Polyethylene Glycol Loxenatide! The First Chinese-produced Long-acting GLP-1R Agonist

The blockbuster diabetes product: long-acting GLP-1 receptor agonist polyethylene glycol loxenatide (trade name: Fulaimei) of Hansoh Pharmaceutical has been marketed on May 7, 2019, which is indicated for type 2 diabetes and administered once every week. Polyethylene glycol loxenatide is the 3^rd long-acting GLP-1 receptor agonist approved for marketing in China following exenatide microspheres (trade name: Bydureon) of AstraZeneca/3SBio and dulaglutide (trade name: Trulicity) of Eli Lilly.

In the diabetes business of Hansoh at present, the first generic variety: Fulaidi (repaglinide) is its core product and also the first generic drug of repaglinide tablets that has passed the consistency evaluation in China, with the market share of about 22.7% in China; the marketing of the polyethylene glycol loxenatide independently developed by it will significantly optimize Hansoh’s diabetes business and bring a long-term driving force to its performance growth!

This article will focus on the long-acting mechanism of GLP-1R agonists and the global GLP-1 receptor agonist market and introduce the market performance of the major GLP-1 receptor agonists!

I. Hansoh Pharmaceutical’s blockbuster innovative diabetes drug: polyethylene glycol loxenatide

There have been mainly 4 GLP-1R agonist drugs approved for marketing in the world so far, separately: Bydureon (exenatide microspheres), Tanzeum (albiglutide), Trulicity (dulaglutide), and Ozempic (semaglutide).

The IND application of polyethylene glycol loxenatide was accepted by CDE in 2007; Phase 3 clinical trial of polyethylene glycol loxenatide was completed by Hansoh in May 2016; the marketing application of the drug was accepted by CDE in Dec. 2017. After nearly 12 years, polyethylene glycol loxenatide is eventually approved for marketing, as a blockbuster diabetes product developed by Hansoh Pharmaceutical.

II. The long-acting mechanism of long-acting GLP-1R agonists

There have been 5 long-acting GLP-1R agonists approved for marketing worldwide so far, separately exenatide microspheres, albiglutide, dulaglutide, semaglutide, and Hansoh Pharmaceutical’s polyethylene glycol loxenatide. This is the result of the joint efforts of many medical surgical supply companies.

Long-acting GLP-1R Agonists Approved for Marketing Worldwide

Natural GLP-1:

HA↓  EGTFTSDV SSYLEGQAAK EFIAWLVKGR G

As a kind of "incretin" naturally secreted by human gastrointestinal (GI) mucosa, GLP-1 can stimulate insulin secretion, however, the natural GLP-1 is easily degraded by the body DPP-IV, with the degradation site being HA|EG, with a very short half-life.

Therefore, the long-acting mechanism of GLP-1 analogs is firstly, blocking DPP-IV degradation, and secondly, increasing the half-life.

1. Exenatide microspheres

Its sequence is consistent with exenatide, and it damages the DPP-IV degradation site, with the long-acting mechanism mainly depending on its microsphere delivery technology, to extend the half-life; it can be injected once every week;

2. albiglutide

Albiglutide also damages the DPP-IV degradation site, with two copies of GLP-1 fused with human albumin, to constitute the long-acting mechanism;

3. Dulaglutide

Dulaglutide damages the DPP-IV degradation site on the one hand, and is fused with IgG4 Fc through the flexible (G)4S linker on the other hand, to extend the half-life;

4. Semaglutide

Semaglutide is also a kind of GLP-1 analog, with the amino acid in position 8 of GLP-1 mutating to 2-aminoisobutyric acid to damage the DPP-IV degradation site and lysine in position 26 acylated with fatty acid to increase binding to plasma albumin and extend the half-life.

5. Polyethylene glycol loxenatide

Polyethylene glycol loxenatide is transformed from loxenatide, and the difference is that position 8 mutates to D-Ala, to block DPP-IV degradation; and with lysine as the linker, loxenatide is PEGylated at cysteine site, with two-branch PEG configuration, to synthesize polyethylene glycol loxenatide.

Related:

The global GLP-1R agonist market rapidly expands

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