the mass of the intestinal tract and / or longitudinal growth of the intestinal tract in subjects having at least moderate renal impairment, wherein no dose adjustment of ZP1848 or the salt is required.

[0034] The present invention further provides a method for increasing the mass of the intestinal tract and / or promoting or increasing longitudinal intestinal growth in subjects having at least moderate renal impairment, comprising the step of administering ZP1848 or a pharmaceutically acceptable salt thereof to the subject, wherein no dose adjustment of ZP1848 or the salt thereof is required.

[0035] The present invention further provides the use of ZP1848 or a pharmaceutically acceptable salt thereof in the preparation of a pharmacopoeia for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in subjects having at least moderate renal impairment, wherein no dose adjustment of ZP1848 or the salt is required.

[0036] Therefore, when teduglutide is used for the same purpose, the patient will typically require a modified dose of teduglutide. The patient may or may not have previously received treatment with, for example, a modified dose of teduglutide.

[0037] In a further embodiment, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in promoting or increasing intestinal mass and / or longitudinal intestinal growth in subjects requiring a modified dose of teduglutide as a result of renal impairment, wherein no dose adjustment of ZP1848 or the salt is required.

[0038] The present invention further provides a method for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in subjects requiring a modified dose of teduglutide as a result of renal impairment, comprising the step of administering ZP1848 or a pharmaceutically acceptable salt thereof to the subject, wherein no dose adjustment of ZP1848 or its salt is required.

[0039] The present invention further provides the use of ZP1848 or a pharmaceutically acceptable salt thereof in the preparation of a pharmacopoeia for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in subjects requiring a modified dose of teduglutide as a result of renal impairment, wherein no dose adjustment of ZP1848 or the salt thereof is required.

[0040] Therefore, the subjects may have at least moderate renal impairment, such as moderate renal impairment, severe renal impairment, or ESRD.

[0041] When teduglutide is prescribed for the same purpose, the patient will typically require an adjusted dose of teduglutide. The patient may or may not have previously received treatment with, for example, an adjusted dose of teduglutide.

[0042] In a further embodiment, the present invention provides ZP1848 or a pharmaceutically acceptable salt thereof for use in promoting or increasing intestinal mass and / or longitudinal intestinal growth in subjects receiving teduglutide at doses adjusted due to renal impairment, wherein no dose adjustment of ZP1848 or the salt is required.

[0043] The present invention further provides a method for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in a subject that has received a dose of teduglutide adjusted for renal impairment, comprising the step of administering ZP1848 or a pharmaceutically acceptable salt thereof to the subject, wherein no dose adjustment of ZP1848 or its salt is required.

[0044] The present invention further provides the use of ZP1848 or a pharmaceutically acceptable salt thereof in the preparation of a pharmacopoeia for increasing intestinal mass and / or promoting or increasing longitudinal intestinal growth in subjects who have received a dose of teduglutide adjusted due to renal impairment, wherein no dose adjustment of ZP1848 or the salt thereof is required.

[0045] Therefore, the subjects would likely have received previously adjusted doses of teduglutide for the same purpose, for example. Typically, the subjects would have at least moderate renal impairment, such as moderate renal impairment, severe renal impairment, or ESRD.

[0046] In such embodiments, the subject may be suffering from a condition in which an increase in intestinal mass and / or promotion or increase of longitudinal intestinal growth is desirable, for example, therapeutic. This includes any of the conditions described elsewhere in this specification, and may include subjects suffering from short bowel syndrome (SBS), for example, those receiving parenteral support.

[0047] In a further embodiment, the present invention provides a pharmaceutical kit comprising ZP1848 or a pharmaceutically acceptable salt thereof, and information that dose adjustment of ZP1848 is unnecessary for subjects with at least moderate renal impairment.

[0048] The above-mentioned ZP1848 or a pharmaceutically acceptable salt will typically be provided as a pharmaceutical composition comprising ZP1848 or the above-mentioned salt in combination with a pharmaceutically acceptable carrier or excipient.

[0049] The above kit may contain one or more individually measured doses of ZP1848 or the above salt, where each individually measured dose is an adjusted dose as described elsewhere in this specification.

[0050] Individual doses may be administered according to the dosing regime described elsewhere in this specification.

[0051] The kit may further contain one or more chemotherapeutic agents, which may be provided as separate pharmaceutical compositions from ZP1848 or its salts.

[0052] Subjects treated according to any aspect of the present invention will typically be administered ZP1848 or a pharmaceutically acceptable salt thereof instead of teduglutide (and any other GLP-2 receptor agonist), i.e., ZP1848 or a related salt will typically be the sole GLP-2 used in the treatment of the subject. Similarly, compositions and kits defined herein typically contain ZP1848 or a related salt as the sole GLP-2 receptor agonist.

[0053] In the context of this invention, a “modified” dose is a dose reduced to account for renal impairment. Therefore, when administered to subjects with at least moderate renal impairment, the dose of teduglutide is reduced by 50% to account for impaired systemic drug clearance in such patients and to avoid excessive exposure to the drug.

[0054] In the case of ZP1848 and its salts, there is no need to adjust the dose in consideration of a patient's renal impairment. Therefore, the dose for such subjects may be the same as that administered to otherwise equivalent subjects with normal renal function. This may be called the “normal,” “standard,” or “unadjusted” dose. Nevertheless, it will be understood that small fluctuations, such as + / - 10%, are acceptable and not considered an “adjusted” dose. Typically, an “adjusted” dose will fluctuate by more than 30%, for example more than 40%, for example about 50%.

[0055] Of course, it will be understood that the “normal” dose can be determined depending on the specific subject, for example, age, sex, weight, medical condition, etc., and / or the intended dosage regime. Again, such variations should not be considered to result in a “adjusted” dose within the scope of the present invention. Rather, unless otherwise specified in the context, “adjusted” should be interpreted as “adjusted with renal function in mind” or similar.

[0056] Administration may follow any appropriate dosing plan.

[0057] For example, administration may be once a day.

