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

Abstract

Glucagon-like peptide-2 (GLP-2) analogues and their medical uses for the treatment of short bowel syndrome (SBS) are disclosed, in particular the medical use of grepaglutide identified in the EASE SBS 1 trial, which demonstrated an improvement in patient quality of life (QoL) and / or an early reduction in patient parenteral support (PS) requirements as treatment with grepaglutide progresses.

Description

[Technical Field]

[0001] The present invention relates to glucagon-like peptide-2 (GLP-2) analogues and their medical use for the treatment of short bowel syndrome (SBS), in particular treatment with grepaglutide resulting in an improvement in patient quality of life (QoL) and / or an early or significant reduction in the parenteral support (PS) required by patients receiving GLP-2 therapy. [Background technology]

[0002] Human GLP-2 is a 33-amino acid peptide with the following sequence: Hy-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-OH. It is derived from specific post-translational processing of proglucagon in enteroendocrine L-cells of the intestine and in specific regions of the brainstem. GLP-2 binds to a single G protein-coupled receptor belonging to the class II glucagon secretin family.

[0003] GLP-2 has been reported to induce significant proliferation of the small intestinal mucosal epithelium by stimulating stem cell proliferation in the crypts and inhibiting apoptosis in the villi (Drucker et al., 1996, Proc. Natl. Acad. Sci. USA 93:7911-7916).GLP-2 also has a growth-promoting effect on the colon. Furthermore, GLP-2 inhibits gastric emptying and gastric acid secretion (Wojdemann et al., 1999, J. Clin. Endocrinol. Metab. 84:2513-2517), enhances intestinal barrier function (Benjamin et al., 2000, Gut 47:112-119), stimulates intestinal hexose transport by upregulating glucose transporters (Cheeseman, 1997, Am. J. Physiol. R1965-71), and increases intestinal blood flow (Guan et al., 2003, Gastroenterology, 125:136-147).

[0004] Glucagon-like peptide-2 receptor analogs have been recognized in the art as having therapeutic potential for the treatment of intestinal disorders. However, native hGLP-2 (a 33-amino acid gastrointestinal peptide) is not useful in clinical settings due to its extremely short half-life in humans: approximately 7 minutes for full-length GLP-2[1-33] and 27 minutes for truncated GLP-2[3-33]. The short half-life is primarily due to degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). Therefore, efforts have been made in the art to develop GLP-2 receptor agonists with better pharmacokinetic characteristics, specifically to improve the half-life of the GLP-2 molecule. For example, GLP-2 analogs with substitutions have been proposed, such as a Gly substitution at position 2 ([hGly2]GLP-2, teduglutide), which increases the half-life from 7 minutes (native GLP-2) to approximately 2 hours. Teduglutide has been approved for the treatment of short bowel syndrome under the names Gattex (USA) and Revestive (Europe).

[0005] WO2006 / 117565 (Zealand Pharma A / S) describes GLP-2 analogs containing one or more substitutions compared to [hGly2]GLP-2, resulting in improved in vivo biological activity and / or improved chemical stability, e.g., as assessed in in vitro stability assays. The molecule disclosed in WO2006 / 117565 is ZP1848 (glepaglutide), which is designed to be stable in liquid formulations. Dosage regimens for GLP-2 analogs, including ZP1848, and its metabolites are described in WO2018 / 229252, which also demonstrate that these compounds are effective in increasing longitudinal intestinal growth. Ready-to-use formulations of ZP1848 are described in WO2020 / 065064. Summary of the Invention

[0006] Broadly, the present invention is based on surprising findings arising from the EASE SBS1 study, a multicenter, placebo-controlled, randomized, parallel-group, double-blind Phase 3 clinical trial (NCT:03690206) investigating the safety and efficacy of treating short bowel syndrome (SBS) with grepaglutide, specifically in relation to study endpoints related to patient quality of life (QoL) and / or parenteral support (PS) required by patients who have progressed on treatment with grepaglutide. Parameters related to change in patient PS required include (a) early onset of significant improvement in PS reduction compared to baseline and (b) time to clinical response defined by time to at least a 20% reduction in PS compared to baseline.

[0007] Results from the EASE SBS1 trial include the surprising finding that both twice-weekly (TW) and once-weekly (OW) doses of glepaglutide resulted in improvement and significant differences compared to placebo when the PGIC, a secondary endpoint of the trial using a patient-reported outcome (PRO) tool in which patients rate the change in their overall condition 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), was assessed at 24 weeks.

[0008] Furthermore, the EASE SBS1 trial specifically found that patients treated twice weekly (TW) experienced a significant reduction in PS volume, a secondary endpoint of the trial, after 12 weeks. This early effect was faster than the effects of alternative treatments using GLP-2 analogs, such as teduglutide, and earlier than previously reported patient responses to glepaglutide treatment, which demonstrated a reduction in PS volume after 20–24 weeks. The early effect is further supported by the significantly faster time to clinical response with glepaglutide TW compared to placebo.

[0009] Without wishing to be bound by any particular theory, the inventors believe that the rapid reduction in the amount of PS required by the patient may be related to the response felt by the patient, e.g., represented by an improvement in PGIC, due to the time lag between the reduction in PS amount and the benefit experienced by the patient.

[0010] In the trial, patients will receive 10 mg of grepaglutide 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) analogue for use in a method for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), the analogue having the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the GLP-2 analog to a patient once a week or twice a week for a period of time, wherein the treatment results in an improvement in the patient's quality of life (QoL).

[0011] In a further aspect, the present invention provides the use of a glucagon-like peptide 2 (GLP-2) analogue for use in the preparation of a medicament for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analogue has the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the use comprises administering the GLP-2 analog to a patient once a week or twice a week for a period of time, and the treatment results in an improvement in the patient's quality of life (QoL).

[0012] 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), comprising administering to a subject a compound of the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein administering the GLP-2 analog to the patient once a week or twice a week for a period of time results in an improvement in the patient's quality of life (QoL).

[0013] In these aspects of the invention, improvement in patient quality of life (QoL) is assessed using Patient Global Change in Condition (PGIC) status, e.g., using a 7-point Likert scale, with responding patients reporting a much improved or much improved condition compared to placebo treatment. In some cases, improvement in a patient's PGIC status is observed at 24 weeks of treatment.

[0014] In a further aspect, the present invention provides a glucagon-like peptide 2 (GLP-2) analogue for use in a method for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), the analogue having the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the GLP-2 analog to a patient once a week or twice a week for a period of time, and wherein the treatment results in a decrease in PS levels 12 weeks after initiation of treatment with the GLP-2 analog.

[0015] In a further aspect, the present invention relates to the use of a glucagon-like peptide 2 (GLP-2) analogue for use in the preparation of a medicament for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), the method comprising: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof to a patient, wherein the method comprises administering the GLP-2 analog to the patient once a week or twice a week for a period of time, and the treatment results in a reduction in PS levels 12 weeks after initiation of treatment with the GLP-2 analog.

