Glucagon-like peptide-2 (GLP-2) analogs and their medical use for the treatment of short bowel syndrome (SBS)

Abstract

The present invention relates to glucagon-like peptide-2 (GLP-2) analogues, in particular ZP1848 (grepaglutide), and their medical use for the treatment of short bowel syndrome (SBS), in particular treatment with grepaglutide, which results in an early or significant reduction in the parenteral support (PS) required in patients receiving GLP-2 therapy and even allows patients to be relieved of the need for PS. In conjunction with a subpopulation of patients becoming SBS-free, patients further reported an improvement in quality of life (QoL).

Description

[Technical Field]

[0001] The present invention relates to glucagon-like peptide-2 (GLP-2) analogues and their medical use for the treatment of short bowel syndrome (SBS), in particular to treatment with glepaglutide, which results in an early or significant reduction in the parenteral support (PS) required in patients receiving GLP-2 therapy and also allows patients to be relieved of the need for PS. [Background technology]

[0002] 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-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-OH (SEQ ID NO: 2). It is derived 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 the crypts and inhibiting apoptosis in the villi (Drucker et al., 1996, Proc. Natl. Acad. Sci. USA 93:7911-7916). GLP-2 also has growth effects 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 intestinal barrier function (Benjamin et al., 2000, Gut 47:112-119), upregulates glucose transporters to stimulate intestinal hexose transport (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.

[0004] The art has recognized that glucagon-like peptide-2 receptor analogs are promising therapeutic agents for the treatment of intestinal disorders. However, native hGLP-2, a 33-amino acid gastrointestinal peptide, has a very short half-life in humans—approximately 7 minutes for full-length GLP-2 [1–33] and 27 minutes for truncated GLP-2 [3–33]—making it useless in clinical practice. The short half-life is primarily due to degradation by the dipeptidyl peptidase IV (DPP-IV) enzyme. Therefore, the art has attempted 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 containing substitutions have been proposed, such as a Gly substitution at position 2 ([hGly2]GLP-2, teduglutide), which extends the half-life from 7 minutes (native GLP-2) to approximately 2 hours. Teduglutide is approved for the treatment of short bowel syndrome under the names Gattex (USA) and Revestive (Western Europe).

[0005] Jeppesen et al. (Gut, 60:902-14, 2011, "Randomized placebo-controlled trial of teduglutide in reducing parenteral nutrition and / or intravenous fluid requirements in patients with short bowel syndrome") reported on a 24-week placebo-controlled trial evaluating the safety of teduglutide and its ability to reduce parenteral support in patients with SBS and intestinal failure. The trial found teduglutide to be safe and well tolerated, but other endpoints of the trial, particularly the potential for PS reduction, failed for statistical reasons.

[0006] Jeppesen et al. (Gastroenterology, 143:1473-81, 2012, "Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure") reported on the 24-week, placebo-controlled STEP trial in which patients with SBS-IF received subcutaneous teduglutide. This trial reported significant reductions in performance status (PS), but no patients achieved complete relief from PS at 24 weeks.

[0007] O'Keefe et al. (Clin. Gastroenterol. Hepatol., 11:815-23, 2013, "Safety and efficacy of teduglutide after 52 weeks of treatment in patients with short bowel intestinal failure") reported on a 28-week, double-blind, extension study in which patients were treated for a total of 52 weeks and investigated the long-term safety, tolerability, and clinical efficacy of teduglutide in patients with SBS-IF during the 52-week treatment period. Because this was an extension study, it included only an active treatment group and therefore was not placebo-controlled.

[0008] WO 2006 / 117565 (Zealand Pharma A / S) describes GLP-2 analogs that contain one or more substitutions compared to [hGly2]GLP-2 and have improved in vivo biological activity and / or improved chemical stability, for example, as assessed by in vitro stability assays. Among the molecules disclosed in WO 2006 / 117565, ZP1848 (grepaglutide) is designed to be stable in liquid formulations. Dosage regimens for GLP-2 analogs, including ZP1848 and its metabolites, are described in WO 2018 / 229252, which also demonstrate that these compounds are effective in increasing longitudinal intestinal growth.

[0009] The use of GLP-2 analogs, including ZP1848, to treat conditions related to bile acid synthesis, hepatic bile acid content, or intestinal bile acid content is described in International Patent Publication No. WO 2020 / 020904.

[0010] A ready-to-use formulation of ZP1848 is described in WO 2020 / 065064. Summary of the Invention [Problem to be solved by the invention]

[0011] Broadly speaking, the present invention is based on surprising findings from the EASE SBS1 and EASE SBS2 trials, multicenter, placebo-controlled, randomized, parallel-group, double-blind Phase 3 clinical trials (NCT:03690206 and NCT:03905707) investigating the safety and efficacy of grepaglutide for the treatment of short bowel syndrome (SBS). These placebo-controlled trials found that in patients with SBS receiving parenteral support (PS), particularly those receiving PS 3 or more days per week, ZP1848 treatment was able to completely free a subset of patients from parenteral support after just a few weeks of treatment. These findings are significant because they are the first results from a placebo-controlled trial demonstrating that freedom from PS is possible in a subset of patients. This is significant because, given the clinical challenges of designing and tailoring a PS plan for patients, along with the associated side effects and complications, significantly impacts the quality of life of patients receiving PS.

[0012] The EASE SBS1 results also included a surprising finding in secondary endpoints using the Patient Global Impression of Change (PGIC), a patient-reported outcome (PRO) tool in which patients rate the change in their overall condition since the start of the study on a 7-point Likert scale (see https: / / www.fda.gov / media / 116277 / download and https: / / www.fda.gov / media / 116281 / download). For example, when PGIC was assessed at week 24, both twice-weekly (TW, p=0.0020) and once-weekly (OW, p<0.0001) administration of glepaglutide resulted in improvement and significant differences compared with placebo. This means that 8 out of 9 patients in the subgroup who were free of PS reported a "markedly improved" or "greatly improved" PGIC status. [Means for solving the problem]

[0013] Accordingly, in a first aspect, the present invention provides a glucagon-like peptide 2 (GLP-2) analogue for use in a method for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), the GLP-2 analogue having the following formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2(1848) (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, the method comprising: (a) providing a human patient suffering from short bowel syndrome and receiving parenteral support (PS); (b) administering 10 mg of a GLP-2 analogue to the patient by subcutaneous injection once or twice weekly for a period of time while the patient continues to receive PS; and (c) After step (b), releasing the patient from PS. Includes.

[0014] In a further aspect, the present invention provides a method of treating short bowel syndrome in a patient in need thereof, comprising the steps of: (a) providing a human patient suffering from short bowel syndrome and receiving parenteral support (PS); (b) administering 10 mg of a GLP-2 analog to the patient by subcutaneous injection once or twice weekly for a period of time while the patient continues to receive PS, wherein the GLP-2 analog has the following formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2(1848) (SEQ ID NO: X) or a pharmaceutically acceptable salt thereof; and (c) after step (b), releasing the patient from PS.

