Glucagon-like peptide-2 (GLP-2) analogs and medical uses thereof for treatment of short bowel syndrome (SBS)

Abstract

The present invention relates to glucagon-like peptide-2 (GLP-2) analogs, and in particular to ZP1848 (Glipaglutide), and its medical use for the treatment of short bowel syndrome (SBS), and in particular to treatments with Glipaglutide, which results in an early stage or a significant reduction in parenteral support (PS) required for patients undergoing GLP-2 treatment, in particular in the treatment of short bowel syndrome (SBS). And even the patient is allowed to get out of the need for PS. Patients also report improvements in their quality of life (QoL) in combination with subpopulations of patients that become SBS non-PS.

Description

Technical Field

[0001] The present invention relates to glucagon-like peptide-2 (GLP-2) analogs and their medical use for the treatment of short bowel syndrome (SBS), and particularly to the treatment using glepaglutide, which results in an early or significant reduction in the parenteral support (PS) required by patients undergoing GLP-2 treatment, and even allows patients to be weaned off the need for PS. Background Art

[0002] Human GLP-2 is a 33-amino acid peptide having 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 the specific post-translational processing of proglucagon in intestinal enteroendocrine L cells and specific regions of the brainstem. GLP-2 binds to a single G protein-coupled receptor belonging to the class II glucagon-secretin family.

[0003] It has been reported that GLP-2 induces significant growth of the small intestinal mucosal epithelium by stimulating stem cell proliferation in the crypts and by inhibiting apoptosis in the villi (Drucker et al., 1996, Proc. Natl. Acad. Sci. USA 93: 7911-7916). GLP-2 also has a growth effect on the colon. In addition, GLP-2 inhibits gastric emptying and gastric acid secretion (Wojdemann et al., 1999, J. Clin. Endocrinol. Metab. 84: 2513-2517), enhances intestinal barrier function (Benjamin et al., 2000, Gut 47: 112-119), stimulates intestinal hexose transport via upregulation of glucose transporters (Cheeseman, 1997, Am. J. Physiol. R1965-71), and increases intestinal blood flow (Guan et al., 2003, Gastroenterology, 125: 136-147). For a review of GLP-2 and its properties, see Burrin et al., 2001, The Journal of Nutrition, 131(3), March 2001, 709-712.

[0004] In the art, it has been recognized that glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of bowel diseases. However, native hGLP-2 (a 33-amino acid gastrointestinal peptide) is not available in a clinical setting due to its very short half-life in humans (about 7 minutes for full-length GLP-2 [1-33] and 27 minutes for truncated GLP-2 [3-33]). To a large extent, the short half-life is due to degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). Thus, attempts have been made in the art to develop GLP-2 receptor agonists with better pharmacokinetic properties, particularly to improve the half-life of GLP-2 molecules. For example, GLP-2 analogs with substitutions have been proposed, such as GLP-2 analogs containing a Gly substitution at position 2 ([hGly2]GLP-2, teduglutide), which increases the half-life from 7 minutes (native GLP-2) to about 2 hours. Teduglutide is approved for the treatment of short bowel syndrome under the name Gattex (in the United States) and under the name Revestive (in Europe).

[0005] Jeppesen et al. (Gut, 60:902-14, 2011, “Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and / or intravenous fluid requirements in patients with short bowel syndrome”) reported a 24-week placebo-controlled study that evaluated the safety of teduglutide and its ability to reduce parenteral support in patients with SBS with intestinal failure. The trial established that teduglutide was safe and well tolerated, but other endpoints of the trial, particularly any possible reduction in PS, failed due to statistics.

[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 a placebo-controlled STEP study in which a 24-week study of subcutaneous administration of teduglutide to patients with SBS-IF was conducted. In this study, a significant reduction in PS was reported, but no patients were completely off PS at week 24.

[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 a 28-week double-blind extension study in which patients were treated for a total of 52 weeks, and the long-term safety, tolerability, and clinical efficacy of teduglutide in patients with SBS-IF were investigated during the 52-week treatment period. Since this was an extension study, it included only the active group and was thus not placebo-controlled.

[0008] WO 2006 / 117565 (Zealand Pharma A / S) describes GLP-2 analogs that contain one of several substitutions compared to [hGly2]GLP-2 and that have improved in vivo bioactivity and / or improved chemical stability, such as as evaluated in in vitro stability assays. Among the molecules disclosed in WO 2006 / 117565, ZP1848 (glepaglutide) has been designed to be stable in liquid formulations. WO 2018 / 229252 describes dosage regimens for GLP-2 analogs (including ZP1848 and its metabolites), which also indicate that these compounds are effective in increasing the longitudinal growth of the intestine.

[0009] WO 2020 / 020904 describes 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.

[0010] WO 2020 / 065064 describes a ready-to-use formulation of ZP1848. Summary of the Invention

[0011] Broadly, the present invention is based on the unexpected findings from the EASE SBS 1 and EASE SBS 2 trials, which were multicenter, placebo-controlled, randomized, parallel-group, double-blind phase 3 clinical trials (NCT: 03690206 and NCT: 03905707) that studied the safety and efficacy of using glepaglutide in the treatment of short bowel syndrome (SBS). These placebo-controlled studies found that treatment with ZP1848 in patients with short bowel syndrome receiving parenteral support (PS), particularly those receiving PS three or more days per week, allowed a subset of patients to completely discontinue parenteral support after only a few weeks of treatment. These findings are significant because they are the first results from placebo-controlled trials showing that discontinuation of PS is possible in a subset of patients. This is significant given the clinical challenges of designing and tailoring PS regimens for patients, the associated side effects and complications, and its significant impact on the quality of life of patients receiving PS.

[0012] The results of the EASE SBS1 trial also included the unexpected finding that the secondary endpoint of the trial using the Patient Global Impression of Change (PGIC) showed improvement and significant differences relative to placebo for both twice weekly (TW, p = 0.0020) and once weekly (OW, p < 0.0001) administration of glepaglutide, such as when PGIC was evaluated at week 24, which is a PRO (patient-reported outcome) tool where patients rate their overall change in status since the start of the trial based on a 7-point Likert scale (see https: / / www.fda.gov / media / 116277 / download and https: / / www.fda.gov / media / 116281 / download). This means that in the subset of patients who discontinued PS, 8 / 9 of the patients reported a PGIC status of "much improved" or "very much improved".

[0013] Accordingly, in a first aspect, the present invention provides a glucagon-like peptide 2 (GLP-2) analogue for use in a method of treating a human patient having short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analogue is represented by the formula or a pharmaceutically acceptable salt thereof: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2, (1848) (SEQ ID NO: 1)

[0014] The method comprises:

[0015] (a) providing a human patient suffering from short bowel syndrome and receiving parenteral support (PS);

[0016] (b) administering 10 mg of a GLP-2 analogue to the patient once or twice a week by subcutaneous injection for a period of time while the patient continues to receive PS; and

[0017] (c) after step (b), withdrawing the patient from PS.

[0018] In another aspect, the present invention provides a method for treating short bowel syndrome in a patient in need 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 once or twice a week by subcutaneous injection for a period of time, wherein the GLP-2 analogue is represented by the following formula or a pharmaceutically acceptable salt thereof: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 , (1848) (SEQ ID NO: X)

[0019] while the patient continues to receive PS; and (c) after step (b), withdrawing the patient from PS.

