[Transfer] GLP-1: from diabetes to a wider field

[Transfer] GLP-1: from diabetes to a wider field

Source: Medicine Note /ARMSTRONG

In the field of diabetic drugs, insulin products have always occupied the main position for century, but insulin may cause hypoglycemia and even severe hypoglycemia and death. Therefore, people have been constantly looking for and exploring new drugs for treating diabetes.

The advantages of the GLP-1 receptor agonist (GLP-1ra) drugs have become the most ideal hypoglycemic drugs at present and the biggest promoter in the diabetic drug market.

In 2021, the global targeted GLP-1RA drug market reached 16 billion US dollars, and the total proportion of Nuo and Nordia and Eli Lili accounted for about 95%. Among them, Lilly's Duraoganptide sales were about $ 6.5 billion, Nor -Nord's Smeglugin peptide was about US $ 5.9 billion, and Leraru peptide was about $ 2.3 billion. Perptons enter the global best -selling medicine TOP20.

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Domestic GLP-1 market

According to data disclosed by Novo Nord, in recent years, the compound growth rate of the global GLP-1RA market has reached 35.7%, which is much higher than the overall market of diabetes drugs and the growth rate of hypoglycemic drug segmentation.

GLP-1ra is not just showing its skills in the international market. In the domestic market, after entering medical insurance, sales have also increased significantly.

Duraoganptide entered the medical insurance in December 2020 after entering the medical insurance, and the sales revenue in the Chinese market in 2021 reached $ 117 million.

Simei Guling peptide was listed in China in April 2021 and was included in medical insurance in December. In the past six months, sales in China reached $ 46 million.

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What exactly is GLP-1ra?

In 1985, Schmidt was separated from the intestinal mucosa to extract the second type of intestinal insulin, and the glycogen-1 (GLP-1), GLP-1, depended on its receptor-GLP-1R to play a role. GLP-1 can promote the secretion of insulin, inhibit the secretion of pancreatic hyperglycemia (high blood glucose can increase blood sugar), stimulate the tolet β cells to release more insulin, and produce the effect of lowering blood sugar. At the same time, delay the speed of stomach emptiness, so that people will not feel hunger, so appetite will decrease, which will help control weight. But a large limitations of natural GLP-1 are that it is particularly short-period in the body. After 2-3 minutes after secretion, it will be degraded by di-peptide (DPP4). 1. It will also be degraded by DPP4 soon.

Based on this, people began to design drugs from two aspects, hoping to transform GLP-1 into drugs for diabetes. On the one hand, through the DPP4 enzyme inhibitor, the GLP-1 degradation in the body is reduced to achieve the effect of hypoglycemic. On the other hand, it is expected to find a longer-acting GLP-1 analog, which can increase the concentration and action time of GLP-1 (analog) in the body.

In 2005, the world's first GLP-1 analog of EXENDIN-4 (Exnatide/ byetta/ Esseanptide) was approved by FDA approved for type 2 diabetes, and 2 stitches (BID) were injected daily. EXENDIN-4 comes from the venom of the Hillary Poison Lizard that can stimulate the secretion of insulin and its degradation speed is slower than the natural GLP-1.

Since then, the competition of the GLP-1RA track has begun. Among them, the "competition" between Iso and Nordi and Eli Lili is the most exciting. Their products have always occupied absolute advantages in the GLP-1ra field.

In 2009, Novo Nord's Liraglutide (1.2/1.8 mg) passed EMA approval and was approved by FDA in January 2010 to treat type 2 diabetes. In addition to the excellent hypoglycemic effect, LIRAGLUTIDE also proves that it has both cardiovascular benefits. As the first injection -type drug once a day, it is an innate natural flaw -the number of injections is too much.

Lilly solved this problem. It integrates the GLP-1 analog (capable of resisting DPP-4 degradation) to IGG4-FC to get Dulaglutide. In 2014, it was approved by FDA for patients with type 2 diabetes. Drug.

In 2017, Nuo and Nord launched a blockbuster product -Smegugu peptide, the improved version of LIRAGLUTIDE. Based on the excellent clinical manifestations of Smeglugin -the best hypoglycemic effect in the diabetic people, the excellent physical reduction effect in obese people, clear cardiovascular benefits, and kidney benefits. Peptide is the ultimate product of the GLP-1ra track, or even type 2 diabetes track.

In 2022, Lilly attacked again and developed a stunning (?) Double -target drug Tirzepatide for the first time. Tirzepatide can activate GLP-1 and GIP receptors at the same time. On May 13, 2022, the medicine was approved by the US FDA. In the Surpass series III clinic, the TirzePatide head defeated Simer Gutan peptide, glycines insulin, and deogin. Challenging the success of the Same Gutu peptide means that a new round of revolution is about to lift, and dual -target hypoglycemic drugs are about to become the main competitors in the field of subsequent hypoglycemic. Where is GLP-1ra stronger?