[0015] In a further aspect, the present invention relates to the use of a glucagon-like peptide 2 (GLP-2) analogue in the preparation of a medicament for the treatment of a human patient having short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analogue has the following formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2(1848) (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the treatment is (a) providing parenteral support to a human patient with short bowel syndrome; (b) administering 10 mg of a GLP-2 analogue to the patient by subcutaneous injection once or twice weekly for a period of time while the patient continues to receive PS; and (c) After step (b), releasing the patient from PS. Provide for use, including

[0016] In these aspects of the invention, the duration in step (b) is 20 weeks to 52 weeks (e.g., 20 weeks to 30 weeks, 24 weeks to 36 weeks, 24 weeks to 48 weeks, 28 weeks to 42 weeks, or 30 weeks to 48 weeks). In some cases, the treatment period during which the GLP-2 analog is administered is 20 weeks, 24 weeks, 28 weeks, 30 weeks, 36 weeks, 42 weeks, 48 ​​weeks, or 52 weeks. Typically, the preferred duration of treatment is 24 weeks, which represents the time point at which the benefits of relief from PS and / or improvement in QoL are clinically observed.

[0017] The medical use or method may further comprise the step of (d) administering 10 mg of a GLP-2 analogue to the patient by subcutaneous injection once or twice weekly after step (c) while the patient is not receiving PS.

[0018] In any of the above medical uses or methods, the patient is treated once or twice a week. In some cases, the patient is treated for at least one year, or at least two years, or at least three years, or at least one to three years. In some cases, treatment with the GLP-2 analog may be continued indefinitely.

[0019] The subpopulation of patients who are completely free of PS is typically at least 5%, or at least 6%, or at least 7%, or at least 8%, or at least 10% of the total cohort treated with the GLP-2 analog. In preferred embodiments, at the start of treatment, patients receive PS two or more times per week, three or more times per week, four or more times per week, five or more times per week, six or more times per week, or daily.

[0020] The subpopulation of patients who achieve complete relief from PS may further be characterized by an improvement in quality of life (QoL). As described herein, this can be assessed using the Patient Global Impression of Change (PGIC) status, for example, responding patients report a status of much improved or markedly improved compared to placebo treatment. Generally, an improvement in the patient's PGIC status can be observed at 24 weeks of treatment. The subpopulation of patients who achieve complete relief from PS and an improvement in QoL is preferably at least 50%, or at least 60%, or at least 70%, or at least 75%, at least 80%, or at least 85% of the subpopulation who achieve complete relief from PS.

[0021] In either the medical use or method, step (b) may comprise administering 10 mg of the GLP-2 analogue to the patient by subcutaneous injection once a week. In either the medical use or method, step (b) may comprise administering 10 mg of the GLP-2 analogue to the patient by subcutaneous injection twice a week.

[0022] In some cases, either in medical use or in the method, the patient has a terminal jejunostomy or ileostomy. In some cases, either in medical use or in the method, the patient has undergone a jejunocolic anastomosis.

[0023] In some cases, either in medical use or in the method, the patient has undergone a jejunoileocolostomy. In some cases, step (b) includes patients receiving an ESPEN guideline level PS of any one of A1, B1, C1, D1, A2, B2, C2, D2, A3, B3, C3, D3, A4, B4, C4, or D4 (see Table 1).

[0024] In the context of the present invention, the term "parenteral support" or "PS" includes the provision of nutrients and / or fluids to a patient undergoing GLP-2 therapy as a means of providing nutrients and / or fluids that are needed by the patient but cannot be fully absorbed due to the patient's condition.

[0025] In the context of the present invention, the term "relief" refers to a patient receiving PS and GLP-2 therapy to improve gastrointestinal function such that all PS is discontinued (i.e., PS is no longer part of the treatment plan).

[0026] In the context of the present invention, the term achieving "oral or enteral autonomy" refers to SBS patients receiving PS and GLP-2 therapy to improve gastrointestinal function until all PS is discontinued (i.e., PS is no longer part of the treatment plan).

[0027] The terms "patient" and "patient" are used interchangeably herein. A patient (or patient) should be understood to be a mammal, typically a human.

[0028] ZP1848 is also effective in increasing intestinal mass and longitudinal intestinal growth, particularly in the small intestine. The individual dosages may be for administration according to the dosing regimens described elsewhere in this specification.

[0029] WO 2018 / 229252 describes ZP1848 as having an unexpectedly long half-life, particularly when delivered by subcutaneous injection, allowing for alternative dosing regimens such as once or twice weekly. Without wishing to be bound by theory, it is believed that the half-life of ZP1848 may be due to a combination of the formation of subcutaneous depots and the formation of metabolites that are slowly released from the subcutaneous depots and are also active at the GLP-2 receptor. The subcutaneous depots may be formed upon administration by reaction of the lysine terminus of ZP1848 with hyaluronic acid in the subcutaneous compartment.

[0030] Thus, a dosing regimen may include multiple doses or courses of doses spaced 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days apart. In preferred embodiments, doses are spaced 3, 3.5, 4, 5, 6, 7, or 8 days apart. In preferred embodiments, doses are spaced 3, 3.5, 4, or 7 days apart. As understood in the art, the time between doses may vary to some extent, and thus not all doses will be spaced exactly the same time apart. This is often at the discretion of the physician. Thus, doses may be spaced apart within a clinically acceptable range, for example, from about 2 to about 10 days, or from about 3 or 4 to about 7 or 8 days.

[0031] Such administration may be suitable for any dosing regimen, but is particularly suitable for once or twice weekly dosing regimens. During the course of treatment, the dosage a patient receives may be the same or different, as directed by the physician.

[0032] In some cases, it may be desirable to divide the total dose into multiple (e.g., two or three) separate doses or administrations, e.g., to space injection sites apart, e.g., to space injection sites at least 5 cm apart. Such spatially separated administrations typically occur substantially simultaneously, e.g., on the same day, within an hour or even closer to each other.

[0033] Preferably, the dosage of the GLP-2 analog used in accordance with the present invention ranges from 0.5 mg to 25 mg per patient once or twice weekly, optionally 1 mg to 20 mg per patient once or twice weekly, optionally 1 mg to 10 mg per patient once or twice weekly, optionally 2 mg to 7 mg per patient once or twice weekly, optionally 5 mg to 7 mg per patient once or twice weekly, or optionally 2 mg to 5 mg once or twice weekly. In one embodiment, the dosage of the GLP-2 analog used in accordance with the present invention is 10 mg per patient once or twice weekly. Patients may receive the same or different dosages throughout the course of treatment, as directed by a physician.

[0034] Preferably, the glucagon-like peptide 2 (GLP-2) analog is administered to the patient by injection, most typically by subcutaneous or intramuscular injection. In some preferred embodiments, the GLP-2 analog may be administered using an injection pen, allowing the patient to self-administer the analog. In some aspects, administration of the GLP-2 analog causes the formation of a subcutaneous depot into which the GLP-2 analog or its metabolites are released. Without wishing to be bound by a particular explanation, the subcutaneous depot may be formed by interaction of the GLP-2 analog administered according to the present invention with hyaluronic acid in the subcutaneous compartment, particularly if the analog contains a lysine terminus.

