TW202436330A - Glucagon-like-peptide-2 (glp-2) analogues and their medical uses for the treatment of short bowel syndrome (sbs) - Google Patents

Abstract

Glucagon-like-peptide-2 (GLP-2) analogues and their medical uses the treatment of short bowel syndrome (SBS) are disclosed, in particular medical uses of glepaglutide identied in the EASE SBS 1 trial demonstrating improved patient Quality of Life (QoL) and/or an early reduction in the parenteral support (PS) required by patients as their treatment with glepaglutide progressed.

Description

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

Invention Field

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 in particular to treatment with glepaglutide, which treatment results in either an improved Quality of Life (QoL) and/or an early or significant reduction in the need for parenteral support (PS) in patients undergoing GLP-2 therapy.

Invention Background

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. It is derived from proglucagon by a specific post-translational processing in the enteroendocrine L cells of the intestine and in specific regions of the brain stem. GLP-2 binds to a single G-protein-coupled receptor belonging to the class II glucagon secretin family.

GLP-2 has been reported to induce significant growth of the mucosal epithelium of the small intestine through stimulation of stem cell proliferation in the crypts and by inhibition of apoptosis of 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), stimulates intestinal hexose transport through upregulation of glucose transport proteins (Cheeseman, 1997, Am. J. Physiol ., R1965-71), and increases intestinal blood flow (Guan et al ., 2003, Gastroenterology , 125: 136-147).

It is known in the art that glucagon-like peptide-2 receptor analogs have therapeutic potential for the treatment of intestinal diseases. However, native hGLP-2, a 33-amino acid gastrointestinal peptide, is not useful in a clinical setting due to its very short half-life in the human body, approximately 7 minutes for full-length GLP-2 [1-33] and approximately 27 minutes for truncated GLP-2 [3-33]. In large part, this short half-life is due to degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). Therefore, 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. By way of example, GLP-2 analogs with substitutions have been proposed, such as, for example, a GLP-2 analog 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 Revestive (in Europe).

WO 2006/117565 (Zealand Pharma A/S) describes GLP-2 analogs which comprise one or more substitutions compared to [hGly2]GLP-2 and which have improved in vivo biological activity and/or improved chemical stability, for example as assessed in an in vitro stability assay. Among the molecules disclosed in WO 2006/117565, ZP1848 (jepaglutide) has been designed to be stable in a liquid formulation. Dosing regimens for GLP-2 analogs comprising ZP1848 and its metabolites are described in WO 2018/229252, which also showed that these compounds are effective for increasing longitudinal growth of the intestine. Ready-to-use formulations of ZP1848 are described in WO 2020/065064.

Summary of the invention

Broadly, the invention is based on surprising findings from the EASE SBS 1 trial, a multicenter, placebo-controlled, randomized, parallel-group, double-blind Phase 3 clinical trial (NCT:03690206) examining the safety and efficacy of jepaglutide for the treatment of short bowel syndrome (SBS), particularly with respect to trial endpoints related to patients' quality of life (QoL) and/or their need for parenteral support (PS) as they progressed on treatment with jepaglutide. The parameters associated with the change in the PS required by patients included: (a) earlier onset of a significant improvement in the reduction in PS volume from baseline, and (b) time to achieve a clinical response, defined as the time to a reduction in PS volume of at least 20% from baseline.

Results from the EASE SBS 1 trial included the surprising finding that one of the trial’s primary endpoints, using the Patient Global Impression of Change (PGIC), a PRO [patient-report outcome] instrument in which patients rate their change in global status from the start of the trial on a 7-point Likert scale (see https://www.fda.gov/media/116277/download and https://www.fda.gov/media/116281/download), resulted in improvements and significant differences in PGIC at week 24 for both twice-weekly (TW) and once-weekly (OW) jepaglutide versus placebo.

Furthermore, the EASE SBS 1 trial found a significant reduction in PS volume after Week 12, a primary endpoint of the trial, particularly for patients treated in the twice-weekly (TW) arm of the trial. This early effect was more rapid than that seen with alternative therapies such as GLP-2 analogs (teduglutide) and more rapid than previously reported responses for patients treated with jepaglutide, which demonstrated a reduction in PS volume after 20-24 weeks. This early effect was further supported by the significantly faster time to clinical response with jepaglutide TW compared to placebo.

Without wishing to be bound by any particular theory, the inventors believe that a rapid reduction in PS volume required by a patient may be linked to a response felt by the patient [e.g., as indicated by improvements in PGIC], and that there may be a lag time between the reduction in PS volume and the benefit experienced by the patient.

In the trial, the patients received 10 mg of jepaglutide in both the twice-weekly (TW) and once-weekly (OW) arms of the trial.

Thus, in a first aspect, the present invention provides a glucagon-like peptide-2 (GLP-2) analog for use in a method for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analog is represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt of the GLP-2 analog), the method comprising administering the GLP-2 analog to the patient once or twice a week over a period of time, wherein the treatment results in an improvement in the patient's quality of life (QoL).

In a further aspect, the present invention provides a use of a glucagon-like peptide-2 (GLP-2) analog 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 analog is represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH ₂ (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt of the GLP-2 analog, the use comprising administering the GLP-2 analog to the patient once or twice a week over a period of time, wherein the treatment results in an improvement in the patient's quality of life (QoL).

In a further aspect, the present invention provides a method for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), the method comprising administering to the patient a glucagon-like peptide-2 (GLP-2) analog represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt of the GLP-2 analog, wherein administration of the GLP-2 analog to the patient once or twice a week over a period of time results in an improvement in the patient's quality of life (QoL).

In these aspects of the invention, the patient's improvement in quality of life (QoL) is assessed using a Patient Global Improvement (PGIC) status, for example using a 7-point Likert scale, where responding patients report a much improved or very improved status when compared to treatment with a placebo. In some cases, the patient's improved PGIC status is observed at week 24 of the treatment.

In a further aspect, the present invention provides a glucagon-like peptide-2 (GLP-2) analog for use in a method for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analog is represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt of the GLP-2 analog, the method comprising administering the GLP-2 analog to the patient once or twice a week over a period of time, wherein the treatment results in a decrease in PS volume at week 12 from the start of treatment with the GLP-2 analog.

In a further aspect, the present invention provides the use of a glucagon-like peptide-2 (GLP-2) analog in the preparation of a medicament for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the method comprises administering to the patient a GLP-2 analog represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH ₂ (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt of said GLP-2 analog, the method comprising administering said GLP-2 analog to said patient once a week or twice a week for a period of time, wherein said treatment results in a decrease in PS volume at week 12 starting from the initiation of treatment with said GLP-2 analog.

In a further aspect, the present invention provides a method for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the method comprises administering to the patient a glucagon-like peptide-2 (GLP-2) analog represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt of the GLP-2 analog, wherein administering the GLP-2 analog to the patient once or twice a week over a period of time from the start of treatment with the GLP-2 analog results in a decrease in PS volume at week 12.

Merely by way of example, in the present invention, starting with treatment with the GLP-2 analog, the treatment may result in a significant and earlier reduction in PS volume at week 12 with a ratio of -2.42 placebo.

In a further aspect, the present invention provides a glucagon-like peptide-2 (GLP-2) analog for use in a method for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analog is represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt of the GLP-2 analog, the method comprising administering the GLP-2 analog to the patient once or twice weekly for a period of time, wherein the treatment results in an early onset of action with a median time to clinical response defined by at least a 20% decrease in PS volume of 55 days or 8 weeks for treatment with 10 mg jepaglutide twice weekly and 161 days or 23 weeks for treatment with 10 mg jepaglutide once weekly.

In a further aspect, the present invention provides a use of a glucagon-like peptide-2 (GLP-2) analog 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 analog is represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH ₂ (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt of the GLP-2 analog, the method comprising administering the GLP-2 analog to the patient once or twice weekly for a period of time, wherein the treatment results in an early onset of action with a median time to clinical response defined by at least a 20% decrease in PS volume of 55 days or 8 weeks for treatment with 10 mg jepaglutide twice weekly and 161 days or 23 weeks for treatment with 10 mg jepaglutide once weekly.

