Battle of GLP-1 delivery technologies

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action.

Keywords: Albumin fusion; Exenatide; Fatty acid conjugate; Fc fusion; GLP-1 receptor agonist; Half-life; Peptide delivery; Pharmacokinetics.

Figure 1.

Peptide sequences and molecular structures of FDA approved GLP-1 RAs.

Figure 2.

(A) Half-life extension mechanisms of acylated GLP-1 analogs. (B) Mean concentration-time profile of liraglutide following single dose of 0.6 mg, 1.2 mg, or 1.8 mg at steady state in healthy male Chinese subjects. Adapted with permission of © John Wiley & Sons, Inc. from Jiang et al. J Clin Pharmacol. 2011;51:1620–7. [72] (C) Mean concentration-time profile of semaglutide following single dose of 1.0 mg at steady-state. Adapted with permission of © John Wiley & Sons, Inc. from Kapitza et al. J Clin Pharmacol. 2015; 55(5):497-504. [73]

Figure 3.

(A) Half-life extension mechanisms of albiglutide. (B) Mean concentration-time profile of albiglutide following a single subcutaneous 30 mg injection. Adapted with permission of © 2015 Taylor & Francis Ltd. from Young et al. Postgraduate Medicine. 126:7, 84-97. www.tandfonline.com [78].

Figure 4.

(A) Half-life extension mechanisms of dulaglutide. (B) FcRn recycling pathway of dulaglutide. (C) Mean concentration-time profile of dulaglutide following single dose of 1.5 mg subcutaneously injected in abdomen, thigh, or arm. Data obtained from an EMA assessment report of Trulicity® [87].

Figure 5.

(A) Release process of exenatide from microspheres. (B) Mean concentration-time profile of exenatide following single dose of Bydureon®. (C) Mean concentration-time profile of exenatide following repeated weekly administrations of Bydureon® (exenatide ER same as exenatide QW) compared with a single administration of Byetta® (exenatide IR). Adapted with permission of © 2011 Adis Data Information BV from Fineman et al. Clin Pharmacokinet 2011; 50 (1).[97]

Figure 6.

Schematic of ITCA 650 (A) and mean concentration-time profile of exenatide following implantation of ITCA 650 (B). With permission of Henry et al. Clinical therapeutics 35.5 (2013): 634-645. [100]

Figure 7.

Market share of GLP-1 RAs in 2016 and 2017.