[0035] In the context of the present invention, the term "parenteral support" or "PS" refers to the provision of nutrients and / or fluids to patients receiving GLP-2 therapy as a means of providing nutrients and / or fluids that are needed by the patient but cannot be fully absorbed due to the patient's condition. Determining the exact amount or volume of PS to provide to SBS patients receiving GLP-2 therapy is difficult because if the PS volume is not adjusted in a timely and appropriate manner, the patient may experience fluid overload, be at risk of dehydration, and not achieve an optimal clinical response to therapy. This is further complicated by the fact that the volume of PS required by a patient typically fluctuates over the course of GLP-2 therapy depending on the patient's response to treatment. Typically, assessment of the amount of PS volume required by a patient as they progress on GLP-2 therapy depends on the duration of therapy and the individual patient's response to therapy. To account for this variability, an initial assessment of PS volume is performed within the first few days of GLP-2 therapy, typically followed by weekly assessments for the first month, monthly assessments for the next 1-3 months, and then every 3-6 months until treatment is terminated. This is important because patients may experience a rapid initial response to GLP-2 therapy, potentially improving small intestinal function even before bowel lengthening is observed. This, in turn, allows for a reduction in PS volume, thereby avoiding the risk of side effects such as fluid overload. The side effects and complications of PS are described in Bielawska and Allard (Nutrients, 9:466–480, 2017; doi:10.3390 / nu9050466) and Cuerda et al. (Clinical Nutrition, 40:5196–5220, 2021; doi.org / 10.1016 / j.clnu.2021.07.002). In addition to the side effects and complications associated with PS, it is known to have a significant impact on patients' quality of life (QoL), making it necessary to include PS in treatment plans.

[0036] Thus, as the patient's need for PS decreases, the method or use may include (a) determining the volume of PS needed by the patient at that point in treatment, (b) comparing it to the baseline PS volume determined at the start of therapy with the GLP-2 analog, and (c) reducing the frequency or volume of PS if the patient shows improved intestinal, e.g., small intestinal, function. Optionally, reducing the frequency or volume of parenteral support (PS) can be performed using the algorithm described in the Examples. As noted in the Examples, in embodiments of the present invention, a subpopulation of patients achieved complete freedom from PS.

[0037] As an example of the relationship between the amount of parenteral support required by a patient and the degree of improvement in intestinal function, it is currently believed that a 40% increase in the length and width of the small intestine will result in at least an additional 10% improvement in small intestinal function or absorptive capacity. Overall, GLP-2 therapy according to the present invention improves small intestinal function or absorptive capacity, and as shown in the Examples, the present inventors have surprisingly discovered that a subpopulation of patients treated with GLP-2 analogs can be completely relieved from the need for parenteral support.

[0038] One of the challenges faced by patients and physicians when initiating GLP-2 therapy is appropriately and individually adjusting the volume of parenteral support (PS) provided to the patient. This is important because if PS volume is not adjusted appropriately in a timely manner, the patient may experience fluid overload, be at risk of dehydration, and not achieve an optimal clinical response to therapy.

[0039] For example, in a previous 24-week study of the GLP-2 analogue teduglutide (Center for Drug Evaluation and Research, Application No. 203441Orig1s000, see p. 16), attempts were made to reduce parenteral nutrition volumes by 10% as early as weeks 4, 8, 12, 16, and 20 after treatment initiation if urine output increased by at least 10% from baseline. Many patients in this study developed fluid overload and stopped drinking water (Jeppesen et al. 2011, Gut 2011;60:902–914). A follow-up 24-week study of subcutaneous teduglutide in patients with SBS-IF (Jeppesen et al. 2012, Gastroenterology 2012;143:1473–1481) recommended a weekly reduction in parenteral nutrition by at least 10%, but no more than 30%, if urine output increased by at least 10% from baseline. However, in this study, patients also experienced fluid overload, especially at the start of treatment.

[0040] Although embodiments of the present invention are described herein by way of example and not by way of limitation, various further aspects and embodiments of the present invention will be apparent to those skilled in the art from this disclosure. Unless the context dictates otherwise, the above feature descriptions and definitions are not limited to any particular aspect or embodiment of the invention, but apply equally to all aspects and embodiments described. [Brief explanation of the drawings]

[0041] [Figure 1]Figure 1 shows the clinical trial design described in Example 1. This phase 3 study was a pivotal, multicenter, placebo-controlled, randomized, parallel-group, double-blind, fixed-dose study designed to confirm the efficacy of grepaglutide in reducing parenteral support (PS) volume in patients with SBS, and to evaluate the efficacy of grepaglutide in other efficacy endpoints, as well as the safety and tolerability of grepaglutide in patients with SBS. A three-arm parallel-group design with a 1:1:1 randomization scheme (two active treatment groups (once and twice weekly) and placebo) was selected to compare dosing regimens. The clinical trial is registered at clinicaltrials.gov: NCT03690206. DETAILED DESCRIPTION OF THE INVENTION

[0042] Throughout the description and claims, the conventional single letter designations for natural amino acids are used. All amino acid residues in the compounds described are typically in the L-configuration. compound ZP1848 can be, for example, a compound of the formula: It is a peptide having the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 (SEQ ID NO: 1). It is understood that the "H-" at the N-terminus indicates a free N-terminal amine (NH2-) group. The "NH2-" at the C-terminus indicates a C-terminal amide group. The terms ZP1848 and glepaglutide may be used interchangeably.

[0043] The present invention encompasses the use of pharmaceutically acceptable salts of ZP1848, as described in more detail below. Any suitable salt may be used, although the acetate salt may be preferred.

[0044] When ZP1848 is injected into the subcutaneous (SC) compartment, two functionally active metabolites are formed: ZP2469 and ZP2711, both of which are C-terminal truncated analogs of ZP1848. Thus, the overall PK profile of ZP1848 includes the effects of ZP1848 and its two major metabolites.

[0045] ZP2469 is the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDK-OH (SEQ ID NO: 3) is a peptide having the formula: ZP2711 is of the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKK-OH (SEQ ID NO: 4) is a peptide having the formula: In the formula, the N-terminal "H-" is as described above, and the C-terminal "-OH" represents a free C-terminal carboxylic acid group.

[0046] In alternative embodiments, the present invention may involve administering ZP2469 and / or ZP2711 alone or in combination with each other or with ZP1848. Teduglutide has the formula: H-HGDGSFSDEMNTILDNLAARDFINWLIQTKITD-OH (SEQ ID NO: 5) is a peptide having the formula: In the formula, the N-terminal "H-" and the C-terminal "-OH" are as defined above.

[0047] Pharmaceutical Compositions and Administration As used herein, GLP-2 analogs may be prepared for storage or administration and formulated as pharmaceutical compositions comprising a therapeutically effective amount of the GLP-2 analog in a pharmaceutically acceptable carrier.

[0048] The therapeutically effective amount of GLP-2 analogue depends on the route of administration, the type of mammal to be treated (typically human), and the physical characteristics of the specific mammal under consideration.These factors and their relationship in determining this amount are well known to skilled practitioners in the medical field.This amount and administration method can be adjusted to achieve optimal effectiveness in delivering peptide to the intestine, but depends on factors such as body weight, diet, concomitant medication, and other factors well known to those skilled in the medical field.