In a further aspect, the present invention provides a method for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the method comprises administering to the patient a glucagon-like peptide-2 (GLP-2) analog represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt of the GLP-2 analog, wherein administration of the GLP-2 analog to the patient once or twice weekly over a period of time results in an advanced onset of action, with a median time to clinical response defined by a reduction in PS volume of at least 20% for twice weekly administration of 10 The duration of treatment was 55 days or 8 weeks for treatment with 10 mg jepaglutide once weekly and 161 days or 23 weeks for treatment with 10 mg jepaglutide once weekly.

In these aspects of the invention, the patient's improvement in quality of life (QoL) is assessed using a Patient Global Improvement (PGIC) status, for example using a 7-point Likert scale, where responding patients report a much improved or very improved status when compared to treatment with a placebo. In some cases, the patient's improved PGIC status is observed at week 24 of the treatment.

The results disclosed herein also show that in some patients, treatment with the GLP-2 analog can achieve complete withdrawal of parenteral support, for example, such that the patient does not require parenteral support after 24 weeks of treatment. This is also referred to as a patient achieving oral or enteral autonomy.

In the context of this case, the term "parenteral support" or "PS" includes providing nutrients and/or fluids to an individual receiving GLP-2 therapy as a means of providing that individual with nutrients and/or fluids that they require but are unable to fully absorb due to their condition.

In the context of this case, the term "oral or intestinal autonomy" means that the patient has previously received PS and GLP-2 therapy to improve their gastrointestinal function to the point where all PS has been withdrawn [i.e., PS is no longer part of their treatment regimen].

The terms "individual" and "patient" are used interchangeably in this specification. It will be understood that the individual (or patient) is a lactating animal, and typically a human.

ZP1848 was also effective in increasing intestinal mass and longitudinal intestinal growth, particularly in the small intestine.

The ZP1848 or a pharmaceutically acceptable salt will typically be provided as a pharmaceutical composition comprising ZP1848 or the salt in combination with a pharmaceutically acceptable carrier or excipient.

As described elsewhere in this specification, the individual doses may be administered via a dosing regimen.

WO 2018/229252 describes: ZP1848 has an unexpectedly long half-life that may enable alternative dosing regimens such as once or twice weekly, especially when delivered by subcutaneous injection. These results are from a Phase II human clinical study with ZP1848, which found that the terminal plasma half-life of the molecule is actually between 5 and 17 days. The terminal plasma half-life is the time required to divide the plasma concentration by 2 after pseudo-equilibrium is reached. 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 a subcutaneous depot, which is slowly released from the subcutaneous depot and is also agonist at the GLP-2 receptor. The subcutaneous depot may be formed at the time of administration via a reaction between the lysine tail of ZP1848 and hyaluronic acid in the subcutaneous compartment.

Thus a once or twice weekly dosing regimen may include several doses or a course of doses separated by 2, 2.5, 3, 3.5, 4, 5, 6 or 7 days. As will be appreciated in the art, the time between doses may vary to the extent that each dose is not separated by exactly the same time. This will generally be indicated at the discretion of the physician, separated in time by a clinically acceptable time range.

In some cases, it may be desirable to divide a total dose into several (e.g., two or three) separate doses or administrations, for example for administration at spaced-apart injection sites, for example at least 5 cm apart. Such spaced-apart administrations will typically be given at substantially the same time, for example on the same day, within less than 1 hour of each other, or even closer in time.

In the context of this case, the term "parenteral support" or "PS" encompasses the provision of nutrients and/or fluids to an individual receiving GLP-2 therapy as a means of providing the individual with nutrients and/or fluids that they require but are unable to fully absorb due to their condition. Determining the correct amount or volume of PS to provide to an individual with SBS receiving GLP-2 therapy is challenging because if the volume of PS is not adjusted in a timely and appropriate manner, the patient may experience fluid overload, be at risk for dehydration, and may not achieve an optimal clinical response to the therapy. This is further complicated because the volume of PS an individual requires, depending on their response to GLP-2 therapy, will typically vary during the course of the therapy. Typically, as GLP-2 therapy progresses, an assessment of the amount of PS the individual requires depends on how long the therapy has been continued and the individual patient's responsiveness to the therapy. In view of this variability, an initial assessment of PS volume may be performed within the first few days of GLP-2 therapy, and typically followed by weekly assessments during the first month, monthly assessments for the next 1-3 months, and every 3-6 months thereafter until the treatment is terminated. This is important because an individual may experience a rapid initial response to GLP-2 therapy, as shown in the example below, by improving small bowel function, for example even before any increase in intestinal length is observed. This in turn allows the PS volume to be reduced, thereby avoiding the risk of side effects such as fluid overload.

Thus, in the medical uses disclosed herein, due to a subject's reduced need for PS, the method or use may comprise the steps of: (a) determining the volume of PS required by the subject at that time point in the treatment, (b) comparing it to a baseline PS volume determined at the start of the therapy with the GLP-2 analog, and (c) reducing the frequency or volume of PS if the subject shows improved intestinal (e.g., small intestine) function. Optionally, a reduction in the frequency or volume of parenteral support (PS) can be performed using the algorithm described in the examples.

As an example of the relationship between the amount of parenteral support a patient requires 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 the function or absorptive capacity of the small intestine. Generally, GLP-2 therapy according to the present invention results in improved small intestinal function or absorptive capacity of at least 10%, more preferably at least 20%, more preferably at least 30%, more preferably at least 40%, and most preferably at least 50%. Additionally or optionally, the amount of parenteral support is reduced over the course of GLP-2 therapy by at least 10%, more preferably at least 20%, more preferably at least 30%, more preferably at least 40%, and most preferably at least 50%. In a preferred embodiment, the reduction in non-oral support is at least 20%.

In yet another related aspect, the present invention addresses one of the challenges faced by patients and physicians when initiating GLP-2 therapy, namely, the appropriate and individualized adjustment of the non-oral 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 an optimal clinical response with the therapy.

For example, in a previous 24-week treatment study with the GLP-2 analog teduglutide (see Center for Drug and Evaluation and Research , application number 203441Orig1s000, page 16), attempts to reduce parenteral nutritional volume by 10% were completed as early as weeks 4, 8, 12, 16, and 20 after the start of treatment if urine output increased by at least 10% from baseline. Many patients in this study suffered from fluid overload and abstinence from alcohol (Jeppesen et al . 2011, Gut 2011; 60:902-914). In a follow-up study [a 24-week study of SBS-IF patients given subcutaneous teduglutide] (Jeppesen et al . 2012, Gastroenterology 2012;143:1473-1481), a weekly reduction in parenteral nutrition of at least 10% but not more than 30% was recommended if urine output increased by at least 10% from baseline. However, in this study, the patients also suffered from fluid overload, especially at the beginning of the treatment.

Thus, as performed in the EASE SBS 1 trial described in the example, the present invention enables early assessment of altered PS fluid requirements (e.g., within days of initiating GLP-2 therapy) and provides an algorithm for adjusting PS volume during a course of GLP-2 therapy, achieving an early onset of clinical response (i.e., >20% PS volume reduction) and a significant reduction in PS after 12 weeks. By way of example, an early onset of action was achieved with a median time to clinical response (at least a 20% reduction in PS volume) of 55 days or 8 weeks for treatment with 10 mg jepaglutide twice weekly and 161 days or 23 weeks for treatment with 10 mg jepaglutide once weekly. Those skilled in the art will appreciate that this approach of using the algorithm to adjust PS volume provides a personalized adjustment of PS volume for each patient. This aspect of the invention can be applied to GLP-2 therapy using the GLP-2 analogs disclosed herein or using GLP-2 analogs known elsewhere in the art (such as teduglutide). Therefore, the algorithms for adjusting the PS volume disclosed in these examples may be used in any aspects of the present invention.

In all aspects of the invention, the method for administering the glucagon peptide-2 (GLP-2) analog optionally comprises administering to the patient several doses of the GLP-2 analog, wherein the doses are separated in time by one week or half a week. In some cases, it may be desirable to divide a total dose into several (e.g., two or three) separate doses, for example for administration at spaced-apart injection sites, for example, the injection sites are spaced at least 5 cm apart.

