GLP-1 receptor agonists have become a hot track for drug research and development, and the domestic market is also expected to reach tens of billions of yuan, and many companies are competing to develop. At the same time, due to the potential risk of thyroid cancer given by regulatory agencies, GLP-1 receptor agonists have recently suffered the "treatment" of ice and fire.
The reporter's investigation found that on the Internet platform, the sales of some weight-loss drugs still have the status quo of lax review and off-label drug sales.
Injections for slimming have obvious results at first
Lin Shi (pseudonym), 27, who works in Shunyi, Beijing, is not thin, but her weight has remained relatively stable, and she never thought that one day, she would go to the hospital because of her weight.
At the beginning of 2022, Lin Shi felt that he had gained weight, and at first he didn't care, feeling that it was related to his work pressure and irregular eating. One day in the second half of the year, Lin Shi suddenly realized that she had gained 20 pounds in less than a year, which made her a little worried about her health. So, Lin Shi came to Peking University International Hospital for treatment. The examination results showed that her endocrine indicators were normal, and the doctor recommended that she try it at the weight loss clinic of another tertiary hospital, and told her that she could lose weight through drugs.
In the weight loss clinic, the doctor first learned about Lin Shi's basic situation, and her BMI (body mass index) at that time had reached 32. Subsequently, Lin Shi did blood routine, human metabolic dynamic measurement analysis, insulin level, creatinine and other tests. After confirming the results, the doctor prescribed a drug called semeglutide for Lin Shi.
The indications approved by semeglutide in China are for the treatment of type 2 diabetes in adults and the reduction of the risk of cardiovascular adverse events in patients with type 2 diabetes mellitus and cardiovascular disease. The weight loss indication of the drug has previously been approved abroad, and it is in clinical trials in China. The hospital where Lin Shi visited was qualified to provide drugs for weight-loss patients.
From the visit to the medication, it takes less than a month. According to the dosage recommended by the doctor, Lin Shi starts from 0.25mg, injects once a week, and then increases the dose according to the doctor's advice. Lin Shi also has a friend who is also losing weight, and the doctor prescribed another drug, liraglutide, which needs to be injected every day.
At first, Lin Shi's weight loss effect was obvious and continuous, from the end of November last year to the beginning of April this year, she lost a total of 11 pounds. However, in early March this year, Lin Shi found that her weight began to remain static, and the doctor suggested that she could increase the dose and inject for another month, she felt that it was difficult to continue to lose weight, so she stopped taking the drug in early April.
Lin Shi calculated that during this period of medication, she spent an average of about 1000,<> yuan per month. By the time of the interview, Lin Shi had stopped taking the drug for nearly three and a half months. Now her weight will also fluctuate a little, and when she sees the weight gain, she will control her diet a little. In fact, since she started taking medication, Lin Shi has also changed her living habits, and she insisted on not ingesting carbs for dinner after injecting drugs, and now she does so almost every day. She feels that the effect of the drug is to help her suppress her appetite, and of course, adjust her eating habits.
This way of losing weight also brought some side effects, which were reflected in Lin Shi's body, namely diarrhea, bowel sounds and nausea. Lin Shi said that these reactions are basically within the range she can tolerate, but she especially stressed that the use of drugs must be carried out under the guidance of a doctor, and do not self-medicate.
A clinician from a tertiary hospital who did not want to be named reminded that the use of drugs to lose weight is in some extreme cases, such as BMI indicators, or the patient's own situation is more special, such as severe joint damage is not suitable for exercise, or internal organ damage, etc., need to use drugs to control the weight. In any case, semeglutide is a prescription drug and must strictly follow the indications. Lin Shi, who has had medication experience, also repeatedly told reporters in an interview that the use of semeglutide must be carried out under the guidance of a doctor throughout the process, and do not self-medicate or adjust the dose by yourself.
The review of drug purchases on Internet platforms is not strict
Although semeglutide, known as the "miracle drug for weight loss", has not yet obtained the indications for weight loss in China, since August 2022, semeglutide has been out of stock in major cities. On the Internet drug sales platform, the price of semeglutide once exceeded 8,<> yuan, which also led to the fact that diabetic patients who originally had the need for hypoglycemic drugs were not worthy of drugs.
In July this year, a reporter from the Beijing News searched on Ali Health, Jingdong Pharmacy and other platforms and found that the supply of semeglutide was relatively sufficient, and various merchants could basically deliver normally. In terms of selling price, taking the 7.1ml specification as an example, the price of one package is basically 5 yuan to 550 yuan, and some merchants have full reduction activities for the drug.