[0058] However, as described in International Publication No. 2018 / 229252, ZP1848 has an unexpectedly long half-life, which may allow for alternative dosing regimes, such as once or twice a week, especially when delivered by subcutaneous injection. While not bound by theory, it is thought that the half-life of ZP1848 may be due to a combination of subcutaneous depot formation and the formation of metabolites that are slowly released from the subcutaneous depot and are also agonists of the GLP-2 receptor. The subcutaneous depot may be formed at the time of administration via a reaction between the lysine tail of ZP1848 and hyaluronic acid in the subcutaneous compartment.

[0059] Therefore, the dosing regime includes multiple doses or a series of doses at intervals of 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days. In a preferred embodiment, the doses are divided at intervals of 3, 3.5, 4, 5, 6, 7, or 8 days. In a preferred embodiment, the doses are divided at intervals of 3, 3.5, 4, or 7 days. As understood in the art, the time between doses may vary to some extent so that each dose is not separated by exactly the same amount of time. This is often directed at the discretion of the physician. Therefore, the doses may be divided within a clinically acceptable time range, for example, about 2 days to about 10 days, or about 3 or 4 days to about 7 or 8 days.

[0060] A typical “usual” or “unadjusted” dose may be in the range of 0.5 mg to 25 mg per subject per administration.

[0061] For example, it may be 1 mg to 20 mg per dose per subject, for example 1 mg to 10 mg per dose per subject, for example 2 mg to 7 mg per dose per subject, for example 5 mg to 7 mg per dose per subject, or 2 mg to 5 mg per dose per subject.

[0062] Alternatively, it may be 5 mg or more and 15 mg or less per subject per dose, for example, 7 mg or more and 12 mg or less per subject per dose, for example, 9 mg or more and 11 mg or less per subject per dose.

[0063] In some embodiments, the dose of the GLP-2 analog used according to the present invention is approximately 10 mg per subject per dose ("approximately" means + / - 10%).

[0064] In some embodiments, the dose of the GLP-2 analog used according to the present invention is a fixed dose of 10 mg per subject.

[0065] These dosages are suitable for any medication regimen, but may be particularly suitable for regimens that administer medication once or twice a week.

[0066] During the course of treatment, the dosage taken by the patient may remain the same or vary, depending on the doctor's instructions.

[0067] In some cases, for example, when administering medication at spaced injection sites, for example, at least 5 cm apart, it may be desirable to divide the total dose into multiple (e.g., two or three) separate doses or administrations. Such spatially separate administrations are usually delivered substantially simultaneously, for example, on the same day, within one hour of each other, or even closer together.

[0068] The embodiments of the present invention will be described below as examples, not as limitations. However, various further aspects and embodiments of the present invention will become apparent to those skilled in the art upon consideration of this disclosure.

[0069] Unless otherwise indicated by the context, the above descriptions and definitions of features are not limited to any particular aspect or embodiment of the present invention, but apply equally to all aspects and embodiments described herein.

[0070] Detailed description of the invention Throughout this specification and the claims, conventional one-letter and three-letter codes for natural amino acids are used. All amino acid residues in the compounds described are typically in the L-configuration.

[0071] compound ZP1848 is a peptide having the following chemical formula, as described, for example, in International Publication No. 2006 / 117565: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 The N-terminal "H-" indicates a free N-terminal amine (NH2-) group. The C-terminal "NH2-" indicates a C-terminal amide group. The terms ZP1848 and glepaglutide can be used interchangeably.

[0072] The present invention encompasses the use of pharmaceutically acceptable salts of ZP1848, as will be described in more detail below. Any suitable salt can be used, but acetate salts may be preferred.

[0073] When ZP1848 is injected into the subcutaneous (SC) compartment, two functionally active metabolites, ZP2469 and ZP2711 (both C-terminally cleaved analogs of ZP1848), are formed. Therefore, the overall PK profile of ZP1848 consists of the effects of ZP1848 and its two major metabolites.

[0074] ZP2469 is a peptide with the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDK-OH

[0075] ZP2711 is a peptide with the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKK-OH Here, the N-terminal "H-" is as described above, and the C-terminal "-OH" indicates a free C-terminal carboxylic acid group.

[0076] Teduglutide is a peptide with the following chemical formula: H-HGDGSFSDEMNTILDNLAARDFINWLIQTKITD-OH Here, the N-terminal "H-" and C-terminal "-OH" are as described above.

[0077] Renal function and its measurement Renal function is usually defined by referring to the glomerular filtration rate (GFR) or estimated glomerular filtration rate (eGFR).

[0078] GFR (unit: ml / min) is derived from inulin. 51 Cr-EDTA, 99m Measurement can be performed using appropriate filtration markers such as Tc-DTPA, iotalamic acid, or iohexol. Those skilled in the art will be familiar with appropriate methods based on monitoring the excretion of the relevant marker in urine over a given period, such as 24 hours.

[0079] eGFR can be calculated from standardized serum creatinine (SCr) values. For example, it can be calculated according to the Modification of Diet in Renal Disease (MDRD) formula (Levey AS et al., Clin Chem. Apr 2007;53(4):766-772), which is based on a body surface area of ​​1.73 m². 2 The normalized values ​​are provided in units of ml / min / 1.73m2.

[0080] [Formula 1] eGFR=175×standardized SCr -1.154 × Age -0.203×1.212 [if Black] ×0.742 [if Female] [SCr(mg / dL)]

[0081] or

[0082] [Formula 2] eGFR=30849×standardized SCr -1.154 × Age -0.203 ×1.212 [if Black] ×0.742 [if Female] [SCr(μmol / L)]

[0083] Alternatively, renal function may be defined by creatinine clearance (Ccr) using the Cockcroft-Gault formula (Cockcroft DW and Gault MH, Nephron 16: 31-41 (1976)):

[0084] [Formula 3] Ccr = [(140 - age) (weight (kg))] / [72 × SCr (mg / 100ml)]

[0085] This is for adult men; for adult women, it decreases by 15%.