[0016] 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), comprising administering to a subject a compound of the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein administering the GLP-2 analog to the patient once a week or twice a week for a period of time results in a reduction in PS levels 12 weeks after initiation of treatment with the GLP-2 analog.

[0017] By way of example, in the present invention, treatment can result in a significant and early reduction in PS levels of -2.42 placebo at 12 weeks from the start of treatment with a GLP-2 analogue. In a further aspect, the present invention provides a glucagon-like peptide 2 (GLP-2) analogue for use in a method for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), the analogue having the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the GLP-2 analog to a patient once a week or twice a week for a period of time, and wherein the treatment results in a rapid onset of effect, with a median time to clinical response defined by at least a 20% reduction in PS levels at day 55 or week 8 for twice-weekly treatment with 10 mg grepaglutide and at day 161 or week 23 for once-weekly treatment with 10 mg grepaglutide.

[0018] In a further aspect, the present invention relates to the use of a glucagon-like peptide 2 (GLP-2) analogue in the preparation of a medicament for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), wherein the GLP-2 analogue has the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the method comprises administering a GLP-2 analog to a patient once a week or twice a week for a period of time, and the treatment results in a rapid onset of efficacy, with a median time to clinical response defined by at least a 20% reduction in PS levels at day 55 or week 8 for twice-weekly treatment with 10 mg grepaglutide and at day 161 or week 23 for once-weekly treatment with 10 mg grepaglutide.

[0019] In a further aspect, the present invention provides a method for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), comprising administering to a subject a compound of the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein administering the GLP-2 analog to the patient once a week or twice a week for a period of time results in an early onset of efficacy, with a median time to clinical response defined by at least a 20% reduction in PS levels at day 55 or week 8 for twice-weekly treatment with 10 mg grepaglutide and at day 161 or week 23 for once-weekly treatment with 10 mg grepaglutide.

[0020] In these aspects of the invention, improvement in patient quality of life (QoL) is assessed using Patient Global Change in Condition (PGIC) status, e.g., using a 7-point Likert scale, with responding patients reporting a much improved or much improved condition compared to placebo treatment. In some cases, improvement in a patient's PGIC status is observed at 24 weeks of treatment.

[0021] The results disclosed herein also show that in some patients, treatment with a GLP-2 analog can completely wean off parenteral support, e.g., the patient no longer requires parenteral support after 24 weeks of treatment, which also refers to patients who achieve oral or enteral autonomy.

[0022] In the present context, the term "parental support" or "PS" includes the provision of nutrients and / or fluids to a subject receiving GLP-2 therapy as a means of providing the subject with nutrients and / or fluids that the subject needs but cannot fully absorb due to the subject's condition.

[0023] In this context, the term achieving "oral or gut autonomy" refers to a patient receiving PS and GLP-2 therapy who improves gastrointestinal function to the point where all PS can be removed (i.e., PS ceases to be part of the treatment regimen).

[0024] The terms "subject" and "patient" are used interchangeably herein. A subject (or patient) will be understood to be a mammal, typically a human. ZP1848 is also effective in increasing intestinal mass and longitudinal growth of the intestine, particularly in the small intestine.

[0025] ZP1848 or a pharmaceutically acceptable salt is typically provided as a pharmaceutical composition comprising ZP1848 or said salt in combination with a pharmaceutically acceptable carrier or excipient. The individual doses may be for administration according to the dosing regimens described elsewhere herein.

[0026] WO 2018 / 229252 describes ZP1848 as having an unexpectedly long half-life, particularly when delivered by subcutaneous injection, which may allow for alternative regimens, such as once or twice weekly administration. These results stem from a Phase 2 human clinical trial using ZP1848, which found that the molecule's peripheral plasma half-life was actually between 5 and 17 days. The peripheral plasma half-life is the time required for the plasma concentration to halve after reaching pseudo-equilibrium. Without wishing to be bound by theory, it is believed that the half-life of ZP1848 may be due to a combination of the formation of subcutaneous deposits and the formation of metabolites that are slowly released from the subcutaneous deposits and are also agonists of the GLP-2 receptor. The subcutaneous deposits may form upon administration due to a reaction between the lysine tail of ZP1848 and hyaluronic acid in the subcutaneous area.

[0027] Thus, a once-weekly or twice-weekly administration regimen may include multiple or sequential administrations spaced 2, 2.5, 3, 3.5, 4, 5, 6, or 7 days apart. As will be appreciated in the art, the time between administrations may vary to some extent, so that each and every administration is not exactly the same time apart. The time intervals within a clinically acceptable range are often guided by the physician's decision.

[0028] In some cases, it may be desirable to divide the total dose into multiple (e.g., 2 or 3) separate doses or administrations, e.g., for administration at spaced injection sites, e.g., at least 5 cm apart. Such spaced administrations are typically provided at substantially the same time, e.g., on the same day, within one hour of each other, or closer in time.

[0029] In this context, the term "parenteral support" or "PS" includes the provision of nutrients and / or fluids to a subject receiving GLP-2 therapy as a means of providing the subject with nutrients and / or fluids that the subject needs but cannot fully absorb due to the subject's condition. Determining the exact amount or amounts of PS to provide to a GLP-2-treated subject with SBS is difficult because if the amount of PS is not adjusted in a timely and appropriate manner, the patient will experience fluid overload, be at risk of dehydration, and not achieve an optimal clinical response to treatment. This is further complicated because the amount of PS a subject needs will typically change over the course of GLP-2 treatment, depending on the subject's response to treatment. Typically, assessment of the amount of PS a subject needs as GLP-2 treatment progresses depends on how long the treatment has been continued and the individual patient's responsiveness to it. To account for this variation, initial assessments of PS amounts were made within the first few days of GLP-2 treatment, then typically assessed weekly for the first month, monthly for the next 1-3 months, and then every 3-6 months until treatment was completed. This is important because, as shown in the following examples, a subject may experience a rapid initial response to GLP-2 treatment that improves small intestinal function, even before an increase in intestinal length is observed. This then allows for a reduction in PS volume, thereby avoiding the risk of side effects such as fluid overload.

[0030] Thus, in the medical uses disclosed herein, if a subject's need for PS is reduced, the method or use may include the steps of (a) determining the amount of PS required by the subject at the time of treatment, (b) comparing it with the baseline amount of PS determined at the start of treatment with the GLP-2 analog, and (c) reducing the frequency or amount of PS such that the subject exhibits improved intestinal, e.g., small intestinal, function. Optionally, reducing the frequency or amount of parenteral support (PS) may be performed using the algorithm described in the Examples.

[0031] By way of illustration 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 can result in at least an additional 10% improvement in small intestinal function or absorptive capacity. Generally, GLP-2 therapy according to the present invention results in an improvement in 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 alternatively, the amount of reduction in parenteral support over the course of GLP-2 therapy is 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 parenteral support is at least 20%.

