In the past year, the hottest drug in the capital market is the GLP-1 (glucagon-like peptide-1) receptor agonist weight loss drug, this type of drug was originally developed for hypoglycemic drugs, but at the same time, it can also suppress appetite, delay gastric emptying, and have a weight loss effect.
Obesity is a global public health problem and an important cause of many chronic diseases, but the treatment of obesity is difficult, and the effect of various weight loss measures is not ideal. The emergence of GLP-1 has opened up a new avenue for the treatment of obesity.
The total market value of the Danish pharmaceutical company Novo Nordisk has exceeded the total GDP of Denmark in one year, and the market value of Eli Lilly Pharmaceuticals, an American pharmaceutical company whose revenue has not yet ranked among the top ten global pharmaceutical companies, has climbed to the top of the market value of global pharmaceutical companies.
The successful development of GLP-1 weight loss drugs has attracted many companies from all over the world to enter the market, and various capitals are competing to chase after it, and the industry war has escalated, and Chinese and foreign companies have actively participated in it. In addition, many pharmaceutical companies are vying to lay out the upstream and midstream industry chain of GLP-1 weight loss drugs, from providing APIs to OEM.
In the face of so many companies entering the game, whether there is a bubble in the GLP-1 diet pill industry and whether GLP-1 diet pills bring abuse problems have also attracted attention.
GLP-1 diet pills that are out of the circle
GLP-1 receptor agonists work by activating GLP-1 receptors, promote insulin secretion in a glucose concentration-dependent manner, inhibit glutinal hyperglycemia secretion and delay gastric emptying, reducing food intake through central appetite suppression. This target was discovered as early as the 80s of the last century. At that time, scientists hoped to develop a new type of hypoglycemic drug on GLP-1, but after natural GLP-1 entered the human body, it would be degraded in less than a few minutes, and the half-life was very short.
For a long time, the development of GLP-1 targets has not attracted much attention from the industry. It wasn't until the 90s that scientists isolated an analogue of GLP-1 in a poisonous lizard, named Exendin-4. Unlike native GLP-1, Exendin-4 is not degraded in animals (mice and dogs) for several hours.
On the basis of Exendin-4, the world's first GLP-1 receptor agonist exenatide, which was developed by Eli Lilly and Amylin in cooperation with the United States, was approved by the US FDA in 2005 for the treatment of adult type 2 diabetes, but a few years after the market, a small number of patients treated with the drug developed pancreatitis and even pancreatic cancer, raising concerns about the safety of exenatide. Although exenatide was subsequently determined by the FDA to have no direct causal link with pancreatic cancer, sales were sluggish.
In 2009, the world's second GLP-1 receptor agonist, liraglutide, developed by Novo Nordisk, was launched in the European Union and the following year in the United States, also for hypoglycemia. In contrast to exenatide, which requires two injections a day, liraglutide only takes one injection a day.
In December 2014, liraglutide was approved by the US FDA for the treatment of obesity, but its application is limited due to its milder effect in the treatment of obesity.
What really makes GLP-1 shine in the field of weight loss is that it has to wait until the launch of semaglutide, another long-acting GLP-1 receptor agonist developed by Novo Nordisk.
Semaglutide was first approved for hypoglycemic drugs. In June 2021, the semaglutide weight loss indication was approved by the US FDA in June 2021, and the drug was named Wegovy. Compared with liraglutide, which requires one injection per day, semaglutide only needs one injection per week, which is more convenient to use and has better patient compliance. What's more, semaglutide is more effective in weight loss.
With the launch of semaglutide, the application of GLP-1 drugs in the treatment of obesity has gradually become popular.
In 2022, Tesla CEO Elon Musk tweeted that he had successfully lost weight, and the secret to weight loss given was fasting and semaglutide injections. With the blessing of Musk's celebrity effect, coupled with the advantages of efficacy in weight loss, semaglutide was successfully brought out of the circle.
Since the launch of semaglutide, the sales volume has increased rapidly. In 2022, the sales of semaglutide will reach US$10.9 billion, becoming the world's first GLP-1 drug with annual sales exceeding US$10 billion, of which the sales of the obesity injection form Wegovy will be about US$880 million.