[0086] To calculate eGFR in children and adolescents (1-18 years), alternative formulas such as the creatinine-based "bedside Schwartz" formula can also be used (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):

[0087] [Formula 4] eGFR = 0.413 × (height / SCr) [height is expressed in cm; SCr mg / 100ml]

[0088] For adults, it may be preferable to calculate eGFR using the MDRD formula.

[0089] For the purpose of calculating eGFR, standardized serum creatinine levels can be measured by isotopic dilution gas chromatography / mass spectrometry (ID-GC / MS), as described, for example, by Stoeckl and Reinauer, Clin. Chem. 1993;39:993-1000. This is the "gold standard" for creatinine measurement.

[0090] It will be understood that other methods and commercially available kits are available for measuring serum creatinine, including enzymatic methods or colorimetric methods such as the Jaffe reaction, in which creatinine reacts with alkaline picrate to form a colored product. Such methods typically employ various compensations or correction factors to more accurately reflect the gold standard results by minimizing interference from bilirubin and pseudo-creatinine chromogens, such as proteins and ketones. An example is the Cobas® CREJ2 (Creatinine Jaffe Second Generation) kit (Roche).

[0091] Current classifications of renal function for research specifically on renal impairment can be found in the "Guidance on Industry Pharmacokinetics in Patients with Renal Impairment – ​​Study Design, Data Analysis, and Effects on Administration, U.S. Department of Health and Human Services, Food and Drug Administration, FDA Center for Drug Evaluation and Research (CDER), September 2020," or the corresponding European "Guidance on the Evaluation of Pharmacokinetics of Medicinal Products in Patients with Renal Impairment, European Medicines Agency, 2015."

[0092] Current clinical guidelines define normal renal function as GFR (or Ccr) ≥ 90 mL / min, or eGFR ≥ 90 mL / min / 1.73m². 2 It can be defined as follows.

[0093] Mild renal impairment can be defined as a GFR (or Ccr) of 60 to less than 90 mL / min, or an eGFR of 60 to 90 mL / min / 1.73m 2 or less.

[0094] Moderate renal impairment can be defined as a GFR (or Ccr) of 30 to less than 60 mL / min, or an eGFR of 30 to 60 mL / min / 1.73m 2 or less.

[0095] Severe renal impairment can be defined as a GFR (or Ccr) of 15 to less than 30 mL / min, or an eGFR of 15 to 30 mL / min / 1.73m 2 or less.

[0096] End-stage renal disease (ESRD) can typically be characterized as a GFR (or Ccr) of less than 15 mL / min, or an eGFR of less than 15 mL / min / 1.73m 2 or less.

[0097] In previous guidelines, the threshold for moderate renal impairment was set at less than 50 mL / min instead of less than 60 mL / min, and as a result, the original guidance for teduglutide indicated a 50% dose reduction for patients with a GFR of less than 50 mL / min. Accordingly, subjects with a GFR (or Ccr) of less than 50 mL / min or an eGFR of 50 mL / min / 1.73m 2 or less will be understood to require no dose adjustment. Under certain circumstances, it may be appropriate to consider this value as the threshold for moderate renal impairment. Accordingly, a subject with at least moderate renal impairment can be considered as a subject having a GFR (or Ccr) of less than 50 mL / min or an eGFR of 50 mL / min / 1.73m 2 or less.

[0098] For the purposes of the present invention, it may be preferable to use a classification of the subject based on a standardized SCr measurement, for example, based on an eGFR measurement calculated by the MDRD formula. SCr is preferably determined by ID-GC / MS, for example, as described above.

[0099] Pharmaceutical composition and administration The described activators can be prepared for storage or administration and formulated as pharmaceutical compositions containing a therapeutically effective amount of the activator in a pharmaceutically acceptable carrier.

[0100] The therapeutically effective dose of the relevant active agent will depend on the route of administration, the type of mammal being treated (typically human), and the physical characteristics of the specific mammal under consideration. These factors and their relationship to the determination of this dose are well known to those skilled in the medical field. This dose and method of administration can be adjusted to achieve optimal efficacy in delivering the peptide to the intestines, but will depend on factors such as body weight, diet, concomitant medications, and other factors well known to those skilled in the medical field.

[0101] The active agent is typically present in an amount effective for the prevention or treatment of related conditions in the subject, such as the treatment or prevention of gastrointestinal and intestinal diseases, or for promoting or increasing the mass of the intestinal tract and / or longitudinal growth of the intestinal tract in the subject's intestines.

[0102] Examples of pharmaceutically acceptable salts are listed in “Remington's Pharmaceutical Sciences”, 17th edition, Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 and the most recent edition, as well as in the Encyclopaedia of Pharmaceutical Technology.

[0103] 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 an acetate salt. In general, it is preferable that the salt is not a chloride salt. Examples of basic salts include cations of alkali metals such as sodium and potassium, alkaline earth metals such as calcium, and ammonium ions. + N(R 3 )3(R 4 The formula includes a salt selected from ), where R 3 and R 4 C is independently substituted as needed. 1-6 -alkyl, substituted C as needed 2-6 - Represents an alkenyl, an aryl (as needed), or a heteroaryl (as needed).

[0104] Acetate is particularly preferred. In this context, the term "ZP1848-acetate" refers to the ZP1848 molecule in acetate form. The acetate of ZP1848 can be represented by the formula (ZP1848), x(CH3COOH), where x is 1.0 to 8.0 (i.e., x is 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, or 8.0). x is not necessarily an integer, as any composition may contain molecules with different numbers of acetate molecules. In some cases, x is 4.0 to 8.0, x is 6.0 to 8.0, or x is 4.0 to 6.5. In other cases, x is 4.0 to 6.0, x is 2.0 to 7.0, x is 3.0 to 6.0, x is 4.0 to 6.0, or x is 4.0 to 8.0.

[0105] As will be apparent to those skilled in the medical field, the "therapeutic effective dose" of the peptide or pharmaceutical composition of the present invention may vary depending on age, weight and species of the mammal being treated, the specific compound used, the specific mode of administration, and the desired effect and therapeutic indication. Since these factors and their relationship to the determination of this dose are well known in the medical field, determining the therapeutically effective dose level and the amount necessary to achieve the desired outcome (e.g., preventing and / or treating the intestinal and gastric-related diseases described herein, as well as other medical indications disclosed herein, or, in the intestine of the subject, inducing or increasing the mass of the intestinal tract and / or longitudinal intestinal growth) is within the realm of those skilled in the art.

