Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome

Hargrove, Diane M.; Alagarsamy, Shanmugarathinam; Croston, Glenn; Laporte, Régent; Qi, Steve; Srinivasan, Karthik; Sueiras-Diaz, Javier; Wiśniewski, Kazimierz; Hartwig, Jennifer; Lu, Mark; Posch, Alexander P.; Wiśniewska, Halina; Schteingart, Claudio D.; Rivière, Pierre; Dimitriadou, Violetta

doi:10.1124/jpet.119.262238

Cited by 39 publications

(58 citation statements)

References 47 publications

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“…Apraglutide ([Gly 2 , Nle 10 , D-Phe 11 , Leu 16 ]-GLP-2) employed further substitutions ( Table 3 ), identified through structure-activity relationship studies of lipophilic amino acid substitutions in positions 11 and 16 of teduglutide, and has been shown to prolong in vivo bioactivity through reduced renal clearance in rodents ( 224 ). Similar findings were observed in monkey and mini-pig ( 225 ), whilst exhibiting excellent specificity and potency for the GLP-2R. The peptide was more efficacious than both teduglutide and another GLP-2 analogue in development, glepaglutide [( 226 ); Table 3 ], and has started recruiting for phase III clinical trials in SBS patients ( 231 ).…”

Section: Glucagon-like Peptide-2mentioning

confidence: 67%

Proglucagon-Derived Peptides as Therapeutics

et al. 2021

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Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.

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Section: Glucagon-like Peptide-2mentioning

confidence: 67%

Proglucagon-Derived Peptides as Therapeutics

et al. 2021

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“…We read with interest the publication entitled "Pharmacological Characterization of Apraglutide a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist for the Treatment of Short Bowel Syndrome" (Hargrove et al, 2020). The authors investigated the pharmacology and pharmacokinetic (PK) properties of apraglutide, comparing it directly with teduglutide and glepaglutide.…”

mentioning

confidence: 99%

“…The authors claim that glepaglutide was identified from a published patent application (WO06117565A2) and described the amino acid sequence of the peptide as well as its counter ion used in their studies (Hargrove et al (2020), Table 1). The amino acid sequence of glepaglutide is however not correct.…”

mentioning

confidence: 99%

Comments on “Pharmacological Characterization of Apraglutide a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist for the Treatment of Short Bowel Syndrome”

Skarbaliene

Larsen

Berner-Hansen

et al. 2021

J Pharmacol Exp Ther

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“…Vehicle and apraglutide were administered by subcutaneous injection 3 times/week for 3, 7 or 10 weeks, followed by a single injection 24 hr prior to euthanization. The frequency of administration was based on the previous pharmacokinetic studies conducted in adult rats (225-250 g) (Hargrove, 2020) and in adult mice (7-10 weeks old or 21-26 g). In mice, specifically, the elimination t½ was in the range of 6 to 11 h with an accumulation ratio of 1.6 observed in male but not in female animals (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Site-Specific and Temporal Effects of Apraglutide, a Novel Long-Acting Glucagon-Like Peptide-2 Receptor Agonist, on Intestinal Growth in Mice

Martchenko

Sweeney

Dimitriadou

et al. 2020

J Pharmacol Exp Ther

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Long-acting glucagon-like peptide-2 receptor (GLP-2R) agonists are well-established to increase intestinal growth in rodents and, most notably, humans with short bowel syndrome. Most of the trophic effects of GLP-2R agonists are reported to be mediated through increased growth of the crypt-villus axis, resulting in enhanced mucosal mass and improved intestinal function. The present study examined the effects of apraglutide, a novel GLP-2R agonist, on the growth of the small and large intestines, after 3, 7 and 10 weeks of treatment in male and female mice. Apraglutide (3mg/kg; 3-times per week) significantly increased small intestinal weight (p<0.001) and length (p<0.001) after 3 weeks of administration, with a further increase in effectiveness after 10 weeks (p<0.01). Crypt depth and villus height were both markedly increased after 3 weeks of apraglutide administration (p<0.001) but did not show any further increase with duration of treatment, whereas crypt number and intestinal circumference were increased after 7 and 10 weeks (p<0.01) but not after 3 weeks of apraglutide treatment. Both the weight and the length of the colon were also enhanced by apraglutide treatment for 3 weeks (p<0.001), and these effects were maintained but did not improve further with continued apraglutide administration. The results of this study demonstrate that the novel, long-acting GLP-2R agonist, apraglutide demonstrates unexpected marked ability to increase intestinal length, as well as exerting time-and location-dependent specificity in its intestinotrophic actions. Significance: The novel long-acting GLP-2R agonist, apraglutide, enhances intestinal weight as well as intestinal length in a time-and site-dependent fashion.

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Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome

Cited by 39 publications

References 47 publications

Proglucagon-Derived Peptides as Therapeutics

Proglucagon-Derived Peptides as Therapeutics

Comments on “Pharmacological Characterization of Apraglutide a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist for the Treatment of Short Bowel Syndrome”

Site-Specific and Temporal Effects of Apraglutide, a Novel Long-Acting Glucagon-Like Peptide-2 Receptor Agonist, on Intestinal Growth in Mice

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