[0020] In another aspect, the present invention provides the use of a glucagon-like peptide 2 (GLP-2) analogue in the preparation of a medicament for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analogue is represented by the following formula or a pharmaceutically acceptable salt thereof: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 , (1848) (SEQ ID NO: 1)

[0021] The treatment comprises:

[0022] (a) providing parenteral support to a human patient suffering from short bowel syndrome;

[0023] (b) administering 10 mg of a GLP-2 analogue to the patient once or twice a week by subcutaneous injection for a period of time while the patient continues to receive PS; and

[0024] (c) after step (b), withdrawing the patient from PS.

[0025] In these aspects of the present invention, the period of time in step (b) is from 20 to 52 weeks (e.g., from 20 to 30 weeks, from 24 to 36 weeks, from 24 to 48 weeks, from 28 to 42 weeks, or from 30 to 48 weeks). In some cases, the treatment duration during the administration of the GLP-2 analog is 20 weeks, 24 weeks, 28 weeks, 30 weeks, 36 weeks, 42 weeks, 48 weeks, or 52 weeks. Generally speaking, the preferred treatment duration is 24 weeks, and this represents the time point at which the benefits of weaning off PS and / or the improvement of QoL are clinically observed.

[0026] The medical use or method may further include: (d) after step (c), administering 10 mg of the GLP-2 analog to the patient once or twice a week by subcutaneous injection, while the patient does not receive PS.

[0027] 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 a duration of at least 1 year, or at least 2 years, or at least 3 years, or at least 1 to 3 years. In some cases, the treatment with the GLP-2 analog can continue indefinitely.

[0028] The subpopulation of patients achieving complete weaning off PS is generally at least 5%, or at least 6%, or at least 7%, or at least 8%, or at least 10% of the entire group treated with the GLP-2 analog. In some preferred aspects, the patient receives PS 2 days or more per week, 3 days or more per week, 4 days or more per week, 5 days or more per week, 6 days or more per week, or daily at the start of the treatment.

[0029] Another characteristic of the subpopulation of patients achieving complete weaning off PS may be the improvement in their quality of life (QoL). As described herein, this can be evaluated using the Patient Global Impression of Change (PGIC) status, such as the status in which the responding patient reports a great improvement or a very great improvement compared to the treatment with placebo. Generally speaking, the improved PGIC status of the patient can be observed at the 24th week of the treatment. In addition to complete weaning off PS, the subpopulation of patients achieving QoL improvement is preferably at least 50%, or at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85% of the subpopulation achieving complete weaning off PS.

[0030] In any of the medical uses or methods, step (b) may include administering 10 mg of the GLP-2 analog to the patient once a week by subcutaneous injection.

[0031] In any of the medical uses or methods, step (b) may include administering 10 mg of the GLP-2 analog to the patient twice a week by subcutaneous injection.

[0032] In some cases, in either a medical use or method, the patient has undergone an end-jejunostomy or ileostomy.

[0033] In some cases, in either a medical use or method, the patient has undergone a jejuno-colic anastomosis.

[0034] In some cases, in either a medical use or method, the patient has undergone a jejuno-ileo-colic anastomosis.

[0035] In some cases, step (b) comprises the patient 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 (see Table 1).

[0036] In this context, the term "parenteral support" or "PS" includes providing nutrients and / or fluids to a patient receiving GLP-2 treatment as a means of providing the patient with nutrients and / or fluids that it needs but cannot fully absorb due to its condition.

[0037] In this context, the term "weaning off" refers to a patient who has received PS and GLP-2 treatment to improve its gastrointestinal function such that all PS are withdrawn (i.e., PS is no longer part of its treatment regimen).

[0038] In this context, the term achieving "oral or enteral autonomy" refers to an SBS patient who has received PS and GLP-2 treatment to improve its gastrointestinal function to the extent that all PS have been withdrawn (i.e., PS is no longer part of its treatment regimen).

[0039] The terms "patient" and "subject" are used interchangeably in this specification. It is understood that the patient (or subject) is a mammal and is typically a human.

[0040] ZP1848 is also effective in increasing intestinal mass and longitudinal intestinal growth, particularly in the small intestine.

[0041] Individual doses can be used for administration by a dosing regimen as described elsewhere in this specification.

[0042] WO 2018 / 229252 describes that ZP1848 has an unexpectedly long half-life, which enables alternative regimens, such as once or twice weekly administration, especially when delivered by subcutaneous injection. Without wishing to be bound by theory, it is believed that the half-life of ZP1848 may be due to a combination of subcutaneous depot formation and metabolite formation, the metabolites being slowly released from the subcutaneous depot and also being agonists for the GLP-2 receptor. The subcutaneous depot may be formed at the time of administration by the reaction between the lysine tail of ZP1848 and hyaluronic acid in the subcutaneous compartment.

[0043] Accordingly, the dosing regimen may comprise 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 time. In a preferred embodiment, the doses are spaced 3, 3.5, 4, 5, 6, 7 or 8 days apart in time. In a preferred embodiment, the doses are spaced 3, 3.5, 4 or 7 days apart in time. As would be understood in the art, the time between doses may vary to some extent such that each and every dose is not spaced exactly the same time apart. This will generally be guided by the physician's judgment. Accordingly, the doses may be spaced a clinically acceptable time range apart, such as from about 2 days to about 10 days, or from about 3 or 4 days to about 7 or 8 days.

[0044] Such doses may be suitable for any dosing regimen, but especially for once or twice weekly dosing regimens.

[0045] During the course of treatment, the doses taken by the patient may be the same or different, according to instructions from the physician.

[0046] In some cases, it may be desirable to divide the total dose into multiple (e.g., two or three) separate doses or administrations, such as for administration at spaced-apart injection sites, such as spacing the injection sites at least 5 cm apart. Such spatially separated administrations will generally be provided substantially simultaneously, such as on the same day, within one hour of each other, or even closer in time.

[0047] Preferably, the dosage of the GLP-2 analog used according to the present invention is from 0.5 mg to 25 mg per patient once or twice a week, optionally from 1 mg to 20 mg per patient once or twice a week, optionally from 1 mg to 10 mg per patient once or twice a week, optionally from 2 mg to 7 mg per patient once or twice a week, optionally from 5 mg to 7 mg per patient once or twice a week or optionally from 2 mg to 5 mg per patient once or twice a week. In one embodiment, the dosage of the GLP-2 analog used according to the present invention is 10 mg per patient once or twice a week. During the course of treatment, the dosage taken by the patient may be the same or different according to the instructions from the physician.

[0048] Preferably, the glucagon-like peptide 2 (GLP-2) analog is administered to the patient by injection, most commonly by subcutaneous injection or intramuscular injection. In some preferred embodiments, the GLP-2 analog can be administered using an injection pen, which allows the patient to self-administer the analog. In some aspects, the administration of the GLP-2 analog results in the formation of a subcutaneous depot from which the GLP-2 analog or its metabolites are released. Without wishing to be bound by any particular interpretation, the subcutaneous depot can be formed by the interaction of the GLP-2 analog administered according to the present invention, particularly when the analog contains a lysine tail, by the reaction between the analogs and with hyaluronic acid in the subcutaneous compartment.