[0106] As used herein, “therapeutic dose” is an amount that alleviates the symptoms of a given condition or pathology, and preferably normalizes the physiological response of an individual having that condition or pathology. The alleviation of symptoms or normalization of the physiological response can be determined using methods routine in the art and may vary depending on the given condition or pathology. In one embodiment, the therapeutic dose is an amount that restores a measurable physiological parameter to substantially the same value as the parameter in an individual without the condition or pathology (preferably within +30%, more preferably within +20%, and even more preferably within 10%).

[0107] In one embodiment of the present invention, administration of the compound or pharmaceutical composition of the present invention is initiated at a lower dose level, and the dose level is increased until the desired effect of prevention / treatment of relevant medical indications, such as intestinal and gastric diseases, or longitudinal intestinal growth is obtained. This will define the therapeutically effective dose. Guidance on appropriate individual doses is provided elsewhere in this specification. However, those skilled in the art will be able to adjust these doses if an alternative dosing regimen is chosen.

[0108] For therapeutic use, the active agent is formulated with a pharmaceutically acceptable carrier suitable for delivering the peptide via a selected route of administration. For the purposes of this invention, peripheral parenteral routes include intravenous, intramuscular, subcutaneous, and intraperitoneal routes of administration. In one embodiment, the route of administration is subcutaneous or subcutaneous administration.

[0109] When administration is parenteral, such as intravenous, subcutaneous, or intramuscular, the injectable pharmaceutical composition can be prepared in conventional forms, either as an aqueous solution or a suspension; the lyophilized solid form is suitable for reconstitution immediately before use, suspension in liquid before injection, or as an emulsion.

[0110] Diluents for reconstituting lyophilized products include appropriate buffers, such as histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer, and MOPS buffer, water, physiological saline, dextrose, mannitol, lactose, trehalose, sucrose, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride; or Tween® 20, Tween® 80, poloxamer (e.g., Pluronic® F-68 or Pluronic® F-127), polyethylene. It may also be water for injection to which surfactants such as glycol have been added, and / or water for injection to which preservatives such as para-, meta-, and ortho-cresol, methyl- and propylparaben, phenol, benzyl alcohol, sodium benzoate, benzoic acid, benzyl benzoate, sorbic acid, propanoic acid, and p-cresol have been added, and / or water for injection to which organic modifiers such as ethanol, acetic acid, citric acid, lactose, or salts thereof have been added.

[0111] Furthermore, if necessary, the injectable pharmaceutical composition may contain small amounts of non-toxic auxiliary substances such as wetting agents or pH buffers. Preparations that enhance absorption (e.g., liposomes, surfactants, and organic acids) may also be used.

[0112] In one embodiment of the present invention, the compound is formulated for administration by infusion or injection, for example, when used as a liquid nutritional supplement for patients receiving complete parenteral nutrition (e.g., neonates, or patients suffering from cachexia or anorexia). Therefore, it is utilized as a sterile, pyrogenic-free aqueous solution and buffered to a physiologically acceptable pH, such as weakly acidic or physiological pH, as needed. Formulations for intramuscular administration may be based on a solution or suspension of a vegetable oil, such as canola oil, corn oil, or soybean oil. These oil-based formulations can be stabilized with antioxidants, such as BHA (butylated hydroxyanisole) and BHT (butylated hydroxytoluene).

[0113] Therefore, the peptide compounds of the present invention can be administered in a vehicle such as distilled water or physiological saline, phosphate-buffered saline, 5% dextrose solution, or oil. The solubility of the active agent can be increased as needed by incorporating dissolution accelerators such as surfactants and emulsifiers.

[0114] The aqueous carrier or vehicle can be supplemented with an amount of gelatin to help depot the active agent at or near the injection site for sustained release of the active agent to the desired site of action, for use as an injectable preparation. Alternative gelling agents such as hyaluronic acid may also be useful as depot agents.

[0115] For example, subcutaneous administration by injection may be particularly preferable in some cases.

[0116] The active agent can also be formulated as a sustained-release implantable device for extended and sustained administration. Such sustained-release formulations may be in the form of a patch placed outside the body. Examples of sustained-release formulations include complexes of biocompatible polymers such as poly(lactic acid), poly(lactic acid-coglycolic acid), methylcellulose, hyaluronic acid, sialic acid, silicates, collagen, and liposomes. Sustained-release formulations may be particularly interesting when it is desirable to provide a high local concentration of the active agent.

[0117] The most appropriate therapeutic dose and treatment plan for a patient will naturally vary depending on the disease or condition being treated and the patient's parameters. While not bound by any particular theory, it is anticipated that doses of 0.1–25 mg per patient, and shorter or longer treatment durations or frequencies, may yield therapeutically beneficial results, particularly a statistically significant increase in small intestinal mass. In some cases, the treatment plan may include the administration of an appropriate maintenance dose to prevent tissue regression that occurs after discontinuation of initial treatment. The most appropriate dose size and administration plan for human use may be derived from the results obtained by this invention and may be confirmed in further clinical trials.

[0118] The human dose of ZP1848 can be used in doses ranging from approximately 0.01 mg / kg body weight to 100 mg / kg body weight, for example, from approximately 0.01 mg / kg body weight to 10 mg / kg body weight, for example, from 10 to 100 μg / kg body weight. In further embodiments, the human dose (total dose) of ZP1848 may be approximately 0.1 mg to 25 mg per patient (between and including 0.1 mg and 25 mg per patient), 0.5 mg to 20 mg per patient (between and including 0.5 mg and 20 mg per patient), for example, 1 mg to 15 mg per patient (between and including 1 mg and 15 mg per patient), or for example, 1 mg to 10 mg per patient (between and including 1 mg and 10 mg per patient), administered once or twice a week, or as multiple doses as defined herein, with intervals 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 used according to the administration patterns disclosed herein, i.e., the same dose may be administered once or twice a week regardless of the patient's body weight. 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 can be used if convenient. The use of fixed doses has the advantage of improving compliance and reducing the risk of patient administration errors, including the risk of miscalculating the dose based on body weight.

