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p. 29 / OVERVIEW ON PEPTIDES
The most outstanding peptide achievement in the last two years
ANTONELLO PESSI
Chief Scientific Officer, PeptiPharma

KEYWORDS: Diabesity; glucagon-like Peptide-1 (GLP-1), half-life extension, medical devices, short open reading frame-encoded polypeptide (SEP).

THE TRANSFORMATIVE EFFECT OF DIABESITY R&D

Research on Type 2 Diabetes (T2D) in conjunction with its main risk factor, obesity (“diabesity”), is having a transformative effect on the whole field of peptide therapeutics, and I have selected Semaglutide as a champion of this research.
Diabesity has reached epidemic proportions worldwide, and better management of the disease is still an unmet medical need. The competition among pharma companies for the huge associated pharmaceutical market ($41B in 2014) has favored a virtuous cycle of large R&D investment, major technical innovation, and large return on investment, partially reinvested in R&D. This research effort has translated into major progress across many areas relevant for peptide therapeutics: the molecules themselves, the technology for half-life extension, slow release/depot formulations, patient-friendly medical devices, and even a promising track to oral formulations. These innovations are expected to spread across therapeutic areas. The situation resembles monoclonal antibodies, which took considerable time to gain acceptance after the first product was commercialized in 1986, but have since become the fastest-growing drug class. Indeed, a once-weekly injectable peptide with a favorable safety profile and lower production cost would have a better profile than a same-target antibody. Semaglutide, that is nearing approval after a successful Phase III, is one such peptide.

SEMAGLUTIDE

Semaglutide belongs to a novel class of T2D therapeutics, the Glucagon Like Peptide-1 receptor (GLP1R) agonists. These peptides increase insulin secretion in a glucose-dependent manner, thus limiting the risk of hypoglycemia that is associated with oral antidiabetic agents (OAD). Moreover, unlike OAD, GLP1R agonists cause weight loss. This drug class is characterized by the steady accumulation of innovations, starting with the approval of Exenatide/Byetta® in 2005, administered twice daily, followed in 2009 by the once-daily fatty-acid (FA) derivatized analog, Liraglutide/Victoza®, and in 2012 by the once-weekly depot formulation of exenatide, marketed as Bydureon®.
Liraglutide uses a principle first described for insulin, i.e. reversible binding to the FA transporter protein albumin, the most abundant protein in human plasma. Its once-weekly analog, Semaglutide is a once-weekly analog differing only for the structure of the linker/FA moiety. Notably, subtle structural variations have considerable effects on PK, highlighting that a comprehensive exploration of SAR was key to success.
So far, once-weekly administration was only possible through conjugation of the peptide to large MW polymers like polyethylene glycol (PEG) or fusion with protein modules, like albumin or the constant region of an antibody. These modifications, however, come with a number of issues, including loss of potency, increased cost, and safety (e.g. PEG-induced kidney vacuolation). The discovery of a simple chemical change that confers weekly half-life extension without the associated issues is a major technology...In order to continue reading this article please register to our website – registration is for free and no fees will be applied afterwards to download contents.

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