The tens of billions of diet pills market will welcome the new hegemon, who will overwhelm the crowd?

9 years ago, South Korea, at the turn of spring and summer.

The weather is particularly fickle, sometimes rainy and sometimes sunny.

An academic symposium on metabolic diseases and diet drugs was held at the Lee Gil-nu Cancer and Diabetes Institute, South Korea.

A female professor from the Affiliated Hospital of Gyacheon University in South Korea said straight to the point: diet pills are either ineffective or have too many side effects, and there is no real weight loss drug.

Nine years later, she must not have thought that with the advent of GLP-1R agonists and Amgen AMG133, this impasse would be broken.

GLP-1R agonist

Bombshells are coming

In recent years, GLP-1 receptor agonists are a hot direction in the development of hypoglycemic drugs, and the potential weight loss effect of GLP-1R is in high demand in the weight loss market, and safe weight loss drugs with dominant effects will become the next bombshell.

In September this year, Novo Nordisk's GLP-1R agonist polypeptide semeglutide injection (somaglutide prefilled injection pen, Novotec) was launched as an adjunct to diet and exercise to improve blood sugar control in patients with type 2 diabetes mellitus (T2DM), and only need to be injected subcutaneously at home once a week.

So far, the number of glucagon-like peptide-1 receptor-1 receptor (GLP-1R) agonists marketed in China has reached 8 (short-acting/fast-acting three: benaglutide, exenatide, risnatide; Long-acting five liraglutide, exenatide microspheres, dulaglutide, polyethylene glycol rosenatide, semeglutide), the market competition is becoming more and more fierce.

For metabolic diseases such as type 2 diabetes, GLP-1R agonists liraglutide, dulaglutide and semeglutide recorded about $15 billion in global sales in 2021 alone.

Since then, second-generation drugs have now emerged, marked by the success of liltisipatide head-to-head semmegatide.

In July this year, Innovent announced that the company's GLP-1R/GCGR (glucagon-like peptide-1 receptor/glucagon receptor) dual agonist mazdutide (R&D code: IBI362) reached the primary endpoint in a multicenter, randomized, placebo/dulaglutide-controlled phase II clinical study in subjects with type 2 diabetes in China.

IBI362 (mazdutide) is a next-generation drug introduced by the company from Eli Lilly to regulate glucose metabolism.

In addition, Huadong Medicine announced in July that the marketing authorization application submitted by its wholly-owned subsidiary for liraglutide injection for obesity or overweight indications was accepted. Before Huadong Medicine submitted the new indication application, there were already GLP-1 receptor agonists used for weight loss in China.

The strongest "diet pills" in history

Good news comes in a lot, especially this month.

Recently, Amgen's new weight loss drug AMG133 at the AHA conference showed a weight loss effect that was potentially superior to that of lilliteepamide and Novonordisk's semeglutide in a monthly dose frequency, which attracted widespread attention (refer to Figure 3).

For overweight patients with BMI 30~40, AMG133 was administered once every four weeks, and after three 12-week treatments, the body weight of the low-dose group decreased by 7.19%, the body weight of the high-dose group decreased by 14.52%, and the weight of the placebo group increased by 1.49%.

No significant side effects were observed, and most were mild and temporary.

Although it is only a small sample of phase 1 clinical data and is not a head-to-head clinic, its initial efficacy exceeds that of tisiparatide and semeglutide; The advantages of monthly dosing are also significant compared to weekly dosing.

Of course, it remains to be seen whether such excellent data can be obtained in the final phase II and phase III clinical trials.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved for the treatment of type 2 diabetes and obesity.

They have seen significant improvements in blood sugar control and weight loss, along with cardioprotective measures for people at risk of cardiovascular disease or pre-existing cardiovascular disease.

Although large peptide drugs are effective in treating diabetes, small molecules may have some advantages. They are better absorbed in the blood and are cheaper to manufacture.

As a result, several companies, including Pfizer, Eli Lilly and vTv Therapeutics, are working on small molecule GLP-1 receptor agonists for oral small molecule heterocyclic GLP-1 receptor agonist drug development.

At present, except for the oral somarutide launched in the United States in September 2019, which is a once-a-day tablet, all others are injectable.

In September this year, Huadong Pharmaceutical announced that its wholly-owned subsidiary has reached a strategic cooperation with Daewon Pharmaceutical in South Korea for the development, production and commercialization of TTP273 in Korea.

TTP273 is an oral small molecule non-peptide GLP-1 receptor agonist used to treat type 2 diabetes. In 2017, Huadong Medicine licensed exclusive development, production and commercialization rights from vTv Therapeutics in 16 Asia-Pacific countries and regions, including China and South Korea.

TTP273 is expected to achieve therapeutic efficacy comparable to GLP-1 injectable drugs currently on the market, while reducing gastrointestinal adverse effects and improving patient compliance. TTP273 is currently undergoing multicenter Phase 2 clinical trials in Chinese mainland and Taiwan.

In addition to GLP-1R agonists, glucokinase activators are also attracting attention, and on October 8, Huatang Ning received marketing approval from the National Medical Products Administration for two indications, namely the treatment of untreated type 2 diabetes patients alone, or the combination with metformin in combination with metformin when blood sugar control alone is poor, to treat adult type 2 diabetes.

Huatangning is a novel mechanism, ectopic allosteric function glucokinase activator, which acts on GK targets in pancreatic islets, intestinal endocrine cells and liver and other glucose storage and output organs, repairs GK function, and reshapes blood glucose homeostasis self-regulation. Relying on improving the body's own glucose disposal ability, so as to solve the clinical problem of blood glucose instability.

brief summary

Previously, effective weight loss methods were gastric bypass surgery.

According to statistics, the average drug or mouth can lose about 5-10% of the body weight, the gastric balloon can lose about 10-15%, and the gastric bypass surgery is 25-35%.

But now, semeglutide weight loss is about 15%, the weight loss effect of bariatric surgery in 1-2 years is 25-30%, the liltisipatide GLP-1/GIP dual-channel agonist has reached a weight loss range of about 20%, and about 1/3 of patients have achieved more than 25% weight loss, almost achieving the surgical effect.

The new batch of hypoglycemic diet drugs represented by GIP/GLP1-R double-action agonists has been launched one after another to bring health to patients.

However, weight loss cannot only look at the effective side and selectively ignore the harmful side.

Hype GLP-1 drugs as diet pills should be alarmed, because in the process, prescription drugs are at risk of being abused, some people may lose weight or because of small losses, and those who really need to use such drugs may also face drug shortages. In the case of oral administration of somaglutide, side effects include digestive discomfort: constipation, bloating, diarrhea, nausea, and symptoms of hypoglycemia that require special attention.