[0049] In this context, the term "parenteral support" or "PS" includes providing nutrients and / or fluids to a patient receiving GLP-2 therapy as a means of providing the patient with nutrients and / or fluids that they need but are unable to fully absorb due to their condition. Determining the correct amount or volume of PS to provide to a patient with SBS receiving GLP-2 therapy is a challenge 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 may not achieve the most optimal clinical response to the treatment. This is further complicated because the volume of PS required by the patient will typically vary during the course of GLP-2 therapy depending on their response to the treatment. Generally speaking, as GLP-2 therapy progresses, the assessment of the amount of PS volume required by the patient depends on how long the treatment has been ongoing and the responsiveness of the individual patient to it. Given this variability, an initial assessment of the PS volume can be made within the first few days of GLP-2 therapy and subsequently typically weekly during the first month, monthly for the next 1 to 3 months, and then every 3 to 6 months thereafter until the end of the treatment. This is important because the patient may experience a rapid initial response to GLP-2 therapy, which improves the function of the small intestine, for example even before any increase in intestinal length is observed. This in turn can reduce the PS volume and thus avoid 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 that PS has a significant impact on the quality of life (QoL) of patients whose treatment regimen requires PS.

[0050] Accordingly, when the patient's need for PS decreases, the method or use may include the steps of: (a) determining the volume of PS required by the patient at that time during the treatment, (b) comparing it to the baseline PS volume determined at the start of treatment with a GLP-2 analogue, and (c) reducing the frequency or volume of PS in the case where the patient shows improvement in intestinal (such as small intestine) function. Optionally, the reduction in the frequency or volume of parenteral support (PS) can be carried out using the algorithms described in the examples. As described in the examples, in some aspects of the invention, a subset of patients achieved complete independence from PS.

[0051] By way of example, to illustrate 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 intestine function or absorptive capacity. In general, GLP-2 treatment according to the present invention results in an improvement in the function or absorptive capacity of the small intestine, and as shown in the examples, the present invention unexpectedly found that a subset of patients treated with a GLP-2 analogue can completely wean off the need for any parenteral support.

[0052] One of the challenges faced by patients and physicians when initiating GLP-2 treatment is the proper and individualized adjustment of the volume of parenteral support (PS) provided to the patient. This is important because if the PS volume is not adjusted in a timely and appropriate manner, the patient may experience fluid overload, risk of dehydration, and may not achieve the optimal clinical response with the treatment.

[0053] For example, in a previous 24-week treatment study with the GLP-2 analogue teduglutide (see Center for Drug and Evaluation and Research, Application No. 203441Orig1s000, page 16), if urine output increased by at least 10% relative to baseline, attempts to reduce the volume of parenteral nutrition by 10% were made at weeks 4, 8, 12, 16, and 20 at the earliest after the start of treatment. Many patients in this study had fluid overload and stopped drinking (Jeppesen et al. 2011, Gut 2011; 60:902-914). In a follow-up study, a 24-week study of patients with SBS-IF who received subcutaneous teduglutide (Jeppesen et al. 2012, Gastroenterology 2012; 143:1473–1481), if urine output increased by at least 10% relative to baseline, it was recommended to reduce parenteral nutrition by at least 10% per week, but not more than 30%. However, in this study, the patients also had fluid overload, especially at the start of treatment.

[0054] Embodiments of the present invention will now be described by way of example and not limitation. However, in light of the present disclosure, many additional aspects and embodiments of the present invention will be apparent to those skilled in the art.

[0055] Unless otherwise indicated in the context, the descriptions and limitations of the above features are not limited to any particular aspect or embodiment of the present invention, and equally apply to all aspects and embodiments described. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1Shows the trial design described in Example 1. This Phase 3 trial was pivotal, multicenter, placebo-controlled, randomized, parallel-group, double-blind, and fixed-dose, and was designed to determine the efficacy of GLP-1 in reducing the volume of parenteral support (PS) in patients with SBS, to evaluate the efficacy of GLP-1 on other efficacy endpoints, and the safety and tolerability of GLP-1 in patients with SBS. A 3-arm treatment was selected, i.e., a parallel-group design with a 1:1:1 randomization scheme (2 active treatment groups [once and twice a week] and placebo) to compare the dosing regimens. This clinical trial was registered on clinicaltrials.gov: NCT03690206. Detailed Description

[0057] Throughout this specification and the claims, conventional single letters are used for natural amino acids. All amino acid residues in the compounds are generally in the L-configuration.

[0058] Compound

[0059] ZP1848 is a peptide having the following formula:

[0060] H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 (SEQ ID NO: 1), as described, for example, in WO2006 / 117565. It should be understood that the N-terminal "H-" represents the free N-terminal amine group (NH 2 -) group. The C-terminal "NH 2 -" represents the C-terminal amide group. The terms ZP1848 and GLP-1 can be used interchangeably.

[0061] The present invention encompasses the use of pharmaceutically acceptable salts of ZP1848, as described in more detail below. Any suitable salt can be used, but acetate is preferably used.

[0062] When ZP1848 is injected into the subcutaneous (SC) compartment, two functionally active metabolites, ZP2469 and ZP2711, are formed, both of which are C-terminal truncated analogs of ZP1848. Thus, the overall PK profile of ZP1848 includes the actions of ZP1848 and its two major metabolites.

[0063] ZP2469 is a peptide having the following formula:

[0064] H-HGEGTFSSELATILDALAARDFIAWLIATKITDK-OH (SEQ ID NO: 3)

[0065] ZP2711 is a peptide having the following formula:

[0066] H-HGEGTFSSELATILDALAARDFIAWLIATKITDKK-OH (SEQ ID NO: 4)

[0067] Wherein the N-terminal “H-” is as described above, and the C-terminal “-OH” represents a free C-terminal carboxylic acid group.

[0068] In some alternative embodiments, the present invention may administer ZP2469 and / or ZP2711 alone or in combination with each other or in combination with ZP1848.

[0069] Teduglutide is a peptide having the following formula:

[0070] H-HGDGSFSDEMNTILDNLAARDFINWLIQTKITD-OH (SEQ ID NO: 5)

[0071] Wherein the N-terminal “H-” and the C-terminal “-OH” are as described above.

[0072] Pharmaceutical Composition and Administration

[0073] The GLP-2 analog as used herein can be formulated into a pharmaceutical composition for storage or administration, and it contains a therapeutically effective amount of the GLP-2 analog in a pharmaceutically acceptable carrier.

[0074] The therapeutically effective amount of the GLP-2 analog will depend on the route of administration, the type of mammal being treated (usually human), and the physical characteristics of the particular mammal under consideration. These factors and their relationship to determining this amount are well known to those skilled in the medical art. The amount and method of administration can be adjusted to achieve the most desirable potency for delivering the peptide to the intestine, but the amount and method of administration will depend on such factors as weight, diet, co-administered medications, and other factors well known to those skilled in the medical art.

[0075] The GLP-2 analog is generally present in an amount effective to prevent or treat related conditions in a patient, such as treating or preventing gastrointestinal-related disorders to improve intestinal mass and / or promote or enhance longitudinal intestinal growth of the intestine.

[0076] Some examples of pharmaceutically acceptable salts are described in “Remington’s Pharmaceutical Sciences”, 17th Edition. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, U.S.A., 1985 and the latest editions, as well as in Encyclopaedia of Pharmaceutical Technology.