[0049] The GLP-2 analogue is typically present in an amount effective to prevent or treat an associated condition, e.g., to treat or prevent a stomach or intestinal related disorder, increase intestinal mass in a patient, and / or promote or increase longitudinal growth of the intestine.

[0050] Examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences", 17th ed., Alfonso R. Gennaro (ed.), Mark Publishing Company, Easton, PA, USA, 1985 and more recent editions, and in the Encyclopaedia of Pharmaceutical Technology.

[0051] 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. Generally, it is preferred that the salt is not a chloride salt. Examples of basic salts include salts in which the cation is an alkali metal ion, such as sodium and potassium, an alkaline earth metal ion, such as calcium and ammonium ion. + N(R 3 )3(R 4 ) and R 3 and R 4 are independently optionally substituted C 1-6 -alkyl, optionally substituted C 2-6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0052] Acetate salts are particularly preferred. In the context of the present invention, the term "ZP1848-acetate" means that the ZP1848 molecule is in the form of an acetate salt. ZP1848 acetate salts 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. Because molecules with different numbers of acetate molecules may exist in any given composition, x is not necessarily an integer. 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 some 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.

[0053] As will be apparent to those skilled in the medical field, a "therapeutically effective amount" of a peptide or pharmaceutical composition of the present invention may vary depending on the age, weight, and species of mammal being treated, the particular compound used, the particular mode of administration, and the desired effect and therapeutic indication. These factors and their relationship to determining this amount are well known in the medical field, and therefore it is within the skill of one in the art to determine a therapeutically effective dosage level, i.e., the amount necessary to achieve a desired result (e.g., prevention and / or treatment of the intestinal and stomach-related disorders described herein, as well as other medical indications disclosed herein, or inducing or increasing intestinal mass and / or longitudinal growth of the intestine in a patient).

[0054] In one embodiment of the present invention, administration of the compound or pharmaceutical composition of the present invention is initiated at a lower dosage level, and the dosage level is increased until the desired effect of preventing / treating relevant medical indications, such as intestinal and stomach-related diseases, or increasing the longitudinal growth of the intestine is achieved. This defines a therapeutically effective amount. Guidelines for appropriate individual dosages are provided elsewhere herein. However, if an alternative dosing regimen is selected, those skilled in the art will be able to adjust these dosages.

[0055] For therapeutic use, the GLP-2 analogue is formulated with a pharmaceutically acceptable carrier suitable for delivering the peptide via a selected administration route. For the purposes of the present invention, the peripheral parenteral route includes intravenous, intramuscular, subcutaneous, and intraperitoneal administration routes. In one embodiment, the administration route is subcutaneous or subcutaneous administration.

[0056] When administration is parenteral, such as intravenous, subcutaneous, or intramuscular injection, the pharmaceutical composition may be prepared in any conventional form, either as an aqueous solution or suspension, as a lyophilized solid suitable for reconstitution immediately prior to use, or as a suspension or emulsion in liquid prior to injection.

[0057] The diluent for reconstitution of the lyophilized product may be, for example, a suitable buffer selected from histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, Tris buffer, Bis-Tris buffer, and MOPS buffer, water, saline, dextrose, mannitol, lactose, trehalose, sucrose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride, or water for injection supplemented with surfactants such as Tween 20, Tween 80, poloxamers such as Pluronic® F-68 or Pluronic® F-127, polyethylene glycol, and / or preservatives such as para-, meta-, and ortho-cresol, methyl- and propylparaben, phenol, benzyl alcohol, sodium benzoate, esters of benzoic acid, benzylbenzoic acid, sorbic acid, propanoic acid, p-hydroxybenzoic acid, and / or organic modifiers such as ethanol, acetic acid, citric acid, lactic acid, or salts thereof.

[0058] In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents or pH buffering agents. Absorption-enhancing preparations (for example, liposomes, surfactants, and organic acids) may also be used.

[0059] In one embodiment of the present invention, the compound is formulated for administration by infusion, for example, when used as a liquid nutritional supplement for patients receiving total parenteral nutrition (e.g., neonates, or patients suffering from cachexia or anorexia), or by injection, for example, subcutaneously, intraperitoneally, or intravenously, and is used in a sterile, pyrogen-free form, optionally as an aqueous solution buffered to a physiologically acceptable pH, for example, slightly acidic or physiological pH.The formulation for intramuscular administration can be based on a solution or suspension of vegetable oil, for example, rapeseed oil, corn oil, or soybean oil.These oil-based formulations can be stabilized by antioxidants, for example, BHA (butylhydroxyanisole) and BHT (butylhydroxytoluene).

[0060] Thus, the peptide compounds of the present invention may be administered in a vehicle such as distilled water or saline, phosphate-buffered saline, 5% dextrose solution, or oil. The solubility of the GLP-2 analog may be enhanced, if desired, by the incorporation of solubility-enhancing agents such as surfactants and emulsifiers.

[0061] Alternative gelling agents, such as hyaluronic acid, may also be useful as depot preparations. Subcutaneous administration, for example by injection, may be particularly preferred. The optimal therapeutic dosage and treatment regimen for a patient will, of course, vary depending on the disease or condition being treated and the patient's parameters. Without wishing to be bound by any particular theory, it is expected that a dosage of 0.1 to 25 mg per patient and a shortened or extended treatment period or frequency will produce therapeutically beneficial results, particularly statistically significant increases in small intestinal mass. In some cases, the treatment regimen may include the administration of a maintenance dose appropriate to prevent tissue regression following cessation of initial treatment. The optimal dosage size and administration regimen for human use will be guided by the results obtained by this invention and may be confirmed through further clinical trials.

[0062] Human dosages of ZP1848 may be used at doses of about 0.01 mg / kg to 100 mg / kg body weight, e.g., about 0.01 mg / kg to 10 mg / kg body weight, e.g., 10 to 100 μg / kg body weight. In further embodiments, human dosages (total doses) of ZP1848 may be 0.1 mg to 25 mg (inclusive) per patient, 0.5 mg to 20 mg (inclusive) per patient, e.g., 1 mg to 15 mg (inclusive) per patient, e.g., 1 mg to 10 mg (inclusive) per patient, once or twice weekly, or multiple doses as defined herein at 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 dosing patterns disclosed herein, i.e., the same dose administered once or twice weekly regardless of patient weight. For example, the 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. For convenience, a 10 mg fixed dose may be used. The use of a fixed dose has the advantages of improving compliance and reducing the risk of patient dosing errors, such as the risk of miscalculating the weight-based dose to be administered.

[0063] In a preferred embodiment, the formulation is a ready-to-use formulation such as those described in WO 2020 / 065064. As used herein, the term "ready-to-use" refers to a formulation that does not require constitution or dilution with a predetermined amount of diluent, such as water for injection or other suitable diluent, prior to use for a designated route of administration.

[0064] As described herein, the liquid formulations of the GLP-2 analogs of the present invention contain a buffer, a non-ionic osmotic agent, and an appropriate amount of arginine to achieve the pH of the final formulation. In accordance with standard pharmaceutical practice, the formulations of the present invention are sterile and / or do not contain 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.