[0119] In preferred embodiments, the formulation is a ready-to-use formulation, such as that described in International Publication No. 2020 / 065064. As used herein, the term “ready to use” refers to a formulation that does not require to be composed of or diluted with a predetermined amount of diluent, such as sterile water for injection or other suitable diluent, before use in a specified route of administration.

[0120] As described herein, the liquid formulations of the GLP-2 analog of the present invention contain a buffer, a nonionic tonicity modifier, and arginine sufficient to provide the pH of the final formulation. In accordance with common 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 formulations. In some cases, the liquid formulations of the present invention are non-aqueous liquid formulations.

[0121] As used herein, the term “buffer” means a pharmaceutically acceptable excipient that stabilizes the pH of a pharmaceutical formulation. 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 include a buffer selected from histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer, and MOPS buffer. This is because these buffers provide a stable formulation in which the GLP-2 analog dissolves and does not viscous, turbidify, or precipitate the peptide drug. In preferred embodiments, the buffer is histidine buffer, for example, L-histidine buffer. Generally, the buffer will be present at a concentration of about 5 mM to about 50 mM, more preferably about 5 mM to about 25 mM, and most preferably about 15 mM. Preferably, the buffer is not phosphate buffer, citrate buffer, citrate / Tris buffer, and / or succinate buffer.

[0122] As used herein, the term “tonicity modifier” means a pharmaceutically acceptable isotonic agent used to adjust the osmotic pressure of a formulation. The formulations of the present invention are preferably isotonic, i.e., have substantially the same osmotic pressure as human serum. The osmotic modifier used in the formulation is preferably a non-ionic osmotic modifier, preferably selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose. A preferred non-ionic tonicity modifier is mannitol, for example, D-mannitol. The concentration of the osmotic modifier will depend on the concentrations of other components of the formulation, especially when the formulation is intended to be isotonic. Typically, the non-ionic osmotic modifier is used at concentrations of about 90 mM to about 360 mM, more preferably about 150 mM to about 250 mM, and most preferably about 230 mM.

[0123] Generally, the components and amounts of the liquid formulation are selected to provide a formulation having a pH of about 6.6 to about 7.4, more preferably about 6.8 to about 7.2, and most preferably about 7.0. A sufficient amount (appropriate amount) of arginine may be added to adjust the pH to be within the desired pH range. From the experiments shown in the examples, it is preferable that pH adjustment is not performed using hydrochloric acid or sodium hydroxide.

[0124] In one embodiment, the liquid formulation comprises ZP1848 at a concentration of about 2 mg / mL to about 30 mg / mL, a buffer selected from the group consisting of, for example, its acetate, histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer, and MOPS buffer (the buffer is present at a concentration of about 5 mM to about 50 mM), a nonionic osmotic regulator selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose (at a concentration of about 90 mM to about 360 mM), and an amount of arginine sufficient to provide a pH of about 6.6 to about 7.4.

[0125] In one embodiment, the liquid formulation comprises ZP1848 at a concentration of about 2 mg / mL to about 30 mg / mL, a buffer selected from the group consisting of, for example, its acetate, histidine buffer, mesylate buffer, and acetate buffer (the buffer is present at a concentration of about 5 mM to about 50 mM), a nonionic osmotic regulator selected from the group consisting of mannitol, sucrose, glycerol, and sorbitol (at a concentration of about 90 mM to about 360 mM), and an amount of arginine sufficient to provide a pH of about 6.6 to about 7.4.

[0126] In further embodiments, the liquid formulation comprises ZP1848, for example its acetate, 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 an amount of arginine sufficient to provide a pH of about 7.0.

[0127] In further embodiments, the liquid formulation comprises ZP1848, for example its acetate, 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 a pH of about 7.0.

[0128] In further embodiments, the liquid formulation comprises ZP1848 acetate (ZP1848-acetate) or HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2acetate (SEQ ID NO: 1) 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 an amount of arginine sufficient to provide a pH of about 7.0.

[0129] In further embodiments, the liquid formulation contains ZP1848 acetate or HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2acetate (SEQ ID NO: 1) at a concentration of approximately 20 mg / mL, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM, and a pH of approximately 7.0.

[0130] In further embodiments, the liquid formulation is an acetate of a glucagon-like peptide 2 (GLP-2) analog having the following formula at a concentration of approximately 20 mg / mL: (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH), The solution contains approximately 15 mM histidine buffer and approximately 230 mM mannitol, with a pH of approximately 7.0, where x is between 1.0 and 8.0.

[0131] In further embodiments, the liquid formulation is an acetate of a glucagon-like peptide 2 (GLP-2) analog having the following formula, administered at a concentration of approximately 20 mg / mL in a once-or twice-daily dosing regimen: (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH), The solution contains approximately 15 mM histidine buffer and approximately 230 mM mannitol, with a pH of approximately 7.0, where x is between 1.0 and 8.0.

[0132] In further embodiments, the liquid formulation is an acetate of a glucagon-like peptide 2 (GLP-2) analog having the following formula, administered at a concentration of approximately 20 mg / mL in a once-or-twice-weekly dosing regimen: (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH), The solution contains approximately 15 mM histidine buffer and approximately 230 mM mannitol, with a pH of approximately 7.0, where x is between 1.0 and 8.0.

[0133] In some cases, the liquid formulation of the present invention further contains a preservative. In some cases, the preservative is selected from the group consisting of benzalkonium chloride, chlorobutanol, methylparaben, and potassium sorbate. Generally, the preservative is present at a concentration of about 0.1% to about 1% of the final formulation volume.