Preferably, the dosage of the GLP-2 analogs used according to the present invention falls within the range of between 0.5 mg and 25 mg (inclusive) per patient once or twice per week, optionally between 1 mg and 20 mg (inclusive) per patient once or twice per week, optionally between 1 mg and 10 mg (inclusive) per patient once or twice per week, optionally between 2 mg and 7 mg (inclusive) per patient once or twice per week, optionally between 5 mg and 7 mg (inclusive) per patient once or twice per week, or optionally between 2 mg and 5 mg (inclusive) per patient once or twice per week. In one embodiment, the dosage of the GLP-2 analogs used according to the present invention is 10 mg (inclusive) per patient once or twice a week. In a course of treatment, the dosage taken by the patient may be the same or different according to the instructions from the physician.

Preferably, the glucagon peptide-2 (GLP-2) analog is administered to the patient by injection, most typically by subcutaneous injection or intramuscular injection. In certain preferred embodiments, the GLP-2 analog may be administered using an injection pen, which allows the patient to self-administer the analog. In certain aspects, the administration of the GLP-2 analog results in the formation of a subcutaneous sustained-release dosage form, from which the GLP-2 analog or its metabolite is released. Without wishing to be limited to any particular explanation, the subcutaneous sustained-release dosage form may be formed through the interaction of the GLP-2 analogs administered according to the present invention (particularly when the analogs contain a lysine tail), through a reaction between the analogs and with hyaluronic acid in the subcutaneous compartment.

The specific embodiments of the present invention will now be described in detail by way of example and not limitation with reference to the attached drawings. However, in view of the disclosure of this case, various other aspects and embodiments of the present invention will be obvious to those skilled in the art.

"And/or" when used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, "A and/or B" is to be taken as specific disclosure of each of (i) A, (ii) B, and (iii) A and B, just as if each were individually set forth herein.

Unless the context dictates otherwise, the descriptions and definitions of features set out above are not limited to any particular aspect or embodiment of the invention, and apply equally to all described aspects and embodiments.

Detailed description of the invention Definition

Throughout the description and claims), the conventional single letter codes for naturally occurring amino acids are used. All amino acid residues in the compounds described are typically in the L-form. Compounds

As described, for example, in WO 2006/117565, ZP1848 is a peptide having the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 . It will be understood that the "H-" at the N-terminus indicates a free hydrogen of the N-terminal amine ( _NH2 group). The " _NH2- " at the C-terminus indicates a C-terminal amide group. The terms "ZP1848" and "jepaglutide" may be used interchangeably.

As described in more detail below, the present invention relates to the use of pharmaceutically acceptable salts of ZP1848. Any suitable salt may be used, although acetate may be preferred.

When ZP1848 is injected into the subcutaneous (SC) compartment, two functionally active metabolites (ZP2469 and ZP2711, both C-terminally truncated analogs of jepaglutide (ZP1848)) are formed. The overall PK profile of ZP1848 thus includes the effects of ZP1848 and its two major metabolites.

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

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

Teduglutide is a peptide having the following chemical formula: H-HGDGSFSDEMNTILDNLAARDFINWLIQTKITD-OH wherein the "H-" at the N-terminus and the "-OH" at the C-terminus are as described above. Pharmaceutical Compositions and Administration

As used herein, the GLP-2 analog may be formulated into a pharmaceutical composition prepared for storage or administration, and the pharmaceutical composition comprises a therapeutically effective amount of the GLP-2 analog in a pharmaceutically acceptable carrier or formulation.

Suitable salts include acid addition salts and alkaline salts. Examples of acid addition salts include hydrochlorates, citrates, chlorides and acetates. Preferably, the salt is an acetate. Generally, it is preferred that the salt is not a chloride salt. Exemplary alkaline salts include salts wherein the cation is selected from alkali metals such as sodium and potassium; alkali earth metals such as calcium; and ammonium ion ⁺ N(R ³ ) ₃ (R ⁴ ), wherein R ³ and R ⁴ independently designate optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted aryl or optionally substituted heteroaryl.

Acetate salts may be particularly preferred. In the context of this application, the term "ZP1848-acetate" means that the ZP1848 molecule is in the form of an acetate salt. The acetate salts of ZP1848 30 may be represented by the formula (ZP1848), x(CH ₃ COOH), 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. In any composition, molecules with different numbers of acetate molecules may be present, so that x is not necessarily a whole number. 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 4.0 to 8.0.

When administration is to be parenteral, such as subcutaneous or intramuscular, the injectable pharmaceutical composition can be prepared in conventional form. Jepaglutide is generally provided as an aqueous liquid formulation, for example, as described in WO 2020/065064 and WO 2020/065063 (the contents of which are incorporated herein by reference in their entirety). Subcutaneous administration may be particularly preferred, for example by injection.

The therapeutic dosing and regimen that is most appropriate for the treatment of a patient will, of course, vary with the disease or condition being treated and according to patient parameters. Without wishing to be bound by any particular theory, it is expected that doses between 0.1 and 25 mg per patient and shorter or longer durations or frequencies of treatment may produce therapeutically useful results, such as a statistically significant increase, particularly in small intestinal mass. In certain instances, the treatment regimen may include the administration of a maintenance dose that is appropriate to prevent tissue degeneration that occurs after discontinuation of initial treatment. The dose size and dosing regimen that are most appropriate for human use may be guided by the results obtained with the present invention and may be confirmed in further clinical trials.

A human dose (total dose) of ZP184 may be between about, such as and including 0.1 mg and 25 mg per patient, between about and including 0.5 mg and 20 mg per patient, such as between about and including 1 mg and 15 mg per patient, such as between about and including 1 mg and 10 mg per patient, once or twice weekly, or several doses separated by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days as defined herein. In certain instances, a fixed dose of ZP1848 may be used according to a dosing pattern disclosed herein, i.e., the same dose regardless of patient weight, administered once or twice weekly. By way of example, the fixed dose may be a dose containing 1.25 mg, 2.5 mg, 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 may be used, as was done in the EASE SBS 1 trial reported in the Examples. The use of fixed dosing has the advantage of increasing compliance and reducing the risk of patient dosing errors (including the risk of miscalculating a weight-based dose to be administered).

In a preferred embodiment, the formulation is a ready-to-use formulation as described in WO 2020/065064. As used herein, the term "ready-to-use" means that a formulation does not require the use of a specified amount of diluent (e.g., water for injection or other suitable diluent) for constitution or dilution prior to use by a specified route of administration.

As described herein, the liquid formulations of the GLP-2 analogs of the present invention comprise a buffer, a non-ionic tonicity modifier, and sufficient arginine (q.s.) to provide the pH of the final formulation. According to normal pharmaceutical practice, the formulations of the present invention are sterile and/or do not contain reducing agents. In preferred cases, the liquid formulations of the present invention are aqueous liquid formulations. In certain cases, the liquid formulations of the present invention are non-aqueous liquid formulations.

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 exemplary screening experiments show that the formulations of the present invention preferably contain a buffer selected from a histidine buffer, a methanesulfonate buffer, an acetate buffer, a glycine buffer, a lysine buffer, a TRIS buffer, a Bis-Tris buffer and a MOPS buffer, because these buffers provide a stable formulation in which the GLP-2 analogs are dissolved and do not become viscous, turbid or cause the peptide drug to precipitate). In 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.

The term "osmotic modifier" as used herein refers to a pharmaceutically acceptable osmotic agent used to modulate the osmotic pressure of the formulation. The formulations of the present invention are preferably isotonic, i.e. they have an osmotic pressure that is substantially the same as that of human serum. The osmotic modifiers used in the formulations are preferably non-ionic osmotic modifiers and are preferably selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose. A preferred non-ionic osmotic modifier is mannitol, such as D-mannitol. The concentration of the osmotic modifier will depend on the concentrations of the other components of the formulation, especially where the formulation is intended to be isotonic. Typically, the ionic osmotic modifier will be applied 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).

Generally, the components and amounts of the liquid formulations are selected to provide a formulation with a pH of about 6.6 to about 7.4 (more preferably a pH of about 6.8 to about 7.2, and most preferably a pH of about 7.0). Arginine may be added in sufficient quantity (q.s.) to adjust the pH so that the pH falls within a desired pH range. Preferably, the pH adjustment is not accomplished using hydrochloric acid or sodium hydroxide.