[0065] As used herein, the term "buffer" refers to 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 indicate that the formulations of the present invention preferably contain a buffer selected from histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, Tris buffer, Bis-Tris buffer, and MOPS buffer because these buffers provide a stable formulation in which the GLP-2 analog dissolves and the peptide drug does not become viscous, cloudy, or precipitate. In a preferred embodiment, the buffer is a histidine buffer, e.g., L-histidine. Generally, the buffer is 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 a phosphate buffer, a citrate buffer, a citrate / Tris buffer, and / or a succinate buffer.

[0066] As used herein, the term "osmotic agent" refers to a pharmaceutically acceptable tonicity 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 agent used in the formulation is preferably a non-ionic osmotic agent, preferably selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose. A preferred non-ionic osmotic agent is mannitol, e.g., D-mannitol. The concentration of the osmotic agent will depend on the concentrations of the other components of the formulation, particularly if the formulation is intended to be isotonic. Typically, the non-ionic osmotic agent is used at a concentration of about 90 mM to about 360 mM, more preferably about 150 mM to about 250 mM, and most preferably about 230 mM.

[0067] Generally, the components and amounts of the liquid formulation are selected to achieve a formulation with 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. Arginine can be added in qs to adjust the pH to within the desired pH range. Experiments shown in the examples indicate that pH adjustment is preferably not performed using hydrochloric acid or sodium hydroxide.

[0068] In one embodiment, the liquid formulation comprises ZP1848 at a concentration of about 2 mg / mL to about 30 mg / mL to achieve a pH of about 6.6 to about 7.4, e.g., its acetate salt, a buffer selected from the group consisting of histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, Tris buffer, Bis-Tris buffer, and MOPS buffer, present at a concentration of about 5 mM to about 50 mM, about 90 mM to about 360 mM of a non-ionic osmotic agent selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose, and an appropriate amount of arginine.

[0069] In one embodiment, the liquid formulation is composed of ZP1848 at a concentration of about 2 mg / mL to about 30 mg / mL to achieve a pH of about 6.6 to about 7.4, e.g., its acetate salt, a buffer selected from the group consisting of histidine buffer, mesylate buffer, and acetate buffer, present at a concentration of about 5 mM to about 50 mM, a non-ionic osmotic adjuster selected from the group consisting of mannitol, sucrose, glycerol, and sorbitol at a concentration of about 90 mM to about 360 mM, and an appropriate amount of arginine.

[0070] In a further embodiment, the liquid formulation comprises ZP1848, e.g., 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 an appropriate amount of arginine to achieve a pH of about 7.0.

[0071] In a further embodiment, the liquid formulation comprises ZP1848, eg, its acetate salt, 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.

[0072] In a further embodiment, the liquid formulation comprises ZP1848 acetate or HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 acetate (SEQ ID NO: 6) 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 appropriate amount of arginine to achieve a pH of about 7.0.

[0073] In a further embodiment, the liquid formulation comprises ZP1848 acetate or HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 acetate (SEQ ID NO: 6) 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 has a pH of about 7.0.

[0074] In a further embodiment, the liquid formulation comprises a compound of the formula: (HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH), where x is 1.0 to 8.0, a glucagon-like peptide 2 (GLP-2) analog acetate salt, a histidine buffer at a concentration of about 15 mM, and mannitol at a concentration of about 230 mM, and the pH is about 7.0.

[0075] In a further embodiment, the liquid formulation contains a compound of formula: (HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH), where x is 1.0 to 8.0, a histidine buffer at a concentration of about 15 mM, and mannitol at a concentration of about 230 mM, and the pH is about 7.0.

[0076] In a further embodiment, the liquid formulation comprises a compound of the formula: (HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH), where x is 1.0 to 8.0, a histidine buffer at a concentration of about 15 mM, and mannitol at a concentration of about 230 mM, and the pH is about 7.0.

[0077] Optionally, the liquid formulations of the present invention further comprise a preservative. Optionally, 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.

[0078] medical conditions The peptides of the present invention are useful as agents for treating individuals suffering from short bowel syndrome.

[0079] ZP1848 or a salt thereof may be therapeutically useful for the treatment of short bowel syndrome (SBS), also known as short bowel syndrome or simply short gut, which results from intestinal reduced absorption due to surgical resection, congenital defect, or disease, and subsequently results in patients being unable to maintain fluid, electrolyte, and nutrient balance with a conventional diet. Overall, despite adaptation within two years after resection, SBS patients experience reduced food intake and fluid loss.

[0080] Human SBS patient types include SBS-intestinal failure (SBS-IF) patients and patients on the border between SBS-intestinal dysfunction (SBS-II) and SBS-intestinal failure (SBS-IF). In some cases, SBS-intestinal failure (SBS-IF) patients are also referred to as SBS-PS if they are dependent on parenteral support, and SBS-intestinal dysfunction (SBS-II) patients are also referred to as SBS-non-PS if they are not dependent on parenteral support. In studies reported in the Examples, the inventors surprisingly discovered that treatment with a GLP-2 analog according to the present invention can relieve a subset of treated patients from the need for PS, i.e., patients who initiated treatment as SBS-PS became SBS-non-PS after treatment. The data in the Examples demonstrate that treatment with ZP1848 allows patients to remain SBS-non-PS for a significant period of time, such as at least 1 year, at least 2 years, or at least 3 years or more, even if they need to continue administering a GLP-2 analog indefinitely after becoming SBS-non-PS (data not shown).

[0081] The range of SBS patient types 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 as described by Schwartz et al., Clinical and Translational Gastroenterology (2016) 7, e142; doi:10.1038 / ctg.2015.69. This distinguishes SBS patients into early and late / late responders. Early responders are currently considered to be patients who respond early to treatment with GLP-2 analogs, such as ZP1848, due to, among other effects, an increase in small intestinal width / diameter, whereas late or late responders are patients who primarily or initially benefit from treatment with GLP-2 analogs due to an increase in small intestinal length. Determining whether a patient is an early or late responder can be used to determine the duration of the treatment regimen with the GLP-2 analog, the timing of the clinical decision to reduce parenteral support, and the interval between tests to determine whether parenteral support can be reduced. Thus, in one embodiment, the patient is a late or late responder. Small intestine length can be measured, for example, by CT scan (computed tomography scan), MRI (magnetic resonance imaging), histology, laparoscopy, or other measurement or technique known in the art.

[0082] GLP-2 analog treatment may increase intestinal mass or longitudinal growth of the intestine, particularly the small intestine, in a patient, e.g., a human patient. ZP1848 or a salt thereof can increase longitudinal growth of the intestine compared to control treatment, as shown in WO 2018 / 229252.

[0083] This ability is particularly valuable for SBS patients, as it results in increased absorptive capacity even after treatment has ceased. Such patients have been treated for at least 1-3 years, e.g., at least 1-4 years, e.g., 1-10 years, e.g., 1-20 years, e.g., 1-35 years, with the goal of inducing longitudinal growth of the intestine.

[0084] As already described herein, therefore, for SBS patients on the border between intestinal dysfunction (SBS-II) or SBS-PS patients and intestinal failure (SBS-IF) or SBS-non-PS patients, a prolonged intestinal course, for example, of 1 to 3 years, requiring weekly or twice-weekly administration during the treatment period, after which the risk of intestinal failure is reduced. This reduces the risk of the need for a central venous catheter and the risk of sepsis associated with the use of the catheter.