[0032] In a further related aspect, the present invention addresses one of the challenges faced by patients and physicians when initiating GLP-2 therapy: the appropriate and individualized adjustment of the amount of parenteral support (PS) provided to the patient. This is important because if the amount of PS is not adjusted in a timely and appropriate manner, the patient may experience fluid overload, be at risk of dehydration, and not achieve an optimal clinical response to the treatment.

[0033] For example, in a previous 24-week treatment trial with the GLP-2 analogue, teduglutide (see Center for Drug and Evaluation and Research, application number 203441 Orig1s000, page 16), attempts to reduce parenteral nutrient absorption by 10% were made as early as 4, 8, 12, 16, and 20 weeks after the start of treatment, provided that urine output increased by at least 10% from baseline. Many patients in this trial developed fluid overload and stopped drinking (Jeppesen et al. 2011, Gut 2011;60:902-914). In a follow-up study, a 24-week trial of patients with SBS-IF given subcutaneous teduglutide (Jeppesen et al. 2012, Gastroenterology 2012;143:1473-1481) recommended a reduction in parenteral nutritional intake of at least 10%, but not more than 30%, weekly if urinary output increased by at least 10% from baseline. However, in this study, patients also suffered from fluid overload, especially at the start of treatment.

[0034] As a result, as implemented in the EASE SBS1 clinical trial described in the Examples, the present invention provides an algorithm for adjusting PS dosage during a course of GLP-2 treatment in a clinical trial that allows for early assessment of altered PS fluid needs (e.g., within days of initiating GLP-2 treatment) and achieves early onset of clinical response (i.e., a >20% reduction in PS levels) and a significant reduction in PS levels after 12 weeks. By way of example, early onset of effect is achieved with a median time to clinical response (at least a 20% reduction in PS levels) of 55 days or 8 weeks for twice-weekly treatment with 10 mg grepaglutide and 161 days or 23 weeks for once-weekly treatment with 10 mg grepaglutide. It will be appreciated by those skilled in the art that this approach of using an algorithm to adjust PS dosage provides for individualized adjustment of PS levels for each patient. This aspect of the present invention is applicable to GLP-2 treatment using GLP-2 analogs disclosed herein or using GLP-2 analogs known in the art, such as teduglutide or apraglutide. Therefore, the algorithm for adjusting the amount of PS disclosed in the Examples can be used in any aspect of the present invention.

[0035] In all aspects of the invention, the methods of administering a glucagon-like peptide 2 (GLP-2) analogue optionally include administering multiple doses of a GLP-2 analogue to a patient, the doses being spaced weekly or semi-weekly. In some cases, it may be desirable to divide the total dose into multiple (e.g., 2 or 3) separate doses, for example, for administration at spaced injection sites, e.g., at least 5 cm apart.

[0036] Preferably, the dose of GLP-2 analogues used in accordance with the present invention ranges between 0.5 mg and 25 mg, inclusive, per patient, once or twice weekly; between 1 mg and 20 mg, inclusive, per patient, once or twice weekly; between 1 mg and 10 mg, inclusive, per patient, once or twice weekly; between 2 mg and 7 mg, inclusive, per patient, once or twice weekly; between 5 mg and 7 mg, inclusive, per patient, once or twice weekly; or between 2 mg and 5 mg, inclusive, per patient, once or twice weekly. In one embodiment, the dose of GLP-2 analogues used in accordance with the present invention is 10 mg inclusive, once or twice weekly. Over the course of treatment, the doses taken by a patient may be the same or different, depending on instructions from a physician.

[0037] Preferably, the glucagon-like peptide 2 (GLP-2) analog is administered to the patient by injection, most typically by subcutaneous or intramuscular injection. In some preferred embodiments, the GLP-2 analog may be administered using an injection pen, allowing the patient to self-administer the analog. In some aspects, administration of the GLP-2 analog causes the formation of a subcutaneous deposit from which the GLP-2 analog or its metabolites are released. Without wishing to be bound by a particular explanation, the subcutaneous deposit may be formed by interaction of the GLP-2 analog administered in accordance with the present invention; specifically, the analog may contain a lysine tail and may be formed by reaction between the analog and hyaluronic acid in the subcutaneous region.

[0038] Embodiments of the present invention will now be described by way of example and not limitation with reference to the accompanying drawings, in which: Various further aspects and embodiments of the invention will however be apparent to those skilled in the art in light of the present disclosure.

[0039] As used herein, "and / or" is used as a specific disclosure of two specified features or components, each with or without the other. For example, "A and / or B" is used as a specific disclosure of (i) A, (ii) B, and (iii) A and B, each as if each were individually set forth herein.

[0040] Unless the context indicates otherwise, the above feature descriptions and definitions are not limited to any particular aspect or embodiment of the present invention, but apply equally to all aspects and embodiments described. [Brief explanation of the drawings]

[0041] [Figure 1] Figure 1 shows the clinical trial design described in the Examples. This phase 3 trial was a pivotal, multicenter, placebo-controlled, randomized, parallel-group, double-blind, fixed-dose study designed to confirm the efficacy of grepaglutide in reducing parenteral support (PS) volume in patients with SBS and to evaluate other efficacy endpoints, as well as the safety and tolerability of grepaglutide in patients with SBS. Three treatment groups were randomized in a 1:1:1 parallel-group design (two active treatment groups [once and twice weekly] and placebo) to compare dosing regimens. The clinical trial was registered at clinicaltrials.gov: NCT033690206. [Figure 2] Figure 2 shows the change in PS volume (L / week) from baseline by visit-treatment strategy estimate (estimand)-primary statistical analysis (MI CR)-LSmeans plot. Abbreviations: TW: twice weekly; OW: once weekly; N: number of patients in the Full Analysis Set; CR: copy reference; MI: multiple imputation; PS: parenteral support. Note: The MMRM model includes treatment group, visit, stratification factors, treatment-visit interaction, and baseline PS volume (L / week) as a covariate. Variance estimation is based on an unstructured covariance matrix within treatment group. Stratification factors: weekly PS volume requirement <12 L / week and >-12 L / week. [Figure 3]Figure 3 shows the visit-treatment strategy estimate (estimand)-primary statistical analysis (MI CR)-LSmeans plot, PS volume (L / week) change from baseline after removal of one technical outlier. Abbreviations: TW: twice weekly; OW: once weekly; N: number of patients in the Full Analysis Set; CR: copy reference; MI: multiple imputation; PS: parenteral support. Note: The MMRM model includes treatment group, visit, stratification factors, treatment-visit interaction, and baseline PS volume (L / week) as a covariate. Variance estimates are based on an unstructured covariance matrix within treatment groups. Stratification factors: weekly PS volume requirement <12 L / week and >-12 L / week. DETAILED DESCRIPTION OF THE INVENTION

[0042] definition Throughout the specification and claims, the conventional single-letter designations for natural amino acids are used. All amino acid residues in the compounds described are typically in the L-configuration.