However, the reporter found in the investigation that semeglutide, which has not yet obtained the indications for weight loss in China, can be easily bought on the Internet platform.
On the merchant platform of Jingdong Pharmacy called "Taimei Yihe Pharmacy Flagship Store", the reporter asked whether semecotide could be used to lose weight, and the merchant gave an answer of "the recommended initial dose is 0.25, and then it will increase according to personal physique". The reporter then tried to buy the drug, and the platform required a prescription first.
After the reporter paid the consultation fee, the doctor matched by the platform first reminded that "this drug is currently only approved for type 2 diabetes in China", and said in response to the reporter's inquiry on whether the drug can be used for weight loss that this indication has not been approved in China. However, after the reporter reported a set of height and weight data that clearly belonged to the obesity level, the doctor said that he met the obesity criteria and clearly replied that the reporter could use the drug. After giving the medication method and asking about the medical history, the reporter got the electronic prescription issued by the doctor.
In Ali Health Pharmacy, the reporter searched with semeglutide as a keyword, and did not see the relevant product sales page. When the reporter returned to the Taobao interface and searched with semeglutide, the results were very different.
The search results show that many platforms have semeglutide products, and the price of products with the same specifications is close to that of Jingdong Pharmacy. In a merchant called "Consid Pharmacy Flagship Store", there are many users who left messages saying that the purchase of the drug is for weight loss, several of them said that it was already a second purchase, and one user left a message saying that "this is the second purchase, I have lost more than ten pounds, I have no diabetes, I just want to lose weight, and there is no adverse reaction." ”
On the page of a merchant called "Haqianyun Pharmacy Flagship Store", a user left a message saying, "(Myself) was 70 kg when I was shot, and now I have 3 injections of 0.5, 63 kg." Don't want to eat, dizziness, nausea, diarrhea, poor sleep quality, etc. ”
Subsequently, the reporter consulted with the "Consid Pharmacy Flagship Store" on the grounds that he wanted to buy the drug, and said that he did not have diabetes, and whether he could use the drug to lose weight. The merchant replied that the mechanism of action of the drug is to prolong the emptying time of the stomach, enhance satiety, but also digest sugar, combined with diet and exercise to achieve better results.
Semeglutide fraud also occurs from time to time. In March this year, the Food and Drug Huanzhisen Brigade of the Public Security Bureau of Zhuji City, Shaoxing, Zhejiang Province, detected the first case of illegal development, production and sales of "semeglutide", a core ingredient for the treatment of type 3 diabetes. It was preliminarily found that the gang headed by Tang Mouqiao and others was located in a certain place in other provinces and produced and sold "light pigment" slimming injections containing the ingredient "semeglutide" in the name of a cosmetics company. Such "three no" counterfeit drug products have flowed into more than 2 provinces across the country through agents at all levels, with a sales amount of more than 20 million yuan.
GLP-1 receptor agonists are sought after
Liraglutide and semeglutide are both popular drugs in the weight loss market.
Liraglutide is the first generation GLP-1 receptor agonist and the world's first long-acting GLP-1 receptor agonist. The drug was first used to treat diabetes and was approved by the U.S. Food and Drug Administration (FDA) in 2010 under the trade name "Victoza." The following year, the drug entered the Chinese market under the trade name "Novolit".
What made GLP-1 receptor agonists famous was the drug's effectiveness in weight loss. Studies have shown that GLP-1 receptor agonists have both weight loss, hypoglycemic and cardiovascular benefits, and are relatively mature, stable and safe targets. According to the "Global Obesity Drug Competition Pattern Analysis Report" released by Lilac Garden Insight database, a total of 8 GLP-1 receptor agonist single-target new drugs have been approved for marketing worldwide, mainly for the treatment of type 2 diabetes. The only GLP-1 receptor agonists that have obtained weight loss indications are liraglutide and semeglutide, both developed by Novo Nordisk.
Among them, the obesity or overweight indication of the original drug of liraglutide injection was approved by the US Food and Drug Administration (FDA) in 2014 under the trade name "Saxenda", which has not been approved in China. According to Novo Nordisk's 2022 annual report, Victoza had global sales of DKK 2022.123 billion (approximately RMB 22.123 billion) in 28 and sales in the Chinese market (including Chinese mainland, Hong Kong and Taiwan) of DKK 14.78 billion (approximately RMB 14.79 billion). Saxenda's global sales for weight loss indications totalled DKK 2022,106 million (approximately RMB76,106 million) in 81.