[0085] GLP-2 analogues can also be used to treat nutritional disorders resulting from, for example, cachexia and anorexia. As described in the Examples, QoL can be assessed using the Patient Global Impression of Change (PGIC) scale (see https: / / www.fda.gov / media / 116277 / download and https: / / www.fda.gov / media / 116281 / download). The PGIC assesses a patient's perceived overall health status on a 7-point single-item scale ranging from "markedly worse" to "markedly improved," i.e., yes / no means that a patient is a responder if they check either "markedly improved" or "greatly improved" on the PGIC questionnaire. The PGIC scale used in the EASE-SBS trial program is a 7-point Likert scale, and patients were asked to check one box in response to the following questions: Here is my overall state since the start of the exam:

[0086] (1) Significant improvement (2) Significant improvement (3) Slight improvement (4) No change (5) Slightly worsened (6) Significant deterioration (7) Significant deterioration Improvement in PGIC was defined as a response of "much improved" or "markedly improved" on a 7-point Likert scale at weeks 4, 12, 20, and 24. Improvement between each grepaglutide treatment regimen compared with placebo was tested using the CMH test adjusting for randomization stratification factors.

[0087] As shown in the Examples, the patient subpopulation of the present invention defined as SBS non-PS may be further characterized by PGIC, for example, if PGIC is assessed at week 24. This means that 8 out of 9 of the subpopulation of patients who were free of PS reported their PGIC status as "much improved" or "markedly improved." [Example]

[0088] 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 analogs administered according to the dosing regimens described herein may be formed according to methods such as solid phase peptide synthesis as described in WO 2006 / 117565, the entire contents of which are expressly incorporated by reference.

[0089] Example 1 Use of Grepaglutide in the Treatment of SBS, EASE SBS1 Clinical Trial (EASE-1) Introduction Grepaglutide (ZP1848, Grepaglutide 1~39Grepaglutide is a GLP-2 analogue with long-acting potential for use in the treatment of short bowel syndrome (SBS). Grepaglutide contains 39 L-amino acids, all of which are naturally occurring. Grepaglutide has nine amino acid substitutions compared to native GLP-2 and a C-terminal tail consisting of six lysine residues, all of which allow for a stable, long-lasting liquid formulation. Following subcutaneous injection of grepaglutide, two functionally active metabolites, namely, ZP2469 (1848 1~34 ) and ZP2711(ZP1848 1~35 ) is formed by truncation within the C-terminus.

[0090] method This phase 3 study was a pivotal, multicenter, placebo-controlled, randomized, parallel-group, double-blind, fixed-dose study designed to confirm the efficacy of grepaglutide in reducing the volume of parenteral support (PS) in patients with SBS, evaluate the efficacy of grepaglutide on other efficacy endpoints, and assess the safety and tolerability of grepaglutide in patients with SBS. A total of 106 patients with SBS were equally randomized to 24 weeks of treatment with grepaglutide 10 mg once or twice weekly or placebo. This clinical trial is registered at clinicaltrials.gov: NCT03690206 (EASE SBS1 trial).

[0091] As shown in Figure 1 , the study was designed as a three-arm parallel-group design with a 1:1:1 randomization scheme (two active treatment groups (once and twice weekly) and placebo) selected to compare dosing regimens.

[0092] Patient population Subject inclusion criteria included: - The diagnosis of SBS is defined as an estimated remaining small bowel continuity of less than 200 cm (equivalent to 79 inches), a recent bowel resection at least 6 months prior to screening, and the patient considered stable with respect to PS needs. No repair surgery is scheduled during the study period.

[0093] - PS is required at least 3 days per week at pre-screening, at the end of the pre-conditioning phase, and during the plateau phase. - Willingness to adhere to an individually prescribed drinking regimen and urine measurements during the 48-hour measurement interval; and - Age ≥ 18 years and ≤ 90 years at the time of screening.

[0094] - Randomization: Maintain stable PS volume for at least 2 weeks prior to randomization. Parenteral support (PS) preparation and stabilization The investigator optimized parenteral support volume for all patients for up to 4 weeks prior to randomization and baseline parenteral support measurements. The preconditioning phase was followed by a stabilization period of 2 to 4 weeks (± 4 days).

[0095] Patients were considered stable if they met all of the following criteria: a) the actual PS usage (volume and content) was consistent with the prescribed PS (a ±10% deviation in volume was allowed); b) the 48-hour urine output was comparable (a maximum ±25% deviation was allowed) at two consecutive visits within a 2-week interval (±4 days, i.e., visits were assumed to be 10–18 days apart), during which oral fluid intake was stable (the difference between the two 48-hour oral intakes was less than 10%) and up to 3.5 L per day; and c) urine output was an average of 1 L or more and 2.5 L or less per day.

[0096] During the screening period and until the end of the fitness phase, an individualized drinking menu was prescribed by the patient and the investigator. All patients were provided with an electronic diary (eDiary) to record data / information related to the study.

[0097] Baseline PS volume Unless otherwise specified, baseline is defined as the day before the first administration of study drug.

[0098] Baseline PS volume (L / week) is defined as the actual PS volume administered during the 7 days prior to Visit 1 (Day 1). Baseline daily urine volume (L / day) is defined as the average of the last two 48-hour urine volume measurements during the stable period.

[0099] Major Exam Period Visit 1 occurred within 2 weeks after the last stabilization visit. All eligible patients who completed the preconditioning and stabilization phases were randomized 1:1:1 to receive either a) glepaglutide 10 mg twice weekly, b) glepaglutide 10 mg once weekly and placebo once weekly, or c) placebo SC twice weekly for the next 24 weeks.

[0100] During the 24-week treatment period, the need for PS was assessed by a 48-hour balance period including urinary measurements, during which patients were required to adhere to an individually predefined water intake menu (timing, volume, and contents), which was recorded in the eDiary.

[0101] The actual volume of PS was continuously recorded by patients in electronic diaries (eDiaries). The investigator recorded the type, contents, and volume of PS used in the eCRF. Once treatment with the study drug was initiated, PS volume could be adjusted at study visits (weeks 1, 2, 4, 8, 12, 16, 20, and 24) according to a predefined algorithm for PS volume reduction if adjustment criteria were met.

[0102] If the average daily urine volume at this visit is at least 10% of the baseline urine volume, New PS volume (weekly) = Current PS volume (weekly) - 7 x absolute increase in daily urine volume from baseline.

[0103] Current PS volume is defined as the most recent prescribed PS volume, i.e., the PS volume the patient was following before the visit. Investigational drug, dosage, and mode of administration Grepaglutide was provided in a single-use vial containing 1 mL (extractable volume 0.5 mL) of a clear, essentially colorless solution for injection containing 20 mg / mL glepaglutide. Patients randomized to active treatment received injections of 10 mg (0.5 mL) of glepaglutide a) twice weekly or b) once weekly and placebo once weekly. Reference therapy: Placebo was provided in a single-use vial containing 1 mL (extractable volume 0.5 mL) of a clear, essentially colorless solution for injection. Patients randomized to placebo treatment received injections of placebo solution (0.5 mL) twice weekly.