In one embodiment, the liquid formulations are composed of: ZP1848, such as an acetate salt thereof, at a concentration of about 2 mg/mL to about 30 mg/mL; a buffer selected from the group consisting of a histidine buffer, a methanesulfonate buffer, an acetate buffer, a glycine buffer, a lysine buffer, a TRIS buffer, a Bis-Tris buffer, and a MOPS buffer, the buffer being present at a concentration of about 5 mM to about 50 mM; a buffer being present at a concentration of about 90 A non-ionic osmotic modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose at a concentration of about 100 mM to about 360 mM; and arginine in an amount sufficient to provide a pH of about 6.6 to about 7.4.

In one embodiment, the liquid formulations are comprised of: ZP1848, such as an acetate salt thereof, at a concentration of about 2 mg/mL to about 30 mg/mL; a buffer selected from the group consisting of a histidine buffer, a methanesulfonate buffer, and an acetate buffer, the buffer being present at a concentration of about 5 mM to about 50 mM; a buffer being present at a concentration of about 90 mM to about 360 mM; A non-ionic osmotic modifier selected from the group consisting of mannitol, sucrose, glycerol and sorbitol at a concentration of mM; and sufficient arginine to provide a pH of about 6.6 to about 7.4.

In another preferred embodiment, the liquid formulations include: ZP1848, such as an acetate salt thereof, 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 sufficient arginine to provide a pH of about 7.0.

In yet another embodiment, the liquid formulations comprise: ZP1848, such as an acetate salt thereof, 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.

In another embodiment, the liquid formulations comprise: ZP1848-acetate or HHGEGTFSSEIATllDAlAARDFIAWLIAT KITDKKKKKK-NH ₂ acetate (SEQ ID NO: 1) at a concentration of about 20 mg/mL, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and sufficient arginine to provide a pH of about 7.0.

In another embodiment, the liquid formulations comprise: ZP1848-acetate or HHGEGTFSSE1ATllDAlAARDFIAWLIAT KITDKKKKKK-NH ₂ acetate (SEQ ID NO: 1) at a concentration of about 20 mg/mL, histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and a pH of about 7.0.

Those skilled in the art will appreciate that where a formulation comprises the GLP-2 analog at a concentration of 20 mg/mL, a patient may be administered a 0.5 mL dose in order to treat the patient with 10 mg of the GLP-2 analog.

In another embodiment, the liquid formulations comprise: an acetate salt of a glucagon peptide-2 (GIP-2) analog having the following chemical formula: (H-HGEGTFSSE1ATllDAlAARDFIAWLIATKITDKKKKKK-NH ₂ ), x(CH ₃ COOH), wherein x is 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.

In another embodiment, in a once or twice daily dosing regimen, the liquid formulations comprise: an acetate salt of a glucagon peptide-2 (GIP-2) analog having the following chemical formula: (H-HGEGTFSSE1ATllDAlAARDFIAWLIATKITDKKKKKK-NH ₂ ), x(CH ₃ COOH), wherein x is 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.

In another embodiment, in a once or twice weekly dosing regimen, the liquid formulations comprise: an acetate salt of a glucagon peptide-2 (GIP-2) analog having the following formula: (H-HGEGTFSSE1ATllDAlAARDFIAWLIATKITDKKKKKK-NH ₂ ), x(CH ₃ COOH), wherein x is 1.0 to 8.0, 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.

In some cases, the liquid formulations of the present invention further comprise a preservative. In some cases, the preservative is selected from the group consisting of benzalkonium chloride, chloro butanol, methyl paraben and potassium sorbate. Generally, the preservative is present in a concentration of about 0.1% to about 1% by volume of the final formulation. Medical conditions

The peptide of the present invention can be used as a medicament for treating an individual suffering from short bowel syndrome. Thus, ZP1848 or a salt thereof may be useful therapeutically and/or preventively for the treatment of short bowel syndrome (SBS) [also known as short bowel syndrome or simply short bowel, which is caused by surgical resection, congenital defects or disease-related loss of intestinal absorption, in which the patient is subsequently unable to maintain a balance of fluids, electrolytes and nutrients on a traditional diet]. Although an adjustment usually occurs within two years after resection, SBS patients have reduced dietary intake and fluid loss.

The category of human patients with SBS includes those with SBS-intestinal failure (SBS-IF) and those on the borderline between SBS-intestinal insufficiency (SBS-II) and SBS-IF. In some cases, patients with SBS-IF are also referred to as SBS-PS when they are dependent on non-oral support, and patients with SBS-II are referred to as SBS non-PS when they are not dependent on non-oral support. In the EASE SBS 1 phase 3 trial reported here, patients with SBS chronic intestinal failure (SBS-CIF) were enrolled in the Evaluating the Efficacy and Safety of Jepaglutide (EASE) trial. The goal of the trial was to reduce the need for PS and improve quality of life (QoL).

Patients with SBS may be further classified into different SBS categories based on their remaining intestinal segments, and the present invention may be used to treat each of these patient groups, for example, those who have undergone an end-jejunostomy or ileostomy, a jejuna-colic anastomosis, or a jejuna-ilea-colic anastomosis.

In the medical uses of the present invention, patients receiving PS may be classified using any of A1, B1, C1, D1, A2, B2, C2, D2, A3, B3, C3, D3, A4, B4, C4 or D4 at an ESPEN guideline level. This is based on the energy and volume of PS required to classify patients into groups [adapted from Pironi L, Arends J, Bozzetti F, et al . ESPEN guidelines on chronic intestinal failure in adults. Clin. Nutr. , 35(2): 247-307; 2016, see table below].

The clinical classification of chronic intestinal failure (CIF) and the volume of intravenous supplements required. CIF is classified into 16 groups: IV energy ^supplementb (kcal/Kg body weight) Volume of ^IV Supplementa (mL) ≤ 1000 1001-2000 2001-3000 ＞3000 0 (A) A1 A2 A3 A4 1-10 (B) B1 B2 B3 B4 11-20 (C) C1 C2 C3 C4 ＞20 (D) D1 D2 D3 D4 ^aCalculated as daily mean of the total volume infused per week¼ (volume per day of infusion x number of infusions per week)/7. ^bCalculated as daily mean of the total volume infused per week¼ (energy per day of infusion x number of infusions per week)/7/kg.

The assessment of the volume of PS required for a patient can be determined as described in the examples in the sections entitled "Procedure" and "Treatment Phase". This approach can be used to calculate clinical parameters used in the present invention to define the physiological and pathological responses of patient categories treated with jepaglutide for SBS. These parameters included: (a) the earlier time to observe a statistically significant improvement in PS volume reduction compared to baseline was reported in the present invention as 12 weeks for treatment TW with 10 mg jepaglutide, which was earlier than the 20 to 24 weeks previously observed in previous studies; and (b) the median time to clinical response, defined by at least a 20% reduction in PS volume, was 55 days or 8 weeks for treatment with 10 mg jepaglutide twice weekly and 161 days or 23 weeks for treatment with 10 mg jepaglutide once weekly.

As described in the examples, QoL may be assessed using a Patient Global Improvement (PGIC) scale (see https://www.fda.gov/media/116277/download and https://www.fda.gov/media/116281/download). The PGIC assesses overall health status as perceived by the patient on a 7-point single-item scale ranging from "very worse" to "very improved," i.e., a yes/no meaning: patients are responders if they check either "very improved" or "much improved" on their PGIC questionnaire. The PGIC scale used in the EASE-SBS trial was a 7-point Likert scale in which patients were asked to check a box in response to a question: Since the start of the trial, my overall status has been: (1) Very improved (2) Much improved (3) Somewhat improved (4) No change (5) Somewhat worse (6) Much worse (7) Very worse.

PGIC improvement was defined as patients reporting a “much improved” or “very improved” on a 7-point Likert scale at each of weeks 4, 12, 20, and 24. Differences between jepaglutide treatment regimens compared with placebo were tested using a CMH test adjusting for this stratification factor.

The results of the EASE SBS 1 clinical trial reported in the Examples found that jepaglutide treatment of SBS-CIF patients was safe, well tolerated, and resulted in improvements in clinically significant patient-centered outcomes (PS requirement, bowel autonomy, and PROs). The onset of action was unexpectedly early for treatment with a GLP-2, with a median time to clinical response of only 8 weeks for TW. There was a significant improvement in the patient-reported outcome measure PGIC for treatment with both jepaglutide TW and jepaglutide OW. The population of SBS patients is considered to be very heterogeneous, and this finding with treatment with a GLP-2 was surprising.