[0043] compound ZP1848 is, for example, a compound of the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 The N-terminal "H-" is understood to represent the hydrogen of the free N-terminal amine (NH group). The C-terminal "NH-" represents the C-terminal amide group. The terms "ZP1848" and "glepaglutide" may be used interchangeably.

[0044] The present invention relates to the use of pharmaceutically acceptable salts of ZP1848, as described in more detail below. Any suitable salt may be used, although the acetate salt may be preferred. When ZP1848 is injected subcutaneously (SC), two functionally active metabolites, ZP2469 and ZP2711, are formed, both of which are C-terminal truncated analogs of ZP1848. Thus, the full PK profile of ZP1848 includes the effects of ZP1848 and its two major metabolites.

[0045] ZP2469 has the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDK-OH is a peptide having the formula: ZP2711 has the formula: H-HGEGTFSSELATILDALAARDFIAWLIATKITDKK-OH is a peptide having the formula: The "H-" at the N-terminus is as above, and the "-OH" at the C-terminus indicates a free C-terminal carboxylic acid group.

[0046] Teduglutide has the formula: H-HGDGSFSDEMNTILDNLAARDFINWLIQTKITD-OH is a peptide having the formula: The N-terminal "H-" and the C-terminal "-OH" are as described above.

[0047] Pharmaceutical Compositions and Administration As used herein, the GLP-2 analogues are formulated as pharmaceutical compositions prepared for storage or administration and include a therapeutically effective amount of the GLP-2 analogue in a pharmaceutically acceptable carrier.

[0048] Suitable salts include acid addition salts and basic salts. Examples of acid addition salts include hydrochloride, citrate, chloride, and acetate salts. Preferably, the salt is an acetate salt. Generally, it is preferred that the salt is not a chloride salt. Examples of basic salts include those in which the cation is selected from alkali metals such as sodium and potassium, alkaline earth metals such as calcium, and ammonium ions +N(R3)3(R4), where R3 and R4 independently represent optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0049] Acetate salts may be particularly preferred. In this context, the term "ZP1848-acetic acid" refers to a ZP1848 molecule in the acetate form. The acetate salt of ZP1848 30 is represented by the formula (ZP1848), x(CHCOOH), 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, there may be molecules with different numbers of acetate molecules, and x is not necessarily a whole integer. In some cases, x is 4.0 to 8.0, x is 6.0 to 8.0, or x is 4.0 to 6.5. In some cases, x is 4.0 to 6.0, x is 2.0 to 7.0, x is 3.0 to 6.0, x is 4.0 to 6.0, or x is 4.0 to 8.0.

[0050] When administration is parenteral, such as subcutaneously or intramuscularly, injectable pharmaceutical compositions can be prepared in conventional forms. Grepaglutide is typically provided as an aqueous solution formulation, for example, as described in WO2020 / 065064 and WO2020 / 065063, the contents of which are incorporated by reference in their entirety. Subcutaneous administration is particularly preferred, for example, by injection.

[0051] The most appropriate therapeutic dose and regimen for treating a patient will, of course, vary depending on the disease or condition being treated and on the patient's parameters. Without wishing to be bound by any particular theory, it is believed that doses between 0.1 mg and 25 mg per patient and short or long durations or frequencies of treatment can produce therapeutically beneficial results, such as statistically significant increases in small intestinal mass in particular. In some cases, the therapeutic regimen may include the administration of an appropriate maintenance dose to prevent tissue regression after discontinuation of initial treatment. The most appropriate dose size and administration regimen for human use can be guided by the results obtained by the present invention and confirmed in further clinical trials.

[0052] A human dose (total dose) of ZP1848 may be between, inclusive, 0.1 mg and 25 mg per patient, between, inclusive, 0.5 mg and 20 mg per patient, for example, between, inclusive, 1 mg and 15 mg per patient, for example, between, inclusive, 1 mg and 10 mg per patient, once or twice weekly or as multiple doses as defined herein separated by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some instances, a fixed dose of ZP1848 may be used according to the dosing pattern disclosed herein, i.e., the dose is the same regardless of patient weight and is given once or twice weekly. By way of example, the fixed dose may be a dose of 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. Advantageously, a fixed dose of 10 mg may be used, as was done in the EASE SBS1 trial reported in the Examples. The use of a fixed dose has the advantage of increasing compliance and reducing the risk of patient dosing errors, including the risk of miscalculating the weight-based dose administered.

[0053] In a preferred embodiment, the formulation is a ready-to-use formulation, as described in WO2020 / 065064. As used herein, the term "ready-to-use" refers to a formulation that does not require constitution or dilution with a specified amount of diluent, such as water for injection or other suitable diluent, prior to use by a designated route of administration.

[0054] As described herein, the GLP-2 analog solution of the present invention contains a buffer, a non-ionic tonicity adjusting agent, and sufficient arginine to provide the pH of the final formulation. In accordance with standard pharmaceutical practice, the formulation of the present invention is sterile and / or does not contain a reducing agent. In preferred cases, the solution of the present invention is an aqueous solution. In some cases, the solution of the present invention is a non-aqueous solution.

[0055] 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. Screening experiments in the Examples demonstrate that the formulations of the present invention preferably contain a buffer selected from histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer, and MOPS buffer, which provide a stable formulation in which the GLP-2 analog dissolves and the peptide drug does not become viscous, turbid, or precipitate. In a preferred embodiment, the buffer is a histidine buffer, e.g., L-histidine. Generally, the buffer is present at a concentration of about 5 mM to about 50 mM, more preferably about 5 mM to about 25 mM, and most preferably about 15 mM. Preferably, the buffer is not a phosphate buffer, a citrate buffer, a citrate / Tris buffer, or a succinate buffer.

[0056] As used herein, the term "osmolality modifier" refers to a pharmaceutically acceptable tonicity modifier used to adjust the osmotic pressure of a formulation. The formulations of the present invention are preferably isotonic, having an osmolality substantially the same as that of human serum. The osmolality modifier used in the formulation is preferably a non-ionic osmolality modifier, preferably selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose. A preferred non-ionic osmolality modifier is mannitol, e.g., D-mannitol. The concentration of the osmolality modifier will depend on the concentrations of the other components of the formulation, particularly if the formulation is intended to be isotonic. Typically, the non-ionic osmolality modifier is used at a concentration of about 90 mM to about 360 mM, more preferably about 150 mM to about 250 mM, and most preferably about 230 mM.

[0057] Typically, the components and amounts of the solution are selected to provide a formulation having a pH of about 6.6 to about 7.4, more preferably about 6.8 to about 7.2, and most preferably about 7.0. Arginine may be added in sufficient quantity to adjust the pH so that it is within the desired pH range. pH adjustment is preferably not performed using hydrochloric acid or sodium hydroxide.

[0058] In one embodiment, the solution comprises ZP1848 at a concentration of about 2 mg / ml to about 30 mg / ml, e.g., its acetate salt, a buffer selected from the group consisting of histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer, and MOPS buffer, present at a concentration of about 5 mM to about 50 mM, a non-ionic osmolality adjuster selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose at a concentration of about 90 mM to about 360 mM, and sufficient arginine to provide a pH of about 6.6 to about 7.4.