[0104] Intervention group and period Treatment duration was 24 weeks across treatment groups: a) Grepaglutide twice weekly: Grepaglutide 10 mg on days 1 and 4 or 5 (same days every week) b) Grepaglutide once weekly: Grepaglutide 10 mg or placebo on days 1 and 4 or 5 (same days every week) c) Placebo: Placebo on days 1 and 4 or 5 (same day every week) The clinical trial protocol, its amendments / updates, and the informed consent form (ICF) and its amendments were reviewed and approved by the national health authority (HA) and independent ethics committee (IEC) or independent review board (IRB) of the country where the trial was conducted before screening.

[0105] Patient Global Impression of Change (PGIC) - Patient-Reported Outcome (PRO) The PGIC was used to investigate the impact of treatment on health-related quality of life (HRQoL).

[0106] Questionnaires were completed in paper form at the clinic visit before any other study-related assessments. PROs were completed by patients participating in the study without assistance from site staff. PROs were completed by patients at home before visiting the clinic. Patients were instructed to complete the PROs in a private location without influence from study team members and without the presence of family or friends. No one was permitted to answer or interpret the items on the patient's behalf. If the patient was unable to read, the investigator or a designated study team member was permitted to read the items / response options aloud to the patient. The investigator or a designated study team member instructed the patient to complete all PRO items and explained that there were no right or wrong answers. The investigator or a designated study team member instructed the patient to answer to the best of their ability and explained that all individual responses would be kept confidential.

[0107] Immediately after completion, PROs were reviewed by the investigator (or designee) for completeness and possible adverse events (AEs). When reviewing PROs for AEs, investigators were instructed not to influence or question patients about the content of their responses to PRO questions. PRO review was documented. If PROs were incomplete, patients were asked to complete all questions, taking care not to prejudice them.

[0108] Investigators and / or delegated study team members received training and instruction on completing PROs prior to the conduct of the study. Patients reported the number of bowel movements / stoma bag emptyings during the 48-hour balance period in their eDiary.

[0109] Improvement at weeks 4, 12, 20, and 24 The PGIC scale used in the EASE-SBS trial program was a 7-point Likert scale, and patients were asked to check one box in response to the following questions: Here is my overall state since the start of the exam:

[0110] (1) Significant improvement (2) Significant improvement (3) Slight improvement (4) No change (5) Slightly worsened (6) Significant deterioration (7) Significant deterioration Improvement in PGIC was defined as a response of "much improved" or "markedly improved" on a 7-point Likert scale at weeks 4, 12, 20, and 24. Improvement between each grepaglutide treatment regimen compared with placebo was tested using the CMH test stratified for randomization stratification factors.

[0111] result 106 SBS patients were randomly assigned to be treated with grepaglutide according to the protocol.

[0112] A total of 106 SBS patients with intestinal failure who were dependent on parenteral support (PS) at least 3 days per week were equally randomized to receive treatment with grepaglutide 10 mg once or twice weekly or placebo. The primary endpoint of the study was the absolute change from baseline in weekly parenteral support volume at 24 weeks.

[0113] Grepaglutide administered twice weekly significantly reduced the total weekly volume of parenteral support compared with placebo at week 24 (p=0.0039). When administered once weekly, glepaglutide treatment also produced a numerical reduction in weekly parenteral support, but this did not achieve statistical significance. At week 24, the mean reduction from baseline in parenteral support was 5.13 liters / week in patients treated with glepaglutide twice weekly and 3.76 liters / week in patients treated with glepaglutide once weekly. Placebo treatment produced a reduction of 2.85 liters / week of parenteral support.

[0114] Clinical response, defined as a reduction of at least 20% from baseline in once-weekly parenteral support volume at both weeks 20 and 24, was significantly higher with twice-weekly glepaglutide compared with placebo (p=0.0243). Of patients receiving twice-weekly glepaglutide, 65.7% achieved a clinical response. Clinical response rates were 45.7% in the once-weekly treatment group and 38.9% in the placebo treatment group.

[0115] In the twice-weekly group, 14% of patients (n=5) were completely free of parenteral support (enteral autonomy). A total of 9 patients treated with grepaglutide achieved enteral autonomy, while no placebo-treated patients were able to discontinue parenteral support.

[0116] Clinical classification of patients based on PS volume (ESPEN guidelines) Based on the energy and volume of PS required, patients are classified into 16 combinations (Source: L, Arends J, Bozzetti F, et al., ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr 2016;35(2):247-307; see Table 1 below).

[0117] [Table 1]

[0118] Anatomical types of SBS Patients were also grouped according to the portion of bowel remaining. Group 1: Terminal jejunostomy or ileostomy Group 2: Jejunocolic anastomosis Group 3: Jejunoileocolic anastomosis As shown in Table 2, grepaglutide administered once (OW) or twice (TW) weekly resulted in complete freedom from parenteral support (enteral autonomy) after 24 weeks of treatment. A total of nine patients treated with grepaglutide achieved enteral autonomy, whereas no placebo-treated patients were able to discontinue parenteral support (data not shown).

[0119] [Table 2]

[0120] Example 2 EASE SBS2 (EASE-2), an extension study evaluating the long-term safety and efficacy of grepaglutide in patients with short bowel syndrome (SBS) A double-blind, phase 3 extension study evaluating the long-term safety and efficacy of grepaglutide in patients with short bowel syndrome (SBS) following the EASE-1 trial the purpose The primary objective of this study was to evaluate the long-term safety of grepaglutide treatment in patients with short bowel syndrome (SBS).

[0121] The secondary objectives of this study are: To evaluate the long-term efficacy of grepaglutide in patients with SBS To evaluate the long-term immunogenicity of grepaglutide and its impact on the pharmacokinetics (PK), efficacy, and safety in patients with SBS To assess the quality of life of SBS patients treated with grepaglutide Study design This was a long-term, double-blind extension study in patients who completed the entire 24-week treatment phase of the lead-in study ("EASE-1") described above in Example 1 and consented to participate in this extension study, referred to as "EASE-2." Additionally, patients were allowed to be screened directly into EASE-2 to obtain additional long-term safety and efficacy data.

[0122] The treatment period for this extension study was 2 years. All patients received grepaglutide at a 10 mg twice-weekly (TW) or once-weekly (OW) dosing schedule. Patients who received grepaglutide TW or OW in EASE-1 continued blinded treatment. Patients who received placebo in EASE-1 were re-randomized 1:1 to blinded treatment with grepaglutide 10 mg TW or OW, and patients directly screened in EASE-2 were randomized 1:1 to blinded treatment with grepaglutide 10 mg TW or OW. To maintain blinding, both treatment arms included TW dosing (glepaglutide or grepaglutide plus placebo).

[0123] Grepaglutide TW: Grepaglutide 10 mg on days 1 and 4 or 5 (same days every week). Grepaglutide OW: Grepaglutide 10 mg or placebo on days 1 and 4 or 5 (same days each week).

[0124] Patients directly screened for EASE-2 attended the screening visit and followed the same run-in period as EASE-1 before randomization to ensure a reliable baseline for assessing the efficacy of grepaglutide treatment in reducing the need for parenteral support (PS).