The range of patient types with SBS was reviewed in Jeppensen, Journal of Parenteral and Enteral Nutrition , 38(1), 8S-13S, May 2014, doi: 10.1177/0148607114520994. Further subdivisions of SBS patient types can be made as described in Schwartz et al ., Clinical and Translational Gastroenterology (2016) 7, e142; doi:10.1038/ctg.2015.69. This divides SBS patients into early responders and late/slow responders. It is currently believed that an early responder is a patient who exhibits, among other benefits, an early benefit on treatment with a GLP-2 analog (such as ZP1848) resulting from an increase in small intestine width/diameter, while a late or slow responder is a patient who benefits most or for the first time from treatment with a GLP-2 analog (resulting in an increase in small intestine length). Determination of whether a subject is an early or a late responder may be used to determine the duration of a treatment regimen with the GLP-2 analog, the timing of any clinical decision to reduce parenteral support, and the interval between trials to determine whether parenteral support can be reduced. Thus, in a particular example, the patient is a late or slow responder. The length of the small intestine may be measured, for example, by computer tomography (CT scan), magnetic resonance imaging (MRI), histology, laparoscopy, or other measurements or techniques known in the art.

A further aspect of the present invention is to increase the intestinal mass or longitudinal growth of the intestine, especially the small intestine, in a patient (e.g., a human patient). As shown in WO 2018/229252, ZP1848 or a salt thereof can increase the longitudinal growth of the intestine relative to a control group.

This ability is particularly valuable to patients with SBS because it results in increased absorptive capacity even after treatment is stopped. Such patients are treated for at least 1 to 3 years, such as at least 1 to 4 years, such as 1 to 10 years, such as 1 to 20 years, such as 1 to 35 years, to achieve the goal of inducing longitudinal growth of the intestine.

As already described herein, patients on the borderline between patients with intestinal insufficiency (SBS-II) or SBS-PS and those with intestinal failure (SBS-IF) or SBS non-PS may therefore be of particular value from having their bowel extended over a course of treatment of 1 to 3 years, after which their risk for intestinal failure is reduced, for example involving weekly or twice-weekly dosing during treatment. This involves a lower risk of the need for a central line and the risk of sepsis associated with its use.

The active ingredients may also be used to treat malnutrition, such as that caused by catharsis and anorexia. Example

The following examples are provided to illustrate preferred aspects of the present invention and are not intended to limit the scope of the present invention. The GLP-2 analog administered according to the dosing regimen described herein can be produced according to the methods (such as solid phase peptide synthesis) described in WO 2006/117565 and PCT/EP2022/087440 filed on December 22, 2022 (the contents of these two cases are expressly incorporated herein by reference in their entirety). Experimental design

This was a multinational, placebo-controlled, randomized, parallel-group, double-blind Phase 3 trial to demonstrate the superiority of 10 mg jepaglutide once weekly (OW) and twice weekly (TW) subcutaneous (SC) injections versus placebo in stable SBS patients. The trial (clinicaltrials.gov identifier: NCT03690206) was conducted at 29 hospital centers (center numbers are in parentheses) across the United States (7), United Kingdom (5), Belgium (1), Canada (3), Denmark (2), France (2), Germany (5), the Netherlands (1), and Poland (3). Patients were randomized 1:1:1 via an interactive web-response system (IWRS) to 24 weeks of treatment with jepaglutide TW or jepaglutide OW or placebo, with trial drug administered SC in the abdomen or thigh. Randomization was performed using a block randomization scheme stratified by the patient's weekly PS volume requirement at baseline (<12 L vs. ≥12 L/week). To maintain the blinding, all 3 treatment groups involved twice-weekly dosing (jepaglutide and/or placebo). The primary and key secondary endpoints are to determine the efficacy of jepaglutide in reducing or eliminating the need for parenteral support (PS).

The management goals of short bowel syndrome (SBS) with intestinal failure (IF) are clinical patient-centric outcomes, including reduced need for parenteral support (PS) and improved quality of life (QoL).

The trial was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonization guidelines, and Good Clinical Practice. An Institutional Review Board or Independent Ethics Committee approved the trial at each center, and all participants gave written informed consent before undergoing any trial-related procedures or assessments. Participants

Key inclusion criteria included: diagnosis of SBS (defined as an estimated length of continuous remnant small bowel less than 200 cm or 79 inches) (Buchman AL, Scolapio J, Fryer J. AGA technical review on short bowel syndrome and intestinal transplantation. Gastroenterology 2003;124(4):1111-34. DOI: 10.1053/gast.2003.50139a.); need for PS at least 3 days per week; presence of a stoma or a continuous colon; and age 18-90 years. In addition, numerous exclusion criteria (some of which were reexamined at randomization) were defined to ensure the validity of efficacy assessments and to exclude patients with significant comorbidities that could bias safety assessments. These included: 2 or more SBS-related or PS-related hospitalizations within 6 months before screening; poorly controlled moderate or severe active inflammatory bowel disease or lesions that interfered with measurements or examinations required for the study; intestinal obstruction; known radiation enteritis or significant villous atrophy; heart disease within the last 6 months before screening; clinically significant abnormal electrocardiogram; acute or unstable chronic liver disease; history of colorectal cancer; liver damage; use of GLP-1, GLP-2, dipeptidyl peptidase (DPP)-4 inhibitors, human growth hormone, somatostatin, or analogs thereof within 3 months before screening; and unstable biologic therapy within 6 months before screening.

After informed consent and initial eligibility determination, patients entered a run-in period consisting of PS optimization and stabilization phases. This was to ensure a reliable baseline for assessing the efficacy of jepaglutide treatment in reducing the need for PS.

During the optimization phase, if the patient was considered unstable or non-optimized, the investigator could change the PS volume and content according to institutional standard practice. Before each optimization visit, the patient measured his or her urine output over a 48-hour period while adhering to a predefined 48-hour beverage menu. During this period, the patient recorded urine output and oral fluid intake in an eDiary. The effectiveness of PS optimization was investigated after 2 weeks. Since more than two rounds of PS optimization were not allowed, this limited the optimization phase to a maximum duration of 4 weeks. During the optimization phase, the investigator and the patient were allowed to redefine and optimize individual beverage menus to best match the patient's needs. Once the beverage menu had been set at the end of the optimization phase, the patient was asked to adhere to this beverage menu during a 48-hour equilibration period throughout the remainder of the trial.

A 2- to 4-week stabilization phase immediately follows the optimization phase (the last optimization phase visit can be considered the first stabilization phase visit). During this phase, changes in the prescribed weekly PS volume or schedule are not permitted. Prior to each stabilization phase visit, the patient measures urine output over a 48-hour period, adheres to a prescribed beverage menu, and reports urine output and oral fluid intake in the eDiary. Stabilization phase visits occurred every 2 weeks until the following PS stability criteria were met to qualify for randomization to investigational product treatment]: • Actual PS use (volume and content) was consistent with the prescribed PS (± 10% deviation of total volume was acceptable), and • 48-hour urine output was similar at two consecutive visits within a 2-week (± 4-day) interval (± 25% deviation was considered acceptable), while oral fluid intake was constant (48-hour oral intake differed by less than 10% at the two visits) and did not exceed 3.5 L/day, and • Urine output averaged ≥ 1 L/day and ≤ 2.5 L/day.

If stabilization cannot be achieved within the 4-week period due to unforeseen events (such as infection, illness or similar events), a second stabilization period of up to 4 weeks is permitted.

During the subsequent 24-week treatment phase, PS needs are assessed through the use of 48-hour equilibration periods associated with the 48 hours just prior to the treatment initiation visit and the 48 hours just prior to the site visits at weeks 1, 2, 4, 8, 12, 16, 20, and 24 after treatment initiation. The equilibration periods involve a fixed beverage menu (predefined individually during the optimization phase) and urine volume measurement, based on which the PS volume can be adjusted according to the following predefined algorithm: • IF: Daily urine volume at this visit is at least 10% higher than baseline urine volume. •THEN: New PS volume (weekly) = current PS volume (weekly) – 7 x absolute increase in daily urine volume relative to baseline.