In the first three quarters of 2023, semaglutide has recorded revenue of $14.8 billion, a year-on-year increase of 86%, of which Wegovy has recorded revenue of $3.2 billion, a year-on-year increase of 481%.
In November 2023, another GLP-1 weight loss drug with better efficacy, tirpatide was approved for marketing in the United States, and the developer is Eli Lilly, which is the industry's first dual-target (GIP/GLP-1) drug. Again, prior to the approval of this indication, it was approved for the treatment of diabetes.
In the Chinese market, the approved indication for semaglutide is hypoglycemia, and the indication for weight loss has not yet been approved. Tirpatide, on the other hand, is not yet available in China.
In 2023, two GLP-1 weight loss drugs have been approved for marketing in the Chinese market, one is a liraglutide analogue from Huadong Medicine (000963.SZ), and the other is benaglutide, an innovative drug of Renhui Biologics, both of which are short-acting drugs.
There are many entrants
Obesity has become a global public health problem. According to Novo Nordisk's estimates, there are about 764 million obese people worldwide.
Before the emergence of semaglutide, there was still a lack of safe and effective weight loss drugs on the market, the market penetration rate of weight loss drugs was very low, changing life Xi and surgery were the main ways to lose weight, but the former was difficult to adhere to, and the latter had a narrow scope of application.
Semaglutide has been successfully developed in the field of weight loss, allowing the outside world to see the huge market potential in the field of weight loss. In 2023, in the capital market, the stock prices of companies represented by Novo Nordisk and Eli Lilly are boiling. In China's capital market, weight loss concept stocks were once chased by various capitals.
According to the China Merchants International Research Report, as of November 2023, there are more than 30 GLP-1 weight loss drugs under development in the world (entering the phase II and above research stage).
The global competition in GLP-1 drug research and development is extremely fierce, and various new molecules are trying to make breakthroughs in terms of efficacy, dosage form, injection frequency, etc. Novo Nordisk and Eli Lilly are still strengthening the "moat" of their weight loss drug business, and both have a number of GLP-1 weight loss products under development. The two companies are also competing to develop oral small molecule GLP-1 weight loss drugs.
In terms of Chinese pharmaceutical companies, there are more than 10 pharmaceutical companies in the development of GLP-1 innovative weight loss drugs, including Hansoh Pharmaceutical, Paige Biotech, CSPC Pharmaceutical Group (01093.HK). HK), Xianweida, Innovent Biologics (01801. HK), Hengrui Pharmaceutical (600276. SH) and other enterprises.
On January 2, 2024, Innovent Biologics announced that it has dosed the first patient in a Phase III clinical study (GLORY-2) of its innovative glucagon-like peptide-1 receptor (GLP-1R)/glucagon receptor (GCGR) dual agonist 9mg in obese subjects in China. This is also the fourth large-scale phase III clinical study conducted by Masdotide. The drug is expected to become the first weight-loss drug in China for a higher base of obese people.
In addition to independent research and development of innovative drugs, some Chinese pharmaceutical companies have gathered to develop generic GLP-1 drugs, mainly focusing on the imitation of liraglutide and semaglutide.
The compound patent for liraglutide expired in 2017 and the crystal patent expired in 2022. Semaglutide patents are normally due to expire in 2026, but the State Intellectual Property Office ruled that all core patents of semaglutide are invalid in 2022, and follow-up litigation has not yet been resolved.
With so many pharmaceutical companies entering the GLP-1 weight loss drug, has there been a bubble in the industry?
Judging from the predictions of various institutions, the market size of weight loss drugs in the future is quite optimistic. JPMorgan Chase predicts that annual sales of GLP-1 weight loss drugs will exceed $100 billion by 2030.
Huaxin Securities believes that in 2020, there will be 507 million overweight or obese people in China, and it is expected that 825 million people will be overweight or obese in 2030, and the domestic weight loss market demand is strong. According to the neutral assessment, the market space of GLP-1 in the field of overweight/obesity in China is expected to reach 46.1 billion yuan.