[0059] In one embodiment, the solution comprises ZP1848 at a concentration of about 2 mg / ml to about 30 mg / ml, e.g., its acetate salt, a buffer selected from the group consisting of histidine buffer, mesylate buffer, and acetate buffer, present at a concentration of about 5 mM to about 50 mM, a non-ionic osmolality adjuster selected from the group consisting of mannitol, sucrose, glycerol, and sorbitol at a concentration of about 90 mM to about 360 mM, and sufficient arginine to provide a pH of about 6.6 to about 7.4.

[0060] In a more preferred embodiment, the solution comprises ZP1848, e.g., its acetate salt, at a concentration of about 20 mg / ml, a histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and sufficient arginine to provide a pH of about 7.0.

[0061] In a further embodiment, the solution comprises ZP1848, eg, an acetate salt thereof, 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.

[0062] In a further embodiment, the solution comprises ZP1848-acetate or H-HGEGTFSSElATllDAlAARDFIAWLIATKITDKKKKKK-NH2 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 sufficient arginine to provide a pH of about 7.0.

[0063] In a further embodiment, the solution comprises ZP1848-acetate or H-HGEGTFSSElATllDAlAARDFIAWLIATKITDKKKKKK-NH2acetate (SEQ ID NO: 1) at a concentration of about 20 mg / ml, histidine buffer at a concentration of about 15 mM, mannitol at a concentration of about 230 mM, and has a pH of about 7.0.

[0064] One skilled in the art will understand that if the formulation contains a GLP-2 analogue at a concentration of 20 mg / mL, to treat a patient with 10 mg of GLP-2 analogue, the patient can be administered a 0.5 ml dose.

[0065] In a further embodiment, the solution contains a compound of the formula: (H-HGEGTFSSElATllDAlAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) [wherein x is 1.0 to 8.0] the acetate salt of a glucagon-like peptide 2 (GlP-2) analog having the formula:

[0066] In a further embodiment, in a once or twice daily dosing regimen, the solution contains a compound of the formula: (H-HGEGTFSSElATllDAlAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) [wherein x is 1.0 to 8.0] the acetate salt of a glucagon-like peptide 2 (GlP-2) analog having the formula:

[0067] In a further embodiment, in a once or twice weekly dosing regimen, the solution contains a compound of the formula: (H-HGEGTFSSElATllDAlAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) [wherein x is 1.0 to 8.0] the acetate salt of a glucagon-like peptide 2 (GlP-2) analog having the formula:

[0068] In some cases, the liquid formulation of the present invention further comprises a preservative. In some cases, the preservative is selected from the group consisting of benzalkonium chloride, chlorobutanol, methylparaben, and potassium sorbate. Typically, the preservative is present at a concentration of about 0.1% to about 1% of the final formulation volume.

[0069] medical conditions The peptides of the present invention are useful as pharmaceuticals for treating individuals suffering from short bowel syndrome. Thus, ZP1848 or a salt thereof may be useful therapeutically and / or prophylactically for the treatment of short bowel syndrome (SBS), also known as short gut syndrome or simply short gut, which results from surgical resection, congenital defects in intestinal absorption, or disease-related defects, and patients are then unable to maintain fluid, electrolyte, and nutritional balance with a conventional diet. Despite adaptation, which usually occurs two years after resection, SBS patients exhibit reduced food intake and fluid deficits.

[0070] Classes of human patients with SBS include those with SBS-intestinal failure (SBS-IF) and those on the border 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 if they are dependent on parenteral support, and patients with SBS-intestinal failure (SBS-II) are also referred to as SBS-non-PS if they are not dependent on parenteral support. In the EASE SBS 1 Phase 3 clinical trial reported herein, patients enrolled in a trial evaluating the efficacy and safety of grepaglutide (EASE) had SBS-chronic intestinal failure (SBS-CIF). The objective of the trial was to reduce the need for PS and improve quality of life (QoL).

[0071] Patients with SBS may be further categorized into different SBS classes based on the portion of bowel remaining, and the present invention may be used to treat each of these patient groups, for example, where the patient has undergone endoscopic jejunostomy or ileostomy, jejuno-colonic anastomosis, or jejuno-ileo-colonic anastomosis.

[0072] In the medical use of the present invention, patients receiving PS can be categorized using any one of the ESPEN guideline levels: A1, B1, C1, D1, A2, B2, C2, D2, A3, B3, C3, D3, A4, B4, C4, or D4, which categorize patients based on the energy and amount of PS they require, and patients can be categorized into combinations (Source: 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).

[0073] Clinical classification of chronic intestinal failure (CIF) and the amount of intravenous support required. CIF is categorized into 16 combinations:

[0074] [Table 1]

[0075] An assessment of the amount of PS required by a patient can be determined as described in the Examples sections entitled "Procedure" and "Treatment Phases." This approach can be used to calculate clinical parameters used herein to define the physiological and pathological response of a class of patients treated for SBS with grepaglutide. These parameters include (a) the early observation of a statistically significant improvement in reduction of PS volume compared to baseline. In this study, we reported a median time to clinical response, defined as at least a 20% reduction in PS volume, at week 12 of treatment with 10 mg grepaglutide, which was faster than observed in a previous 20-24 week study, and (b) at day 55 or week 8 of twice-weekly treatment with 10 mg grepaglutide and day 161 or week 23 of once-weekly treatment with 10 mg grepaglutide.

[0076] As described in the Examples, QoL can be assessed using the Patient Global Change in Condition (PGIC) scale (see https: / / www.fda.gov / media / 116277 / download and https: / / www.fda.gov / media / 116281 / download). The PGIC assesses the patient's perceived overall health on a 7-point single-item scale ranging from "much worse" to "much improved," i.e., yes / no means a patient is a responder if they mark either "much improved" or "improved" on their PGIC questionnaire.

[0077] Since starting the trial, my overall condition has been: (1) Much improved (2) Significant improvement (3) Slight improvement (4) No change (5) It got a little worse (6) It has gotten significantly worse (7) It has gotten much worse PGIC improvement was defined as patients reporting "improved" or "very improved" on a 7-point Likert scale at each of weeks 4, 12, 20, and 24. Differences between each grepaglutide treatment regimen compared with placebo were tested using the CMH test, adjusting for stratification factors.

[0078] Results from the EASE SBS 1 clinical trial, reported in the Examples, found that treatment of patients with SBS-CIF with glepaglutide was safe, tolerable, and resulted in clinical improvement and meaningful patient-centered outcomes (PS needs, enteral autonomy, and PROs). The onset of effect was surprisingly rapid with GLP-2 treatment, with a median time to clinical response of just 8 weeks with TW. Treatment with glepaglutide with both TW and OW resulted in significant improvements in the patient-reported outcome measure, PGIC. The SBS patient population is considered highly heterogeneous, and this finding is surprising with GLP-2 treatment.

