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GLP-2

GLP-2

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GLP-2

As a hormone with 33 amino acids, GLP-2 is a peptide-encoded carboxyterminal to the sequence of GLP-1 in the precursor gene. Since GLP-2 was originally reported to stimulate intestinal growth, there has been huge interest in the potential therapeutic uses for treating diseases such as short bowel syndrome (SBS), in which the loss of a large section of bowel due to intestinal resection occurs.

GLP-2 Analogs for Therapeutic Use

However, the short half-life of native GLP-2 requires constant infusion, thus limiting their use as therapeutic agents. To address this problem, novel GLP-2 agents have been developed, one of which is already commercially available (teduglutide), and others (apraglutide and glepaglutide) are in the late stage of clinical development.

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Fig. Sequence of GLP-2 and GLP-2 analogs (Teduglutide, Apraglutide, Glepaglutide, Elsiglutide).

Teduglutide

The active ingredient of teduglutide is [gly2]-hGLP-2, a recombinant GLP-2R agonist based on the 33-amino acid natural hormone. Teduglutide was developed by Shire (now acquired by Takeda) and approved to treat Short Bowel Syndrome (SBS) under the brand names Gattex (USA, FDA) and Revestive (Europe, EMA). The peptide is designed by a single amino acid mutation at the N-terminus (replacing glycine in position 2 with alanine), which makes it less susceptible to degradation by DPP-4 and extends the half-life to about 2 hours.

Glepaglutide

Glepaglutide (ZP1848), with the sequence [Gly2, Glu3, Thr5, Ser8, Leu10, Ala11,16,24,28] hGLP-2(1-33)-(Lys)6-NH2, is a highly potent GLP-2 selective 39 amino acid peptide. Zealand Pharma developed gepaglutide by various peptide design strategies. These strategies include i) six lysine residues are added at the C-terminus to alter the charge state that affect solubility and physicochemical properties; ii) four residues with alanine are substituted in the region connecting the seven transmembrane binding sites to the extracellular structural domain binding residues; iii) N-terminal region is altered and optimized with five changes to improve pharmacokinetic and potency properties.

Apraglutide

Apraglutide (with the code name FE 203799) was initially found by Ferring Pharmaceuticals. The amino acid of native GLP-2 peptide is substituted or modification at position 2, 10, 11, 16, and C terminal to produce apraglutide with the sequence ([Gly2,Nle10, D-Phe11,Leu16]hGLP-2-(1-33)-NH2). In detail, GLP-2 positions 2 and 10 are substituted with glycine and norleucine; and position 11 is hydrophobically substituted with D-phenylalanine; position 16 with leucine and finally C-terminal amidation modification.

Elsiglutide

The sequence of a GLP-2 peptide analogue, Elsiglutide (ZP1846), is [Gly2, Glu3, Ser8, Leu10, Ser11, Ala16, Ala24, Ala28] hGLP-2(1-33)-(Lys)6. It is associated with another GLP-2 compound being developed by Zeeland Pharma. Elsiglutide is developed for the treatment of chemotherapy-induced diarrhea.

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GLP-2 Analogs Pipelines

Generic name

Brand Name/Altermative name

Expression System

Indications

Manufacturer

Latest stage

Teduglutide

Gly(2)-GLP-2, SHP633, ALX-0600, TAK-63, Gattex, Revestive, レベスティブ

E. coli

Short bowel syndrome (SBS), malabsorption syndrom

Shire, Takeda

Approved

Glepaglutide

ZP-1848, long-acting, 39AA

Pending Update

inflammatory bowel disease, short bowel syndrome, kidney disease

Zealand Pharma

Submit for approval, Phase III

HM-15912

Fc-coupling protein, chemical conjugation

Pending Update

Short bowel syndrome (SBS)

Hanmi Pharmaceutical

Phase II

SHP-681

Fc fusion protein, GLP-2 Analog-Fc Fusion, TAK-681, SHP 681

Pending Update

Short bowel syndrome (SBS)

Shire, Takeda

Phase I

Teduglutide Recombinant

Ted, PJ009

Pending Update

Short bowel syndrome (SBS)

Chongqing Paijin Biotechnology

Phase I

GX-G8

Long acting GLP-2, Genexine

Pending Update

Short bowel syndrome (SBS)

Genexine, Inc.

Phase I

Apraglutide

FE-203799, FE 203799

synthetic peptides

Short bowel syndrome (SBS)

VectivBio, Asahi Kasei

Phase III

Dapiglutide

ZP-7570

synthetic peptides

Obese, Short bowel syndrome (SBS)

Zealand Pharma A/S

Phase II

Elsiglutide

ZP-1846

synthetic peptides

diarrhea

Zealand Pharma A/S

Phase II

GLP-2

Pending Update

synthetic peptides

Short bowel syndrome (SBS), Intestinal failure

Alberta Health Services

Phase II

Long-acting GLP-2

Pending Update

Pending Update

Short bowel syndrome (SBS)

OPKO Biologics (formerly Prolor Biotech),

Pre-clinical

Oral GLP-2

Pending Update

Pending Update

Gastrointestinal diseases

Applied Molecular Transport, Inc.

Pre-clinical

NM-003

GLP-2-XTEN, chemical conjugation, long-acting GLP-2 agonist, NB-1002

E. coli

Short bowel syndrome (SBS)

9 Meters Biopharma, Naia Ltd.

Pre-clinical

PE-0503

GLP-2-ELP

Pending Update

Short bowel syndrome (SBS)

PhaseBio Pharmaceuticals

Pre-clinical

GLP-2 Analogs

Oral GLP2 analogs

Pending Update

Gastrointestinal diseases

Entera Bio

Pre-clinical
Reference:

[1] Suzuki R, Brown GA, Christopher JA, Scully CCG, Congreve M. J Med Chem. 2020 Feb 13;63(3):905-927. doi: 10.1021/acs.jmedchem.9b00835.

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