[0125] During the study, the actual volume and type of PS administered were continuously recorded by the patients in an electronic diary (eDiary). The investigator recorded the type, contents, and volume of PS prescribed.

[0126] PS volumes could be adjusted at or between visits according to the following algorithm, the same as that used in EASE-1: Daily urine volume at this visit must be at least 10% of the baseline urine volume. New PS volume (weekly) = Current PS volume (weekly) - (7 x absolute change in daily urine volume from baseline).

[0127] For patients transitioning from EASE-1, baseline urine volume (L per day) for EASE-2 was defined as the mean of the last two 48-hour urine volume measurements during the stable phase of EASE-1. For patients directly screened into EASE-2, baseline urine volume was defined as the mean of the two 48-hour urine volumes prior to the first visit of EASE-2. During the 24-month treatment phase, patients adhered to an individually prescribed drinking regimen and recorded urine volume during the 48-hour measurement period prior to the study visit in their eDiary.

[0128] From the seventh visit onwards (i.e., after 12 weeks of study drug treatment), patients recruited at selected sites in EASE-2 were to be enrolled (with separate consent) in a self-directed pharmacokinetic (PK) substudy with more extensive PK sampling to provide additional information on the PK profile of grepaglutide and its main active metabolite in patients with SBS. The goal was to enroll approximately 45 patients. At the interim cutoff, 12 patients (6 in each treatment group) had enrolled in the PK substudy.

[0129] After completing the treatment phase, all patients were offered to participate in an additional extension study called "EASE-3" to continue receiving grepaglutide. Patients who did not participate in EASE-3 were followed for 4 weeks after completing the treatment phase of EASE-2.

[0130] As described in Example 1, in addition to the nine patients released at week 24, four patients initially randomized to placebo (i.e., grepaglutide-naive patients) were released after six months of active treatment in the extension study EASE 2. The relevant baseline characteristics of these patients are shown in Table 3 below.

[0131] [Table 3]

[0132] While the present invention has been described in conjunction with the exemplary embodiments set forth above, many equivalent modifications and variations will be apparent to those skilled in the art upon reading this disclosure. Accordingly, the exemplary embodiments of the invention described are considered to be illustrative and not limiting. Various changes can be made to the described embodiments without departing from the spirit and scope of the invention. All documents cited herein are expressly incorporated by reference.

Claims

1. 1. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analogue has the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH ２ (1848) (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, and the method comprises: (a) providing a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS); (b) administering 10 mg of a GLP-2 analogue to the patient by subcutaneous injection once or twice weekly for a period of time while the patient continues to receive PS; and (c) after step (b), releasing the patient from PS. Glucagon-like peptide 2 (GLP-2) analogs, including:

2. 2. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment according to claim 1, wherein the duration of step (b) is from 20 weeks to 52 weeks.

3. 3. The glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment according to claim 2, wherein the duration of step (b) is from 24 to 36 weeks.

4. (d) after step (c), while the patient is not receiving PS, administering 10 mg of a GLP-2 analogue to the patient by subcutaneous injection once or twice weekly.

4. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 1 to 3, further comprising:

5. 5. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 1 to 4, wherein the patient is treated once or twice weekly for at least 1 to 3 years.

6. 6. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of any one of claims 1 to 5, wherein the patient has maintained SBS non-PS status for at least 1 year, optionally at least 2 years, optionally at least 3 years or more.

7. 7. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 1 to 6, wherein the improvement in the patient's quality of life (QoL) is assessed using the Patient Global Impression of Change (PGIC) status.

8. 8. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of claim 7, wherein PGIC status is measured using a 7-point Likert scale, with responding patients reporting a status of much improved or markedly improved compared to treatment with placebo.

9. 9. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to claim 7 or claim 8, wherein improved PGIC status in the patient is observable at 24 weeks of treatment.

10. 10. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of any one of claims 1 to 9, wherein step (b) comprises administering 10 mg of the GLP-2 analogue to the patient by subcutaneous injection once a week.

11. 11. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of any one of claims 1 to 10, wherein step (b) comprises administering 10 mg of the GLP-2 analogue to the patient by subcutaneous injection twice a week.

12. 12. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 1 to 11, wherein the patient has had a terminal jejunostomy or ileostomy.

13. 13. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 1 to 12, wherein the patient has had a jejunocolic anastomosis.

14. 13. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 1 to 12, wherein the patient has undergone a jejunoileocolostomy.

15. 15. The glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of any one of claims 1 to 14, wherein step (b) comprises patients receiving PS at an ESPEN guideline level of any one of A1, B1, C1, D1, A2, B2, C2, D2, A3, B3, C3, D3, A4, B4, C4, or D4.

16. 1. A method of treating short bowel syndrome in a patient in need thereof, comprising: (a) providing a human patient suffering from short bowel syndrome and receiving parenteral support (PS); (b) administering to the patient 10 mg of a GLP-2 analogue by subcutaneous injection once or twice weekly for a period of time while the patient continues to receive PS, wherein the GLP-2 analogue has the formula: H-HGEGTFSSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (1848) (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, and (c) after step (b), releasing the patient from PS. A method comprising:

17. 17. The method of claim 16, wherein the duration of step (b) is between 20 weeks and 52 weeks.

18. 18. The method of claim 17, wherein the duration of step (b) is between 24 and 36 weeks.

19. 19. The method of any one of claims 16 to 18, further comprising the step of: (d) administering 10 mg of a GLP-2 analogue to the patient by subcutaneous injection once or twice weekly after step (c) while the patient is not receiving PS.

20. 20. The method of any one of claims 16 to 19, wherein the patient is treated once or twice weekly for at least 1 to 3 years.

21. 22. The method of any one of claims 16 to 21, wherein the patient has maintained SBS non-PS status for at least 1 year, optionally at least 2 years, optionally at least 3 years or more.

22. 22. The method of any one of claims 16 to 21, wherein the improvement in the patient's quality of life (QoL) is assessed using the Patient Global Impression of Change (PGIC) status.

23. 23. The method of any one of claims 16 to 22, wherein PGIC status uses a 7-point Likert scale, with responding patients reporting a status of much improved or markedly improved compared to treatment with placebo.

24. 24. The method of claim 22 or claim 23, wherein the patient's improved PGIC status is observable at 24 weeks of treatment.

25. 25. The method of any one of claims 16 to 24, wherein step (b) comprises administering 10 mg of the GLP-2 analogue to the patient by subcutaneous injection once a week.

26. 26. The method of any one of claims 16 to 25, wherein step (b) comprises administering 10 mg of the GLP-2 analogue to the patient by subcutaneous injection twice weekly.

27. 27. The method of any one of claims 16 to 26, wherein the patient has had a terminal jejunostomy or ileostomy.

28. 28. The method of any one of claims 16 to 27, wherein the patient has had a jejunocolic anastomosis.

29. 29. The method of any one of claims 16 to 28, wherein the patient has had a jejunoileocolostomy.

30. 30. The method of any one of claims 16-29, wherein step (b) comprises patients receiving PS at an ESPEN guideline level of any one of A1, B1, C1, D1, A2, B2, C2, D2, A3, B3, C3, D3, A4, B4, C4, or D4.

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