[0134] Medical condition The peptide of the present invention is useful as an agent for preventing or treating individuals suffering from gastrointestinal disorders, including the upper gastrointestinal tract of the esophagus, by administering an effective amount of ZP1848 or a salt thereof as described herein. Stomach and intestinal disorders include ulcers of any etiology (e.g., peptid ulcers, drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption syndromes, short-gut syndrome, inflammatory bowel disease, celiac sprue (e.g., those resulting from gluten-sensitive bowel syndrome or celiac disease), tropical sprue, hypogammaglobulinemia sprue, enteritis, ulcerative colitis, small intestine damage, and chemotherapy-induced diarrhea / mucositis (CID).

[0135] Generally, as described above, individuals who would benefit from increased small intestinal mass and / or the maintenance of the structure and function of the normal small intestinal mucosa are candidates for treatment with ZP1848 or its salts. Specific conditions that can be treated with ZP1848 include various forms of sprue, including celiac sprue, which results from a toxic reaction to α-gliadin due to heat and may be a consequence of gluten-sensitive enteropathy or celiac disease, characterized by significant loss of small intestinal villi (villaes); tropical sprue, which results from infection and is characterized by partial flattening of the villi (villaes); and hypogammaglobulinemia sprue, which is commonly observed in patients with various immune disorders or hypogammaglobulinemia and is characterized by a significant decrease in villi height. The therapeutic effect of treatment with ZP1848 or its salts can be monitored by intestinal biopsy to examine villi morphology, by biochemical evaluation of nutrient absorption, by weight gain in the patient, or by improvement of symptoms associated with these conditions.

[0136] Another specific condition that can be treated with ZP1848 or its salts, or in which ZP1848 or its salts may be therapeutically and / or prophylactically useful, is short gut syndrome (SBS), also known as short gut syndrome or simply short gut. This is caused by malabsorption in the intestines due to surgical resection, congenital defects, or disease-related malabsorption, after which the patient is unable to maintain a balance of fluids, electrolytes, and nutrients on a conventional diet. Dietary intake and fluid loss in SBS patients are generally reduced, although indications typically occur within two years of resection.

[0137] The class of human patients with SBS includes patients with SBS-intestinal failure (SBS-IF) and patients on the borderline between SBS-intestinal insufficiency (SBS-II) and SBS-IF. In some cases, patients with SBS-IF who depend on parenteral support are also called SBS-PS, and patients with SBS-II who do not depend on parenteral support are also called SBS-nonPS.

[0138] The range of patient types for SBS is reviewed in Jeppensen, Journal of Parenteral and Enteral Nutrition, 38(1), 8S-13S, May 2014, doi: 10.1177 / 0148607114520994. SBS patient types can be further classified along the lines described in Schwartz et al., Clinical and Translational Gastroenterology (2016) 7, e142; doi:10.1038 / ctg.2015.69. This classifies SBS patients into early responders and late / slow responders. Early responders are considered to be patients who show an early response to treatment with GLP-2 analogs such as ZP1848, particularly due to an increase in the width / diameter of the small intestine, among several other effects. On the other hand, late responders or slow responders are considered to be patients who receive little to no benefit from treatment with GLP-2 analogs due to an increase in small bowel length. Determining whether a subject is an early responder or a late responder can be used to determine the duration of the treatment plan with GLP-2 analogs, the timing of the clinical decision to reduce parenteral support, and the interval between examinations to determine whether reduction of parenteral support is possible. Thus, in one embodiment, the patient is either a late responder or a slow responder. Small bowel length can be measured, for example, by CT scan (computed tomography), MRI (magnetic resonance imaging), histology, laparoscopy, or other measurement methods or techniques known in the art.

[0139] In this context, the term “parenteral support” or “PS” includes providing nutrients and / or water to subjects receiving GLP-2 therapy as a means of providing nutrients and / or water that are needed but which, due to the subject’s condition, cannot be fully absorbed.

[0140] Other conditions that can be treated, or for which ZP1848 or its salts may be useful prophylactically, include radiation enteritis, infectious enteritis or post-infectious enteritis, and small intestinal damage caused by cancer chemotherapy agents or toxic agents.

[0141] This may require administering ZP1848 or a salt thereof before, concurrently with, or after a series of chemotherapy or radiotherapy to mitigate chemotherapy side effects such as diarrhea, abdominal colic, and vomiting, and to reduce resulting structural and functional damage to the intestinal epithelium caused by chemotherapy or radiotherapy. Preferably, administration is initiated one, two, three, four, five, six, or seven days before the start of the chemotherapy or radiotherapy cycle. Preferably, administration is initiated the day before or on the same day as the start of the chemotherapy or radiotherapy cycle, and thereafter administered once or twice a week.

[0142] Intestinal damage and dysfunction are well known side effects of cancer chemotherapy. Administration of chemotherapy is often accompanied by undesirable gastrointestinal side effects such as mucositis, diarrhea, bacterial invasion, malabsorption, abdominal colic, gastrointestinal bleeding, and vomiting. These side effects are clinical consequences of structural and functional damage to the intestinal epithelium and often necessitate a reduction in the dose and frequency of chemotherapy. Administration of ZP1848 or a salt thereof may enhance nutritional effects in the intestinal crypts and rapidly provide new cells to replace damaged intestinal epithelium after chemotherapy. The ultimate goal is to reduce the morbidity associated with gastrointestinal damage in patients undergoing chemotherapy while creating an optimal chemotherapy plan for cancer treatment. According to the present invention, a concurrent prophylactic or therapeutic measure can be provided to patients undergoing or planning to undergo radiotherapy.

[0143] Stem cells in the small intestinal mucosa are particularly susceptible to the cytotoxic effects of chemotherapy due to their rapid 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 malabsorption and barrier dysfunction of the small intestine. For example, widely used chemotherapeutic agents such as 5-FU, irinotecan, and methotrexate have been shown to increase apoptosis and cause 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). Chemotherapy agents have been shown to increase apoptosis in intestinal crypts within 24 hours of administration, and subsequently decrease villi area, crypt length, mitotic count per crypt, and intestinal cell height three days after chemotherapy in humans (Keefe et al., Gut 2000;47:632-7). Therefore, structural changes in the small intestine directly lead to intestinal dysfunction and, in some cases, diarrhea.