[0077] Suitable salts include acid addition salts and basic salts. Some examples of acid addition salts include hydrochloride salts, citrate salts, chloride salts, and acetate salts. Preferably, the salt is an acetate salt. Generally, preferably the salt is not a chloride salt. Some examples of basic salts include salts in which the cation is selected from the following: alkali metals (such as sodium and potassium); alkaline earth metals (such as calcium); and ammonium ions + N(R 3 ) 3 (R 4 ) wherein R 3 and R 4 independently represent an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted aryl, or an optionally substituted heteroaryl.

[0078] Acetate salts can be particularly preferred. In the context of the present invention, the term "ZP1848-acetate" refers to the form in which the ZP1848 molecule is an acetate salt. The acetate salt of ZP1848 can be represented by the formula (ZP1848),x(CH 3 COOH) wherein x is from 1.0 to 8.0, i.e., wherein x is 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, or 8.0. In any composition, molecules with different numbers of acetate molecules can be present such that x is not necessarily an integer. In some cases, x is from 4.0 to 8.0, x is from 6.0 to 8.0 or x is from 4.0 to 6.5. In some cases, x is from 4.0 to 6.0, x is from 2.0 to 7.0, x is from 3.0 to 6.0, x is from 4.0 to 6.0 or x is from 4.0 to 8.0.

[0079] It will be apparent to those skilled in the medical art that the "therapeutically effective amount" of the peptides or pharmaceutical compositions of the present invention can vary depending on: age, body weight, and the mammalian species being treated, the particular compound being used, the particular mode of administration, and the desired effect, as well as the therapeutic indication. Since these factors and their relationship to determining such amounts are well known in the medical art, the determination of the therapeutically effective dose level, the amount necessary to achieve the desired result (e.g., prevention and / or treatment of the intestine- and stomach-related diseases described herein and other medical indications disclosed herein in a patient, or the desired result of improving intestinal quality and / or inducing or enhancing longitudinal intestinal growth of the intestine) will be within the purview of those skilled in the art.

[0080] In one embodiment of the invention, administration of the compounds or pharmaceutical compositions of the invention is initiated at a low dose level and the dose level is increased until the desired effect of preventing / treating a relevant medical indication such as enteric and gastric related diseases or enhancing the longitudinal growth of the intestine is achieved. This will define the therapeutically effective amount. Guidelines for appropriate individual doses are provided elsewhere in this specification. However, in the case of an alternative dosing regimen being selected, the person skilled in the art will be able to adjust these doses.

[0081] For therapeutic use, the GLP-2 analogues are formulated with a pharmaceutically acceptable carrier that is suitable for delivering the peptide by the selected route of administration. For the purposes of the present invention, the parenteral routes include intravenous, intramuscular, subcutaneous and intraperitoneal routes of administration. In one embodiment, the route of administration is the subcutaneous route or subcutaneous administration.

[0082] When to be administered parenterally, e.g. intravenously, subcutaneously or intramuscularly, the injectable pharmaceutical composition can be prepared in conventional forms, such as aqueous solutions or suspensions; in lyophilized solid forms suitable for immediate reconstitution before use; or in suspensions in a liquid before injection; or as an emulsion.

[0083] The diluent for reconstituting the lyophilized product can be a suitable buffer, such as 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, which is added with detergents (e.g. Tween 20, Tween 80, poloxamer (e.g. pluronic F-68 or pluronic F-127), polyethylene glycol), and / or added with preservatives (e.g. p-cresol, m-cresol and o-cresol; methyl p-hydroxybenzoate and propyl p-hydroxybenzoate; phenol; benzyl alcohol; sodium benzoate; benzoic acid; benzyl benzoate; sorbic acid; propionic acid; esters of p-hydroxybenzoic acid), and / or added with organic modifiers (e.g. ethanol, acetic acid, citric acid, lactic acid, or their salts).

[0084] Additionally, if desired, the injectable pharmaceutical composition may contain small amounts of non-toxic auxiliary substances, such as wetting agents or pH buffers. Absorption enhancing formulations (e.g., liposomes, detergents and organic acids) can be used.

[0085] In one embodiment of the invention, the compound is formulated for administration by infusion, for example when used as a liquid nutritional supplement for a patient receiving total parenteral nutrition therapy (e.g., a neonate or a patient suffering from cachexia or anorexia); or for administration by injection, such as subcutaneous, intraperitoneal or intravenous administration, and is thus presented as an aqueous solution in a sterile and pyrogen-free form and optionally buffered to a physiologically tolerable pH (e.g., slightly acidic or physiological pH). Formulations for intramuscular administration may be based on solutions or suspensions in vegetable oils (e.g., canola oil, corn oil or soybean oil). These oil-based formulations may be stabilized by antioxidants such as BHA (butylated hydroxianisole) and BHT (butylated hydroxytoluene).

[0086] Thus, the peptide compounds of the invention may be administered in a carrier (e.g., distilled water) or in saline, phosphate-buffered saline, 5% dextrose solution or oil. If desired, the solubility of the GLP-2 analog may be enhanced by incorporating solubility enhancers (e.g., detergents and emulsifiers).

[0087] Alternative gelling agents (e.g., hyaluronic acid) may also be used as depot agents.

[0088] Subcutaneous administration may be particularly preferred, for example by injection.

[0089] The therapeutically optimal dosage and regimen for a patient will, of course, vary with the disease or condition to be treated and according to patient parameters. Without wishing to be bound by any particular theory, it is contemplated that dosages of 0.1 to 25 mg / patient and shorter or longer treatment durations or frequencies may produce therapeutically useful results, such as, in particular, a statistically significant increase in small intestine mass. In some cases, the treatment regimen may include administration of a maintenance dose suitable for preventing tissue degeneration that occurs after cessation of the initial treatment. The dosage size and dosing regimen most suitable for human use may be guided by the results obtained by the present invention and confirmed in further clinical trials.

[0090] The human dose of ZP1848 can be used at a dose of about 0.01 mg / kg to 100 mg / kg body weight, such as at a dose of about 0.01 mg / kg to 10 mg / kg body weight, such as 10 to 100 μg / kg body weight. In some other embodiments, the human dose (total dose) of ZP1848 can be about, for example, 0.1 mg to 25 mg per patient and including the end values, 0.5 mg to 20 mg per patient and including the end values, such as 1 mg to 15 mg per patient and including the end values, such as 1 mg to 10 mg per patient and including the end values, once or twice a week or in multiple doses spaced 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days apart in time as defined herein. In some cases, a fixed dose of ZP1848 (i.e., a dose that is the same regardless of the patient's body weight) can be used according to the dosing regimens disclosed herein, administered once or twice a week. By way of example, the fixed dose can be a dose of 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg or 15 mg. Conveniently, a fixed dose of 10 mg can be used. The use of a fixed dose has the advantage of improving compliance and reducing the risk of patient dosing errors (including the risk of miscalculating the weight-based dose to be administered).

[0091] In some preferred embodiments, the formulation is a ready-to-use formulation as described in WO 2020 / 065064. The term "ready-to-use" as used herein refers to a formulation that does not require construction or dilution with a specified amount of diluent (such as water for injection or other suitable diluent) prior to use by the designated route of administration.

[0092] As described herein, the liquid formulation of the GLP-2 analog of the present invention comprises a buffer, a non-ionic tonicity modifier, and an appropriate amount of arginine to provide the pH of the final formulation. In accordance with conventional pharmaceutical practice, the formulations of the present invention are sterile and / or free of reducing agents. In some cases, the liquid formulation of the present invention is an aqueous liquid formulation. In some cases, the liquid formulation of the present invention is a non-aqueous liquid formulation.