Semeglutide is a second-generation GLP-1 receptor agonist developed by Novo Nordisk. In April 2021, semeglutide was approved in China for the treatment of type 4 diabetes in adults and to reduce the risk of cardiovascular adverse events in patients with type 2 diabetes combined with cardiovascular disease. In June 2, the weight loss indication of semeglutide was approved by the FDA, and the drug became the first once-weekly GLP-2021 receptor agonist for weight management. Clinical studies have shown that after 6 weeks of treatment with subcutaneous injection of semeglutide once a week, the average weight loss of obese or overweight patients in the 1.1 mg dose group is about 1%; Weight loss ranged from 12% to 2% at 4 weeks. Semeglutide is also known as the "miracle drug for weight loss", with sales of $6.68 billion in 17. In the first quarter of this year, the three dosage forms of semeglutide achieved a total revenue of DKK 18.2022 billion (about USD 109.285 billion), with a significant growth rate.
In the global GLP-1 market, Eli Lilly is another company to watch.
In June, Eli Lilly announced that data from a Phase II study of the experimental drug retatrutide showed that at 6 weeks, retatrutide (24 mg, 1 mg, 4 mg or 8 mg) met the primary endpoint of efficacy assessment in obese or overweight participants without diabetes, with an average weight loss of 12.17%. In the secondary endpoint, a mean weight loss of 5.48% at the end of 24 weeks of treatment. Retatrutide is Lilly's investigational agonist targeting glucose-dependent insulin stimulating polypeptide, glucagon-like peptide 2 and glucagon receptors. The data of 1.24% weight loss in one year makes it the most obvious weight loss effect among GLP-2 drugs.
In addition, another GIP/GLP-1 receptor agonist from Lilly, telpotide, showed in a study that the drug (10 mg and 15 mg) achieved weight loss effects superior to placebo in a 72-week study, with participants losing weight by 15.7%.
The attractive market has attracted companies to enter the market
According to the Medic Cube database, as of the end of June this year, there are more than 6 new GLP-150 drugs under research worldwide. According to the Lilac Garden Insight database, as of the end of June this year, 1 new GLP-6 drugs in China have entered the clinical stage. From the perspective of the time distribution of declared projects, there has been a significant increase in recent years, from an average of 112-1 clinical projects declared per year from 2016 to 2020 to 5 in 6 and 2021 in 20.
Huadong Pharmaceutical's liraglutide injection is a biosimilar of the original drug and adopts a different production process from Novo Nordisk. In June 2021, Huadong Medicine completed the clinical research of liraglutide (diabetes indication), which was approved for marketing in March this year. On July 6, 3, Huadong Medicine said that the marketing authorization application for liraglutide injection for obesity or overweight indications was accepted. On the evening of July 2022, Huadong Pharmaceutical issued an announcement that the marketing authorization application for the indication of liraglutide injection for obesity or overweight declared by its subsidiary Sino-US East China was approved, which is the first GLP-7 (glucagon-like peptide 13) receptor agonist approved for weight loss indication in China, and the first liraglutide analogue approved for marketing in China. Up to now, Huadong Pharmaceutical's R&D investment in the liraglutide injection project (including diabetes indications, obesity or overweight indications) is about 7 million yuan.
In the research and development track of liraglutide biosimilars, in addition to the approved Huadong Pharmaceutical, the weight loss indication of liraglutide biosimilars of Shuanglu Pharmaceutical and Wanbang Pharmaceutical has also progressed to phase III clinical trials. In addition, Yizhuang International Protein Drug Co., Ltd. and Novobot Biotechnology, a subsidiary of Aimeke Holdings, are also conducting clinical trials for weight loss indications.
In the R&D layout of semeglutide, the competition of local enterprises is also quite fierce. On June 6, Chia Tai Tianqing submitted a clinical trial application for GLP-7 biosimilar simeglutide injection to the State Food and Drug Administration, and one week later, on June 1, Sihuan Pharmaceutical, a Hong Kong listed company, announced that the clinical trial application (IND application) for the treatment of type 6 diabetes mellitus developed by Huisheng Biologics, a non-wholly-owned subsidiary, has been accepted by the State Food and Drug Administration, which is also the first glucagon-like peptide-13 (GLP-2) analog submitted by Huisheng Biologics.