[0079] The spectrum of patient types with SBS is outlined in Jeppensen, Journal of Parenteral and Enteral Nutrition, 38(1), 8S-13S, May 2014, doi:10.1177 / 0148607114520994. Further division of SBS patient types can be made along the lines described in Schwartz et al., Clinical and Translational Gastroenterology (2016) 7, e142; doi:10.1038 / ctg.2015.69. This divides SBS patients into fast responders and late / slow responders. Currently, fast responders are individuals who show a rapid response to treatment with GLP-2 analogs, such as ZP1848, due to, among other effects, an increase in small intestinal width / diameter, while late or slow responders are considered to be patients who derive most or initial benefit from treatment with GLP-2 analogs due to an increase in small intestinal length. The determination of whether a subject is a fast or slow responder can be used to determine the duration of the treatment regimen with the GLP-2 analog, the timing of any clinical decisions to reduce parenteral support, and the interval between tests to determine whether parenteral support can be reduced. Thus, in one embodiment, the patient is a slow or slow responder. Small intestine length can be measured, for example, by CT scan (computed tomography), MRI (magnetic resonance imaging), histology, laparoscopy, or other measurements or techniques known in the art.

[0080] A further aspect of the present invention relates to increasing intestinal mass or longitudinal growth of the intestine, particularly of the small intestine, in a patient, e.g., a human patient. ZP1848 or a salt thereof can increase longitudinal growth of the intestine compared to a control treatment, as shown in WO2018 / 229252.

[0081] This ability is particularly useful in patients with SBS, as it results in increased absorptive capacity even after treatment has stopped. Such patients are treated for at least 1-3 years, such as at least 1-4 years, for example 1-10 years, for example 1-20 years, for example 1-35 years, with the aim of inducing longitudinal growth of the intestine.

[0082] As previously described herein, SBS patients on the border between intestinal failure (SBS-II) or SBS-PS patients and intestinal failure (SBS-IF) or SBS non-PS patients would therefore be particularly efficacious in having a lengthened bowel over a 1-3 year treatment course, including, for example, weekly or twice-weekly administration for the duration of treatment, followed by a reduced risk of intestinal failure, including a reduced risk of the need for a central catheter and the risk of sepsis associated with its use.

[0083] The active agents may be used for the treatment of malnutrition resulting from, for example, cachexia and anorexia. [Example]

[0084] The following examples are provided to illustrate preferred embodiments of the present invention and are not intended to limit the scope of the invention. The GLP-2 analogs administered according to the dosing regimens described herein may be made according to methods such as solid phase peptide synthesis as described in WO2006 / 117565 and PCT / EP2022 / 087440 filed December 22, 2022, the contents of which are expressly incorporated by reference in their entireties.

[0085] Clinical trial design This was a multinational, placebo-controlled, randomized, parallel-group, double-blind, Phase 3 trial demonstrating the superiority of 10 mg of glepaglutide administered subcutaneously (SC) once weekly (OW) and twice weekly (TW) compared with placebo in patients with stable SBS. The trial (clinicaltrials.gov identifier: NCT03690206) was conducted at 29 medical centers (number of centers 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 a web-based automated response system to 24 weeks of treatment with either glepaglutide TW, glepaglutide OW, or placebo, administered SC in either the abdomen or thigh. Randomization was performed using a block randomization scheme stratified by patients' weekly PS volume requirement at baseline (<12 L per week vs. ≥12 L / week). To maintain blinding, all three treatment groups included twice-weekly administration (glepaglutide and / or placebo). The primary and key secondary endpoints aimed to confirm the efficacy of glepaglutide in reducing or eliminating the need for parenteral support (PS).

[0086] Management of short bowel syndrome (SBS) with intestinal failure (IF) aims at patient-centered clinical outcomes, including reduced need for parenteral support (PS) and improved quality of life (QoL).

[0087] The clinical 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 provided written informed consent before undergoing any study-related procedures or evaluations.

[0088] participants Key inclusion criteria included a diagnosis of SBS, defined as a contiguous remaining small bowel with an estimated length shorter 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.); PS requirement of at least 3 days per week; presence of a continuous colostomy or colon; and age 18 to 90 years. In addition, a number of exclusion criteria were defined (some of which were rechecked at the time of randomization) to ensure the validity of efficacy assessments and to exclude patients with significant comorbidities that could bias safety assessments. These include more than two SBS-related or PS-related hospitalizations within the six months prior to screening; moderately or severely active, poorly controlled inflammatory bowel disease or fistulas interfering with necessary measurements or experiments in the clinical trial; intestinal obstruction; known radiation enteritis or marked villous atrophy; cardiac disease within the last six months prior to 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 their analogs within the three months prior to screening; and unstable biologic therapy within the six months prior to screening.

[0089] procedure After informed consent and initial verification of eligibility criteria, patients entered a lead-in phase consisting of a PS optimization and stabilization phase to ensure a reliable baseline for assessing the efficacy of grepaglutide treatment in reducing PS requirements.

[0090] During the optimization phase, the treating physician could modify the PS volume and content according to the study's standard practice if the patient was unstable or not optimized. Prior to each optimization visit, patients' urine output was measured over a 48-hour period while adhering to the prescribed 48-hour beverage menu. During this period, patients recorded their urine output and oral fluid intake in their eDiary. The effect of PS optimization was examined after 2 weeks. Because up to two PS optimizations were possible, this limited the optimization phase to a maximum duration of 4 weeks. During the optimization phase, the treating physician and patient could redefine and optimize the individual beverage menu to best meet the patient's needs. Once the beverage menu was established at the end of the optimization phase, patients were required to adhere to this beverage menu for the 48-hour balance period throughout the remainder of the study.

[0091] A stabilization phase of 2-4 weeks duration immediately follows the optimization phase (the last optimization phase visit can serve as the first stabilization phase visit). No change in weekly PS volume or schedule of treatment is permitted during this phase. Prior to each stabilization phase visit, patients had their urine output measured over a 48-hour period while adhering to a set beverage menu, and urine output and oral fluid intake were recorded in the eDiary. Stabilization phase visits occurred every 2 weeks until the following PS stability criteria for appropriate randomization to study drug treatment were met: Actual PS usage (quantity and content) in accordance with the prescribed PS (a deviation of ±10% of the total amount is allowed) The 48-hour urine output at two consecutive visits within a 2-week interval (± 4 days) was similar (a deviation of ± 25% was considered acceptable), while oral fluid intake was consistent (oral intake at the two 48-hour intervals differed by less than 10%) and did not exceed 3.5 L per day. Urine output was on average ≥ 1 L / day and ≤ 2.5 L / day.

