TSRI-Calibr Team Creates Novel Platform for Generating Long-Acting Drug Candidates

LA JOLLA, CA – March 31, 2016 – To improve the effectiveness of peptide hormones as treatments for chronic diseases such as diabetes and obesity, scientists at The Scripps Research Institute (TSRI) and the California Institute for Biomedical Research (Calibr) have developed new peptide stabilization platform technology.

As a drug class, peptides offer exquisite specificity and potency, but also present challenges associated with poor stability and short half-life, which can create the need for frequent injections and result in poor patient compliance and overall compromised efficacy.

The new study, published recently online ahead of print by the journal Proceedings of the National Academy of Sciences (PNAS), describes the development of a novel strategy that incorporates a serum protein-binding motif into a covalent side-chain “staple,” which rigidifies the bioactive portion of the peptide leading to increased stability and potency.

As a proof-of-concept, this strategy was successfully applied to generate a highly potent, long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes and obesity.

The researchers demonstrated that the new GLP-1R agonist, E6, significantly improved half-life and glucose tolerance following an oral glucose challenge in rodents. Chronic treatment using E6 significantly decreased body weight and fasting blood glucose, improved lipid metabolism and reduced hepatic steatosis in diet-induced obese mice.

Moreover, the high potency and solubility of E6 permitted the administration of this peptide using MicroCor®, a novel transdermal delivery system developed by Corium International, Inc. In collaboration with scientists at Corium, E6 was successfully formulated in the MicroCor dissolving microstructure transdermal delivery system, and a single five-minute application of the microstructure patch on guinea pigs resulted in bioavailability comparable to subcutaneous injections.

Importantly, corresponding improvements in glucose tolerance were sustained for up to four days in guinea pigs following a single application. This delivery approach may offer an effective and patient-friendly alternative to currently marketed GLP-1 injectables and can likely be extended to other peptide hormones.

The scientists are now applying this technology to drug candidates for the treatment of other chronic metabolic, cardiovascular and inflammatory diseases.

The first authors of the paper, titled Long-acting, Potent GLP-1 Analog Delivered in Microstructure-based Transdermal Patch,” were Peng-Yu Yang of TSRI and Calibr and Huafei Zou of Calibr. The senior authors for the study were Peter G. Schultz of TSRI and Calibr and Weijun Shen and Ashley Woods of Calibr. Other authors were Xiaozhou Luo of TSRI; Elizabeth Chao, Lance Sherwood, Vanessa Nunez, Herlinda Quirino and Gus Welzel of Calibr; and Michael Keeney, Esi Ghartey-Tagoe, Zhongli Ding, Guohua Chen and Parminder Singh of Corium International.

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