In addition, a number of companies, including CSPC, I-Mab, Hengrui Pharmaceutical, and Gan&Lee Pharmaceutical, have established a presence in the GLP-1 receptor agonist field. Among them, the GLP-1 receptor agonist weekly preparation GZR18, independently developed by Gan & Lee Pharmaceutical, is also conducting clinical trials for type 2 diabetes, obesity and overweight weight management. Nuotech's new, long-acting GLP-1 peptide analog SPN0103-009 injection has also entered the clinic, which is intended to be used to treat type 2 diabetes and obesity, and eventually expand to non-alcoholic fatty liver disease and Alzheimer's disease without drugs.
According to the report "Nutrition and Chronic Diseases of Chinese Residents (2020)", more than 50% of adult residents are overweight or obese. Before Huadong Medicine obtained the indications of liraglutide injection for obesity or overweight, only one drug in China was approved for the treatment of obese or overweight patients, and there was a huge unmet clinical demand for compliant, safe and effective weight control drugs. The industry expects that driven by innovative drugs, the market size of China's diet drugs will reach 2025.87 billion yuan by 2030 and will maintain rapid growth to 149.<> billion yuan in <>.
Eight GLP-8 receptor agonist single-target new drugs were approved worldwide
Drug name manufacturer
Liraglutide (weight loss) Novo Nordisk
Duraglutide Lillyce
Semeglutide (weight loss) Novo Nordisk
Exenatide AstraZenecadeca
Benaglu Peptide Renhui Biological
Lisnatide Sanofi
Abilutide GlaxoSmithKline
Losenatide Hausen Pharmaceutical
Industry Reminder
A basin of "cold water" from regulators
GLP-1 receptor agonist drugs are still in their infancy in China, and their market share is significantly lagging behind the rest of the world. According to CICC statistics, China's GLP-1 receptor agonist drug market will expand at a compound annual growth rate of up to 57% and reach 2025.156 billion yuan in <>.
Whether in the international or domestic market, the competition in the GLP-1 market is between Novo Nordisk and Eli Lilly. From the aforementioned drug sales, Novo Nordisk has the advantage. In the domestic market, in 2022, Novo Nordisk's market share in the GLP-1 field is about 64.4%. Not far behind, in April, Eli Lilly registered a Phase III clinical trial, a "head-to-head" trial with semeglutide, designed to evaluate the efficacy and safety of telpotide versus smeglutide in adults with obese or overweight adults with weight-related comorbidities and non-type 4 diabetes.
While Novo Nordisk and Eli Lilly are competing in the field of GLP-1 receptor agonist weight loss, there are also companies that are not progressing smoothly in the research and development of this target.
This year, AstraZeneca and Pfizer have successively terminated the research and development of GLP-1 receptor agonist drugs. First, AstraZeneca announced the termination of clinical development of its oral GLP-1 drug candidate, AZD0186, due to its efficacy and tolerability not being superior to other drugs currently under development or already on the market. As early as April this year, AstraZeneca has abandoned the GLP-4/GCGR dual-target agonist Cotadutide, and the relevant research has entered the 1b/2 stage, but the data performance is not bright, the research data shows that the drug has not shown more obvious advantages in terms of glucose reduction and weight loss, compared with the GLP-3 class drug liraglutide that has been marketed.
At the end of June, another well-known pharmaceutical company, Pfizer, also terminated the development of its oral GLP-6 candidate, Lotiglipon (once daily), a decision based on safety considerations, specifically, pharmacokinetic data from the Phase I Drug Interaction Study and elevated aminotransferases measured in Phase I and ongoing Phase II studies.
A bigger basin of "cold water" comes from regulators.
Almost at the same time as Pfizer's termination action, the European Medicines Agency (EMA) issued a safety "warning" for GLP-1 drugs. According to the report, the EMA believes that GLP-1 drugs have a potential risk of thyroid cancer, and requires pharmaceutical companies such as Novo Nordisk, Eli Lilly and AstraZeneca to provide supplementary information by July 7.
This is not a new problem, some industry insiders said in an interview with the media that in early animal experimental studies, the association between such drugs and thyroid tumors has been found in mice. In addition, when the FDA initially approved the weight loss indication of semeglutide, it specifically reminded that the prescription information of the drug contained a black box warning to inform medical professionals and patients of the potential risk of thyroid cancer. In addition, the drug should not be used in patients with a personal or family history of medullary thyroid cancer. Public information shows that the black-box warning is the FDA's highest level of indication of adverse drug events.
Novo Nordisk said this is one way to monitor potential adverse events of approved drugs and said it would conduct a comprehensive assessment of all relevant data. A Lilly spokesperson responded by saying, "The company is working with regulators on two studies to investigate the association of GLP-1 drugs with thyroid cancer risk." ”
Beijing News reporter Zhang Xiulan