[0093] The term "buffer" as used herein 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. The screening experiments in the examples showed that the formulations of the present invention preferably contain a buffer selected from the group consisting of histidine buffers, mesylate buffers, acetate buffers, glycine buffers, lysine buffers, TRIS buffers, Bis-Tris buffers, and MOPS buffers, because these buffers provide a stable formulation in which the GLP-2 analog is dissolved and does not become viscous, turbid, or precipitate the peptide drug. In some preferred embodiments, the buffer is a histidine buffer, such as L-histidine. Generally, the buffer will be present at a concentration of about 5 mM to about 50 mM, more preferably at a concentration of about 5 mM to about 25 mM, and most preferably at a concentration of about 15 mM. Preferably, the buffer is not a phosphate buffer, a citrate buffer, a citrate / Tris buffer, and / or a succinate buffer.

[0094] The term "tonicity modifier" as used herein refers to a pharmaceutically acceptable tonicity agent used to adjust the tonicity of a formulation. The formulations of the present invention are preferably isotonic, i.e., they have substantially the same osmotic pressure as human serum. The tonicity modifier used in the formulation is preferably a non-ionic tonicity modifier and is preferably selected from mannitol, sucrose, glycerol, sorbitol, and trehalose. The preferred non-ionic tonicity modifier is mannitol, such as D-mannitol. The concentration of the tonicity modifier will depend on the concentration of the other components of the formulation, especially when the formulation is intended to be isotonic. Generally, the non-ionic tonicity modifier will be used at a concentration of about 90 mM to about 360 mM, more preferably at a concentration of about 150 mM to about 250 mM, and most preferably at a concentration of about 230 mM.

[0095] 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 a pH of about 6.8 to about 7.2, and most preferably a pH of about 7.0. Arginine can be added in an amount sufficient (quantum sufficit, q.s.) to adjust the pH such that it is within the desired pH range. According to the experiments shown in the examples, it is preferred not to use hydrochloric acid or sodium hydroxide for pH adjustment.

[0096] In one embodiment, the liquid formulation consists of: ZP1848 (such as its acetate) at a concentration of about 2 mg / mL to about 30 mg / mL; 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; a non-ionic tonicity regulator selected from mannitol, sucrose, glycerol, sorbitol, and trehalose at a concentration of about 90 mM to about 360 mM; and an appropriate amount of arginine to provide a pH of about 6.6 to about 7.4.

[0097] In one embodiment, the liquid formulation consists of: ZP1848 (such as its acetate) at a concentration of about 2 mg / mL to about 30 mg / mL; 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 tonicity regulator selected from mannitol, sucrose, glycerol, and sorbitol at a concentration of about 90 mM to about 360 mM; and an appropriate amount of arginine to provide a pH of about 6.6 to about 7.4.

[0098] In another embodiment, the liquid formulation contains ZP1848 (such as 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 appropriate amount of arginine to provide a pH of about 7.0.

[0099] In another embodiment, the liquid formulation contains ZP1848 (such as 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.

[0100] In another embodiment, the liquid formulation contains ZP1848-acetate or H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 acetate (SEQ ID NO: 6), histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and an appropriate amount of arginine to provide a pH of about 7.0.

[0101] In another embodiment, the liquid formulation contains ZP1848-acetate or H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2Acetate (SEQ ID NO: 6), a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and a pH of about 7.0.

[0102] In another embodiment, the liquid formulation comprises acetate of a glucagon-like peptide 2 (GLP-2) analogue having the formula (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH 3 COOH) (where x is from 1.0 to 8.0) at a concentration of about 20 mg / mL, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and a pH of about 7.0.

[0103] In another embodiment, the liquid formulation comprises acetate of a glucagon-like peptide 2 (GLP-2) analogue having the formula (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH 3 COOH) (where x is from 1.0 to 8.0) at a concentration of about 20 mg / mL, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and a pH of about 7.0, for a once-daily or twice-daily dosing regimen.

[0104] In another embodiment, the liquid formulation comprises acetate of a glucagon-like peptide 2 (GLP-2) analogue having the formula (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH 3 COOH) (where x is from 1.0 to 8.0) at a concentration of about 20 mg / mL, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and a pH of about 7.0, for a once-weekly or twice-weekly dosing regimen.

[0105] In some cases, the liquid formulation of the present invention further comprises a preservative. In some cases, the preservative is a preservative selected from the following: 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.

[0106] Medical Condition

[0107] The peptide of the present invention can be used as an agent for treating an individual suffering from short bowel syndrome.

[0108] ZP1848 or a salt thereof can be therapeutically used to treat short bowel syndrome (SBS), also known as short gut syndrome or simply short gut, which is caused by surgical resection, congenital defects, or disease-related intestinal absorptive losses, where the patient is subsequently unable to maintain fluid, electrolyte, and nutrient balance on a regular diet. Although adaptation typically occurs within two years after resection, dietary intake and fluid losses are reduced in SBS patients.

[0109] 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-intestinal failure (SBS-IF). In some cases, patients with SBS-intestinal failure (SBS-IF) are also referred to as SBS-PS when they are dependent on parenteral support, and patients with SBS-intestinal insufficiency (SBS-II) are also referred to as SBS non-PS if they are not dependent on parenteral support. In the studies reported in the examples, the inventors unexpectedly found that treatment with a GLP-2 analogue according to the invention enabled the treated patient subgroup to become independent of the need for PS, i.e., patients who were initially treated as SBS-PS and became SBS non-PS after treatment. The data in the examples showed that treatment with ZP1848 enabled patients to become SBS non-PS for a statistically significant period of at least 1 year, at least 2 years, or at least 3 years or longer (data not shown), even though continued administration of the GLP-2 analogue was required even after the patients became SBS non-PS, even indefinitely.

[0110] The range of patient types with SBS is reviewed in Jeppensen, Journal of Parenteral and Enteral Nutrition, 38(1), 8S - 13S, May 2014, doi:10.1177 / 0148607114520994. Further subdivision of SBS patient types can be carried out in the manner 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. The present invention believes that: early responders are patients who exhibit an early effect, among other effects, on treatment with a GLP-2 analogue (such as ZP1848) that causes an increase in the width / diameter of the small intestine, while late or slow responders are patients who primarily or initially benefit from treatment with a GLP-2 analogue that causes an increase in the length of the small intestine. The determination of whether a patient is an early or late responder can be used to determine the duration of the treatment regimen with a GLP-2 analogue, the timing of any clinical decision to reduce parenteral support, and the interval between tests for determining whether parenteral support can be reduced. Thus, in one embodiment, the patient is a late or slow responder. The length of the small intestine can be measured, for example, by CT scan (computed tomography scan), MRI (magnetic resonance imaging), histology, laparoscopy, or other measurements or techniques known in the art.

[0111] GLP-2 analogue treatment can result in an increase in intestinal mass or longitudinal growth of the intestine, particularly the small intestine, in patients (such as in human patients). As shown in WO 2018 / 229252, ZP1848 or its salt is capable of increasing the longitudinal growth of the intestine relative to a control treatment.

[0112] This ability has particular value in patients with SBS because it will also result in an increased absorptive capacity after treatment cessation. Such patients will be treated for at least 1 to 3 years, for example at least 1 to 4 years, for example 1 to 10 years, for example 1 to 20 years, for example 1 to 35 years, with the aim of inducing longitudinal growth of the intestine.

