Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Glaesner, Wolfgang; Vick, Andrew; Millican, Rohn; Ellis, Bernice; Tschang, Sheng-Hung; Tian, Yu; Bokvist, Krister; Brenner, Martin; Köester, Anja; Pørksen, Niels; Etgen, Garret J.; Bumol, Tom

doi:10.1002/dmrr.1080

Cited by 244 publications

(223 citation statements)

References 24 publications

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“…The incidence of antibodies in the present study was lower than in other GLP‐1 compounds with an exendin‐4 backbone (exenatide twice daily, 44–60% 32; exenatide once weekly, 61–68% 33, 34; and lixisenatide, approximately 70% 35); the lower incidence in the present study is probably attributable to the design of the dulaglutide molecule 36.…”

Section: Discussioncontrasting

confidence: 74%

Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

Miyagawa

Odawara

Takamura

et al. 2015

Diabetes Obesity Metabolism

175

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AimsTo examine the efficacy and safety of once‐weekly dulaglutide monotherapy (0.75 mg) compared with placebo and once‐daily liraglutide (0.9 mg) in Japanese patients with type 2 diabetes.MethodsThis was a phase III, 52‐week (26‐week primary endpoint), randomized, double‐blind, placebo‐controlled, open‐label comparator (liraglutide) trial comparing 492 Japanese patients with type 2 diabetes (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70) who were aged ≥20 years. Patients and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide. The primary objective evaluated the superiority of dulaglutide versus placebo on change from baseline in glycated haemoglobin (HbA1c) at 26 weeks. Analyses were performed on the full analysis set.ResultsAt 26 weeks, once‐weekly dulaglutide was superior to placebo and non‐inferior to once‐daily liraglutide for HbA1c change from baseline [least squares mean difference: dulaglutide vs placebo −1.57% (95% confidence interval −1.79 to −1.35); dulaglutide vs liraglutide −0.10% (95% confidence interval −0.27 to 0.07)]. The most frequently reported adverse events were nasopharyngitis, constipation, diarrhoea, nausea, abdominal distension and decreased appetite; only decreased appetite was different between the dulaglutide and liraglutide groups [dulaglutide, n = 2 (0.7%); liraglutide, n = 8 (5.8%); p = 0.003]. Nine (1.8%) patients experienced hypoglycaemia [dulaglutide, n = 6 (2.1%); liraglutide, n = 2 (1.5%); placebo, n = 1 (1.4%)], with no event being severe.ConclusionsIn Japanese patients with type 2 diabetes, once‐weekly dulaglutide (0.75 mg) was superior to placebo and non‐inferior to once‐daily liraglutide (0.9 mg) for reduction in HbA1c at 26 weeks. Dulaglutide was safe and well tolerated.

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Section: Discussioncontrasting

confidence: 74%

Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

Miyagawa

Odawara

Takamura

et al. 2015

Diabetes Obesity Metabolism

175

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“…The GLP-1 analog portion of dulaglutide is approximately 90% homologous to native human GLP-1. Three alterations to the GLP-1 portion of the molecule were incorporated to optimize its clinical profile, including protection from DPP-4 inactivation, increased solubility, and reduction of immunogenicity [20]. The addition of the IgG4 fragment crystallizable (Fc) portion helped to decrease the rate of renal clearance of dulaglutide.…”

Section: Introductionmentioning

confidence: 99%

Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers

Anderson¹,

Thieu

Boye

et al. 2016

Postgraduate Medicine

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Approximately 90% of T2D patients in the US are diagnosed and treated in the primary care setting, and the majority of the burden of disease management falls to primary care providers. Here, we discuss the clinical data for once weekly dulaglutide, e.g. the results of seven completed Phase 3 trials, patient preference studies, patient reported outcomes (PRO), and clinical data surrounding the dulaglutide administration device. Dulaglutide 1.5 mg once weekly demonstrated superiority to placebo, metformin, sitagliptin, exenatide BID, and insulin glargine (in 2 trials), and non-inferiority to liraglutide in reduction of HbA1c from baseline, with an acceptable safety profile. Dulaglutide-treated patients achieved the composite endpoint of an HbA1c <7.0% with no hypoglycemia, no severe hypoglycemia, and no weight gain significantly more than metformin, sitagliptin, exenatide BID or insulin glargine treated patients. Dulaglutide consistently showed an early onset of glycemic control, lasting up to 104 weeks. Additionally, PRO and patient preference data support the benefit of once weekly dulaglutide for the treatment of T2D. ARTICLE HISTORY

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“…The molecule is a recombinant fusion of glucagon-like peptide-1 (GLP-1) analog consisting of two identical disulfide-linked chains covalently linked to a modified IgG4 heavy chain-Fc fragment, which are fused together by a small peptide linker ( Figure 3C) [4]. The GLP-1 analog portion of dulaglutide contains 3 mutations compared to the native GLP-1 peptide.…”

Section: Selected Igg-fc Fusion Molecules In Clinical Usementioning

confidence: 99%

“…The arginine change at position 36 at the junction between the GLP-1 moiety and the linker sequence to glycine de-immunizes the fusion protein. The IgG4 Fc region of dulaglutide was optimized to reduce interaction with Fcγ receptor I and to eliminate half-antibody formation [4]. In addition, the C-terminal lysine was removed from the IgG-Fc.…”

Section: Selected Igg-fc Fusion Molecules In Clinical Usementioning

confidence: 99%

“…Recent advances in pharmacological engineering and design revealed the potential of fusion protein molecules to help prolonging intervals between doses. Among them, several fragment crystallizable (Fc)-fusion proteins have been successfully implemented in the treatment of various diseases, including autoimmune and inflammatory, cancer, infectious, cardiovascular and type 2 diabetes mellitus [4][5][6][7][8]. The current article intends to provide a brief review for clinicians on Fc-fusion protein technology.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A New Approach to Drug Therapy: Fc-Fusion Technology

Pechtner¹,

Ca²,

Le³

et al. 2017

Primary Health Care

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Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Cited by 244 publications

References 24 publications

Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers

A New Approach to Drug Therapy: Fc-Fusion Technology

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