Zhou Jingye, founder and CEO of Chengyi Biotech, said in an interview with the first financial reporter that the market for the use of GLP-1 in weight loss drugs has just opened, and the overall market is still growing rapidly.
"From the perspective of the competitive landscape on the GLP-1 track, two more competitive products have emerged in the short term, one is oral small molecule GLP-1 receptor agonists, which have considerable market potential in the future due to their ease of use and low cost, and the other is multi-target drugs, such as dual-target or three-target peptide injection drugs, which are represented by Eli Lilly's tirpatide. Zhou Jingye said.
Zhou Jingye said that the development of oral small molecule GLP-1 drugs is still quite difficult, but if there is a first-mover advantage in this category, the competitiveness will be highlighted.
Another person from a pharmaceutical company engaged in the research and development of weight loss drugs told the first financial reporter that weight loss targets a wide range of people, involving more than 400 million people in the Chinese market, compared with anti-cancer drugs, the market is huge. Although the competition in the diet drug track is very volatile, if it can fight to the top four in the industry, it is expected to break through from the market, which tests the R&D efficiency of pharmaceutical companies. "The GLP-1 weight loss drug currently under development is based on semaglutide, and if the efficacy is lower than semaglutide, it is difficult to win in the market. ”
Escalating competition
At present, there are still companies entering the field of weight loss drugs, and the competition has escalated.
At the beginning of December 2023, the Swiss pharmaceutical giant Roche returned to the field of weight loss drugs, and an acquisition of more than $3 billion once again pushed the competition track of weight loss drugs to a climax.
The target of Roche's acquisition is also Carmot Therapeutics, a Swiss pharmaceutical company, which is committed to the research and development of metabolic disease therapies such as diabetes and weight loss, and has a number of GLP-1 drugs under development, including 2 GLP-1R/GIPR dual-target peptide agonists and 1 small molecule GLP-1 receptor agonist, but drug development is still in the early stage.
In September 2008, Chugai, a subsidiary of Roche, awarded Eli Lilly to OWL833, a small molecule GLP-1 drug in a Phase I clinical trial, with a meagre down payment of $50 million. As everyone knows, OWL833 has now become a star oral small molecule weight loss drug Orforglipron under development by Eli Lilly.
It can be said that Roche, who "got up early in the morning and rushed to a late set", tried his best to make up for his regrets in diet pills.
In the race of weight loss pills, there are many large multinational pharmaceutical companies, and some companies are becoming more and more courageous.
In the first half of 2023, AstraZeneca twice gave up the development of two self-developed GLP-1 weight loss drugs, but a temporary abandonment does not mean a permanent abandonment, and in November 2023, the company announced that it had reached an authorization license for new drugs for cardiometabolic diseases and obesity with Chinese pharmaceutical company Chengyi Biotech, and obtained the global rights and interests of Chengyi Biotech's next-generation oral glucagon-like peptide-1 receptor agonist (GLP-1RA) ECC5004 as monotherapy and combination therapy. This is the largest deal for AstraZeneca's early-stage clinical program in China, with a cumulative cost of more than US$2 billion.
In terms of Chinese companies, there are also those who are running.
In November 2023, vaccine company Zhifei Biotech announced that it would acquire 100% of the shares of Chen'an Biotechnology held by Zhirui Investment and Zhang Gaoxia in cash. According to reports, focusing on the field of metabolic diseases such as diabetes and obesity, a clear pipeline layout of GLP-1 similar drugs and insulin analogues has been formed.
GLP-1 weight loss drugs are popular, which is also stimulating the expansion of GLP-1 upstream and midstream industry chains. Some capital has switched to the "gold rush" of the upstream industrial chain of GLP-1.
GLP-1 peptide drugs are difficult to synthesize, and after semaglutide weight loss indications were approved overseas, there was a shortage of supply.
China Merchants International said in the research report that the peptide industry chain includes downstream drug research and development companies, midstream CDMO (contract development and manufacturing organization) companies, and upstream reagents, consumables and equipment companies. According to its calculations, the upstream and midstream industry chains of peptide drugs account for about 15% of the value of the entire peptide industry chain.
