Dosage regimes for the administration of glucagon-like-peptide-2 (glp-2) analogues

Pending Publication Date: 2020-01-02
ZEALAND PHARM AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0035]Preferably, the method includes the initial steps of determining the baseline volume and/or determining the daily urine volume. Some or all of the steps of the method may be repeated during the course of the GLP-2 therapy received by the subject. Preferably, the first assessment and the determination of changes in the PS volume adjustments is done early in the GLP-2 therapy, such as a few days after the start of the GLP-2 therapy, such as 2, 3, 4, 5, 6, 7 days after start of the GLP-2 therapy. Preferably, the time between repeat testing to determine changes in the PS volume adjustments is initially weekly and later about every 1 to 3 months. For example, in one embodiment, the method may be used at weeks 1, 2, 4, 8 and 12 after commencement of treatment with the GLP-2 analogue, adjusting the PS volume in response to the effects of treatment. The weekly PS volume administered should be monitored and adjusted throughout treatment with the GLP-2 analogue (e.g. glepaglutide) in order to avoid fluid overload. Generally, as the absorptive capacity of the intestines increases after treatment with the GLP-2 analogue, typically by elongation or thickening of the small intestine,

Problems solved by technology

However, the native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a useful in a clinical setting due to its very short half-life in humans of around 7 minutes for full length GLP-2 [1-33] and 27 minutes for truncated GLP-2 [3-33].
However, a major difficulty with the delivery of suc

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Example

Example 1. Synthesis of ZP1848 Metabolites

[0127]Solid phase peptide synthesis was performed on a CEM Liberty Peptide Synthesizer using standard Fmoc chemistry. TentaGel S Ram S resin (1.33 g; 0.25 mmol / g) was swelled in DMF (10 ml) prior to use and transferred between tube and reaction vessel using DCM and DMF.

Coupling

[0128]An Fmoc-amino acid in DMF / DCM (2:1; 0.2 M; 5 ml) was added to the resin in a CEM Discover microwave unit together with COMU / DMF (0.5 M; 2 ml) and DIPEA&DMF (2.0 M; 1 ml). The coupling mixture was heated to 75° C. for 5 min while nitrogen was bubbled through the mixture. The resin was then washed with DMF (4×10 ml). Fmoc-Phe-Ser(Psi Me,Me,Pro)-OH pseudoproline was used for amino acid number six and seven.

Deprotection

[0129]Piperidine / DMF (20%; 10 ml) was added to the resin for initial deprotection and the mixture was heated by microwaves (30 sec; 40° C.). The reaction vessel was drained and a second portion of piperidine / DMF (20%; 10 ml) was added and heated (75° C...

Example

Example 2. GLP-2R EC50 Measurements

Generation of Cell Line Expressing Human GLP-2 Receptors

[0132]The hGLP2-R was purchased from MRC-geneservice, Babraham, Cambridge as an Image clone: 5363415 (11924-I17). For subcloning into a mammalian expression vector, primers for subcloning were obtained from DNA-Technology, Risskov, Denmark. The 5′ and 3′ primers used for the PCR reaction include terminal restriction sites for cloning and the context of the 5′ primer is modified to a Kozak consensus without changing the sequence of the product encoded by the ORF. A standard PCR reaction was run using Image clone 5363415 (11924-I17) as a template with the above mentioned primers and Polymerase Herculase II Fusion in a total vol. of 50 μl. The generated PCR product was purified using GFX PCR and Gel band purification kit, digested with restriction enzymes and cloned into the mammalian expression vector using Rapid DNA Ligation Kit. Ligation reaction was transformed to XL10 Gold Ultracompetent cel...

Example

Example 3: Pharmacokinetic and Pharmacodynamic Profiling of GLP-2 Analogues

[0135]A phase 2 clinical trial was conducted to i.a. determine the PK profile of ZP1848 and metabolites in human SBS patients.

Method

[0136]The study was designed as a randomized, cross-over and double-blinded with three different doses of ZP1848 (10 mg, 1 mg, 0.1 mg) in 16 SBS patients.

[0137]The study protocol was approved by the Danish Medical Agency and The Danish Committee on Health Research Ethics.

[0138]The 18 SBS patients (16 patients completed the study) were randomized evenly and in a double-blinded fashion to each of the six cross-over dose level combinations: 10 mg / 1 mg, 10 mg / 0.1 mg, 1 mg / 10 mg, 1 mg / 0.1 mg, 0.1 mg / 10 mg, 0.1 mg / 1 mg of ZP1848. The patients were injected once daily (QD) subcutaneously with the above doses of ZP1848.

[0139]Blood samples for PK analysis were collected on several study visits throughout the study period: the study comprised a 1st baseline balance study (4 days), a 1st tr...

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Abstract

Dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues and their medical use are disclosed, for example in the treatment and/or prevention of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy and radiation therapy. Dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues for inducing longitudinal growth of the intestines are described, for example for the treatment of patients with short bowel syndrome (SBS). Medical uses for adjusting the volume of parenteral support (PS) provided to subjects receiving treatment with GLP-2 analogues in response to the treatment and to algorithms for determining PS volume changes are also described.

Description

SEQUENCE LISTING[0001]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jul. 12, 2019 is named ‘50412-113001—Sequence Listing’ and is 4,592 bytes in size.FIELD OF THE INVENTION[0002]The present invention relates to dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues and their medical use, for example in the treatment and / or prevention of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy and radiation therapy. The present invention further relates to dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues for inducing longitudinal growth of the intestines, for example for the treatment of patients with short bowel syndrome (SBS). The present invention further relates to medical uses for adjusting the volume of parenteral support (PS) provided to subje...

Claims

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Application Information

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IPC IPC(8): A61K38/26A61K9/00A61P1/00
CPCA61K38/26A61P1/00A61K9/0019C07K14/605
Inventor SONNE, KIMMOURITZEN, ULRIKGLERUP, PETERJEPPESEN, PALLE BEKKER
Owner ZEALAND PHARM AS
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