Since the use of animal insulin in 1922 to treat diabetes, in 100 years, the global discovery and invention of about nine major categories of diabetes therapy drugs: sulfa, dual-crickets, α-glycosidase inhibitors, insulinin, insulinin Class, tzds (TZDS), Greya, GLP-1ra, DPP-IV inhibitors, SGLT-2 inhibitors.

Among these 9 categories of drugs, insulin has the longest history and has been used for nearly a century, but it may cause patients to increase weight and have low blood sugar risks. The injection is frequent. The market size has been declining in recent years. In the traditional oral medication, as the first choice for the initial choice of diabetes, the dual -dual -dual -duplex can be used alone in the early stage of diabetes, which is generally used with other diabetic therapy drugs; sulfonyl drugs and Gilena have hypoglycemia and weight gain. Adverse reactions; α-glycosidase inhibitors to reduce the amplitude of glycated hemoglobin; TZDS has the side effects of weight gain; SGLT2 inhibitors can easily lead to urinary system infection.

GLP-1RA reduces the level of glycated hemoglobin in non-insulin products. The longer half-life can achieve it for a week or even more for a long time. The hypoglycemic effect of GLP-1 is blood glucose dependence, so the risk of hypoglycemia is extremely low. Not only is it similar to insulin hypoglycemic effects, but also appetite control, weight loss and cardiovascular benefit. These benefits are not available in insulin and most oral hypoglycemic drugs.

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From diabetes to a wider field

Clinically, GLP-1RA shows good weight loss effects. In December 2014, the FDA approved the weight loss indication of the first GLP-1RA, Norra Twita peptide. The first opportunity for Lichel peptides is to rely on its better clinical data. According to the clinical data of the third phase, 3 mg Liluugu peptides are used every day. After 56 weeks, about 62%of obese patients weighed 5%, and 34%of patients' weight decreased by 10%.

In recent years, the GLP-1 receptor target is becoming the mainstream direction of the development of weight loss pills. In June 2021, a high -dose Wegovy was approved by FDA to treat patients with overweight or obesity. The approval of the results of the STEP 3 clinical trial items, and patients with clinical trials treated with Wegovy were alleviated by an average weight of 17-18%within 68 weeks.

The above two products contributed a revenue of 8.4 billion Dan Ying Crown (about $ 1.283 billion) in 2021, an increase of nearly 50%year -on -year.

The Tirzepatide data of Lilly showed that the weight loss effect of the TirzePatide treatment group at the 72nd week was significantly better than the placebo control group, with an average weight loss of up to 22.5% (24kg), and 63% of patients with a high dose group of 15mg were reduced. Weighing more than 20%.

In addition to obesity, many pharmaceutical companies are also developing a variety of indications. Taking Nuo and Nord as an example, the indications explored by Smegtugin include reducing cardiovascular risk, NASH, CKD, Alzheimer's disease, etc. The new indications explored by Tirzepatide include Nash, HFPEF, sleep apnea, CKD, etc.

Hongyun Hua Ning and GLP-1ra

As a domestic innovative pharmaceutical company in China, Hongyun Huining has also had a layout in the GLP-1RA field, and it iterative innovation and upgrading has been conducted at the same time.

The first generation of products is the only ultra-long GLP-1ra in the world. The indication is type 2 diabetes. It is administered once every two weeks, which greatly increases the patient's compliance. At present, the product is already in the clinical stage of III.

GMA102 is the world's first antibody drug developed directly in the world developed by Hua Ning, and it is also the only new antibody new antibody with GLP-1R preference (BIASED). Compared with the existing GLP-1RA drugs, the antibody molecular safety window is large, which can achieve higher dosage doses and occupy obvious advantages in safety. Compared with the du sugar peptide and Smeglugin, the effects are comparable, the side effects are smaller, and it is not necessary to administer it by gradually increasing the dosage titer.

The second-generation product GMA106 is a fusion protein formed by a antagonistic GIPR antibody and GLP-1 molecule. As a new M-Body drug molecule for dual targets, on the one hand, it controls the metabolism of sugar and regulates blood glucose; on the other hand, it controls the accumulation of fat in the body, so it can also regulate blood glucose and fat accumulation at the same time. This product has the characteristics of long half -life of antibody drugs and small dosage, and has obvious advantages in terms of effectiveness, longness and safety. For obesity, diabetes, and fatty liver diseases, it is expected to have better curative effect.

On this basis, the third -generation product has been developed, which is a multi -functional candidate.Starting from the two aspects of controlling fat increase and removing fat survival, the goals of better weight loss and the treatment of non -alcoholic fatty liver disease.With the continued research and development of GLP-1RA drugs, its indications have also begun to move from diabetes to a wider field, bringing more convenient medication experience to patients, as well as sugar reduction, weight loss, cardiovascular benefit, etc.The improvement of more health. In the future, we look forward to the continuous innovation of the GLP-1 track, which can bring more and better drugs to patients and help human health!

Reference materials:

GLP-1 of the past and present-pursuit of Best-in-Class GLP-1ra

Diabetic drugs have changed in a century. Who is ups and downs in the second half?

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