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One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer

Nature Biomedical Engineering volume 1, Article number: 0078 (2017) Cite this article

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Abstract

Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes due to pleiotropic effects, such as the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-life owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics lead to 10 days of glycaemic control in three different mouse models of diabetes, as well as the reduction of glycosylated haemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.

Nearly 30 million adults in the United States are diabetic, with over 1.7 million new cases diagnosed in 2012. It is estimated that diabetes causes $176 billion direct medical costs annually, and there were over 455,000 emergency room visits due to diabetes-related glycaemic crises in 20111. These statistics highlight the staggering burden of this disease on the healthcare system. Of those afflicted, over 90% of adult diabetes cases are type 2. Yet, despite the long list of treatment options among a growing number of drug classes, nearly half of diagnosed type 2 cases are not properly managed2. These patients routinely fail to reach established glycaemic targets, due largely to the tapering efficacy of monotherapies over time, and inadequate patient adherence to prescribed treatment regimens, which often require frequent and complicated meal-specific dosing. Furthermore, many of the most widely prescribed medications are plagued by undesirable side effects, including weight gain and a risk of hypoglycemia3.

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Figure 1: A set of GLP1–ELP fusions with constant number of repeats but varied Tt was characterized and tested in vivo.
Figure 2: A set of GLP1–ELP fusions with constant Tt at the injected concentration but varied Mw was characterized and tested in vivo.
Figure 3: GLP1–ELP fusions were effective at controlling blood glucose levels for up to 10 days in three murine models of diabetes.
Figure 4: GLP1–ELP opt depots persist in the SC space and enhance the drug’s pharmacokinetics.
Figure 5: Injectable SC depots of GLP1–ELPopt release drug into circulation that can be quantified up to 17–21 days in non-human primates.

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Acknowledgements

A.C. acknowledges the support of NIH through grant R01-DK091789. K.M.L. acknowledges the support of the NSF through a Graduate Research Fellowship. We thank D. Drucker for providing BHK cells for assaying in vitro activity, G. A. Johnson and Duke’s Center for In Vivo Microscopy for use of their U-SPECT-II/CT imaging equipment, and M. R. Zalutsky for allowing us to use his laboratory and equipment to conduct radiolabelling experiments. K.L. thanks C. Gilroy for productive discussions on in vitro and in vivo experiments. The authors all sincerely thank K. Gerken, who provided pathology expertise and helped to analyse and interpret injection site histology, as well as the Duke Research Immunohistology Shared Resource Lab who processed the skin samples. Finally, we would like to thank J. Jowett, D. Sendecki and C. Woods of PhaseBio Pharmaceuticals, who helped to express and purify fusion protein for the non-human primate experiment.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Duke University, Durham, 27708, North Carolina, USA

    Kelli M. Luginbuhl, Jeffrey L. Schaal, Eric M. Mastria, Xinghai Li, Samagya Banskota & Ashutosh Chilkoti

  2. PhaseBio Pharmaceuticals, Inc., Malvern, Pennsylvania, 19355, USA

    Bret Umstead & Susan Arnold

  3. Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Mark Feinglos & David D’Alessio

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  1. Kelli M. Luginbuhl
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Contributions

K.M.L. and A.C. conceived and designed the research. K.M.L., J.L.S., X.L. and B.U. performed the experiments. S.B. provided materials for the imaging study. S.A. helped to plan and organize the non-human primate study. M.F. and D.D. provided expertise in endocrinology for the design of in vivo studies. E.M.M. assisted in statistical analysis and interpretation of in vivo results. K.M.L. and A.C. analysed the results and wrote the manuscript. J.L.S., E.M.M. and D.D. edited the manuscript.

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Correspondence to Ashutosh Chilkoti.

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A.C. is a scientific advisor and is on the board of directors for PhaseBio Pharmaceuticals, which has licensed the ELP technology for drug delivery applications from Duke University.

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Luginbuhl, K., Schaal, J., Umstead, B. et al. One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer. Nat Biomed Eng 1, 0078 (2017). https://doi.org/10.1038/s41551-017-0078

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