[0113] As already described herein, SBS patients on the borderline between intestinal insufficiency (SBS-II) or SBS-PS patients and intestinal failure (SBS-IF) or SBS non-PS may thus have particular value in terms of lengthening their intestine over a treatment period of 1 to 3 years, after which the risk of their intestinal failure is reduced, for example involving administration once a week or twice a week during the treatment period. This involves a lower risk of the need for a central catheter and the risk of sepsis associated with its use.

[0114] GLP-2 analogs can also be used to treat malnutrition, such as malnutrition caused by cachexia and anorexia.

[0115] As described in the examples, QoL can be evaluated 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 evaluates the overall health status as perceived by the patient on a seven-point single-item scale, ranging from "very much worse" to "much improved", i.e., "yes / no", which means that if the patient checks "much improved" or "very much improved" in their PGIC questionnaire, the patient is a responder. The PGIC scale used in the EASE-SBS trial program is a 7-point Likert scale, which requires the patient to check a box when answering the following question:

[0116] My overall status since the start of the trial has been:

[0117] (1) Very much improved

[0118] (2) Much improved

[0119] (3) Minimally Improved

[0120] (4) No change

[0121] (5) Minimally Worse

[0122] (6) Much Worse

[0123] (7) Very Much Worse

[0124] PGIC improvement was defined as responding "much improved" or "very much improved" on the 7-point Likert scale at each of weeks 4, 12, 20, and 24. The improvement between each liraglutide treatment regimen compared to placebo was tested using a CMH test adjusted for random stratification factors.

[0125] As shown in the examples, the patient subset of the present invention defined as SBS non-PS can be additionally characterized by PGIC, for example when PGIC is evaluated at week 24. This means that in the patient subset that has discontinued PS, 8 / 9 of the patients reported a PGIC status of "much improved" or "very much improved".

[0126] Example

[0127] The following examples are provided to illustrate some preferred aspects of the invention and are not intended to limit the scope of the invention. The GLP-2 analogues administered according to the dosage regimens described herein can be prepared by methods of solid-phase peptide synthesis as described, for example, in WO 2006 / 117565, the content of which is hereby expressly incorporated by reference in its entirety.

[0128] Example 1: Use of Glucagon-like Peptide-2 in the Treatment of Short Bowel Syndrome, EASE SBS 1 Clinical Trial (EASE-1)

[0129] Introduction

[0130] Glepaglutide (ZP1848, glepaglutide 1-39 ) is a potent long-acting GLP-2 analogue that is used for the treatment of short bowel syndrome (SBS). Glepaglutide contains 39 L-amino acids, all of which are naturally occurring. Compared to native GLP-2, glepaglutide has 9 amino acid substitutions and the C-terminal tail consists of 6 lysine residues, all of which enable it to be formulated as a stable and persistent liquid formulation. After subcutaneous injection of glepaglutide, two functionally active metabolites, namely ZP2469 (1848 1-34 ) and ZP2711 (ZP1848 1-35 ) are formed by cleavage within the C-terminus.

[0131] Methods

[0132] This Phase 3 trial was a pivotal, multi-center, placebo-controlled, randomized, parallel-group, double-blind and fixed-dose trial designed to determine the efficacy of glepaglutide in reducing the volume of parenteral support (PS) in SBS patients and to evaluate the efficacy of glepaglutide at other efficacy endpoints as well as the safety and tolerability of glepaglutide in patients with SBS. A total of 106 SBS patients were randomly assigned equally to receive treatment with 10 mg glepaglutide once weekly, twice weekly or placebo for 24 weeks. This clinical trial was registered on clinicaltrials.gov: NCT03690206 (EASE SBS1 trial).

[0133] As Figure 1 shown, the trial was designed as a 3-arm treatment, i.e., a parallel-group design with a 1:1:1 randomization scheme (2 active treatment groups [once and twice weekly] and placebo) was chosen to compare the dosing regimens.

[0134] Patient Population

[0135] Key patient inclusion criteria included:

[0136] - The diagnosis of SBS is defined as an estimated remaining small bowel continuity of less than 200 cm [equal to 79 inches], with the most recent bowel resection performed at least 6 months prior to screening, and the patient is considered stable in terms of PS requirements. No restorative surgery is planned during the trial;

[0137] - Based on the assessments before screening and at the end of the optimization and stabilization phases, there is a PS requirement for at least 3 days per week;

[0138] - Willingness to comply with an individually pre - defined drinking menu and urine measurements during 48 - hour measurement intervals;

[0139] - Age ≥ 18 years and ≤ 90 years at screening; and

[0140] - At randomization: Maintain a stable PS volume for at least 2 weeks prior to randomization.

[0141] Parenteral Support (PS) Optimization and Stabilization Phase

[0142] Within up to 4 weeks prior to randomization and baseline measurement of parenteral support, the investigators optimized the parenteral support volume for all patients. After optimization was a stabilization phase of 2 to 4 weeks (± 4 days).

[0143] A patient is considered stable if all of the following criteria are met: a) The actual PS usage (volume and content) matches the prescribed PS (a deviation of ± 10% of the volume is acceptable); and b) The 48 - hour urine volumes at two consecutive visits within a 2 - week interval (± 4 days, i.e., the visit interval should be 10 to 18 days) are similar (a maximum deviation of ± 25% is acceptable), with constant oral fluid intake (the difference in two 48 - hour oral intakes is less than 10%), and a maximum of 3.5 L / day, and c) The average urine volume is ≥ 1 L / day and ≤ 2.5 L / day.

[0144] During the screening period and until the end of the optimization phase, the individual drinking menu is determined by the patient and the investigator. All patients are equipped with an electronic diary (eDiary) to record trial - related data / information.

[0145] Baseline PS Volume

[0146] Unless otherwise stated, the baseline is defined as Day 1 prior to the first administration of the investigational product.

[0147] The baseline PS volume (L / week) is defined as the actual PS volume received during the 7 - day period prior to the first visit (Day 1). The baseline daily urine volume (L / day) is defined as the average of the last two 48 - hour urine volumes measured during the stabilization phase.

[0148] Main trial period

[0149] The first visit is completed within 2 weeks after the last stable phase visit. All eligible patients who completed the optimization and stable phases are randomly assigned in a 1:1:1 ratio to receive: a) 10 mg of semaglutide twice weekly, b) 10 mg of semaglutide once weekly and placebo once weekly, or c) placebo SC twice weekly for the next 24 weeks.

[0150] During the 24-week treatment phase, the PS requirement is evaluated through a 48-hour equilibration period (involving urine measurement), and during this period, patients are required to adhere to their individually pre-specified drinking schedule (time, volume, and content) and record this in the eDiary.

[0151] The actual volume of the PS is continuously recorded by the patient in the electronic diary (eDiary). The investigator records the type, content, and volume of the PS used in the eCRF. Once treatment with the investigational product is initiated, the PS volume can be adjusted at trial visits (at weeks 1, 2, 4, 8, 12, 16, 20, and 24) if the adjustment criteria are met and according to the pre-specified PS volume reduction algorithm:

[0152] IF: The average daily urine volume at the current visit is at least 10% higher than the baseline urine volume.

[0153] THEN: New PS volume (per week) = Current PS volume (per week) - 7 × Absolute increase in daily urine volume relative to baseline.