[0144] Gastrointestinal mucositis following cancer chemotherapy, while gradually resolving, is a growing problem because, once it develops, it is essentially untreatable. Studies using the commonly used cell proliferation inhibitors 5-FU and irinotecan have demonstrated that effective chemotherapy with these drugs primarily affects the structural integrity and function of the small intestine, while the colon is less sensitive and responds mainly with increased mucus formation (Gibson et al., J Gastroenterol Hepatol. Sep;18(9):1095-1100, 2003; Tamaki et al., J Int Med Res. 31(1):6-16,2003).

[0145] ZP1848 may be useful in preventing and / or treating gastrointestinal injury and side effects of chemotherapy agents. This potentially important therapeutic application could be applied to, but is not limited to, currently used chemotherapy agents such as: 5-FU, altretamine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxycarbamide, idarubicin, ifosfamide, irinotecan, and liposomal doxorubicin. doxorubicin, leucovorin, lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, larcitrexed, streptozocin, tegafururacil, temozolomide, thiotepa, thioguanine / thioguanine, topotecan, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, chrysanthanspase, cyclophosphamide, cytarabine dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxycarbamide, idarubicin, ifosfamide, irinotecan, liposomal doxorubicin, leucovorin, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, larcitrexed, streptozocin, tegafururacil, temozolomide, thiotepa, thioguanine / thioguanine, topotecan, treosulfan, vinblastine, vincristine, vindesine, and vinorelbine.

[0146] Further aspects of the present invention relate to increasing the mass of the intestinal tract or longitudinal intestinal growth, particularly the small intestine, in patients, such as human patients. ZP1848 or a salt thereof can increase longitudinal intestinal growth compared to a control treatment, as shown in International Publication No. 2018 / 229252.

[0147] This performance is particularly valuable for SBS patients because it leads to increased absorption capacity even after treatment is discontinued. Such patients will likely be treated for at least 1–3 years, for example, at least 1–4 years, for example, 1–10 years, for example, 1–20 years, or for example, 1–35 years, with the aim of inducing longitudinal growth of the intestinal tract.

[0148] Therefore, as already described herein, prolonging the bowel with a 1-3 year course of treatment may be of particular value to patients with intestinal failure (SBS-II) or SBS-PS, and to SBS patients bordering on intestinal failure (SBS-IF) or SBS non-PS. Subsequently, the risk of intestinal failure is reduced, for example by administering the medication once or twice a week during the treatment period. This reduces the need for a central venous catheter and the risk of sepsis associated with its use.

[0149] The active agents may also be used to treat malnutrition resulting from cachexia and loss of appetite, for example. [Modes for carrying out the invention]

[0150] Examples The following examples are provided to illustrate preferred embodiments of the present invention and are not intended to limit the scope of the invention. The GLP-2 analog administered according to the dosing regimen described herein can be prepared according to methods such as solid-phase peptide synthesis described in International Publication No. 2006 / 117565, which is expressly incorporated by reference in its entirety.

[0151] Example 1: Pharmacokinetic (PK) profiles of glepaglutide and its two major active metabolites in subjects with varying degrees of renal function. the purpose Glepaglutide (ZP1848, grepaglutide) 1-39 Glepaglutide is a potent, long-acting GLP-2 analog currently in Phase 3 trials for the treatment of short bowel syndrome (SBS). Glepaglutide consists of 39 L-amino acids, all of which are naturally occurring. Compared to natural GLP-2, glepaglutide has a C-terminal tail consisting of 9 amino acid substitutions and 6 lysine residues, all of which enable a stable, long-lasting liquid formulation.

[0152] Following subcutaneous injection of glepaglutide, two functionally active metabolites are obtained from cleavage within the C-terminus, namely ZP2469(1848) 1-34 ) and ZP2711(ZP1848 1-35 ) is formed.

[0153] Patients with short bowel syndrome are at risk of developing renal impairment, and in such cases, dose adjustment of glepaglutide may be justified. Therefore, a Phase 1 clinical trial was conducted to investigate the pharmacokinetics of glepaglutide after a single dose in subjects with renal impairment and subjects with normal renal function.

[0154] The clinical research protocol, its modifications / updates, the Informed Consent Form (ICF), and its modifications were reviewed and approved by an independent ethics committee (IEC) prior to screening.

[0155] method This study was designed as a two-stage, open-label, multi-center, non-randomized trial to evaluate the pharmacokinetic effects (PK) of a single subcutaneous dose of 10 mg of glepaglutide in subjects with varying degrees of renal function. Renal function was calculated using estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) formula.

[0156] Sixteen subjects of Caucasian descent were enrolled, of which four were matched controls with end-stage renal disease (ESRD) not undergoing dialysis (eGFR < 15 mL / min), four with severe renal impairment (eGFR < 30 mL / min), and eight with normal renal function (eGFR > 90 mL / min) (Table 1). Except for eGFR, vital statistics were similar across the group (Table 1).

[0157] Glepaglutide (ZP1848, 10 mg) was provided in a single-use vial containing 1 mL (extractable volume 0.5 mL) of a colorless, clear solution for subcutaneous injection with a glepaglutide concentration of 20 mg / mL.

[0158] After a single 10 mg dose of glepaglutide was administered intraabdominally, PK blood samples were collected over 14 days. Glepaglutide, ZP2469, and ZP2711 in the PK samples were analyzed using a GLP-validated LC / MS / MS assay.

[0159] The primary PK parameter is the area under the curve (AUC) between the dose and the last measurable concentration. t Extrapolating ) to infinity (AUC inf ), 0~168 hours (AUC 0-168 ) calculated using the formula, and the maximum plasma concentration (C max The following calculations were performed for glepaglutide, ZP2469, and ZP2711. The constructed analyte "glepaglutide-total" (glepaglutide + ZP2469 + ZP2711) was used as the primary endpoint and analyzed using a non-compartmental approach.

[0160] result In subjects with severe renal impairment and ESRD, there were no statistically significant differences in primary PK parameters compared to healthy eligible subjects. In particular, total exposure (AUC) to glepaglutide after a single subcutaneous administration. 0-168h ) and peak plasma concentration (C max Regarding this, there were no clinically relevant differences between subjects with severe renal impairment / ESRD and subjects with normal renal function.