The actual volume and type of PS used was recorded by the patient on an ongoing basis in an eDiary. In general, patients were to remain well hydrated during the trial. Urine production was to be maintained above 1 L/day for all patients according to treatment guidelines (Pironi L, Arends J, Bozzetti F, et al . ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr 2016;35(2):247-307. DOI: 10.1016/j.clnu.2016.01.020). Once study drug treatment had been initiated, PS volume could be adjusted at 1, 2, 4, 8, 12, 16, 20, and 24 weeks according to the predefined algorithm above. Changes to PS levels are at the investigator's discretion, and deviations from the algorithm for PS adjustment are permitted if clinical conditions such as signs of dehydration or fluid overload are present. The reasons for deviations from the algorithm should be documented in the eCRF.

The researcher could take into account unscheduled visits (after a 48-hour measurement period) to adjust PS.

Other efficacy parameters included body weight and patient-reported outcomes. Safety data were recorded throughout the trial.

Due to continued uncertainty regarding the prognosis of COVID-19 worldwide in 2022 and possible consequences for trial conduct and completion, enrollment was closed early. The resulting final trial population was 106 patients and based only on a priori assumptions, the power of jepaglutide once or twice weekly to show superiority over placebo on the primary endpoint was approximately 95%. Statistical analysis

The primary endpoint was the change in actual weekly PS volume from baseline to week 24, regardless of whether treatment was discontinued. The primary endpoint analysis used a repeated measures approach based on restricted maximum probability (REML) to compare the mean change in actual weekly PS volume from baseline at week 24 between treatment groups. The model used actual weekly PS volume assessments at weeks 1, 2, 4, 8, 12, 16, 20, and 24 (derived as actual weekly PS volume received during a valid 7-day period) as an independent variable and included covariates for treatment group, baseline actual weekly PS volume, visit (categorical variable), stratification factors (weekly PS volume requirement, <12 L/week vs. ≥12 L/week), and visit-by-treatment group interaction. Variability estimates were based on an unstructured covariation matrix that did not assume a specific correlation structure for repeated weekly PS volume measurements across patients over time. In this mixed-effects model for repeated measures (MMRM), the primary comparisons were the contrast (difference in least squares means) between the jepaglutide-treated group and the placebo group at the Week 24 visit. Missing values were imputed using multiple imputation methods. Of the 4 key secondary endpoints, the 3 responder endpoints were analyzed using the Cochran-Mantel-Haenszel test adjusted for the stratification factor (baseline weekly PS volume need <12 L/week vs. ≥12 L/week). Missing values for these endpoints were imputed as nonresponse. Differences between jepaglutide treatment groups compared to placebo for the remaining key secondary endpoint of reduction in weekly PS volume from baseline to Week 12 were analyzed using the mixed effects model for repeated measures (MMRM) described for the primary endpoint. A parallel gating procedure (testing hierarchy) was applied to protect the overall Type I error rate expressed as alpha when testing the primary and key secondary endpoints across the two jepaglutide treatment groups versus placebo. Patient Global Improvement (PGIC) Patient-Reported Outcomes (PROs)

The PGIC was used to investigate health-related quality of life (HRQoL).

Questionnaires were completed in paper form at the site visit, prior to any other trial-related assessments. The PROs were completed by patients enrolled in the trial without the assistance of site personnel. The PROs were completed at home by the patient before the clinic visit. Patients were instructed to complete the PROs in a private area without the interference of trial team members or accompanying family or friends. No one was allowed to answer or explain items to the patient. If the patient was unable to read, the investigator or a designated trial team member was allowed to read the items/answer options aloud to the patient. The investigator or designated trial team member guided the patient to complete each item in the PROs and explained that there were no right or wrong answers. The investigator or a designated trial team member coaches the patient to give the best answers possible and explains that all individual responses remain confidential.

Upon completion, the PROs were reviewed by the Investigator (or designee) immediately for completeness and potential adverse events (AEs). When reviewing the PROs for AEs, the Investigator was instructed not to influence nor question the patient on the content of his or her responses to PRO questions. Review of the PROs was documented. If an item was not found in the PROs, the patient was asked to answer all questions, taking care not to bias the patient.

Prior to the implementation of the trial, the investigator and/or designated trial team members received training and guidance on completing the PROs.

Patients reported their bowel movements/stoma bag emptying during the 48-hour equilibrium period in an eDiary. Improvement at 4 , 12 , 20 , and 24 weeks

The PGIC scale used in the EASE-SBS trial was a 7-point Likert scale in which patients were asked to check a box in response to the question: “Since the start of the trial, my overall condition has been: (1) Very improved (2) Much improved (3) Somewhat improved (4) No change (5) Somewhat worse (6) Much worse (7) Very worse”.

PGIC improvement was defined as a 7-point Likert scale response of "very improved" or "very improved" at each of Weeks 4, 12, 20, and 24. Improvement between the various jepaglutide treatment regimens compared with placebo was tested using a CMH test with stratification for the randomization stratification factor. Results

106 patients were randomized and 102 completed the trial. Treatment groups were generally balanced with respect to patient demographics and baseline characteristics.

Jepaglutide was assessed to be safe and well tolerated. Adverse events were reported more frequently in the jepaglutide group than in the placebo group, primarily attributable to mild injection site reactions. PS Required

Jepaglutide TW treatment significantly reduced the need for PS relative to placebo (mean change, -5.13 vs. -2.85 L/week; estimated difference, -2.28 L/week [-3.83; -0.73] 95% CI; p = 0.0039). Jepaglutide TW was also superior to placebo in terms of the proportion of patients achieving a clinical response (65.7% vs. 38.9%; estimated difference, 26.6% [4.3; 48.9] 95% CI; p = 0.0243) and the percentage of patients achieving a reduction in the number of days of PS of ≥ 1 day/week (51.4% vs. 19.4%; estimated difference, 31.7% [11.4; 51.9] 95% CI; p = 0.0043).

As shown in the results reported in Table 1, TW treatment showed an earlier onset of effect, as the time to achieve clinical response was significantly shorter than placebo ( p = 0.0043), with a median time to response of 55 days [29; 85] 95% CI. Table 1 Time to achieve a clinical response (PS volume reduction of at least 20% compared with baseline ) Glepa 10 mg TW Glepa 10 mg OW Placebo Statistics (N=35) (N=35) (N=36) Number of respondents (%) 28 (80.0%) 20 (57.1%) 16 (44.4%) Median time to response (days)(1) 55 [ 29 ; 85] 161 [ 30 ; .] Unavailable Sun's test p- value (1) 0.0043 0.2758 Note: (1) The interval limits are taken into account. References for Sun's test: Sun, J. (1996), A Nonparametric Test for Interval-Censored Failure Time Data with Application to AIDS Studies, Statistics in Medicine , 15, 1387-1395.