[0154] The current PS volume is defined as the most recently specified PS volume, i.e., the PS volume that the patient should follow prior to the visit.

[0155] Investigational product administered, dose, and regimen

[0156] Semaglutide will be provided in single-use vials containing 1 mL (extractable volume of 0.5 mL) of a clear, essentially colorless injectable solution containing 20 mg / mL of semaglutide. Patients randomized to active treatment receive a) 10 mg (0.5 mL) of semaglutide injected twice weekly or b) 10 mg (0.5 mL) of semaglutide injected once weekly and placebo once weekly.

[0157] Reference treatment: Placebo will be provided in single-use vials containing 1 mL (extractable volume of 0.5 mL) of a clear, essentially colorless injectable solution. Patients randomized to placebo treatment receive placebo solution injected twice weekly (0.5 mL).

[0158] Intervention group and duration

[0159] The treatment duration for each treatment group was 24 weeks:

[0160] a) Dulaglutide twice a week: 10 mg dulaglutide on Day 1 and on Day 4 or 5 (the same days of the week every week)

[0161] b) Dulaglutide once a week: 10 mg dulaglutide or placebo on Day 1 and on Day 4 or 5 (the same days of the week every week)

[0162] c) Placebo: placebo on Day 1 and on Day 4 or 5 (the same days of the week every week).

[0163] The clinical study protocol, its amendments / updates, and the informed consent form (ICF) and its amendments were reviewed and approved by the Health Authorities (HA) of the country where the trial was conducted and the Independent Ethics Committee (IEC) or Independent Review Board (IRB) prior to screening.

[0164] Patient Global Impression of Change (PGIC) - Patient-Reported Outcome (PRO)

[0165] The PGIC was used to investigate the effect of the study treatment on health-related quality of life (HRQoL).

[0166] The questionnaire was completed in paper form during the site visit before any other trial-related assessments. The PRO was completed by the patients enrolled in the trial without the assistance of on-site personnel. The PRO was completed at home by the patients before they attended the clinic visit. The patients were instructed to complete the PRO in a private area without being influenced by the trial team members or accompanied by family or friends. No one was allowed to answer or interpret items for the patients. If the patient was unable to read, the researcher or delegated trial team member was allowed to read the items / answer options aloud to the patient. The researcher or delegated trial team member instructed the patient to complete each item in the PRO and explained that there were no right or wrong answers. The researcher or delegated trial team member instructed the patient to give the best answer possible and explained that all individual responders would be kept confidential.

[0167] The integrity of the PRO and potential adverse events (AEs) were reviewed immediately after completion by the investigator (or designated person). When reviewing the AEs of the PRO, the investigator was instructed not to influence or question the content of the patient's response to the PRO questions. The review of the PRO was documented. If an entry was missing from the PRO, the patient was asked to answer all questions, taking care not to bias the patient.

[0168] Before the trial began, the investigators and / or members of the delegated trial team received training and instruction on completing the PRO.

[0169] Patients reported their number of bowel movements / ostomy bag emptyings during the 48-hour equilibration period in the eDiary.

[0170] Improvement at Weeks 4, 12, 20, and 24

[0171] The PGIC scale used in the EASE-SBS trial was a 7-point Likert scale that required patients to check a box when answering the following question:

[0172] "My overall status since the start of the trial has been:

[0173] (1) Great improvement

[0174] (2) Much improvement

[0175] (3) Minimal improvement

[0176] (4) No change

[0177] (5) Minimal worsening

[0178] (6) Much worsening

[0179] (7) Extreme worsening".

[0180] PGIC improvement was defined as responding "much improvement" or "great improvement" on the 7-point Likert scale at each of Weeks 4, 12, 20, and 24. The improvement between each liraglutide treatment regimen compared to placebo was tested using the Cochran-Mantel-Haenszel (CMH) test stratified for the randomization stratification factors.

[0181] Results

[0182] One hundred and six SBS patients were randomly assigned and treated with liraglutide according to the protocol.

[0183] A total of 106 SBS patients with intestinal failure who were dependent on parenteral support (PS) at least three days per week were randomly assigned equally to receive treatment with 10 mg of liraglutide administered once or twice weekly or placebo. The primary endpoint of the trial was the absolute change in the volume of parenteral support per week relative to baseline at 24 weeks.

[0184] Compared with placebo, liraglutide administered twice weekly significantly reduced the total volume of parenteral support per week at 24 weeks (p = 0.0039). When administered once weekly, liraglutide treatment also led to a reduction in the amount of parenteral support per week, however this did not reach statistical significance. At 24 weeks, the mean reduction in parenteral support relative to baseline in patients treated with liraglutide twice weekly was 5.13 L / week, and the mean reduction in parenteral support relative to baseline in patients treated with liraglutide once weekly was 3.76 L / week. Placebo treatment led to a reduction in parenteral support of 2.85 L / week.

[0185] Clinical response, defined as patients achieving at least a 20% reduction in the volume of parenteral support per week relative to baseline at both 20 and 24 weeks, was significantly higher with liraglutide twice weekly compared with placebo (p = 0.0243). Among patients receiving liraglutide twice weekly, 65.7% achieved clinical response. Whereas 45.7% and 38.9% of patients achieved clinical response in the once weekly and placebo treatment groups, respectively.

[0186] In the twice weekly dosing group, 14% of patients (n = 5) became completely free of parenteral support (enteral autonomy). A total of 9 patients treated with liraglutide achieved enteral autonomy, whereas no patients treated with placebo were able to discontinue parenteral support.

[0187] Clinical classification of patients based on PS volume (ESPEN guidelines)

[0188] Based on the energy and volume of PS required, patients were divided into 16 combinations (adapted from Pironi 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).

[0189] Table 1. Clinical classification of chronic intestinal failure and volume of intravenous supplementation required, IF is divided into 16 combinations

[0190]

[0191] aCalculated as the daily average of the total volume infused per week 1 / 4 (volume infused daily × number of infusions per week) / 7.

[0192] b Calculated as the daily average of the total energy infused per week 1 / 4 (energy infused daily × number of infusions per week) / 7 / Kg.

[0193] Anatomical SBS categories

[0194] Patients were also grouped according to their remaining intestinal segments

[0195] Group 1: Terminal - jejunostomy or ileostomy

[0196] Group 2: Jejunocolic anastomosis

[0197] Group 3: Jejunal - ileal - colonic anastomosis.

[0198] As shown in Table 2 below, after 24 weeks of treatment, once weekly (OW) or twice weekly (TW) administration of semaglutide led to complete discontinuation of parenteral support (enteral autonomy). A total of 9 patients treated with semaglutide achieved enteral autonomy, while no patients treated with placebo were able to discontinue parenteral support (data not shown).

[0199] Table 2.

[0200]

[0201] Example 2: Extension Trial to Evaluate the Long-term Safety and Efficacy of Glucagon-like Peptide-2 in Patients with Short Bowel Syndrome (SBS), EASE SBS2 (EASE-2) ​

[0202] After the EASE - 1 trial, a double - blind, phase 3, extension trial to evaluate the long - term safety and efficacy of semaglutide in patients with short bowel syndrome (SBS).

[0203] Objective

[0204] The primary objective of this trial was to evaluate the long - term safety of semaglutide treatment in patients with short bowel syndrome (SBS).