[0161] Grepaglutide 合計 The geometric mean ratio is AUC 0-168 For this, 0.96 [90% CI: 0.69-1.35], C max The value for this parameter was 0.90 [90% CI: 0.62-1.31]. Therefore, the total exposure to glepaglutide in subjects with renal impairment was 4% and 10% lower, respectively, for the two PK parameters compared to healthy subjects, but this is not considered clinically relevant. Grepaglutide 合計 Exposure levels were similar in subjects with renal impairment and healthy subjects with normal renal function. This suggests that renal function does not affect systemic exposure to glepaglutide, and therefore dose adjustments of glepaglutide are unnecessary in patients with renal impairment.

[0162] The geometric mean ratio of ZP2469 is AUC 0-168 For this, 0.96 [90% CI: 0.667-1.38], C max The CI for this was 0.91 [90% CI: 0.595-1.39].

[0163] The geometric mean ratio of the ZP2711 is AUC. 0-168 For this, 0.89 [90% CI: 0.616-1.29], C max The result for this was 0.81 [90% CI: 0.572-1.15].

[0164] [Table 1]

[0165] eGFR was calculated according to the Modified Dietary Therapy for Renal Disease (MDRD) formula (Levey AS et al., Clin Chem. Apr 2007;53(4):766-772).

[0166] While the present invention has been described in relation to the exemplary embodiments described above, many equivalent modifications and variations will become apparent to those skilled in the art if this disclosure is given. Therefore, the exemplary embodiments of the present invention described herein are illustrative and not limiting. Various modifications can be made to the embodiments described without departing from the spirit and scope of the invention. All documents referenced herein are expressly incorporated by reference.

Claims

1. A pharmaceutical composition comprising ZP1848 or a pharmaceutically acceptable salt thereof for the prevention or treatment of gastrointestinal disorders in subjects having at least severe renal impairment, wherein no dose adjustment of ZP1848 or the salt is required to account for the renal impairment of the subject, and the gastrointestinal disorder is ulcer, digestion disorder, malabsorption syndrome, short-gut syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemia sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small intestine damage, or short bowel syndrome (SBS).

2. The pharmaceutical composition according to claim 1, wherein the subject has been previously treated with a modified dose of teduglutide.

3. The pharmaceutical composition according to claim 1 or 2, wherein the subject has severe renal impairment or end-stage renal disease (ESRD).

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disorder is short bowel syndrome (SBS) in a subject receiving parenteral support (PS).

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disorder is radiation enteritis, infectious enteritis or post-infectious enteritis, or small intestinal damage caused by toxic agents or other chemotherapeutic agents.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disorder is a side effect of chemotherapy or radiotherapy in a human subject.

7. A pharmaceutical composition comprising ZP1848 or a pharmaceutically acceptable salt thereof for increasing the mass of the intestinal tract and / or promoting or increasing longitudinal intestinal growth in subjects having at least severe renal impairment, wherein no dose adjustment of ZP1848 or the salt is required to take into account the renal impairment of the subject.

8. The pharmaceutical composition according to claim 7, wherein the subject has been previously treated with a modified dose of teduglutide.

9. The pharmaceutical composition according to claim 7 or 8, wherein the subject has severe renal impairment or ESRD.

10. The pharmaceutical composition according to any one of claims 7 to 9, wherein the subject is suffering from short bowel syndrome (SBS).

11. The pharmaceutical composition according to claim 10, wherein the subject is receiving parenteral support.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the ZP1848 or a pharmaceutically acceptable salt is administered via a dosing regime comprising multiple doses or a series of doses at intervals of 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days.

13. The pharmaceutical composition according to claim 12, wherein the administration plan is an administration plan once or twice a week.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the individual unadjusted dose is 1 mg or more and 20 mg or less per dose per subject.

15. The pharmaceutical composition according to claim 14, wherein the individual unadjusted dose is 5 mg or more and 15 mg or less per dose per subject.

16. The pharmaceutical composition according to claim 14, wherein the individual unadjusted dose is 7 mg or more and 12 mg or less per dose per subject.

17. The pharmaceutical composition according to claim 14, wherein the individual unadjusted dose is 9 mg or more and 11 mg or less per dose per subject.

18. The pharmaceutical composition according to claim 14, wherein the individual unadjusted dose is 10 mg + / - 10% per dose per subject.

19. A pharmaceutical kit for the prevention or treatment of gastrointestinal disorders, comprising ZP1848 or a pharmaceutically acceptable salt thereof, The aforementioned gastric or intestinal disorders include ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemia sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small intestine damage, or short bowel syndrome (SBS); Radiation enteritis, infectious enteritis or post-infectious enteritis, or small intestinal damage caused by toxic agents or other chemotherapeutic agents; or These are side effects of chemotherapy or radiotherapy in human subjects. The kit further includes information that dose adjustment of ZP1848 is unnecessary for subjects with at least severe renal impairment.

20. The kit according to claim 19, wherein the ZP1848 or a pharmaceutically acceptable salt is provided as a pharmaceutical composition comprising the ZP1848 or the salt in combination with a pharmaceutically acceptable carrier or excipient.

21. A kit according to claim 19 or 20, comprising one or more individually measured doses of ZP1848 or the salt thereof, wherein each dose is between 1 mg and 20 mg.

22. A kit according to claim 21, comprising one or more individually measured doses of ZP1848 or the salt thereof, wherein each dose is 5 mg or more and 15 mg or less.

23. A kit according to claim 21, comprising one or more individually measured doses of ZP1848 or the salt thereof, wherein each dose is 7 mg or more and 12 mg or less.

24. A kit according to claim 21, comprising one or more individually measured doses of ZP1848 or the salt thereof, wherein each dose is 9 mg or more and 11 mg or less.

25. The kit according to claim 21, wherein each individual dose is 10 mg + / - 10%.

26. The kit according to any one of claims 19 to 25, further comprising one or more chemotherapeutic agents.

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