[0092] If stabilization is not achieved within 4 weeks due to unforeseen events such as infection, illness, etc., a second stabilization phase of up to 4 weeks is possible. During the subsequent 24-week treatment phase, PS needs were assessed using a 48-hour balance period for the 48 hours leading up to the treatment initiation visit and the 1, 2, 4, 8, 12, 16, 20, and 24 week visits after treatment initiation. The balance period included a fixed beverage menu (pre-specified individually during the optimization phase) and urine volume measurements, based on which PS amounts could be adjusted according to the following pre-specified algorithm: Daily urine output at the current visit is at least 10% greater than baseline urine output.

[0093] Then, new weekly PS volume = current weekly PS volume - 7 x absolute increase in daily urine volume from baseline. The amount and type of PS actually used were continuously recorded by the patient in the eDiary. Patients generally maintained a well-hydrated state throughout the study. Urine production was maintained above 1 L per day in all patients, in accordance with 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 was initiated, PS volume could be adjusted at weeks 1, 2, 4, 8, 12, 16, 20, and 24 according to the predefined algorithm described above. Changes in PS content were at the discretion of the treating physician; deviations from the algorithm for PS adjustment were permitted, for example, if clinical conditions, such as signs of dehydration or fluid overload, were present. The rationale for deviations from the algorithm was documented in the eCRF.

[0094] Unscheduled visits (prior to the 48-hour measurement period) may be considered by the treating physician to adjust PS. Other efficacy parameters included body weight and patient-reported outcomes. Safety data were recorded throughout the study period.

[0095] Recruitment of participants closed earlier than usual due to the ongoing uncertainty of global projections for COVID-19 in 2022 and the likely outcome of trial conduct and completion. As a result, with a final study population of 106 patients and based only on a priori assumptions, there was approximately 95% power to demonstrate superiority of once-weekly or twice-weekly grepaglutide compared to placebo in the primary endpoint.

[0096] statistical analysis The primary endpoint was the change in actual weekly PS volume from baseline to week 24, regardless of whether treatment was interrupted. The primary endpoint analysis applied a restricted maximum likelihood (REML)-based repeated measures method to compare treatment groups with respect to the mean change from baseline in actual weekly PS volume at week 24. The model used actual weekly PS volume assessments at weeks 1, 2, 4, 8, 12, 16, 20, and 24 (generated as actual weekly PS volume received during the valid 7-day period) as independent variables and included covariates for treatment group, baseline actual weekly PS volume, visit (a categorical variable), stratification factors (weekly PS volume requirement <12 L / week vs. ≥12 L / week), and the interaction between visit and treatment group. Variance estimation was based on an unstructured covariance matrix and did not assume a specific correlation structure for repeated measurements of weekly PS volume within patients over time. The primary comparison was between the grepaglutide and placebo groups at the 24-week visit (least-squares mean difference) in this repeated measures mixed-effects model (MMRM). Missing values ​​were imputed using multiple imputation. Of the four key secondary endpoints, three responder endpoints were analyzed using the Cochran-Mantel-Haenszel test adjusted for stratification factors (baseline weekly PS volume requirement <12 L / week vs. ≥12 L / week). Missing values ​​for these endpoints were imputed as non-response. For the remaining key secondary endpoint of reduction in weekly PS volume from baseline to week 12, differences between each grepaglutide treatment group vs. placebo were analyzed using the repeated measures mixed-effects model (MMRM) described by the primary endpoint. A parallel gatekeeping method (hierarchical testing) was applied to protect the overall type I error probability α (alpha) when testing the primary and key secondary endpoints across the two grepaglutide treatment groups vs. placebo.

[0097] Patient Global Condition Change (PGIC) Patient-reported outcomes (PROs) The PGIC was used to examine the effect of treatment on health-related quality of life (HRQoL).

[0098] The questionnaire was completed in paper format at the clinic visit before any other study-related assessments. The PRO was completed by patients enrolled in the study without the assistance of on-site personnel. The PRO was completed at home before patients visited the clinic. Patients were instructed to complete the PRO in a private area, free from influence from study team members or accompanied by a family member or friend. No one was allowed to answer or interpret the patient's items. If the patient was unable to read, the treating physician or a seconded study team member was allowed to read the items / response options aloud to the patient. The treating physician or seconded study team member instructed the patient to complete all items on the PRO and explained that there were no right or wrong answers. The treating physician or seconded study team member instructed the patient to answer to the best of their ability and explained that all individual responses would not be made public.

[0099] Immediately after completion, PROs were reviewed by the investigator (or designee) for completeness and potential adverse events (AEs). When reviewing PROs for AEs, investigators were instructed not to influence or question patients about the content of their responses to PRO questions. PRO reviews were documented. If entries were missing in the PRO, patients were asked to answer all questions, taking care not to bias patients.

[0100] The investigators and / or seconded study team members were trained and instructed on completing the PROs before conducting the study. Patients recorded the number of bowel movements / emptying of the stoma bag in their eDiary during the 48-hour balance period.

[0101] Improvement at weeks 4, 12, 20, and 24 The PGIC scale used in the EASE-SBS clinical trial program was a 7-point Likert scale with patients asked to check one box in response to the questions: "From the start of the trial, my overall condition was: (1) Much improved (2) Significant improvement (3) Slight improvement (4) No change (5) It got a little worse (6) It has gotten significantly worse (7) It has gotten much worse.” PGIC improvement was defined as responding "improved" or "very improved" on a 7-point Likert scale at each of weeks 4, 12, 20, and 24. Improvement between each grepaglutide treatment regimen compared with placebo was examined using the CMH trial with stratification by randomization stratification factors.

[0102] result 106 patients were randomized, and 102 completed the study. Treatment groups were well balanced overall with regard to patient demographics and baseline characteristics.

[0103] Grepaglutide was assessed to be safe and tolerable. More adverse events were reported in the glepaglutide treatment group than in the placebo group, mainly due to mild injection site reactions. PS necessity Grepaglutide TW treatment significantly reduced PS requirements compared with placebo (mean change of -5.13 vs. -2.85 L / week; estimated difference of -2.28 L / week [-3.83; -0.73] 95% CI; p=0.0039). Grepaglutide TW was also superior to placebo in the proportion of patients achieving a clinical response (65.7% vs. 38.9%; estimated difference of 26.6% [4.3; 48.9] 95% CI; p=0.0243) and in the proportion of patients achieving a reduction in PS ≥ 1 day / week (51.4% vs. 19.4%; estimated difference of 31.7% [11.4; 51.9] 95% CI; p=0.0043).

[0104] TW treatment showed an early onset of effect, with the time to clinical response being significantly shorter compared with placebo (=0.0043), with a median time to response of 55 days [29;85] 95% CI, as shown by the results reported in Table 1.

[0105] [Table 2]

[0106] TW treatment with grepaglutide resulted in a significant and early improvement in the decline in PS mass at 12 weeks, as shown by the results reported in Table 2 and FIG.

[0107] [Table 3]

[0108] No statistically significant differences were observed for glepaglutide OW versus placebo for these endpoints, but dose-dependent trends were observed. Of particular note, enteral autonomy was achieved in 5 (14%), 4 (12%), and 0 patients receiving glepaglutide TW, OW, and placebo, respectively.