On November 29, 2023, Chengdu Taihe Weiye Biotechnology Co., Ltd., which focuses on the protection of amino acids and peptide drug intermediates, announced the completion of nearly 300 million yuan in Series A+ financing. According to reports, the funds obtained in this round of financing will be mainly used to accelerate the commissioning of the company's 240 acres of second-phase factories and the construction of 500-acre third-phase factories.
Interestingly, in the financing of Taihe Weiye, the Moutai Goldstone Fund funded by Kweichow Moutai, a liquor company, as a limited partner, appeared in it, which is also the first public investment of Moutai Goldstone Fund after the completion of the filing in August 2023.
Misuse concerns
Overweight and obesity are major risk factors for a variety of chronic diseases, including cancer, hypertension, cardiovascular disease, diabetes, liver and kidney disease. The health and economic burden associated with overweight and obesity is severe.
The World Obesity Alliance defines BMI ≥25 as overweight and BMI ≥30 as obese. China defines a BMI of ≥24 as overweight and a BMI of ≥28 as obesity. BMI, which is the square ratio of weight (kg) to height (m).
With the popularization of the GLP-1 weight loss concept in the market, the signs of abuse of related drugs are looming. Some people who do not meet the criteria for overweight or obesity because they have obesity anxiety are given off-label drugs.
According to the research report released by China Merchants International, in the first three quarters of 2023, diabetes sales accounted for about 81% of global GLP-1 drug sales, and some of them were used off-label for the treatment of obesity.
Jiang Yiwen, chief physician of the endocrinology department of Foshan Fosun Chancheng Hospital, told the first financial reporter that the intervention for weight loss and lifestyle has a certain effect, but it needs to be adhered to, and the weight loss process will be relatively slow. GLP-1 is more effective in weight loss, but there are still some side effects, the more common side effects are nausea, vomiting, and indigestion.
"In the outpatient clinic, we often encounter some patients who ask for GLP-1 weight loss drugs, but whether these patients are suitable for use, we will conduct a multi-faceted assessment, such as checking pancreatic function, body mass index, blood sugar, etc., and also rule out a history of thyroid tumors. It is also not recommended for older people who have weakened gastrointestinal function. ”
Ji Linong, director of the endocrinology department of Peking University People's Hospital, once told the first financial reporter that he was more worried that some people used drugs without the supervision of a doctor, which would bring many safety risks. The correct use of weight-loss drugs is not to change the form, but to improve blood sugar and blood pressure, and ultimately to achieve health.
Some markets believe that due to the certain consumption attributes of GLP-1 weight loss products, the sales channels may be very different from traditional prescription drugs, and the out-of-hospital market may become the main sales channel for weight loss GLP-1 products. With the launch of GLP-1 weight loss drugs in China, some drugs have entered the medical aesthetic channel for sale.
Unlike over-the-counter drugs, which can be purchased by patients, GLP-1 is a prescription drug that is strictly regulated and must be prescribed, purchased and used by a medical professional. In medical institutions, doctors will strictly control the use of GLP-1 weight loss drugs.
However, in the out-of-hospital market, there are still blind spots in how to regulate the rational use of GLP-1 weight loss drugs. Some people have also easily prescribed related drugs through e-commerce channels. In addition, some aesthetic practitioners have exaggerated the efficacy of the drug on social media.
Some investors told the first financial reporter that if the abuse of GLP-1 diet pills is serious, it will inevitably lead to stricter supervision.
Insiders of East China Medicine told the first financial reporter that the company's liraglutide injection has been sold in hundreds of large hospitals in China, and the number is still growing rapidly. In addition, the company is also actively deploying the out-of-hospital market, including online platforms and offline pharmacies, and the top 100 domestic chains have basically completed the development and coverage, or completed communication and negotiation, and are actively distributing goods.
"The company has always strictly abided by laws and regulations and the requirements of integrity and self-discipline to engage in production and business activities. Liraglutide injection is a prescription drug that requires a prescription from a doctor to purchase and use. Even if it is promoted in aesthetic medical institutions, patients need to be prescribed by an aesthetic doctor who has the right to prescribe it before they can purchase it. East China Medicine insiders said.
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