As shown in the results reported in Table 2 and Figure 2, TW treatment with jepaglutide resulted in a significant and earlier improvement in the reduction of PS volume at 12 weeks. Table 2 Change from baseline in PS volume (L/ week ) by visit - treatment policy estimated - primary statistical analysis ( MI CR) For placebo Treatment group n Time point LS mean [95% CI] Difference [95 CI] p -value Glepa 10 mg TW (n=35) 35 Week 1 -0.09 [-0.34; 0.16] -0.07 [-0.35; 0.21] 0.6174 35 Week 2 -0.80 [-1.37;-0.23] -0.40 [-1.06; 0.27] 0.2438 35 Week 4 -1.81 [-2.76;-0.85] -0.78 [-1.91; 0.35] 0.1773 35 Week 8 -3.20 [-4.29;-2.12] -1.54 [-2.93;-0.14] 0.0312 35 Week 12 -4.32 [-5.48;-3.17] -2.42 [-3.95;-0.90] 0.0019 35 Week 16 -4.53 [-5.63;-3.42] -2.15 [-3.58;-0.73] 0.0030 35 Week 20 -4.87 [-6.00;-3.75] -2.29 [-3.77;-0.80] 0.0026 35 Week 24 -5.13 [-6.24;-4.02] -2.28 [-3.83;-0.73] 0.0039 Glepa 10 mg OW (n=35) 35 Week 1 -0.07 [-0.15; 0.01] -0.05 [-0.21; 0.11] 0.5593 35 Week 2 -0.70 [-1.30;-0.09] -0.30 [-0.99; 0.40] 0.4039 35 Week 4 -1.93 [-2.97;-0.90] -0.90 [-2.10; 0.30] 0.1397 35 Week 8 -2.61 [-3.73;-1.49] -0.95 [-2.37; 0.48] 0.1935 35 Week 12 -2.78 [-3.89;-1.67] -0.88 [-2.37; 0.62] 0.2491 35 Week 16 -2.91 [-4.10;-1.72] -0.54 [-2.03; 0.95] 0.4792 35 Week 20 -2.85 [-4.42;-1.28] -0.26 [-2.11; 1.58] 0.7784 35 Week 24 -3.13 [-4.99;-1.28] -0.28 [-2.43; 1.86] 0.7968 Placebo (n=36) 36 Week 1 -0.02 [-0.16; 0.12] 36 Week 2 -0.40 [-0.74;-0.06] 36 Week 4 -1.03 [-1.63;-0.43] 36 Week 8 -1.67 [-2.55;-0.79] 36 Week 12 -1.90 [-2.90;-0.90] 36 Week 16 -2.37 [-3.27;-1.47] 36 Week 20 -2.59 [-3.56;-1.61] 36 Week 24 -2.85 [-3.93;-1.77] Abbreviations: TW, twice weekly; OW, once weekly; N, number of patients in the full analysis population; CI, confidence interval; CR, replicate-reference; MI, multiple imputation; PS, parenteral support. Note: The MMRM model included treatment group, visit, stratification factor, treatment-visit interaction as factors, and baseline PS volume (L/week) as a covariate. Variance estimates were based on an unstructured covariance matrix within treatment group. Stratification factor: Weekly PS volume requirement, < 12 L/week and >= 12 L/week.

No statistically significant differences were established for jepaglutide OW versus placebo for these endpoints, but a dose-dependent trend was observed. Of particular note, 5 (14%), 4 (12%), and 0 patients receiving jepaglutide TW, OW, and placebo, respectively, achieved bowel independence.

TW was seen to have an earlier onset of action and a significantly shorter time to clinical response compared with placebo ( p = 0.0043), and this finding was further supported by a significant reduction in PS requirements after 12 weeks of TW treatment ( p = 0.0019).

In addition, the EASE SBS 1 trial examined the time to achieve the clinical response as defined by at least a 20% reduction in PS volume compared to baseline (placebo), a further clinical parameter defining the nature of the response in SBS patients to treatment with jepaglutide 10 mg TW or OW. The results of this analysis are presented in Table 1.

This showed that treatment with jepaglutide resulted in an earlier onset of action, with a median time to clinical response (at least a 20% reduction in PS volume) of 55 days or 8 weeks for TW treated with 10 mg jepaglutide and 161 days or 23 weeks for OW treated with 10 mg jepaglutide.

As shown in Tables 3 and 4, the improvements in PROs with PGIC were significantly different for jepaglutide TW ( p = 0.0020) and OW ( p < 0.0001) compared with placebo. Table 3 Overall PGIC status estimated by visit - to-treat policy ( observed data ) For placebo Treatment group n Time point LS mean [95% CI] Difference [95 CI] p -value Glepa 10 mg TW (n=35) 35 Week 4 -0.97 [-1.30;-0.64] -0.74 [-1.15;-0.34] 0.0005 33 Week 12 -1.08 [-1.57;-0.59] -0.66 [-1.25;-0.07] 0.0280 31 Week 20 -1.12 [-1.51;-0.73] -0.42 [-0.94; 0.11] 0.1178 30 Week 24 -1.27 [-1.73;-0.81] -0.84 [-1.35;-0.33] 0.0020 Glepa 10 mg OW (n=35) 29 Week 4 -0.77 [-1.01;-0.54] -0.54 [-0.87;-0.21] 0.0019 30 Week 12 -1.08 [-1.38;-0.78] -0.66 [-1.10;-0.22] 0.0041 28 Week 20 -0.93 [-1.30;-0.57] -0.23 [-0.74; 0.28] 0.3656 32 Week 24 -1.24 [-1.50;-0.98] -0.81 [-1.16;-0.46] <.0001 Placebo (n=36) 35 Week 4 -0.23 [-0.48; 0.02] 34 Week 12 -0.42 [-0.76;-0.08] 32 Week 20 -0.70 [-1.07;-0.33] 32 Week 24 -0.43 [-0.67;-0.19] Abbreviations: TW, twice weekly; OW, once weekly; N, number of patients in the full analysis population; CI, confidence interval; MMRM model included treatment group, visit, stratification factor, treatment-visit interaction as factors, and baseline PS volume (L/week) as a covariate. PGIC: Patient Global Improvement Scale. Note: Variance estimates are based on an unstructured covariance matrix within treatment group. Stratification factor: Weekly PS volume requirement, < 12 L/week and >= 12 L/week. Table 4 Overall PGIC status ( yes / no improved, yes / no much improved / very much improved ) at Week 24 - Treatment Policy Estimated Quantity ( Observed Data ) - Statistical Analysis (NR) For placebo Parameters Treatment group n / N (%) Difference [95 CI] p -value PGIC Improved Glepa 10 mg TW (N=35) 22 / 35 (62.9%) 26.6 [ 4.3; 48.9] 0.0259 Glepa 10 mg OW (N=35) 27 / 35 (77.1%) 40.5 [ 19.6; 61.4] 0.0006 Placebo (N=36) 13 / 36 (36.1%) PGIC Much Improved/Very Improved Glepa 10 mg TW (N=35) 17 / 35 (48.6%) 42.9 [ 24.8; 61.0] <0.0001 Glepa 10 mg OW (N=35) 11 / 35 (31.4%) 25.4 [ 8.3; 42.4] 0.0058 Placebo (N=36) 2 / 36 (5.6%) Abbreviations: TW, twice weekly; OW, once weekly; N, number of patients in the full analysis population; CI, confidence interval; NR: nonresponse interpolation; PGIC: Patient Global Improvement Scale. Note: The difference in the percentage of responders between each jepaglutide treatment group and placebo was tested using the Cochran-Mantel-Haenszel method adjusted for the stratification factor.

Improvements in patient-reported outcomes on PGIC were seen in 62.9% of patients using TW, compared to 36.1% of patients using placebo. Furthermore, 77.1% of patients using OW were seen to improve on PGIC, and the difference compared to placebo was statistically significant (0 < 0.0001). Further analysis

Further analysis of the results of the EASE SBS 1 trial revealed a technical outlier in the OW treatment group, where we suspected that the Week 20 and Week 24 PS volume data were erroneously high at the time of database lock (DBL). This led to a re-evaluation of the trial results, resulting in Table 5 below and a further comparison in Figure 3. Table 5 For placebo Treatment group n Time point LS mean [95% CI] Difference [95 CI] p -value Glepa 10 mg TW (n=35) 35 Week 1 -0.09 [-0.34; 0.16] -0.07 [-0.35; 0.21] 0.6241 35 Week 2 -0.80 [-1.37;-0.22] -0.40 [-1.06; 0.27] 0.2453 35 Week 4 -1.81 [-2.76;-0.85] -0.78 [-1.91; 0.35] 0.1783 35 Week 8 -3.20 [-4.29;-2.12] -1.53 [-2.93;-0.14] 0.0315 35 Week 12 -4.32 [-5.48;-3.17] -2.42 [-3.95;-0.90] 0.0019 35 Week 16 -4.52 [-5.63;-3.42] -2.15 [-3.58;-0.73] 0.0031 35 Week 20 -4.87 [-6.00;-3.75] -2.29 [-3.77;-0.80] 0.0026 35 Week 24 -5.13 [-6.24;-4.02] -2.28 [-3.83;-0.73] 0.0039 Glepa 10 mg OW (n=35) 35 Week 1 -0.07 [-0.15; 0.01] -0.05 [-0.21; 0.11] 0.5552 35 Week 2 -0.70 [-1.30;-0.09] -0.30 [-0.99; 0.40] 0.4030 35 Week 4 -1.94 [-2.97;-0.90] -0.91 [-2.11; 0.30] 0.1393 35 Week 8 -2.52 [-3.73;-1.49] -0.85 [-2.25; 0.55] 0.2354 35 Week 12 -2.77 [-3.89;-1.67] -0.87 [-2.37; 0.63] 0.2547 35 Week 16 -3.06 [-4.10;-1.72] -0.68 [-2.11; 0.75] 0.3500 35 Week 20 -3.33 [-4.42;-1.28] -0.75 [-2.25; 0.75] 0.3301 35 Week 24 -3.76 [-4.99;-1.28] -0.91 [-2.43; 0.71] 0.2700 Placebo (n=36) 36 Week 1 -0.02 [-0.16; 0.12] 36 Week 2 -0.40 [-0.75;-0.06] 36 Week 4 -1.03 [-1.63;-0.43] 36 Week 8 -1.67 [-2.55;-0.79] 36 Week 12 -1.90 [-2.90;-0.90] 36 Week 16 -2.37 [-3.27;-1.47] 36 Week 20 -2.59 [-3.56;-1.61] 36 Week 24 -2.85 [-3.93;-1.77] Abbreviations: TW, twice weekly; OW, once weekly; N, number of patients in the full analysis population; CI, confidence interval; CR, replicate-reference; MI, multiple imputation; PS, non-oral support. Note: The MMRM model included treatment group, visit, stratification factor, treatment-visit interaction as factors, and baseline PS volume (L/week) as a covariate. Variance estimates were based on an unstructured covariance matrix within treatment group. Stratification factor: Weekly PS volume requirement, < 12 L/week and >= 12 L/week.