[0109] The early onset of effect was seen by a significantly shorter time to clinical response with TW compared to placebo (p=0.0043), a finding that further supports the significant reduction in PS requirement after 12 weeks of treatment with TW (p=0.0019).

[0110] Additionally, the EASE SBS 1 trial investigated time to clinical response, defined by a reduction in PS from baseline (placebo) of at least 20%, an additional clinical parameter that defines the nature of the response of SBS patients to treatment with grepaglutide 10 mg TW or OW. The results of this analysis are presented in Table 1.

[0111] This indicates that treatment with grepaglutide results in an early onset of efficacy, with a median time to clinical response (at least a 20% reduction in PS volume) of 55 days or 8 weeks for TW treatment with 10 mg grepaglutide and 161 days or 23 weeks for OW treatment with 10 mg grepaglutide.

[0112] PGIC improvement Improvements in PROs using PGIC showed significant differences compared to placebo for both glepaglutide TW (p=0.0020) and OW (p<0.0001), as shown in Tables 3 and 4.

[0113] [Table 4]

[0114] [Table 5]

[0115] Improvements in patient-reported outcomes, PGIC, were seen in 62.9% of patients treated with TW compared with 36.1% of patients treated with placebo. Furthermore, improvements in PGIC were seen in 77.1% of patients treated with OW, a difference that was statistically significant compared with placebo (0 < 0.0001).

[0116] Further analysis Further analysis of the EASE SBS 1 trial results revealed one technical outlier in the OW treatment group, where PS volume data at weeks 20 and 24 were erroneously considered to be high Database Lock (DBL). This led to a reevaluation of the trial results and further comparisons in Table 5 and Figure 3 below.

[0117] [Table 6]

[0118] This reassessment did not result in any changes to the overall study conclusions, with only a small change within groups, a decrease in PS in the OW arm of the study from baseline of 3.13 L / week to 3.76 L / week. conclusion Grepaglutide treatment of patients with SBS-CIF was safe, tolerable, and resulted in clinical improvement and meaningful patient-centered outcomes (PS needs, enteral autonomy, and PROs). The onset of effect was surprisingly rapid for treatment with a GLP-2 analog, with a median time to clinical response of just 8 weeks with TW. Treatment with glepaglutide in both TW and OW resulted in significant improvements in the patient-reported outcome measure, PGIC. Given that the SBS patient population is considered highly heterogeneous, this finding is surprising with GLP-2 treatment.

[0119] While the present invention has been described in conjunction with the exemplary embodiments above, many equivalent embodiments and variations will be apparent to those skilled in the art given this disclosure. Accordingly, the exemplary embodiments of the invention described are considered to be illustrative and not limiting. Various modifications to the described embodiments can be made without departing from the spirit and scope of the invention. All documents cited herein are expressly incorporated by reference.

Claims

1. 1. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), the method comprising administering to said patient a compound of the formula: H-HGEGTFSSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the GLP-2 analog to a patient once a week or twice a week for a period of time, and wherein the treatment results in an improvement in the patient's quality of life (QoL).

2. 2. The glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of claim 1, wherein the improvement in the patient's quality of life (QoL) is assessed using the Patient Global Change Indicator (PGIC) status.

3. 3. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of claim 2, using a 7-point Likert scale, with responding patients reporting their PGIC status as well improved or very much improved compared to treatment with placebo.

4. 4. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 1 to 3, wherein an improvement in the patient's PGIC status is observable at 24 weeks of treatment.

5. 5. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of any one of claims 1 to 4, wherein the treatment further comprises reducing the frequency or amount of parenteral support the patient receives.

6. 6. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of claim 5, wherein the method comprises administering 10 mg of a GLP-2 analogue to the patient by subcutaneous injection twice a week, and comprises reducing the frequency or amount of parenteral support the patient receives at 12 weeks from the start of treatment with the GLP-2 analogue.

7. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment according to any one of claims 1 to 6, wherein the treatment results in an early onset of effect, with a median time to clinical response defined by a reduction in PS volume of at least 20% at day 55 or week 8 for twice-weekly treatment with 10 mg grepaglutide and at day 161 or week 23 for once-weekly treatment with 10 mg grepaglutide.

8. 8. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to claim 6 or 7, wherein the patient does not require parenteral support after 24 weeks of treatment.

9. 1. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), the method comprising administering to said patient a compound of the formula: H-HGEGTFSSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the GLP-2 analog to a patient once a week or twice a week for a period of time, and wherein the treatment results in a decrease in PS levels at 12 weeks from the start of treatment with the GLP-2 analog.

10. 10. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to claim 9, wherein the treatment results in a significant and early reduction in PS levels of -2.42 placebo at 12 weeks from the start of treatment with the GLP-2 analogue.

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

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

13. 1. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for the treatment of a human patient suffering from short bowel syndrome (SBS) and receiving parenteral support (PS), the method comprising the steps of: H-HGEGTFSSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, (ZP1848, SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the GLP-2 analog to a patient once a week or twice a week for a period of time, and wherein the treatment results in a rapid onset of effect, with a median time to clinical response defined by at least a 20% reduction in PS levels at day 55 or week 8 for twice-weekly treatment with 10 mg grepaglutide and at day 161 or week 23 for once-weekly treatment with 10 mg grepaglutide.

14. 14. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to claim 13, wherein the treatment further results in an improvement in the quality of life (QoL) of the patient.

15. 15. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to claim 14, wherein the improvement in the patient's quality of life (QoL) is assessed using the Patient Global Change Indicator (PGIC) status.

16. 16. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of claim 15, using a 7-point Likert scale, with responding patients reporting their PGIC status as well improved or very much improved compared to treatment with placebo.

17. 17. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 13 to 16, wherein an improvement in the patient's PGIC status is observable at 24 weeks of treatment.

18. 18. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 13 to 17, wherein the patient does not require parenteral support after 24 weeks of treatment.

19. 19. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 13 to 18, wherein the method comprises administering 10 mg of the GLP-2 analogue to the patient by subcutaneous injection twice a week.

20. 19. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 13 to 18, wherein the method comprises administering 10 mg of the GLP-2 analogue by subcutaneous injection to the patient once a week.

21. 21. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of any one of claims 1 to 20, wherein the patient has short bowel syndrome with intestinal failure (SBS-IF) or SBS chronic IF (SBS-CIF).

22. 22. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 1 to 21, wherein the patient has undergone a terminal jejunostomy or ileostomy, a jejuno-colonic anastomosis or a jejuno-ileo-colonic anastomosis.

23. 23. A glucagon-like peptide 2 (GLP-2) analogue for use in a method for treatment according to any one of claims 1 to 22, wherein the method comprises administering the GLP-2 analogue using an injection pen.

24. 24. A glucagon-like peptide 2 (GLP-2) analogue for use in the method for treatment of any one of claims 1 to 23, 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.

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