[0205] The secondary objectives of this trial were:

[0206] · To evaluate the long - term efficacy of semaglutide treatment in SBS patients

[0207] · To evaluate the long - term immunogenicity of semaglutide and its impact on pharmacokinetics (PK), efficacy, and safety in SBS patients

[0208] · To evaluate the quality of life of SBS patients treated with semaglutide.

[0209] Trial Design

[0210] This is a long-term, double-blind, extension trial for patients who completed the entire 24-week treatment phase of the lead-in trial (“EASE-1”) described in Example 1 above and consented to participate in this extension trial called “EASE-2”. In addition, patients are allowed to be directly screened into EASE-2 to obtain additional long-term safety and efficacy data.

[0211] The treatment duration of this extension trial is 2 years. All patients received semaglutide treatment at a dose regimen of 10 mg twice a week (TW) or once a week (OW). Patients who received TW or OW semaglutide in EASE-1 continued their blinded treatment. Patients who received placebo in EASE-1 were re-randomized at a 1:1 ratio to blinded treatment with 10 mg semaglutide TW or OW, and patients directly screened into EASE-2 were randomized at a 1:1 ratio to blinded treatment with 10 mg semaglutide TW or WO. Both treatment groups involved TW administration (semaglutide or semaglutide + placebo) to maintain blinding.

[0212] · Semaglutide TW: 10 mg semaglutide on Day 1 and on Day 4 or 5 (the same day of the week each week).

[0213] · Semaglutide OW: 10 mg semaglutide or placebo on Day 1 and on Day 4 or 5 (the same day of the week each week).

[0214] Patients directly screened into EASE-2 had a screening visit before randomization and followed the same run-in phase as EASE-1. This was to ensure a reliable baseline for evaluating the efficacy of semaglutide treatment in reducing the need for parenteral support (PS).

[0215] During the trial, the actual volume and type of PS were continuously recorded by the patients in an electronic diary (eDiary). The researchers recorded the type, content, and volume of the prescribed PS.

[0216] The PS volume can be adjusted at or between visits according to the following algorithm, which is the same as the algorithm used for EASE-1:

[0217] IF: The daily urine volume at the current visit is at least 10% higher than the baseline urine volume.

[0218] THEN: New PS volume (per week) = Current PS volume (per week) - (7 × absolute change in daily urine volume relative to baseline).

[0219] For patients transferred from EASE-1, the baseline urinary volume (L / day) in EASE-2 was defined as the mean of the last two 48-hour urinary volumes measured during the stable phase of EASE-1. For patients directly screened into EASE-2, the baseline urinary volume was defined as the mean of two 48-hour urinary volumes before the first visit in EASE-2. During the 24-month treatment phase, patients recorded their urinary volume in the eDiary during a 48-hour measurement period before the trial visit, while adhering to an individually predetermined drinking schedule.

[0220] Starting from the 7th visit (i.e., 12 weeks after treatment with the investigational product), patients recruited at selected sites in EASE-2 will be included (after separate consent) in a voluntary PK substudy that has a more extensive pharmacokinetic (PK) sampling to provide additional information on the PK profile of semaglutide and its major active metabolite in SBS patients. The aim is to include approximately 45 patients. At the time of the interim cutoff, 12 patients (6 in each treatment group) had participated in the PK substudy.

[0221] After completion of the treatment phase, all patients were offered entry into an additional extension trial called "EASE-3" and continued to receive semaglutide. For patients who did not enter EASE-3, follow-up visits were conducted 4 weeks after completion of the treatment phase in EASE-2.

[0222] In addition to the 9 patients who withdrew at week 24 as described in Example 1, four patients initially randomized to the placebo group (i.e., patients who did not receive semaglutide) withdrew after 6 months of active treatment in the extension trial EASE 2. The relevant baseline characteristics of these patients are shown in Table 3 below.

[0223] Table 3.

[0224]

[0225] ***

[0226] Although the invention has been described in connection with the above exemplary embodiments, many equivalent modifications and variations will be apparent to those skilled in the art when the present disclosure is given. Accordingly, the exemplary embodiments of the invention set forth are considered to be illustrative rather than restrictive. Various changes may 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. A glucagon-like peptide 2 (GLP-2) analogue for use in a method of treating human patients suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analogue is represented by the following formula or a pharmaceutically acceptable salt thereof: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,(1848)(SEQ ID NO:1) The method comprises: (a) providing a human patient suffering from short bowel syndrome and receiving parenteral support (PS); (b) administering 10 mg of the GLP-2 analogue to the patient once or twice a week by subcutaneous injection for a period of time while the patient continues to receive the PS; and (c) after step (b), weaning the patient off the PS.

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

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

4. The glucagon-like peptide 2 (GLP-2) analogue for use in the treatment method according to any one of claims 1 to 3, the method further comprises: (d) after step (c), administering 10 mg of the GLP-2 analogue to the patient once or twice a week by subcutaneous injection while the patient is not receiving PS.

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

6. The glucagon-like peptide 2 (GLP-2) analogue for use in the treatment method according to any one of claims 1 to 5, wherein the patient maintains an SBS non-PS state for at least 1 year, optionally at least 2 years and optionally at least 3 years or longer.

7. The glucagon-like peptide 2 (GLP-2) analogue for use in the treatment method according to any one of claims 1 to 6, wherein the improvement in the quality of life (QoL) of the patient is evaluated using the patient global impression of change (PGIC) status.

8. The glucagon-like peptide 2 (GLP-2) analogue for use in the treatment method according to claim 7, wherein the PGIC status uses a 7-point Likert scale, wherein the status of responders reporting much improvement or great improvement compared to treatment with placebo.

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

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

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

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

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

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

15. A glucagon-like peptide 2 (GLP-2) analogue for use in the treatment method according to any one of claims 1 to 14, wherein step (b) comprises the patient receiving PS at the 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. A method for treating short bowel syndrome in a patient in need 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 once or twice a week by subcutaneous injection over a period of time, wherein the GLP-2 analogue is represented by the following formula or a pharmaceutically acceptable salt thereof: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,(1848)(SEQ ID NO:1) while the patient continues to receive the PS; and (c) after step (b), withdrawing the patient from the PS.

17. The method according to claim 16, wherein the period of time in step (b) is 20 to 52 weeks.

18. The method according to claim 17, wherein the period of time in step (b) is 24 to 36 weeks.

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

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

21. The method according to any one of claims 16 to 21, wherein the patient maintains the SBS non-PS state for at least 1 year, optionally at least 2 years and optionally at least 3 years or longer.

22. The method according to any one of claims 16 to 21, wherein the improvement in the quality of life (QoL) of the patient is evaluated using the patient global impression of change (PGIC) status.

23. The method according to any one of claims 16 to 22, wherein the PGIC status uses a 7-point Likert scale, wherein the status of a responding patient reports a great improvement or a very great improvement compared to treatment with a placebo.

24. The method according to claim 22 or claim 23, wherein the improved PGIC status of the patient is observable at week 24 of the treatment.

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

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

27. The method according to any one of claims 16 to 26, wherein the patient has undergone an end-jejunostomy or an ileostomy.

28. The method according to any one of claims 16 to 27, wherein the patient has undergone a jejuno-colic anastomosis.

29. The method according to any one of claims 16 to 28, wherein the patient has undergone a jejuno-ileo-colic anastomosis.

30. The method according to any one of claims 16 to 29, wherein step (b) comprises the patient 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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