This reassessment did not result in any changes to the overall trial conclusions, with one small change for the OW arm of the trial: the PS reduction from baseline within that arm changed from 3.13 L/week to 3.76 L/week. Conclusion

Treatment of SBS-CIF patients with jepaglutide was safe, well tolerated, and resulted in improvements in clinically significant patient-centered outcomes (PS requirement, bowel autonomy, and PROs). The onset of action was unexpectedly early for treatment with a GLP-2 analog, with a median time to clinical response of only 8 weeks for TW. There was a significant improvement in the patient-reported outcome measure PGIC for both jepaglutide TW and jepaglutide OW. The population of SBS patients is considered to be very heterogeneous, and this finding with treatment with GLP-2 was surprising.

Although the present invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when the disclosure of this case is given. Therefore, the exemplary embodiments of the present invention described herein are considered to be illustrative rather than restrictive. Various changes to the described embodiments may be made without departing from the spirit and scope of the present invention. All documents cited herein are expressly incorporated herein by reference.

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

Figure 2 shows the change in PS volume (L/week) from baseline using the visit-treatment policy estimand-primary statistical analysis (MI CR) in an LSmeans plot. Abbreviations: TW, twice weekly; OW, once weekly; N, number of patients in full analysis set; CR, replicate-reference; MI, multiple imputation; PS, parenteral support. Note: The MMRM model included treatment group, visit, stratification factor, treatment-by-visit interaction as factors and baseline PS volume (L/week) as a covariate. Variance estimation was based on an unstructured covariance matrix within treatment groups. Stratification factors: weekly PS volume requirement, < 12 L/week and > - 12 L/week.

Figure 3 shows the change in PS volume (L/week) from baseline using the visit-treatment policy estimated-primary statistical analysis (MI CR)-LS mean plot after excluding one technical outlier. Abbreviations: TW, twice weekly; OW, once weekly; N, number of patients in the full analysis population; CR, replicate-reference; MI, multiple imputation; PS, non-oral support. Note: The MMRM model included treatment group, visit, stratification factor, treatment-visit interaction as factors, and baseline PS volume (L/week) as covariates. Variance estimates were based on an unstructured covariance matrix within treatment group. Stratification factors: weekly PS volume requirements, < 12 L/week and > - 12 L/week.

TW202436330A_113103186_SEQL.xml

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Claims (24)

A glucagon-like peptide-2 (GLP-2) analog for use in a method for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analog is represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, the method comprising administering the GLP-2 analog to the patient once or twice a week for a period of time, wherein the treatment results in an improvement in the patient's quality of life (QoL). The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment as claimed in claim 1, wherein the improvement in the patient's quality of life (QoL) is assessed using a Patient Global Impression of Change (PGIC) status. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment as claimed in claim 2, wherein the PGIC status uses a 7-point Likert scale, with responding patients reporting a much improved or very improved status when compared to treatment with a placebo. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment of any one of claims 1 to 3, wherein improved PGIC status of the patient is observable at week 24 of the treatment. The GLP-2 analog for use in the method of treatment as claimed in any of the preceding claims, wherein the treatment further comprises reducing the frequency or volume of parenteral support received by the patient. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment of claim 5, comprising reducing the frequency or volume of parenteral support received by the patient at week 12 from the initiation of treatment with the GLP-2 analog, wherein the method comprises administering 10 mg of the GLP-2 analog to the patient twice weekly by subcutaneous injection. The GLP-2 analog for use in the method of treatment of any of the preceding claims, wherein the treatment results in an earlier onset of action with a median time to clinical response defined by at least a 20% reduction in PS volume of 55 days or 8 weeks for treatment with 10 mg glepaglutide twice weekly and 161 days or 23 weeks for treatment with 10 mg glepaglutide once weekly. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment of claim 6 or claim 7, wherein the patient does not require parenteral support after 24 weeks of the treatment. A glucagon-like peptide-2 (GLP-2) analog for use in a method for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analog is represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, the method comprising administering the GLP-2 analog to the patient once or twice a week over a period of time, wherein the treatment results in a decrease in PS volume at week 12 from the start of treatment with the GLP-2 analog. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment of claim 9, wherein from the initiation of treatment with the GLP-2 analog, the treatment results in a significant and earlier reduction in PS volume of -2.42 placebo at week 12. The glucagon-like peptide-2 (GLP-2) analogue of any of the preceding claims for use in the method of treatment, wherein the method comprises administering 10 mg of the GLP-2 analogue to the patient once a week by subcutaneous injection. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment of any one of claims 1 to 10, wherein the method comprises administering 10 mg of the GLP-2 analog to the patient twice a week by subcutaneous injection. A glucagon-like peptide-2 (GLP-2) analog for use in a method for treating a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analog is represented by the following chemical formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK- _NH2 (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, the method comprising administering the GLP-2 analog to the patient once or twice a week for a period of time, wherein the treatment results in an early onset of action with a median time to clinical response defined by a reduction in PS volume of at least 20% for twice weekly administration of 10 The duration of treatment was 55 days or 8 weeks for treatment with 10 mg jepaglutide once weekly and 161 days or 23 weeks for treatment with 10 mg jepaglutide once weekly. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment of claim 13, wherein the treatment further results in an improvement in the patient's quality of life (QoL). The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment as claimed in claim 14, wherein the improvement in the patient's quality of life (QoL) is assessed using a patient global improvement (PGIC) status. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment as claimed in claim 15, wherein the PGIC status uses a 7-point Likert scale, with responding patients reporting a much improved or very improved status when compared to treatment with a placebo. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment of any one of claims 13 to 16, wherein improved PGIC status in the patient is observable at week 24 of the treatment. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment of any one of claims 13 to 17, wherein the patient does not require parenteral support after 24 weeks of the treatment. The glucagon-like peptide-2 (GLP-2) analog for use in a method of treatment as claimed in any one of claims 13 to 18, wherein the method comprises administering 10 mg of the GLP-2 analog to the patient twice a week by subcutaneous injection. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment of any one of claims 13 to 18, wherein the method comprises administering 10 mg of the GLP-2 analog to the patient once a week by subcutaneous injection. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment as claimed in any of the preceding claims, wherein the patient has short bowel syndrome with intestinal failure (SBS-IF) or SBS-chronic IF (SBS-CIF). The GLP-2 analog for use in the method of treatment as claimed in any preceding claim, wherein the patient has undergone a terminal jejunostomy or ileostomy, a jejunocolectomy or a jejunoileocolectomy. The glucagon-like peptide-2 (GLP-2) analogue for use in a method of treatment as claimed in any of the preceding claims, wherein the method comprises administering the GLP-2 analogue using an injection pen. The glucagon-like peptide-2 (GLP-2) analog for use in the method of treatment as claimed in any of the preceding claims, wherein the patient receives parenteral support 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.