Eli Lilly's GIPR/GLP-1R Dual Agonist Tirzepatide Patent Layout

On May 13, 2022, the U.S. Food and Drug Administration approved Eli Lilly and Company's Mounjaro™ (tirzepatide) injection as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. In the 40-week results of the head-to-head Phase 3 SURPASS-2 clinical trial in type 2 diabetes, it demonstrated superiority in both blood sugar (A1C) and body weight reduction compared to Novo Nordisk's semaglutide for injection.

In the field of type 2 diabetes treatment, although there are 8 families of hypoglycemic compounds (biguanides, sulfonylureas, glinides, alpha-glucosidase inhibitors, DPPIV inhibitors, GLP1 analogs, thiazolidinediones and SGLT2 inhibitors), but its effectiveness in the treatment of patients with type 2 diabetes remains to be improved. At present, a number of companies have deployed dual-target and multi-target agonist hypoglycemic drugs, deployed GIP/GLP-1 receptor dual agonists, or GIP/GLP-1/GCG receptor triple-target agonists. There are 10 R&D companies, including 26 products.

Among them, tirzepatide is the first and currently only FDA-approved GIP/GLP-1 receptor dual agonist. As shown in the figure below, tirzepatide (LY3298176) is able to bind to GIPR and GLP-1R, and this dual agonism improves glycemic control and body weight in patients with type 2 diabetes with acceptable safety and tolerability.

In view of the current excellent performance of tirzepatide, various companies will definitely increase their research and development efforts, and the competition in this field will become increasingly fierce, and Eli Lilly, which has a first-mover advantage, has also built its own moat with patents.

First, the most important compound/sequence patents.

As shown above, the primary structure of tirzepatide is based on the GIP amino acid sequence, and aminoisobutyric acid (Aib) at position 2 is important to prevent physiological degradation and inactivation by DPP4, maximizing the stability of the helix. The lysine residue at position 20 is conjugated to a C20 fatty diacid moiety through a linker to improve the half-life and achieve long-acting injection once a week.

In view of this structural feature, the patent family represented by US9474 has protected its sequence and modified structure, and in independent claim 1, the sequence is more specifically limited, and the length of the side chain is limited in a wide range, from The rights clearly protect the sequence of tirzepatide and the specific structure of the side chain

The Chinese equivalents are written in a similar way, and the protection of tirzepatide is more precise. Since the sequence protection of the independent claim 1 is extremely specific, from the perspective of this patent family, it seems that there is room for the structural transformation of tirzepatide.

However, Eli Lilly's sequence protection for tirzepatide is not limited to this. Another patent family claims a variety of peptide chains, all of which are intermediates for the preparation of tirzepatide. These intermediates are either similar to the sequence of tirzepatide, or are tirzepatide. sequence fragment, or the structure of the side chain is protected alone. Therefore, the structural modification of tirzepatide most likely falls within the scope of protection of these intermediates.

Secondly, the therapeutic use of tirzepatide has also laid out a more comprehensive application.

Tirzepatide is currently approved for type 2 diabetes, and the indications under investigation include obesity, cardiovascular risk-related diseases, heart failure, and nonalcoholic steatohepatitis.

The indications claimed in the patent include: type 2 diabetes, improved weight management, chronic kidney disease, atherosclerosis, non-alcoholic fatty liver disease, obesity, and diabetic nephropathy, fully covering the indications for clinical trials.

The US cognate of this patent also specifically claims to administer a dose of 2.5 mg once a week for 4 weeks, after which the dose is maintained at 5, 10 or 15 mg in 2.5 mg increments. It is maintained for 4 weeks after dosing, and this dosing also covers the doses given in the FDA-approved labeling.

In addition, Eli Lilly has also laid out patent protection for the formulation composition and delivery device of tirzepatide. The formulation patent claims the same ingredients as the FDA specification, and defines that the composition of tirzepatide is provided in an injection device.

Corresponding to the currently approved injectable administration of tirzepatide, Eli Lilly is claiming an injectable drug delivery device as shown below.

In addition, Eli Lilly has also applied for patents protecting two oral delivery devices for tirzepatide, one that expands after reaching the gastrointestinal tract and allows the drug to diffuse and absorb through the mucosa of the gastrointestinal tract, and the other that Activated in the tract and administered to the wall of the gastrointestinal tract, some parts degrade after administration, and other parts (smoother parts) fall off and are excreted through the gastrointestinal tract.

These two patents have opened up the author's imagination of oral biopharmaceutical preparations. Combined with the sales of Novo Nordisk Smegglutide tablets and the clinical expectations for oral biopharmaceutical preparations, we can expect the future development of oral preparations of tirzepatide. 

By browsing the patents of tirzepatide, we can see the following technological advances: dual-target agonists, resulting in better metabolic regulation with fewer side effects, longer dosing intervals through structural modification, and more convenient mode of administration. It is believed that the launch of tirzepatide can bring better treatment prospects to patients with type 2 diabetes.